- Kinetic Evidence for the Intermediacy of 1-Azirines in the Gas-Phase Thermal Isomerization of 3H-Isoxazoles to α-Carbonylacetonitrile Derivatives
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Thermal isomerization of 5-methylisoxazole and 5-amino-4-methylisoxazole to acetylacetonitrile and 2-cyanopropionamide, respectively, was studied in a flow system.The activation parameters are reported.According to the experimental results, a concerted 1,3 sigmatropic shift to 1-azirines is proposed as the rate-limiting step in these reactions.A general reaction mechanism for the isomerization of isoxazoles into 1-azirines, oxazoles, and α-carbonylacetonitrile derivatives is discussed.
- Perez, Jorge D.,Yranzo, Gloria I.,Wunderlin, Daniel A.
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Read Online
- Synthesis of some novel pyrazolo[3,4-b]pyridine and pyrazolo[3,4-d]pyrimidine derivatives bearing 5,6-diphenyl-1,2,4-triazine moiety as potential antimicrobial agents
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The reaction of 5,6-diphenyl-3-hydrazino-1,2,4-triazine (1) with bis(methylthio)methylene]malononitrile (2) afforded 5-amino-1-(5,6-diphenyl-1,2,4-triazin-3-yl)-3-(methylthio)-1H-pyrazole-4-carbonitrile (3). Compound 3 reacted with thiourea to give 3,4-di
- El-Sayed Ali, Tarik
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Read Online
- Design, synthesis, and in vitro anticancer screening of novel pyrazolinyl-pyrazole/1, 2, 3-triazole hybrids
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Novel hybrids, pyrazolinylpyrazoles, and pyrazolinyltriazoles were designed, synthesized, and screened for their anticancer activity. Eleven compounds were selected by the National Cancer Institute (NCI)/USA for anticancer screening at single high dose (10?5 M) in full NCI 60 cell panels. Two compounds: 4-aminopyrazole-5-carbonitrile, 5c (NSC-747630/1) and ethyl 4-aminopyrazole-5- carboxylate, 7d (NSC-747634/1) were the most active candidates of the series and were selected for further evaluation at five dose screening as they displayed significant growth inhibition with full panel median growth inhibition (GI50) 5.47 and 2.24 μM, respectively. Both 5c and 7d hybrids exhibited broad spectrum antitumor activity; however 7d showed moderate selectivity (selectivity ratio 3.6) toward leukemia.
- Ismail, Magda M. F.,Abdulwahab, Hanan G.,Elnagdi, Mohamed H.
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Read Online
- Synthesis of Novel 3-Acetyl-2-aminothiophenes and Investigation of their Behaviour in the Reaction with Vilsmeier-Haack Reagent
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Through an investigation into the behaviour of 3-acetyl-2-aminothiophene in the reaction with Vilsmeier-Haack reagent, an efficient method for the synthesis of 4-chlorothieno[2,3-b]pyridine derivatives has been established. Gewald's classical synthesis starting from cyanoacetone, ketones and elemental sulphur has been applied to produce the starting materials.
- Abdelwahab, Ahmed B.,Hanna, Atef G.,Kirsch, Gilbert
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- AMIDITE COMPOUND AND METHOD FOR PRODUCING POLYNUCLEOTIDE USING SAID COMPOUND
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The present invention provides an amidite compound represented by formula (1) which enables a synthesis of RNA with high purity, and the method for preparing a polynucleotide by using the same compound. (In the formula (1), wherein R represents the following formula (wherein Ra and Rb are identical to or different from each other and each represents a methyl group, an ethyl group, or a hydrogen atom, with the proviso that Ra and Rb does not represent a hydrogen atom, n is an integer of 1 to 5), and Ba represents a group containing optionally protected nucleobase structure, and G1 and G2 are identical to or different from each other and each represents a protecting group for a hydroxy group, and G3 are identical to or different from each other and each represents an alkyl group.
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Paragraph 0173-0174
(2021/08/06)
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- Identification of diphenylalkylisoxazol-5-amine scaffold as novel activator of cardiac myosin
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To identify novel potent cardiac myosin activator, a series of diphenylalkylisoxazol-5-amine compounds 4–7 have been synthesized and evaluated for cardiac myosin ATPase activation. Among the 37 compounds, 4a (CMA at 10 μM = 81.6%), 4w (CMA at 10 μM = 71.2%) and 6b (CMA at 10 μM = 67.4%) showed potent cardiac myosin activation at a single concentration of 10 μM. These results suggested that the introduction of the amino-isoxazole ring as a bioisostere for urea group is acceptable for the cardiac myosin activation. Additional structure–activity relationship (SAR) studies were conducted. Para substitution (-Cl, –OCH3, -SO2N(CH3)2) to the phenyl rings or replacement of a phenyl ring with a heterocycle (pyridine, piperidine and tetrahydropyran) appeared to attenuate cardiac myosin activation at 10 μM. Additional hydrogen bonding acceptor next to the amino group of the isoxazoles did not enhance the activity. The potent isoxazole compounds showed selectivity for cardiac myosin activation over skeletal and smooth muscle myosin, and therefore these potent and selective isoxazole compounds could be considered as a new series of cardiac myosin ATPase activators for the treatment of systolic heart failure.
- Boggu, Pulla Reddy,Venkateswararao, Eeda,Manickam, Manoj,Sharma, Niti,Kang, Jong Seong,Jung, Sang-Hun
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- One-Pot Four-Component Coupling Approach to Polyheterocycles: 6 H-Furo[3,2- f]pyrrolo[1,2- d][1,4]diazepine
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A novel polyheterocyclic chemical space, 6H-furo[3,2-f]pyrrolo[1,2-d][1,4]diazepine, was generated by a one-pot four-component coupling reaction where multiple bonds (three C-C, one C-O, and one C-N) were formed through a domino sequence. Two heterocyclic rings (furan and diazepine) were sequentially constructed from the monocyclic pyrrole derivative under environment-friendly reaction conditions to furnish the tricyclic fused scaffold.
- Yoon, Seok Hyun,Kim, Sung June,Kim, Ikyon
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p. 15082 - 15091
(2020/12/02)
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- Discovery, synthesis and characterization of a series of (1-alkyl-3-methyl-1H-pyrazol-5-yl)-2-(5-aryl-2H-tetrazol-2-yl)acetamides as novel GIRK1/2 potassium channel activators
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The present study describes the discovery and characterization of a series of 5-aryl-2H-tetrazol-3-ylacetamides as G protein-gated inwardly-rectifying potassium (GIRK) channels activators. Working from an initial hit discovered during a high-throughput screening campaign, we identified a tetrazole scaffold that shifts away from the previously reported urea-based scaffolds while remaining effective GIRK1/2 channel activators. In addition, we evaluated the compounds in Tier 1 DMPK assays and have identified a (3-methyl-1H-pyrazol-1-yl)tetrahydrothiophene-1,1-dioxide head group that imparts interesting and unexpected microsomal stability compared to previously-reported pyrazole head groups.
- Sharma, Swagat,Kozek, Krystian A.,Abney, Kristopher K.,Kumar, Sushil,Gautam, Nagsen,Alnouti, Yazen,David Weaver,Hopkins, Corey R.
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p. 791 - 796
(2019/02/06)
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- Benzimidazolyl-pyrazolo[3,4- b]pyridinones, Selective Inhibitors of MOLT-4 Leukemia Cell Growth and Sea Urchin Embryo Spiculogenesis: Target Quest
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1,3-Substituted pyrazolo[3,4-b]pyridinones 11-18 were synthesized by a three-component condensation of Meldrum's acid with aryl aldehydes and 1,3-substituted 5-aminopyrazoles. Their biological activity was evaluated using the in vivo phenotypic sea urchin embryo assay and the in vitro cytotoxicity screen against human cancer cell lines. In the sea urchin embryo model, 1-benzimidazolyl-pyrazolo[3,4-b]pyridinones 11 caused inhibition of hatching and spiculogenesis at sub-micromolar concentrations. These compounds also selectively and potently inhibited growth of the MOLT-4 leukemia cell line. Subsequent structure-activity relationship studies determined the benzimidazolyl fragment as an essential pharmacophore for both effects. We applied numerous techniques for target identification. A preliminary QSAR target identification search did not result in tangible leads. Attempts to prepare a relevant photoaffinity probe that retained potency in both assays were not successful. Compounds 11 were further characterized for their activity in a wild-type versus Notch-mutant leukemia cell lines, and in in vitro panels of kinases and matrix metalloproteinases. Using a series of diverse modulators of spiculogenesis as standards, we excluded multiple signaling networks including Notch, Wnt/β-catenin, receptor tyrosine kinases (VEGF/VEGFR, FGF/FGFR), PI3K, and Raf-MEK-ERK as possible targets of 11. On the other hand, matrix metalloproteinase-9/hatching enzyme was identified as one potential target.
- Lichitsky, Boris V.,Komogortsev, Andrey N.,Dudinov, Arkady A.,Krayushkin, Mikhail M.,Khodot, Evgenii N.,Samet, Alexander V.,Silyanova, Eugenia A.,Konyushkin, Leonid D.,Karpov, Alexei S.,Gorses, Delphine,Radimerski, Thomas,Semenova, Marina N.,Kiselyov, Alex S.,Semenov, Victor V.
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supporting information
p. 805 - 816
(2019/12/02)
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- Preparation method for 3-amino-5-methylisoxazole
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The invention discloses a preparation method for 3-amino-5-methylisooxazole, belonging to the technical field of organic chemistry. The preparation method is completed through three steps: with an easily-available raw material namely ethyl acetate as a starting material, carrying out a reaction with acetonitrile in the presence of an alkali metal so as to form acetyl acetonitrile, then carrying out a reaction with p-toluenesulfonhydrazide so as to form hydrazone, and carrying out a ring closing reaction with hydroxylamine under an alkaline condition so as to obtain the 3-amino-5-methylisoxazole. According to the invention, raw materials in the reactions are common; chloroform or carbon tetrachloride in a traditional method are avoided; and analogous isomers of the 3-amino-5-methylisoxazoleare not detected in the reaction process.
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Paragraph 0025; 0033; 0041
(2018/04/03)
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- Application of 5-aminopyrazole compounds to plant growth regulation aspect
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The invention discloses application of 5-aminopyrazole compounds to plant growth regulation aspect in the technical field of pesticide compounds, in particular to application of the 5-aminopyrazole compounds shown by the formula to the plant growth regulation aspect, particularly the application to the plant growth inhibition. The formula I is shown in the description. The compound shown in the formula I can be used as a weedicide; weeds in places such as highway and railway can be killed through regulating the concentration of the 5-aminopyrazole compounds, wherein the R1 is hydrogen or alkylor phenyl or substituted phenyl; R2 is alkyl; R3 is hydrogen or halogen.
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Paragraph 0014; 0023-0029
(2018/05/16)
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- Corresponding amine nitrile and method of manufacturing thereof
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The invention relates to a manufacturing method of nitrile. Compared with the prior art, the manufacturing method has the characteristics of significantly reduced using amount of an ammonia source, low environmental pressure, low energy consumption, low production cost, high purity and yield of a nitrile product and the like, and nitrile with a more complex structure can be obtained. The invention also relates to a method for manufacturing corresponding amine from nitrile.
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Paragraph 0153; 0154; 0155; 0162; 0163
(2018/05/07)
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- Synthesis of aminopyrazole analogs and their evaluation as CDK inhibitors for cancer therapy
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We synthesized a library of aminopyrazole analogs to systematically explore the hydrophobic pocket adjacent to the hinge region and the solvent exposed region of cyclin dependent kinases. Structure-activity relationship studies identified an optimal substitution for the hydrophobic pocket and analog 24 as a potent and selective CDK2/5 inhibitor.
- Rana, Sandeep,Sonawane, Yogesh A.,Taylor, Margaret A.,Kizhake, Smitha,Zahid, Muhammad,Natarajan, Amarnath
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supporting information
p. 3736 - 3740
(2018/10/24)
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- The Convenient Synthesis of 11-Methyl-3,8-disubstituted-12-aryl-3,4,7,8,9,12-hexahydro-1H-chromeno[2,3-b]quinoline-1,10(2H)-dione Derivatives
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The 2-arylidene-3-oxobutanenitrile derivatives 2 were prepared by the Knoevenagel condensation between aldehydes and 3-oxobutanenitrile 1, which was obtained by acid hydrolysis of β-aminocrotononitrile. 3-Acetyl-2-amino-4H-chromen-5(6H)-one derivatives 3 were synthesized by reaction of 2-arylidene-3-oxobutanenitrile 2 and 5-substituted-1,3-cyclohexanedione in ethylene glycol. The 11-methyl-3,8-disubstituted-12-aryl-3,4,7,8,9,12-hexahydro-1H-chromeno[2,3-b]quinoline-1,10(2H)-dione derivatives 4 were obtained by Friedl?nder reaction of compounds 3 with 5-substituted-1,3-cyclohexanedione, using p-toluenesulfonic acid monohydrate as catalyst. The structures of all novel compounds were characterized by elemental analysis, IR, MS, and 1H NMR spectra. The crystal and molecular structure of compound 4f has been determined by single crystal XRD analysis.
- Han, Guang-Fan,Zhao, Li-Jun,Chen, Li-Zhuang,Du, Jia-Wei,Wang, Zhong-Xia
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p. 1219 - 1225
(2015/08/06)
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- Facile, novel and efficient synthesis of new pyrazolo[3,4-b]pyridine products from condensation of pyrazole-5-amine derivatives and activated carbonyl groups
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An efficient synthesis of novel ethyl-1,3,4-triphenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylate products has been achieved via condensation of pyrazole-5-amine derivatives and activated carbonyl groups, in refluxing acetic acid. This process has been found to be useful in the preparation of new N-fused heterocycle products in good to excellent yields.
- Ghaedi,Bardajee,Mirshokrayi,Mahdavi,Shafiee,Akbarzadeh
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p. 89652 - 89658
(2015/11/10)
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- HETEROCYCLIC MODULATORS OF LIPID SYNTHESIS AND COMBINATIONS THEREOF
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Heterocyclic modulators of lipid synthesis are provided as well as pharmaceutically acceptable salts thereof; pharmaceutical compositions comprising such compounds; and methods of treating conditions characterized by disregulation of a fatty acid synthase pathway by the administration of such compounds and combinations of such compounds and other therapeutic agents.
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Page/Page column 301
(2015/07/07)
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- HETEROCYCLIC COMPOUNDS FOR THE INHIBITION OF PASK
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Disclosed herein are new heterocyclic compounds and compositions and their application as pharmaceuticals for the treatment of disease. Methods of inhibiting PAS Kinase (PASK) activity in a human or animal subject are also provided for the treatment of diseases such as diabetes mellitus.
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Page/Page column 44
(2012/11/08)
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- Development and a practical synthesis of the JAK2 inhibitor LY2784544
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The route selection and process research and development of a practical synthesis for JAK2 inhibitor LY2784544 is described. The first-generation synthesis route, similar to that used in discovery for derivatization of a benzylic amine moiety, was 14 overall steps and possessed several steps that required extensive development for large-scale production. Route selection considerations led to a modified synthesis that utilized a novel vanadium-catalyzed carbon-carbon bond-forming arylation reaction for incorporation of the key benzylic morpholine moiety. A protecting group used to mask an amino pyrazole unit was modified from PMB to tert-butyl, resulting in a dramatic reduction in the overall length of the route. These two major changes resulted in an eight-step synthesis, which was six steps shorter than the first-generation synthesis. In the pilot plant, the new synthesis was scaled to produce >100 kg of LY2784544 in high yield and purity under GMP conditions. The overall development including the vanadium-catalyzed C-C bond-forming methodology, a ketone reductive deoxygenation, and a palladium-catalyzed amination is described.
- Mitchell, David,Cole, Kevin P.,Pollock, Patrick M.,Coppert, David M.,Burkholder, Timothy P.,Clayton, Joshua R.
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body text
p. 70 - 81
(2012/05/31)
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- INDAZOLE COMPOUNDS USEFUL AS KETOHEXOKINASE INHIBITORS
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The present invention is directed to substituted indazole compounds, pharmaceutical compositions of these compounds and methods of use thereof. The compounds of the present invention are ketohexokinase (KHK) inhibitors, useful for treating or ameliorating a KHK mediated metabolic disorders and/or diseases such as obesity, Type II diabetes mellitus and Metabolic Syndrome X.
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Page/Page column 51
(2011/11/06)
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- The pyrolysis of isoxazole revisited: A new primary product and the pivotal role of the vinylnitrene. A low-temperature matrix isolation and computational study
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This paper describes the pyrolysis of parent isoxazole and of its 5-methyl and 3,5-dimethyl derivatives by the high-pressure pulsed pyrolysis method, where activation of the precursor molecules occurs predominantly by collisions with the host gas (Ar in our case), rather than with the walls of the pyrolysis tube, where catalyzed processes may occur. The products were trapped at 15 K in Ar matrices and were characterized by vibrational spectroscopy. Thereby, hitherto unobserved primary products of pyrolysis of isoxazole and of its 5-methyl derivative, 3-hydroxypropenenitrile or 3-hydroxybutenenitrile, respectively, were observed. E-Z photoisomerization could be induced in the above hydroxynitriles. On pyrolysis of isoxazole, ketenimine and CO were observed as decomposition products, but this process did not occur when the 5-methyl derivative was pyrolyzed. Instead, the corresponding ketonitrile was formed. In the case of 3,5-dimethylisoxazole, 2-acetyl-3-methyl-2H-azirine was detected at moderate pyrolysis temperatures, whereas at higher temperatures, 2,5-dimethyloxazole was the only observed rearrangement product (next to products of dissociation). These findings are rationalized on the basis of quantum chemical calculations. Thereby it becomes evident that carbonyl-vinylnitrenes play a pivotal role in the observed rearrangements, a role that had not been recognized in previous theoretical studies because it had been assumed that vinylnitrenes are closed-shell singlet species, whereas they are in fact open-shell singlet biradicaloids. Thus, the primary processes had to be modeled by the multiconfigurational CASSCF method, followed by single-point MR-CISD calculations. The picture that emerges from these calculations is in excellent accord with the experimental findings; that is, they explain why some possible products are observed while others are not.
- Nunes, Claudio M.,Reva, Igor,Pinho E Melo, Teresa M. V. D.,Fausto, Rui,Solomek, Tomas,Bally, Thomas
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supporting information; experimental part
p. 18911 - 18923
(2012/02/05)
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- Process for the preparation of substituted pyrimidine derivatives
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The present invention is directed to processes for the preparation of substituted pyrimidine derivatives, useful as intermediates in the synthesis of histamine H4 receptor modulators, and to intermediates in H4 modulator synthesis.
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Page/Page column 13
(2010/02/16)
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- Facile iterative synthesis of 2,5-terpyrimidinylenes as nonpeptidic α-helical mimics
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A facile iterative synthesis of 2,5-terpyrimidinylenes that are structurally analogous to α-helix mimics is presented. Condensation of amidines with readily prepared α,β-unsaturated α-cyanoketones gives 5-cyano-substituted pyrimidines. Iterative transformation of the 5-cyano group into an amidine allows synthesis of 2,5-terpyrimidinylenes with variable groups at the 4-, 4′-, and 4′′-positions. These compounds are designed to mimic the i, i + 4, and i + 7 sites of an α-helix.
- Anderson, Laura,Zhou, Mingzhou,Sharma, Vasudha,McLaughlin, Jillian M.,Santiago, Daniel N.,Fronczek, Frank R.,Guida, Wayne C.,McLaughlin, Mark L.
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supporting information; experimental part
p. 4288 - 4291
(2010/08/06)
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- ALPHA-HELIX MIMETIC USING A 2,5-OLIGOPYRIMIDINE SCAFFOLD
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Alpha-helix mimetics and associated methods of making are provided. These compounds are constructed using a 2,5-oligopyrimidine scaffold. The semi-rigid scaffold holds individual side chain-like residues in orientations that mimic the orientations of side chain residues of an ?-helical protein domain. The new scaffold is easier to make than previous scaffolds and has much more favorable physical properties than previous alpha-helix mimics. The amphiphilic alpha-helix mimetics have application for making libraries and for treating diseases or conditions effected by the inhibition or disruption of interactions with the alpha helix of a protein.
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Page/Page column 52
(2010/08/08)
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- The Boulton-Katritzky rearrangement of isocarboxazid
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(Chemical Equation Presented) Isocarboxazid rearranges on heating to 5-acetonyl-2-benzyl-4-hydroxy-1,2,3-triazole in DMF at 150°C, in the ionic liquid, [bmin]HSO4- at 100°C or as a melt at 105°C. This is the first reported example of the Boulton-Katritzky rearrangement of an acyl hydrazide.
- Van Arnum, Susan D.,Niemczykapi, Henry J.
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scheme or table
p. 909 - 913
(2010/01/11)
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- Optimization of 5-phenyl-3-pyridinecarbonitriles as PKCθ inhibitors
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The key intermediate, 4-chloro-5-iodo-3-pyridinecarbonitrile, allowed for ready optimization of the PKCθ inhibitory activity of a series of 3-pyridinecarbonitriles. Analog 13b with a 4-methylindol-5-ylamino group at C-4 and a 4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl group at C-5 had an IC50 value of 7.4 nM for the inhibition of PKCθ.
- Boschelli, Diane H.,Wang, Daniel,Prashad, Amar S.,Subrath, Joan,Wu, Biqi,Niu, Chuan,Lee, Julie,Yang, Xiaoke,Brennan, Agnes,Chaudhary, Divya
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body text
p. 3623 - 3626
(2010/04/26)
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- Design, synthesis, and biological evaluation of classical and nonclassical 2-amino-4-oxo-5-substituted-6-methylpyrrolo[3,2-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors
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We designed and synthesized a classical antifolate N-{4-[(2-amino-6-methyl- 4-oxo-3,4-dihydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]benzoyl}-L-glutamic acid 4 and 11 nonclassical analogues 5-15 as potential dual thymidylate synthase (TS) and dihydrofolate reductase (DHFR) inhibitors. The key intermediate in the synthesis was N-(4-chloro-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2,2- dimethylpropanamide, 29, to which various 5-benzyl substituents were attached. For the classical analogue 4, the ester obtained from the N-benzylation reaction was deprotected and coupled with diethyl L-glutamate followed by saponification. Compound 4 was a potent dual inhibitor of human TS (IC 50 = 46 nM, about 206-fold more potent than pemetrexed) and DHFR (IC50 = 120 nM, about 55-fold more potent than pemetrexed). The nonclassical analogues were marginal inhibitors of human TS, but four analogues showed potent T. gondii DHFR inhibition along with >100-fold selectivity compared to human DHFR.
- Gangjee, Aleem,Li, Wei,Yang, Jie,Kisliuk, Roy L.
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- Identification of 4-aminopyrazolylpyrimidines as potent inhibitors of Trk kinases
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The design, synthesis and biological evaluation of a series of 4-aminopyrazolylpyrimidines as potent Trk kinase inhibitors is reported. High-throughput screening identified a promising hit in the 4- aminopyrazolylpyrimidine chemotype. Initial optimization of the series led to more potent Trk inhibitors. Further optimization using two strategies resulted in significant improvement of physical properties and led to the discovery of 10z (AZ-23), a potent, orally bioavailable Trk A/B inhibitor. The compound offers the potential to test the hypothesis that modulation of Trk activity will be of benefit in the treatment of cancer and other indications in vivo.
- Wang, Tao,Lamb, Michelle L.,Scott, David A.,Wang, Haixia,Block, Michael H.,Lyne, Paul D.,Lee, John W.,Davies, Audrey M.,Zhang, Hai-Jun,Zhu, Yanyi,Gu, Fei,Han, Yongxin,Wang, Bin,Mohr, Peter J.,Kaus, Robert J.,Josey, John A.,Hoffmann, Ethan,Thress, Ken,MacIntyre, Terry,Wang, Haiyun,Omer, Charles A.,Yu, Dingwei
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scheme or table
p. 4672 - 4684
(2009/07/25)
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- Substituted Cyanopyridines as protein kinase inhibitors
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The present teachings provide compounds of formula I and their pharmaceutically acceptable salts, hydrates, and esters, wherein R1, R2, and X are as defined herein. The present teachings also provide methods of making the compounds of formula I, and methods of treating autoimmune and inflammatory diseases by administering a therapeutically effective amount of a compound or compounds of formula I to a mammal including a human.
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Page/Page column 23
(2008/06/13)
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- A convenient preparation of 3-Acetyl-5-methylisoxazole
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Starting from 2,5-hexanedione (4), a one-pot preparation of 3-acetyl-5-methylisoxazole (1) is described. 3-Acetyl-5-methylisoxazole (1) is a useful compound for the preparation of 3-oxobutyronitrile (10) and for 3-vinyl-(5-methyl isoxazolyl) ketone (2).
- Sauers, Ronald R.,Van Arnum, Susan D.
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p. 655 - 658
(2007/10/03)
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- A thio-staudinger reaction: Thermolysis of a vinyl azide in the presence of t-butyl mercaptan
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The thermal decomposition of E-3-azido-3-hexene-2,5-dione (1) in protic media gave rise to several novel reactions of the azide 1 including adducts derived from keteneimine 11. Reaction with t-butyl mercaptan yielded two products, keteneimine-derived mercaptan addition product 20 and a sulfenimine 6. Trapping of a vinyl nitrene intermediate or a thio-Staudinger reaction was considered as a possible mechanism for the formation of sulfenimine 6. The absence of the vinyl nitrene addition products 3 and 5 when the thermal decomposition was conducted in either methanol or t-butylamine suggests a thio-Staudinger reaction is operative.
- Sauers, Ronald R.,Van Arnum, Susan D.
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p. 2169 - 2181
(2007/10/03)
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- Pharmaceutical compounds
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Compounds of the following formula have pharmaceutical properties: STR1 in which X is R'(HO)C=C(CN)--, R1 (CO)--CH(CN)-- or STR2 R1 and R2 are each hydrogen or C1-6 alkyl, R3, R4, R5 and R6 are each hydrogen, hydroxy, halogen, nitro, cyano, carboxy, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, halo-substituted C1-4 alkyl, halo-substituted C1-4 alkoxy, halo-substituted C1-4 alkylthio, C2-5 alkoxycarbonyl, optionally substituted phenyl, optionally substituted phenoxy, R'R"N-- where R' and R" are each hydrogen or C1-4 alkyl or R'"CONH-- where R'" is C1-4 alkyl, or a group of the formula --CR7 R8 R9 in which R7, R8 and R9 are each C1-6 alkyl, halo-substituted C1-6 alkyl or optionally substituted phenyl, or R7 and R8, together with the carbon atom to which they are attached, form a cycloalkyl group containing 3 to 7 carbon atoms, or R7, R8 and R9 together with the carbon atom to which they are attached, form a bicycloalkyl group containing 4 to 9 carbon atoms, and Y is a 5- or 6-membered heterocyclic ring excluding pyrazole; and salts thereof.
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- N-phenyl amide compounds
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Compounds of the following formula have pharmaceutical properties: STR1 in which X is R1 (HO)C=C(CN)--, R1 (CO)--CH(CN)-- or STR2 R1 and R2 are each hydrogen or C1-6 alkyl, R3, R4 and R5 are each hydrogen, hydroxy, halogen, nitro, cyano, carboxy, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, halo-substituted C1-4 alkyl, halo-substituted C1-4 alkoxy, halo-substituted C1-4 alkylthio, C2-5 alkoxycarbonyl, optionally substituted phenyl, optionally substituted phenoxy, R'R"N- where R' and R" are each hydrogen or C1-4 alkyl R'"CONH-- where R'" is C1-4 alkyl, R6, R7 and R8 are each C1-6 alkyl, halo-substituted C1-6 alkyl or optionally substituted phenyl, or R6 and R7, together with the carbon atom to which they are attached, form a cycloalkyl group containing 3 to 7 carbon atoms, or R6, R7 and R8 together with the carbon atom to which they are attached, form a bicycloalkyl group containing 4 to 9 carbon atoms; and salts thereof.
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- 4-AMINOETHYLENE DERIVATIVES OF 2-METHYLBENZOTRIAZOLE
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N-Methylation of 4(7)-nitrobenzotriazole (I) afforded a mixture of three isomers; one of them, 4-nitro-2-methylbenzotriazole (II) could easily be isolated.Catalytical hydrogenation of II led to the corresponding amine which in turn, afforded products of nucleophilic substitution IVa-IVi on reaction with alkoxymethylene derivatives IIIa - IIIi.Thermal cyclocondensation of IVi yielded 7-ethoxycarbonyl-6,9-dihydro-6-oxo-2-methyl-2H-triazoloquinoline (V).The structure of all products was deduced from the IR, UV, 1H and 13C NMR spectral data.
- Milata, Viktor,Ilavsky, Dusan,Goljer, Igor,Lesko, Jan,Chahinian, Marc,Henry-Basch, Erica
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p. 1038 - 1048
(2007/10/02)
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- Biomimetic Syntheses of Pretetramides. 2. A Synthetic Route Based on a Preformed D Ring
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A route to pretetramides has been developed on the basis of tandem condensations of homophthalate esters with the dianion of methyl acetoacetate to give aromatic bis(diketo esters), which cyclize spontaneously to anthracene diesters.A further condensation of one of the ester groups with acetamide synthons gives anthracene ester-keto amides, which can be cyclized to naphthacenecarboxamides.By this technique dimethyl 3-methoxyhomophthalate (2b) was condensed with the dilithium salt of methyl acetoacetate to give anthracene diester (4b).Protection of the hydroxyl groups followed by treatment with the dilithium salt of N-(trimethylsilyl)acetamide gave anthracene ester-keto amide 6, which cyclized to pretetramide (1) on treatment with HBr in acetic acid.The procedure for synthesis of pretetramide was modified to permit separate addition of the ketide chains.By use of the aliphatic mono ester (7b) of 3-methoxyhomophthalic acid, chain extension was brought about at the aliphatic carboxyl group by condensation with the dilithium salt of tert-butyl acetoacetate.This product was cyclized to isocoumarin 9b by treatment with acetic anhydride.Completion of the backbone was achieved in a single condensation by treatment of 9b with trianion 18 of 3,5-dioxohexanenitrile (prepared from the nitrile or indirectly by cleavage of isoxazole 17 with LDA) to give anthrone 32.A variety of other condensations of the trianion 18 was performed with electrophiles to demonstrate the utility of the reagent.The synthesis of pretetramide from anthrone 32 was completed by treatment with HI/phenol.
- Harris, Thomas M.,Harris, Constance M.,Oster, Timothy A.,Brown, Larry E.,Lee, John Y.-C.
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p. 6180 - 6186
(2007/10/02)
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- Phase Transfer Generation of Acyltetracarbonyliron Anions: their Role in the Phase Transfer Carbonylation of Reactive Halides to give Carboxylic Acids and Symmetrical and Unsymmetrical Ketones
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Acyltetracarbonyliron anions RCOFe(CO)4(1-) (3) are readily synthesised under mild phase transfer (PT) conditions from pentacarbonyliron and reactive organic halides; the in situ generated anions (3) (R = ArCH2) are the true catalysts in the PT carbonylation of benzyl halides to give ketones or carboxylic acids.
- Laurent, Pascale,Tanguy, Guy,Abbayes, Herve des
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p. 1754 - 1756
(2007/10/02)
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- Synthesis of 3-Oxo-8-oxabicyclooct-6-ene-2-carbonitriles from γ-Bromo-β-oxonitriles and Furan via Cycloaddition of 1-Cyanoallylium-2-olates
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Some γ-bromo-β-oxonitriles 3 react with furan in the presence of silver oxide to form stereoselectively the title compounds 7.Satisfying yields are obtained only with those bromides 3, whose γ-carbon is tertiary or which are monoalkylated both at the α- and γ-carbon atoms.The results are explained by a cycloaddition of 1-cyanoallylium-2-olate intermediates (14) to the 1,3-diene system of the furan.With cyclic γ-bromo-β-oxonitriles (6) two types of cycloadducts were observed: 3-bromo-3-methyl-2-oxocyclohexanecarbonitrile (6b) and 3-bromo-2-oxocyclododecanecarbonitrile (6d) form the tricyclic cycloadduts 10b and d, analogs of the bicyclic adducts 7.With 3-bromo-2-oxocyclohexanecarbonitrile (6a) and 3-bromo-5-tert-butyl-2-oxocyclohexanecarbonitrile (6e), however, the carbonyl oxygen is connected with an α-carbon of the furan to give the tricyclic cycloadducts 12Aa and Ae.The structure endo-2,endo-4-dimethyl-3-oxo-8-oxabicyclooct-6-ene-exo-2-carbonitrile (7eα) was determined by X-ray analysis.
- Foehlisch, Baldur,Herter, Rolf,Wolf, Elisabeth,Stezowski, John J.,Eckle, Emil
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p. 355 - 380
(2007/10/02)
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- Nucleosides. 117. Synthesis of 4-Oxo-8-(β-D-ribofuranosyl)-3H-pyrazolo-1,3,5-triazine (OPTR) via 3-Amino-2N-carbamoyl-4-(β-D-ribofuranosyl)pyrazole (ACPR) Derivatives
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Reaction of 2-formyl-2-(2,3-O-isoprpylidene-5-O-trityl-D-ribofuranosyl)acetonotrile (VII) with semicarbazide hydrochloride followed by sodium ethoxide treatment afforded α,β-mixture of 3-amino-2N-carbamoyl-4-(2,3-O-isopropylidene-5-O-trityl-D-ribofuranosyl)pyrazole (IX).Conversion of IX to 4-oxo-8-(2,3-O-isopropylidene-5-O-trityl-D-ribofuranosyl)-3H-pyrazolo-1,3,5-triazine (XIII) was achieved by treatment of IX with ethylorthoformate.The β-isomer IXb gave only β-isomer XIIIb, and the α-isomer was converted exclusively into the α-isomer XIIIa.Upon deprotection with 3percent n-butanolic hydrogen chloride, both IXa and IXb gave the same mixture of the α- and β-isomers of 3-amino-2N-carbamoyl-4-(D-ribosyl)pyrazole, which were separated by chromatography. The syntheses of the hitherto unknown compounds, 3-amino-2N-carbamoylpyrazole (IVa) and its 4-methyl analog (IVb) are also reported.Experimental details of the synthesis of 3-amino-4-(2,3-O-isopropylidene-5-O-trityl-β-D-ribofuranosyl)pyrazole (XIIb), an important intermediate for "purine-like" C-nucleosides, are also described.
- Chu, C. K.,Watanabe, K. A.,Fox, J. J.
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p. 1435 - 1439
(2007/10/02)
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- Compositions containing cis-2-benzoyl-3-hydroxy-crotononitrile used to treat inflammation and joint deterioration
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This disclosure describes compositions of matter useful as anti-inflammatory agents and as inhibitors of the progressive joint deterioration characteristic of arthritic disease, and the methods of meliorating inflammation and of inhibiting joint deterioration in mammals therewith, the active ingredients of said composition of matter being certain cis-2-benzoyl-3-hydroxy-2-alkenonitriles and/or the pharmacologically acceptable cationic salts thereof.
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- Cis-2-benzoyl-3-hydroxy-2-alkenonitriles as anti-inflammatory agents
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This disclosure describes new compounds and compositions of matter useful as anti-inflammatory agents and as inhibitors of the progressive joint deterioration characteristic of arthritic disease and the methods of meliorating inflammation and of inhibiting joint deterioration in mammals therewith, the novel active ingredients of said compositions of matter being certain substituted cis-2-benozyl-3-hydroxy-2-alkenonitriles and/or the pharmacologically acceptable cationic salts thereof.
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- Amidoxime derivatives
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Novel amidoxime derivatives having the following structural formula (IV) of (IV'): STR1 wherein R1 represents methyl or ethyl group and R2 represents hydrogen or methyl group, useful as a raw material for 3-amino-5-methyl isoxazole, are prepared from β-amino crotonitrile. Said isoxazole, useful as an intermediate for various medicines, may be prepared without producing any by-products of isomer.
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