- Method for synthesizing monoamine-protected piperazine-(R/S)2-formate
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The invention discloses a method for synthesizing monoamine-protected piperazine-(R/S)2-formate, wherein the method comprises the steps: by using 2-piperazinecarboxylate as a raw material, protecting1,4-site amines by using different protective groups, and salifying by using different chiral amines, resolving to obtain a single chiral compound; and finally, using pyridine or DMAP and other pyridine analogues as an alkali, reacting oxalyl chloride, triphosgene, phosgene, thionyl chloride and other similar acyl chlorides in anhydrous tetrahydrofuran, 2-methyl tetrahydrofuran or toluene and other solvents, and finally adding methanol, ethanol, isopropanol, benzyl alcohol and other alcohol reagents to generate the target product capable of removing carboxylic acid ortho-amino protecting groups in a positioned manner and esterifying carboxylic acid. Amino groups on piperazine are separately protected through simple three-step reaction, chiral resolution is performed by utilizing the characteristics of acid, finally, protonated intermediates are formed through organic alkali and carboxylic acid, anhydride is formed by the protonated intermediates and ortho-amino groups, formic acid esterification is performed by utilizing alcohol to replace ring opening, and a final product is obtained.
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Page/Page column 0021-0023
(2021/02/06)
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- Bis(vinylsulfonyl)piperazines as efficient linkers for highly homogeneous antibody-drug conjugates
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Disulfide re-bridging strategy has demonstrated significant advantages in the construction of homogeneous antibody drug conjugates (ADCs). However, a major issue that disulfide scrambling at the hinge region of antibody leads to the formation of “half-antibody” has appeared for many re-bridging linkers. We present bis(vinylsulfonyl)piperazines (BVP) as efficient linkers to selectively re-bridge disulfides at the antigen-binding fragment (Fab) regions and produce highly homogeneous conjugates with a loading of two drugs without disulfide scrambling. We also found that optically active (S)-configuration linkers led to more sufficient conjugation compared with (R)-configuration. The BVP-linked ADCs demonstrated superior efficacy and antigen-selectivity in vitro cytotoxicity.
- Huang, Rong,Sheng, Yao,Wei, Ding,Yu, Jianghui,Chen, Hongli,Jiang, Biao
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- Piperazine compound and application thereof in preparation of chemokine receptor CCR2 antagonist
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The invention relates to a piperazine compound as shown in a formula (I) and an application of the piperazine compound in preparation of a chemokine receptor CCR2 antagonist or a medicine for treatingCCR2-mediated diseases.
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Paragraph 0180-0184
(2020/07/28)
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- Hitting a Moving Target: Simulation and Crystallography Study of ATAD2 Bromodomain Blockers
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Small molecule ligand binding to the ATAD2 bromodomain is investigated here through the synergistic combination of molecular dynamics and protein crystallography. A previously unexplored conformation of the binding pocket upon rearrangement of the gatekeeper residue Ile1074 has been found. Further, our investigations reveal how minor structural differences in the ligands result in binding with different plasticity of the ZA loop for this difficult-to-drug bromodomain.
- Dolbois, Aymeric,Batiste, Laurent,Wiedmer, Lars,Dong, Jing,Brütsch, Manuela,Huang, Danzhi,Deerain, Nicholas M.,Spiliotopoulos, Dimitrios,Cheng-Sánchez, Iván,Laul, Eleen,Nevado, Cristina,?led?, Pawe?,Caflisch, Amedeo
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supporting information
p. 1573 - 1580
(2020/09/16)
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- SPIRO-LACTAM NMDA RECEPTOR MODULATORS AND USES THEREOF
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Disclosed are compounds having potency in the modulation of NMDA receptor activity. Such compounds can be used in the treatment of conditions such as depression and related disorders. Orally delivered formulations and other pharmaceutically acceptable delivery forms of the compounds, including intravenous formulations, are also disclosed.
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Page/Page column 28-29
(2018/03/01)
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- A General Amino Acid Synthesis Enabled by Innate Radical Cross-Coupling
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The direct union of primary, secondary, and tertiary carboxylic acids with a chiral glyoxylate-derived sulfinimine provides rapid access into a variety of enantiomerically pure α-amino acids (>85 examples). Characterized by operational simplicity, this radical-based reaction enables the modular assembly of exotic α-amino acids, including both unprecedented structures and those of established industrial value. The described method performs well in high-throughput library synthesis, and has already been implemented in three distinct medicinal chemistry campaigns.
- Ni, Shengyang,Garrido-Castro, Alberto F.,Merchant, Rohan R.,de Gruyter, Justine N.,Schmitt, Daniel C.,Mousseau, James J.,Gallego, Gary M.,Yang, Shouliang,Collins, Michael R.,Qiao, Jennifer X.,Yeung, Kap-Sun,Langley, David R.,Poss, Michael A.,Scola, Paul M.,Qin, Tian,Baran, Phil S.
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supporting information
p. 14560 - 14565
(2018/10/24)
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- Application of piperazine structure containing compound to preparation of LSD1 (Lysine Specific Demethylase 1) inhibitor
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The invention discloses application of a piperazine structure containing compound to the preparation of a histone lysine specific demethylase (LSD1) inhibitor. The structural general formula of the compound is as shown in the following descriptions (wherein, A is hydrogen, carbonyl or thiocarbonyl) or a configurational isomer and a pharmaceutical salt thereof, or is as shown in the following descriptions or a pharmaceutical salt thereof. The compound has an obvious inhibition effect on the LSD1, can be prepared into the LSD1 inhibitor, and is used for preventing and treating a disease related to the activity of the histone LSD1.
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Paragraph 0039
(2017/09/29)
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- Discovery of novel 2-((pyridin-3-yloxy)methyl)piperazines as α7 nicotinic acetylcholine receptor modulators for the treatment of inflammatory disorders
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Herein we report the design, synthesis, and structure-activity relationships for a new class of α7 nicotinic acetylcholine receptor (nAChR) modulators based on the 2-((pyridin-3-yloxy)methyl)piperazine scaffold. The oxazolo[4,5-b]pyridine, (R)-18, and 4-methoxyphenylurea, (R)-47, were identified as potent and selective modulators of the α7 nAChR with favorable in vitro safety profiles and good oral bioavailability in mouse. Both compounds were shown to significantly inhibit cellular infiltration in a murine model of allergic lung inflammation. Despite the structural and in vivo functional similarities in the compounds, only (R)-18 was shown to be an agonist. Compound (R)-47 demonstrated silent agonist activity. These data support the hypothesis that the anti-inflammatory activity of the α7 nAChR is mediated by a signal transduction pathway that is independent of ion current.
- Clark, Roger B.,Lamppu, Diana,Libertine, Lyn,McDonough, Amy,Kumar, Anjali,LaRosa, Greg,Rush, Roger,Elbaum, Daniel
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p. 3966 - 3983
(2014/06/09)
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- COVALENT INHIBITORS OF KRAS G12C
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Irreversible inhibitors of G12C mutant K-Ras protein are provided. Also disclosed are methods to modulate the activity of G12C mutant K-Ras protein and methods of treatment of disorders mediated by G12C mutant K-Ras protein.
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Paragraph 0531
(2014/09/30)
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- PIPERAZINE DERIVATIVES AS CAV2.2 CALCIUM CHANNEL BLOCKERS
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The invention relates to novel piperazine compounds; to processes for their preparation; to pharmaceutical compositions containing the compounds; and to the use of the compounds in therapy to treat diseases for which blocking the Cav2.2 calcium channels is beneficial, i.e. in particular to treat pain.
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Page/Page column 23-24
(2012/08/07)
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- COMPOUNDS, THEIR PHARMACEUTICAL COMPOSITIONS AND THEIR USES AS IDH1 MUTANTS INHIBITORS FOR TREATING CANCERS
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Provided are compounds of formula (I), wherein X, Y, Z, W, V, R2, R3 and m are defined as in the description. Their pharmaceutical compositions and their uses as IDH1 mutants inhibitors for treating cancers are also provided
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Page/Page column 112-113
(2013/02/28)
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- Methods of Treating Aneurysmal Dilatation, Blood Vessel Wall Weakness and Specifically Abdominal Aortic and Thoracic Aneurysm Using Matrix Metalloprotease-2 Inhibitors
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The present invention provides methods of treating aneurysmal dilatation, blood vessel wall weakness, and specifically abdominal aortic aneurysm and thoracic aneurysm by inhibiting MMPs and ADAM-10. Such compounds are useful in the in vitro study of the r
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- Tricyclic heterocyclic compound and use thereof
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The present invention provides a tricyclic heterocyclic compound having a serotonin 5-HT2C receptor activation action and the like. A 5-HT2C receptor activator containing a compound represented by the formula (I): wherein each symbol is as defined in the specification, or a salt thereof or a prodrug thereof.
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Page/Page column 34
(2009/12/28)
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- N-PHENYL HYDRAZIDES AS MODULATORS OF THE GHRELIN RECEPTOR
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The present invention relates to novel compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein: each R1 is independently selected from the group consisting of Cl, Br, CH3 and CF3; X is carbon or nitrogen; R1a is H or a straight C1-3 alkyl group; R2a is H or a methyl group R2 is selected from the group consisting of C1-3alkyl, H and -(CH2)n-, wherein n is 3 or 4 and the terminal carbon of the chain is bonded to the carbon atom adjacent to the nitrogen bearing the R2 group, such that a fused 6,5 or 6,6-bicyclic ring is formed. Y is selected from the group consisting of: phenyl which may be unsubstituted or substituted by one or more substituents independently selected from the group consisting of C1-3alkyl, C1-3alkoxy, halogen, C1-3alkyl substituted by 1 to 7 fluoro atoms and C1-3alkoxy substituted by 1 to 7 fluoro atoms; pyridyl which may be unsubstituted or substituted by one or more substituents independently selected from the group consisting of C1-3alkyl, OCH3, CF3, CN, and halogen; naphthyl which may be unsubstituted or substituted by one or more substituents independently selected from the group consisting of F and OCH3; pyrimidinyl; imidazo[1,2-a]pyridine-6-yl; benzothiophen-2-yl; benzothiophen-5-yl; benzofuran-2-yl; dibenzo[b,d]furan-3-yl; dibenzo[b,d]thiophen-2-yl; dibenzo[b,d]thiophen-4-yl; 1,3- benzodioxol-5-yl; 2,3-dihydro-1,4-benzodioxin-5-yl; 2,3-dihydro-1,4-benzodioxin-6-yl; 2,3- dihydro-1-benzofuran-4-yl; 2,2-difluoro-1,3-benzodiox-4-yl; pyridazinyl; imidazolyl; oxazolyl; pyrazolyl; thiazolyl; and triazolyl; with the proviso that when Y is 2,3-dihydro-1,4-benzodioxin-6-yl, R1 is not Cl; processes for their preparation, intermediates useble in these processes, pharmaceutical compositions containing them and their use in therapy, for example as modulators of of the growth hormone secretagogue receptor (also referred to as the ghrelin receptor or GHSR1a receptor) and/or for the treatment and/or prophylaxis of a disorder mediated by the ghrelin receptor.
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Page/Page column 157-158
(2009/01/24)
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- Constrained analogues of tocainide as potent skeletal muscle sodium channel blockers towards the development of antimyotonic agents
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1-Benzyl-N-(2,6-dimethylphenyl)piperidine-3-carboxamide and 4-benzyl-N-(2,6-dimethylphenyl)piperazine-2-carboxamide, two conformationally restricted analogues of tocainide, were designed and synthesized as voltage-gated skeletal muscle sodium channel blockers. They showed, with respect to tocainide, a marked increase in both potency and use-dependent block.
- Catalano, Alessia,Carocci, Alessia,Corbo, Filomena,Franchini, Carlo,Muraglia, Marilena,Scilimati, Antonio,De Bellis, Michela,De Luca, Annamaria,Camerino, Diana Conte,Sinicropi, Maria Stefania,Tortorella, Vincenzo
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p. 2535 - 2540
(2008/12/23)
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- An orthogonal protection strategy for the synthesis of 2-substituted piperazines
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Tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-ones are readily prepared from the bis-carbamate protected piperazine-2-carboxylic acids and serve as orthogonally protected piperazines from which a variety of 2-substituted piperazines can be prepared. Sodium benzylate and sodium phenoxides react at the C-5 carbon of the oxazolidinone to yield 2-(benzyloxymethyl)piperazines and 2-(phenoxymethyl)piperazines, respectively. The tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-ones also provide convenient scaffolds from which 2-benzyl- and 2-phenethylpiperazines are prepared.
- Clark, Roger B.,Elbaum, Daniel
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p. 3057 - 3065
(2007/10/03)
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- NOVEL PIPERAZINES, PHARMACEUTICAL COMPOSITIONS AND METHODS OF USE THEREOF
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Disclosed are novel piperazine derivatives that act as agonists of the α7 nAChR. Also disclosed are phannaceutical compositions, methods of treating inflammatory conditions, methods of treating CNS disorders, methods for inhibiting cytokine release from mammalian cells and methods for the preparation of the novel compounds.
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Page/Page column 72-73
(2008/06/13)
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- Novel compounds and therapeutic uses thereof
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The invention discloses a novel series of compound represented by general formula (I), its derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, pharmaceutically acceptable salts, solvates wherein X, n, k, z, R1, R2, R3, R4, R5 and R6 are as defined in the specification that are useful in (i) normalizing elevated blood glucose levels in diabetes, (ii) treating disorders related to glucose intolerance and (iii) for scavenging free radicals of mammals. The invention also discloses pharmaceutically acceptable composition comprising these compounds, method for preparation of the compounds as defined above and method of treating mamnnals including human beings by administering an effective amount of said compounds to a subject in need thereof. The invention further discloses use of these compounds in the manufacture of a medicament useful for treatment of different disease conditions as stated above.
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- Pharmaceutical compounds
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This invention relates to compounds of formula (I) where R1 to R12, —W—V—, —X—Y—, m and n have the values defined in claim 1, their preparation and use as pharmaceuticals.
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- Substituted piperazines
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Compounds are provided that act as potent antagonists of the CCR1 receptor, and which have been further confirmed in animal testing for inflammation, one of the hallmark disease states for CCR1. The compounds are generally aryl piperazine derivatives and are useful in pharmaceutical compositions, methods for the treatment of CCR1-mediated diseases, and as controls in assays for the identification of competitive CCR1 antagonists.
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- BENZPYRIDO CYCLOHEPTANE COMPOUNDS USEFUL FOR INHIBITION OF FARNESYL PROTEIN TRANSFERASE
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Novel compounds of Formula (1.0) are disclosed. Also disclosed is a method of inhibiting farnesyl protein transferase function and therefore inhibiting the abnormal growth of cells. The method comprises administering a compound of formula (1.0) to a biological system. In particular, the method inhibits the abnormal growth of cells in a mammal such as a human being.
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- Novel compounds and therapeutic uses thereof
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The invention discloses a novel series of compound represented by general formula (I), its derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, pharmaceutically acceptable salts, solvates wherein X, n, k, z, R1, R2, R3, R4, R5 and R6 are as defined in the specification that are useful in (i) normalizing elevated blood glucose levels in diabetes, (ii) treating disorders related to glucose intolerance and (iii) for scavenging free radicals of mammals. The invention also discloses pharmaceutically acceptable composition comprising these compounds, method for preparation of the compounds as defined above and method of treating mammals including human beings by administering an effective amount of said compounds to a subject in need thereof. The invention further discloses use of these compounds in the manufacture of a medicament useful for treatment of different disease conditions as stated above.
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- The relationship between physicochemical properties, in vitro activity and pharmacokinetic profiles of analogues of diamine-containing efflux pump inhibitors
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Following the optimization of diamine-containing efflux pump inhibitors with respect to in vitro potentiation activity, in vivo stability and acute toxicity, we addressed the question of how to control the pharmacokinetic properties of the series. Upon in
- Watkins, William J.,Landaverry, Yakira,Leger, Roger,Litman, Renee,Renau, Thomas E.,Williams, Nicole,Yen, Rose,Zhang, Jason Z.,Chamberland, Suzanne,Madsen, Deidre,Griffith, David,Tembe, Vrushali,Huie, Keith,Dudley, Michael N.
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p. 4241 - 4244
(2007/10/03)
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- Efflux pump inhibitors
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Compounds are described which have efflux pump inhibitor activity. Also described are methods of using such efflux pump inhibitor compounds and pharmaceutical compositions which include such compounds.
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- Substituted 1,4-piperazine-heteroaryl derivatives as 5-HT1D receptor agonists
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A class of 1,4-disubstituted piperazine derivatives, further substituted on one of the carbon atoms of the piperazine ring, are selective agonists of 5-HT1 -like receptors, being potent agonists of the human 5-HT1Dα receptor subtype whilst possessing at least a 10-fold selective affinity for the 5-HT1Dα receptor subtype relative to the 5-HT1Dβ 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-HT1D receptors is indicated, while eliciting fewer side-effects, notably adverse cardiovascular events, than those associated with non-subtype-selective 5-HT1D receptor agonists.
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