- PARP1 INHIBITORS
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The present invention relates to azaquinolone compounds of Formula (I), and their use in medicine. Formula (I)
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Page/Page column 36-37
(2021/01/29)
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- Benzoxaborole Antimalarial Agents. Part 5. Lead Optimization of Novel Amide Pyrazinyloxy Benzoxaboroles and Identification of a Preclinical Candidate
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Carboxamide pyrazinyloxy benzoxaboroles were investigated with the goal to identify a molecule with satisfactory antimalarial activity, physicochemical properties, pharmacokinetic profile, in vivo efficacy, and safety profile. This optimization effort discovered 46, which met our target candidate profile. Compound 46 had excellent activity against cultured Plasmodium falciparum, and in vivo against P. falciparum and P. berghei in infected mice. It exhibited good PK properties in mice, rats, and dogs. It was highly active against the other 11 P. falciparum strains, which are mostly resistant to chloroquine and pyrimethamine. The rapid parasite in vitro reduction and in vivo parasite clearance profile of 46 were similar to those of artemisinin and chloroquine, two rapid-acting antimalarials. It was nongenotoxic in an Ames assay, an in vitro micronucleus assay, and an in vivo rat micronucleus assay when dosed orally up to 2000 mg/kg. The combined properties of this novel benzoxaborole support its progression to preclinical development.
- Zhang, Yong-Kang,Plattner, Jacob J.,Easom, Eric E.,Jacobs, Robert T.,Guo, Denghui,Freund, Yvonne R.,Berry, Pamela,Ciaravino, Vic,Erve, John C. L.,Rosenthal, Philip J.,Campo, Brice,Gamo, Francisco-Javier,Sanz, Laura M.,Cao, Jianxin
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p. 5889 - 5908
(2017/07/22)
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- Regiodivergent Enantioselective γ-Additions of Oxazolones to 2,3-Butadienoates Catalyzed by Phosphines: Synthesis of α,α-Disubstituted α-Amino Acids and N,O-Acetal Derivatives
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Phosphine-catalyzed regiodivergent enantioselective C-2- and C-4-selective γ-additions of oxazolones to 2,3-butadienoates have been developed. The C-4-selective γ-addition of oxazolones occurred in a highly enantioselective manner when 2-aryl-4-alkyloxazol-5-(4H)-ones were employed as pronucleophiles. With the employment of 2-alkyl-4-aryloxazol-5-(4H)-ones as the donor, C-2-selective γ-addition of oxazolones took place in a highly enantioselective manner. The C-4-selective adducts provided rapid access to optically enriched α,α-disubstituted α-amino acid derivatives, and the C-2-selective products led to facile synthesis of chiral N,O-acetals and γ-lactols. Theoretical studies via DFT calculations suggested that the origin of the observed regioselectivity was due to the distortion energy that resulted from the interaction between the nucleophilic oxazolide and the electrophilic phosphonium intermediate.
- Wang, Tianli,Yu, Zhaoyuan,Hoon, Ding Long,Phee, Claire Yan,Lan, Yu,Lu, Yixin
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supporting information
p. 265 - 271
(2016/01/25)
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- SYNTHESIS OF AN INTERMEDIATE OF AN ANTIVIRAL COMPOUND
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Process for the preparation of a cyclopropylamide compound which is useful as a structural unit in a process for the preparation of a viral protease inhibitor.
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Page/Page column 21-22
(2013/09/26)
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- Crucial role of β-elimination in determining regio- and chemoselectivity of the rhodium-catalyzed hydroformylation of N -allylpyrroles: A new approach to 5,6-dihydroindolizines
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Rhodium-catalyzed hydroformylation of the chiral (S)-3-alkyl-3-pyrrol-1- ylprop-1-enes at 100 atmospheres total pressure and 25C led to the preferential formation of the branched 3-alkyl-2-methyl-3-pyrrol-1-ylpropanals. At 30 atmospheres and 125°C, the linear 4-alkyl-4-pyrrol-1-ylbutanals were obtained: these aldehydes are not the final products, but evolve into more stable 5,6-dihydroindolizines, with the same optical purity as the starting olefins, via a domino cyclization-dehydration process. According to the generally accepted mechanism for rhodium-catalyzed hydroformylation, the regioselectivity, and then the final chemoselectivity, can be rationalized by taking into account that while at room temperature no -elimination occurs, at high temperature the -elimination involves the branched rhodium-alkyl intermediate only.
- Settambolo, Roberta
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scheme or table
p. 2915 - 2921
(2010/10/21)
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- Mechanism-based inhibitors of serine proteases with high selectivity through optimization of S′ subsite binding
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A series of mechanism-based inhibitors designed to interact with the S′ subsites of serine proteases was synthesized and their inhibitory activity toward the closely-related serine proteases human neutrophil elastase (HNE) and proteinase 3 (PR 3) was inve
- Li, Yi,Dou, Dengfeng,He, Guijia,Lushington, Gerald H.,Groutas, William C.
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experimental part
p. 3536 - 3542
(2009/10/23)
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- QUINAZOLINEDIONE CHYMASE INHIBITORS
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Disclosed are small molecule inhibitors which are useful in treating various diseases and conditions involving Chymase.
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Page/Page column 52-53
(2009/04/25)
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- PREPARATION AND USE OF BIPHENYL-4-YL-CARBONYLAMINO ACID DERIVATIVES FOR THE TREATMENT OF OBESITY
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This invention relates to certain biphenyl-4-yl carbonylamino acid compounds, compositions, and methods for treating or preventing obesity and related diseases.
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Page/Page column 36
(2010/11/08)
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- PYRAZOLO [1,5-ALPHA] PYRIMIDINYL DERIVATIVES USEFUL AS CORTICOTROPIN-RELEASING FACTOR (CRF) RECEPTOR ANTAGONISTS
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CRF receptor antagonists are disclosed which may have utility in the treatment of a variety of disorders, including the treatment of disorders manifesting hypersecretion of CRF in mammals. The CRF receptor antagonists of this invention have the following structure: (I); and pharmaceutically acceptable salts, esters, solvates, stereoisomers and prodrugs thereof, wherein R1, R2a, R2b, Y, Het, n, o, R6, Ar and R7 are as defined herein. Compositions containing a CRF receptor antagonist in combination with a pharmaceutically acceptable carrier are also disclosed, as well as methods for use of the same.
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Page/Page column 51-52
(2008/06/13)
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- Resolution of non-protein amino acids via the microbial protease-catalyzed enantioselective hydrolysis of their N-unprotected esters
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In the Aspergillus oryzae protease-catalyzed ester hydrolysis, substitution of N-unprotected amino acid esters for the corresponding N-protected amino acid esters resulted in a large enhancement of the hydrolysis rate, while the enantioselectivity was deteriorated strikingly when the substrates employed were the conventional methyl esters. This difficulty was overcome by employing esters bearing a longer alkyl chain such as the isobutyl ester. Utilizing this ester, amino acids carrying an aromatic side chain were resolved with excellent enantioselectivities (E=50 to >200). With amino acids bearing an aliphatic side chain also, good results in terms of the hydrolysis rate and enantioselectivity were obtained by employing such an ester as the isobutyl ester. Moreover, the enantioselectivity proved to be enhanced further by conducting the reaction at low temperature. This procedure was applicable to the case where the enantioselectivity was not high enough even by the use of the isobutyl ester.
- Miyazawa, Toshifumi,Imagawa, Kiwamu,Minowa, Hiroe,Miyamoto, Toyoko,Yamada, Takashi
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p. 10254 - 10261
(2007/10/03)
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- PYRAZOLE COMPOUNDS FOR TREATMENT OF NEURODEGENERATIVE DISORDERS
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The invention provides compounds of Formula (I): wherein R1,R2,R3, R4,R6,R7, R8 and A are as defined. Compounds of formula (I) have activity inhibiting production of Aβ-peptide. The invention also provides pharmaceutical compositions and methods for treating diseases, for example Alzheimer's disease, in mammals comprising compounds of Formula (I).
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- Stereodivergent addition of allylmetal reagents to imines derived from (R)2,3-Di-O-benzylglyceraldehyde by appropriate selection of metal and double stereodifferentiation
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The addition of allylmetal reagents to N-benzylimines derived from (R)-2,3-di-O-benzylglyceraldehyde has been achieved with high yields and diastereoselectivities. Homoallylamine 2a of syn configuration is obtained preferentially with allylmagnesium bromide, whereas homoallylamine 2a of anti configuration is obtained as the major reaction product with allyl-9-borabicyclo[3.3.1]nonane. Appropriate combinations of the allylmetal reagent and imines derived from (R)-2,3-di-O-benzylglyceraldehyde and (S)- or (R)-1-phenylethylamine afforded syn or anti homoallylamines with total stereocontrol through double stereodifferentiation processes. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.
- Badorrey, Ramon,Cativiela, Carlos,Diaz-de-Villegas, Maria D.,Diez, Roberto,Galvez, Jose A.
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p. 3763 - 3767
(2007/10/03)
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- New 2-(2'-phenyl-9'-benzyl-8'-azapurin-6'-ylamino)-carboxylic acid methylesters as ligands for A1 adenosine receptors.
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Synthesis of a series of new 2-phenyl-9-benzyl-8-azaadenines bearing on N6 an alkyl or aralkyl chain having a carbonyloxymethyl group on the carbon bound to N6 were reported. The ester group could assure to the molecule a better water-solubility than the 8-azaadenines 2, 6 and 9 substituted with lipophilic groups synthesised in the past. Compounds synthesised demonstrated only little capability of binding A1 adenosine receptors.
- Biagi,Giorgi,Pacchini,Livi,Scartoni
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p. 929 - 931
(2007/10/03)
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- Radical reaction initiated and stereocontrolled by zinc chloride
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The reaction of allyltributyltin with methyl 2-[N-((4S)-4-(1-methylethyl)-2-oxazolidinone-3-carbamoyl)amino]-2-bromoacetate (5 a) was accelerated at -50°C in the presence of AIBN and stopped in the presence of galvinoxyl, indicating that the reaction proceeds through a radical mechanism. The reaction was accelerated dramatically at -78°C in the presence of ZnCl2·OEt2, and the ZnCl2-mediated reaction was stopped in the presence of galvinoxyl. In the presence of 2 equiv ZnCl2·OEt2, the reaction afforded methyl (2R)-2-[N-((4SH-(1-methylethyl)-2-oxazolidinone-3-carbamoyl)amino]-4-pentenoate {6a(R)} with high diastereoselectivity (93:7). Taken together, ZnCl2·OEt2 works as a radical initiator as well as chelating agent.
- Yamamoto, Yoshinori,Onuki, Setsuko,Yumoto, Masatoshi,Asao, Naoki
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p. 765 - 780
(2007/10/03)
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- Nor-statine and nor-cyclostatine polypeptides
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Polypeptides and derivatives thereof containing nor-statine and nor-cyclostatine are useful for inhibiting the angiotensinogen-cleaving action of the enzyme renin.
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- RELATIONSHIPS BETWEEN THE STRUCTURE AND THE PHYTOTOXICITY OF THE FUNGAL TOXIN TENUAZONIC ACID
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Tenuazonic acid (3-acetyl 5-sec-butyl pyrrolidine-2,4-dione) is a metabolite produced by the fungal pathogen of rice Pyricularia oryzae.It inhibits growth of plants by interferring with protein synthesis at the ribosome level.We have synthesized analogues of tenuazonic acid with various substituents at C-3 and C-5.Substituents at C-5 other than sec-butyl or n-propyl, decrease the phytotoxicity of the analogues.But substitutions at C-3 abolish the toxicity.Thus, tenuazonic acid seems to have the optimal structure for phytotoxicity.Tenuazonic acid induces rice leaf defence reactions (browning) of reactive varieties which are resistant to P. oryzae.Some of the analogues synthesized have a low level of phytotoxicity and are able to induce this leaf browning of the reactive rice varieties.Thus different structural features are required for phytotoxicity and for leaf browning.Key Word Index - Tenuazonic acid; pyrrolidine-2,4-diones; rice; phytotoxicity; Pyricularia oryzae; structure-activity.
- Lebrun, M. H.,Nicolas, L.,Boutar, M.,Gaudemer, F.,Ranomenjanahary, S.,Gaudemer, A.
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