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2-substituted (2SR)-2-amino-2-((1SR,2SR)-2-carboxycycloprop-1- yl)glycines as potent and selective antagonists of group II metabotropic glutamate receptors. 2. Effects of aromatic substitution, pharmacological characterization, and bioavailability

In this paper we describe the synthesis of a series of alpha-substituted analogues of the potent and selective group II metabotropic glutamate receptor (mGluR) agonist (1S,1’S,2’S)-carboxycyclopropylglycine (2, L-CCG 1). Incorporation of a substituent on the amino acid carbon converted the agonist 2 into an antagonist. All of the compounds were prepared and tested as a series of four isomers, i.e., two racemic diastereomers. On the basis of the improvement in affinity realized for the alpha-phenylethyl analogue 3, in this paper we explored the effects of substitution on the aromatic ring as a strategy to increase the affinity of these compounds for group II mGluRs. Affinity for group II mGluRs was measured using [3H]glutamic acid (Glu) binding in rat forebrain membranes. Antagonist activity was confirmed for these compounds by measuring their ability to antagonize (1S,3R)-1- aminocyclopentane-1,3-dicarboxylic acid-induced inhibition of forskolin stimulated cyclic-AMP in RGT cells transfected with human mGluR2 and mGluR3. Meta substitution on the aromatic ring of 3 with a variety of substituents, both electron donating (e.g., methyl, hydroxy, amino, methoxy, phenyl, phenoxy) and electron withdrawing (e.g., fluorine, chlorine, bromine, carboxy, trifluoromethyl) gave from 1.5- to 4.5-fold increases in affinity. Substitution with p-fluorine, as in 97 (IC50 = 0.022 ¡À 0.002), was the exception. Here, a greater increase in affinity was realized than for either the ortho- or meta-substituted analogues; 97 was the most potent compound resulting from monosubstitution of the aromatic. At best, only modest increases in affinity were realized for certain compounds bearing either two chlorines or two fluorines, and two methoxy groups gave no improvement in affinity (all examined in a variety of substitution patterns). Three amino acids, 4, 5, and 104, were resolved into their four constituent isomers, and affinity and functional activity for group II mGluRs was found to reside solely in the S,S,S-isomers of each, consistent with 1. With an IC50 = 2.9 ¡À 0.6 nM, the resolved xanthylmethyl compound 168 was the most potent compound from this SAR. Amino acid 168 demonstrated high plasma levels following intraperitoneal (ip) administration and readily penetrated into the brain. This compound, however, had only limited (~5%) oral bioavailability. Systemic administration of 168 protected mice from limbic seizures produced by the mGluR agonist 3,5-dihydroxyphenylglycine, with an ED50 = 31 mg/kg (ip, 60 min preinjection). Thus, 168 represents a valuable tool to study the role of group II mGluRs in disease.

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Reference£º
Benzodioxan,
1,4-Benzodioxane | C8H8O2 – PubChem

Archives for Chemistry Experiments of 5-(Bromomethyl)-2,3-dihydro-1,4-benzodioxine

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Design, synthesis and biological evaluation of FLT3 covalent inhibitors with a resorcylic acid core

A series of simplified ring-opened resorcylic acid lactone (RAL) derivatives were conveniently synthesized to target FLT3 and its mutants either irreversibly or reversibly. Our design of covalent FLT3 inhibitors is based on cis-enone RALs (e.g., L-783,277) that have a beta-resorcylic acid as the core structure. The designed compounds contain three types of Michael acceptors (acrylamide, vinylsulfonamide and maleimide) as potential covalent traps of a cysteine residue at the binding site of kinases. A variety of functional substitutions were also introduced to maximize the binding interactions. Biological evaluations revealed that compound 17, despite the presence of a highly reactive maleimide Michael acceptor, is a potent covalent FLT3 inhibitor which shows some specificity in cellular assays. On the other hand, compounds 2 and 6 containing acrylamide or vinylsulfonamide groups are reversible towards FLT3 binding, and are potent and selective inhibitors of mutant FLT3-ITD versus wt-FLT3. They also inhibit cell proliferation in FLT3-ITD expressing cell line MV-4-11 as compared to wt-FLT3 expressing cell line THP-1 and non-FLT3 cell lines (K562, HL60 and Hek-293T).

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Benzodioxan,
1,4-Benzodioxane | C8H8O2 – PubChem

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SUBSTITUTED FUSED BICYCLIC AMINES AS MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY

The present application describes modulators of CCR3 of formula (Ia) and (Ib): or pharmaceutically acceptable salt forms thereof, wherein Z, R1, R2, R3, R4, R5, R5′, R 6, a, b, c, d, and u are as defined herein. In addition, methods of treating and preventing inflammatory diseases such as asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis using said modulators are disclosed.

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Benzodioxan,
1,4-Benzodioxane | C8H8O2 – PubChem

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HETEROCYCLE SUBSTITUTED PYRIDINE DERIVATIVE ANTIFUNGAL AGENTS

Described herein are heterocycle substituted pyridine derivative antifungal agents and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for the treatment of fungal diseases and infections.

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Benzodioxan,
1,4-Benzodioxane | C8H8O2 – PubChem

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New betulinic acid derivatives as potent proteasome inhibitors

In this study, 22 new betulinic acid (BA) derivatives were synthesized and tested for their inhibition of the chymotrypsin-like activity of 20S proteasome. From the SAR study, we concluded that the C-3 and C-30 positions are the pharmacophores for increasing the proteasome inhibition effects, and larger lipophilic or aromatic side chains are favored at these positions. Among the BA derivatives tested, compounds 13, 20, and 21 showed the best proteasome inhibition activity with IC50 values of 1.42, 1.56, and 1.80 muM, respectively, which are three to fourfold more potent than the proteasome inhibition controls LLM-F and lactacystin.

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Benzodioxan,
1,4-Benzodioxane | C8H8O2 – PubChem

Discovery of 5-(Bromomethyl)-2,3-dihydro-1,4-benzodioxine

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Substitute 1-(piperidin-4-yl)-3-(aryl)-isothioureas, their preparation and therapeutic use

The invention concerns compounds of formula (I) wherein: R1 and R2, identical or different, represent a saturated or unsaturated alkyl radical, branched or not and containing 1 to 7 carbon atoms; R3 to R8, identical or different, represent a hydrogen, an alkyl branched or not and containing 1 to 5 carbon atoms, an acyloxy, branched or not and containing 1 to 5 carbon atoms, a halogeno, nitro, hydroxy, acyl or alkoxy group containing 1 to 5 carbon atoms, a dialkylamino group containing 1 to 5 carbon atoms, a trifluoromethyl or trifluoro methoxyl group; Z represents an oxygen or sulphur atom or methylene; m represents an integer between 0 and 4 inclusively; n represents an integer between 2 and 7 inclusively; and their pure enantiomers and mixtures, the therapeutically acceptable mineral or organic salts of the compounds of formula (I) and their possible hydrates.

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Benzodioxan,
1,4-Benzodioxane | C8H8O2 – PubChem

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Novel benzodifuran analogs as potent 5-HT2A receptor agonists with ocular hypotensive activity

A series of 8-substituted benzodifuran analogs was prepared and evaluated for 5-HT2A receptor binding and activation. Several compounds containing ether and ester functionality were found to be potent agonists. Topical ocular administration of 5, 18, and 25 effectively reduced intra-ocular pressure in the hypertensive cynomolgus monkey eye in the range of 25-37%.

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Benzodioxan,
1,4-Benzodioxane | C8H8O2 – PubChem

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Anti-AIDS agents. 78. Design, synthesis, metabolic stability assessment, and antiviral evaluation of novel betulinic acid derivatives as potent anti-human immunodeficiency virus (HIV) agents

In a continuing study of potent anti-HIV agents, seventeen 28,30-disubstituted betulinic acid (BA, 1) derivatives and seven novel 3,28-disubstituted BA analogues were designed, synthesized, and evaluated for in vitro antiviral activity. Among them, compound 21 showed an improved solubility and equal anti-HIV potency (EC50 = 0.09 muM) when compared to HIV entry inhibitors 3b (IC9564, (3R,4S)-N?-[N-[3beta-hydroxylup-20(29)-en- 28-oyl]-8-aminooctanoyl]-4-amino-3-hydroxy-6-methylheptanoic acid) and 4 (A43-D, [[N-[3beta-O-(3?,3?-dimethylsuccinyl)-lup-20(29)-en-28-oyl]-7- aminoheptyl]carbamoyl]methane). Using a cyclic secondary amine to form the C-28 amide bond increased the metabolic stability of the derivatives significantly in pooled human liver microsomes. The most potent compounds 47 and 48 displayed potent anti-HIV activity with EC50 values of 0.007 and 0.006 muM, respectively. These results are slightly better than that of bevirimat (2, 3?,3?-dimethylsuccinylbetulinic acid), which is currently in phase IIb clinical trials. Compounds 47 and 48 should serve as attractive promising leads to develop next generation, metabolically stable, 3,28-disubstituted bifunctional HIV-1 inhibitors as clinical trials candidates.

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Reference£º
Benzodioxan,
1,4-Benzodioxane | C8H8O2 – PubChem

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DDQ-mediated Direct C(sp3)-H Cyanation of Benzyl Ethers and 1,3-Diarylpropenes under Solvent- and Metal-free Conditions

A direct cyanation of benzyl ethers and 1,3-diarylpropenes with TMSCN was performed under solvent- and metal-free conditions. This oxidative cross dehydrative coupling (CDC) reaction was promoted by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and provided rapid access to a broad range of nitriles in good to excellent yields.

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Reference£º
Benzodioxan,
1,4-Benzodioxane | C8H8O2 – PubChem

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A iron catalyzed cross-coupling reaction for the dehydrogenation of specification meeting National etherally method (by machine translation)

The invention discloses a iron catalyzed cross-coupling reaction for the dehydrogenation of specification meeting National etherally method, which belongs to the technical field of catalytic synthesis, the reaction formula is as follows: The invention non-toxic inexpensive for the iron does catalyst, silicon reagent as the accelerator, the oxidizing agent under the effect of the cross-coupling reaction for the dehydrogenation of specification meeting National synthetic ether. The invention using environment-friendly iron catalyst, safe and pollution-free silicon reagent promoters, in the dehydrogenation of specification meeting National cross-coupling reaction, has good functional group compatibility, substrate and wide range of application. (by machine translation)

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Reference£º
Benzodioxan,
1,4-Benzodioxane | C8H8O2 – PubChem