- Endohedral Hydrogen Bonding Templates the Formation of a Highly Strained Covalent Organic Cage Compound**
-
A highly strained covalent organic cage compound was synthesized from hexahydroxy tribenzotriquinacene (TBTQ) and a meta-terphenyl-based diboronic acid with an additional benzoic acid substituent in 2’-position. Usually, a 120° bite angle in the unsubstituted ditopic linker favors the formation of a [4+6] cage assembly. Here, the introduction of the benzoic acid group is shown to lead to a perfectly preorganized circular hydrogen-bonding array in the cavity of a trigonal-bipyramidal [2+3] cage, which energetically overcompensates the additional strain energy caused by the larger mismatch in bite angles for the smaller assembly. The strained cage compound was analyzed by mass spectrometry and 1H, 13C and DOSY NMR spectroscopy. DFT calculations revealed the energetic contribution of the hydrogen-bonding template to the cage stability. Furthermore, molecular dynamics simulations on early intermediates indicate an additional kinetic effect, as hydrogen bonding also preorganizes and rigidifies small oligomers to facilitate the exclusive formation of smaller and more strained macrocycles and cages.
- Sch?fer, Natalie,Bühler, Michael,Heyer, Lisa,R?hr, Merle I. S.,Beuerle, Florian
-
-
Read Online
- Carboxyl Methyltransferase Catalysed Formation of Mono- and Dimethyl Esters under Aqueous Conditions: Application in Cascade Biocatalysis
-
Carboxyl methyltransferase (CMT) enzymes catalyse the biomethylation of carboxylic acids under aqueous conditions and have potential for use in synthetic enzyme cascades. Herein we report that the enzyme FtpM from Aspergillus fumigatus can methylate a broad range of aromatic mono- and dicarboxylic acids in good to excellent conversions. The enzyme shows high regioselectivity on its natural substrate fumaryl-l-tyrosine, trans, trans-muconic acid and a number of the dicarboxylic acids tested. Dicarboxylic acids are generally better substrates than monocarboxylic acids, although some substituents are able to compensate for the absence of a second acid group. For dicarboxylic acids, the second methylation shows strong pH dependency with an optimum at pH 5.5–6. Potential for application in industrial biotechnology was demonstrated in a cascade for the production of a bioplastics precursor (FDME) from bioderived 5-hydroxymethylfurfural (HMF).
- Ashbrook, Chloe,Carnell, Andrew J.,Goulding, Ellie,Hatton, Harry,Johnson, James R.,Kershaw, Neil M.,McCue, Hannah V.,Rigden, Daniel J.,Ward, Lucy C.
-
supporting information
(2022/02/21)
-
- Visible-Light-Enabled Carboxylation of Benzyl Alcohol Derivatives with CO2 Using a Palladium/Iridium Dual Catalyst
-
A highly efficient carboxylation of benzyl alcohol derivatives with CO2 using a palladium/iridium dual catalyst under visible-light irradiation was developed. A wide range of benzyl alcohol derivatives could be employed to provide benzylic carboxylic acids in moderate to high yields. Mechanistic studies indicated that the oxidative addition of benzyl alcohol derivatives was possibly the rate-determining-step. It was also found that a switchable site-selective carboxylation between benzylic C?O and aryl C?Cl moieties could be achieved simply by changing the palladium catalyst.
- Jin, Yushu,Toriumi, Naoyuki,Iwasawa, Nobuharu
-
-
- Suppressing carboxylate nucleophilicity with inorganic salts enables selective electrocarboxylation without sacrificial anodes
-
Although electrocarboxylation reactions use CO2as a renewable synthon and can incorporate renewable electricity as a driving force, the overall sustainability and practicality of this process is limited by the use of sacrificial anodes such as magnesium and aluminum. Replacing these anodes for the carboxylation of organic halides is not trivial because the cations produced from their oxidation inhibit a variety of undesired nucleophilic reactions that form esters, carbonates, and alcohols. Herein, a strategy to maintain selectivity without a sacrificial anode is developed by adding a salt with an inorganic cation that blocks nucleophilic reactions. Using anhydrous MgBr2as a low-cost, soluble source of Mg2+cations, carboxylation of a variety of aliphatic, benzylic, and aromatic halides was achieved with moderate to good (34-78%) yields without a sacrificial anode. Moreover, the yields from the sacrificial-anode-free process were often comparable or better than those from a traditional sacrificial-anode process. Examining a wide variety of substrates shows a correlation between known nucleophilic susceptibilities of carbon-halide bonds and selectivity loss in the absence of a Mg2+source. The carboxylate anion product was also discovered to mitigate cathodic passivation by insoluble carbonates produced as byproducts from concomitant CO2reduction to CO, although this protection can eventually become insufficient when sacrificial anodes are used. These results are a key step toward sustainable and practical carboxylation by providing an electrolyte design guideline to obviate the need for sacrificial anodes.
- Corbin, Nathan,Lazouski, Nikifar,Manthiram, Karthish,Steinberg, Katherine,Yang, Deng-Tao
-
p. 12365 - 12376
(2021/10/08)
-
- Visible-light photoredox-catalyzed selective carboxylation of C(sp3)?F bonds with CO2
-
It is highly attractive and challenging to utilize carbon dioxide (CO2), because of its inertness, as a nontoxic and sustainable C1 source in the synthesis of valuable compounds. Here, we report a novel selective carboxylation of C(sp3)?F bonds with CO2 via visible-light photoredox catalysis. A variety of mono-, di-, and trifluoroalkylarenes as well as α,α-difluorocarboxylic esters and amides undergo such reactions to give important aryl acetic acids and α-fluorocarboxylic acids, including several drugs and analogs, under mild conditions. Notably, mechanistic studies and DFT calculations demonstrate the dual role of CO2 as an electron carrier and electrophile during this transformation. The fluorinated substrates would undergo single-electron reduction by electron-rich CO2 radical anions, which are generated in situ from CO2 via sequential hydride-transfer reduction and hydrogen-atom-transfer processes. We anticipate our finding to be a starting point for more challenging CO2 utilization with inert substrates, including lignin and other biomass.
- Bo, Zhi-Yu,Chen, Lin,Gao, Tian-Yu,Jing, Ke,Lan, Yu,Liu, Shi-Han,Luo, Shu-Ping,Yan, Si-Shun,Yu, Bo,Yu, Da-Gang
-
supporting information
p. 3099 - 3113
(2021/11/16)
-
- Desulfonylative Electrocarboxylation with Carbon Dioxide
-
Electrocarboxylation of organic halides is one of the most investigated electrochemical approaches for converting thermodynamically inert carbon dioxide (CO2) into value-added carboxylic acids. By converting organic halides into their sulfone derivatives, we have developed a highly efficient electrochemical desulfonylative carboxylation protocol. Such a strategy takes advantage of CO2as the abundant C1 building block for the facile preparation of multifunctionalized carboxylic acids, including the nonsteroidal anti-inflammatory drug ibuprofen, under mild reaction conditions.
- Zhong, Jun-Song,Yang, Zi-Xin,Ding, Cheng-Lin,Huang, Ya-Feng,Zhao, Yi,Yan, Hong,Ye, Ke-Yin
-
supporting information
p. 16162 - 16170
(2021/09/02)
-
- Spiroindoline-Capped Selective HDAC6 Inhibitors: Design, Synthesis, Structural Analysis, and Biological Evaluation
-
Histone deacetylase inhibitors (HDACi) have emerged as promising therapeutics for the treatment of neurodegeneration, cancer, and rare disorders. Herein, we report the development of a series of spiroindoline-based HDAC6 isoform-selective inhibitors based on the X-ray crystal studies of the hit 6a. We identified compound 6j as the most potent and selective hHDAC6 inhibitor of the series. Biological investigation of compounds 6b, 6h, and 6j demonstrated their antiproliferative activity against several cancer cell lines. Western blotting studies indicated that they were able to increase tubulin acetylation, without significant variation in histone acetylation state, and induced PARP cleavage indicating their apoptotic potential at the molecular level. 6j induced HDAC6-dependent pSTAT3 inhibition.
- Saraswati, A. Prasanth,Relitti, Nicola,Brindisi, Margherita,Osko, Jeremy D.,Chemi, Giulia,Federico, Stefano,Grillo, Alessandro,Brogi, Simone,McCabe, Niamh H.,Turkington, Richard C.,Ibrahim, Ola,O'Sullivan, Jeffrey,Lamponi, Stefania,Ghanim, Magda,Kelly, Vincent P.,Zisterer, Daniela,Amet, Rebecca,Hannon Barroeta, Patricia,Vanni, Francesca,Ulivieri, Cristina,Herp, Daniel,Sarno, Federica,Di Costanzo, Antonella,Saccoccia, Fulvio,Ruberti, Giovina,Jung, Manfred,Altucci, Lucia,Gemma, Sandra,Butini, Stefania,Christianson, David W.,Campiani, Giuseppe
-
supporting information
p. 2268 - 2276
(2020/12/17)
-
- Method for converting benzyl borate compounds into phenylacetic acid and derivatives thereof by carbon dioxide
-
The invention discloses a method for converting benzyl borate compounds into phenylacetic acid and derivatives thereof by carbon dioxide. The method comprises the steps: dissolving the benzyl borate compounds and an alkali in an organic solvent in the absence of a metal catalyst, introducing carbon dioxide into the reaction system, carrying out a reaction at the temperature of 50-150 DEG C for 3-72 hours, and acidifying to obtain phenylacetic acid or the derivatives thereof. The method is a green, simple and efficient method for synthesizing phenylacetic acid and the derivatives thereof, greenhouse gas carbon dioxide is used as a carbon source in the reaction, no transition metal catalyst is used, and the method is environmentally friendly, economical and high in efficiency.
- -
-
Paragraph 0040-0041
(2020/03/06)
-
- Autocatalytic Synthesis of Thioesters via Thiocarbonylation of gem-Difluoroalkenes
-
Herein, we report a new method for the synthesis of acyethanethioates via thiocarbonylation of gem-difluoroalkenes with thiols. This reaction provides a new pathway to prepare thioesters under mild conditions without the use of any additives. Mechanistic
- Jiang, Xinpeng,Wang, Guan,Zheng, Zicong,Yu, Xiaohui,Hong, Ye,Xia, Haoqi,Yu, Chuanming
-
supporting information
p. 9762 - 9766
(2020/12/21)
-
- Oxidation of Alkynyl Boronates to Carboxylic Acids, Esters, and Amides
-
A general efficient protocol was developed for the synthesis of carboxylic acids, esters, and amides through oxidation of alkynyl boronates, generated directly from terminal alkynes. This protocol represents the first example of C(sp)?B bond oxidation. This approach displays a broad substrate scope, including aryl and alkyl alkynes, and exhibits excellent functional group tolerance. Water, primary and secondary alcohols, and amines are suitable nucleophiles for this transformation. Notably, amino acids and peptides can be used as nucleophiles, providing an efficient method for the synthesis and modification of peptides. The practicability of this methodology was further highlighted by the preparation of pharmaceutical molecules.
- Li, Chenchen,Li, Ruoling,Zhang, Bing,Zhao, Pei,Zhao, Wanxiang
-
supporting information
p. 10913 - 10917
(2020/05/25)
-
- ONO-8430506: A Novel Autotaxin Inhibitor That Enhances the Antitumor Effect of Paclitaxel in a Breast Cancer Model
-
Lysophosphatidic acid (LPA) is a bioactive lipid mediator that elicits a number of biological functions, including smooth muscle contraction, cell motility, proliferation, and morphological change. LPA is endogenously produced by autotaxin (ATX) from extracellular lysophosphatidylcholine (LPC) in plasma. Herein, we report our medicinal chemistry effort to identify a novel and highly potent ATX inhibitor, ONO-8430506 (20), with good oral availability. To enhance the enzymatic ATX inhibitory activity, we designed several compounds by structurally comparing our hit compound with the endogenous ligand LPC. Further optimization to improve the pharmacokinetic profile and enhance the ATX inhibitory activity in human plasma resulted in the identification of ONO-8430506 (20), which enhanced the antitumor effect of paclitaxel in a breast cancer model.
- Hiramatsu, Atsushi,Hirooka, Yasuo,Hisaichi, Katsuya,Imagawa, Akira,Iwaki, Yuzo,Katoh, Makoto,Kobayashi, Juta,Komichi, Yuka,Maeda, Tatsuo,Matsumura, Naoya,Moriguchi, Hideki,Nakatani, Shingo,Nishiyama, Taihei,Ohhata, Akira,Okabe, Yasuyuki,Okada, Masahiro,Ota, Hiroto,Saga, Hiroshi,Sugiyama, Tetsuya,Watanabe, Toshihide,Yamamoto, Shingo
-
supporting information
p. 1335 - 1341
(2020/07/06)
-
- BIARYL COMPOUND, PREPARATION METHOD AND USE THEREFOR
-
The present invention belongs to the technical field of chemical pharmaceuticals, and relates to a compound represented by general formula (I) or formula (II) and a preparation method thereof. The compounds are biaryl derivatives with RORγt activation activity. The biaryl derivatives disclosed in this invention can effectively activate the RORγt protein receptor, and thereby promote the differentiation of Th17 cells and increasing the production of IL-17, which can be used as an immune modulator for the treatment of various cancers or viral infection-related diseases.
- -
-
Paragraph 0127; 0129
(2020/01/02)
-
- Preparation method of acid with different substituent groups
-
The invention discloses a preparation method of an acid with different substituent groups. A terminal alkyne is lithiated with n-butyllithium, and then reacts with isopropoxyboronic acid pinacol ester, hydrogen chloride is added to achieve quenching, then the obtained reaction product is oxidized by an oxidizing agent, and the oxidized reaction product is separated and purified to obtain the acid.The method of the invention has the advantages of simplicity in operation, one-pot process preparation, no metal catalysis, nontoxic reagents, greenness, environmental friendliness and high atomic utilization rate, and provides a novel and quick way for preparing the acid with different substituent groups; and the obtained acid is an important fine chemical product, and can be widely used in fields of medicines, pesticides, spices and other industries.
- -
-
Paragraph 0068-0072
(2019/10/23)
-
- A Metallaphotoredox Strategy for the Cross-Electrophile Coupling of α-Chloro Carbonyls with Aryl Halides
-
Here, we demonstrate that a metallaphotoredox-catalyzed cross-electrophile coupling mechanism provides a unified method for the α-arylation of diverse activated alkyl chlorides, including α-chloroketones, α-chloroesters, α-chloroamides, α-chlorocarboxylic acids, and benzylic chlorides. This strategy, which is effective for a wide variety of aryl bromide coupling partners, is predicated upon a halogen atom abstraction/nickel radical-capture mechanism that is generically successful across an extensive range of carbonyl substrates. The construction and use of arylacetic acid products have further enabled two-step protocols for the delivery of valuable building blocks for medicinal chemistry, such as aryldifluoromethyl and diarylmethane motifs.
- Chen, Tiffany Q.,MacMillan, David W. C.
-
supporting information
p. 14584 - 14588
(2019/09/17)
-
- Electrogenerated Sm(II)-Catalyzed CO2 Activation for Carboxylation of Benzyl Halides
-
Sm(II)-catalyzed carboxylation of benzyl halides is reported through the electrochemical reduction of CO2. The transformation proceeds under mild reaction conditions to afford the corresponding phenylacetic acids in good to excellent yields. This user-friendly and operationally simple protocol represents an alternative to traditional strategies, which usually proceeds through the C(sp3)-halide activation pathway.
- Bazzi, Sakna,Schulz, Emmanuelle,Mellah, Mohamed
-
supporting information
p. 10033 - 10037
(2019/12/24)
-
- Visible-Light-Driven External-Reductant-Free Cross-Electrophile Couplings of Tetraalkyl Ammonium Salts
-
Cross-electrophile couplings between two electrophiles are powerful and economic methods to generate C-C bonds in the presence of stoichiometric external reductants. Herein, we report a novel strategy to realize the first external-reductant-free cross-electrophile coupling via visible-light photoredox catalysis. A variety of tetraalkyl ammonium salts, bearing primary, secondary, and tertiary C-N bonds, undergo selective couplings with aldehydes/ketone and CO2. Notably, the in situ generated byproduct, trimethylamine, is efficiently utilized as the electron donor. Moreover, this protocol exhibits mild reaction conditions, low catalyst loading, broad substrate scope, good functional group tolerance, and facile scalability. Mechanistic studies indicate that benzyl radicals and anions might be generated as the key intermediates via photocatalysis, providing a new direction for cross-electrophile couplings.
- Liao, Li-Li,Cao, Guang-Mei,Ye, Jian-Heng,Sun, Guo-Quan,Zhou, Wen-Jun,Gui, Yong-Yuan,Yan, Si-Shun,Shen, Guo,Yu, Da-Gang
-
p. 17338 - 17342
(2019/01/04)
-
- Ruthenium-catalyzed umpolung carboxylation of hydrazones with CO2
-
The first ruthenium-catalyzed umpolung carboxylation of hydrazones with CO2 to generate important aryl acetic acids is reported. Besides aldehyde hydrazones, a variety of ketone hydrazones, which have not been successfully applied in previous umpolung reactions with other reactive electrophiles, also show high reactivity and selectivity under mild conditions. Moreover, this operationally simple protocol features good functional group tolerance, is readily scalable, and offers easy derivation of important structures, including bioactive felbinac and adiphenine. Computational studies reveal that this umpolung reaction proceeds through the generation of a Ru-nitrenoid followed by concerted [4 + 2] cycloaddition with CO2.
- Yan, Si-Shun,Zhu, Lei,Ye, Jian-Heng,Zhang, Zhen,Huang, He,Zeng, Huiying,Li, Chao-Jun,Lan, Yu,Yu, Da-Gang
-
p. 4873 - 4878
(2018/06/07)
-
- Design, synthesis, SAR and biological investigation of 3-(carboxymethyl)rhodanine and aminothiazole inhibitors of Mycobacterium tuberculosis Zmp1
-
Sixteen 3-(carboxymethyl)rhodanines, and twelve aminothiazoles as rhodanine-mimetics were designed, synthesized and tested as inhibitors of the Zmp1 enzyme from Mycobacterium tuberculosis (Mtb). Almost all rhodanines (5a–d, 5f–n, and 7a–b) exhibited Zmp1 inhibition with IC50 values in the range 1.3–43.9 μM, whereas only aminothiazoles 12b and 12d proved active with IC50 values of 41.3 and 35.7 μM, respectively. Structure-activity relationships (SAR) were coupled with molecular modeling studies to highlight structural determinants for Zmp1 inhibition. Moreover, rhodanines 5a and 5c induced 23.4 and 53.8% of Mtb growth inhibition in THP-1 infected cells, respectively, at the non-toxic concentration of 10 μg/ml. This work represents a step forward in targeting Zmp1 by small molecules.
- Mori, Mattia,Deodato, Davide,Kasula, Mohan,Ferraris, Davide M.,Sanna, Adriana,De Logu, Alessandro,Rizzi, Menico,Botta, Maurizio
-
supporting information
p. 637 - 641
(2018/02/06)
-
- Isoflavone amide type derivative, preparation method and medical application thereof
-
The invention relates to the field of medicinal chemistry, and relates to an isoflavone amide type derivative, a preparation method and a medical application thereof, in particular to an isoflavone amide type derivative with the general formula (I), a preparation method thereof, medicine compositions including the isoflavone amide type derivative and a medical application thereof, especially an application of the isoflavone amide type derivative as a medicine for preventing or curing hyperlipemia, obesity or type II diabetes. The general formula (I) is shown in the description.
- -
-
Paragraph 0015; 0062; 0063; 0064
(2016/10/10)
-
- SELECTIVE HDAC6 INHIBITORS
-
The present invention provides hydroxamic acids of the formula described herein, that have activity toward inhibiting histone deacetylases, and in particular HDAC6. Also contemplated are pharmaceutical compositions and methods of use of an effective amount of the hydroxamic acid compounds provided, for treating a disease in a subject. In certain embodiments, the subject is afflicted with cancer, neurodegenerative disease, or HIV infection.
- -
-
Page/Page column 53
(2015/07/15)
-
- Electrochemical direct carboxylation of benzyl alcohols having an electron-withdrawing group on the phenyl ring: One-step formation of phenylacetic acids from benzyl alcohols under mild conditions
-
Electrochemical direct carboxylation of benzyl alcohols having an electron-withdrawing group on the phenyl ring was successfully carried out by constant current electrolysis using an undivided cell equipped with a platinum plate cathode and a magnesium rod anode in DMF in the presence of carbon dioxide. Reductive cleavage of the C-O bond followed by fixation of carbon dioxide efficiently took place at the benzylic position without any additive to give the corresponding phenylacetic acids in good yields in one step under neutral and mild conditions.
- Senboku, Hisanori,Yoneda, Kenji,Hara, Shoji
-
p. 6772 - 6776
(2016/01/30)
-
- Palladium-catalyzed silver-mediated α-arylation of acetic acid: A new approach for the α-arylation of carbonyl compounds
-
A new approach for the α-arylation of acetic acid through Pd-catalyzed silver-mediated direct C-H arylation of acetic acid with aryl iodides was developed. This protocol provided a straightforward method for the synthesis of a diverse set of α-phenylacetic acids. Palladium served on a silver platter: A new approach for the α-arylation of acetic acid through Pd-catalyzed silver-mediated direct C-H arylation of acetic acid with aryl iodides is presented. This protocol provides a straightforward method for the synthesis of a diverse set of α-phenylacetic acids. Deuteration experiments are performed to help elucidate the reaction mechanism.
- Wu, Guo-Jie,Guan, Jing,Han, Fu-She,Zhao, Yu-Long
-
p. 1589 - 1593
(2014/06/24)
-
- NOVEL MOLECULES THAT SELECTIVELY INHIBIT HISTONE DEACETYLASE 6 RELATIVE TO HISTONE DEACETYLASE 1
-
The compounds of the present invention are HDAC6 selective inhibitors which are identified on the basis of accumulation of acetylated tubulin without accumulation of acetylated histones. Histone deacetylase or "HDAC" refers to enzymes capable of cleaving an acetyl group (-C(=0)CH3) from proteins, including histone and microtubulins. Compositions comprising the molecules and methods for their use to inhibit the activity of histone deacetylase, including for treatment, are also disclosed.
- -
-
Page/Page column 46; 48; 49
(2013/04/24)
-
- SELECTIVE HDAC INHIBITORS
-
This disclosure is related to compounds having the structure (I) wherein Ar1, Ar2, R1 - R6, Z, m, n, o, and p are defined herein. This disclosure also relates to pharmaceutical compositions comprising the above compounds and methods for their use.
- -
-
Page/Page column 89-90
(2011/12/04)
-
- CHROMONE INHIBITORS OF S-NITROSOGLUTATHIONE REDUCTASE
-
The present invention is directed to inhibitors of S-nitrosoglutathione reductase (GSNOR), pharmaceutical compositions comprising such GSNOR inhibitors, and methods of making and using the same.
- -
-
Page/Page column 39
(2011/09/15)
-
- NOVEL S-NITROSOGLUTATHIONE REDUCTASE INHIBITORS
-
The present invention is directed to inhibitors of S-nitrosoglutathione reductase (GSNOR), pharmaceutical compositions comprising such GSNOR inhibitors, and methods of making and using the same.
- -
-
Page/Page column 49
(2011/09/15)
-
- Electrochemical carboxylation of benzylic carbonates: Alternative method for efficient synthesis of arylacetic acids
-
Electrochemical carboxylation of benzylic carbonates was successfully performed as an alternative method for the synthesis of phenylacetic acids by using a one-compartment cell equipped with a Pt plate cathode and an Mg rod anode in CH3CN to afford the corresponding phenylacetic acids in good yields.
- Ohkoshi, Masashi,Michinishi, Jun-Ya,Hara, Shoji,Senboku, Hisanori
-
experimental part
p. 7732 - 7737
(2010/10/21)
-
- AMINOALKYLAZOLE DERIVATIVES AS HISTAMINE-3 ANTAGONISTS
-
The present invention provides a compound of formula I: and the use thereof for the treatment of a central nervous system disorder related to or affected by the histamine-3 receptor.
- -
-
Page/Page column 26-27
(2009/02/11)
-
- Discovery of hydrolytic catalysts in a peptidocalixarene library by binding assay with a transition state analogue for the hydrolysis
-
Hydrolytic catalysts were found in a peptidocalixarene library by binding assay with a transition state analogue for the hydrolysis. The rate of the reaction can be specifically enhanced up to 50-fold in the presence of the discovered catalyst. The Royal
- Hioki, Hideaki,Nishimoto, Ryosuke,Kawaguchi, Kota,Kubo, Miwa,Harada, Kenichi,Fukuyama, Yoshiyasu
-
supporting information; experimental part
p. 7194 - 7196
(2010/03/25)
-
- N-substituted-azacyclylamines as histamine-3 antagonists
-
The present invention provides a compound of formula I and the use thereof for the treatment of a central nervous system disorder related to or affected by the histamine-3 receptor.
- -
-
Page/Page column 31
(2010/11/28)
-
- Synthesis and evaluation of a classical 2,4-diamino-5-substituted-furo[2,3-d]pyrimidine and a 2-amino-4-oxo-6-substituted-pyrrolo[2,3-d]pyrimidine as antifolates
-
Two classical antifolates, a 2,4-diamino-5-substituted furo[2,3-d]pyrimidine and a 2-amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidine, were synthesized as potential inhibitors of dihydrofolate reductase (DHFR) and thymidylate synthase (TS). The synthese
- Gangjee, Aleem,Yang, Jie,McGuire, John J.,Kisliuk, Roy L.
-
p. 8590 - 8598
(2008/02/08)
-
- 1,2-BIS-(SUBSTITUTED-PHENYL)-2-PROPEN-1-ONES AND PHARMACEUTICAL COMPOSITIONS THEREOF
-
The invention relates to compounds, pharmaceutical compositions and methods of using compounds of the general formula (I), or its pharmaceutically acceptable salt or ester, wherein the substituents are defined in the application.
- -
-
Page/Page column 89
(2010/02/15)
-
- INHIBITORS OF HISTONE DEACETYLASE
-
The invention relates to a series of compounds useful for inhibiting histone deacetylase (HDAC) enzymatic activity. The invention also provides a method for inhibiting histone descetylase in a cell using said compounds as well as a method for treating cell proliferative diseases and conditions using said HDAC inhibitors. Further, the invention provides pharmaceutical compositions comprising the HDAC inhibiting compounds and a pharmaceutically acceptable carrier.
- -
-
Page/Page column 89
(2010/02/14)
-
- NOVEL BENSOPHENONE DERIVATIVES OR SALTS THEREOF
-
A benzophenone derivative represented by the following formula: whereinR1 represents, for example, an optionally substituted heterocyclic group, or a substituted phenyl group; Z represents, for example, an alkylene group; R2 represents, for example, a carboxyl group optionally protected with alkyl;R3 represents, for example, an optionally protected hydroxyl group; R4 represents, for example, an optionally substituted cycloalkyloxy group; and R5 represents, for example, a hydrogen atom, ???or a salt thereof has anti-arthritic activity, inhibits bone destruction caused by arthritis, and provides high safety and excellent pharmacokinetics and thus is useful as therapeutic agent for arthritis. These compounds have inhibitory effect on AP-1 activity and are useful as preventive or therapeutic agent for diseases in which excessive expression of AP-1 is involved.
- -
-
-
- CARBAMIC ACID COMPOUNDS COMPRISING AN ESTER OR KETONE LINKAGE AS HDAC INHIBITORS
-
This invention pertains to certain carbamic acid compounds of the formula (I), which inhibit HDAC (histone deacetylase) activity: wherein: J is a linking functional group and is independently: -O-C(=O)- or -C(=O)-O- or - C(=O)-; Cy is a cyclyl group and is independently: C3-20carbocyclyl, C3-20heterocyclyl, or C5-20aryl; and is optionally substituted; Q1 is a cyclyl leader group, and is independently a divalent bidentate group obtained by removing two hydrogen atoms from a ring carbon atom of a saturated monocyclic hydrocarbon having from 4 to 7 ring atoms, or by removing two hydrogen atoms from a ring carbon atom of saturated monocyclic heterocyclic compound having from 4 to 7 ring atoms including 1 nitrogen ring atom or 1 oxygen ring atom; and is optionally substituted; Q2 is an acid leader group, and is independently: C1-8alkylene; and is optionally substituted; or: Q2 is an acid leader group, and is independently: C5-20arylene; C5-20arylene-C1-7alkylene; C1-7alkylene-C5-20arylene; or C1-7alkylene-C5-20arylene-C1-7alkylene; and is optionally substituted; and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms, and prodrugs thereof. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit HDAC,and in the treatment of conditions mediated by HDAC, cancer, proliferative conditions, psoriasis, etc.
- -
-
Page 106; 119; 72; 76
(2008/06/13)
-
- HETERO BIARYL DERIVATIVES AS MATRIX METALLOPROTEINASE INHIBITORS
-
This invention provides compounds defined by Formula I or a pharmaceutically acceptable salt thereof, wherein Rl, Q, S, T, U, V, and R2 are as defined in the specification. The invention also provides pharmaceutical compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, as defined in the specification, together with a' pharmaceutically acceptable carrier, diluent, or excipient. The invention also provides methods of inhibiting an MMP-13 enzyme in an animal, comprising administering to the animal a compound of Formula I, or a pharmaceutically acceptable salt thereof. The invention also provides methods of treating a disease mediated by an MMP-13 enzyme in a patient, comprising administering to the patient a' compound of Formula I, or a pharmaceutically acceptable salt thereof, either alone or in a pharmaceutical composition. The invention also provides methods of treating diseases such as heart disease, multiple sclerosis, osteo- and rheumatoid arthritis, arthritis other than osteo- or rheumatoid arthritis, cardiac insufficiency,,inflammatory bowel, disease, heart failure, age-related macular degeneration, chronic obstructive pulmonary disease, asthma, periodontal diseases, psoriasis, atherosclerosis, and osteoporosis in a patient, comprising administering to the patient a compound of Formula I, or a pharmaceutically, acceptable salt thereof, either alone or in a pharmaceutical composition. The invention also provides combinations, comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, together with another pharmaceutically active, component as described in the specification.
- -
-
Page/Page column 111
(2008/06/13)
-
- Synthesis of phenylacetic acids under rhodium-catalyzed carbonylation conditions
-
Benzyl halides are efficiently carbonylated to phenylacetic acids in the presence of a catalytic amount of the dimer of chloro(1,5-cyclooctadiene)rhodium(I) in formic acid. Under these reaction conditions, sensitive functionalities such as esters and nitriles are tolerated and the phenylacetic acids are obtained in good to high yields. (C) 2000 Elsevier Science Ltd.
- Giroux,Nadeau,Han
-
p. 7601 - 7604
(2007/10/03)
-
- Repaglinide and related hypoglycemic benzoic acid derivatives
-
The structure-activity relationships in two series of hypoglycemic benzoic acid derivatives (5, 6) were investigated. Series 5 resulted from meglitinide (3) when the 2-methoxy was replaced by an alkyleneimino residue. Maximum activity was observed with the cis-3,5-dimethylpiperidino (5h) and the octamethyleneimino (5l) residues. Series 6 resulted from the meglitinide analogon 4 bearing an inversed amido function when the 2-methoxy, the 5- fluoro, and the α-methyl residue were replaced by a 2-piperidino, a 5- hydrogen, and a larger α-alkyl residue, respectively. An alkoxy residue ortho to the carboxy group further increased activity and duration of action in the rat. The most active racemic compound, 6al (R4 = isobutyl; R = ethoxy), turned out to be 12 times more active than the sulfonylurea (SU) glibenclamide (1). Activity was found to reside predominantly in the (S)- enantiomers. Compared with the SUs 1 and 2 (glimepiride), the most active enantiomer, (S)-6al (AG-EE 623 ZW; repaglinide; ED50 = 10 μg/kg po), is 25 and 18 times more active. Repaglinide turned out to be a useful therapeutic for type 2 diabetic patients; approval was granted recently by the FDA and the EMEA. From investigations on the pharmacophoric groups in compounds of type 5 and 6, it was concluded that in addition to the two already known - the acidic group (COOH; S02NH) and the amidic spacer (CONH; NHCO) - the ortho residue R1 (alkyleneimino; alkoxy; oxo) must be regarded as a third one. A general pharmacophore model suitable for hypoglycemic benzoic acid derivatives, SUs, and sulfonamides is proposed (Figure 6). Furthermore, from superpositions of low-energy conformations (LECs) of 1, 2, and (S)-6al, it was concluded that a common binding conformation (LEC II; Figure 10B) may exist and that differences in binding to the SU receptor and in the mechanism of insulin release between repaglinide and the two SUs may be due to specific hydrophobic differences.
- Grell, Wolfgang,Hurnaus, Rudolf
-
p. 5219 - 5246
(2007/10/03)
-
- Use of Phosphorus Pentoxide. Preparation of Half-esters through Selective Esterification
-
Methyl 2-,3-,4-carboxyphenylacetate and methyl 2-,3-,4-carboxyphenoxyacetate have been prepared through selective esterification of the aliphatic carboxylic acid function of the corresponding dicarboxylic acids using a mixture of phosphorus pentoxide (1 part), anhydrous copper sulphate (5 parts) and anhydrous sodium sulphate (5 parts).All the isomeric half-esters have been prepared through partial hydrolysis of the corresponding dimethylesters.
- Banerjee, Amalendu,Adak, Mohini Mohan,Das, Sankar,Banerjee, Santa,Sengupta, Saumitra
-
-
