- Preparation method of (R)-3-hydroxybutyryl-(R)-3-hydroxybutyrate
-
The invention discloses a preparation method of (R)-3-hydroxybutyryl-(R)-3-hydroxybutyrate. The preparation method comprises the following steps: (1) subjecting a compound (III) to reacting with paratoluensulfonyl chloride in a first solvent in the presence of alkali to obtain a compound (II); and (2) subjecting the compound (II) to reacting with (R)-3-hydroxybutyrate in a second solvent, or subjecting the compound (II) to reacting with (R)-3-hydroxybutyric acid in the presence of alkali. According to the invention, a route is simple, protection/deprotection reaction is avoided, the product can be obtained through two-step reaction from easily available raw materials, total yield is larger than or equal to 70%, and the purity of the product is larger than or equal to 95% without refining; and the method has the advantages of mild process conditions, no need for special equipment, low cost and suitability for industrial amplification, and related reagents and solvents are cheap and easy to obtain.
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Paragraph 0036-0043; 0049-0051; 0053; 0054
(2021/07/01)
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- Achieving in Vivo Target Depletion through the Discovery and Optimization of Benzimidazolone BCL6 Degraders
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Deregulation of the transcriptional repressor BCL6 enables tumorigenesis of germinal center B-cells, and hence BCL6 has been proposed as a therapeutic target for the treatment of diffuse large B-cell lymphoma (DLBCL). Herein we report the discovery of a series of benzimidazolone inhibitors of the protein-protein interaction between BCL6 and its co-repressors. A subset of these inhibitors were found to cause rapid degradation of BCL6, and optimization of pharmacokinetic properties led to the discovery of 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (CCT369260), which reduces BCL6 levels in a lymphoma xenograft mouse model following oral dosing.
- Bellenie, Benjamin R.,Cheung, Kwai-Ming J.,Varela, Ana,Pierrat, Olivier A.,Collie, Gavin W.,Box, Gary M.,Bright, Michael D.,Gowan, Sharon,Hayes, Angela,Rodrigues, Matthew J.,Shetty, Kartika N.,Carter, Michael,Davis, Owen A.,Henley, Alan T.,Innocenti, Paolo,Johnson, Louise D.,Liu, Manjuan,De Klerk, Selby,Le Bihan, Yann-Va?,Lloyd, Matthew G.,McAndrew, P. Craig,Shehu, Erald,Talbot, Rachel,Woodward, Hannah L.,Burke, Rosemary,Kirkin, Vladimir,Van Montfort, Rob L. M.,Raynaud, Florence I.,Rossanese, Olivia W.,Hoelder, Swen
-
p. 4047 - 4068
(2020/04/20)
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- SUBSTITUTED BENZIMIDAZOLONES AS ANTI-CANCER AGENTS
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The present invention relates to compounds of Formula I that function as inhibitors of BCL6 (B-cell lymphoma 6) activity: Formula (I) wherein X, R1, R2, and R3 are each as defined herein. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions in which BCL6activity is implicated.
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Paragraph 00258
(2020/06/10)
-
- Heterocyclic compound as TRK inhibitor
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The present invention relates to a compounds, a pharmaceutical compositions containing the compound, preparation methods of the compound and the pharmaceutical composition, and uses of the compound and the pharmaceutical composition as TRK inhibitors, wherein the compound is a compound represented by a formula I, or a pharmaceutically acceptable salt, a prodrug, a solvent compound, a polymorph, anisomer and a stable isotope derivative thereof. The invention further relates to uses of the compound in treatment or prevention of TRK-mediated related diseases such as tumors, and a method for treating the diseases by using the compound.
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Paragraph 0074; 0078; 0086
(2020/01/12)
-
- 2 Tyrosine kinase mediated signal transduction inhibitors
-
Disclosed herein are compounds of Formula (), and pharmaceutically acceptable salts thereof, wherein R, R, R, R, R, X, X, X, X, X, and n are as defined herein, pharmaceutical compositions comprising same, and methods of preparation and use.
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-
Paragraph 0487; 0488; 0489
(2019/09/17)
-
- NOVEL SUBSTITUTED XANTHINE DERIVATIVES
-
The present invention relates to substituted xanthine derivatives, pharmaceutical compositions containing them and their use in therapy, particularly in the treatment of conditions having an association with TRPC5 containing ion channels.
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-
Page/Page column 57
(2019/01/30)
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- BENZIMIDAZOLONE DERIVED INHIBITORS OF BCL6
-
The present invention relates to compounds of Formula I that function as inhibitors of BCL6 (B-cell lymphoma 6) activity: wherein X1, X2, R1, R2 and R3 are each as defined herein. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions in which BCL6 activity is implicated.
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Paragraph 00366
(2018/12/13)
-
- Regio- and Enantioselective Sequential Dehalogenation of rac-1,3-Dibromobutane by Haloalkane Dehalogenase LinB
-
The hydrolytic dehalogenation of rac-1,3-dibromobutane catalyzed by the haloalkane dehalogenase LinB from Sphingobium japonicum UT26 proceeds in a sequential fashion: initial formation of intermediate haloalcohols followed by a second hydrolytic step to produce the final diol. Detailed investigation of the course of the reaction revealed favored nucleophilic displacement of the sec-halogen in the first hydrolytic event with pronounced R enantioselectivity. The second hydrolysis step proceeded with a regioselectivity switch at the primary position, with preference for the S enantiomer. Because of complex competition between all eight possible reactions, intermediate haloalcohols formed with moderate to good ee ((S)-4-bromobutan-2-ol: up to 87 %). Similarly, (S)-butane-1,3-diol was formed at a maximum ee of 35 % before full hydrolysis furnished the racemic diol product.
- Gross, Johannes,Faber, Kurt,Hall, Mélanie,Prokop, Zbyněk,Janssen, Dick
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p. 1437 - 1441
(2016/12/24)
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- Isolation, Structure Elucidation, and (Bio)Synthesis of Haprolid, a Cell-Type-Specific Myxobacterial Cytotoxin
-
Myxobacteria are well-established sources for novel natural products exhibiting intriguing bioactivities. We here report on haprolid (1) isolated from Byssovorax cruenta Har1. The compound exhibits an unprecedented macrolactone comprising four modified amino acids and a polyketide fragment. As configurational assignment proved difficult, a bioinformatic analysis of the biosynthetic gene cluster was chosen to predict the configuration of each stereocenter. In-depth analysis of the corresponding biosynthetic proteins established a hybrid polyketide synthase/nonribosomal peptide synthetase origin of haprolid and allowed for stereochemical assignments. A subsequent total synthesis yielded haprolid and corroborated all predictions made. Intriguingly, haprolid showed cytotoxicity against several cell lines in the nanomolar range whereas other cells were almost unaffected by treatment with the compound.
- Steinmetz, Heinrich,Li, Jun,Fu, Chengzhang,Zaburannyi, Nestor,Kunze, Birgitte,Harmrolfs, Kirsten,Schmitt, Viktoria,Herrmann, Jennifer,Reichenbach, Hans,H?fle, Gerhard,Kalesse, Markus,Müller, Rolf
-
supporting information
p. 10113 - 10117
(2016/08/16)
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- METHOD FOR PRODUCING 3-BUTENE-2-OL
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PROBLEM TO BE SOLVED: To provide a method for efficiently producing racemic 3-butene-2-ol having an (S)- or (R)-configuration. SOLUTION: There is provided a method for producing racemic 3-butene-2-ol, wherein an ammonium salt compound represented by the following general formula (1) (wherein, R1, R2 or R3 represents an alkyl group, an aryl group or an aralkyl group; X- represents OH-, HCO3-, CO32-, R4O-, R5CO2-, R6SO3- (R4, R5 or R6 represents an alkyl group, an aryl group or an aralkyl group) and a halide ion; n represents 0.5 when X- is CO32- and n represents 1 when X- is other than CO32-; the carbon atom marked with * is an asymmetric carbon atom) is subjected to Hofmann elimination. COPYRIGHT: (C)2016,JPOandINPIT
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Paragraph 0073; 0074
(2016/11/07)
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- 2alpha-Methyl and 2beta-Methyl Analogs of 19,26-Dinor-1alpha,25-Dihydroxyvitamin D3 and Their Uses
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This invention discloses 2α-methyl and 2β-methyl analogs of 19,26-dinor-1α,25-dihydroxyvitamin D3 and pharmaceutical uses therefor. These compounds exhibit in vitro biological activities evidencing use as an anti-cancer agent and for the treatm
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Page/Page column 6; 13
(2012/11/13)
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- Synthesis and evaluation of a broad range of new chiral phosphine-carbene ligands for asymmetric hydrogenation
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A straightforward and gram scale synthesis (six-step synthesis from enantioenriched β-hydroxy esters) of new structurally simple phosphine-carbene ligands bearing a single stereogenic centre has been achieved. Enantioselectivities of up to 60-63% could be achieved in the hydrogenation of methylstilbene and dehydroaminoacids when the reactions were performed under 20-50 bar hydrogen pressure.
- Passays, Johan,Ayad, Tahar,Ratovelomanana-Vidal, Virginie,Gaumont, Annie-Claude,Jubault, Philippe,Leclerc, Eric
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experimental part
p. 562 - 574
(2011/06/19)
-
- 2-Methylene-19,26-Dinor-(20R,22E,25R)-Vitamin D Analogs
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This invention discloses 2-methylene-19,26-dinor-(20R,22E,25R)-vitamin D analogs, and specifically 2-methylene-19,26-dinor-(20R,22E,25R)-1α,25-dihydroxyvitamin D3, and pharmaceutical uses therefor. This compound exhibits transcription activity
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Page/Page column 4; 7
(2010/02/17)
-
- 2-Methylene-19,26-Dinor-(20S,22E,25R)-Vitamin D Analogs
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This invention discloses 2-methylene-19,26-dinor-(20S,22E,25R)-vitamin D analogs, and specifically 2-methylene-19,26-dinor-(20S,22E,25R)-1α,25-dihydroxyvitamin D3, and pharmaceutical uses therefor. This compound exhibits transcription activity
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Page/Page column 4; 7
(2010/02/17)
-
- Removal of the 26-methyl group from 19-nor-1α,25-dihydroxyvitamin D3 markedly reduces in vivo calcemic activity without altering in vitro VDR binding, HL-60 cell differentiation, and transcription
-
Twelve new analogues of 19-nor-1α,25-dihydroxyvitamin D3 (5-16) were prepared by convergent syntheses, employing the Wittig Horner reaction. The necessary Grundmann type ketones (45-48), possessing fixed configurations of the hydroxyl group at
- Grzywacz, Pawel,Chiellini, Grazia,Plum, Lori A.,Clagett-Dame, Margaret,Deluca, Hector F.
-
experimental part
p. 8642 - 8649
(2011/03/20)
-
- 2-Methylene-(20S,25R)-19,26-Dinor-Vitamin D Analogs
-
This invention discloses 2-methylene-(20S,25R)-19,26-dinor-vitamin D analogs, and specifically 2-methylene-(20S,25R)-19,26-dinor-1α,25-dihydroxyvitamin D3, and pharmaceutical uses therefor. This compound exhibits pronounced activity in arrestin
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Page/Page column 4; 7
(2009/07/17)
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- A large-scale synthesis of enantiomerically pure γ-hydroxy-organochalcogenides
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Enantiomerically pure (R)- and (S)-γ-hydroxy-organochalcogenides are prepared using poly-[R]-3-hydroxybutanoate (PHB) as the starting material.
- Princival, Jefferson L.,de Oliveira, Morilo S.C.,Dos Santos, Alcindo A.,Comasseto, Joao V.
-
experimental part
p. 2699 - 2703
(2010/04/29)
-
- The discovery of tertiary-amine LXR agonists with potent cholesterol efflux activity in macrophages
-
The liver X receptors (LXR) play a key role in cholesterol homeostasis and lipid metabolism. SAR studies around tertiary-amine lead molecule 2, an LXR full agonist, revealed that steric and conformational changes to the acetic acid and propanolamine groups produce dramatic effects on agonist efficacy and potency. The new analogs possess good functional activity, demonstrating the ability to upregulate LXR target genes, as well as promote cholesterol efflux in macrophages.
- Marino Jr., Joseph P.,Kallander, Lara S.,Ma, Chun,Oh, Hye-Ja,Lee, Dennis,Gaitanopoulos, Dimitri E.,Krawiec, John A.,Parks, Derek J.,Webb, Christine L.,Ziegler, Kelly,Jaye, Michael,Thompson, Scott K.
-
scheme or table
p. 5617 - 5621
(2010/04/30)
-
- VITAMIN D ANALOG - RAK, METHODS AND USES THEREOF
-
Compounds of formula IA or IB are provided where X1, X2 and X3 are independently selected from H or hydroxy protecting groups and R1 is selected from straight or branched chain alkyl groups having from 1 to 8 ca
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-
Page/Page column 11
(2008/06/13)
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- Diastereoselective route to (2R,5S)- and (2S,5S)-2-methyl-1,6-dioxaspiro[4.5]decane, a pheromone component of the wasp Paravespula vulgaris
-
A diastereoselective approach to (2R,5S)- and (2S,5S)-2-methyl-1,6-dioxaspiro[4.5]decane 1 and 1a is described. The route starts with an alkylation reaction among the cyclopentanone N,N-dimethylhydrazone 6 and the chiral iodides (R)-3 or (S)-3, derived from the enantiomers of ethyl β-hydroxybutyrate, controlling the estereocenter at C-2 of the molecules. The alkylated products 7 and 7a were easily transformed into the 1,8-O-TBS-1,8-dihydroxy-5-nonanones 9 and 9a in four steps, and a subsequent stereoselective spiroketalization, in acidic media, afforded a Z:E mixture (1:2) of compounds 1 and 1a.
- Zarbin, Paulo H. G.,De Oliveira, Alfredo R. M.,Delay, Carlos E.
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p. 6849 - 6851
(2007/10/03)
-
- Benzimidazole derivatives
-
A novel benzimidazole derivative or a salt thereof is provided, which is represented by the formula: wherein R1represents an alkyl group, etc., R2represents a substituted or unsubstituted aromatic lower alkyl group, R3represents an alkyl group, etc., and -X- is represented by the following formula (V): etc. This derivative or a salt thereof is useful as medicine.
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-
-
- First enantioselective synthesis of (-)-seiridin the major phytotoxic metabolite of Seiridium species pathogenic for cypress
-
The first enantioselective synthesis of seiridin, a phytotoxic dialkylsubstituted butenolide produced by three Seiridium species, fungi pathogenic for cypress, is described. The short sequence, which leads to optically pure compound 1, would be useful to
- Bonini, Carlo,Chiummiento, Lucia,Evidente, Antonio,Funicello, Maria
-
p. 7285 - 7286
(2007/10/02)
-
- A simple enantioselective synthesis of γ-valerolactone
-
The readily available biopolymer, poly-(R)-3-hydroxybutyrate was converted to (R)-(+)-γ-valerolactone in 32% overall yield in a simple 4 stage procedure.
- O'Neill,Lindell,Simpson,Willis
-
p. 117 - 118
(2007/10/02)
-
- Lewis Base-catalysed Asymmetric Diels-Alder Reaction
-
The 1,3-dienyldioxaazaboracene 8, derived from 1,3-dienylboronate 6 and the chiral aminodiol 4, undergoes asymmetric Diels-Alder resction with N-phenylmaleimide much faster and with higher stereoselectivity than does 1,3-dienylboronate 7.
- Wang, Xuebao
-
p. 1515 - 1517
(2007/10/02)
-
- C-Metallierte Chirale Alkoxide als d2- and d3- Reagenzien fuer die Synthese enantiomerenreiner Producte (EPC-Synthese)
-
The chloroalcohols (S)-1-chloro-2-propanol (1), (S)-1-chloro-2-methyl-2-pentanol (4), (R)-3-chloro-2-methyl-1-propanol (7), (R)-4-chloro-2-butanol-(10), and (2R,3R)-4-chloro-3-methyl-2-butanol (14), readily available from the esters of lactic, 3-hydroxy-2-methylpropionic, and 3-hydroxybutanoic acid are subjected to sequential metallation first with BuLi (or MeMgCl) and then with lithium naphthalenide (or Li metal powder) to give solutions of the highly reactive C-metallated alkoxides 15,22, 26, 27, and 28 respectively.- These chiral d2- and d3-reagents may be added to aldehydes ( non-diastereoselectively), ketones and CO2 to give 1,3- or 1,4-dioles (18-21, 14, 29-33) or γ-lactones (35,36).Thiolations with dibenzyl disulfide (->16, 34) and a deuteration ( ->17, (S)-(1-2H)propan-2-ol) were also carried out.Independent synthesis of (S)-1-benzylthio-2-propanol (16) and comparison of the specific rotations establish that no loss of enantiomeric purity occurs on the metallation route.The results described represent an extension of the applicability of simple chiral building blocks to EPC-synthesis.
- Najera, Carmen,Yus, Miguel,Seebach, Dieter
-
p. 289 - 300
(2007/10/02)
-
- Access to (S)-2-Methyloxetane and the Precursor (S)-1,3-Butanediol of Hight Enantiomeric Purity
-
(S)-2-Methyloxetane (1) and its precursor (S)-1,3-butanediol (2) were prepared in low to moderate chemical yield with less than 0.5percent racemization from (S)-ethyl lactate (4) and from (2S,3S)-allothreonine (14b).For the first time the enantiomeric purities of both the starting material and the product (1) were carefully determined by high-precision capillary gas chromatography on optically active resolving stationary phases.The validity of the quadrant rule, correlating the relative configuration of alkyloxiranes with the order of elution from manganese(II) bis (3) by complexation gas chromatography, is also confirmed for 2-methyloxetane (1).
- Hintzer, Klaus,Koppenhoefer, Bernhard,Schurig, Volker
-
p. 3850 - 3854
(2007/10/02)
-
- STEREOSPECIFIC TOTAL SYNTHESIS AND ABSOLUTE CONFIGURATION OF A MACROCYCLIC LACTONE ANTIBIOTIC, A26771B
-
The total synthesis of a sixteen-membered macrocyclic lactone antibiotic, A26771B and its absolute configuration are described by using D-glucose as a chiral source.
- Tatsuta, Kuniaki,Nakagawa, Akira,Maniwa, Shunji,Kinoshita, Mitsuhiro
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p. 1479 - 1482
(2007/10/02)
-