185836-75-3Relevant articles and documents
CYCLIC TETRAMER COMPOUNDS AS PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9 (PCSK9) INHIBITORS FOR THE TREATMENT OF METABOLIC DISORDERS
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Paragraph 0666; 0669; 0670, (2020/06/16)
The disclosure relates to inhibitors of PCSK9 useful in the treatment of cholesterol lipid metabolism, and other diseases in which PCSK9 plays a role, having the Formula (I): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, N-oxide, or tautomer thereof, wherein R1, R1, R1, R1, R1, R1, R1, R1, R1, X1, X2, and X3 are described herein.
Discovery of the First Potent, Selective, and Orally Bioavailable Signal Peptide Peptidase-Like 2a (SPPL2a) Inhibitor Displaying Pronounced Immunomodulatory Effects in Vivo
Velcicky, Juraj,Bodendorf, Ursula,Rigollier, Pascal,Epple, Robert,Beisner, Daniel R.,Guerini, Danilo,Smith, Philip,Liu, Bo,Feifel, Roland,Wipfli, Peter,Aichholz, Reiner,Couttet, Philippe,Dix, Ina,Widmer, Toni,Wen, Ben,Brandl, Trixi
, p. 865 - 880 (2018/02/17)
Signal peptide peptidase-like 2a (SPPL2a) is an aspartic intramembrane protease which has recently been shown to play an important role in the development and function of antigen presenting cells such as B lymphocytes and dendritic cells. In this paper, we describe the discovery of the first selective and orally active SPPL2a inhibitor (S)-2-cyclopropyl-N1-((S)-5,11-dioxo-10,11-dihydro-1H,3H,5H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazepine-2,1′-cyclopropan]-10-yl)-N4-(5-fluoro-2-methylpyridin-3-yl)succinamide 40 (SPL-707). This compound shows adequate selectivity against the closely related enzymes γ-secretase and SPP and a good pharmacokinetic profile in mouse and rat. Compound 40 significantly inhibited processing of the SPPL2a substrate CD74/p8 fragment in rodents at doses ≤10 mg/kg b.i.d. po. Oral dosing of 40 for 11 days at ≥10 mg/kg b.i.d. recapitulated the phenotype seen in Sppl2a knockout (ko) and ENU mutant mice (reduced number of specific B cells and myeloid dendritic cells). Thus, we believe that SPPL2a represents an interesting and druggable pharmacological target, potentially providing a novel approach for the treatment of autoimmune diseases by targeting B cells and dendritic cells.
Oxazinanones as chiral auxiliaries: Synthesis and evaluation in enolate alkylations and aldol reactions
Davies, Stephen G.,Garner, A. Christopher,Roberts, Paul M.,Smith, Andrew D.,Sweet, Miles J.,Thomson, James E.
, p. 2753 - 2768 (2008/02/10)
Homochiral β-amino esters (prepared on multigram scale by lithium amide conjugate addition) are readily transformed into oxazinanones. N-Acyl derivatives of oxazinanones undergo stereoselective enolate alkylation reactions, with higher stereoselectivities observed for the enolate alkylation of (R)-N-propanoyl-4-iso-propyl-6,6-dimethyl-oxazinan-2-one than the corresponding Evans oxazolidin-2-one. A C(4)-iso-propyl stereodirecting group within the oxazinanone conveys higher stereoselectivity than the analogous C(4)-phenyl substituent. gem-Dimethyl substitution at C(6) within the oxazinanone framework facilitates exclusive exocyclic cleavage upon hydrolysis to furnish α-substituted carboxylic acid derivatives and the parent oxazinanone in good yield. Asymmetric aldol reactions of a range of aromatic and aliphatic aldehydes with the chlorotitanium enolate of (R)-N-propanoyl-4-iso- propyl-6,6-dimethyl-oxazinan-2-one proceed with excellent diastereoselectivity. Hydrolysis of the aldol products affords homochiral α-methyl-β- hydroxy-carboxylic acids. The Royal Society of Chemistry 2006.
Process for preparation of dicarboxylic acid monoesters
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, (2008/06/13)
A process for producing a dicarboxylic acid monoester which comprises subjecting a dicarboxylic acid monoester or an alkali metal salt of a dicarboxylic acid monoester and a metal alkoxide to transesterification in the presence of an organic solvent, or a process for producing a dicarboxylic acid monoester which comprises subjecting a dicarboxylic acid monoester or an alkali metal salt of a dicarboxylic acid monoester and an alcohol to transesterification in the presence of a metal alkoxide.
Chemo-enzymatic synthesis of chiral 2-substituted succinic acid derivatives
Bailey, Murray D.,Halmos, Ted,Adamson, Dan,Bordeleau, Josee,Grand-Maitre, Chantal
, p. 3285 - 3295 (2007/10/03)
Prochiral discrimination by the biocatalyst Alcalase, an enzyme preparation of subtilisin Carlsberg, was used to effect enantio- and regioselective monohydrolysis of a variety of (RS)-2-substituted succinate diesters to afford the corresponding half esters in modest to excellent enantiomeric excesses (>99%). Exploitation of malonate chemistry, as well as recycling of the unhydrolyzed isomer from the enantioselective hydrolysis, has resulted in a process which is both practical and economical.
A general method for the synthesis of enantiomerically pure β- substituted, β-amino acids through α-substituted succinic acid derivatives
Evans, David A.,Wu, Leester D.,Wiener, John J. M.,Johnson, Jeffrey S.,Ripin, David H. B.,Tedrow, Jason S.
, p. 6411 - 6417 (2007/10/03)
A general procedure for the synthesis of enantiopure β-substituted, β- amino acids is presented. Alkylation of the sodium enolates derived from chiral N-acyloxazolidinone imides 2 (R = Me, i-Pr, t-Bu, Ph, Bn) with tert- butyl bromoacetate afforded the 2-substituted succinate derivatives 3 in good yields (82-89%) and with high selectivity (≥ 93;7). Following hydrolysis, Curtius rearrangement of the resulting carboxylic acid provided the enantiopure benzyloxycarbonyl (Cbz)-protected β-amino esters 6 in good yields (74-79%).
Heterocyclic compouds
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, (2008/06/13)
A compound of the general formula wherein: n is 0 or 1; M1 is an amino group; Q is an aromatic heterocyclic group containing a basic nitrogen atom; M2 is an imino group; L is a template group; and A is an acidic group, or an ester or amide derivative thereof, or a sulphonamide group; and pharmaceutically acceptable salts and pro-drugs thereof, for use in the treatment of a disease in which platelet aggregation mediated by the binding of adhesion molecules to GPIIb-IIIa is involved. Novel compounds are also disclosed.
Dynamic Kinetic Resolution Utilizing 2-Oxoimidazolidine-4-carboxylate as a Chiral Auxiliary: Stereoselective Alkylation of α-Bromo Amides with Malonic Ester Enolates
Kubo, Akira,Kubota, Hitoshi,Takahashi, Masami,Nunami, Ken-Ichi
, p. 5830 - 5837 (2007/10/03)
Stereoselective carbon-carbon bond formation by dynamic kinetic resolution using tert-butyl (4S)-1-methyl-2-oxoimidazolidine-4-carboxylate (1) as a chiral auxiliary was developed. Reaction of a diastereomeric mixture of tert-butyl (4S)-3-[(2RS)-2-bromoacyl]-1-methyl-2-oxoimidazolidine-4-carboxylates (2) with a malonic ester enolate in HMPA predominantly afforded tert-butyl (4S)-3-[(2R)-2-alkyl-3,3-bis(alkoxycarbonyl)propionyl]-1-methyl-2- oxoimidazolidine-4-carboxylate [(S,R)-8] in good yields. The stereoselectivity of this reaction was in accordance with our working hypothesis based on the conformational analysis of 2 and elucidated the unique characteristics of 1 as a novel chiral auxiliary for dynamic kinetic resolution. The alkylated products (S,R)-8e,j,k were easily converted to chiral α-alkyl succinic acid derivatives and chiral β-amino acid derivatives, both of which have been known as key building blocks for the syntheses of a variety of biologically active compounds.
