- ANTI-BLUE LIGHT COMPOUND, PREPARATION METHOD AND APPLICATION THEREOF
-
Disclosed is a blue light absorbing compound, its preparation method and use. The compound has high stability and is suitable for high temperature processing conditions as well as outdoor application. A method of covalently bonding a blue light absorbing compound with an ultraviolet light absorbing compound for increasing its stability is also provided. The compound is capable of absorbing or blocking ultraviolet light (UVA, UVB) and blue light to protect eyes. But long-wavelength blue light can be absorbed diminishingly, so that the transmitted light has a particularly good visual experience.
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Paragraph 0135; 0138
(2021/07/30)
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- Synthesis and anti-rheumatoid arthritis activities of 3-(4-aminophenyl)-coumarin derivatives
-
Rheumatoid arthritis is a chronic systemic disease characterised by an unknown aetiology of inflammatory synovitis. A large number of studies have shown that synoviocytes show tumour-like dysplasia in the pathological process of RA, and the changes in the expression of related cytokines are closely related to the pathogenesis of RA. In this thesis, a series of novel 3-(4-aminophenyl) coumarins containing different substituents were synthesised to find new coumarin anti-inflammatory drugs for the treatment of rheumatoid arthritis. The results of preliminary activity screening showed that compound 5e had the strongest inhibitory activity on the proliferation of fibroid synovial cells, and it also had inhibitory effect on RA-related cytokines IL-1, IL-6, and TNF-α. The preliminary mechanism study showed that compound 5e could inhibit the activation of NF-κB and MAPKs signal pathway. The anti-inflammatory activity of compound 5ein?vivo was further determined in the rat joint inflammation model.
- Miao, Yuhang,Yang, Jie,Yun, Yinling,Sun, Jie,Wang, Xiaojing
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p. 450 - 461
(2021/02/19)
-
- Natural-product-inspired design and synthesis of two series of compounds active against Trypanosoma cruzi: Insights into structure–activity relationship, toxicity, and mechanism of action
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Chemical scaffolds of natural products have historically been sources of inspiration for the development of novel molecules of biological relevance, including hit and lead compounds. To identify new compounds active against Trypanosoma cruzi, we designed and synthesized 46 synthetic derivatives based on the structure of two classes of natural products: tetrahydrofuran lignans (Series 1) and oxazole alkaloids (Series 2). Compounds were screened in vitro using a cellular model of T. cruzi infection. In the first series of compounds, 11 derivatives of hit compound 5 (EC50 = 1.1 μM) were found to be active; the most potent (7, 8, and 13) had EC50 values of 5.1–34.2 μM. In the second series, 17 analogs were found active at 50 μM; the most potent compounds (47, 49, 59, and 63) showed EC50 values of 24.2–49.1 μM. Active compounds were assessed for selectivity, hemocompatibility, synergistic potential, effects on mitochondrial membrane potential, and inhibitory effect on trypanothione reductase. All active compounds showed low toxicity against uninfected THP-1 cells and human erythrocytes. The potency of compounds 5 and 8 increased steadily in combination with benznidazole, indicating a synergistic effect. Furthermore, compounds 8, 47, 49, 59, and 63 inhibited parasitic mitochondria in a dose-dependent manner. Although increased reactive oxygen species levels might lead to mitochondrial effects, the results indicate that the mechanism of action of the compounds is not dependent on trypanothione reductase inhibition. In silico calculation of chemical descriptors and principal component analysis showed that the active compounds share common chemical features with other trypanocidal molecules and are predicted to have a good ADMET profile. Overall, the results suggest that the compounds are important candidates to be further studied for their potential against T. cruzi.
- Grand, Lucie,Popowycz, Florence,Schenkel, Eloir Paulo,Steindel, Mario,da Rosa, Rafael,Campos Bernardes, Lílian Sibelle,Dambrós, Bibiana Paula,H?ehr de Moraes, Milene,Jacolot, Ma?wenn
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-
- Preparation method of 4-formylbenzoic acid
-
The invention provides a preparation method of 4-formylbenzoic acid, and the method comprises the following steps: by using 4-methylbenzoyl chloride as a raw material, performing chlorinating to obtain 4-chloromethylbenzoyl chloride, performing hydrolyzing to obtain 4-chloromethyl benzoic acid, and reacting with urotropine to obtain 4-formylbenzoic acid. The method provided by the invention is simple in process, does not need special equipment and is relatively low in cost; moreover, the method provided by the invention is relatively high in product yield and purity, and large-scale industrialproduction is easy to realize. The result of the embodiment shows that the yield of each step of the preparation method of the 4-formylbenzoic acid provided by the invention is greater than or equalto 90%, and the purity of the finally obtained 4-formylbenzoic acid is greater than or equal to 99.7%.
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Paragraph 0058; 0060; 0063; 0065; 0067; 0069
(2020/11/23)
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- Novel polycyclic compound
-
The invention provides a novel polycyclic compound as well as a synthesis method and application thereof. The compound of the present invention includes a plurality of carbocyclic and/or heterocyclicstructures having visible or fluorescent light emitting groups and covalently bonded to at least one ultraviolet and/or visible (blue) light absorbing group to provide stability. The compound providedby the invention can be used as a light conversion agent, a dye, a pigment, a fluorescent agent and an ultraviolet light or blue light absorbent, and can be applied to optical films, agricultural films, optical discs (disks), optical lenses, goggles, skin care, cosmetics, illumination, coatings, adhesives, light stabilizers, panels and other products.
- -
-
Paragraph 0262; 0267-0268
(2020/07/06)
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- Synthesis method of imatinib and imatinib mesylate
-
The invention relates to a synthesis method of imatinib and imatinib mesylate. The method comprises the following steps: condensing 3-acetylpyridine and N,N-dimethylformamide dimethyl acetal which aretaken as initial raw materials to obtain 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one, then reacting with 2-methyl-5-nitrophenylguanidine nitrate to form a pyrimidine ring, performing nitro reductionto obtain N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine, amidating the N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine and 4-(chloromethyl)benzoyl chloride, performing affinitysubstitution with 1-methylpiperazine to obtain imatinib, and salifying the imatinib and methanesulfonic acid. The products obtained by the method have the advantages of few impurities, simplicity in post-treatment, high total yield, greenness, environmental protection and safety, and is suitable for a production process for large-scale industrial production of imatinib mesylate.
- -
-
Paragraph 0092-0095
(2020/05/02)
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- Synthetic method of procarbazide hydrochloride intermediate
-
The invention discloses a synthetic method of a procarbazide hydrochloride intermediate. The preparation method comprises the following step: in a solvent, in the presence of a hydrolysis agent, carrying out hydrolysis reaction as shown in the specification on a compound as shown in a formula II to obtain a compound as shown in a formula I. The preparation method disclosed by the invention has theadvantages of high yield, high purity and stable process, and is suitable for industrial production.
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Paragraph 0060-0062; 0066; 0067
(2020/05/14)
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- Base-promoted Lewis acid catalyzed synthesis of quinazoline derivatives
-
A one-pot protocol has been developed for the synthesis of quinazolinones from amide-oxazolines with TsCl via a cyclic 1,3-azaoxonium intermediate and 6π electron cyclization in the presence of a Lewis acid and base. The process is operationally simple and has a broad substrate scope. This method provides a unique strategy for the construction of quinazolinones.
- Cui, Xin-Feng,Hu, Fang-Peng,Huang, Guo-Sheng,Lu, Guo-Qiang
-
supporting information
p. 4376 - 4380
(2020/10/20)
-
- Synthesis, Biological Activities and Docking Studies of Novel 4-(Arylaminomethyl)benzamide Derivatives as Potential Tyrosine Kinase Inhibitors
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A number of new compounds containing the 4-(aminomethyl)benzamide fragment as a linker were designed and synthesized, and their biological activities were evaluated as potential anticancer agents. The cytotoxicity activity of the designed compounds was studied in two hematological and five solid cell lines in comparison with the reference drugs. Targeted structures against eight receptor tyrosine kinases including EGFR, HER-2, HER-4, IGF1R, InsR, KDR, PDGFRa, and PDGFRb were investigated. The majority of the compounds showed a potent inhibitory activity against the tested kinases. The analogues 11 and 13 with the (trifluoromethyl)benzene ring in the amide or amine moiety of the molecule were proven to be highly potent against EGFR, with 91% and 92% inhibition at 10 nM, respectively. The docking of synthesized target compounds for nine protein kinases contained in the Protein Data Bank (PDB) database was carried out. The molecular modeling results for analogue 10 showed that the use of the 4-(aminomethyl)benzamide as a flexible linker leads to a favorable overall geometry of the molecule, which allows one to bypass the bulk isoleucine residue and provides the necessary binding to the active center of the T315I-mutant Abl (PDB: 3QRJ).
- Kalinichenko, Elena,Faryna, Aliaksandr,Kondrateva, Viktoria,Vlasova, Alena,Shevchenko, Valentina,Melnik, Alla,Avdoshko, Olga,Belko, Alla
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-
- Palladium-catalyzed Mizoroki-Heck reactions in water using thermoresponsive polymer micelles
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Palladium-catalyzed Mizoroki-Heck reactions were carried out in water using thermoresponsive polymer micelles. The micelles were generated from thermoresponsive block copolymers consisting of a poly(N-isopropylacrylamide) (PNIPAAm) segment and a hydrophilic segment such as nonionic poly(ethylene glycol) (PEG) (2) and anionic poly(sodium p-styrenesulfonate) (PSSNa) (9). These copolymers exhibited lower critical solution temperature (LCST) behavior at ca. 40–50 °C and showed thermal stimuli-induced formation and dissociation of micelles. The copolymers formed micelles in aqueous solution at higher temperature, where catalytic reactions proceeded. At lower temperature, the micelles dissociated to form a clear solution, enabling efficient extraction of the products from aqueous reaction mixture. In the presence of these copolymers, palladium complexes catalyzed the coupling reactions between aryl iodides and alkene compounds inside the hydrophobic micelle cores in water under relatively milder conditions. Extraction of the products from the aqueous solution of 2 or 9 was found to be efficient enough in comparison with conventional surfactants.
- Suzuki, Noriyuki,Takabe, Taiga,Yamauchi, Yoshiko,Koyama, Shun,Koike, Rina,Rikukawa, Masahiro,Liao, Wei-Ting,Peng, Wen-Sheng,Tsai, Fu-Yu
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p. 1351 - 1358
(2019/02/06)
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- Synthesis and biological evaluation of 3–(4-aminophenyl)-coumarin derivatives as potential anti-Alzheimer’s disease agents
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The work is focused on the design of drugs that prevent and treat Alzheimer’s disease (AD) and its complications. A series of 3–(4-aminophenyl)-coumarin derivatives designed, synthesised, fully characterised and evaluated in vitro/vivo. The biological assay experiments showed that some compounds displayed a clearly selective inhibition for acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Among all compounds, compound 4m exhibited the highest AChE inhibition with an IC50 value of 0.091 ± 0.011 μM and compound 4k exhibited the highest BuChE inhibition with an IC50 value of 0.559 ± 0.017 μM. A zebrafish behaviour analyser (Zebrobox) was used to determine the behavioural effects of the active compound on the movement distance of the aluminium chloride-induced zebrafish. Compound 4m offered a potential drug design concept for the development of therapeutic or preventive agents for AD and its complications.
- Hu, Yu-Heng,Yang, Jie,Zhang, Yun,Liu, Ke-Chun,Liu, Teng,Sun, Jie,Wang, Xiao-Jing
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p. 1083 - 1092
(2019/06/06)
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- Ligustrazine derivative, and preparation method and applications thereof
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The invention provides a ligustrazine derivative, and a preparation method and applications thereof. The ligustrazine derivative is capable of treating IAA induced hypoxic injury, promoting neuron cell proliferation, promoting cell synapsis lengthening, and can be used for treating stroke and neurodegenerative diseases.
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-
Paragraph 0020; 0081; 0095; 0096; 0097
(2019/08/12)
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- Revefenacin intermediate, preparation method thereof and preparation method of revefenacin
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The invention relates to the field of pharmaceutical synthesis, in particular to a revefenacin key intermediate (II), and also relates to a preparation method of the intermediate (II) and a method forpreparing revefenacin as shown in a formula (I) through the intermediate (II). The intermediate (II) is prepared from a compound (IV) and a compound (V) which are subjected to an amidation reaction.The revefenacin can be obtained from the intermediate (II) through a substitution reaction. A synthesis route is mild in condition, the conversion rate and selectivity are high, the reaction yield andthe reaction efficiency are high, energy consumption is low, post-treatment is convenient, reaction operation is easy and convenient, and the method for preparing the revefenacin shown in the formula(I) through the intermediate (II) is more suitable for industrial production.
- -
-
Paragraph 0040; 0042; 0045; 0047
(2019/12/25)
-
- Preparation method of 4-chloromethyl benzoyl chloride
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The invention discloses a preparation method of 4-chloromethyl benzoyl chloride, wherein the preparation method comprises the steps: (1) a step of undergoing a chlorination reaction of 4-methylebnzenemethanol with chlorine gas under the action of a catalyst dibenzoyl peroxide to prepare a 4-hydroxymethyl trichlorobenzene crude product; (2) a step of undergoing a hydrolysis reaction of the 4-hydroxymethyl trichlorobenzene crude product prepared in the step (1) with water; and (3) a step of undergoing an acylation reaction of the hydrolysis product of the step (2) with excessive oxaloyl chlorideunder the action of a catalyst DMF, to prepare the target product 4-chloromethyl benzoyl chloride. The process has the advantages of easy availability of raw materials, low price, simple operation, fewer side reactions in the whole process, low energy consumption, high product quality, low product cost, and fewer three wastes; the total product yield is 85-90% and the purity is 99% or more.
- -
-
Paragraph 0027; 0030; 0031; 0034; 0035; 0038
(2018/10/26)
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- Synthesis of phthalic acid derivatives: Via Pd-catalyzed alkoxycarbonylation of aromatic C-H bonds with alkyl chloroformates
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A Pd(ii)-catalyzed alkoxycarbonylation of aromatic C-H bonds with alkyl chloroformates has been developed. A broad range of benzamides and alkyl chloroformates are compatible with this protocol. The reaction is operationally simple and scalable. The direct group could be readily removed to access substituted phthalic acid esters (PAEs), 1,2-dibenzyl alcohols and phthalamides. Besides alkoxycarbonylation of benzamide β-C-H bonds, γ-alkoxycarbonylation of 2-phenylacetamide is also feasible.
- Liao, Gang,Chen, Hao-Ming,Shi, Bing-Feng
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supporting information
p. 10859 - 10862
(2018/10/02)
-
- Synthesis, characterization, and in?vitro evaluation and in silico molecular docking of thiourea derivatives incorporating 4-(trifluoromethyl)phenyl moiety
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A series of acyl thiourea derivatives bearing 4-(trifluoromethyl)phenyl moiety (7 compounds) has been synthesized and characterized by FT-IR, 1H and 13C NMR spectroscopy and elemental analyses. The molecular structure of five compounds (2, 4, 5, 6 and 7) was determined by single crystal X-ray diffraction analysis. The crystal structures revealed that the carbonyl thiourea units in all determined compounds are mostly planar due in part to the formation of intramolecular N[sbnd]H?O[dbnd]C and C[sbnd]H?S[dbnd]C hydrogen bonds that form two S (6) rings. The intermolecular contacts of five crystal structures have been preformed based on the Hirshfeld surface and their associated 2D fingerprint plots. All the synthesized compounds were preliminarily screened for their in?vitro anti-fungal activity. Especially, compounds 4, 5 and 6 showed a good anti-fungal activity for four different kinds of fungi. Furthermore, all prepared thiourea derivatives were screened for antioxidant potential activity by DPPH free radical scavenging and the excellent activity were found compounds 5 and 6 with the IC50value of 191.75?μg/mL and 189.75?μg/mL, respectively. In silico molecular docking studies were performed to screen the thiourea derivatives against heat shock protein HSP90.
- Qiao, Lei,Huang, Jie,Hu, Wei,Zhang, Yu,Guo, Jiajia,Cao, Wenli,Miao, Kanghua,Qin, Baofu,Song, Jirong
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p. 149 - 159
(2017/03/22)
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- Aniline pyrimidine compound and its preparation and use
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The invention belongs to the field of synthesis of medicaments, and relates to an aniline pyrimidine compound of a general formula (I), in particular to an N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino] phenyl]-benzamide of which the 4th site is substituted by a quaternary heterocyclic ring, a preparation method for the compound and application in medicine. In vitro anti-tumor activity test results show that the in vitro anti-tumor activity IC50 value of the compound on MKN-45 gastric cancer strains is nM level and the compound can obviously inhibit activity of tumor cells and can be used for preparing new anti-tumor medicaments.
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-
Paragraph 0029; 0034; 0043; 0044
(2019/06/09)
-
- Design, synthesis and biological evaluation of colchicine derivatives as novel tubulin and histone deacetylase dual inhibitors
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A new class of colchicine derivatives were designed and synthesized as tubulin-HDAC dual inhibitors. Biological evaluations of these hybrids included the inhibitory activity of HDAC, tubulin polymerization analysis, in vitro cell cycle analysis in HCT-116 cells and cytotoxicity against different cancer cell lines. Hybrid 6d behaved as potent HDAC-tubulin dual inhibitor and showed comparable cytotoxicity with colchicine. Compound 11a exhibited powerful tubulin inhibitory activity, moderate anti-HDAC activity and the most potent cytotoxicity (IC50 Combining double low line 2-105 nM).
- Zhang, Xuan,Kong, Yannan,Zhang, Jie,Su, Mingbo,Zhou, Yubo,Zang, Yi,Li, Jia,Chen, Yi,Fang, Yanfen,Zhang, Xiongwen,Lu, Wei
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p. 127 - 135
(2015/04/14)
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- NOVEL COMPOUNDS AS HISTONE DEACETYLASE 6 INHIBITORS AND PHARMACEUTICAL COMPOSITIONS COMPRISING THE SAME
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The present invention relates to novel compounds having histone deacetylase 6 (HDAC6) inhibitory activity, isomers thereof, or pharmaceutically acceptable salts thereof, the use thereof for the preparation of therapeutic medicaments, pharmaceutical compositions comprising the same, a method of treating disease using the composition, and methods for preparing the novel compounds. The novel compounds according to the present invention have histone deacetylase 6 (HDAC6) inhibitory activity, and are effective for the prevention or treatment of HDAC6-associated diseases, including cancer, inflammatory diseases, autoimmune diseases, neurological diseases and neurodegenerative disorders.
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-
Paragraph 1957; 1958
(2015/10/05)
-
- Rhodium(iii)-catalyzed C-H/C-C activation sequence: Vinylcyclopropanes as versatile synthons in direct C-H allylation reactions
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Succession of C-H activation and C-C activation was achieved by using a single rhodium(iii) catalyst. Vinylcyclopropanes were used as versatile coupling partners. Mechanistic studies suggest that the olefin insertion step is rate-determining and a facile β-carbon elimination is involved, which represents a novel ring opening mode of vinylcyclopropanes. This journal is
- Wu, Jia-Qiang,Qiu, Zhi-Ping,Zhang, Shang-Shi,Liu, Jing-Gong,Lao, Ye-Xing,Gu, Lian-Quan,Huang, Zhi-Shu,Li, Juan,Wang, Honggen
-
supporting information
p. 77 - 80
(2015/01/09)
-
- Copper/silver-mediated direct ortho-ethynylation of unactivated (hetero)aryl C-H bonds with terminal alkyne
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A copper/silver-mediated oxidative ortho-ethynylation of unactivated aryl C-H bonds with terminal alkyne has been developed.The reaction uses the removable PIP directing group and features broad substrate scope, high functional-group tolerance, and compatibility with a wide range of heterocycles, providing an efficient synthesis of aryl alkynes. This procedure highlights the potential of copper catalysts to promote unique, synthetically enabling C-H functionalization reactions that lie outside of the current scope of precious metal catalysis.
- Liu, Yue-Jin,Liu, Yan-Hua,Yin, Xue-Song,Gu, Wen-Jia,Shi, Bing-Feng
-
supporting information
p. 205 - 209
(2015/02/19)
-
- Glycosylation efficiencies on different solid supports using a hydrogenolysis-labile linker
-
Automated oligosaccharide assembly requires suitable linkers to connect the first monosaccharide to a solid support. A new hydrogenolysis-labile linker that is stable under both acidic and basic conditions was designed, synthesized and coupled to different resins. Glycosylation and cleavage efficiencies on these functionalized solid supports were investigated, and restrictions for the choice of solid support for oligosaccharide synthesis were found.
- Collot, Mayeul,Eller, Steffen,Weishaupt, Markus,Seeberger, Peter H.
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supporting information
p. 97 - 105
(2013/03/13)
-
- Block copolymer route towards poly(vinylidene fluoride)/poly(methacrylic acid)/nickel nanocomposites
-
PVDF-based block copolymers have been employed as precursors for the construction of PVDF/PMAA/Ni nanocomposites. New poly(tert-butyl methacrylate)-block-poly(vinylidene fluoride)-block-poly(tert-butyl methacrylate) (PtBMA-b-PVDF-b-PtBMA) triblock copolymers were synthesized via atom transfer radical polymerization (ATRP) of tBMA from chlorine-terminated PVDF macroinitiators. The alternating crystalline-amorphous lamellar nanostructure and the spherulitic microstructure indicate the dominant role of crystallization of the PVDF segments during structure formation. The polar β-crystalline phase of PVDF has been detected within the block copolymer films. Hydrolysis of the tBMA segments and subsequent backfilling of the remaining polymer template with nickel through electroless metal deposition generated PVDF/PMAA/Ni nanocomposites. The β-polymorph was preserved during hydrolysis and electroless plating, as well as the lamellar morphology.
- Voet, Vincent S. D.,Hermida-Merino, Daniel,Ten Brinke, Gerrit,Loos, Katja
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p. 7938 - 7946
(2013/07/05)
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- Acylsulfonamide safety-catch linker: Promise and limitations for solid-phase oligosaccharide synthesis
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Safety-catch linkers are useful for solid-phase oligosaccharide synthesis as they are orthogonal to many common protective groups. A new acylsulfonamide safety-catch linker was designed, synthesized and employed during glycosylations using an automated carbohydrate synthesizer. The analysis of the cleavage products revealed shortcomings for oligosaccharide synthesis.
- Yin, Jian,Eller, Steffen,Mayeul, Collot,Seeberger, Peter H.
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supporting information
p. 2067 - 2071
(2013/02/22)
-
- Synthesis of several imidazo[2,1-b]thiazoles
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Imidazo[2,1-b]thiazole derivatives were obtained from 2-aminothiazoles or 2-amino-2-thiazolines and 4-chloromethyl-co-bromoacetophenone in three steps. The product syntheses take place in convenient conditions with yields between 50 and 70 %.
- Bratulescu, George
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experimental part
p. 350 - 352
(2012/08/07)
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- NOVEL FIVE-MEMBERED RING COMPOUND
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Disclosed is a five-membered ring compound represented by formula (1) or a pharmaceutically acceptable salt thereof. The compound inhibits infiltration of leukocytes including eosinophils and lymphocytes, and is effective as a drug for treating various inflammations. The compound is highly safe and can be administered for a long period. A pharmaceutical product containing the five-membered ring compound or a pharmaceutically acceptable salt thereof is also disclosed. (In the formula, R1 represents a halogen atom or a phenyl group which may be substituted by a C1-C3 alkyl group or a C1-C3 alkoxy group; R2 represents a C1-C3 alkylene group which may be substituted by a C1-C3 alkyl group or a carbonyl group; R3 represents a C1-C3 alkyl group; R4 and R5 independently represent a hydrogen atom or a C1-C3 alkyl group, or -N(R4)R5 may represent a morpholino group which may be substituted by a C1-C3 alkyl group; Y2 represents a C2-C4 alkylene group; and R6 represents a hydrogen atom, a halogen atom, a C1-C3 alkyl group or a C1-C3 alkoxy group.)
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Page/Page column 11
(2011/02/17)
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- COMPOUNDS FOR TREATING MUSCULAR DYSTROPHY
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Compounds of formula (I): wherein X, L1, R1, L2, R2, R3, and R4 are as defined herein, are useful in the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia.
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Page/Page column 50
(2010/12/29)
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- NAPHTHYLACETIC ACIDS
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The invention is concerned with the compounds of formula (I) and pharmaceutically acceptable salts and esters thereof, wherein X, Q, and R1-R6 are defined in the detailed description and claims. In addition, the present invention relates to methods of manufacturing and using the compounds of formula (I) as well as pharmaceutical compositions containing such compounds. The compounds of formula (I) are antagonists or partial agonists at the CRTH2 receptor and may be useful in treating diseases and disorders associated with that receptor such as asthma.
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Page/Page column 95-96
(2010/06/15)
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- A facile total synthesis of imatinib base and its analogues
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Imatinib and its analogues were successfully synthesized by an improved method in 19.5-46.2% total yield of six main steps. Pyrimidinyl amine was prepared by the reaction of enaminone and guanidine nitrate without the use of a toxic cyanamide. N-(2-Methyl-5-nitrophenyl)-4-(pyridin-3-yl) pyrimidin-2-amine as a key intermediate for the synthesis of imatinib was prepared by coppercatalyzed iV-arylation of heteroarylamme in 82% yield. The copper salts were used instead of the expensive palladium compounds in this C-N bond-forming reaction. The intermediate nitro compound was reduced by a N2H 4.H2O/FeCl3/C system using water as a solvent in good yield.
- Liu, Yi-Feng,Wang, Cui-Ling,Bai, Ya-Jun,Han, Ning,Jiao, Jun-Ping,Qi, Xiao-Li
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p. 490 - 495
(2013/01/03)
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- PROCESS FOR THE PREPARATION OF THE ANTI-CANCER DRUG IMATINIB AND ITS ANALOGUES
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The present invention discloses a process of the manufacture of imatinib of formula (Ia) and its new analogues I (b-d) through the intermediate of formula (II). The mesylate (methane sulfonate ) salt of imatinib base (Ia[(4-(4-methylpiperazin-1-ylmethyl)-N4 [methyl-3-(4-pyridin-3-yl)pyrimidn-2-yl amino)phenyl]benzamide])is a popular life -saving drug to treat chronic myelogenous leukemia (CML).
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-
- Amide substituted imidazoquinolines
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Imidazoquinoline and tetrahydroimidazoquinoline compounds that contain amide functionality at the 1-position are useful as immune response modifiers. The compounds and compositions of the invention can induce the biosynthesis of various cytokines and are useful in the treatment of a variety of conditions including viral diseases and neoplastic diseases.
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-
-
- Amide substituted imidazoquinolines
-
Imidazoquinoline and tetrahydroimidazoquinoline compounds that contain amide functionality at the 1-position are useful as immune response modifiers. The compounds and compositions of the invention can induce the biosynthesis of various cytokines and are useful in the treatment of a variety of conditions including viral diseases and neoplastic diseases.
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-
- N-Cycloalkanoyl-L-phenylalanine derivatives as VCAM/VLA-4 antagonists.
-
A systematic structure-activity relationship investigation of the lead compound 1 resulted the identification of several N-[(substituted alkyl)cycloalkanoyl]-4-[((2,6-dichlorophenyl)carbonyl)amino]-L-phenylalanine derivatives as potent VCAM/VLA-4 antagonists. The data are consistent with a model of these compounds in which these alkanoylphenylalanines reside in a compact gauche (-) bioactive conformation.
- Sidduri, Achyutharao,Tilley, Jefferson W,Hull, Kenneth,Lou, Jian Ping,Kaplan, Gerry,Sheffron, Allen,Chen,Campbell, Robert,Guthrie, Robert,Huang, Tai-Nan,Huby, Nicholas,Rowan, Karen,Schwinge, Virginia,Renzetti, Louis M
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p. 2475 - 2478
(2007/10/03)
-
- Flash vacuum pyrolysis of stabilised phosphorus ylides. Part 16. Model studies for the construction of conjugated polymers
-
Reaction of a range of bis(ylides) with acid chlorides has been used to prepare the bis(oxoylides) 11-15. Similarly a range of simple ylides react with bis(acid chlorides) to give bis(oxoylides) 19-27 with the isomeric structure. Flash vacuum pyrolysis (FVP) of one example of the first type results in extrusion of Ph3P rather than the expected Ph3PO while six examples of the second type do extrude Ph3PO upon FVP at 500 °C to afford the bis(alkynes) 28. Examples of the corresponding bis(tributylphosphonium ylides) have also been prepared but attempts to construct a tetrakis(oxoylide) 31 using a stepwise approach were unsuccessful. Fully assigned 13C NMR spectra are presented for six of the bis(oxoylides).
- Aitken, R. Alan,Drysdale, Martin J.,Hill, Lawrence,Lumbard, Keith W.,Maccallum, James R.,Seth, Shirley
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p. 11039 - 11050
(2007/10/03)
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- Nonclassical 2,4-diamino-5-aryl-6-ethylpyrimidine antifolates: Activity as inhibitors of dihydrofolate reductase from Pneumocystis carinii and Toxoplasma gondii and as antitumor agents
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Twelve novel 2,4-diamino-5-(4'-benzylamino)- and 2,4-diamino-5-[4'-(N- methylbenzylamino)-3'-nitrophenyl]-6-ethylpyrimidines bearing 4-substituents on the benzylamino or N-methylbenzylamino aryl ring were synthesized and evaluated as nonclassical inhibitors of Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase (DHFR). Compounds were prepared by reaction of 2,4-diamino-5-(4'-chloro-3'-nitrophenyl)-(8) or 2,4-diamino-5-(4'-fluoro-3'- nitrophenyl)-6-ethylpyrimidine (15) with the appropriate 4-substituted (CO2H, CO2Me, SO2NH2, dioxolan-2-yl, CHO, dimethyloxazolin-2-yl) benzylamine or N-methylbenzylamine derivative. Compounds 25-29 were synthesized from 2,4-diamino-5-{4'-[N-(4''-carboxybenzyl)amino]-3'- nitrophenyl}-6-ethylpyrimidine (10) and the corresponding amine (NH3, MeNH2, Me2NH, piperidine, diethyl L-glutamate) via isobutyl mixed anhydride coupling; hydrolysis of the diethyl L-glutamate 29 afforded the L-glutamate analogue 30. The compounds exhibited potent inhibitory activity against T. gondii (IC50 values 0.0018-0.14 μM) and rat liver (IC50 values 0.0029- 0.27 μM) DHFR, with a 4-substituent invariably enhancing binding to both enzymes relative to the unsubstituted benzoprim (5) or methylbenzoprim (6). Modest selectivity for T. gondii enzyme was observed with several analogues, whereas all of the compounds were relatively weak inhibitors of P. carinii DHFR and exhibited no selectivity. Selected analogues were evaluated for in vivo antitumor activity against the methotrexate-resistant M5076 murine reticulosarcoma, with 2,4-diamino-5-{4'-[N-[4''-(N'- methylcarbamoyl)benzyl]-N-methylamino]-3'-nitrophenyl}-6-ethylpyrimidine (14) (K(i) for rat liver DHFR = 0.000 35 ± 0.000 29 nM) combining significant antitumor activity with minimal toxicity.
- Robson, Claire,Meek, Michelle A.,Grunwaldt, Jan-Dierk,Lambert, Peter A.,Queener, Sherry F.,Schmidt, Dirk,Griffin, Roger J.
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p. 3040 - 3048
(2007/10/03)
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- Polyalky and poly(oxyalkylene) benzyl amine esters and fuel compositions containing the same
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A fuel additive having the formula: STR1 wherein A1 is amino, lower alkylamino or dialkylamino, or a polyamine radical; R1 and R2 are independently hydrogen, hydroxy, lower alkyl or lower alkoxy; R3 and R4 are independently hydrogen or lower alkyl; x is an integer from 0 to 10; n is an integer from 0 to 100; and when n is 0 to 10, R5 is polyalkyl having an average molecular weight of 450 to 5,000; and when n is 5 to 100, R5 is hydrogen, alkyl, phenyl, aralkyl, alkaryl or an acyl group having the formula: STR2 wherein R6 is alkyl, phenyl, aralkyl or alkaryl.
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- solitaire-Porphyrazines: Synthetic, structural, and spectroscopic investigation of complexes of the novel binucleating norphthalocyanine-2,3-dithiolato ligand
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We have developed the synthesis of unsymmetrical metalloporphyrazines of the form M[pz(A:B3)], where A and B refer to two different types of peripheral functionality, and have used it to prepare new bi- and trimetallic solitaire-porphyrazines in which A represents a mono- or bimetallic moiety. The macrocyclic complexes described are based on the binucleating ligand, [M(norphthalocyanine-2,3-dithiolate)]2-, [M(norpc)]2-. This can be thought of as a metalloporphyrazine where B is a fused benzo ring; A represents two thiolates fused at the β-pyrrole positions to form a dithiolene moiety that can bind a transition-metal ion in addition to one within the macrocyclic cavity. solitaire-Porphyrazines have been synthesized by chelation of [(L-L)M']2+ to the [M(norpc)]2- ligand where M = '2H', Ni, Cu, or Mn-Cl, L-L is a bis(diphosphino) or bis(diamino) group and M' = Ni, Pd, or Pt. Crystal structures have been obtained for 11b, where the [H2(norpc)]2- ligand coordinates the diphosphinopalladium moiety, [Pd(dppf)]2+, by the two thiolate sulfur atoms at its periphery, and for 11h, with the diaminoplatinum moiety, [Pt(teeda)]2+, bound to the periphery of the [Ni(norpc)]2- ligand. In crystals 11b and 11h, the molecules appear as face-to-face dimers. However, the dimer of 11b and the two crystallographically independent dimers of 11h each shows a distinctly different degree of overlap. The electronic absorption spectra of a series of porphyrazines in which the two peripheral sulfur atoms form thioether moieties with a modified benzyl-protecting group (6-10) show that the peripheral asymmetry of the macrocyclic framework causes a strong splitting of the (π-π*) Q-band. In contrast, when the peripheral sulfurs bind a metal ion to form solitaire-porphyrazines 11a-h. the optical spectra closely resemble that of the symmetrical pc, with unsplit Q band. The EPR spectrum of solitaire 11d, where M = Cu, L-L = a bis(diphosphino) cap, M' = Pd, has features consistent with other square-planar copper(II) porphyrins and phthalocyanines. Cyclic voltammograms of compound 11b shows two reversible ring reductions at potentials similar to those of H2(pc) as well as a reversible oxidation associated with the ferrocene portion of the Pd(dppf) moiety.
- Baumann,Nasir,Sibert,White,Olmstead,Williams,Barrett,Hoffman
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p. 10479 - 10486
(2007/10/03)
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- Antibody catalyzed hydrolysis of enol ethers
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The hydrolysis of alkyl enol ethers to their corresponding carbonyl compounds proceeds by rate determining protonation of the β-carbon to form an activated oxocarbonium ion intermediate and is catalyzed by acids (Kresge, A. J.; Chiang, Y. J. Chem. Soc. B 1967, 53). It can be catalyzed by antibodies with very high enantioselectivity of protonation at the β-carbon to form optically pure carbonyl compounds (Reymond, J.-L.; Janda, K. D.; Lerner, R. A. J. Am. Chem. Soc. 1992, 114, 2257). In the present study, the pH profile of the antibody 14D9 (anti-1) catalyzed, enantioselective hydrolysis of enol ether 4 between pH = 3.1 and pH = 7.2 has been measured in both H2O and D2O at 20°C. The kinetic solvent isotope effect is (kH/kD)cat = 1.75 for the antibody catalyzed reaction and (kH/kD)uncat = 1.92 for the background reaction. The Michaelis-Menten constant Km for substrate 4 changes from 35 μM at low pH to 190 μM. at high pH. Saturation of the catalytic activity is observed at low pH. These observations are consistent with general acid catalysis by an ionizable side chain with pK = 5.2, presumably a carboxyl group, in the active site. A maximum rate acceleration kcat/kuncat = 8200 is obtained at the high pH end of the profile, and a maximum turnover number of 9.75 × 10-5 s-1 is obtained at the low pH end. Enol ethers 15-21 are also catalytically hydrolyzed by 14D9. The maximum turnover numbered measured is 0.39 s-1 with 17 at pH = 6.0 at 20°C. The catalytic effect kcat/kuncat is influenced by the structure of the enol ether. Catalysis increases by a factor of 12 between 15 and its β-methyl analog 4 and by a factor of 34 between the six-membered ring enol ether 19 and its five-membered ring analog 17. These rate effects may reflect the principle of strain in catalysis. They suggest that hydrophobic interactions directly participate in transition-state stabilization, which is unexpected for an acid-base reaction usually discussed in terms of proton relay mechanisms. The implication of these findings for the design and improvement of antibody catalysts is discussed.
- Reymond, Jean-Louis,Jahangiri, Guiti K.,Stoudt, Catherine,Lerner, Richard A.
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p. 3909 - 3917
(2007/10/02)
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- Synthesis and Properties of Diethyl 5,10-Dihetera-5,10-dihydroindenoindene-2,7-dicarboxylates
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A series of six heterocyclic diesters 1b-6b containing all combinations of nitrogen, sulfur, and selenium has been prepared from a common precursor, diethyl 2,2'-dinitrostilbene-4,4'-dicarboxylate.Electrochemical analysis showed oxidation potential increases in the order NA liquid crystals.A new synthetic method leading to the indoloindazole ring system has been found.
- Kaszynski, Piotr,Dougherty, Dennis A.
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p. 5209 - 5220
(2007/10/02)
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- Quinazoline Antifolate Thymidylate Synthase Inhibitors: Bridge Modifications and Conformationally Restricted Analogues in the C-2-Methyl Series
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Several C2-methylquinazoline-based antifolates (14-26) have been prepared in which the C9,N10 bridge has been replaced by the reversed N9,C10 unit.This series was extensively studied by incorporating further substituents at N9 and C10 as well as by modifications to the p-aminobenzoate ring.The C-2-methylquinazoline analogues 29, 30, and 31 containing the methyleneoxa, methylenethia, and thia bridge units were also synthesized.In general these isosteric replacements of the bridge unit in the parent C2-methyl-N10-propargylquinazoline antifolate 2 were much less potent as inhibitors of isolated thymidylate synthase (TS) but several were at least as potent as inhibitors of L1210 cell growth in culture.The fusion of the p-aminobenzoate ring into the bicyclic systems 75 and 76 also reduced activity against TS but again gave highly cytotoxic compounds.The cytotoxicities were largely prevented by thymidine, confirming that TS in the major locus.
- Marsham, Peter R.,Jackman, Ann L.,Hayter, Anthony J.,Daw, Melanie R.,Snowden, Jayne L.,et al.
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p. 2209 - 2218
(2007/10/02)
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- SOLUBILITY OF CHLORINE AND HYDROGEN CHLORIDE IN p-TOLUOYL CHLORIDE AND IN THE PRODUCTS OF ITS CHLORINATION IN THE SIDE CHAIN.
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In view of the absence of literature data on solubilities of chlorine and hydrogen chloride in the system under consideration and the need to have such data for determination of the kinetic parameters of the chlorination reaction, the authors studied the solubility of chlorine and hydrogen chloride in p-toluoyl chloride and in the products of its chlorination in the side chain (chloro-, dichloro-, and trichloromethylbenzoyl chlorides). The results of this investigation show that the solubilities of chlorine and hydrogen chloride in acyl chlorides depend appreciably on temperature and less on the nature of the compounds. Determination of the dependence of solubility of chlorine in p-toluoyl chloride at 40 degree on the partial pressure of chlorine in the gas phase gave a linear relationship, indicating that the system obeys Henry's law.
- Korotkii,Alymova,Uspenskaya,Emel'yanov,Motsarev
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p. 1095 - 1097
(2007/10/02)
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- Novel stilbene compounds
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Stilbene compounds of the formula STR1 in which the rings A, B and C can carry non-chromophoric substituents, R1 is hydrogen, alkyl which is unsubstituted or substituted by non-chromophoric substituents, or aryl which is unsubstituted or substituted by non-chromophoric substituents, and R2 is a carboxyl group or a functional derivative thereof, a cyano group, a sulphonic acid ester group, a sulphonamide group or a sulphonyl group, and the use thereof as fluorescent brightening agents for high-molecular organic material.
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- Novel polymerization initiators
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Benzoyl peroxide compounds containing reactive substituents are used to initiate the formation of telechelic polymers.
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