41661-47-6

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Inherited blinding diseases retinitis pigmentosa (RP) and a subset of Leber's congenital amaurosis (LCA) are caused by the misfolding and mistrafficking of rhodopsin molecules, which aggregate and accumulate in the endoplasmic reticulum (ER), leading to photoreceptor cell death. One potential therapeutic strategy to prevent the loss of photoreceptors in these conditions is to identify opsin-binding compounds that act as chemical chaperones for opsin, aiding its proper folding and trafficking to the outer cell membrane. Aiming to identify novel compounds with such effect, a rational ligand-based approach was applied to the structure of the visual pigment chromophore, 11-cis-retinal, and its locked analogue 11-cis-6mr-retinal. Following molecular docking studies on the main chromophore binding site of rhodopsin, 49 novel compounds were synthesized according to optimized one-to seven-step synthetic routes. These agents were evaluated for their ability to compete for the chromophore binding site of opsin, and their capacity to increase the trafficking of the P23H opsin mutant from the ER to the cell membrane. Different new molecules displayed an effect in at least one assay, acting either as chemical chaperones or as stabilizers of the 9-cis-retinal-rhodopsin complex. These compounds could provide the basis to develop novel therapeutics for RP and LCA.

The present invention provides compounds, compositions thereof, and methods of using the same.

A deep eutectic solvent of glucose-urea was found to be an inexpensive and effective reaction medium in the synthesis of piperidin-4-one derivatives. In this work, 3-methyl-2,6-diphenyl piperidin-4-one (4a), 3,5-dimethyl-2,6-diphenylpiperidin-4-one (4b), 2,6-diphenylpiperidin-4-one (4c), piperidin-4-one (4d), 3,5-dimethylpiperidin-4-one (4e), 3-methyl-2,6-di(2-hydroxyphenyl)piperidin-4-one (4f), 3,5-dimethyl 2,6-di(2-hydroxyphenyl)piperidin-4one (4g) were synthesized using a deep eutectic solvent (DES) of glucose and urea with the percentage composition of 60:40. The yields of these products were 82, 78, 75, 68, 72, 70 and 70 %, respectively. The products obtained were characterized by FT-IR and 1H NMR spectroscopic techniques. A synthesis of piperidin-4-one derivatives by using this green solvent was considered to be new environmentally safe synthetic method.

The invention discloses a synthesis method of an intermediate 4-piperidone. The method comprises the following steps: adding beta-alanine methyl ester into ethanol, placing the raw material into a reaction kettle, adding ethylene, uniformly mixing the raw materials, cooling the raw materials to 0-10 DEG C, adding a catalyst aid and sodium ethoxide, stirring the raw materials for reaction, and cooling a reaction product to room temperature after the reaction is finished; and performing reduced pressure distillation to remove ethanol; adding DMF into a reaction kettle, uniformly stirring and mixing the components, heating the mixture to 110-130 DEG C, and carrying out reflux reaction under a stirring condition for 1-2 hours; cooling the reaction product to room temperature, extracting the reaction product with ethyl acetate, performing evaporation to remove ethyl acetate, and carrying out reduced pressure distillation to obtain the 4-piperidone. The synthesis method disclosed by the invention adopts a one-pot method, does not need an intermediate purification step, reduces resource waste, is simple to operate, short in production process, high in raw material conversion rate and relatively low in production cost, and has relatively high economic benefits.

An efficient oxidation and functionalization of C-H bonds with an inorganic-ligand supported iron catalyst and hydrogen peroxide to prepare the corresponding ketones was achieved using the bromide ion as a promoter. Preliminary mechanistic investigations indicated that the bromide ion can bind to FeMo6 to form a supramolecular species (FeMo6·2Br), which can effectively catalyze the reaction.

The invention belongs to the technical field of chemical medicine intermediate synthesis, and particularly relates to a synthesis method of a bacterial infection resistant medicine intermediate. Liquid ammonia and acrylic ester are used as raw materials for preparing a diester type secondary amine compound 1; then, through cyclization, piperidone is prepared; then, scientific reaction catalysts, temperature and time are used; substitution reaction of secondary amine and iso-propyl iodide is used; the target product is synthesized through six-step reaction; the yield of the whole route reachesup to 35 percent.

Synthesis and characterization of a new silica-coated magnetite nanocatalyst are described. This catalyst was prepared through a multistep procedure consisting of surface modification, functionalization with the product of an Ugi multicomponent reaction, and immobilization of Co3O4 on silica-coated magnetite nanoparticles. The prepared nanocatalyst was characterized using various techniques such as Fourier-transform infrared and energy-dispersive X-ray spectroscopies, thermal and elemental analyses, X-ray diffraction, and field-emission scanning and transmission electron microscopies. The catalyst showed high catalytic activity for the aerobic oxidation of alcohols in acetonitrile as the solvent at mild temperatures and reusability for five repeated runs without loss of its activity.

The invention discloses a compound shown in a formula I, and pharmaceutically acceptable salts, stereoisomers, solvates or predrugs. The symptoms are defined in claim requirements. The compound shownin the formula I has good inhibiting activity on ALK (anaplastic lymphoma kinase), and can be used for preparing medicines for adjusting the activity of the ALK activity or treating the ALK-related diseases, especially nonsmall-cell lung cancer drugs. (The formula I is shown in the attached figure.).

Compounds that modulate the oxidoreductase enzyme indoleamine 2,3- dioxygenase, and compositions containing the compounds, are described herein. The use of such compounds and compositions for the treatment and/or prevention of a diverse array of diseases, disorders and conditions, including cancer- and immune-related disorders, that are mediated by indoleamine 2,3-dioxygenase is also provided.

Abstract To give further insight into the influence of the structural modifications of enones and dienones on their antiproliferative properties, 25 derivatives of enones: (E)-2-benzylidene-1-cyclohexanones, (E)-2-benzylidene-1-tetralones, (E)-2-benzylidene-1-indanone, and dienones: (E,E)-2,5- or 2,6-dibenzylidene-1-cyclanones, (E,E)-3,5-dibenzylidene-4-piperidones were synthesized using a newly developed "one-pot" synthetic method. Due to the fact that all of them have the same aryl substituents (phenyl or 4-chlorophenyl) in the arylidene moiety, it is possible to compare the relevant contribution of the single-point structural modifications (type of ring or N-substitution) on their potency on the basis of their IC 50 values. Their antiproliferative activity was evaluated against the following four human adherent cancer cell lines: HeLa, A431, A2780, and MCF7. The cytotoxicity screen has revealed that the dibenzylidene dienones in general dominate the monobenzylidene enones in this respect. The nitrogen-containing heterocyclic dienones at the same time displayed higher inhibitory properties toward these human carcinoma cell lines compared with their homocyclic dienone analogs. One of the eight newly prepared 4-piperidone derivatives, N-(γ-oxobutyl)-(E,E)-3,5-bis(p-chlorobenzylidene)-4-piperidone is as potent a cell growth inhibitor (IC 50 of 0.438-1.409 μM) as the N-methyl-(E,E)-3,5-bis(p-chlorobenzylidene)-4-piperidone (IC 50 of 0.447-1.048 μM), one of the most active among the previously described compounds in this series. Catalytic hydrogen-transfer isomerization of compounds with two exocyclic benzylidene double bonds to derivatives with endocyclic double bonds results in the complete loss of antiproliferative activity. The structural modifications and 50 % inhibitory concentration (IC 50) values resulted in correlations which can promote the design of more potent derivatives of the 4-piperidone dienones.

The invention provides compounds that are modulators of neuropeptide Y (NPY) receptors, which can be selective inhibitors of NPY receptor Y2R. NPY receptor modulatory compounds are of the general formula Ar2-Y-Ar1-W-Ar3, wherein the variables are as defined herein. Compounds of the invention can be used for treatment of malconditions in patients wherein modulation of an NPY receptor is medically indicated, for example including drug or alcohol abuse, anxiety disorders, depression, stress-related disorders, neurological disorders, nerve degeneration, osteoporosis or bone loss, sleep/wake disorders, cardiovascular diseases, obesity, anorexia, inovulation, fertility disorders, angiogenesis, cell proliferation, learning and memory disorders, migraine and pain.

Tuberculosis afflicts an estimated 2 billion people worldwide and causes 1.3 million deaths annually. Chemotherapeutic solutions rely on drugs developed many years ago, with only one new therapeutic having been approved in the last 40 years. Given the rise of drug-resistant strains, there is an urgent need for the development of a more robust drug development pipeline. GlaxoSmithKline recently placed the structures and activities of 177 novel anti-tubercular leads in the public domain, as well as the results of ongoing optimisation of some of the series. Since many of the compounds arose from screening campaigns, their provenance was unclear and synthetic routes were in many cases not reported. Here we present the efficient synthesis of several novel analogues of one family of the GSK compounds termed "Spiros"-using an oxa-Pictet-Spengler reaction. The new compounds are attractive from a medicinal chemistry standpoint and some were potent against the virulent strain, suggesting this class is worthy of further study. The research was carried out using open source methodology, providing the community with full access to all raw experimental data in real time.

A simple, highly reproducible protocol for the hydrogenation of alkenes and alkynes and for the hydrogenolysis of O-benzyl ethers has been developed. The method features the in situ preparation of an active Pd0/C catalyst from Pd(OAc)2 and charcoal, in methanol. The mild reaction conditions (25°C) and low catalyst loading required (0.025 mol%), as well as the absence of contamination of the product by palladium residues (0/C: It's a kind of magic! A sustainable, simple and highly reproducible protocol for the hydrogenation of alkenes and alkynes (see scheme) and for the hydrogenolysis of O-benzyl ethers has been developed with an in situ generated Pd0/C catalyst. The homemade Pd0/C catalyst allows mild reaction conditions (25°C, 1 atm H2) and low catalyst loading (as low as 0.025 mol%), without any contamination of the product by palladium residues (4 ppb).

We recently identified bis(amide) CCG-1423 (1) as a novel inhibitor of RhoA/C-mediated gene transcription that is capable of inhibiting invasion of PC-3 prostate cancer cells in a Matrigel model of metastasis. An initial structure-activity relationship study focusing on bioisosteric replacement of the amides and conformational restriction identified two compounds, 4g and 8, with improved selectivity for inhibition of RhoA/C-mediated gene transcription and attenuated cytotoxicity relative to 1. Both compounds were also capable of inhibiting cell invasion with equal efficacy to 1 but with less attendant cytotoxicity.

The synthesis of a new series of 1β-methylcarbapenems having pyrrolidine and piperidine moieties is described. Their in-vitro antibacterial activities against both Gram-positive and Gram-negative bacteria were tested and the effect of substituents on the pyrrolidine ring was investigated. A particular compound III b having an oxime-pyrrolidine moiety showed the most potent antibacterial activity.

The present invention has its object to provide a 2,3,4,5-tetrahydro-1H-1,5-benzodiazepine derivative represented with the Formula (1) , or the pharmaceutically acceptable salt, which is effective as a therapeutic and prophylactic agent for diabetes, diabetic nephropathy, or glomerulosclerosis.

There is provided a compound having Formula (I) wherein each of R1, R2, R4, R5, R6 and R7 are independently selected from (a) H, (b) R17, -OC(R17)3, -OCH(R17)2, -(OCH2R)17, -C(R17)3, -CH(R17)2, or -CH2R17 wherein R17 is a halogen; (c) -CN; (d) optionally substituted alkyl, (e) optionally substituted heteroalkyl; (f) optionally substituted aryl; (g) optionally substituted heteroaryl; (h) optionally substituted arylalkyl; (i) optionally substituted heteroarylalkyl; (j) hydroxy; (k) alkoxy; (l) aryloxy; (m) -SO2-alkyl; and (n) -N(R11)C(O)R13; wherein the optional substituents of (d) (e) (f) (h) and (i) are selected from the group consisting of: C1-6 alkyl, halo, cyano, nitro, haloalkyl, hydroxy, alkoxy, carboxy, carboxyalkyl, carboxamide, mercapto, amino, alkylamino, dialkylamino, sulfonyl, sulfonamido, aryl and heteroaryl ; each of rings A and B are selected from five or six membered carbon rings optionally containing one or more hetero atoms selected from N, S, and O and optionally having fused thereto a further ring; X is an optional group selected from O, S, S=O, S(=O)2, C=O, S(=O)2NR8, C=ONR9, NR10, wherein R8, R9 and R10 are independently selected from H and hydrocarbyl, wherein n and p are independently selected from O and 1 ; Y is (R11)1-3 wherein each R11 is independently selected from NR12, CR13R14, S(=O)2 and C=O, wherein R12, R13 and R14 are independently selected from H and hydrocarbyl; Z is selected from (i) six or seven membered ring containing carbon and at least one nitrogen, which may be optionally substituted wherein the substituents may together form further ring fused thereto; and (ii) a -R15-NR16- group wherein R15 is an optionally substituted C1-6 alkyl chain and R16 is selected from H and hydrocarbyl; and R3 is selected from Formula (A).

The discovery and optimization of a novel class of potent CCR3 antagonists is described. Details of synthesis and SAR are given together with some ADME properties of selected compounds. An optimal balance between activities, physicochemical properties, and in vitro metabolic stability was reached by the proper choice of substituents.

Oxazolidinone analogs bearing substituted piperidine or azetidine C-rings are described. Analogs with a methyl group at the 3-position of the azetidine ring or the 4-position of the piperidine ring exhibited reduced mitochondrial protein synthesis inhibition while retaining good antibacterial potency.

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A cyclic amine compound represented by the following general formula (1): wherein, R1, R2 and R3 each independently represent a hydrogen atom or an alkoxy group;W1 and W2 each independently represent N or CH;X represents O, NR4, CONR4 or NR4CO;R4 represents a hydrogen atom, or an alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl group; andl, m and n each represents a number of 0 or 1, a salt thereof and a hydrate thereof are provided. These compounds have inhibitory effects on both cell adhesion and cell infiltration and are useful as anti-asthmatic agents, anti-allergic agents, anti-rheumatic agents, anti-arteriosclerotic agents, anti-inflammatory agents, anti-Sjogren's syndrome agents or the like.

A new protocol based on a solid-supported thiol was developed for high yielding deprotection of o-nitrobenzensulfonyl amides derived from primary and secondary amines. The reaction can be carried out at room temperature for 24 hours or accelerated by microwave irradiation, going to completion in six minutes. Georg Thieme Verlag Stuttgart.

Alkyl groups can be cleaved efficiently and selectively from tertiary alkyl amines using propargyl chloroformate. The propargyloxycarbonyl (Poc) protected secondary amines thus obtained can be deblocked under neutral and mild conditions using benzyltriethylammonium tetrathiomolybdate. The generality and compatibility of the method have been studied with a wide range of functionalities. Alkyl groups can be cleaved efficiently and selectively from tertiary alkyl amines using propargyl chloroformate. The propargyloxycarbonyl (Poc) protected secondary amines thus obtained can be deblocked under neutral and mild conditions using benzyltriethylammonium tetrathiomolybdate. The generality and compatibility of the method have been studied with a wide range of functionalities.

A cyclic amine compound represented by the following general formula (1): wherein, R1, R2 and R3 each independently represent a hydrogen atom or an alkoxy group; W1 and W2 each independently represent N or CH; X represents O, NR4, CONR4 or NR4CO; R4 represents a hydrogen atom, or an alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl group; and l, m and n each represents a number of 0 or 1, a salt thereof and a hydrate thereof are provided. These compounds have inhibitory effects on both cell adhesion and cell infiltration and are useful as anti-asthmatic agents, anti-allergic agents, anti-rheumatic agents, anti-arteriosclerotic agents, anti-inflammatory agents, anti-Sjogren's syndrome agents or the like.

The present invention relates to substituted benzothiazole derivitives and to their pharmaceutically acceptable salts useful for the treatment of diseases related to the adenosine receptor.

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