- HEPATITIS B VIRAL ASSEMBLY EFFECTORS
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Novel assembly effector compounds having a therapeutic effect against hepatitis B viral (HBV) infection are disclosed. Assembly effector molecules described herein can lead to defective viral assembly and also may affect other viral activities associated with chronic HBV infection. Also disclosed is a process to synthesize disclosed compounds, method of treatment of HBV by administration of disclosed compounds, and use of these compounds in the manufacture of medicaments against HBV.
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Paragraph 00121
(2015/05/05)
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- Identification of N-acyl 4-(5-pyrimidine-2,4-dionyl)phenylalanine derivatives and their orally active prodrug esters as dual-acting alpha4-beta1 and alpha4-beta7 receptor antagonists
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N-Acyl 4-(5-pyrimidine-2,4-dionyl)phenylalanine derivatives of type 4 were designed to replace the 2,6-dichlorobenzoylamine portion of compound 1 in order to identify novel compounds with improved potency against α4-integrins. Several derivatives were identified as very potent dual-acting α4-integrin, α4β1 and α4β7 antagonists. Investigation of a limited number of prodrug esters led to the discovery of the ethyl ester prodrug 42, which demonstrated good intestinal fluid stability and good permeability. Despite low solubility, 42 gave acceptable blood levels of 30 when dosed orally in non-human primates. Additionally, 42 had an overall excellent profile and was selected for clinical trials. Investigation of N-acyl 4-(5-pyrimidine-2,4-dionyl)phenylalanine derivatives led to the discovery of several very potent dual-acting α4-integrin antagonists. Ethyl ester prodrug 42 advanced to human clinical trials based on the excellent intestinal fluid stability, good permeability and superior efficacy in non-human primates.
- Sidduri, Achyutharao,Tilley, Jefferson W.,Lou, Jianping,Tare, Nadine,Cavallo, Gary,Frank, Karl,Pamidimukkala, Anjula,Choi, Duk Soon,Gerber, Louise,Railkar, Aruna,Renzetti, Louis
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p. 1026 - 1031
(2013/03/14)
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- ANTIVIRAL PYRIMIDINES
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Disclosed herein are novel compounds comprising substituted pyrimidines, pyrazolopyrimtdines, and imidazolopyrimidines, the syntheses thereof, and compositions thereof, including pharmaceutical compositions, comprising the novel pyrimidines, pyrazolopyrimtdines, imidazolpyrimidines and related compounds. Such compounds function to inhibit entry of viruses of the Flaviviridae family, including Hepatitis C virus (HCV), into cells that are susceptible to virus infection. These compounds are useful for the treatment, therapy and/or prophylaxis of viral diseases and infection, including HCV infection.
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Page/Page column 44-45
(2010/11/03)
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- INSECTICIDAL PYRIMIDINYL ARYL HYRDRAZONES
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Pyrimidinyl aryl hydrazones are effective at controlling insects.
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Page/Page column 6-7
(2009/04/24)
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- Synthesis and insecticidal/acaricidal activity of novel 3-(2,4,6- trisubstituted phenyl)uracil derivatives
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A series of novel 3-(2,4,6-trisubstituted phenyl)uracil derivatives has been synthesised and assayed for insecticidal/acaricidal activity. The assay indicated certain requirements for optimal insecticidal activity, which can be summarised as follows: (a) the substituents on the phenyl ring should possess hydrophobicity and electron-withdrawing properties, and the sum of their volumes determines the level of activity; (b) the substituent at the 6- position on the uracil ring should also possess electron-withdrawing properties and hydrophobicity, together with the correct volume; (c) the 1- position on the uracil ring should be unsubstituted for activity against Nephotettix cincticeps and Epilachna vigintioctopunctata, but substituents with length C3 to C4 may be optimal for activity against Tetranychus urticae; (d) certain substituents at the 5-position of the uracil ring give activity against E vigintioctopunctata and T urticae, but not against N cincticeps; (e) a thiocarbonyl group at the 2-position of the uracil ring is less effective than a carbonyl group. Of the compounds assayed, 3-(2,6-dichloro-4- trifluoromethylphenyl)-6-trifluoromethyluracil showed high activity against all the species assayed. (C) 2000 Society of Chemical Industry.
- Yagi, Kazuo,Akimoto, Kazuhiko,Mimori, Norihiko,Miyake, Toshiro,Kudo, Masaki,Arai, Kazutaka,Ishii, Shigeru
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- 6-Substituted and 5,6-disubstituted derivatives of uridine: Stereoselective synthesis, interaction with uridine phosphorylase, and in vitro antitumor activity
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Stereoselective procedures are described for the synthesis of 6- alkyluridines by Lewis acid-catalyzed condensation of (a) trimethylsilylated 6-alkyl-4-alkylthiouracils with 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D- ribofuranose (ABR) and (b) trimethylsilylated 6-alkyl-3-benzyluracils with ABR. The 4-methylthio group was subsequently removed with the use of 1 N trifluoroacetic acid and the 3-benzyl group by a new modified procedure with the use of the complex BBr3-THF. Furthermore, 6-(hydroxymethyl)uridine (39) and 5-fluoro-6-(hydroxymethyl)uridine (40) were obtained by sequential oxidation with SeO2 and reduction with tetrabutylammonium borohydride of the 6-methyl group of 6-methyluridine (5) and 5-fluoro-6-methyluridine (35), and their corresponding 6-fluoromethyl congeners 41 and 42 were obtained by DAST treatment of 39 and 40, respectively. For all the foregoing nucleosides in the fixed syn conformation about the glycosyl bond, 1H NMR spectroscopy further demonstrated that the pentose rings exist predominantly in the conformation N (3'-endo). Most of the nucleosides were weak substrates of Escherichia coli pyrimidine nucleoside phosphorylase. Enhanced susceptibility to phosphorolysis was exhibited by two of them, 39 and 41, with 6-CH2OH and 6-CH2F substituents capable of formation of an additional hydrogen bond with the enzyme. The 5-fluoro-6-substituted uridines were the poorest substrates. Cytotoxicities of the nucleosides were examined vs the human tumor cell lines MOLT-3, U-937, K-562, and IM-9, as well as PHA-stimulated human lymphocytes. Two of the analogues, 5-fluoro-6-(fluoromethyl)uridine (42) and 5-fluoro-6- (hydroxymethyl)uridine (40), exhibited cytotoxicities comparable to that of 5-fluorouracil.
- Felczak, Krzysztof,Drabikowska, Alicja K.,Vilpo, Juhani A.,Kulikowski, Tadeusz,Shugar, David
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p. 1720 - 1728
(2007/10/03)
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- Pyrimidines. 7. A Study of the Chlorination of Pyrimidines with Phosphorus Oxychloride in the Presence of N,N-Dimethylaniline
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The chlorination of 6-trifluoromethyluracils by phosphorus oxychloride in the presence of N,N-dimethylaniline was studied and compared with results obtained with 6-methyluracils. 6-Trifluoromethyluracils and its 5-chloro analog afforded moderate yields of the di- and trichloropyrimidines, accompanied by good yields of the 2-N-methylanilino by-products, after a 3-hour reaction time.After 24 hours, the 2-N-methylanilinopyrimidines were the primary or sole products.A small yield of 2,4-bis(N-methylanilino)-6-trifluoromethylpyrimidine was also obtained.The 6-methyluracils afforded high yields of the di- and trichloropyrimidines, after 3 and 24 hours, along with minor amounts of the 2-N-methylanilino by-products.After 48 hours, the proportion of 2,4-dichloro-6-methylpyrimidine decreased, and the 2-N-methylanilino product increased. 2-Chloro-4-methylanilino-6-methylpyrimidine and bis(2-N-methylanilino)-6-methylpyrimidine were also formed in small amounts.The chlorination products from 5-chloro-6-methyluracil remained constant over 188 hours of reaction time. It appears that the Π electron distribution around the ring, as influenced by the substituents, controls the course of the chlorination and by-product formation.Since the amination by a tertiary amine is a type of Hoffmann reaction, the presence of the chlorine in 5 position of the ring adds steric hindrance and thus enhances the regiospecificity of the formation of by-products.
- Gershon, Herman,Grefig, Anthony T.
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p. 1161 - 1167
(2007/10/02)
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