135936-16-2Relevant academic research and scientific papers
4-Amino-2-(aryl)-butylbenzamides and their conformationally constrained analogues. Potent antagonists of the human neurokinin-2 (NK2) receptor
MacKenzie, A. Roderick,Marchington, Allan P.,Middleton, Donald S.,Newman, Sandra D.,Selway, Christopher N.,Terrett, Nicholas K.
, p. 2211 - 2215 (2007/10/03)
A library, evaluating a range of piperazines, piperidines and acyclic amines, as replacements for the 4-hydroxy-4-phenylpiperidine moiety in lead (1b) was prepared. These efforts identified the 4-((N)-benzimidazolone)piperidine analogue (2a) which was further optimised using classical single-compound synthesis to yield the 3-((N)-morpholino)azetidine (2j). Conformationally constrained analogues of (2j), generally offered no potency advantage in this particular series.
Ccr5 modulators benzimidazoles or benzotriazoles
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, (2008/06/13)
The invention concerns compounds of formula (I), wherein the variables are defined herein; processes for preparing them, compositions comprising them and their use in modulating CCR5 receptor activity.
Structure-activity relationships of 1-alkyl-5-(3,4-dichlorophenyl)-5-{2-[(3-substituted)-1-azetidinyl]ethyl} -2-piperidones. 1. Selective antagonists of the neurokinin-2 receptor
MacKenzie, A. Roderick,Marchington, Allan P.,Middleton, Donald S.,Newman, Sandra D.,Jones, Barry C.
, p. 5365 - 5377 (2007/10/03)
The design, synthesis, and pharmacological evaluation of a novel class of neurokinin-2 (NK2) antagonists 1-alkyl-5-(3,4-dichlorophenyl)-5-{2-[(3-substituted)- 1-azetidinyl]ethyl}-2-piperidones (5-44) are described. These compounds are formally derived from 2 by incorporating the metabolically vulnerable N-methylamide function into a more stable six-membered ring lactam 4, resulting in increased stability in human liver microsome (HLM) preparations relative to 2 (T1/2(HLM) of 30 min vs 2 receptor in the Rabbit pulmonary artery (RPA) assay (pA2 = 9.3) and increased in vitro metabolic stability (T1/2(HLM) = 70 min) relative to 4. Metabolic route identification studies revealed that N-benzyl oxidation was a major route in this relatively lipophilic lead (log D = 3.2). Further exploration of the N-lactam substituent SAR targeting reduced lipophilicity to attenuate P-450 metabolism revealed that incorporation of a cyclopropylmethyl group in this region of the molecule gave a balance of good potency and high metabolic stability. For example, the significantly less lipophilic analogue 29 (log D = 2.3) possessed both good functional potency (RPA, pA2 = 8. 1) and high in vitro metabolic stability (T1/2(HLM) = 120 min). Optimization in this N-cyclopropylmethyllactam series by modification of the nature of the azetidine 3-substituent as a strategy to further increase potency and moderate log D led to the identification of sulfamide analogue 33, which possessed both excellent metabolic stability in vitro (T1/2(HLM) > 120 min) and high potency in both RPA (pA2 = 8.9) and human bladder smooth muscle (pKb = 8.9) functional assays. In addition, NK2 antagonist 33 (IC50 = 4 nM) showed excellent selectivity over both the related human neurokinin receptors h-NK1 (IC50 = 7.9 μM) and h-NK3 (IC50 = 1.8 μM) in radioligand binding studies.
Quaternary ammonium compounds as tachykinin antagonists
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, (2008/06/13)
The present invention provides a compound of formula (I) wherein R is phenyl, C3-C7cycloalkyl or heteroaryl, each of which being optionally benzo- or C3-C7cycloalkyl-fused and optionally substituted, including in the benzo- or C3-C7cycloalkyl-fused portion, by from 1 to 3 substituents each independently selected from C1-C4alkyl, fluoro(C1-C4)alkyl, C1-C4alkoxy, fluoro(C1-C4)alkoxy, phenoxy, C2-C4alkanoyl, halo, C1-C4alkoxycarbonyl, C3-C7cycloalkyl, —S(O)m(C1-C4alkyl), cyano, —NR2R3, —S(O)mNR2R3, —NR4(C1-C4alkanoyl) and —CONR2R3, or R is 2,3-dihydrobenzo[b]furanyl or chromanyl; R1is H or C1-C6alkyl; W is a direct link, methylene or ethylene; X is unbranched C2-C4alkylene; Y is phenyl, naphthyl, benzyl, pyridyl, thienyl or C3-C7cycloalkyl, each of which being optionally substituted by from 1 to 3 substituents each independently selected from C1-C4alkyl, fluoro(C1-C4)alkyl, C1-C4alkoxy, fluoro(C1-C4)alkoxy, halo and cyano; Ar is phenyl, naphthyl, benzyl, thienyl, benzo[b]thienyl or indolyl, each of which being optionally substituted by from 1 to 3 substituents each independently selected from C1-C4alkyl, fluoro(C1-C4)alkyl, C1-C4alkoxy, fluoro(C1-C4)alkoxy, halo and cyano, or Ar is 1,3-benzodioxolan-4 or 5-yl or 1,4-benzodioxan-5 or 6-yl; ZAis a pharmaceutically acceptable anion; with the proviso that when W is a direct link and R is optionally fused and optionally substituted heteroaryl, said heteroaryl is linked by a ring carbon atom to the carbonyl group. The compounds are tachykinin antagonists.
3-Azetidinylalkylpiperidines or -pyrrolidines as tachykinin antagonists
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, (2008/06/13)
The present invention provides compounds of formula (I) and the pharmaceutically acceptable salts thereof. Such compounds and salts are tachykinin antagonists.
SUBSTITUTED N-METHYL-N-(4-(4-(1H-BENZIMIDAZOL-2-YL) {1,4}DIAZEPAN-1-YL)-2-(ARYL)BUTYL) BENZAMIDES USEFUL FOR THE TREATMENT OF ALLERGIC DISEASES
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, (2008/06/13)
The present invention relates to novel N-methyl-N-(4-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)-2-(aryl)butyl)benzamide derivatives of the formula: STR1 stereoisomers thereof, and pharmaceutically acceptable salts thereof which are useful as histamine receptor antagonists and tachykinin receptor antagonists. Such antagonists are useful in the treatment of allergic rhinitis, including seasonal rhinitis and sinusitis; inflammatory bowel diseases, including Crohn's disease and ulcerative colitis; asthma; bronchitis; and emesis.
(Azetidin-1-ylalkyl) lactams as tachykinin antagonists
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, (2008/06/13)
The present invention provides compounds of formula (I) and the pharmaceutically acceptable salts thereof, wherein R is C3 -C7 cycloalkyl, aryl or C1 -C6 alkyl, said C1 -C6 alkyl, said C1 -C6 alkyl being optionally substituted by fluoro, COOH, --COO(C1 -C4 alkyl), C3 -C7 cycloalkyl, adamantyl, aryl or het1, and said C3 -C7 cycloalkyl being optionally substituted by 1 or 2 substituents each independently selected from C1 -C4 alkyl, C3 -C7 cycloalkyl, C1 -C4 alkoxy, hydroxy, fluoro, fluoro (C1 -C4) alkyl and fluoro (C1 -C4) Alkoxy; R1 is phenyl, naphthyl, thienyl, benzothienyl or indolyl, each optionally substituted by 1 or 2 substituents each independently selected from C1 -C4 alkyl, C1 -C4 alkoxy, halo and trifluormethyl; R2 is --CO2 H, --CONR3 R4, --CONR5 (C3 -C7 cycloalkyl), --NR5 (C2 -C5 alkanoyl), --NR3 R4, --NR5 CONR5 R6, (C3 -C7 cycloalkyl-C1 -C4 alkyl)R5 N--, --NR5 COCF3, --NR5 SO2 CF3, --NR5 (SO2 C1 -C4 alkyl), --NR5 SO2 NR5 R6, --NR5 (SO2 aryl), --N(aryl) (SO2 C1 -C4 alkyl), --OR5, --O(C3 -C7 cycloalkyl), --SO2 NR5 R6, het3 or a group of formulas: (a), (b), (c), (d), (e), (f), (g) or (h); X is C1 -C4 alkylene; X1 is a direct link or C1 -C6 alkylene; X2 is a direct link, CO, SO2, or NR5 CO; and m is 0, 1 or 2; together with intermediates used in the preparation of compositions containing and the use as tachykinin angatonists of such derivatives. STR1
SUBSTITUTED N-METHYL-N-(4-(PIPERIDIN-1-YL)-2-(ARYL)BUTYL)BENZAMIDES USEFUL FOR THE TREATMENT OF ALLERGIC DISEASES
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, (2008/06/13)
The present invention relates to novel substituted N-methyl-N-(4-(piperidin-1-yl)-2-(aryl)butyl)benzamide derivatives of the formula STR1 stereoisomers thereof, and pharmaceutically acceptable salts thereof which are useful as histamine receptor antagonists and tachykinin receptor antagonists. Such antagonists are useful in the treatment of allergic rhinitis, including seasonal rhinitis and sinusitis; inflammatory bowel diseases, including Crohn's disease and ulcerative colitis; asthma; bronchitis; and emesis.
