cas 220060-08-2, 2-Methyl-L-proline Methyl ester hydrochloride

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BICYCLIC COMPOUNDS AND METHODS FOR THEIR USE IN TREATING PITT HOPKINS SYNDROME
Embodiments of this invention provide compounds, compositions, methods, and uses for therapeutic diketopiperazines, including cyclic G-2-Allyl Proline and other cyclic Glycyl Proline compounds to treat Pitt Hopkins Syndrome and symptoms thereof, as well a
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Page/Page column 38; 39

(2021/04/30)

Design and Synthesis of 56 Shape-Diverse 3D Fragments
Fragment-based drug discovery is now widely adopted for lead generation in the pharmaceutical industry. However, fragment screening collections are often predominantly populated with flat, 2D molecules. Herein, we describe a workflow for the design and synthesis of 56 3D disubstituted pyrrolidine and piperidine fragments that occupy under-represented areas of fragment space (as demonstrated by a principal moments of inertia (PMI) analysis). A key, and unique, underpinning design feature of this fragment collection is that assessment of fragment shape and conformational diversity (by considering conformations up to 1.5 kcal mol?1 above the energy of the global minimum energy conformer) is carried out prior to synthesis and is also used to select targets for synthesis. The 3D fragments were designed to contain suitable synthetic handles for future fragment elaboration. Finally, by comparing our 3D fragments with six commercial libraries, it is clear that our collection has high three-dimensionality and shape diversity.
Atobe, Masakazu,Blakemore, David C.,Bond, Paul S.,Chan, Ngai S.,De Fusco, Claudia,Downes, Thomas D.,Firth, James D.,Hubbard, Roderick E.,Jones, S. Paul,Klein, Hanna F.,O'Brien, Peter,Roughley, Stephen D.,Vidler, Lewis R.,Waddelove, Laura,Whatton, Maria Ann,Wheldon, Mary C.,Woolford, Alison J.-A.,Wrigley, Gail L.
supporting information

(2020/07/13)

Discovery of Pamiparib (BGB-290), a Potent and Selective Poly (ADP-ribose) Polymerase (PARP) Inhibitor in Clinical Development
Poly (ADP-ribose) polymerase (PARP) plays a significant role in DNA repair responses; therefore, this enzyme is targeted by PARP inhibitors in cancer therapy. Here we have developed a number of fused tetra- or pentacyclic dihydrodiazepinoindolone derivatives with excellent PARP enzymatic and cellular PARylation inhibition activities. These efforts led to the identification of pamiparib (BGB-290, 139), which displays excellent PARP-1 and PARP-2 inhibition with IC50 of 1.3 and 0.9 nM, respectively. In a cellular PARylation assay, this compound inhibits PARP activity with IC50 = 0.2 nM. Cocrystal of pamiparib shows similar binding sites with PARP with other PARP inhibitors, but pamiparib is not a P-gp substrate and shows excellent drug metabolism and pharmacokinetics (DMPK) properties with significant brain penetration (17-19%, mice). The compound is currently being investigated in phase III clinical trials as a maintenance therapy in platinum-sensitive ovarian cancer and gastric cancer.
Wang, Hexiang,Ren, Bo,Liu, Ye,Jiang, Beibei,Guo, Yin,Wei, Min,Luo, Lusong,Kuang, Xianzhao,Qiu, Ming,Lv, Lei,Xu, Hong,Qi, Ruipeng,Yan, Huibin,Xu, Dexu,Wang, Zhiwei,Huo, Chang-Xin,Zhu, Yutong,Zhao, Yuan,Wu, Yiyuan,Qin, Zhen,Su, Dan,Tang, Tristin,Wang, Fan,Sun, Xuebing,Feng, Yingcai,Peng, Hao,Wang, Xing,Gao, Yajuan,Liu, Yong,Gong, Wenfeng,Yu, Fenglong,Liu, Xuesong,Wang, Lai,Zhou, Changyou
p. 15541 - 15563
(2020/12/22)

Chiral amination sulfoxide and preparation method thereof (by machine translation)
The invention belongs to the field of organic synthesis, and discloses chiral amination sulfoxide which has the structure of a general formula I. Wherein R is hydrogen or R1 And R2 Each independently selected from one of the following structures: hydrogen, alkyl, alkoxy, ester, trifluoromethyl, trifluoromethoxy, trifluoromethylthio. Halogens, alkynyl groups, alkenyl groups, amino groups, cyano groups, hydroxyl groups, aldehyde groups, carboxyl groups, nitro groups, amide groups, benzene rings, and bonded benzene ring fused rings to naphthalene; R3 Selected from the group consisting of phenyl, optionally substituted phenyl, aryl, heteroaryl, styryl, alkyl, haloalkyl and the like. The method comprises the following steps: forming a complex with a tert-butyl cyclopentadienyl metal iridium complex, forming a complex with the modified chiral proline, and activating C-H bond of enantioselective induced sulfoxide to obtain chiral sulphoxide. The synthetic method disclosed by the invention is high in yield and good in enantioselectivity, and the obtained amidated sulfoxide can be derivatized to obtain a chiral ligand. (by machine translation)
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Paragraph 0127; 0137-0138

(2020/11/12)

INTEGRIN ANTAGONISTS
The present disclosure provides therapeutic agents including those of the formula: wherein the variables are defined herein. Also provided are pharmaceutical compositions, kits and articles of manufacture comprising such therapeutic agents. Methods of using the therapeutic agents are also provided.
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Page/Page column 74

(2018/05/24)

Spatial Configuration and Three-Dimensional Conformation Directed Design, Synthesis, Antiviral Activity, and Structure-Activity Relationships of Phenanthroindolizidine Analogues
Our recent investigation on the antiviral activities against tobacco mosaic virus (TMV) of phenanthroindolizidine alkaloid analogues preliminarily revealed that the basic skeleton and substitution pattern at the C13a position of the molecule, which are cl
Su, Bo,Cai, Chunlong,Deng, Meng,Wang, Qingmin
p. 2039 - 2045
(2016/03/30)

HETEROCYCLIC COMPOUND
An object of the present invention is to provide a compound having a superior CH24H inhibitory action, which is useful as an agent for the prophylaxis or treatment of epilepsy, neurodegenerative disease and the like. The present invention relates to a compound represented by the formula: wherein each symbol is as defined in the specification, or a salt thereof.
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Paragraph 0350

(2015/11/09)

CYCLIC AMINE DERIVATIVES AS EP4 RECEPTOR ANTAGONISTS
There is described a novel group of cyclic amine derivative compounds, having an EP4 receptor antagonistic activity and specifically pharmaceutical compounds which are useful for the treatment or alleviation of Prostaglandin E mediated diseases. The present invention therefore relates to novel compounds which are selective antagonists of the EP4 subtype of PGE2 receptors with analgesic and antinflammatory activity, processes for their preparation, pharmaceutical compositions containing them and their use as medicaments, inter alia for the treatment or alleviation of Prostaglandin E mediated diseases such as acute and chronic pain, osteoarthritis, inflammation-associated disorder as arthritis, rheumatoid arthritis, cancer, migraine and endometriosis.
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Paragraph 0511; 0512; 0513

(2015/03/31)

NEUROPROTECTIVE BICYCLIC COMPOUNDS AND METHODS FOR THEIR USE IN TREATING AUTISM SPECTRUM DISORDERS AND NEURODEVELOPMENTAL DISORDERS
Embodiments of this invention provide compositions and methods for therapeutic use of diketopiperazines including cyclic G-2-Allyl Proline and other cyclic Glycyl Proline compounds to treat symptoms of Autism Spectrum Disorders and Neurodevelopmental Diso
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(2015/02/19)

1 -(CYCLOPENT-2-EN-1 -YL)-3-(2-HYDROXY-3-(ARYLSULFONYL)PHENYL)UREA DERIVATIVES AS CXCR2 INHIBITORS
The invention relates to 1-(3-sulfonylphenyl)-3-(cyclopent-2-en-1-yl)urea derivatives, and their use in treating or preventing diseases and conditions mediated by the CXCR2 receptor. In addition, the invention relates to compositions containing the derivatives and processes for their preparation.
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Page/Page column 123

(2015/12/18)

CYCLIC AMINE DERIVATIVES AS EP4 RECEPTOR AGONISTS
There is described a group of novel cyclic amine derivative compounds having an EP4 receptor agonistic activity. Specifically, the compounds according to the invention are provided with analgesic, antinflammatory, antiglaucoma activity, and also with anti-osteoporosis and antiulcerative activity. The present invention therefore relates to novel cyclic amine derivative compounds, processes for their preparation, pharmaceutical compositions containing them and their use as medicaments, inter alia for the treatment or alleviation of Prostaglandin E mediated diseases such as pain, glaucoma, ulcerative colitis and osteoporosis.
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Paragraph 0265-0266

(2014/09/03)

TREATMENT OF AUTISM SPECTRUM DISORDERS USING GLYCYL-L-2-METHYLPROLYL-L-GLUTAMIC ACID
This invention provides compounds, compositions and methods for treating Autism Spectrum Disorders (ASD) using glycyl-2-methyIprolyl-glutamic acid (G-2-MePE) and analogs thereof. Autism Spectrum Disorders include Autism, Autistic Disorder, Asperger Syndro
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Page/Page column 32; 33

(2014/06/23)

CYCLIC AMINE DERIVATIVES AS EP4 RECEPTOR AGONISTS
There is described a group of novel cyclic amine derivative compounds having an EP4 receptor agonistic activity. Specifically, the compounds according to the invention are provided with analgesic, antiinflammatory, antiglaucoma activity, and also with anti-osteoporosis and antiulcerative activity. The present invention therefore relates to novel cyclic amine derivative compounds, processes for their preparation, pharmaceutical compositions containing them and their use as medicaments, inter alia for the treatment or alleviation of Prostaglandin E mediated diseases such as pain, glaucoma, ulcerative colitis and osteoporosis.
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Page/Page column 29

(2013/03/26)

CYCLIC AMINE DERIVATIVES AS EP4 RECEPTOR ANTAGONISTS
There is described a novel group of cyclic amine derivative compounds, having an EP4 receptor antagonistic activity and specifically pharmaceutical compounds which are useful for the treatment or alleviation of Prostaglandin E mediated diseases. The present invention therefore relates to novel compounds which are selective antagonists of the EP 4 sub type of PGE2 receptors with analgesic and antinflammatory activity, processes for their preparation, pharmaceutical compositions containing them and theiruse as medicaments, inter alia for the treatment or alleviation of Prostaglandin E mediated diseases such as acute and chronic pain, osteoarthritis, inflammation-associated disorder as arthritis, rheumatoid arthritis, cancer, migraine and endometriosis.
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Page/Page column 67

(2013/03/26)

The first enantioselective approach to 13a-methyl-14- hydroxyphenanthroindolizidine alkaloids - Synthetic studies towards hypoestestatin 2
The first enantioselective approach to 13a-methyl-14- hydroxyphenanthroindolizidine alkaloids was achieved in six linear steps from phenanthryl alcohol and features a highly substrate-dependent Parham cycloacylation and Seebach's enantioselective alkylation as the key steps. The route is concise, protecting-group free, provides access to all stereoisomers, and works on a gram scale. In addition to the putative structure of hypoestestatin 2, the other three stereoisomers and two structurally related analogues were synthesized, none of which shows identical NMR spectra to those reported for natural hypoestestatin 2, which indicates that further structure revision is required. By using Seebach's stereoselective alkylation and Parham cyclization as key steps, the first strategy for the synthesis of 14-hydroxy-13a-methylphenanthroindolizidine alkaloids was developed. The route is practical (six steps in 30 % overall yield) and adaptable for all stereoisomers. In addition, we demonstrate for the first time that the structure of hypoestestatin 2 was misassigned.
Su, Bo,Deng, Meng,Wang, Qingmin
p. 1979 - 1985
(2013/05/08)

Discovery of 2-alkyl-1-arylsulfonylprolinamides as 11β-hydroxysteroid dehydrogenase type 1 inhibitors
On the basis of scaffold hopping, a novel series of 2-alkyl-1- arylsulfonylprolinamides was discovered as 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) inhibitors. A representative compound 4ek, obtained through SAR and structure optimization studies, demonstrates excellent in vitro potency against 11β-HSD-1 and dose-dependent in vivo inhibition of 11β-HSD-1 in a prednisone/prednisolone transformation biomarker study in mice.
Yu, Jianxin,Liu, Haiyan,Xia, Guangxin,Liu, Lin,Xu, Zhenmin,Chen, Qian,Ma, Chen,Sun, Xing,Xu, Jiajun,Li, Hua,Li, Ping,Shi, Yufang,Liu, Xuejun,Shen, Jingkang,Xiong, Bing
supporting information
p. 793 - 798,6
(2020/09/15)

TREATMENT OF AUTISM SPECTRUM DISORDERES USING GLYCYL-L-2-METHYLPROLYL-L-GLUTAMIC ACID
This invention provides compounds, compositions and methods for treating Autism Spectrum Disorders (ASD) using glycyl-2-methylprolyl-glutamic acid (G-2-MePE) and analogs thereof. Autism Spectrum Disorders include Autism, Autistic Disorder, Asperger Syndro
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Page/Page column 29; 30

(2012/08/08)

NOVEL INHIBITORS OF HEPATITIS C VIRUS REPLICATION
The embodiments provide compounds of the general Formulae I, II, III, IV, or V as well as compositions, including pharmaceutical compositions, comprising a subject compound. The embodiments further provide treatment methods, including methods of treating a hepatitis C virus infection and methods of treating liver fibrosis, the methods generally involving administering to an individual in need thereof an effective amount of a subject compound or composition.
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Page/Page column 210-211

(2011/07/06)

Further evidence for 2-alkyl-2-carboxyazetidines as γ-turn inducers
(Chemical Equation Presented) Reverse turns, a common motif in proteins and peptides, have attracted attention due to their relevance in a wide variety of biological processes. In an attempt to artificially imitate and stabilize these turns in short pepti
Baeza, Jose Luis,Gerona-Navarro, Guillermo,Thompson, Kevin,De Vega, M. Jesus Perez,Infantes, Lourdes,Garcia-Lopez, M. Teresa,Gonzalez-Muniz, Rosario,Martin-Martinez, Mercedes
supporting information; experimental part
p. 8203 - 8211
(2010/02/17)

2-SUBSTITUTED PROLINE BIS-AMIDE OREXIN RECEPTOR ANTAGONISTS
The present invention is directed to 2-substituted proline bis-amide compounds which are antagonists of orexin receptors, and which are useful in the treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which orexin receptors are involved.
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Page/Page column 37

(2008/06/13)

CYCLIC GLYCYL-2-ALLYL PROLINE IMPROVES COGNITIVE PERFORMANCE IN IMPAIRED ANIMALS
Embodiments of this invention provide methods for therapeutic use of cyclic G-2-Allyl Proline to treat cognitive disorders as well as manufacture of medicaments including tablets, capsules, injectable solutions that are useful for treatment of such condit
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Page/Page column 20

(2008/12/05)

ANALOGS OF GLYCYL-PROLYL-GLUTAMATE
Embodiments of this invention include novel analogs of Glycyl-Prolyl-Glutamate (GPE) and compositions containing such analogs of GPE. Of these, certain analogs have modified proline residues. Other embodiments of this invention include uses of analogs of GPE to protect neural cells from degeneration and/or death in response to injury or disease. Disorders treatable with compounds and compositions of this invention include hypoxia/ischemia, toxic injury, and chronic neurodegenerative disorders including Parkinson''s disease.
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Page/Page column 31

(2008/06/13)

Synthesis of proline-modified analogues of the neuroprotective agent glycyl-L-prolyl-glutamic acid (GPE)
The synthesis of ten proline-modified analogues of the neuroprotective tripeptide GPE is described. Five of the analogues incorporate a proline residue with a hydrophobic group at C-2 and two further analogues have this side chain locked into a spirolactam ring system. The pyrrolidine ring was also modified by replacing the γ-CH2 group with sulfur and/or incorporation of two methyl groups at C-5.
Harris, Paul W.R.,Brimble, Margaret A.,Muir, Victoria J.,Lai, Michelle Y.H.,Trotter, Nicholas S.,Callis, David J.
p. 10018 - 10035
(2007/10/03)

NEUROPROTECTIVE BICYCLIC COMPOUNDS AND METHODS FOR THEIR USE
Embodiments of this invention provide novel cyclic compounds structurally related to diketopiperazines and methods for their therapeutic use. Such compounds are neuroprotective and have utility as therapeutic agents for treatment of diseases, injuries and
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Page/Page column 32

(2010/02/11)

Design, construction and properties of peptide N-terminal cap templates devised to initiate α-helices. Part 2. Caps derived from N-[(2S)-2-chloropropionyl]-(2S)-Pro-(2S)-Pro-(2S,4S)-4-thioPro-OMe
Recently, we designed 12-membered macrocyclic template caps to entrain peptides into α-helical structures, based on the covalent connection of the first and fourth residues of proline containing tetrapeptides. It was not possible to complete the synthesis of the templates from the acyclic precursors and it appeared that the generation of large molecular dipoles, caused by aligning the carbonyl groups, prevented reaction. While this work was in progress, Kemp's group published the structure of a 12-membered macrocyclic triproline template designed to initiate an α-helix that was very similar in structure to one of our own targets. However, the compound failed to cyclise in a conformation required for α-helix initiation and one or more carboxamide dipoles were not aligned. Here we provide a detailed conformational analysis of the system and test two methods for forcing the acyclic precursor into the macrocyclic conformation required for helix initiation. The first is the destabilisation of unwanted conformations in the transition state for cyclisation, and the second is the stabilisation of the favoured transition state structure through the introduction of a hydrogen-bonding interaction. Both strategies were unsuccessful and the reasons are discussed. A successful strategy which does not require the carbonyl dipoles to align in the transition state is presented in the following paper.
Lewis, Arwel,Wilkie, John,Rutherford, Trevor J.,Gani, David
p. 3777 - 3793
(2007/10/03)