- β-LACTAM COMPOUNDS, THEIR PREPARATION AND USE AS ANTIBACTERIAL AGENTS
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Provided are β-lactam compounds of formula (I), their preparation and use as antibiotic agents for the treatment of bacterial infections: Wherein X, W, R 1, R 2 and R 3 are defined herein.
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Paragraph 0071-0072
(2022/02/15)
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- Synthesis and Antibacterial Activities of Amidine Substituted Monocyclic β-Lactams
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Background: Mononcyclic β-lactams are regarded as the most resistant class of β-lactams against a series of β-lactamases, although they possess limited antibacterial activity. Aztreonam, being the first clinically approved monobactam, needs broad-spectrum efficacy through structural modification. Objective: We strive to synthesize a number of monocyclic β-lactams by varying the substituents at N1, C3, and C4 positions of azetidinone ring and study the antimicrobial effect on variable bacterial strains. Methods: Seven new monobactam derivatives 23a-g, containing substituted-amidine moieties linked to the azetidinone ring via thiazole linker, were synthesized through multistep synthesis. The final compounds were investigated for their in vitro antibacterial activities using the broth microdilution method against ten bacterial strains of clinical interest. The minimum inhibitory concentrations (MICs) of newly synthesized derivatives were compared with aztreonam, ceftazidime, and mero-penem, existing clinical antibiotics. Results: All compounds 23a-g showed higher antibacterial activities (MIC 0.25 μg/mL to 64 μg/mL) against tested strains as compared to aztreonam (MIC 16 μg/mL to >64 μg/mL) and ceftazidime (MIC >64 μg/mL). However, all compounds, except 23d, exhibited lower antibacterial activity against all tested bacterial strains compared to meropenem. Conclusion: Compound 23d showed comparable or improved antibacterial activity (MIC 0.25 μg/mL to 2 μg/mL) to meropenem (MIC 1 μg/mL to 2 μg/mL) in the case of seven bacterial species. Therefore, compound 23d may be a valuable lead target for further investigations against multi-drug resistant Gram-negative bacteria.
- Gao, Yuanyu,He, Lili,Iqbal, Zafar,Ji, Jinbo,Ji, Jingwen,Liu, Yuanbai,Mu, Yangxiu,Myo, Ko Ko,Sun, Jian,Tang, Dong,Yang, Haikang,Yang, Zhixiang,Zhai, Lijuan
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p. 574 - 588
(2022/03/09)
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- Cephalosporin drug intermediate and synthesis method thereof
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The invention provides a cephalosporin drug intermediate and a synthesis method thereof, and belongs to the technical field of medicine synthesis. The synthesis method comprises the following steps: d) reacting a compound with a structure as shown in a formula (IV) with stannic oxide to obtain a compound with a structure as shown in a formula (V-1); and e) reacting the compound with the structureas shown in the formula (V-1) with sodium hydroxide to obtain a compound with a structure as shown in a formula (V-2); and according to the synthetic method of the cephalosporin drug intermediate provided by the invention, the obtained cephalosporin drug intermediate can be used as a cephalosporin antibiotic intermediate for preparing cephalosporin antibiotics. The method has the advantages of wide raw material sources, reasonable reaction route, mild reaction conditions and high product yield, and is suitable for large-scale production.
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Paragraph 0071-0075
(2020/12/30)
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- Low-Temperature Reactions of α-Bromopropanoyl Chloride with Lithium Derivative of Ethyl Acetate
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The reaction of 2-bromopropanoyl chloride with lithium ethyl acetate generated in situ by the reaction of equimolar amounts of lithium diisopropylamide with ethyl acetate forms, depending on the conditions (temperature, time, reagent ratio), diethyl 2,2′-(3-methyloxirane-2,2-diyl)diacetate, 2,2-dibromo-N,N-diisopropylpropanamide, and ethyl (5-methyl-4-oxo-4,5-dihydrofuran-2-yl)acetate as minor by-products along with the expected acylation product ethyl 4-bromo-3-oxopentanoate. The reaction with 2 or 5 equiv of lithium ethyl acetate (–78°C → –20°C) gave, together with the mentioned α-bromo ester, ethyl (5-methyl-4-oxo-4,5-dihydrofuran-2-yl)acetate formed as a result of transformations of the adduct of the second LiCH2CO2Et molecule and ethyl-4-bromo-3-oxopentanoate. The reaction 2-bromopropanoyl chloride with sodium malonic ester involves acylation of enol form of the primary expected acylation product to afford dimethyl |2-bromo-1-[(2-bromopropanoyl)oxy]propylidene-malonate.
- Valiullina,Khasanova,Galeeva,Selezneva,Miftakhov
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p. 1726 - 1730
(2020/01/11)
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- SHMT INHIBITORS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same.
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Paragraph 00298
(2018/06/30)
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- INHIBITORS OF RENAL OUTER MEDULLARY POTASSIUM CHANNEL
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Novel spirocyclic compounds of formula I: and pharmaceutically acceptable salts thereof are disclosed as inhibitors of the ROMK (Kir1.1) channel. The compounds may be used as diuretic and/or natriuretic agents and for the therapy and prophylaxis of medical conditions including cardiovascular diseases such as hypertension, heart failure and chronic kidney disease and conditions associated with excessive salt and water retention. Pharmaceutical compositions and methods of treatment are also included.
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Page/Page column 84
(2015/07/15)
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- INHIBITORS OF THE RENAL OUTER MEDULLARY POTASSIUM CHANNEL
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Novel spirocyclic compounds of formula I: and pharmaceutically acceptable salts thereof are disclosed as inhibitors of the ROMK (Kir1.1) channel. The compounds may be used as diuretic and/or natriuretic agents and for the therapy and prophylaxis of medical conditions including cardiovascular diseases such as hypertension, heart failure and chronic kidney disease and conditions associated with excessive salt and water retention. Pharmaceutical compositions and methods of treatment are also included.
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Page/Page column 85
(2015/07/15)
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- INHIBITORS OF THE RENAL OUTER MEDULLARY POTASSIUM CHANNEL
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The present invention provides compounds of Formula I and the pharmaceutically acceptable salts thereof, which are inhibitors of the ROMK (Kir1.1) channel. The compounds may be used as diuretic and/or natriuretic agents and for the therapy and prophylaxis of medical conditions including cardiovascular diseases such as hypertension, heart failure and conditions associated with excessive salt and water retention.
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Page/Page column 47
(2014/02/16)
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- SPIRO - FUSED PIPERIDINE DERIVATIVES FOR USE AS INHIBITORS OF THE RENAL OUTER MEDULLARY POTASSIUM CHANNEL
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The present invention provides compounds of Formula I and the pharmaceutically acceptable salts thereof, which are inhibitors of the ROMK (Kir1.1) channel. The compounds may be used as diuretic and/or natriuretic agents and for the therapy and prophylaxis of medical conditions including cardiovascular diseases such as hypertension, heart failure and conditions associated with excessive salt and water retention.
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Page/Page column 50
(2014/02/16)
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- INHIBITORS OF THE RENAL OUTER MEDULLARY POTASSIUM CHANNEL
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The present invention provides compounds of Formula (I) and the pharmaceutically acceptable salts thereof, which are inhibitors of the ROMK (Kir11) channel. The compounds may be used as diuretic and/or natriuretic agents and for the therapy and prophylaxis of medical conditions including cardiovascular diseases such as hypertension, heart failure and chronic kidney disease and conditions associated with excessive salt and water retention.
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Page/Page column 43
(2014/10/04)
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- Exploration of novel 2-alkylimino-1,3-thiazolines: T-type calcium channel inhibitory activity
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We have developed combinatorial libraries of new 2-alkylimino-1,3- thiazolines with four diversity points, consisting of more than 500 compounds, in a parallel synthetic fashion. The synthetic strategy was based on the construction of a large library aimed at the discovery of new compounds with T-type calcium channel inhibitory activity through structure modifications of hit compound 2. The syntheses of the compounds of Chemset A with four diversity points were accomplished by the condensation of thioureas 5 with α-haloketones 6{1-66} having two diversity points each. A library of phthalimidyl 1,3-thiazolines 24 was synthesized to provide Chemset B, which allowed the introduction of other diversity points through the nucleophilic character of the amino nitrogen. A sublibrary, Chemset C, was constructed from the libraries of Chemset A and Chemset B by functionalization of the C-4 position of the 1,3-thiazoline ring. The products containing ester or acid groups at the C-4 position of the 1,3-thiazoline ring were used in amide synthesis to give a new sublibrary within Chemset C. Deprotection of the phthalimidyl moiety of 24 followed by the reaction with benzoyl chloride gave the corresponding sublibrary in Chemset C. Another sublibrary which includes secondary amino derivatives was obtained by reduction of the amide moiety or reductive amination of 23 with phenyl aldehyde. The selected compounds from the generated libraries were evaluated with respect to inhibition of T-type calcium channels, where some of them have exhibited promising activity.
- Han, Minsoo,Nam, Kee Dal,Shin, Dongyun,Jeong, Nakcheol,Hahn, Hoh-Gyu
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experimental part
p. 518 - 530
(2010/08/20)
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- THIAZOLE DERIVATIVES AS CXCR3 RECEPTOR MODULATORS
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The invention encompasses compounds of Formula I (I) or pharmaceutically acceptable salts thereof, which are antagonist of the CXCR3 chemokine receptor useful for the treatment or prevention of pathogenic inflammatory processes, autoimmune diseases or graft rejection processes. Methods of use and pharmaceutical compositions are also encompassed.
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Page/Page column 104-105
(2008/06/13)
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- Synthesis of a high-affinity Fluorescent PPARγ ligand for high-throughput fluorescence polarization assays
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Members of the peroxisome proliferator activated receptor (PPAR) family of transcription factors are under investigation as molecular targets for the treatment of numerous diseases including Alzheimer's, asthma, atherosclerosis, inflammation, multiple sclerosis, cancer, and diabetes. We employed the X-ray crystal structure of the PPARγ subtype complexed with the potent small molecule agonist GI262570 (farglitazar) to design and synthesize a novel fluorescent and high-affinity probe for homogeneous and high-throughput fluorescent polarization (FP) assays. Examination of this X-ray structure revealed that the phenyl carbon atom meta to the oxazole moiety of GI262570 is exposed to solvent at the bottom of a narrow protein cavity. A derivative of GI262570 was synthesized bearing a linear phenylacetylene-derived side chain comprising propargylamine coupled to fluorescein. This fluorescent analogue was designed to project the fluorophore into the adjacent protein cavity with minimal effects on receptor affinity and maximal effects on fluorescence polarization properties. The recombinant PPARγ ligand binding domain protein bound tightly and specifically to this probe with K d=61±14 nM as determined by FP measurements. Competition binding assays with known PPARγ ligands provided Ki values that were highly correlated with analogous values obtained by scintillation proximity (SP) assays. This fluorescent PPARγ probe enables high-throughput and homogenous FP assays for the identification of novel endogenous and exogenous PPARγ ligands, and this rational ligand design approach may be applied to other therapeutically important members of the nuclear hormone receptor superfamily.
- DeGrazia, Michael J.,Thompson, Jerry,Vanden Heuvel, John P.,Peterson, Blake R.
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p. 4325 - 4332
(2007/10/03)
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- Cephalosporins
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Antibacterially active novel cephalosporins of the formula STR1 in which R1 represents alkyl, alkenyl, alkoxy, alkylthio, halogen, trifluoromethyl or trifluoromethoxy, R2 represents hydrogen or an organic radical, R3 repre
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- Drug-induced modifications of the immune response. 12. 4,5-Dihydro-4-oxo-2-(substituted amino)-3-furancarboxylic acids and derivatives as novel antiallergic agents
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The synthesis of a series of novel 4,5-dihydro-4-oxo-2-(substituted amino)-3-furancarboxylic acids, salts, esters, and amides is described. The title compounds when tested in the mediator-induced dermal vascular permeability and active anaphylaxis assays in rats demonstrated moderate to potent antiallergic activity. The [2-trans-(4-methyl-phenyl)cyclopropyl]amino analogue 53 emerged as the most active derivative. Thus, when administered intraperitoneally to rate at a dose of 100 mg/kg, it inhibited the action of the mediators serotonin, histamine, and bradykinin by 100%. In the active anaphylaxis assay in rats, compound 30 suppressed the edema by 81% at a dose of 100 mg/kg, following intraperitoneal administration.
- Mck,Zazulak,Radov,baer,Steward,Elzer,Kinsolving,Georgiev
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p. 1910 - 1918
(2007/10/02)
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