127607-62-9Relevant articles and documents
EFFLUX-PUMP INHIBITORS AND THERAPEUTIC USES THEREOF
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Page/Page column 201, (2016/12/26)
The present invention relates to compounds of formula I or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein ASC is -N(R8)(R9)ASC-1 ASC-1 is Ring A represents a 4- to 6-membered saturated ring containing carbon atoms as ring members in addition to the nitrogen atom and wherein one CH2 moiety in ring A is optionally replaced by CH(R21) and wherein one carbon atom in ring A that is not adjacent to the nitrogen atom is optionally replaced by O, and wherein ring A is connected to X via a carbon atom; X represents a bond, -CH2- or -C(=O)-; ARl, AR2 represent independently phenyl or a 5- to 6- membered heteroaryl ring containing one to three heteroatoms selected from O, S and N, wherein AR1 is connected to LI via a carbon atom, and wherein AR2 is connected to L1 and L2 via a carbon atom; R1, R2, R3 represent independently hydrogen, halogen, cyano, hydroxyl, C1-C6alkyl, C1-C6haloalkyl, C3- C8cycloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, -C1-C6alkylene-N(R12)R13, -N(R12)R13, -C(O)OR11l, - C(O)N(R12)R13, -S(O)OR11 or phenyl; R4 represents hydroxyl, hydrogen, halogen, nitro, cyano, amino, C1-C6alkyl optionally substituted by 1 to 5 R14, C2-C6alkenyl optionally substituted by 1 to 5 R14, C2-C6alkynyl optionally substituted by 1 to 5 R14, C1-C6alkoxy optionally substituted by 1 to 5 R14, C2-C6alkenyloxy optionally substituted by 1 to 5 R14, C2-C6alkynyloxy optionally substituted by 1 to 5 R14, -C(O)OR15, -CHO, -C(O)N(R16)R17, -C1- C6alkylene-N(R9)(R16)R17, -O-Cycle-P or -O-Cycle-Q; R5, R6, R7 represent independently hydrogen, halogen, cyano, Cl-C6alkyl, C1-C6haloalkyl, Cl-C6alkoxy or C1-C6haloalkoxy; R8 represents hydrogen, methyl or ASC-1; R9 is methyl or absent, and wherein when R9 is present the respective nitrogen atom carries a positive charge; R10 represents hydrogen or methyl; Rl11 represents independently at each occurrence hydrogen or C1-C6alkyl; R12, R13 represent independently at each occurrence hydrogen or C1-C6alkyl; R14 represents independently at each occurrence halogen, cyano, hydroxyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C8cycloalkyl, -C(O)OR11, -CHO, -C(O)N(R12)R13, -C1-C6alkylene-N(R12)R13, Cycle-P, O-Cycle-P, Cycle-Q or O-Cycle-Q; Cycle-P represents independently at each occurrence a saturated or partially unsaturated C3-C8 carbocyclic ring optionally substituted by 1 to 3 R18, or a saturated or partially unsaturated C3-C8 heterocyclic ring optionally substituted by 1 to 3 Rl 8 containing carbon atoms as ring members and one or two ring members independently selected from N(R9)(R12), N(R9) and O; Cycle-Q represents independently at each occurrence phenyl optionally substituted by 1 to 3 R19 or a 5- to 6-membered heteroaryl ring containing one to four heteroatoms selected from O, S and N, optionally substituted by 1 to 3 R19; R15 represents independently at each occurrence hydrogen or C1-C6alkyl optionally substituted by 1 to 5 R14; R16 and R17 represent independently at each occurrence hydrogen or C1-C6alkyl optionally substituted by 1 to 5 R14; R18 and R19 represent independently at each occurrence halogen, cyano, hydroxyl, oxo, amino, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, Cl-C4haloalkoxy or -CO(O)R11; R20 represents independently at each occurrence hydrogen or methyl; R21 represents N(R20)2 or CH2-N(R20)2; LI represents -CH=CH-, -CH2-O-, -O-CH2-, -CH2-O-CH2-,-CH2-S-, -S-CH2-, -CH2-S(O)-, -CH2-S(O2)-, -S(O)-CH2-; -S(O2)-CH2-, -C(CH3)(CH3)-, -C(=O)-NH-, -NH-C(=O)-, -CH2-CH2-, -CH=CH-CH2-, - CH2-NH-C(=O)-, -C(=O)-NH-CH2, -C≡C-, -S(O2)-NH-CH2-, -S(02)-NH, -O-CH2-CH2-O-, -O-, -NH- CH2-, -CH2-NH-, -CH2-CH2-O-, or -NH-C(=O)-CH2-O-, or a bond; L2 represents Cl-C7alkylene, wherein one or more CH2 moieties in the alkylene are optionally replaced independently by -N(R9)(R20)-, -CH(N(R9)(R20)(R20))-, or -C(=0)-, wherein within L2 there are no adjacent C(=O) moieties or adjacent -N(R9)(R20)- moieties, and wherein the terminal moiety of L2 is not - N(R9)(R20)-, or L2 represents -O-C1-C6alkylene-, or L2 represents a bond, providing that X represents - CH2- when L2 is a bond; as well as methods of using the compounds of formula I for treating or preventing bacterial infections.
ALDOSTERONE SYNTHASE INHIBITOR
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Paragraph 0016; 0076; 0080, (2018/10/10)
PROBLEM TO BE SOLVED: To provide a compound having aldosterone synthase inhibition effect useful for treatment of primary aldosteronism causing hypertension or hypokalemia by overproduction of aldosterone, and a pharmaceuticals containing the compound. SOLUTION: There are provided an imidazole compound including 4-[5-(2-fluoroethyl)-1H-imidazole-1-ylmethyl]-3-iodobenzonitrile, 1-(3-bromo-4-cyanobenzyl)-1H-imidazole-5-carboxylic acid methyl, 1-(2-iodo-4-nitrobenzyl)-1H-imidazole-5-carboxylic acid methyl, 1-(3,5-di-tert-butylphenyl)-1H-imidazole-5-carboxylic acid methyl, 1-(2H-chromene-2-on-6-ylmethyl)-1H-imidazole-5-carboxylic acid methyl and 1-(2H-chromene-2-on-6-ylmethyl)-5-iodo-1H-imidazole as examples, and pharmaceuticals containing the compound. COPYRIGHT: (C)2015,JPOandINPIT
Discovery and in vivo evaluation of potent dual CYP11B2 (aldosterone synthase) and CYP11B1 inhibitors
Meredith, Erik L.,Ksander, Gary,Monovich, Lauren G.,Papillon, Julien P. N.,Liu, Qian,Miranda, Karl,Morris, Patrick,Rao, Chang,Burgis, Robin,Capparelli, Michael,Hu, Qi-Ying,Singh, Alok,Rigel, Dean F.,Jeng, Arco Y.,Beil, Michael,Fu, Fumin,Hu, Chii-Whei,Lasala, Daniel
, p. 1203 - 1207 (2014/01/06)
Aldosterone is a key signaling component of the renin-angiotensin- aldosterone system and as such has been shown to contribute to cardiovascular pathology such as hypertension and heart failure. Aldosterone synthase (CYP11B2) is responsible for the final three steps of aldosterone synthesis and thus is a viable therapeutic target. A series of imidazole derived inhibitors, including clinical candidate 7n, have been identified through design and structure-activity relationship studies both in vitro and in vivo. Compound 7n was also found to be a potent inhibitor of 11β-hydroxylase (CYP11B1), which is responsible for cortisol production. Inhibition of CYP11B1 is being evaluated in the clinic for potential treatment of hypercortisol diseases such as Cushing's syndrome.
