- Design, synthesis and evaluation of aromatic heterocyclic derivatives as potent antifungal agents
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To further enhance the anti-Aspergillus efficacy of our previously discovered antifungal lead compounds (1), a series of aromatic heterocyclic derivatives were designed, synthesized and evaluated for in vitro antifungal activity. Many of the target compounds showed good inhibitory activity against Candida albicans and Cryptococcus neoformans. In particular, the isoxazole nuclei were more suited for improving the activity against Aspergillus spp. Among these compounds, 2-F substituted analogues 23g and 23h displayed the most remarkable in vitro activity against Candida spp., C. neoformans, A. fumigatus and fluconazole-resistant C.alb. strains, which is superior or comparable to the activity of the reference drugs fluconazole and voriconazole. Notably, the compounds 23g and 23h exhibited low inhibition profiles for various isoforms of human cytochrome P450 and excellent blood plasma stability.
- Zhao, Shizhen,Zhang, Xiangqian,Wei, Peng,Su, Xin,Zhao, Liyu,Wu, Mengya,Hao, Chenzhou,Liu, Chunchi,Zhao, Dongmei,Cheng, Maosheng
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- PYRIMIDINE HYDRAZIDE COMPOUNDS AS PGDS INHIBITORS
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This invention is directed to a compound wherein R1, R2, R3, R4 and L1 are as defined herein, a pharmaceutical composition comprising the compound, and the use of the compound to treat allergic and/or
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Page/Page column 72-73
(2008/12/04)
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- PYRIMIDINE AMIDE COMPOUNDS AS PGDS INHIBITORS
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This invention is directed to a compound of formula (I): wherein R1, R2, R3 and L1 are as defined herein, a pharmaceutical composition comprising the compound, and the use of the compound to treat allergic and/or inflammatory disorders, particularly disorders such as allergic rhinitis, asthma and/or chronic obstructive pulmonary disease (COPD).
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Page/Page column 35
(2010/11/26)
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- CARBOXAMIDE DERIVATIVES
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Compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein P, W, X, Y, R2, R3, r and s are as defined in the specification, processes for preparing such compounds, pharmaceutical compositions comprising such compounds and their use in therapy
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- Inhibitors of NF-kappaB and AP-1 gene expression: SAR studies on the pyrimidine portion of 2-chloro-4-trifluoromethylpyrimidine-5-[N-(3', 5'-bis(trifluoromethyl)phenyl)carboxamide].
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We investigated the structure-activity relationship studies of N-[3, 5-bis(trifluoromethyl)phenyl][2-chloro-4-(trifluoromethyl)pyrimidin-5 -yl]carboxamide (1), an inhibitor of transcription mediated by both NF-kappaB and AP-1 transcription factors, with the goal of improving its potential oral bioavailability. Compounds were examined for cell-based activity, were fit to Lipinski's rule of 5, and were examined for potential gastrointestinal permeability using the intestinal epithelial cell line, Caco-2. Selected groups were substituted at the 2-, 4-, and 5-positions of the pyrimidine ring using solution-phase combinatorial methodology. The introduction of a fluorine in the place of 2-chlorine of 1 resulted in a compound with comparable activity. However, other substitutions at the 2-position resulted in a loss of activity. The trifluoromethyl group at the 4-position could be replaced with a methyl, ethyl, chlorine, or phenyl without a substantial loss of activity. The carboxamide group at the 5-position is critical for activity. If it was moved to the 6-position, the activity was lost. The 2-methyl analogue of 1 (81) showed comparable in vitro activity and improved Caco-2 permeability compared to 1.
- Palanki,Erdman,Gayo-Fung,Shevlin,Sullivan,Goldman,Ransone,Bennett,Manning,Suto
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p. 3995 - 4004
(2007/10/03)
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- Pyrimidine carboxamides and related compounds and methods for treating inflammatory conditions
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Compounds having utility as antinflammatory agents in general and, more specifically, for the prevention and/or treatment of immunoinflammatory and autoimmune diseases are disclosed. The compounds are pyrimidine- or pyrazine-containing compounds and, in one embodiment, are carboxyamides of the same. Methods are also disclosed for preventing and/or treating inflammatory conditions by administering to an animal in need thereof an effective amount of a compound of this invention, preferably in the form of a pharmaceutical composition.
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- Reaction of 2-Dimethylaminomethylene-1,3-diones with Dinucleophiles. VIII. Synthesis of Ethyl and Methyl 2,4-Disubstituted 5-Pyrimidinecarboxylates
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Reaction of ethyl or methyl 2-dimethylaminomethylene-3-oxoalkanoates with N-C-N dinucleophiles such as guanidine, acetamidine or benzamidine afforded in high yields the relative esters of 4-substituted 2-amino-, 2-methyl- or 2-phenyl-5-pyrimidinecarboxylic acids, respectively.These esters were hydrolyzed to the corresponding carboxylic acids, which were converted by heating to 4-substituted 2-pyrimidinamines, 2-methyl or 2-phenylpyrimidines, respectively, generally in excellent yields.The 4-unsubstituted ethyl 2-amino-, 2-methyl- and 2-phenyl-5-pyrimidinecarboxylateswere obtained in moderate yields by reaction of the above dinucleophiles with ethyl 2,2-diformylacetate.These esters were hydrolyzed and the corresponding acids (with the exception of the 2-methyl derivative) were decarboxylated to give 2-pyrimidinamine and 2-phenylpyrimidine in satisfactory yields.
- Schenone, Pietro,Sansebastiano, Laura,Mosti, Luisa
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p. 295 - 305
(2007/10/02)
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- Optically active pyridylethanol derivative
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A novel optically active pyridylethanol derivative having a high twistability and also a superior temperature characteristic is provided, which derivative is expressed by the formula STR1 wherein R is an alkyl group of alkoxy group each of 1 to 20 carbon atoms or hydrogen atom, m and n each represent 0 or 1, STR2 each independently represent STR3 wherein Y is any one of H, halogen atom or CN and STR4 is a pyridine ring the N atom of which may be present at an optionally chosen site thereof.
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- SYNTHESIS OF 2,5'-BIPYRIMIDINES FROM SUBSTITUTED 5-CYANOPYRIMIDINES
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The Pinner method was applied to substituted 5-cyanopyrimidines to obtain 5-aminopyrimidines, which were condensed with acrolein derivatives to synthesize compounds that contain a 2,5-bipyrimidine fragment.
- Mamaev, V. P.,Mikhaleva, M. A.,Shadrina, A. I.
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p. 303 - 307
(2007/10/02)
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