- Synthesis, Antiviral Potency, in Vitro ADMET, and X-ray Structure of Potent CD4 Mimics as Entry Inhibitors That Target the Phe43 Cavity of HIV-1 gp120
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In our attempt to optimize the lead HIV-1 entry antagonist, NBD-11021, we present in this study the rational design and synthesis of 60 new analogues and determination of their antiviral activity in a single-cycle and a multicycle infection assay to derive a comprehensive structure-activity relationship (SAR). Two of these compounds, NBD-14088 and NBD-14107, showed significant improvement in antiviral activity compared to the lead entry antagonist in a single-cycle assay against a large panel of Env-pseudotyped viruses. The X-ray structure of a similar compound, NBD-14010, confirmed the binding mode of the newly designed compounds. The in vitro ADMET profiles of these compounds are comparable to that of the most potent attachment inhibitor BMS-626529, a prodrug of which is currently undergoing phase III clinical trials. The systematic study presented here is expected to pave the way for improving the potency, toxicity, and ADMET profile of this series of compounds with the potential to be moved to the early preclinical development.
- Curreli, Francesca,Kwon, Young Do,Belov, Dmitry S.,Ramesh, Ranjith R.,Kurkin, Alexander V.,Altieri, Andrea,Kwong, Peter D.,Debnath, Asim K.
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p. 3124 - 3153
(2017/04/21)
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- METHYL SULFANYL PYRMIDMES USEFUL AS ANTIINFLAMMATORIES, ANALGESICS, AND ANTIEPILEPTICS
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The present invention relates to pyrimidine derivatives of Formula (Ia) and (Ib) (including tautomers, isomers, prodrugs, and pharmaceutically acceptable salts thereof). Said compounds are useful in the treatment of pain (such as neuropathic pain), inflammation, and epilepsy (by acting as anticonvulsants). Methods of medical treatment making use of said compounds, as well as additional compounds of Formula (IIa) and (IIb), are also disclosed.
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Page/Page column 112
(2010/12/18)
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- Synthesis and properties of NLO chromophores with fine-tuned gradient electronic structures
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A novel series of heterocycle-based NLO chromophores based on different combinations of auxiliary donor (i.e., benzene, thiophene and pyrrole) and auxiliary acceptor (i.e., thiazole with different regiochemistries) were designed and synthesized. Due to the different electron-rich and poor nature of the auxiliary donors and acceptors, respectively, the resulting NLO chromophores have systematically varied ground-state electronic structures, as evidenced by the 1H NMR, CV and UV-vis investigations. The nonlinear optical properties of the resulting NLO chromophores were studied by UV-vis spectroscopy, Hyper-Rayleigh scattering (HRS), and semi-empirical computations. All the chromophores have very large molecular hyperpolarizabilities (β1000 nm) in the range of 704-1500 × 10-30 esu (or β0, 318-768 × 10-30 esu), which showed a great sensitivity to the gradient electronic structures. Upon increasing the electron density from benzene to thiophene and to pyrrole, substantial increases in β0 were observed; significantly larger β0 values were also observed for NLO chromophores based on "matched" thiazole (C2 is connected to the acceptor) than those based on "un-matched" thiazole (C5 is connected to the acceptor). TGA investigations showed good thermal stability for the resulting NLO chromophores. However, with the increase of electron density of the auxiliary donor, a decrease in thermal and photochemical stability was observed. It is interesting to note that NLO chromophores based on triarylamine as the donor and thiazole as the auxiliary acceptor exhibited not only high thermal stability but also very large β0 values.
- Ma, Xiaohua,Ma, Fei,Zhao, Zhenhua,Song, Naiheng,Zhang, Jianping
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supporting information; experimental part
p. 2975 - 2985
(2010/05/02)
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- Chemical Compounds
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This invention relates to non-steroidal compounds that are modulators of androgen, glucocorticoid, mineralocorticoid, and progesterone receptors, and also to the methods for the making and use of such compounds.
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Page/Page column 59
(2009/07/17)
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- Rapid and efficient synthesis of stable isotope labeled [ 13C4, D4]-5-(hydroxymethyl)thiazole: Versatile building block for biologically interesting compounds
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5-(Hydroxymethyl)thiazole is a versatile building block for many biologically active compounds. A rapid and efficient four- step synthesis of its stable isotope labeled counterpart with four 13C and four deuterium atoms in 32% total yield is reported. Condensation of [13C 2]-chloro acetic acid with [13C]-thiourea gave [ 13C3]-2,4-thiazolidinedione. Reaction of [ 13C3]-2,4-thiazolidinedione with phosphorus oxybromide and [13C, D]-DMF (Me2N13CDO) produced [ 13C4 D]-2,4-dibromo- thiazole-5-carboxaldehyde. The resultant aldehyde was then reduced by sodium borodeuteride to [ 13C4, D2]-(2,4-dibromo- thiazol-5-yl)-methanol. Catalytic deuteration of [13C4, D2]-(2,4- dibromo-thiazol-5-yl)-methanol by palladium black with deuterium gas at 1 atm pressure and room temperature produced completely de-brominated [ 13C4, D4]-5-(hydro- xymethyl)thiazole. De-bromination of the 2,4-dibromothiazole by the catalysis of palladium black provides a simple and convenient synthetic method for the stable isotope labeled and potentially radioactive isotope labeled thiazole compounds. Copyright
- Lin, Ronghui,Salter, Rhys,Gong, Yong
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body text
p. 110 - 113
(2009/10/24)
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- BROADSPECTRUM SUBSTITUTED BENZISOXAZOLE SULFONAMIDE HIV PROTEASE INHIBITORS
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The present invention concerns the compounds having the formula N-oxides, salts, stereoisomeric forms, racemic mixtures, prodrugs esters and metabolites thereof.It further relates to their use as broadspectrum HIV protease inhibitors, processes for their preparation as well as pharmaceutical compositions and diagnostic kits comprising them. It also concerns combinations thereof with another anti-retroviral agent, and to their use in assays as reference compounds or as reagents.
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Page/Page column 26
(2008/06/13)
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- Retroviral protease inhibiting compounds
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A compound comprising a substituent of the formula (II) is disclosed as an HIV protease inhibitor. Intermediates for making such compounds and processes for making such intermediates are also disclosed.
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- Hydroxyethylamino sulphonamides useful as retroviral protease inhibitors
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PCT No. PCT/US94/09139 Sec. 371 Date Jan. 24, 1996 Sec. 102(e) Date Jan. 24, 1996 PCT Filed Aug. 23, 1994 PCT Pub. No. WO95/06030 PCT Pub. Date Mar. 2, 1995The invention relates to sulfonamide-containing hydroxyethylamine protease inhibitor compounds, their process of making, composition and method of use for inhibiting retroviral proteases such as human immunodeficiency virus.
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- Process for the preparation of 5-hydroxymethylthiazoles
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The present invention discloses a process for the preparation of a hydroxymethylthiazole compound having formula 3: The process of the invention comprises reacting a halomethyl thiazole having the formula: STR1 with water, at an elevated temperature. Optionally, the reaction can be carried out in the presence of a base, such as sodium carbonate, which can react with any acid formed. In the process of the invention, X is a halogen atom; and R6 is selected from the group consisting of hydrogen, and halogen atoms. The invention also contemplates the preparation of acid addition salts of the hydroxymethylthiazole, compound 3.
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- RETROVIRAL PROTEASE INHIBITING COMPOUNDS
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A compound of the formula: STR1 is disclosed as an HIV protease inhibitor. Methods and compositions for inhibiting an HIV infection are also disclosed.
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- Inactivation of O6-alkylguanine-DNA alkyltransferase. 1. Novel O6-(hetarylmethyl)guanines having basic rings in the side chain.
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A number of novel guanine derivatives containing heterocyclic moieties at the O6-position have been synthesized using a purine quaternary salt which reacts with alkoxides under mild conditions. Initially O6-substituents were investigated in which the benzene ring of the known agent, O6-benzylguanine, was replaced by unsubstituted heterocyclic rings. The ability of these agents to inactivate the DNA repair protein O6-alkylguanine-DNA alkyltransferase (ATase), both as pure recombinant protein and in the human lymphoblastoid cell line Raji, has been compared with that of O6-benzylguanine. The present paper focuses on O6-substituents with basic rings, and under standard conditions several of them proved more effective than benzyl for inactivation of both recombinant and Raji ATase. Among the pyridine derivatives, the 2-picolyl compound 7 is not very active in contrast to the 3- and 4-picolyl compounds, and this influenced our choice of isomers of other basic ring systems for study. Since halogen substitution in the thiophene ring considerably increased the activity (17 versus 6), similar modifications in the pyridine series were examined. The more polar O6-substituents in this study are on the whole compatible with the stereochemical requirements of the ATase protein, and their pharmacological properties may be valuable in subsequent in vivo investigations, particularly the thenyl (6), 5-thiazolylmethyl (12), 5-bromothenyl (17), and 2-chloro-4-picolyl (21) derivatives.
- McElhinney,Donnelly,McCormick,Kelly,Watson,Rafferty,Elder,Middleton,Willington,McMurry,Margison
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p. 5265 - 5271
(2007/10/03)
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- Process for the preparation of 5-hydroxymethylthiazole
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5-Hydroxymethylthiazole is prepared in an improved manner by reducing 5-formylthiazole using a borane compound. Particularly advantageous in this case is the use of 5-formylthiazole which has been obtained by reaction of a 2-halomalonaldehyde compound with thioformamide in the presence of less than 5% by weight of water (based on the reaction mixture).
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- Process for preparation of 5-hydroxymethylthiazole
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A process for the preparation of 5-hydroxymethylthiazole comprises reacting a compound of the formula, STR1 with a carboxylic acid salt (optimally in the presence of a quaternary ammonium salt) and hydrolyzing the resulting ester. Subsequent dechlorination gives 5-hydroxymethylthiazole.
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- Process for the preparation of disubstituted carbonates
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The present invention relates to a process for the preparation of cabonate compounds useful for the preparation of compounds which are human immunodeficiency virus (HIV) protease inhibitors. The compounds have formula I: STR1 wherein R9 is hydrogen or lower alkyl, and the thiazolyl ring can be unsubituted or substituted with a lower alkyl group.
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- Discovery of ritonavir, a potent inhibitor of HIV protease with high oral bioavailability and clinical efficacy
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The structure-activity studies leading to the potent and clinically efficacious HIV protease inhibitor ritonavir are described. Beginning with the moderately potent and orally bioavailable inhibitor A-80987, systematic investigation of peripheral (P3 and P2') heterocyclic groups designed to decrease the rate of hepatic metabolism provided analogues with improved pharmacokinetic properties after oral dosing in rats. Replacement of pyridyl groups with thiazoles provided increased chemical stability toward oxidation while maintaining sufficient aqueous solubility for oral absorption. Optimization of hydrophobic interactions with the HIV protease active site produced ritonavir, with excellent in vitro potency (EC50 = 0.02 μM) and high and sustained plasma concentrations after oral administration in four species. Details of the discovery and preclinical development of ritonavir are described.
- Kempf, Dale J.,Sham, Hing L.,Marsh, Kennan C.,Flentge, Charles A.,Betebenner, David,Green, Brian E.,McDonald, Edith,Vasavanonda, Sudthida,Saldivar, Ayda,Wideburg, Norman E.,Kati, Warren M.,Ruiz, Lisa,Zhao, Chen,Fino, Lynnmarie,Patterson, Jean,Molla, Akhteruzzaman,Plattner, Jacob J.,Norbeck, Daniel W.
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p. 602 - 617
(2007/10/03)
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- Pharmaceutical composition
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A solid pharmaceutical composition is disclosed which comprises a pharmaceutically acceptable adsorbent or a mixture of pharmaceutically acceptable adsorbents to which is adsorbed a mixture of (1) a pharmaceutically acceptable organic solvent or a mixture of pharmaceutically acceptable organic solvents, (2) an HIV protease inhibiting compound and (3) one or more pharmaceutically acceptable acids. The solid composition can optionally be encapsulated in a hard gelatin capsule.
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- Pharmaceutical composition for inhibiting HIV protease
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A pharmaceutical composition is disclosed which comprises a solution of an HIV protease inhibiting compound in a pharmaceutically acceptable organic solvent comprising a mixture of (1) (a) a solvent selected from propylene glycol and polyethylene glycol or (b) a solvent selected from polyoxyethyleneglycerol triricinoleate, polyethylene glycol 40 hydrogenated castor oil, fractionated coconut oil, polyoxyethylene (20) sorbitan monooleate and 2-(2-ethoxyethoxy)ethanol or (c) a mixture thereof and (2) ethanol or propylene glycol.
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- A novel and efficient synthesis of 5-(hydroxymethyl)thiazole: An important synthon for preparing biologically active compounds
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A novel and efficient synthesis of 5-(hydroxymethyl)thiazole, an important synthon for the preparation of biologically active compounds, is described. The research also provides additional insight into the properties of halothiazoles.
- Kerdesky,Seif
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p. 2639 - 2645
(2007/10/02)
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- Catalytic hydrogenation of halothiazoles
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The hydrogenation of halothiazoles is described. The best results were obtained utilizing 10% palladium on carbon as catalyst at four atmospheres of pressure with the bromide derivatives.
- Kerdesky,Seif
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p. 4081 - 4086
(2007/10/03)
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- Pyrethrinoid esters of thiazole alcohols
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In all possible stereoisomer forms and mixtures thereof of the formula STR1 wherein one of R1, R2 or R3 is: STR2
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- RETROVIRAL PROTEASE INHIBITING PIPERAZINE COMPOUNDS
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Retroviral protease inhibiting compounds of the formula: STR1 are disclosed.
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- RETROVIRAL PROTEASE INHIBITING COMPOUNDS
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A retroviral protease inhibiting compound of the formula: STR1 is disclosed wherein R 1, R 2, R 5, R 6, Y m and Y' n are herein defined.
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