cas 77716-01-9, 3-Benzyl-7-oxo-3-aza-bicyclo[3.3.1nonan-9-one

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THERAPEUTICALLY ACTIVE BICYCLIC-SULPHONAMIDES AND PHARMACEUTICAL COMPOSITIONS
Pharmaceutical compounds have a bicyclic-sulphonamide structure and pharmaceutical compositions including the compounds may be used in therapy as brain-cell-death protectants and may be used, for example, in the treatment of chronic neurodegenerative diseases. The compounds are active as inhibitors of N-acylethanolamine-hydrolysing acid amidase (NAAA) and may be used for the therapeutic treatment and prevention of pain and inflammatory disorders and other disorders which benefit from the modulation of fatty acid ethanolamides, particularly palmitoylethanolamide (PEA).
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Paragraph 0092

(2019/05/18)

FXR receptor agonist
The present invention discloses an FXR receptor agonist, belongs to the technical field of medicine, and particularly relates to a compound represented by a formula (I), a pharmaceutically acceptablesalt, an ester or a stereoisomer thereof, wherein R, R, R, M, L, L1, W, A , B, Q, m and n are defined in the specification. The present invention further relates to a preparation method of the compound, a pharmaceutical preparation, and applications in preparation of drugs for treatment and/or prevention of nonalcoholic fatty liver disease, primary biliary cirrhosis, lipid metabolism disorder, diabetic complication, malignant tumors and other related diseases mediated by FXR receptors. The formula I is defined in the specification.
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Paragraph 0616; 0618; 0619; 0620

(2019/02/10)

Discovery of MK-8282 as a Potent G-Protein-Coupled Receptor 119 Agonist for the Treatment of Type 2 Diabetes
The ever-growing prevalence of type 2 diabetes in the world has necessitated an urgent need for multiple orally effective agents that can regulate glucose homeostasis with a concurrent reduction in body weight. G-Protein coupled receptor 119 (GPR119) is a GPCR target at which agonists have demonstrated glucose-dependent insulin secretion and shows beneficial effects on glycemic control. Herein, we describe our efforts leading to the identification of a potent, oral GPR-119 agonist, MK-8282, which shows improved glucose tolerance in multiple animal models and has excellent off-target profile. The key design elements in the compounds involved a combination of a fluoro-pyrimidine and a conformationally constrained bridged piperidine to impart good potency and efficacy.
Neelamkavil, Santhosh F.,Stamford, Andrew W.,Kowalski, Timothy,Biswas, Dipshikha,Boyle, Craig,Chackalamannil, Samuel,Xia, Yan,Jayne, Charles,Neustadt, Bernard,Hao, Jinsong,Liu, Hong,Dai, Xing,Baker, Hana,Hawes, Brian,O'Neill, Kim,Tang, Huadong,Greenlee, William J.
supporting information
p. 457 - 461
(2018/05/23)

PYRAZOLOPYRIMIDINE INHIBITORS OF IRAK4 ACTIVITY
The present invention relates to pyrazolopyrimidine inhibitors of IRAK4 of formula (I) and provides compositions comprising such inhibitors, as well as methods therewith for treating IRAK4-mediated or -associated conditions or diseases.
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Page/Page column 79; 80

(2016/09/26)

CROSS-LINKED CYCLIC AMINE COMPOUNDS AND AGENTS FOR PEST CONTROL
Agents for pest control comprising cyclic amine compounds represented by the formula (1) or salts thereof or N-oxides thereof as an active ingredient, wherein Cy 1 represents an unsubstituted or substituted 5-membered heterocycle or unsubstituted or substituted group represented by the formula (a) below, wherein Y 1 and Y 2 each independently represents nitrogen or carbon and symbol * represents the bonding positions.
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Paragraph 0115; 0116

(2015/11/16)

BRIDGED PIPERIDINE DERIVATIVES
The present invention relates to compounds of formula I hetaryl I, hetaryl II, R1, R2, R3, Y, m, and o or to pharmaceutically active acid addition salts thereof. The present compounds of formula I are modulators for amyloid beta and thus, they may be useful for the treatment or prevention of a disease associated with the deposition of β-amyloid in the brain, in particular Alzheimer's disease, and other diseases such as cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementia pugilistica and Down syndrome.
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Page/Page column 27

(2012/09/11)

BRIDGED PIPERIDINE DERIVATIVES
The present invention relates to compounds of formula (l); hetaryl I is a five or six membered heteroaryl group, containing 1 to 3 heteroatoms, selected from S or N; hetaryl II is a six membered heteroaryl group, containing 1 to 3 heteroatoms, selected from S or N, or is a two membered ring system containing 1 to 4 heteroatoms selected from S, or N, wherein at least one ring is aromatic in nature; R1 is lower alkyl, lower alkoxy, lower alkyl substituted by halogen or halogen; R2 is lower alkyl, lower alkyl substituted by halogen, halogen, lower alkoxy, cycloalkyl substituted by lower alkyl or lower alkyl substituted by halogen, or is lower alkyl substituted by hydroxy, or is furyl, or is O-benzyl, (CH2)p-phenyl, optionally substituted by halogen, lower alkoxy, lower alkyl substituted by halogen, lower alkyl or by cyano; R3 is hydrogen or lower alkyl; Y is (CH2)n-, -CH2OCH2-, -CH2O-, CH2S-, -CH2SCH2- and is bonded to two of the ring carbon atoms, bonding being to either the ring carbon atoms a and b or the ring carbon atoms c and d; p is 0 or 1; m is 0, 1 or 2; if m is 2 then R1 may be the same or different; -75- n is 2 or 3; o is 0, 1 or 2, if o is 2, then R2 may be the same or different; or to pharmaceutically active acid addition salts thereof. The present compounds of formula I are modulators for amyloid beta and thus, they may be useful for the treatment or prevention of a disease associated with the deposition of β-amyloid in the brain, in particular Alzheimers disease, and other diseases such as cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementia pugilistica and Down syndrome.
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Page/Page column 58

(2012/09/21)

INDOLYLPYRIMIDINES AS MODULATORS OF GPR119
The present invention relates to compounds of Formula (I) that are useful for treating, preventing and/or managing the diseases, disorders, syndromes or conditions modulated by GPR119 receptor activity. The invention also relates to the process for preparation of the compounds, pharmaceutical compositions thereof. The invention further relates to methods of treating, preventing and/or managing diseases, disorders syndromes or conditions associated with the modulation of GPR119 receptor by using either alone or in combinations of Formula (I).
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Page/Page column 53-54

(2012/03/26)

Activation of the G-protein-coupled receptor 119: A conformation-base hypothesis for understanding agonist response
The synthesis and properties of the bridged piperidine (oxaazabicyclo) compounds 8, 9, and 11 are described. A conformational analysis of these structures is compared with the representative GPR119 ligand 1. These results and the differences in agonist pharmacology are used to formulate a conformation-based hypothesis to understand activation of the GPR119 receptor. We also show for these structures that the agonist pharmacology in rat masks the important differences in human pharmacology.
McClure, Kim F.,Darout, Etzer,Guimar?es, Cristiano R. W.,Deninno, Michael P.,Mascitti, Vincent,Munchhof, Michael J.,Robinson, Ralph P.,Kohrt, Jeffrey,Harris, Anthony R.,Moore, Dianna E.,Li, Bryan,Samp, Lacey,Lefker, Bruce A.,Futatsugi, Kentaro,Kung, Daniel,Bonin, Paul D.,Cornelius, Peter,Wang, Ruduan,Salter, Eben,Hornby, Sam,Kalgutkar, Amit S.,Chen, Yue
experimental part
p. 1948 - 1952
(2011/05/19)

An approach to azabicyclo[ n.3.1]alkanes by double mannich reaction
Chlorotrimethylsilane-promoted double Mannich annulation of ketones using N,N-bis(methoxymethyl)benzylamine has been explored. It has been shown that the structure of the substrate drastically influenced the outcome of the reaction. The method allows azabicyclo[n.3.1]alkane derivatives (n=2-5) to be obtained in good yields. Georg Thieme Verlag Stuttgart New York.
Mityuk, Andrey P.,Denisenko, Aleksandr V.,Dacenko, Oleksandr P.,Grygorenko, Oleksandr O.,Mykhailiuk, Pavel K.,Volochnyuk, Dmitriy M.,Shishkin, Oleg V.,Tolmachev, Andrey A.
experimental part
p. 493 - 497
(2010/04/26)

BICYCLIC HETEROCYCLE DERIVATIVES AND USE THEREOF AS GPR119 MODULATORS
The present invention relates to Bicyclic Heterocycle Derivatives of Formula (I), compositions comprising a Bicyclic Heterocycle Derivative, and methods of using the Bicyclic Heterocycle Derivatives for treating or preventing obesity, diabetes, a metaboli
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Page/Page column 87

(2010/04/03)

3-OXA-7-AZABICYCLO[3.3.1]NONANES
Compounds of Formula (I) that modulate the activity of the G-protein-coupled receptor GPR119 and their uses in the treatment of diseases linked to the modulation of the G-protein-coupled receptor GPR119 in animals are described herein.
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Page/Page column 24

(2010/10/03)

GPR 119 MODULATORS
Compounds of Formula (I) that modulate the activity of the G -protein-coupled receptor GPFM 19 and their uses in the treatment of diseases linked to the modulation of the G-protein-coupled receptor GPR119 in animals are described herein.
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Page/Page column 49-50

(2010/11/18)

BRIDGED CYCLIC AMINE COMPOUND AND PEST CONTROL AGENT
A cyclic amine compound represented by the formula (1): [wherein Cy1 represents an (un)substituted aromatic ring; X represents oxygen, sulfur, (un)substituted nitrogen, sulfinyl, or sulfonyl; R1a and R2a/s
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Page/Page column 40-41

(2010/11/27)

Solid-phase development of chiral phosphoramidite ligands for enantioselective conjugate addition reactions
The development of a method for the optimization of chiral ligands for the steric steering of enantioselective Cu-catalyzed conjugate additions of Zn-alkyls to enones is described. The method is based on combinatorial principles and solid-phase techniques. It includes the combinatorial synthesis of chiral bispidine-derived ligands embodying a phosphoramidite group on the solid phase and their investigation in immobilized form in the conjugate addition of ZnEt2 to cyclohexenone as test reaction. The best identified ligands were also synthesized separately and investigated in its soluble form. The results obtained for the polymer-bound ligands correctly mirrored the performance of the soluble ligands. The library embodied members giving ee values varying between 3 and 67%. The "positional scanning" approach proved to be invalid for the study of the ligand system, indicating that this approach in general should be applied with care. Taken together, the method allowed for rapid and efficient optimization of the ligands and led to the development of the first enantioselective, Cu-catalyzed conjugate addition reaction with a polymer-bound ligand.
Huttenloch, Oliver,Laxman, Eltepu,Waldmann, Herbert
p. 4767 - 4780
(2007/10/03)

Chiral bicyclic phosphoramidites - A new class of ligands for asymmetric catalysis
The development of new ligands for catalytic asymmetric C-C bond formation is of great interest to organic synthesis. We describe here a new class of chiral phosphoramidites that embody one or two binaphthol units attached to an achiral azabicyclic [3.3.1] or [3.3.0] framework. These ligands were easily accessible from (R)-1,1′-binaphthyl-2,2′-dioxaphosphorchloridite (4) and the corresponding heterobicyclic core 1, 2, or 3. They were employed in enantioselective Cu-catalyzed additions of different dialkylzinc reagents to cyclic and acyclic enones. The chiral ketones were obtained with an enantiomeric ratio up to 91:9. The choice of the best ligand proved to be strongly dependent on each substrate. In addition, ligand 6 was found to be the most suitable for Rh-catalyzed hydrogenations of α,β-unsaturated esters, giving rise to dimethyl 2-methylsuccinate and methyl N-acetylalaninate with enantiomer ratios up to 95:5.
Huttenloch, Oliver,Spieler, Jan,Waldmann, Herbert
p. 671 - 675
(2007/10/03)

N-substituted 3-oxa-and 3-thia-7-azabicyclo[3.3.1]nonanes as potential precursors of antiarrhythmics
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Tyagi, Sameer,Couch, Kevin M.,Garrison, Gregory L.,Berlin, K. Darrell,Scherlag, Benajmin J.,Patterson, Eugene,Lazzara, Ralph
p. 413 - 421
(2007/10/03)

3,7,9-Triheterabicyclodecan-10-ones: An Unusual Family of Heterocycles Obtained from 3,7-Diheterabicyclononan-9-ones
A series of new 3,7,9-triheterabicyclodecan-10-ones is reported for the first time.Members of the family of 3,7-diheterabicyclononan-9-ones served as precursors of the title compounds.Spectral evidence suggests the 3,7,9-triheterabicyclodecan-10-ones exist in a chair-boat (CB) ->/nonan-9-one precursors in solution may influence the ease of oxygen and nitrogen insertion in the ring enlargement to give the title molecules.Confirmation that three members of the bicyclodecan-10-ones exist in BC forms in the solid state was achieved via single crystal X-ray diffraction analysis for 7-benzyl-3-thia-7,9-diazabicyclodecan-10-one (4a), 3,7-dibenzyl-3,7,9-triazabicyclodecan-10-one (4c), and 3,7-dibenzyl-9-oxa-3,7-diazabicyclodecan-10-one (4d).
Garrison, Gregory L.,Berlin, K. Darrell,Scherlag, Benjamin J.,Lazzara, Ralph,Patterson, Eugene,et al.
p. 7670 - 7678
(2007/10/02)

THE MANNICH CONDENSATION WITH 1-HETERA-4-CYCLOHEXANONES. THE NOVEL FORMATION OF 7-BENZYL-3-HETERA-7-AZABICYCLONONAN-9-ONES, 3,6-DIBENZYLHEXAHYDRO-8a-METHOXY 5H-4a,8-(METHANOHETERAMETHANO)-2H-PYRIDO-1,3-OXAZINES, AND 2,4,10,12-TETRABENZYL-2,4,10,12-TETRAAZA-15-HETERADISPI...
We report for the first time the formation of unusual multicyclic products from the condensation of 1-hetera-4-cyclohexanones in a Mannich reaction with benzylamine, formaldehyde, and acetic acid in methanol.In addition to the expected ketones, namely 7-benzyl-3-hetera-7-azabicyclononan-9-ones, there were obtained from 4-thianone and 4-selenanone the following systems.Repeated Mannich condensations produced 3,6-dibenzylhexahydro-8a-(methoxy-5H-4a,8-(methanothiomethano)-2H-pyrido-1,3-oxazine, 3,6-dibenzylhexahydro-8a-methoxy-5H-4a,8-(methanoselenomethano)-2H-pyrido-1,3-oxazine, 2,4,10,12-tetrabenzyl-2,4,10,12-tetraaza-15-thiadispiro-hexadecan-7-one, and 2,4,10,12-tetrabenzyl-2,4,10,12-tetraza-15-selenadispirohexadecan-7-one.Single crystal X-ray diffraction analysis confirmed the structures of the first three solids.Using tetrahydro-4H-pyran-4-one, it was possible to obtain 7-benzyl-3-oxa-7-azabicyclononan-9-one and 2,4,10,12-tetrabenzyl-2,4,10,12-tetraaza-15-oxadispirohexadecan-7-one.To the best of our knowledge, these systems have not been previously recorded, and the method reported herein is a one-step approach.NMR analyses, including 1H, 13C, and 15N analyses, were completed and support all of the structures described herein.A mechanism is briefly outlined to explain the formation of these novel polycyclic heterocycles. - Key words: Mannich reaction; 1-hetera-4-cyclohexanones; 3,6-dibenzylhexahydro-8a-methoxy-5H-4a,8-(methanoheteromethano)-2H-pyrido--1,3-oxazine; 2,4,10,12-tetrabenzyl-2,4,10,12-tetraaza-15-heteradispirohexadecan-7-one; 7-benzyl-3-hetera-7-azabicyclononan-9-ones; selenium and sulfur derivatives.
Smith, Gary S.,Berlin, K. Darrell,Zisman, Stan A.,Holt, Elizabeth M.,Green, Vicki A.,Helm, Dick Van Der
p. 91 - 112
(2007/10/02)

Syntheses and a Conformational Study of Certain Selected 3-Oxa-7-azabicyclononan-9-ones. Single-Crystal X-ray Diffraction Analysis of 6,8-Bis(2-chlorophenyl)-3-oxa-7-azabicyclononan-9-one.
Isomers of 2,4,6,8-tetraphenyl-3-oxa-7-azabicyclononan-9-ones, 6,8-bis(2-chlorophenyl)-3-oxa-7-azabicyclononan-9-one, and N-benzyl-3-oxa-7-azabicyclononan-9-one have been prepared by Mannich-type cyclocondensations with appropiate tet
Arjunan, Palanisamy,Berlin, K. Darrell,Barnes, Charles L.,Helm, Dick van der
p. 3196 - 3204
(2007/10/02)