- ANTIVIRAL COMPOUNDS, COMPOSITIONS AND METHODS OF USE
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Provided herein are antiviral compounds having the structure of Formula (I) and compositions thereof for use in the treatment of viral infection. In particular, the compounds of Formula (I) are capable of interfering with the export of viral mRNA processing as reflected in the altered accumulation of viral RNA isoforms as well as transport from the nucleus to the cytoplasm. Such compounds show a reduction of HIV, adenovirus and coronavirus infection of cells. The invention provides compounds that may be suitable for the treatment of HIV/AIDS. (Formula (I))
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Page/Page column 24-25
(2021/06/26)
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- 2-Trifluoromethylthiazole-5-carboxamides: Analogues of a Stilbene-Based Anti-HIV Agent that Impact HIV mRNA Processing
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The observation that stilbene 3 (5350150) blocks HIV replication through its impact on HIV mRNA processing prompted a program to develop non-cytotoxic analogues that maintain its mechanism of action. This initially involved replacement of the central double bond in 3 by an amide function and the quinoline motif by a 2-aminobenzothiazole subunit, as in 12jj (R′ = Cl), 12pp (R = NO2), and 12vv (R = CF3). On the basis of the possible CF3 NO2 bioisostere relationship in 12vv and 12pp, compound 23 was prepared and also found to be active. In the final step, the thiazole compounds 28 (GPS488) (EC50 = 1.66 μM) and 29 (GPS491) (EC50 = 0.47 μM) were prepared and evaluated. Similar activity and cell viability values (therapeutic index (TI = CC50/EC50) values of 50-100) were observed in primary peripheral blood mononuclear cells. Furthermore, they remained active against a panel of HIV mutant strains displaying resistance to individual drugs used in antiretroviral therapy. It was determined that compound 29 suppressed expression of the HIV-1 structural protein Gag and altered HIV-1 RNA accumulation, decreasing the abundance of RNAs encoding the structural proteins while increasing levels of viral RNAs encoding the regulatory proteins, a pattern similar to that seen for compound 3.
- Brockman, Mark A.,Brumme, Zabrina L.,Chabot, Benoit,Cheung, Peter K.,Cochrane, Alan,Grierson, David S.,Zamiri, Maryam
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supporting information
p. 1818 - 1823
(2021/11/16)
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- Raltitrexed pharmaceutical composition and preparation method thereof
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The invention relates to a raltitrexed pharmaceutical composition which is high in safety and a preparation method thereof. The raltitrexed pharmaceutical composition comprises raltitrexed and thiophene related substances, wherein the content of the thiophene related substances is not higher than 0.3%. The raltitrexed pharmaceutical composition is good in safety, effectiveness and stability and can relieve the blood toxicity of the raltitrexed to a certain degree.
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Paragraph 0049; 0050
(2018/04/02)
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- Impurity B of raltitrexed, and preparation method and application thereof
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The invention discloses a potential blood system toxic impurity B of raltitrexed, a preparation method thereof, and a use of the impurity B as an impurity reference substance.
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Paragraph 0019; 0040; 0041; 0057; 0072; 0087
(2018/03/01)
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- DERIVATIVES OF 1-PHENYL-2-PYRIDINYL ALKYL ALCOHOLS AS PHOSPHODIESTERASE INHIBITORS
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Derivatives of 1-phenyl-2-pyridinyl alkyl alcohols according to formula (I) are useful as inhibitors of the phosphodiesterase 4 (PDE4) enzyme.
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Paragraph 0317; 0318
(2014/01/07)
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- DERIVATIVES OF 1-PHENYL-2-PYRIDINYL ALKYL ALCOHOLS AS PHOSPHODIESTERASE INHIBITORS
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The invention relates to inhibitors of the phosphodiesterase 4 (PDE4) enzyme. More particularly, the invention relates to compounds that are derivatives of 1 -phenyl-2-pyridinyl alkyl alcohols, methods of preparing such compounds, compositions containing them and therapeutic use thereof.
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Page/Page column 77-78
(2014/01/08)
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- ANTI-CANCER DRUGS AND USES RELATING THERETO FOR METASTATIC MALIGNANT MELANOMA AND OTHER CANCERS
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The present invention discloses triazene analogs of the general formula (I) and formula (II), their tautomeric forms, stereoisomers, polymorphs, hydrates, solvates, and pharmaceutically acceptable salts thereof for the metastatic malignant melanoma and other cancers including but not limited to lymphomas, sarcomas, carcinomas, and gliomas. The invention further discloses a process for the preparation of the above said triazene analogs of formula (I) and formula (II), and their pharmaceutically acceptable compositions.
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Page/Page column 38-39
(2010/04/06)
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- Clean and selective oxidation of aromatic alcohols using silica-supported Jones' reagent in a pressure-driven flow reactor
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By exploiting the high surface to volume ratio obtained within continuous flow reactors, we are able to oxidise selectively an array of primary alcohols to either the aldehyde or carboxylic acid, depending on the flow rates employed, demonstrating a degree of reaction control unattainable in traditional stirred reactors.
- Wiles, Charlotte,Watts, Paul,Haswell, Stephen J.
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p. 5261 - 5264
(2007/10/03)
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- Heterocyclic amides with anti-tuberculosis activity
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Compounds having the general structure: wherein A is selected from the group consisting of oxygen, sulfur, and NR15, and R15 is selected from the group consisting of H, alkyl, aryl, substituted alkyl, and substituted aryl; B,D, and E are each independently selected from the group consisting of CH, nitrogen, sulfur and oxygen; R1 is selected from the group consisting of nitro, halo, alkyl ester, arylsulfanyl, arylsulfinyl, arylsulfonyl and sulfonic acid; t is an integer from 1 to 3; and X is a substituted amide, and methods of using the novel compounds for treating infections caused by microorganisms, including Mycobacterium tuberculosis.
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- 6H-THIENO`2, 3-B!PYRROLE DERIVATIVES AS ANTAGONISTS OF GONADOTROPIN RELEASING HORMONE (GNRH)
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The invention relates to a group of novel thieno-pyrrole compounds of Formula (I): wherein: R1, R2, R3, R4 and R5 are as defined in the specification, which are useful as gonadotrophin releasing hormone antagonists. The invention also relates to pharmaceutical formulations of said compounds, methods of treatment using said compounds and to processes for the preparation of said compounds.
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- Toward an understanding of the chemical etiology for DNA minor-groove recognition by polyamides
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Crescent-shaped polyamides composed of aromatic amino acids, i.e., 1-methyl-1H-imidazole Im, 1-methyl-1H-pyrrole Py, and 3-hydroxy-1H-pyrrole Hp, bind in the minor groove of DNA as 2:1 and 1:1 ligand/DNA complexes. DNA-Sequence specificity can be attributed to shape-selective recognition and the unique corners or pairs of corners presented by each heterocycle(s) to the edges of the base pairs on the floor of the minor groove. Here we examine the relationship between heterocycle structure and DNA-sequence specificity for a family of five-membered aromatic amino acids. By means of quantitative DNase-I footprinting, the recognition behavior of polyamides containing eight different aromatic amino acids, i.e., 1-methyl-1H-pyrazole Pz, 1H-pyrrole Nh, 5-methylthiazole Nt, 4-methylthiazole Th, 3-methylthiophene Tn, thiophene Tp, 3-hydroxythiophene Ht, and furan Fr, were compared with the polyamides containing the parent-ring amino acids Py, Im, and Hp for their ability to discriminate between the four Watson - Crick base pairs in the DNA minor groove. Analysis of the data and molecular modeling showed that the geometry inherent to each heterocycle plays a significant role in the ability of polyamides to differentiate between DNA sequences. Binding appears sensitive to changes in curvature complementarity between the polyamide and DNA. The Tn/Py pair affords a modest 3-fold discrimination of T · A vs. A · T and suggests that an S-atom in the thiophene ring prefers to lie opposite T not A.
- Marques, Michael A.,Doss, Raymond M.,Urbach, Adam R.,Dervan, Peter B.
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p. 4485 - 4517
(2007/10/03)
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- Synthesis and in vitro antitumor activity of thiophene analogues of 5-chloro-5,8-dideazafolic acid and 2-methyl-2-desamino-5-chloro-5,8-dideazafolic acid
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N-[5-[N-(2-Amino-5-chloro-3,4-dihydro-4-oxoquinazolin-6-yl)methylamino]-2- thenoyl]-L-glutamic acid (6) and N-[5-[N-(5-chloro-3,4-dihydro-2-methyl-4-oxoquinazolin-6-yl)methylamino]-2- thenoyl]-L-glutamic acid (7), the first reported thiophene analogues of 5-chloro-5,8-dideazafolic acid, were synthesized and tested as inhibitors of tumor cell growth in culture. 4-Chloro-5-methylisatin (10) was converted stepwise to methyl 2-amino-5-methyl-6-chlorobenzoate (22) and 2-amino-5-chloro-3,4-dihydro-6-methyl-4-oxoquinazoline (19). Pivaloylation of the 2-amino group, followed by NBS bromination, condensation with di-tert-butyl N-(5-amino-2-thenoyl)-L-glutamate (28), and stepwise cleavage of the protecting groups with ammonia and TFA yielded 6. Treatment of 9 with acetic anhydride afforded 2,6-dimethyl-5-chlorobenz[1,3-d]oxazin-4-one (31), which on reaction with ammonia, NaOH was converted to 2,6-dimethyl-5-chloro-3,4-dihydroquinazolin-4-one (33). Bromination of 33, followed by condensation with 28 and ester cleavage with TFA, yielded 7. The IC50 of 6 and 7 against CCRF-CEM human leukemic lymphoblasts was 1.8±0.1 and 2.1±0.8 μM, respectively.
- Forsch, Ronald A.,Wright, Joel E.,Rosowsky, Andre
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p. 2067 - 2076
(2007/10/03)
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- Pyrrolidinyl and pyrrolinyl ethylamine compounds as kappa agonists
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A compound of the following formula: and the salts thereof wherein A is hydrogen, halo, or hydroxy, broken line represents an optional double bond with proviso that if the broken line is a double bond, then A is absent; Ar1is optionally substituted phenyl; Ar2is aryl or heteroaryl selected from phenyl, napththyl, or pyridyl, the aryl or heteroaryl being optionally substituted; R1is hydrogen, hydroxy, or C1-C4alkyl; and R2and R3are independently selected from optionally substituted C1-C7alkyl, C3-C6cycloalkyl, C2-C6alkenyl, C2-C6alkynyl, or R2and R3, together with the nitrogen atom to which they are attached, form an optionally substituted pyrrolidine. These compounds are useful as kappa agonists.
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- Mechanism of inactivation of γ-aminobutyric acid aminotransferase by (S)-4-amino-4,5-dihydro-2-thiophenecarboxylic acid
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(S)-4-Amino-4,5-dihydro-2-thiophenecarboxylic acid ((S)-6) was previously synthesized (Adams, J. L.; Chen, T. M.; Metcalf, B. W. J. Org. Chem. 1985, 50, 2730-2736.) as a heterocyclic mimic of the natural product gabaculine (5-amino-1,3-cyclohexadienylcarboxylic acid), a mechanism-based inactivator of γ-aminobutyric acid aminotransferase (GABA-AT) (Rando, R. R. Biochemistry 1977, 16, 4604). Inactivation of GABA-AT by (S)-6 is time-dependent and protected by substrate. Two methods were utilized to demonstrate that, in addition to inactivation, about 0.7 equiv per inactivation event undergoes transamination. Inactivation results from the reaction of (S)-6 with the pyridoxal 5-phosphate (PLP) cofactor. The adduct was isolated and characterized by ultraviolet-visible spectroscopy, electrospray mass spectrometry, and tandem mass spectrometry. All of the results support a structure (11) that derives from the predicted aromatization inactivation mechanism (Scheme 2) originally proposed by Metcalf and co-workers for this compound. This is only the third example, besides gabaculine and L-cycloserine, of an inactivator of a PLP-dependent enzyme that acts via an aromatization mechanism.
- Fu, Mengmeng,Nikolic, Dejan,Van Breemen, Richard B.,Silverman, Richard B.
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p. 7751 - 7759
(2007/10/03)
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- Fibrinogen receptor antagonists
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Fibrinogen receptor antagonists of the general formula: and which includes, for example, the compounds of formula STR1 are useful for inhibiting the binding of fibrinogen to blood platelets, inhibiting the aggregation of blood platelets, treating thrombus formation or embolus formation, and preventing thrombus or embolus formation.
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- Phosphorylamides, their preparation and use
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A phosphorylamide derivative represented by the general formula (I): STR1 wherein R represents an amino group that may be substituted, or a salt thereof, possesses potent antibacterial activity against Helicobacter bacterium, especially Helicobacter pylori, and is useful for prevention or treatment of digestive diseases caused by Helicobacter bacterium, solely or in combination with an antacid or an acid secretion inhibitor.
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- Carbapenem antibiotic compounds
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The present invention relates to carbapenems and provides a compound of the formula (I) STR1 wherein: R1 is 1-hydroxyethyl, 1-fluoroethyl or hydroxymethyl; R2 is hydrogen or C1-4 alkyl; R3 is hydrogen or C1-4 alkyl; and the thienyl ring is optionally further substitued by one or two substituents selected from halo, cyano, C1-4 alkyl, nitro, hydroxy, carboxy, C1-4 alkoxy, trifluoromethyl, C1-4 alkoxycarbonyl, amino, C1-4 alkylamino, di-C1-4 alkylamino, sulfonic acid, C1-4 alkylS(O)n -- (wherein n is 0-2), C1-4 alkanoylamino, C1-4 alkanoyl(N-C1-4 alkyl)amino, carbamoyl, C1-4 alkylcarbamoyl, di-C1-4 alkylcarbamoyl and N-C1-4 alkanesulfonamido; or by a tetramethylene group attached to adjacent carbon atoms on the thienyl ring; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof. Processes for their preparation, intermediates in their preparation, their use as therapeutic agents and pharmaceutical compositions containing them are also described.
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- Antibiotic penem compounds
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The present invention provides a compound of the formula (I) STR1 wherein: R1 is 1-hydroxyethyl, 1-fluoroethyl or hydroxymethyl; R2 is hydrogen or C1-4 alkyl; Z is carboxy, sufonic acid, tetrazol-5-yl or C 1-4 alkylsulfonylcarbamoyl (--CONHSO2 C1-4 alkyl); A is a phenyl or thienyl ring; and A is optionally further substituted by one or two substituents or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof. Processes for their preparation, intermediates in their preparation, their use as therapeutic agents and pharmaceutical compositions containing them.
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- Antibiotic compounds
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The present invention relates to carbapenems and provides a compound of the formula (I) STR1 wherein: R1 is 1-hydroxyethyl, 1-fluoroethyl or hydroxyethyl; R2 is hydrogen or C1-4 alkyl; R3 is hydrogen or C1-4 alkyl; P is of the formula (IA), (IB) or (IC) STR2 and in the formula (IB) the naphthyl group may be bonded to the nitrogen of the linking carbamoyl group at either ring; Z is carboxy, sulfonic acid, sulfinic acid, C1-4 alkanamidosulfonyl (--SO2 NHCOC1-3 alkyl), benzamidosulfonyl, C1-4 alkylsulfonylcarbamoyl (--CONHSO2 C1-4 alkyl), phenylsulfonylcarbamoyl, C1-4 alkoxy carbamoyl, hydroxycarbamoyl, sulfoamino, N--C1-4 alkanesulfonamido, cyanocarbamoyl, cyanosulfamoyl, tetrazol-5-yl, 3-hydroxyisoxazol-4-yl and 3-hydroxyisoxazol-5-yl; and P is optionally further substituted provided that when P is of the formula (IA) or (IC), Z is not carboxy; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof. Processes for their preparation, intermediates in their preparation, their use as therapeutic agents and pharmaceutical compositions containing them are also described.
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- Carbapenem antibiotic compounds
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The present invention provides a compound of the formula: STR1 or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof wherein: A is a group of the formula (IA) or (IB): STR2 R1 is 1-hydroxyethyl, 1-fluoroethyl or hydroxymethyl; R2 is hydrogen or C1-4 alkyl; R3 and R4 are the same or different and are a variety of substituents X is alkanediyl containing 1-6 carbon atoms optionally interrupted by O, S(O)x (wherein x is zero, one or two), --CONR5 -- or --NR5 -- or wherein R5 is hydrogen or C1-4 alkyl; or X is alkenediyl containing 1-6 carbon atoms optionally interrupted by O, S(O)x or --NR5 --.
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- Synthesis of a series of nitrothiophenes with basic or electrophilic substituents and evaluation as radiosensitizers and as bioreductively activated cytotoxins
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A series of 2- and 3-nitrothiophene-5-carboxamides bearing N-(ω-aminoalkyl) side chains has been prepared by treatment of the thiophenecarbonyl chloride with the appropriate (protected) ω-aminoalkylamine. Analogous N-(oxiranylmethyl)nitrothiophene-5-carboxamides have been synthesized by epoxidation of the corresponding N-allylamide. Compounds in both classes were evaluated in vitro both as radiosensitizers of hypoxic mammalian cells and as selective bioreductively activated cytotoxins. The most potent radiosensitizers were those agents with strong tertiary amine bases or oxiranes in the side chain. Studies in vivo showed that 2-methyl-N-[2-(dimethylamino)ethyl]-3-nitrothiophene-5-carboxamide caused slight radiosensitization of the KHT sarcoma in mice given 0.34 mmol kg-1. However, administration of this and related tertiary amines at higher doses was precluded by systemic toxicity.
- Threadgill,Webb,O'Neill,Naylor,Stephens,Stratford,Cole,Adams,Fielden
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p. 2112 - 2120
(2007/10/02)
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- Process for preparing a thiophene derivative
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A process for preparing 5-nitro-2-thenoic acid by oxidation of the corresponding aldehyde is described.
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- Factors controlling the Selectivity of ipso-Attack in Homolytic Aromatic Substitutions. Reactions of Alkyl Radicals with Nitrothiophen Derivatives
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The reactions of the nearly electroneutral methyl and of the nucleophilic 1-adamantyl radical with some selected nitrothiophen derivatives have been investigated in order to elucidate the factors which control the positional selectivity of radical addition to an aromatic substrate.With 5-nitro-2-X-thiophens (II), (V), and (VI) and 3,5-dinitro-2-methoxycarbonylthiophen (III) the adamantyl radical gave exclusively the products of ipso-attack, whereas the methyl radical selectively added at the unsubstituted 4-position.On the other hand, with 4-nitro-2-methoxycarbonylthiophen (I) both radicals added at the 5-position and with 4,5-dinitro-2-methoxycarbonylthiophen (IV) both radicals gave the products of ipso-substitution by displacing the nitro-group from the 5-position.These changes in positional selectivity are explained by assuming that the nature of the transition state of the addition step changes as a function of the polar character of the radical and of the electron deficiency of the aromatic substrates.
- Cogolli, Pietro,Maiolo, Filippo,Testaferri, Lorenzo,Tiecco, Marcello,Tingoli, Marco
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p. 1331 - 1335
(2007/10/02)
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