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The present invention relates to new sulfonamide URAT-1 inhibitor compounds of formula (I) or a pharmaceutically acceptable salt thereof: to compositions containing them, to processes for their preparation and to intermediates used in such processes, and to methods of treatment, wherein R1, R2, R3, R4, R5 and R6 are as defined in the description.

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An original oxidative ring contraction of easily accessible cyclobutene derivatives for the selective formation of cyclopropylketones (CPKs) under atmospheric conditions is reported. Comprehensive mechanistic studies are proposed to support this novel, yet unusual, rearrangement. Insights into the mechanism ultimately led to simplification and generalization of the ring contraction of cyclobutenes using mCPBA as an oxidant. This unique and functional group tolerant transformation proceeds under mild conditions at room temperature, providing access to a new library of polyfunctionalized motifs. With CPKs being attractive and privileged pharmacophores, the elaboration of such a simple and straightforward strategy represents a highly valuable tool for drug discovery and medicinal chemistry. Additionally, the described method was employed to generate a pool of bioactive substances and key precursors in a minimum number of steps.

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The present invention provides a bicyclic triazolone derivative represented by the formula:J-Ar [wherein, J is and Ar is ], which has excellent selective weeding activity and weed killer containing the said bicyclic triazolone derivative.

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The invention relates to inhibitors of glucosylceramide synthase (GCS) useful for the treatment of metabolic diseases, such as lysosomal storage diseases, either alone or in combination with enzyme replacement therapy, cystic disease and for the treat­ment of cancer

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Heterometallic Zn2Ln2 [Ln = Gd (1), Eu (2), Tb (3), Dy (4)] discrete molecules with edge-defective cubane structure are assembled from a multifunctional fluorescent conjugate ligand and LnIII/ZnII mixed-metal ions; they exhibit the tunable luminescence, including ligand-based yellow-green light emission for 1 and 4 and lanthanide-center emission for 2 and 3. The multiple stimuli-responsive photoluminescences were investigated to show a two-step thermal-responsive luminescence increase in the intensity upon cooling and piezochromic luminescence.

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Substitution at the ortho position of N-(3,4-dimethyl-5-isoxazolyl) benzenesulfonamide led to the identification of the biphenylsulfonamides as a novel series of endothelin-A (ETA) selective antagonists. Appropriate substitutions on the pendant phenyl ring led to improved binding as well as functional activity. A hydrophobic group such as isobutyl or isopropoxyl was found to be optimal at the 4′-position. Introduction of an amino group at the 2′-position also led to improved analogues. Combination of the optimal 4′- isobutyl substituent with the 2′-amino function afforded an analogue (20, BMS-187308) with improved ET(A) binding affinity and functional activity. Compound 20 also has good oral activity in inhibiting the pressor effect caused by an ET-1 infusion in rats. Doses of 10 and 30 mumol/kg iv 20 attenuated the pressor responses due to the administration of exogenous ET-1 to conscious monkeys, indicating that the compound inhibits the in vivo activity of endothelin-1 in nonhuman primates.

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A method for preparation of crown ethers containing a pyridazine ring based on 1,2-dihydro-3,6-dioxopyridazine was developed. 1998 Plenum Publishing Corporation.

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3′-Heteroarylmethyl analogues (1)-(8) of the natural thyroid hormone 3,3′,5-tri-iodo-L-thyronine (T3) were synthesized as potential selective (cardiac-sparing) thyromimetics.The diphenyl ether moiety was constructed by condensation of 3-substituted 4-methoxyphenols with a 3,5-dinitro-L-tyrosine derivative.Synthesis of the key phenols (28)-(32) required the in situ preparation, at low temperatures, of the novel metallated species 2-lithio-5-methoxypyridine (14), 5-lithio-2-methoxypyrimidine (15), 5-lithio-2-methylpyridine (16), 5-bromo-4-lithio-2-methoxypyridine (18) , and 2,6-difluoro-3-lithiopyridine (19), followed by reaction with the benzaldehyde (20).Alternative routes to the pyridazone (36) and thiazolone (37) phenols were developed from the benzyl bromide (33).Structure-activity relationships indicate that selective thyromimetic activity is associated with 2-oxyheteroaren-5-ylmethyl 3′-substitution, as found in the pyridone (1), pyridazinone (2), hydroxypyridine (4) and thiazolone (8).The location of the oxy substituent in the heterocycle is critical for both hormonal activity and for binding to the T3 receptor.

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Discovery of a highly selective, potent, and safe non-carboxylic acid, non-hydantoin inhibitor of aldose reductase (AR) capable of potently blocking the excess glucose flux through the polyol pathway that prevails under diabetic conditions has been a long-standing challenge. In response, we did high-throughput screening of our internal libraries of compounds and identified 6-phenylsulfonylpyridazin-2H-3-one, 8, which showed modest inhibition of AR, both in vitro and in vivo. Initial structure-activity relationships concentrated on phenyl substituents and led to 6-(2,4-dichlorophenylsulfonyl)-2/f-pyridazin- 3-one, 81, which was more potent than 8, both in vitro and in vivo. Incorporation of extant literature findings with other aldose reductase inhibitors, including zopolrestat, resulted in the title inhibitor, 19m, which is one of the most potent and highly selective non-carboxylic acid, non-hydantoin inhibitors of AR yet described (IC50, 1 nM; ED 90 vs sciatic nerve sorbitol and fructose, respectively, 0.8 and 4.0 mg/kg). In rats, its oral bioavailability is 98% and it has a favorable plasma t1/2 (26 ± 3 h).

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A family of platinum group metal complexes containing bidentate pyridazine-NHC ligands (L1 = 3,6-bis(N-n-methylimidazolyl)pyridazine dichloride, L2 = 3,6-bis(N-n-butylimidazolyl)pyridazine dichloride) have been synthesized. The typical mechanism of the reactions for these syntheses involved an in situ carbene transfer reactions. Reaction of L1/L2 with silver oxide in absence of light yielded silver-NHC complexes (1) and (2). When, the respective metal precursors were added to the silver-NHC complexes, transmetallation occurred with the possible isolation of the following cationic complexes: [(eta6-C6H6)Ru(L)Cl]2+ {L = L1 (3), L2 (5)}, [(eta6-p-iPrC6H 4Me)Ru(L)Cl]2+ {L = L1 (4), L2 (6)}, [Cp *Rh(L)Cl]2+ {L = L1 (7), L2 (9)} and [Cp *Ir(L)Cl]2+ {L = L1 (8), L2 (10)}. All these complexes were stable in ambient atmosphere, and could be obtained in good yield. All these complexes were characterized by spectroscopic analyses. The molecular structure of the complex 9 was determined by single crystal X-ray diffraction studies.

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