- [3+2] Cycloaddition-mediated synthesis of 3-methylsulfanyl-pyrrolidine-3-carboxylic acid methyl ester
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1,3-Dipolar cycloaddition reactions are fundamental processes in organic chemistry. Herein we report [3+2] annulation of thiomethylacrylate 2 and azomethine ylide precursor 3 towards the synthesis of novel 3-methylsulfanyl-pyrrolidine 5. Alternatively, we
- Boga, Sobhana B.,Alhassan, Abdul-Basit,Cooper, Alan B.,Shih, Neng-Yang,Doll, Ronald J.
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- X-ray Structure-Guided Discovery of a Potent, Orally Bioavailable, Dual Human Indoleamine/Tryptophan 2,3-Dioxygenase (hIDO/hTDO) Inhibitor That Shows Activity in a Mouse Model of Parkinson’s Disease
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Human indoleamine 2,3-dioxygenase 1 (hIDO1) and tryptophan 2,3-dioxygenase (hTDO) have been closely linked to the pathogenesis of Parkinson’s disease (PD); nevertheless, development of dual hIDO1 and hTDO inhibitors to evaluate their potential efficacy against PD is still lacking. Here, we report biochemical, biophysical, and computational analyses revealing that 1H-indazole-4-amines inhibit both hIDO1 and hTDO by a mechanism involving direct coordination with the heme ferrous and ferric states. Crystal structure-guided optimization led to23, which manifested IC50values of 0.64 and 0.04 μM to hIDO1 and hTDO, respectively, and had good pharmacokinetic properties and brain penetration in mice.23showed efficacy against the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse motor coordination deficits, comparable to Madopar, an anti-PD medicine. Further studies revealed that different from Madopar,23likely has specific anti-PD mechanisms involving lowering IDO1 expression, alleviating dopaminergic neurodegeneration, reducing inflammatory cytokines and quinolinic acid in mouse brain, and increasing kynurenic acid in mouse blood.
- Ning, Xiang-Li,Li, Yu-Zhi,Huo, Cui,Deng, Ji,Gao, Cheng,Zhu, Kai-Rong,Wang, Miao,Wu, Yu-Xiang,Yu, Jun-Lin,Ren, Ya-Li,Luo, Zong-Yuan,Li, Gen,Chen, Yang,Wang, Si-Yao,Peng, Cheng,Yang, Ling-Ling,Wang, Zhou-Yu,Wu, Yong,Qian, Shan,Li, Guo-Bo
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p. 8303 - 8332
(2021/06/30)
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- TRPML MODULATORS
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The present invention provides compounds, pharmaceutically acceptable compositions thereof, and methods of using the same.
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Paragraph 0317
(2021/06/26)
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- Discovery of 3(S)-thiomethyl pyrrolidine ERK inhibitors for oncology
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Compound 5 (SCH772984) was identified as a potent inhibitor of ERK1/2 with excellent selectivity against a panel of kinases (0/231 kinases tested @ 100 nM) and good cell proliferation activity, but suffered from poor PK (rat AUC PK @10 mpk = 0 μM h; F% =
- Boga, Sobhana Babu,Alhassan, Abdul-Basit,Cooper, Alan B.,Doll, Ronald,Shih, Neng-Yang,Shipps, Gerald,Deng, Yongqi,Zhu, Hugh,Nan, Yang,Sun, Robert,Zhu, Liang,Desai, Jagdish,Patel, Mehul,Muppalla, Kiran,Gao, Xiaolei,Wang, James,Yao, Xin,Kelly, Joseph,Gudipati, Subrahmanyam,Paliwal, Sunil,Tsui, Hon-Chung,Wang, Tong,Sherborne, Bradley,Xiao, Li,Hruza, Alan,Buevich, Alexei,Zhang, Li-Kang,Hesk, David,Samatar, Ahmed A.,Carr, Donna,Long, Brian,Black, Stuart,Dayananth, Priya,Windsor, William,Kirschmeier, Paul,Bishop, Robert
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p. 2029 - 2034
(2018/05/16)
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- Protected Chloroethyl and Chloropropyl Amines as Conformationally Unrestricted Annulating Reagents
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The purpose of this letter is to document the use of protected chloroethyl and chloropropyl amines as conformationally unrestricted ambiphilic reagents that undergo annulation reactions with Michael acceptors. This reaction is wide in scope and utilizes r
- Shi, Qing,Meehan, Mariah C.,Galella, Michael,Park, Hyunsoo,Khandelwal, Purnima,Hynes, John,Dhar, T. G. Murali,Marcoux, David
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supporting information
p. 337 - 340
(2018/01/28)
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- Preparation method of 1-BOC-3-hydroxymethyl pyrrolidine
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The invention discloses a preparation method of 1-Boc-3-hydroxymethyl pyrrolidine. The preparation method uses epichlorohydrin as a raw material, 3-hydroxymethyl pyrrolidine is obtained through reduction and cyclization reaction, then the 1-Boc-3-hydroxymethyl pyrrolidine is prepared through Boc protection reaction, then 1-BOC-3-methyl formate pyrrolidine is prepared through carboxylation reaction and esterification reaction, and finally the 1-BOC-3-methyl formate pyrrolidine and lithium aluminum hydride are catalyzed by a catalyst to prepare the 1-BOC-3-hydroxymethyl pyrrolidine. The preparation method is high in product synthesis rate, high in product purity and low in production cost, and the raw materials are cheap and easy to obtain.
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- (3,4-DICHLORO-PHENYL)-((S)-3-PROPYL-PYRROLIDIN-3-YL)-METHANONE HYDROCHLORIDE AND MANUFACTURING PROCESSES
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The present invention is concerned with a novel process for the preparation of a compound of formula I and its hydrates The compounds of formula I and the corresponding hydrates are pharmaceutically active substances.
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Paragraph 0502-0503
(2015/02/25)
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- (3,4-DICHLORO-PHENYL)-((S)-3-PROPYL-PYRROLIDIN-3-YL)-METHANONE HYDROCHLORIDE AND MANUFACTURING PROCESSES
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The present invention is concerned with a novel process for the preparation of a compound of formula I and its hydrates, as well as with a crystall polymorph thereof. The compounds of formula (I) and the corresponding hydrates are pharmaceutically active substances.
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Page/Page column 108; 109
(2013/11/18)
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- Design, synthesis, and biological evaluation of new monoamine reuptake inhibitors with potential therapeutic utility in depression and pain
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Two new series of monoamine triple reuptake inhibitors (TRIs) have been discovered through scaffold homologation of our recently reported series of 3,3-disubstituted pyrrolidine TRIs. The regioisomeric 2- and 3-ketopyrrolidines demonstrated high levels of
- Lucas, Matthew C.,Weikert, Robert J.,Carter, David S.,Cai, Hai-Ying,Greenhouse, Robert,Iyer, Pravin S.,Lin, Clara J.,Lee, Eun Kyung,Madera, Ann Marie,Moore, Amy,Ozboya, Kerem,Schoenfeld, Ryan C.,Steiner, Sandra,Zhai, Yansheng,Lynch, Stephen M.
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supporting information; scheme or table
p. 5559 - 5566
(2011/02/22)
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- Enzymatic resolution of n-substituted-β-prolines
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A general and straightforward strategy for enzymatic resolution of N-substituted-β-proline has been successfully designed and developed in our research laboratories. A first affinity screen is followed by ratio enzyme/substrate optimization to source our
- Mendiola, Javier,Garcia-Cerrada, Susana,De Frutos, Oscar,De La Puente, Maria Luz,Gu, Rui Lin,Khau, Vien V.
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scheme or table
p. 292 - 296
(2010/04/22)
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- COMPOUNDS THAT ARE ERK INHIBITORS
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Disclosed are the ERK inhibitors of formula 1.0: and the pharmaceutically acceptable salts, and solvates thereof. Q is a tetrahydopyridinyl ring. All other substitutents are as defined herein. Also disclosed are methods of treating cancer using the compounds of formula 1.0.
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Page/Page column 242
(2009/10/18)
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- POLYCYCLIC INDAZOLE DERIVATIVES AND THEIR USE AS ERK INHIBITORS FOR THE TREATMENT OF CANCER
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Disclosed are the ERK inhibitors of formula 1.0: (Chemical formula should be inserted here as it appears on abstract in paper form) and the pharmaceutically acceptable salts, esters and solvates thereof. Q is a piperidine or piperazine ring that can have a bridge or a fused ring. The piperidine ring can have a double bond in the ring. All other substitutents are as defined herein. Also disclosed are methods of treating cancer using the compounds of formula 1.0.
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Page/Page column 221
(2009/01/24)
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- Synthesis of functionalized nitrogen heterocycles by radical decarboxylation of β- and γ-amino acids
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Iodinated or oxygenated nitrogen heterocycles are obtained by radical decarboxylation of β- and γ-amino acids. This mild, versatile reaction is applied to the synthesis of bioactive products, such as 4-arylpiperidines, hydroxylated piperidines, and new antifungal agents.
- Boto, Alicia,Hernandez, Rosendo,De Leon, Yolanda,Murguia, Jose R.,Rodriguez-Afonso, Abigail
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p. 673 - 682
(2007/10/03)
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- Novel phosphorus radical-based routes to horsfiline
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(Chemical Equation Presented) Radicals derived from the phosphorus reagents, ethylpiperidine hypophosphite (EPHP) and diethylphosphine oxide (DEPO), are used in two related approaches to synthesis of the alkaloid horsfiline (1). In particular, DEPO proves
- Murphy, John A.,Tripoli, Regis,Khan, Tanweer A.,Mali, Umesh W.
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p. 3287 - 3289
(2007/10/03)
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- Cathepsin cysteine protease inhibitors
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This invention relates to a novel class of compounds which are cysteine protease inhibitors, including but not limited to, inhibitors of Cathepsins K and L. These compounds are useful for treating diseases in which inhibition of bone resorption is indicated, such as osteoporosis.
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- Preparation of cyclic and bicyclic β-amino acids derivatives from methyl 6-ethoxy-5,6-dihydro-4h-1,2-oxazine-4-carboxylate
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The readily available methyl 6-ethoxy-5,6-dihydro-4H-1,2-oxazine-4-carboxylate (1) was alkylated at C-4 and acylated at the nitrogen atom. 1,2-Oxazine 1 and the resulting new substituted 1,2-oxazines 2 and 3 were suitable precursors for the preparation of derivatives of β-proline, nipecotic acid, as well as indolizine-6- and quinolizine-3-carboxylic acids.
- Tishkov, Alexander A.,Reissig, Hans-Ulrich,Ioffe, Sema L.
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p. 863 - 866
(2007/10/03)
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- THIADIAZOLES USEFUL IN THE TREATMENT OF SENILE DEMENTIA
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A class of novel thiadiazoles, substituted on one of the ring carbon atoms with a non-aromatic azacyclic or azabicyclic ring system, and substituted on the other ring carbon atom with a substituent of low lipophilicity, or a hydrocarbon substituent; are potent muscarinic agonists, and have good CNS penetrability. The compounds are therefore useful in the treatment of neurological and mental illnesses, and are also of benefit in the treatment of severe painful conditions.
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- Synthesis and muscarinic activities of 1,2,4-thiadiazoles
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A series of novel 1,2,4-thiadiazoles bearing a mono- or bicyclic amine at C5 were prepared. Quinuclidine and 1-azabicyclo[2.2.1]heptane derivatives were synthesized by reaction of the lithium enolate of the 3-methoxycarbonyl compounds followed by ester hy
- MacLeod,Baker,Freedman,Patel,Merchant,Roe,Saunders
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p. 2052 - 2059
(2007/10/02)
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