- Histamine H3 receptor antagonists with peptidomimetic (keto)piperazine structures to inhibit Aβ oligomerisation
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Alzheime?s disease (AD) is the most prominent neurodegenerative disorder with high medical need. Protein-protein-interactions (PPI) interactions have a critical role in AD where β-amyloid structures (Aβ) build toxic oligomers. Design of disease modifying multi target directed ligand (MTDL) has been performed, which disable PPI on the one hand and on the other hand, act as procognitive antagonists at the histamine H3 receptor (H3R). The synthetized compounds are structurally based on peptidomimetic amino acid-like structures mainly as keto, diketo-, or acyl variations of a piperazine moiety connected to an H3R pharmacophore. Most of them showed low nanomolar affinities at H3R and some with promising affinity to Aβ-monomers. The structure–activity relationships (SAR) described offer new possibilities for MTDL with an optimized profile combining symptomatic and potential causal therapeutic approaches in AD.
- Falkenstein, Markus,Reiner-Link, David,Zivkovic, Aleksandra,Gering, Ian,Willbold, Dieter,Stark, Holger
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- (S)-3-(2-(4-(BENZYL)-3-OXOPIPERAZIN-1-YL)ACETAMIDO)-4-OXO-5-(2,3,5,6-TETRAFLUOROPHENOXY)PENTANOIC ACID DERIVATIVES AND RELATED COMPOUNDS AS CASPASE INHIBITORS FOR TREATING CARDIOVASCULAR DISEASES
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The present invention relates to (S)-3-(2-(4-(benzyl)-3-oxopiperazin-l- yl)acetamido)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid derivatives and related compounds as caspase inhibitors for treating e.g. cardiovascular, kidney, liver, lung, skin, joints, CNS, inflammatory and autoimmune diseases.
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Paragraph 00323; 00335
(2020/01/24)
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- INHIBITORS OF INDOLEAMINE 2,3-DIOXYGENASE AND METHODS OF THEIR USE
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The present invention provides compounds of formula (I): wherein all of the variables are as defined herein. These compounds are inhibitors of indoleamine 2,3-dioxygenase (IDO), which may be used as medicaments for the treatment of proliferative disorders, such as cancer, viral infections and/or autoimmune diseases.
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Page/Page column 108-109
(2020/02/16)
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- NOVEL SUBSTITUTED PIPERAZINE AMIDE COMPOUNDS AS INDOLEAMINE 2, 3-DIOXYGENASE (IDO) INHIBITORS
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Disclosed herein are compounds of formula (I) which are inhibitors of an IDO enzyme: (I). Also disclosed herein are uses of the compounds in the potential treatment or prevention of an IDO-associated disease or disorder. Also disclosed herein are compositions comprising these compounds. Further disclosed herein are uses of the compositions in the potential treatment or prevention of an IDO-associated disease or disorder.
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Page/Page column 160
(2020/06/19)
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- 2-PHENYLIMIDAZO[4,5-B]PYRIDIN-7-AMINE DERIVATES USEFUL AS INHIBITORS OF MAMMALIAN TYROSINE KINASE ROR1 ACTIVITY
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Compound of formula (I′) or (I′′) or a pharmaceutically acceptable salt thereof. The compound is an inhibitor of mammalian kinase enzyme activity, including ROR1 tyrosine kinase activity and may be used in the treatment of disorders associated with such activity.
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Page/Page column 115-116
(2018/03/26)
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- Transition-Metal-Free Amine Oxidation: A Chemoselective Strategy for the Late-Stage Formation of Lactams
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A metal-free strategy for the formation of lactams via selective oxidation of cyclic secondary and tertiary amines is described. Molecular iodine facilitates both chemoselective and regioselective oxidation of C-H bonds directly adjacent to a cyclic amine. The mild conditions, functional group tolerance, and substrate scope are demonstrated using a suite of diverse small molecule cyclic amines, including clinically approved drug scaffolds.
- Griffiths, Robert J.,Burley, Glenn A.,Talbot, Eric P. A.
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supporting information
p. 870 - 873
(2017/02/26)
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- 6 Phenyl or 6 Pyridin 3 YL Indazole Derivatives and Methods of Use
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Compounds of formula (I) and pharmaceutically acceptable salts, esters, amides, or radiolabelled forms thereof, wherein R1, R2, R3, R4, R5, R6, and X are as defined in the specification, are useful in treating conditions or disorders prevented by or ameliorated by Tropomysin receptor kinases (Trk). Methods for making the compounds are disclosed. Also disclosed are pharmaceutical compositions of compounds of formula (I), and methods for using such compounds and compositions.
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Paragraph 0650
(2017/01/19)
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- 6-PHENYL- OR 6-(PYRIDIN-3-YL)INDAZOLE DERIVATIVES AND METHODS OF USE
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Compounds of formula (I) and pharmaceutically acceptable salts, esters, amides, or radiolabelled forms thereof, wherein R1, R2, R3, R4, R5, R6, and X are as defined in the specification, are useful in treating conditions or disorders prevented by or ameliorated by Tropomysin receptor kinases (Trk). Methods for making the compounds are disclosed. Also disclosed are pharmaceutical compositions of compounds of formula (I), and methods for using such compounds and compositions.
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Page/Page column 150; 151
(2015/08/06)
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- Discovery of DA-1229: A potent, long acting dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes
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A series of β-amino amide containing substituted piperazine-2-one derivatives was synthesized and evaluated as inhibitors of dipeptidyl pepdidase-4 (DPP-4) for the treatment of type 2 diabetes. As results of intensive SAR study of the series, (R)-4-[(R)-3-amino-4-(2,4,5-trifluorophenyl)- butanoyl]-3-(t-butoxymethyl)-piperazin-2-one (DA-1229) displayed potent DPP-4 inhibition pattern in several animal models, was selected for clinical development.
- Kim, Heung Jae,Kwak, Woo Young,Min, Jong Pil,Lee, Jae Young,Yoon, Tae Hyun,Kim, Ha Dong,Shin, Chang Yell,Kim, Mi Kyung,Choi, Song Hyen,Kim, Hae Sun,Yang, Eun Kyoung,Cheong, Ye Hwang,Chae, Yu Na,Park, Kyung Jin,Jang, Ji Myun,Choi, Soo Jung,Son, Moon Ho,Kim, Soon Hoe,Yoo, Moohi,Lee, Bong Jin
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scheme or table
p. 3809 - 3812
(2011/07/31)
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- Arylpiperazine derivatives and uses thereof
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Compounds of the formula: or pharmaceutically acceptable salts thereof, wherein Ar, R1, R2, R3 and R4 are as defined herein. Also provided are pharmaceutical compositions, methods of using, and methods of preparing the compounds.
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Page/Page column 14-15
(2009/09/05)
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- Design, synthesis and preliminary pharmacological evaluation of new piperidine and piperazine derivatives as cognition-enhancers
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A series of 2-oxopiperazine, 4-aminomethyl-, 3-amino- and 3-aminomethylpiperidine analogues of DM235 (sunifiram) and MN19 (sapunifiram), two previously reported potent cognition-enhancers, have been synthesized and tested in the mouse passive-avoidance test. The compounds display minimal effective doses in the range 0.3-10 mg/kg. Although the new substances do not show improved activity when compared to the parent compounds, some useful information has been obtained to understand structure-activity relationships. In addition, the 3-aminopiperidine moiety appears to be a promising scaffold to synthesize new drugs endowed with cognition-enhancing activity.
- Martini, Elisabetta,Ghelardini, Carla,Dei, Silvia,Guandalini, Luca,Manetti, Dina,Melchiorre, Michele,Norcini, Monica,Scapecchi, Serena,Teodori, Elisabetta,Romanelli, Maria Novella
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p. 1431 - 1443
(2008/09/18)
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- Rational design of novel, potent piperazinone and imidazolidinone BACE1 inhibitors
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Guided by structure-based design, we synthesized two novel series of potent inhibitors of BACE1 and generated extensive SAR around both the prime and non-prime side binding pockets. The key feature of both series is a cyclic amine motif specifically crafted to achieve interactions with both the flap and with the S2′ pocket.
- Cumming,Le,Babu,Carroll,Chen,Favreau,Gaspari,Guo,Hobbs,Huang,Iserloh,Kennedy,Kuvelkar,Li,Lowrie,McHugh,Ozgur,Pan,Parker,Saionz,Stamford,Strickland,Tadesse,Voigt,Wang,Wu,Zhang,Zhang
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experimental part
p. 3236 - 3241
(2009/04/07)
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- PHENOXYACETIC ACID DERIVATIVES USEFUL FOR TREATING RESPIRATORY DISEASES
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The invention relates to substituted phenoxyacetic acids as useful pharmaceutical compounds for treating respiratory disorders, pharmaceutical compositions containing them, and processes for their preparation.Formula (I)
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Page/Page column 116
(2008/06/13)
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- SUBSTITUTED AMIDE BETA SECRETASE INHIBITORS
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Disclosed are novel compounds of the formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R1, R2, R3, R4 and X are as defined in the specification. Also disclosed are pharmaceutical compositions comprising the compounds of formula (I). Also disclosed are methods of treating cognitive or neurodegenerative diseases such as Alzheimer's disease. Also disclosed are methods of treating a cognitive or neurodegenerative disease comprising administering to a patient I need of such treatment a combination of at least one compound of formula (I) and at least one compound selected from the group consisting of β-secretase inhibitors other than those of formula (I), HMG-CoA reductase inhibitors, gamma-secretase inhibitors, non-steroidal anti-inflammatory agents, N-methyl-D-aspartate receptor antagonists, cholinesterase inhibitors and anti-amyloid antibodies.
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Page/Page column 37; 38
(2010/10/19)
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- MACROCYCLIC BETA-SECRETASE INHIBITORS
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Disclosed are novel compounds of the formula (I): or a pharmaceutically acceptable salt or solvate thereof, wherein R1, R2, R3, n and X are as defined in the specification. Also disclosed are pharmaceutical compositions comprising the compounds of formula (I). Also disclosed are methods of treating cognitive or neurodegenerative diseases such as Alzheimer's disease. Also disclosed are methods of treating a cognitive or neurodegenerative disease comprising administering to a patient I need of such treatment a combination of at least one compound of formula (I) and at least one compound selected from the group consisting of -secretase inhibitors other than those of formula (I), HMG-CoA reductase inhibitors, gamma-secretase inhibitors, non-steroidal anti-inflammatory agents, N-methyl-D-aspartate receptor antagonists, cholinesterase inhibitors and anti-amyloid antibodies.
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Page/Page column 29-30
(2010/10/19)
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- CYCLIC AMINE BASE-1 INHIBITORS HAVING A HETEROCYCLIC SUBSTITUENT
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Disclosed are novel compounds of the formula (I)or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is formula (I) X is -0-, -C(R14)2- or -N(R)-; Z is -C(R14)2- or -N(R)-; t is 0, 1, 2 or 3; each R and R2 is independently H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, alkenyl or alkynyl; each R14 is H, alkyl, alkenyl, alkynyl, halo, -CN, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, -OR35, -N(R24)(R25)or -SR35; R41 is alkyl, cycloalkyl, -S02(alkyl), -C(O)-alkyl, -C(O)-cycloalkyl or -alkyl-NH-C(O)CH3; and the remaining variables are as defined in the specification. Also disclosed are pharmaceutical compositions comprising the compounds of formula I and methods of treating cognitive or neurodegenerative diseases with compounds of formula (I). Also disclosed are pharmaceutical compositions and methods of treatment comprising compounds of formula I in combination with other agents useful in treating cognitive or neurodegenerative diseases.
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Page/Page column 59-60
(2008/06/13)
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- CYCLIC AMINE BACE-1 INHIBITORS HAVING A BENZAMIDE SUBSTITUENT
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Disclosed are compounds of the formula or a pharmaceutically acceptable salt or solvate thereof, wherein R is-C(O)-N(R27)(R28) or and the remaining variables are as defined in the specification. Also disclosed are pharmaceutical compositions comprising the compounds of formula I. Also disclosed are methods of treating cognitive or neurodegenerative diseases such as Alzheimer’s disease. Also disclosed are pharmaceutical compositions and methods of treating cognitive or neurodegenerative diseases comprising the compounds of formula I in combination with a β-secretase inhibitor other than those of formula I, an HMG-CoA reductase inhibitor, a gamma-secretase inhibitor, a non-steroidal anti-inflammatory agent, and N-methyl-D-aspartate receptor antagonist, a cholinesterase inhibitor or an anti-amyloid antibody.
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Page/Page column 76
(2008/06/13)
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- Diastereoselectivity in the cycloaddition of 1-benzyl-2-piperazinone nitrone with alkenes
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The diastereoselectivity of the [2 + 3]-cycloaddition of 1-benzyl-2-piperazinone nitrone with several alkenes has been examined. exo-Type cycloadducts predominated for most substrates. Georg Thieme Verlag Stuttgart.
- Bernotas, Ronald C.,Sing, Lily,Friedrich, Dirk
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p. 465 - 469
(2007/10/03)
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- Cis-imidazolines
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The present invention provides compounds according to formula I having the designations provided herein, and pharmaceutically acceptable salts and esters thereof. These compounds inhibit the interaction of MDM2 protein with a p53-like peptide and have antiproliferative activity.
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- BICYCLIC HETEROARYL-ALKYLENE-(HOMO)PIPERAZINONES AND THIONE ANALOGUES THEREOF, THEIR PREPARATION, AND THEIR USE OF AS SELECTIVE AGONISTS OF 5HT1-LIKE RECEPTORS
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A class of piperazinones, homopiperazinones and thione analogues thereof, substituted at the 1-position by an optionally substituted alkenyl, alkynyl, aryl-alkyl or heteroaryl-alkyl moiety, and linked at the 4-position via an alkylene spacer to a fused bicyclic heteroaromatic moiety, typically indolyl, are selective agonists of 5-HT. sub.1-like receptors, being potent agonists of the human 5-HT 1Dα receptor subtype while possessing at least a 10-fold selective affinity for the 5-HT 1Dα receptor subtype relative to the 5-HT 1D. beta. subtype; they are therefore useful in the treatment and/or prevention of clinical conditions, in particular migraine and associated disorders, for which a subtype-selective agonist of 5-HT 1D receptors is indicated, while eliciting fewer side-effects, notably adverse cardiovascular events, than those associated with non-subtype-selective 5-HT 1D receptor agonists.
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- Synthesis of a 1-benzylpiperazin-2-one nitrone and its reaction with alkynes and alkenes
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A novel 1-benzylpiperazin-2-one nitrone has been synthesized. It readily undergoes [3 + 2] cycloadditions with alkynes and alkenes to give Δ4-isoxazolines and isoxazolidines, respectively, which can be reductively opened to 3-substituted piperazin-2-ones and 1,3-amino alcohols.
- Bernotas, Ronald C.,Adams, Ginette
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p. 7339 - 7342
(2007/10/03)
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- Piperazinone and piperazine polypeptides
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Piperazinone polypeptides which are useful as analgesics and psychotherapeutic agents as well as processes to produce them are described.
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