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Design and synthesis of HDAC inhibitors to enhance the therapeutic effect of diffuse large B-cell lymphoma by improving metabolic stability and pharmacokinetic characteristics
Histone deacetylases (HDAC) are clinically validated and attractive epigenetic drug targets for human cancers. Several HDAC inhibitors have been approved for cancer treatment to date, however, clinical applications have been limited due to the poor pharmacokinetics, bioavailability, selectivity of the HDAC inhibitors and most of them need to be combined with other drugs to achieve better results. Here, we describe our efforts toward the discovery of a novel series of lactam-based derivatives as selective HDAC inhibitors. Intensive structural modifications lead to the identification of compound 24g as the most active Class I HDAC Inhibitor, along with satisfactory metabolic stability in vitro (t1/2, human = 797 min) and the desirable oral bioavailability (F = 92%). More importantly, compound 24g showed good antitumor efficacy in a TMD-8 xenograft model (TGI = 77%) without obvious toxicity. These results indicated that Class I HDAC Inhibitor could be potentially used to treat certain diffuse large B-cell lymphoma therapeutics.
Cui, Hao,Hong, Qianqian,Wei, Ran,Li, Hongmei,Wan, Chunyang,Chen, Xin,Zhao, Shuang,Bu, Haizhi,Zhang, Bingxu,Yang, Dexiao,Lu, Tao,Chen, Yadong,Zhu, Yong
(2021/12/27)

TMSOTf-mediated approach to 1,3-oxazin-2-one skeleton through one-pot successive reduction-[4 + 2] cyclization process of imides with ynamides
A one-pot approach to access functionalized 1,3-oxazin-2-one skeleton has been developed through successive reduction and subsequent [4 + 2] cyclization process of N-Boc lactams with ynamides by TMSOTf. As a result, a number of five to seven membered ring fused bicyclic [1,2-c][1,3]oxazin-1-ones 12a-m and tricyclic derivatives 13a-f were obtained in moderate to excellent yields with excellent regioselectivities. Moreover, linear N-Boc amides 9a-e were also amenable to this transformation, and the desired 3,4-dihydro-1,3-oxazin-2-ones 14a-m were readily achieved in moderate yields with excellent regioselectivities.
Zhang, Chen-Chen,Huo, Zhi-Peng,Tang, Mei-Lin,Liang, Yong-Xi,Sun, Xun
supporting information

(2021/03/15)

N-(AZAARYL)CYCLOLACTAM-1-CARBOXAMIDE DERIVATIVE, PREPARATION METHOD THEREFOR, AND USE THEREOF
An N-(azaaryl)cyclolactam-1-carboxamide derivative having a structure of formula (I), a preparation method therefor, and a use thereof are disclosed in the application. Each substituent are defined in the specification and claims. The series of compounds of the application can be widely applied in the preparation of drugs for treating cancer, tumor, autoimmune disease, metabolic disease or metastatic disease, particularly for treating ovarian cancer, pancreatic cancer, prostate cancer, breast cancer, cervical cancer, glioblastoma, multiple myeloma, metabolic disease, neurodegenerative disease, primary tumor site metastasis or osseous metastasis cancer, and are expected to be developed into a new generation of CSF-1R inhibitor drugs.
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Paragraph 0143; 0253; 0254

(2020/03/23)

Br?nsted Acid-Catalyzed Aza-Ferrier Reaction of N, O-Allenyl Acetals: Synthesis of β-Amino-α-methylene Aldehydes
A Tf2NH-catalyzed aza-Ferrier reaction of N,O-allenyl acetals was reported. This protocol provided various types of β-amino-α-methylene aldehydes as the products. The N,O-allenyl acetal substrates were easily prepared by base-induced isomerization of N,O-propargyl acetals with Triton B. The N,O-propargyl acetals were prepared from the corresponding aldehydes or lactams. Further synthetic applications of the products were also described.
Tayama, Eiji,Ishikawa, Yuki
supporting information
p. 9405 - 9414
(2020/08/14)

A Unified Strategy for the Synthesis of Difluoromethyl- And Vinylfluoride-Containing Scaffolds
Here, we report a general method for the synthesis of quaternary and tertiary difluoromethylated compounds and their vinylfluoride analogues. The strategy, which relies on a two-step sequence featuring a C-selective electrophilic difluoromethylation and either a palladium-catalyzed decarboxylative protonation or a Krapcho decarboxylation, is practical, scalable, and high yielding. Considering the generality of the method and the attractive properties offered by the difluoromethyl group, this approach provides a valuable tool for late-stage functionalization and drug development.
Duchemin, Nicolas,Buccafusca, Roberto,Daumas, Marc,Ferey, Vincent,Arseniyadis, Stellios
supporting information
p. 8205 - 8210
(2019/10/16)

A Straightforward Synthesis of Six-Membered-Ring Heterocyclic α-Aminophosphonic Acids from N-Acyliminium Ions
A convenient synthesis of phosphonic analogues of pipecolic acid and its heterocyclic analogues is reported. The major step of the elaborated procedure is the introduction of the phosphonate group into the skeleton of the appropriate cyclic amide through N-acyliminium ions. The former ones were obtained by preparation of the hemiaminals or their methyl ethers from the N-protected cyclic amides. Finally, the reaction with trimethyl phosphite in the presence of BF3·OEt2 afforded the desired phosphonates, which were converted into phosphonic acids by the hydrolysis of phosphonate moiety with simultaneous cleavage of the nitrogen protecting groups.
Argüello-Velasco, Rubén Oswaldo,Sánchez-Mu?oz, Grecia Katherine,Viveros-Ceballos, José Luis,Ordó?ez, Mario,Kafarski, Pawel
(2019/06/24)

Carbazole-containing amides and ureas: Discovery of cryptochrome modulators as antihyperglycemic agents
A series of novel carbazole-containing amides and ureas were synthesized. A structure–activity relationship study of these compounds led to the identification of potent cryptochrome modulators. Based on the desired pharmacokinetic/pharmacodynamic parameters and the results of efficacy studies in db/db mice, compound 50 was selected for further profiling.
Humphries, Paul S.,Bersot, Ross,Kincaid, John,Mabery, Eric,McCluskie, Kerryn,Park, Timothy,Renner, Travis,Riegler, Erin,Steinfeld, Tod,Turtle, Eric D.,Wei, Zhi-Liang,Willis, Erik
supporting information
p. 293 - 297
(2018/01/04)

Synthetic Path To Pharmaceutically Acceptable Vismodegib
The present invention relates to a new route of synthesis to obtain pharmaceutically acceptable Vismodegib. In addition, besides the synthesis also suitable pharmaceutical compositions and the use of the compound for the treatment of basal-cell carcinomas
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Paragraph 0031; 0033; 0034

(2018/10/19)

Senolytic activity of piperlongumine analogues: Synthesis and biological evaluation
Selective clearance of senescent cells (SCs) has emerged as a potential therapeutic approach for age-related diseases, as well as chemotherapy- and radiotherapy-induced adverse effects. Through a cell-based phenotypic screening approach, we recently identified piperlongumine (PL), a dietary natural product, as a novel senolytic agent, referring to small molecules that can selectively kill SCs over normal or non-senescent cells. In an effort to establish the structure-senolytic activity relationships of PL analogues, we performed a series of structural modifications on the trimethoxyphenyl and the α,β-unsaturated δ-valerolactam rings of PL. We show that modifications on the trimethoxyphenyl ring are well tolerated, while the Michael acceptor on the lactam ring is critical for the senolytic activity. Replacing the endocyclic C2–C3 olefin with an exocyclic methylene at C2 render PL analogues 47–49 with increased senolytic activity. These α-methylene containing analogues are also more potent than PL in inducing ROS production in WI-38 SCs. Similar to PL, 47–49 reduce the protein levels of oxidation resistance 1 (OXR1), an important oxidative stress response protein that regulates the expression of a variety of antioxidant enzymes, in cells. This study represents a useful starting point toward the discovery of senolytic agents for therapeutic uses.
Liu, Xingui,Wang, Yingying,Zhang, Xuan,Gao, Zhengya,Zhang, Suping,Shi, Peizhong,Zhang, Xin,Song, Lin,Hendrickson, Howard,Zhou, Daohong,Zheng, Guangrong
p. 3925 - 3938
(2018/06/19)

Ruthenium-Pincer-Catalyzed Hydrogenation of Lactams to Amino Alcohols
By using the commercially available ruthenium pincer complex (Ru-MACHO-BH) as a catalyst, the challenging direct hydrogenation of lactams and analogues has been successfully accomplished to deliver corresponding value-added amino alcohols in good-to-excellent yields under mild reaction conditions. Remarkably, in addition to N-protected lactams, unprotected ones could also be readily reduced in the presence of a catalytic amount of weak base or even under neutral reaction conditions, which further highlights the broad substrate scope and the protocol efficiency.
Chen, Jiangbo,Wang, Jiaquan,Tu, Tao
p. 2559 - 2565
(2018/07/30)

Substituted heteroaryl compounds and compositions and uses thereof
The invention provides a substituted heteroaryl compound and a composition thereof, and applications of the compound and the composition. The compound is a compound as shown in a formula I, or stereoisomer, tautomer, oxynitride, solvate, metabolite, pharmaceutically-acceptable salt or prodrug of the compound as shown in the formula I. The invention also provides a pharmaceutical composition containing the above-mentioned compound; and the above-mentioned compound and the pharmaceutical composition are capable of adjusting the activity of JAK kinases and are applied in prevention, treatment, therapy and alleviation of JAK kinase mediated diseases or disorders.
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Paragraph 0583; 0584; 0585; 0586

(2017/12/27)

Substituted heteroaryl compounds and compositions and uses thereof
The invention provides a substituted ceteroary compound as well as a composition and a purpose thereof. The substituted ceteroary compound is a compound shown as a formula (I) or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of the pharmaceutically acceptable salt of the compound shown as the formula (I) and is used for regulating diseases or disorders mediated by one kind or various kinds of Janus kinase activities. The invention also provides a medicine composition containing the compound and a method of treating or alleviating the disease or disorder degree of a patient by inhibiting the Janus kinase activity.
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Paragraph 0740; 0741; 0742; 0743

(2018/01/04)

Synthesis of functionalised azepanes and piperidines from bicyclic halogenated aminocyclopropane derivatives
A series of 6,6-dihalo-2-azabicyclo[3.1.0]hexane and 7,7-dihalo-2-azabicyclo[4.1.0]heptane compounds were prepared by the reaction of dihalocarbene species with N-Boc-2,3-dihydro-1H-pyrroles or -1,2,3,4-tetrahydropyridines. Monochloro substrates were synthesised as well, using a chlorine-to-lithium exchange reaction. The behaviour of several aldehydes and ketones under reductive amination conditions with deprotected halogenated secondary cyclopropylamines was investigated, showing that this transformation typically triggers cyclopropane ring cleavage to give access to interesting nitrogen-containing ring-expanded products.
Chen, Cheng,Kattanguru, Pullaiah,Tomashenko, Olesya A.,Karpowicz, Rafa?,Siemiaszko, Gabriela,Bhattacharya, Ahanjit,Calasans, Vinícius,Six, Yvan
supporting information
p. 5364 - 5372
(2017/07/10)

Potent, selective and orally bioavailable leucine-rich repeat kinase 2 (LRRK2) inhibitors
Familial Parkinson's disease cases have recently been associated with the leucine rich repeat kinase 2 (LRRK2) gene. It has been hypothesized that inhibition of the LRRK2 protein may have the potential to alter disease pathogenesis. A dihydrobenzothiophene series of potent, selective, orally bioavailable LRRK2 inhibitors were identified from a high-throughput screen of the internal Merck sample collection. Initial SAR studies around the core established the series as a tractable small molecule lead series of LRRK2 inhibitors for potential treatment of Parkinson's disease. It was also found that incorporation of a lactam into the core drastically improved the CNS and DMPK properties of these small molecules.
Greshock, Thomas J.,Sanders, John M.,Drolet, Robert E.,Rajapakse, Hemaka A.,Chang, Ronald K.,Kim, Boyoung,Rada, Vanessa L.,Tiscia, Heather E.,Su, Hua,Lai, Ming-Tain,Sur, Sylvie M.,Sanchez, Rosa I.,Bilodeau, Mark T.,Renger, John J.,Kern, Jonathan T.,McCauley, John A.
p. 2631 - 2635
(2016/05/09)

Horner-Wadsworth-Emmons approach to piperlongumine analogues with potent anti-cancer activity
Natural products with anti-cancer activity play a vital role in lead and target discovery. We report here the synthesis and biological evaluation of the plant-derived alkaloid, piperlongumine and analogues. Using a Horner-Wadsworth-Emmons coupling approach, a selection of piperlongumine-like compounds were prepared in good overall yield from a novel phosphonoacetamide reagent. A number of the compounds displayed potent anti-cancer activity against colorectal (HCT 116) and ovarian (IGROV-1) carcinoma cell lines, via a mechanism of action which may involve ROS generation. Contrary to previous reports, no selective action in cancer cell (MRC-5) was observed for piperlongumine analogues.
Han, Li-Chen,Stanley, Paul A.,Wood, Paul J.,Sharma, Pallavi,Kuruppu, Anchala I.,Bradshaw, Tracey D.,Moses, John E.
p. 7585 - 7593
(2016/08/16)

SUBSTITUTED HETEROARYL COMPOUNDS AND METHODS OF USE
The present invention provides novel heteroaryl compounds, pharmaceutical acceptable salts and formulations thereof useful in preventing, treating or lessening the severity of a JAK-mediated disease. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of JAK-mediated disease.
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Paragraph 0359

(2016/12/22)

Synthesis of Supramolecular Iridium Catalysts and Their Use in Enantioselective Visible-Light-Induced Reactions
Iridium complexes were prepared which are covalently linked via a bipyridine ligand to a chiral octahydro-1H-4,7-methanoisoindol-1-one skeleton. The skeleton allows for two-point hydrogen bonding to prochiral lactams, which can be processed in iridium-catalyzed photochemical reactions. Attempts to use the iridium complexes in reactions, which typically involve photoinduced electron transfer, failed to provide the desired enantioselectivity. If employed as triplet sensitizers the complexes showed an improved performance and moderate enantioselectivities (up to 29% ee) were achieved in a photochemical epoxide rearrangement.
B?hm, Alexander,Bach, Thorsten
supporting information
p. 1056 - 1060
(2016/05/19)

AZOCANE AND AZONANE DERIVATIVES AND METHODS OF TREATING HEPATITIS B INFECTIONS
Provided herein are compounds useful for the treatment of HBV infection in a subject in need thereof, pharmaceutical compositions thereof, and methods of inhibiting, suppressing, or preventing HBV infection in the subject.
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Paragraph 0298; 0299; 0300

(2016/10/11)

Lactam histone deacetylase inhibitors
The invention relates to the field of medicinal chemistry, and specifically relates to lactam histone deacetylase inhibitors, preparation methods thereof, medicine compositions containing the histone deacetylase inhibitors, and applications of the inhibit
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Paragraph 0090; 0091

(2016/10/09)

SUBSTITUTED HETEROARYL COMPOUNDS AND METHODS OF USE
The present invention provides new heteroaryl compounds, pharmaceutical acceptable salts and formulations thereof useful in preventing, treating or lessening the severity of JAK-mediated diseases. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of JAK-mediated diseases.
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Paragraph 395

(2015/07/07)

CARBAZOLE-CONTAINING AMIDES, CARBAMATES, AND UREAS AS CRYPTOCHROME MODULATORS
The subject matter herein is directed to carbazole-containing amide, carbamate, and urea derivatives and pharmaceutically acceptable salts or hydrates thereof of structural formula I wherein the variable R1, R2, R3, R4, R5, R6, R7, A, D, E, G, J, L, M, Q, a, and b are accordingly described. Also provided are pharmaceutical compositions containing the compounds of formula I to treat a Cry-mediated disease or disorder, such as diabetes, complications associated with diabetes, Cushing's syndrome, NASH, NAFLD, asthma, and COPD.
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Paragraph 0281

(2015/10/28)

SUBSTITUTED IMIDAZO[1,2-a]PYRIDINE COMPOUNDS AS TROPOMYOSIN RECEPTOR KINASE A (TrkA) INHIBITORS
The present application relates to a series of substituted imidazo[1,2-a]pyridine compounds of formula (I), pharmaceutically acceptable salts, pharmaceutically acceptable solvates or stereoisomers thereof, their use as tropomyosin receptor kinase (Trk) family protein kinase inhibitors, method of making and pharmaceutical compositions comprising such compounds.
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Paragraph 0591; 0592

(2016/01/15)

Design, synthesis, antiviral activity, and structure-activity relationships (SARs) of two types of structurally novel phenanthroindo/quinolizidine analogues
To investigate the influence of the variation of the original skeletons of natural phenanthroindo/quinolizidine alkaloids on antiviral activities, two types of structurally totally novel analogues 7a, 7b, 16a, and 16b were designed, synthesized, and evaluated against tobacco mosaic virus (TMV) for the first time. Bioassay results indicated that all four of the newly designed analogues showed good to excellent antiviral activities, among which analogue 16a dispalyed comparable activity with that of ningnanmycin, perhaps one of the most successful commercial antiviral agents, thus emerging as a potential inhibitor of plant virus and serving as a new lead for further optimization. Further structure-activity relationships are also discussed, demonstrating for the first time that the same changes of the original skeletons of phenanthroindolizidine and phenanthroquinolizidine exihibted totally different antiviral activities results, providing some original and useful information about the preferential conformation for maintaining high activities.
Su, Bo,Chen, Fazhong,Wang, Lizhong,Wang, Qingmin
p. 1233 - 1239
(2014/03/21)

Design, synthesis, antiviral activity, and structure-activity relationships (SARs) of two types of structurally novel phenanthroindo/quinolizidine analogues
To investigate the influence of the variation of the original skeletons of natural phenanthroindo/quinolizidine alkaloids on antiviral activities, two types of structurally totally novel analogues 7a, 7b, 16a, and 16b were designed, synthesized, and evaluated against tobacco mosaic virus (TMV) for the first time. Bioassay results indicated that all four of the newly designed analogues showed good to excellent antiviral activities, among which analogue 16a dispalyed comparable activity with that of ningnanmycin, perhaps one of the most successful commercial antiviral agents, thus emerging as a potential inhibitor of plant virus and serving as a new lead for further optimization. Further structure-activity relationships are also discussed, demonstrating for the first time that the same changes of the original skeletons of phenanthroindolizidine and phenanthroquinolizidine exihibted totally different antiviral activities results, providing some original and useful information about the preferential conformation for maintaining high activities.
Su, Bo,Chen, Fazhong,Wang, Lizhong,Wang, Qingmin
p. 1233 - 1239
(2015/04/22)

Laccase/2,2,6,6-tetramethylpiperidinoxyl radical (TEMPO): An efficient catalytic system for selective oxidations of primary hydroxy and amino groups in aqueous and biphasic media
Copper salts/2,2,6,6-tetramethylpiperidinoxyl radical (TEMPO) catalytic systems enable efficient aerobic oxidations of primary alcohols but they generally show a reduced reactivity in aqueous medium. Herein, we report an oxidative catalytic system composed of Trametes versicolor laccase and TEMPO, which is able to work in buffer solutions at room temperature using ambient air. Although this catalytic system displays great efficiency in aqueous systems, the addition of methyl tert-butyl ether allows the reduction of TEMPO loading, also enhancing the solubility of hydrophobic compounds. This practical methodology promotes the chemoselective aerobic oxidation of hydroxy or amino groups, leading to interesting organic derivatives such as aldehydes, lactones, hemiaminals or lactams.
Díaz-Rodríguez, Alba,Martínez-Montero, Lía,Lavandera, Iván,Gotor, Vicente,Gotor-Fernández, Vicente
supporting information
p. 2321 - 2329
(2014/07/21)

Oxidative transformation of cyclic ethers/amines to lactones/lactams using a DIB/TBHP protocol
A novel C-H oxidation of cyclic ethers and amines to the corresponding lactones and lactams was developed using a DIB/TBHP protocol. The reaction is mild and no metallic reagent is involved. In addition, study shows that the electronic properties of the substituents could affect the selectivity of oxidation. The Royal Society of Chemistry 2013.
Zhao, Yi,Ang, Jascelyn Qian Lin,Ng, Angela Wan Ting,Yeung, Ying-Yeung
p. 19765 - 19768
(2013/11/06)

1,4-Elimination/Br?nsted acid catalyzed aza-Ferrier reaction sequence as an entry to β-amino-β,γ-unsaturated aldehydes
The 1,4-elimination reaction of (Z)-N-Boc-2-(4-methoxy-2-alkenyloxy)amines with Br?nsted acids catalyzed aza-Ferrier reaction of the 1,4-eliminated product, thus obtained, afforded various β-amino-β,γ-unsaturated aldehydes. The scope and limitation of thi
Tayama, Eiji,Horikawa, Kouki,Iwamoto, Hajime,Hasegawa, Eietsu
supporting information
p. 2745 - 2752
(2013/04/10)

Model studies on the synthesis of madangamine alkaloids. Assembly of the macrocyclic rings
Using simplified model derivatives, the assembly of the macrocyclic rings of madangamines, including the 13- and 14-membered D rings of madangamines C-E, the all-cis-triunsaturated 15-membered D ring of madangamine A, and the (Z,Z)-unsaturated 11-membered E ring common to madangamines A-E, has been studied.
Proto, Stefano,Amat, Mercedes,Pérez, Maria,Ballette, Roberto,Romagnoli, Federica,Mancinelli, Andrea,Bosch, Joan
experimental part
p. 3916 - 3919
(2012/09/22)

Asymmetric organocatalytic intramolecular aza-michael addition of enone carbamates: Catalytic enantioselective access to functionalized 2-substituted piperidines
The synthetically useful functionalized 2-substituted piperidines containing a lateral ketone group have been strategically accessed via an organocatalytic enantioselective intramolecular aza-Michael addition of enone carbamates, in which a novel internal substrate combination of the enone moiety as Michael acceptor and the carbamate moiety as Michael donor was revealed in asymmetric bifunctional organocatalysis. This heteroatom conjugate addition, which was realized by using a catalytic chiral Cinchona-based primary-tertiary diamine and an achiral Bronsted acid, mostly proceeded in high yield and good to excellent stereocontrol (up to 99% ee). This reaction provides an alternative catalytic asymmetric method for installing the stereogenic nitrogen-containing carbon center in functionalized 2-substituted piperidines, leading to the development of a straightforward and expeditious synthesis of some naturally occurring bioactive 2-substituted piperidine alkaloids. Copyright
Liu, Jian-Dong,Chen, Ying-Chun,Zhang, Guo-Biao,Li, Zhi-Qiang,Chen, Peng,Du, Ji-Yuan,Tu, Yong-Qiang,Fan, Chun-An
supporting information; experimental part
p. 2721 - 2730
(2011/12/04)

NHC-Catalyzed intramolecular redox amidation for the synthesis of functionalized lactams
A very efficient NHC-catalyzed lactamization reaction is reported. For most cases, the ring expansion reaction proceeds to cleanly furnish five- and six-membered N-Ts and N-Bn lactams, without the need for further purification. Evidence is presented suggesting a dual role for the stoichiometric base: (1) deprotonation of the triazolium precatalyst and (2) activation of the nitrogen leaving group through hydrogen bonding.
Thai, Karen,Wang, Li,Dudding, Travis,Bilodeau, Francois,Gravel, Michel
supporting information; experimental part
p. 5708 - 5711
(2011/03/19)

Photochemical rearrangement of N -chlorolactams: A route to N -heterocycles through concerted ring contraction
We report a novel ring contraction allowing the direct conversion of N-chlorolactams to their corresponding ring-contraction N-heterocycles upon photolysis. Results show that the rearrangement occurs with a variety of N-chlorolactams and that the greater the substitution at the migrating carbon, the greater the yield of product. Importantly, stereochemistry at the migrating carbon is conserved in the product. Rearranged products were isolated as their methyl carbamates in yields varying from 17% to 58%, with the major side product being the recyclable parent lactam.
Winter, Dana K.,Drouin, Alexandre,Lessard, Jean,Spino, Claude
supporting information; experimental part
p. 2610 - 2618
(2010/06/17)

Nitrogen ylide-mediated cyclopropanation of lactams and lactones
Cyclopropanation of α,β-unsaturated δ-lactams and δ-lactones mediated by nitrogen ylides is described. The process tolerates different alkyl halides and gives efficiently bicyclo[4.1.0]heptanes in a totally stereoselective manner. On the other hand, ε-lac
Villar, Irene Suarez del,Gradillas, Ana,Domínguez, Gema,Pérez-Castells, Javier
supporting information; experimental part
p. 3095 - 3098
(2010/08/07)

One-pot formation of piperidine- and pyrrolidine-substituted pyridinium salts via addition of 5-alkylaminopenta-2,4-dienals to N-acyliminium ions: Application to the synthesis of (±)-nicotine and analogs
Addition of 5-alkylaminopenta-2,4-dienals onto N-acyliminium ions, generated in situ from α-hydroxycarbamates derived from pyrrolidine or piperidine, in the presence of zinc triflate, followed by dehydrative cyclization, allowed the formation of pyridinium salts substituted at their 3-position by a five- or six-membered nitrogen heterocycle. Subsequent N-dealkylation of the pyridinium moiety and deprotection of the secondary amine or reduction of the carbamate function led to (±)-nicotine and analogs.
Peixoto, Sabrina,Nguyen, Tuan Minh,Crich, David,Delpech, Bernard,Marazano, Christian
supporting information; experimental part
p. 4760 - 4763
(2010/12/25)

Synthesis of 5-amino- and 4-hydroxy-2-phenylsulfonylmethylpiperidines
Suitable protected 5-amino- and 4-hydroxy-2-phenylsulfonylmethylpiperidines were synthesized from functionalized N-benzyloxycarbonylpiperidin-l-ones through the opening of lactam ring by methyl phenyl sulfone carbanion followed by reductive aminocyclization.
Masse, Julien,Langlois, Nicole
experimental part
p. 417 - 432
(2009/09/06)

Organometallic enantiomeric scaffolding: General access to 2-substituted oxa- and azabicyclo[3.2.1]octenes via a Bronsted acid catalyzed [5 + 2] cycloaddition reaction
6-Substituted TpMo(CO)2(η-2,3,4-pyranyl)- and TpMo(CO) 2(η-2,3,4-pyridinyl) scaffolds (Tp = hydridotrispyrazolylborato) function as reaction partners in an efficient regio- and stereocontrolled synthesis of functionalized oxa- and az
Garnier, Ethel C.,Liebeskind, Lanny S.
p. 7449 - 7458
(2008/12/22)

Phosphinates as new electrophilic partners for cross-coupling reactions
The use of enol phosphinates as electrophiles for cross-coupling reactions has been explored. Both boronic acids (Suzuki-Miyaura reaction) and stannanes (Stille reaction) couple efficiently with lactam derived phosphinates. The 2008 Royal Society of Chemi
Guo, Jun,Harling, John D.,Steel, Patrick G.,Woods, Tom M.
supporting information; experimental part
p. 4053 - 4058
(2009/06/28)

Discovery of 3-piperidinyl-1-cyclopentanecarboxamide as a novel scaffold for highly potent CC chemokine receptor 2 antagonists
Introduction of ring restrictions to a linear aminobutyramide CC chemokine receptor 2 (CCR2) antagonist lead (2) led to the discovery of a 1,3-disubstituted cyclopentane scaffold with enhanced hCCR2 receptor binding and antagonist activity. (1S,3R)-N-[3,5
Yang, Lihu,Butora, Gabor,Jiao, Richard X.,Pasternak, Alex,Zhou, Changyou,Parsons, William H.,Mills, Sander G.,Vicario, Pasquale P.,Ayala, Julia M.,Cascieri, Margaret A.,MacCoss, Malcolm
p. 2609 - 2611
(2008/02/05)

DIPEPTIDYL PEPTIDASE-IV INHIBITING COMPOUNDS, METHODS OF PREPARING THE SAME, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME AS AN ACTIVE AGENT
The present invention relates to novel compounds exhibiting good inhibitory activity versus Dipeptidyl Peptidase-IV(DPP-IV), methods of preparing the same and pharmaceutical compositions containing the same as an active agent.
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Page/Page column 25

(2010/11/24)

Synthesis of Cα methylated carboxylic acids: Isosteres of arginine and lysine for use as N-terminal capping residues in polypeptides
Replacement of the N-terminal α-amine with the isosteric methyl functionality in bioactive peptides can influence various pharmacokinetic parameters, including hydrophobicity and stability. Cα methylated amino acid analogues are thus of great interest to expand the repertoire of nonnatural synthons available as N-terminal 'capping' residues for peptide-based drug design. Several novel arginine and lysine analogues stereoselectively modified in the Cα position with a methyl group in place of the α-amine were prepared.
Orwig, Kevin S.,Dix, Thomas A.
p. 7007 - 7009
(2007/10/03)

An expeditious, high-yielding construction of the food aroma compounds 6-acetyl-1,2,3,4-tetrahydropyridine and 2-acetyl-1-pyrroline
The key compound responsible for the aroma of bread, 6-acetyl-1,2,3,4- tetrahydropyridine (1), has been constructed in an efficient three-step procedure from 2-piperidone in an overall yield of 56%. Compound 1 was liberated in the final step under basic conditions. A related synthetic route produced 2-acetyl-1-pyrroline (2), the principal component of cooked rice, in 10% overall yield.
Harrison, Tyler J.,Dake, Gregory R.
p. 10872 - 10874
(2007/10/03)

METHOD FOR PRODUCTION OF Γ(A),Γ(B)-UNSATURATED AMIDE COMPOUNDS
The invention relates to a method for production of α,β-unsaturated amide compounds of general formula (I): whereby (A) a protective group is introduced into a molecule of general formula (II) to give a compound of formula (III), (B) the compound obtained is reacted in the presence of (i) a dehydrogenation catalyst and (ii) a suitable oxidation agent and (C) the protective groups are removed.
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Page/Page column 13

(2010/02/10)

Nucleophilic synthesis of enantiopure 2-(tributylstannyl)pyrrolidines and piperidines
trans-Cumylcyclohexanol (TCC) is used as a chiral auxiliary for the stereoselective addition of tributyltinlithium to N-acylpyrrolidinium/ piperidinium ion with 70-80% diastereoselectivity at 0°C. After removal of the minor diastereomer by radial chromato
Gawley, Robert E.,Barolli, Graciela,Madan, Sachin,Saverin, Michele,O'Connor, Sean
p. 1759 - 1761
(2007/10/03)

A One-Pot Process for the Enantioselective Synthesis of Amines via Reductive Amination under Transfer Hydrogenation Conditions
(Equation presented) Cyclic amines may be prepared via a sequence of deprotection followed by intramolecular reductive amination of t-Boc-protected amino ketones under asymmetric transfer hydrogenation conditions. In cases where the corresponding imine reaction proceeds with high enantioselectivity, this is reflected in the one-step process.
Williams, Glynn D.,Pike, Richard A.,Wade, Charles E.,Wills, Martin
p. 4227 - 4230
(2007/10/03)

Diastereoselective conjugate addition of organocuprates to chiral racemic olefinic amido esters. Formal total synthesis of paroxetine
The diastereoselective conjugate addition of an organocopper reagent to a chiral racemic olefinic amido ester has been used as the key step in a formal total synthesis of paroxetine.
Cossy, Janine,Mirguet, Olivier,Gomez Pardo, Domingo,Desmurs, Jean-Roger
p. 475 - 482
(2007/10/03)

Novel pyrrolyllactone and pyrrolyllactam indolinones as potent cyclin-dependent kinase 2 inhibitors
Cyclin-dependent kinases (CDKs) are essential in the control of cell cycle progression. Inhibition of CDKs represents a new approach for pharmacological intervention in the treatment of a variety of proliferative diseases, especially cancer. Based on the crystal structure of CDK2 in complex with an imidazole indolinone compound 1 (SU9516), lead optimization through modeling, synthesis, and SAR studies has led to the discovery of a novel series of pyrrolyllactone and pyrrolyllactam indolinones as potent CDK2 inhibitors.
Li, Xiaoyuan,Huang, Ping,Cui, Jingrong Jean,Zhang, Jennifer,Tang, Cho
p. 1939 - 1942
(2007/10/03)

Pharmaceuticals
The present invention provides compounds of formula (I) as well as the use of such compounds in pharmaceutical compositions and methods of treatment. The compounds described herein represent a class of TAFIla inhibitors suitable for use in treating condit
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(2008/06/13)

3-alkyl-3-phenyl-piperidines
PCT No. PCT/US97/15443 Sec. 371 Date Jan. 22, 1998 Sec. 102(e) Date Jan. 22, 1998 PCT Filed Sep. 2, 1997 PCT Pub. No. WO98/11090 PCT Pub. Date Mar. 19, 1998The small nonpeptides of the instant invention are tachykinin antagonists of formula or a pharmaceutically acceptable salt thereof wherein: R1 is straight or branched alkyl of from 5 to 15 carbon atoms, aryl, or heteroaryl; R2 is hydrogen, hydroxy, amino, or thiol; R3 is aryl, arylsulfonylmethyl, or saturated or unsaturated heterocycle; R4 is from 1 to 4 groups each independently selected from halogen, alkyl, hydroxy, and alkoxy; n is an integer of from 2 to 6; and the carbon atom of (CH2)n group can be replaced by oxygen, nitrogen, or sulphur. The compounds are highly selective and functional NK3 antagonists expected to be useful in the treatment of pain, depression, anxiety, panic, schizophrenia, neuralgia, addiction disorders, inflammatory diseases, gastrointestinal disorders, vascular disorders, and neuropathological disorders.
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(2008/06/13)

Enantioselective syntheses of 2-alkyl- and 2,6-dialkylpiperidine alkaloids: preparations of the hydrochlorides of (-)-coniine, (-)-solenopsin A, and (-)-dihydropinidine.
[reaction: see text] Sequences of lithiation-substitution, enantioselective hydrogenation, and diastereoselective lithiation-substitution provide efficient highly enantioselective syntheses of 2-substituted and cis and trans 2,6-disubstituted piperidines.
Wilkinson,Stehle,Beak
p. 155 - 158
(2007/10/03)

Asymmetric synthesis of novel quaternary α-hydroxy-δ-lactam dipeptide surrogates
Application of the Sharpless AD protocol to a series of α-(E)-benzylidene-δ-lactam precursors followed by selective deoxygenation provided efficient synthetic routes to the chiral quaternary α-hydroxy-γ-lactam derivatives 4 and 5. These functionalized intermediates and the diol precursors 3 are regarded as novel types of D-Phe-Pro dipeptide surrogates that are useful as enzyme active site probes.
Minami, Nathaniel K.,Reiner, John E.,Semple, J. Edward
p. 2625 - 2628
(2007/10/03)

Highly stereoselective reduction of acyclic α-sulfinyl ketimines: Synthesis of enantiomerically pure β-aminosulfoxides
The DIBAL reduction of enantiomerically pure α-sulfinyl ketimines can be achieved almost completely stereoselectively under ZnX2 catalysis, regardless of the alkyl or aryl substituent at nitrogen and the aliphatic (cyclic or acyclic) or aromati
Garcia Ruano, Jose L.,Cifuentes, Marta M.,Lorente, Antonio,Rodriguez Ramos, Jesus H.
p. 4607 - 4618
(2007/10/03)