- Coordination chemistry of flexible benzene-1,3,5-tricarboxamide derived carboxylates; Notable structural resilience and vaguely familiar packing motifs
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Flexible benzene-1,3,5-tricarboxamides (BTAs), organic species well-known for their tendencies to form functional soft-materials by virtue of their complementary hydrogen bonding, are explored as structurally reinforcing supramolecular building blocks in
- Lynes, Amy D.,Hawes, Chris S.,Byrne, Kevin,Schmitt, Wolfgang,Gunnlaugsson, Thorfinnur
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Read Online
- Iversatile bung intermediate II and synthetic method thereof
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The invention relates to the field of pharmaceutical chemistry synthesis, and in particular relates to an immortal plug intermediate II and a synthesis method thereof. The synthesis method comprises the following steps of 4 - aminobenzene acetic acid and
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Paragraph 0037-0039
(2021/11/10)
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- HETEROCYCLIC COMPOUNDS AS INHIBITORS OF FIBROBLAST GROWTH FACTOR RECEPTOR
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Disclosed are heterocyclic compounds as inhibitors of FGFR-4 represented by formula (I). Also disclosed is a pharmaceutical composition that includes an inhibitor of FGFR-4. The compounds maybe used to treat diseases mediated with abnormality of FGFR-4 and /or FGF19, such as hepatocellular carcinoma and other forms of cancer.
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Page/Page column 130
(2020/09/03)
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- 2-Arylamino-6-ethynylpurines are cysteine-targeting irreversible inhibitors of Nek2 kinase
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Renewed interest in covalent inhibitors of enzymes implicated in disease states has afforded several agents targeted at protein kinases of relevance to cancers. We now report the design, synthesis and biological evaluation of 6-ethynylpurines that act as covalent inhibitors of Nek2 by capturing a cysteine residue (Cys22) close to the catalytic domain of this protein kinase. Examination of the crystal structure of the non-covalent inhibitor 3-((6-cyclohexylmethoxy-7H-purin-2-yl)amino)benzamide in complex with Nek2 indicated that replacing the alkoxy with an ethynyl group places the terminus of the alkyne close to Cys22 and in a position compatible with the stereoelectronic requirements of a Michael addition. A series of 6-ethynylpurines was prepared and a structure activity relationship (SAR) established for inhibition of Nek2. 6-Ethynyl-N-phenyl-7H-purin-2-amine [IC50 0.15 μM (Nek2)] and 4-((6-ethynyl-7H-purin-2-yl)amino)benzenesulfonamide (IC50 0.14 μM) were selected for determination of the mode of inhibition of Nek2, which was shown to be time-dependent, not reversed by addition of ATP and negated by site directed mutagenesis of Cys22 to alanine. Replacement of the ethynyl group by ethyl or cyano abrogated activity. Variation of substituents on the N-phenyl moiety for 6-ethynylpurines gave further SAR data for Nek2 inhibition. The data showed little correlation of activity with the nature of the substituent, indicating that after sufficient initial competitive binding to Nek2 subsequent covalent modification of Cys22 occurs in all cases. A typical activity profile was that for 2-(3-((6-ethynyl-9H-purin-2-yl)amino)phenyl)acetamide [IC50 0.06 μM (Nek2); GI50 (SKBR3) 2.2 μM] which exhibited >5-10-fold selectivity for Nek2 over other kinases; it also showed > 50% growth inhibition at 10 μM concentration against selected breast and leukaemia cell lines. X-ray crystallographic analysis confirmed that binding of the compound to the Nek2 ATP-binding site resulted in covalent modification of Cys22. Further studies confirmed that 2-(3-((6-ethynyl-9H-purin-2-yl)amino)phenyl)acetamide has the attributes of a drug-like compound with good aqueous solubility, no inhibition of hERG at 25 μM and a good stability profile in human liver microsomes. It is concluded that 6-ethynylpurines are promising agents for cancer treatment by virtue of their selective inhibition of Nek2. This journal is
- Bayliss, Richard,Boxall, Kathy,Carbain, Benoit,Coxon, Christopher R.,Fry, Andrew M.,Golding, Bernard T.,Griffin, Roger J.,Hardcastle, Ian R.,Harnor, Suzannah J.,Mas-Droux, Corine,Matheson, Christopher J.,Newell, David R.,Richards, Mark W.,Sivaprakasam, Mangaleswaran,Turner, David,Cano, Céline
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supporting information
p. 707 - 731
(2020/08/24)
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- Synthetic method of poly-substituted dimethyl amino phenyl acetic acid compound
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The invention relates to a synthesis method of a poly-substituted dimethyl amino phenyl acetic acid compound. The synthesis method comprises the following steps: carrying out methyl esterification reaction on a compound shown in a formula I to obtain a co
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Paragraph 0046-0049
(2021/03/05)
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- Preparation method of methyl p-aminophenylacetate
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An embodiment of the invention provides a preparation method of methyl p-aminophenylacetate and relates to the field of chemical synthesis. According to the preparation method, benzyl cyanide is adopted as a starting material and subjected to nitration, hydrolysis, esterification, reduction and other steps in sequence, and methyl p-aminophenylacetate is obtained with high yield. The preparation method adopts a reasonable route, is simple to operate, does not have quite high requirement for equipment and is suitable for large-scale industrial production, and the raw material is widely sourced.
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Paragraph 0060; 0061; 0062; 0063; 0064
(2019/01/14)
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- Perfluorinated HDAC inhibitors as selective anticancer agents
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A series of potent histone deacetylase inhibitors is presented that incorporate alkyl or perfluorinated alkyl chains. Several new compounds show greater in vitro antiproliferative activity than the clinically approved inhibitor, SAHA. Furthermore, the new
- Walton, James W.,Cross, Jasmine M.,Riedel, Tina,Dyson, Paul J.
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p. 9186 - 9190
(2017/11/14)
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- COMPOUNDS USEFUL AS CSF1 MODULATORS
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This invention relates to novel compounds and to pharmaceutical compositions comprising the novel compounds. More specifically, the invention relates to compounds useful as Colony Stimulating Factor 1 Receptor (cFMS) modulators (e.g. cFMS inhibitors). This invention also relates to processes for preparing the compounds, uses of the compounds in treatment and methods of treatment employing the compounds. Specifically, the invention relates to the use of the compounds for the treatment of cancer and autoimmune diseases.
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Paragraph 00249; 00250; 00251
(2016/04/26)
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- Nitrogen Mustard Derivatives
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The disclosure includes compounds of Formula (1): wherein X1, X2, Q, Z, R1, and R2 are defined herein. Also disclosed is a method for treating a neoplastic disease or an immune disease with these compounds.
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Paragraph 0088-0089
(2014/10/16)
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- HETEROARYL INHIBITORS OF PDE4
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The present invention relates to compounds and methods useful as inhibitors of phosphodiesterase 4 (PDE4) for the treatment or prevention of disease.
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Paragraph 0530
(2014/05/24)
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- Trifluoroacetic acid: An efficient catalyst for paal-knorr pyrrole synthesis and its deprotection
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In the present work, we demonstrated a simple and an efficient method for the condensation of substituted aryl/heteroaryl amines with acetonylacetone in the presence of trifluoro acetic acid to afford the corresponding 2,5-dimethyl-1-substitued pyrroles using Paal-Knorr synthesis in excellent yields. Trifluoroacetic acid was used under reflux condition for the deprotection of 2,5-dimethyl-1-substitued pyrroles to their corresponding substituted aryl/heteroaryl amines in moderate yields. 2,5-Dimethyl-1-substitued pyrrole were characterized by NMR and LC-MS. The yield of the compounds was found to be excellent.
- Venugopala, K. Narayanaswamy,Prasanna, Renuka T.,Odhav, Bharti
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p. 8685 - 8689
(2013/11/06)
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- IMIDAZO [4, 5 -C] PYRIDINE DERIVATIVES USEFUL FOR THE TREATMENT OF DEGENERATIVE AND INFLAMMATORY DISEASES
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Novel imidazolopyridines according to Formula I, able to inhibit JAK are disclosed, wherein R1 and Cy are as disclosed herein. These compounds may be prepared as a pharmaceutical composition, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, allergic or inflammatory conditions, autoimmune diseases, proliferative diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IL6 or interferons.
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Paragraph 0017
(2013/08/28)
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- SUBSTITUTED HETEROCYCLIC ACETAMIDES AS KAPPA OPIOID RECEPTOR (KOR) AGONISTS
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The present invention relates to a series of substituted compounds having the general formula (I), including their ste reoisomers and/or their pharmaceutically acceptable salts, wherein R1, R2, R3. R4, R5, and R6 are as defined herein. This invention also relates to methods of making these compounds including intermediates. The compounds of this invention are effective at the kappa (κ) opioid receptor (KOR) site. Therefore, the compounds of this invention are useful as pharmaceutical agents, especially in the treatment and/or prevention of a variety of central nervous system disorders (CNS), including but not limited to acute and chronic pain, and associated disorders, particularly functioning peripherally at the CNS.
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Page/Page column 68; 69
(2013/09/26)
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- Iron-catalyzed hydrosilylation of esters
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The first hydrosilylation of esters catalyzed by a well defined iron complex has been developed. Esters are converted to the corresponding alcohols at 100 °C, under solvent-free conditions and visible light activation. Copyright
- Bezier, David,Venkanna, Gopaladasu T.,Castro, Luis C. Misal,Zheng, Jianxia,Roisnel, Thierry,Sortais, Jean-Baptiste,Darcel, Christophe
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supporting information; experimental part
p. 1879 - 1884
(2012/09/22)
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- Halogenation of 4-hydroxy/amino-3-methoxyphenyl acetamide TRPV1 agonists showed enhanced antagonism to capsaicin
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As an extension of our analysis of the effect of halogenation on thiourea TRPV1 agonists, we have now modified selected 4-hydroxy(or 4-amino)-3- methoxyphenyl acetamide TRPV1 agonists by 5- or 6-halogenation on the aromatic A-region and evaluated them for potency for TRPV1 binding and regulation and for their pattern of agonism/antagonism (efficacy). Halogenation shifted the functional activity at TRPV1 toward antagonism with a greater extent of antagonism as the size of the halogen increased (I > Br > Cl), as previously observed for the thiourea series. The extent of antagonism was greater for halogenation at the 5-position than at the 6-position, in contrast to SAR for the thiourea series. In this series, compounds 55 and 75 showed the most potent antagonism, with Ki (ant) = 2.77 and 2.19 nM, respectively, on rTRPV1 expressed in Chinese hamster ovary cells. The compounds were thus ca. 40-60-fold more potent than 6′-iodononivamide.
- Kang, Dong Wook,Kim, Yong Soo,Lim, Kwang Su,Kim, Myeong Seop,Pearce, Larry V.,Pavlyukovets, Vladimir A.,Tao, Andy K.,Lang-Kuhs, Krystle A.,Blumberg, Peter M.,Lee, Jeewoo
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experimental part
p. 8092 - 8105
(2011/01/13)
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- Efficient reducing system based on iron for conversion of nitroarenes to anilines
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Reduction of nitroarenes with low solubility in EtOH-H2O to anilines easily occurs in a Fe-NH4Cl-acetone-H2O system, and treatment of the same nitroarenes with Fe-NH4Cl-EtOH-H2O hardly furnished the corresponding products. Under the reaction condition, the reducible or hydrolysable groups are not affected.
- Xiao, Zhu-Ping,Wang, Ying-Chun,Du, Gao-Yu,Wu, Jun,Luo, Tao,Yi, Shou-Fu
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experimental part
p. 661 - 665
(2011/03/19)
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- Salicylate-urea-based soluble epoxide hydrolase inhibitors with high metabolic and chemical stabilities
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We investigated N-adamantyl-N′-phenyl urea derivatives as simple sEH inhibitors. Salicylate ester derivatives have high inhibitory activities against human sEH, while the free benzoic acids are less active. The methyl salicylate derivative is a potent sEH inhibitor, which also has high metabolic and chemical stabilities; suggesting that such inhibitors are potential lead molecule for bioactive compounds acting in vivo.
- Kasagami, Takeo,Kim, In-Hae,Tsai, Hsing-Ju,Nishi, Kosuke,Hammock, Bruce D.,Morisseau, Christophe
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supporting information; experimental part
p. 1784 - 1789
(2009/12/03)
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- THIAZOLE DERIVATIVES AND USE THEREOF
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The present invention is related to thiazole derivatives of Formula (I) in particular for the treatment and/or prophylaxis of autoimmune disorders and/or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial or viral infections, kidney diseases, platelet aggregation, cancer, transplantation, graft rejection or lung injuries.
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Page/Page column 171
(2008/06/13)
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- Zn2+-Chelating Motif-Tethered Short-Chain Fatty Acids as a Novel Class of Histone Deacetylase Inhibitors
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Among various classes of histone deacetylase (HDAC) inhibitors, short-chain fatty acids exhibit the least potency, with IC50 in the millimolar range. We rationalized that this weak potency was, in part, attributable to their inability to access the zinc cation in the HDAC active-site pocket, which is pivotal to the deacetylation catalysis. We thus explored the structural optimization of valproate, butyrate, phenylacetate, and phenylbutyrate by coupling them with Zn2+-chelating motifs (hydroxamic acid and o-phenylenediamine) through aromatic ω-amino acid linkers. This strategy has led to a novel class of Zn2+-chelating, motif-tethered, short-chain fatty acids that exhibited varying degrees of HDAC inhibitory potency. One hydroxamatetethered phenylbutyrate compound, N-hydroxy-4-(4-phenylbutyrylamino)benzamide (HTPB), displayed nanomolar potency in inhibiting HDAC activity. Exposure of several cancer cell lines to HTPB at the submicromolar level showed reduced cell proliferation accompanied by histone hyperacetylation and elevated p21WAF/CIP1 expression, which are hallmark features associated with intracellular HDAC inhibition.
- Lu, Qiang,Yang, Ya-Ting,Chen, Chang-Shi,Davis, Melanie,Byrd, John C.,Etherton, Mark R.,Umar, Asad,Chen, Ching-Shih
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p. 467 - 474
(2007/10/03)
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- Phenylacetamido-thiazole derivatives, process for the preparation and their use as antitumor agents
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Compounds represented by formula (I), as defined in the description, wherein R is a hydrogen atom or a methyl group and R1 is a group as defined in the specification, or a pharmaceutically acceptable salt thereof, are disclosed; the said compounds are use
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- Inhibitors of histone deacetylase
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The invention relates to the inhibition of histone deacetylase. The invention provides compounds and methods for inhibiting histone deacetylase enzymatic activity. The invention also provides compositions and methods for treating cell proliferative diseases and conditions.
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- PESTICIDAL INDAZOLE OR BENZOTRIAZOLE DERIVATIVES
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A compound of formula (I) wherein G is either (i) or (ii), where M1 or M2 is bonded to A; n is 0 or 1; when G is (i), D is S, NR7, CR8-CR9, CR8-N, CR8-N(O), N-CR9 or N(O)-CR9; when G is (ii), D is S or NR7; E is N, N-oxide or CR10; M1 is OC(-Y), N(R11)C(-Y), N-C(OR12), N-C(SR13) or N-C(NR14R15) where O or N is the atom of attachment to the ring containing D and E; M2 is N-C(-Y) where N is the atom of attachment to the ring containing D and E; Y is O, S or NR16; J is N or CR17; and A, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14 and R15 are each certain organic or inorganic groups. These compounds are useful in fungicidal, insecticidal, acaricidal, molluscicidal and hematicidal compositions.
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Page/Page column 85
(2008/06/13)
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- NAPHTHALENE AMIDES HAVING LEUKOTRIENE-ANTAGONISTIC ACTION
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Naphthalene amides of formula (I) wherein the substituent containing A is bound to the 6- or 7- position of the 2-naphthol system; the substituent containing B is bound to the benzene ring at any free position; R is hydrogen or methyl; R is hydrogen, fluorine, chlorine or -OCH3, which is bound to the naphthalene system at any positions except the 2- and the one occupied by the other substituent; R is hydrogen, fluorine, chlorine or bromine; A- is -CO-NR- or -NR-CO- group, wherein R is hydrogen or methyl; B is a 5-tetrazolyl or -COOR group, wherein R is hydrogen, a (C1-C4)-alkyl or a phenylalkyl group of less than 10 carbon atoms; m is 0 or 1; n and p are integers from 0 to 6, with the proviso that n + p is less or equal to 6; as well as the solvates and pharmaceutically acceptable salts thereof, have leukotriene antagonistic action.
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- Design and synthesis of a novel class of histone deacetylase inhibitors.
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Histone deacetylase inhibitors (HDACs) have emerged as a novel class of antiproliferative agents. Utilizing structure-based design, the synthesis of a series of sulfonamide hydroxamic acids is described. Further optimization of this series by substitution of the terminal aromatic ring yielded HDAC inhibitors with good in vitro and in vivo activities.
- Lavoie,Bouchain,Frechette,Woo,Abou-Khalil,Leit,Fournel,Yan,Trachy-Bourget,Beaulieu,Li,Besterman,Delorme
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p. 2847 - 2850
(2007/10/03)
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- Antidiabetic agents
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The instant invention is concerned with aryl and heteroaryl oxyacetic acid type compounds which are useful antidiabetic compounds. Compositions and methods for the use of the compounds in the treatment of diabetes and related diseases and for lowering triglyceride levels are also disclosed.
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- Development of a novel oxidatively removable and recyclable linker for combinatorial solid phase synthesis
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An appropriately derivatized phenanthridine is shown to behave as a novel, reusable linker which is based on a disubstituted amide anchorage and forms an acid group on oxidative cleavage, but tolerates exposure to acidic, basic and reductive reaction cond
- Li, Wen-Ren,Hsu, Nai-Mu,Chou, Hsueh-Hsuan,Lin, Sung Tsai,Lin, Yu-Sheng
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p. 401 - 402
(2007/10/03)
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- Substituent effects on the kinetics of reductively-initiated fragmentation of nitrobenzyl carbamates designed as triggers for bioreductive prodrugs
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4-Nitrobenzyl carbamates are of interest as triggers for bioreductive drugs, particularly in conjunction with the E. coli B nitroreductase, which efficiently reduces them to the corresponding hydroxylamines. These then fragment to release highly toxic amine-based toxins. While many 4-nitrobenzyl carbamate derivatives have been evaluated as bioreductive drugs, there has been no systematic study of substituent effects on the rate of this fragmentation (which should be as fast as possible following reduction). We therefore prepared a series of 2-, 3- and α-substituted 4-[N-methyl-N-(4-nitrobenzyloxycarbonyl)amino]phenylacetamides as model compounds to study these effects. The majority of the carbamates were prepared by in situ formation of the chloroformate of the appropriate 4-nitrobenzyl alcohol and reaction with methyl 4-(methylamino)phenylacetate, followed by ester hydrolysis and 1,1′-carbonyl-diimidazole (CDI) mediated coupling with N,N-dimethylaminoethylamine. The hydroxylamines were generated by 60Co γ-ray irradiation of the nitro compounds in aqueous phosphate-buffered-propan-2-ol. The reactions were analysed by reverse-phase HPLC to determine the maximum half-life (Mt1/2) of the hydroxylamines generated, and the extent of release of amine from these after 10 half-lives (t∞). The parent (unsubstituted) hydroxylaminobenzyl carbamate had a Mt1/2 of 16 min under these conditions, while that of the corresponding α-methyl analogue was 9.5 min. Electron-donating substituents on the benzyl ring also accelerated fragmentation, with the data being fitted to the equation log(Mt1/2) = 0.57σ + 1.30, where σ represents σp for 2-substituents and σm for 3-substituents. The acceleration of fragmentation of the hydroxylamines with increasing substituent electron-donation is consistent with the proposed mechanism, and is presumably due to stabilisation of the developing positive charge on the benzylic carbon. The extent of release of amine (t∞) also increased with increasing substituent electron-donation. These data suggest that the standard 4-nitrobenzyl carbamate trigger for nitroreductase enzyme (NTR) prodrugs can likely be improved on, by increasing the rate of fragmentation by the use of α-methyl and/or electron-donating benzyl substituents. The Royal Society of Chemistry 1999.
- Hay, Michael P.,Sykes, Bridget M.,Denny, William A.,O'Connor, Charmian J.
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p. 2759 - 2770
(2007/10/03)
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- Substituted benzene derivatives useful as neuraminidase inhibitors
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A compound of the Formula (I): STR1 or pharmaceutically-suitable salts or prodrug forms thereof, wherein: n is 0-1; m is 0; p is 0-1; R1 is --CO2 H; R2 is selected from the group consisting of H, --OH, and --NH2 ; R3 is H; R4 is --C(O)NHR8 ; R5 is --NHC(R6)NH2 R6 is selected from the group consisting of =NH, =NOH, =NCN, =O, and =S; and R8 is selected from the group consisting of C1 -C4 linear or branched alkyl substituted with 0-3 halogens on each carbon.
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- Structure-activity studies for a novel series of N-(arylethyl)-N- (1,2,3,4-tetrahydronaphthalen-1-ylmethyl)-N-methylamines possessing dual 5- HT uptake inhibiting and α2-antagonistic activities
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In search of an α2-antagonist/5-HT uptake inhibitor as a potential new class of antidepressant with a more rapid onset of action, compound 3 was prepared and observed to possess high affinity for the α2-receptor (K(i) = 6.71 nM) and
- Meyer, Michael D.,Hancock, Arthur A.,Tietje, Karin,Sippy, Kevin B.,Prasad, Rajnandan,Stout, David M.,Arendsen, David L.,Donner, B. Greg,Carroll, William A.
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p. 1049 - 1062
(2007/10/03)
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- Lupane derivatives, their preparation and the pharmaceutical compositions which contain them
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The present invention relates to new lupane dervivatives of the general formula: STR1 to their salts, to their preparation and to the pharmaceutical compositions which contain them.
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