- CGRP ANTAGONIST COMPOUNDS
-
The disclosures herein relate to novel compounds of Formula (1a): and salts thereof, wherein W, Z, L, R1and R2 are defined herein, and their use in treating, preventing, ameliorating, controlling or reducing the risk of disorders associated with CGRP receptors.
- -
-
Page/Page column 120-121
(2020/12/30)
-
- NON-PEPTIDE OPIOID RECEPTOR MODULATORS
-
Non-peptide MOR opioid receptor modulators are provided. The compounds exhibit predominantly central activity and are used to treat e.g. opioid addiction. The compounds described herein are generally delivered (administered) in a pharmaceutical compositio
- -
-
Page/Page column 15
(2020/03/15)
-
- CGRP ANTAGONIST COMPOUNDS
-
The disclosures herein relate to novel compounds of Formula (1): and salts thereof, wherein A1, A2, Q, X, R1, R2 and R3 are defined herein, and their use in treating, preventing, ameliorating, control
- -
-
Page/Page column 40; 41
(2020/12/30)
-
- Design, Synthesis, and Biological Evaluation of the Third Generation 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4′-pyridyl)carboxamido]morphinan (NAP) Derivatives as μ/κ Opioid Receptor Dual Selective Ligands
-
μ opioid receptor (MOR) agonists have been widely applied for treating moderate to severe pain. However, numerous adverse effects have been associated with their application, including opioid-induced constipation (OIC), respiratory depression, and addicti
- Zheng, Yi,Obeng, Samuel,Wang, Huiqun,Jali, Abdulmajeed M.,Peddibhotla, Bharath,Williams, Dwight A.,Zou, Chuanchun,Stevens, David L.,Dewey, William L.,Akbarali, Hamid I.,Selley, Dana E.,Zhang, Yan
-
supporting information
p. 561 - 574
(2019/01/30)
-
- HETEROARYLDIHYDROPYRIMIDINE DERIVATIVES AND METHODS OF TREATING HEPATITIS B INFECTIONS
-
Provided herein are compounds useful for the treatment of HBV infection in a subject in need thereof, pharmaceutical compositions thereof, and methods of inhibiting, suppressing, or preventing HBV infection in the subject.
- -
-
Page/Page column 39; 40
(2019/01/17)
-
- COMPOUNDS
-
Disclosed are compounds of the formula (I) and pharmaceutically acceptable salts thereof: (I) wherein R1, R2, R3, R4, R5, R6, R8, R9, X, X1, X2, X3, L1 and n are as defined herein. The compounds are inhibitors of adrenomedullin receptor subtype 2 (AM2). Also disclosed are the compounds for use in the treatment of diseases modulated AM2, including proliferative diseases such as cancer; pharmaceutical compositions comprising the compounds; methods for preparing the compounds;and intermediates useful in the preparation of the compounds.
- -
-
Page/Page column 313
(2018/12/13)
-
- PIPERIDINE COMPOUNDS AS PCSK9 INHIBITORS
-
One aspect of the invention relates to a series of new PCSK9 inhibitor compounds comprising piperidine ring structures, including compounds of formula (I) and/or pharmaceutically acceptable salts thereof. Another aspect of the invention relates to methods of treating PCSK9 receptor related diseases comprising administration of one or more compounds of formula (I) or a pharmaceutically acceptable salt thereof.
- -
-
Paragraph 0263; 0264; 0265
(2018/11/21)
-
- Preparation method of 2-((1S3aR7aR)-5-tert-butyloxycarbonyltetrahydrofuro[3,4]piperidine-1)acetic acid
-
The invention relates to a preparation method of 2-((1S3aR7aR)-5-tert-butyloxycarbonyltetrahydrofuro[3,4]piperidine-1)acetic acid. The preparation method comprises 11 steps: carrying out esterification on a dicarboxylic acid piperidine compound 1 in thionyl chloride to obtain a diester compound 2; then reducing a pyridine ring by utilizing palladium carbon to obtain a compound 3; then taking the compound 3 to react with Boc acid anhydride to obtain a Boc protected compound 4; hydrolyzing the compound 4 by utilizing lithium hydroxide to obtain a dicarboxylic acid compound 5; carrying out ring closure in acetic anhydride to obtain a compound 6; carrying out reduction and ring opening by utilizing NaBH4 to obtain a mixture of position isomerism compounds 7A and 7B; carrying out the ring closure in the presence of iodomethane and potassium carbonate to generate position isomerism lactone 8A and 8B; step 8, reducing the 8A, obtained by column passing separation, by utilizing DIBAH (Diisobutylaluminum Hydride) to obtain a compound 9; carrying out Wittig reaction to obtain a compound 10; carrying out Michael addition under an alkaline condition to obtain a compound 11; finally, hydrolyzing the compound 11 under the alkaline condition to obtain a final compound.
- -
-
Paragraph 0007
(2017/12/27)
-
- Design, Synthesis, and Evaluation of the Highly Selective and Potent G-Protein-Coupled Receptor Kinase 2 (GRK2) Inhibitor for the Potential Treatment of Heart Failure
-
A novel class of therapeutic drug candidates for heart failure, highly potent and selective GRK2 inhibitors, exhibit potentiation of β-adrenergic signaling in vitro studies. Hydrazone derivative 5 and 1,2,4-triazole derivative 24a were identified as hit compounds by HTS. New scaffold generation and SAR studies of all parts resulted in a 4-methyl-1,2,4-triazole derivative with an N-benzylcarboxamide moiety with highly potent activity toward GRK2 and selectivity over other kinases. In terms of subtype selectivity, these compounds showed enough selectivity against GRK1, 5, 6, and 7 with almost equipotent inhibition to GRK3. Our medicinal chemistry efforts led to the discovery of 115h (GRK2 IC50 = 18 nM), which was obtained the cocrystal structure with human GRK2 and an inhibitor of GRK2 that potentiates β-adrenergic receptor (βAR)-mediated cAMP accumulation and prevents internalization of βARs in β2AR-expressing HEK293 cells treated with isoproterenol. Therefore, 115h appears to be a novel class of therapeutic for heart failure treatment.
- Okawa, Tomohiro,Aramaki, Yoshio,Yamamoto, Mitsuo,Kobayashi, Toshitake,Fukumoto, Shoji,Toyoda, Yukio,Henta, Tsutomu,Hata, Akito,Ikeda, Shota,Kaneko, Manami,Hoffman, Isaac D.,Sang, Bi-Ching,Zou, Hua,Kawamoto, Tetsuji
-
p. 6942 - 6990
(2017/09/07)
-
- And circular PI3K inhibitors (by machine translation)
-
The invention belongs to the field of medical technology, in particular to general formula (I) and of the everted shown in the PI3K inhibitor, or a pharmaceutically acceptable salt, ester, stereo isomers, solvates, wherein R 1, R 2, R 3 as defined in the specification. The invention also relates to methods of preparing such compounds, pharmaceutical formulations containing these compounds and pharmaceutical compositions, use of these compounds in the preparation and treatment and/or prevention of proliferative diseases of application of the medicament. (by machine translation)
- -
-
Paragraph 0402; 0403; 0404
(2016/10/08)
-
- Minimizing CYP2C9 Inhibition of Exposed-Pyridine NAMPT (Nicotinamide Phosphoribosyltransferase) Inhibitors
-
NAMPT inhibitors may show potential as therapeutics for oncology. Throughout our NAMPT inhibitor program, we found that exposed pyridines or related heterocyclic systems in the left-hand portion of the inhibitors are necessary pharmacophores for potent cellular NAMPT inhibition. However, when combined with a benzyl group in the center of the inhibitors, such pyridine-like moieties also led to consistent and potent inhibition of CYP2C9. In an attempt to reduce CYP2C9 inhibition, a parallel synthesis approach was used to identify central benzyl group replacements with increased Fsp3. A spirocyclic central motif was thus discovered that was combined with left-hand pyridines (or pyridine-like systems) to provide cellularly potent NAMPT inhibitors with minimal CYP2C9 inhibition. Further optimization of potency and ADME properties led to the discovery of compound 68, a highly potent NAMPT inhibitor with outstanding efficacy in a mouse tumor xenograft model and lacking measurable CYP2C9 inhibition at the concentrations tested.
- Zak, Mark,Yuen, Po-Wai,Liu, Xiongcai,Patel, Snahel,Sampath, Deepak,Oeh, Jason,Liederer, Bianca M.,Wang, Weiru,O'Brien, Thomas,Xiao, Yang,Skelton, Nicholas,Hua, Rongbao,Sodhi, Jasleen,Wang, Yunli,Zhang, Lei,Zhao, Guiling,Zheng, Xiaozhang,Ho, Yen-Ching,Bair, Kenneth W.,Dragovich, Peter S.
-
p. 8345 - 8368
(2016/10/03)
-
- Efficient and Selective Cu/Nitroxyl-Catalyzed Methods for Aerobic Oxidative Lactonization of Diols
-
Cu/nitroxyl catalysts have been identified that promote highly efficient and selective aerobic oxidative lactonization of diols under mild reaction conditions using ambient air as the oxidant. The chemo- and regioselectivity of the reaction may be tuned by changing the identity of the nitroxyl cocatalyst. A Cu/ABNO catalyst system (ABNO = 9-azabicyclo[3.3.1]nonan-N-oxyl) shows excellent reactivity with symmetrical diols and hindered unsymmetrical diols, whereas a Cu/TEMPO catalyst system (TEMPO = 2,2,6,6-tetramethyl-1-piperidinyl-N-oxyl) displays excellent chemo- and regioselectivity for the oxidation of less hindered unsymmetrical diols. These catalyst systems are compatible with all classes of alcohols (benzylic, allylic, aliphatic), mediate efficient lactonization of 1,4-, 1,5-, and some 1,6-diols, and tolerate diverse functional groups, including alkenes, heterocycles, and other heteroatom-containing groups.
- Xie, Xiaomin,Stahl, Shannon S.
-
supporting information
p. 3767 - 3770
(2015/04/14)
-
- AMINOQUINAZOLINE DERIVATIVES AND THEIR SALTS AND METHODS OF USE
-
The present invention relates to the field of medicine. Provided herein are aminoquinazoline derivatives, their salts and pharmaceutical formulations useful in modulating the protein tyrosine kinase activity, and in modulating inter- and/or intra-cellular signaling. Also provided herein are pharmaceutically acceptable compositions comprising the aminoquinazoline compounds and methods of using the compositions in the treatment of hyperproliferative disorders in mammals, especially humans.
- -
-
Paragraph 0609-0610
(2014/08/19)
-
- AMINOQUINAZOLINE DERIVATIVES AND THEIR SALTS AND METHODS OF USE
-
The present invention relates to the field of medicine. Provided herein are aminoquinazoline derivatives, their salts and pharmaceutical formulations useful in modulating the protein tyrosine kinase activity, and in modulating inter-and/or intra-cellular signaling. Also provided herein are pharmaceutically acceptable compositions comprising the aminoquinazoline compounds and methods of using the compositions in the treatment of hyperproliferative disorders in mammals, especially humans.
- -
-
Paragraph 00380
(2013/06/05)
-
- A convenient procedure for bis-esterification of cyclic anhydrides
-
Aromatic and aliphatic cyclic anhydrides are chemoselectively and conveniently transformed to the corresponding diesters by the use of DBU and appropriate alkyl/allyl halides. This bis-esterification reaction has been exemplified mostly with dimethyl esters. But in some cases, mixed dialkyl esters are also prepared.
- Jana, Amit Kumar,Karmakar, Raju,Dinda, Bidyut Kumar,Mitra, Prithiba,Ghosh, Ketaki,Karmakar, Rajdip,Mal, Dipakranjan
-
p. 975 - 979
(2012/10/29)
-
- Synthesis and structure-activity relationships of 5,6,7,8-tetrahydropyrido[3,4-b]pyrazine-based hydroxamic acids as HB-EGF shedding inhibitors
-
HB-EGF Shedding inhibitors have been expected to become effective medicines for skin diseases caused by the proliferation of keratinocytes. In order to discover novel HB-EGF shedding inhibitors and clarify their structure-activity relationships, 5,6,7,8-tetrahydronaphthylidine-based hydroxamic acid and 5,6,7,8-tetrahydropyrido[3,4-b]pyrazine-based hydroxamic acids have been synthesized. Among the synthesized compounds, the ethoxyethoxy derivative 3o and the methoxypropoxy derivative 3p exhibited much more potent HB-EGF shedding inhibitory activity than CGS 27023A. The structural modification of 5,6,7,8-tetrahydropyrido[3,4-b]pyrazine-based hydroxamic acids enabled us to establish the following structure-activity relationships; the existences of the hydroxamic acid, the sulfonamide, and the phenyl moieties are crucial for a potent HB-EGF shedding inhibitory activity, and the stereochemistry of the alpha carbon of hydroxamic acid is also important. In addition, from the comparison of their HB-EGF shedding inhibitory activities with their MMPs inhibitory activities, we found that the S1′ pocket of the responsible enzyme for HB-EGF shedding is deep unlike that of MMP-1.
- Yoshiizumi, Kazuya,Yamamoto, Minoru,Miyasaka, Tomohiro,Ito, Yasuko,Kumihara, Hiroshi,Sawa, Masaaki,Kiyoi, Takao,Yamamoto, Takeshi,Nakajima, Fumio,Hirayama, Ryoichi,Kondo, Hirosato,Ishibushi, Etsuko,Ohmoto, Hiroshi,Inoue, Yoshimasa,Yoshino, Kohichiro
-
p. 433 - 450
(2007/10/03)
-
- Photodetachment of zwitterions: Probing intramolecular coulomb repulsion and attraction in the gas phase using pyridinium dicarboxylate anions
-
Zwitterions are critically important in many biological transformations and are used in numerous chemical processes. The consequences of electrostatic effects on reactivity and physical properties, however, are largely unknown. In this work, we report the results of negative ion photoelectron spectra of nine isomeric pyridinium dicarboxylate zwitterions and three nonzwitterionic methoxycarbonylpyridine carboxylate isomers (-O2CPyrCO2CH3). Information about the intramolecular electrostatic interactions was directly obtained from the photoelectron spectra. The adiabatic and vertical detachment energies were measured and understood in terms of intramolecular Coulombic forces. Calculations at the B3LYP and CCSD(T) level were performed and compared to the experimental electron binding energies. Structures, relative stabilities, and the electron detachment sites also were obtained from the calculations.
- Wang, Xue-Bin,Dacres, Jelena E.,Yang, Xin,Broadus, Katherine M.,Lis, Lev,Wang, Lai-Sheng,Kass, Steven R.
-
p. 296 - 304
(2007/10/03)
-
- Synthesis of (2S*,4R*,5S*)-piperidinetricarboxylic acid, a non-proteinogenic amino acid isolated from clitocybe acromelalga
-
(255*,4R*,5S*)-Piperidinetricarboxylic acid isolated from a poisonous mushroom Clitocybe acromelalga was synthesized along with its stereoisomers and their depolarizing activity was tested.
- Hashimoto, Kimiko,Higashibayashi, Shuhei,Shirahama, Haruhisa
-
p. 581 - 588
(2007/10/03)
-
- Facile access to novel 1,4-dihydroxynaphthalene-2,3-dicarboximides and heterofused analogs
-
A variety of novel 1,4-dihydroxynaphthalene-2,3-dicarboximides and heterofused analogs were prepared by a convenient one-pot base-catalyzed condensation of N-substituted succinimides with aromatic ortho diester derivatives.
- Murray, William M.,Semple, J. Edward
-
p. 1180 - 1182
(2007/10/03)
-
- Behavior of Pyridinium Salts Obtained from Derivatives of Pyridinedicarboxylic Acids in Basic Solutions. Addition of Hydroxide or Alkoxide To Form 1,2-Dihydropyridine Intermediates
-
The N-alkylated pyridinium salts obtained from the diethyl esters, N-ethyl amides, and N,N-diethyl amides of pyridine-3,5-dicarboxylic acid exhibit ultraviolet absorptions of moderate intensity in the region of 350 nm when dissolved in 95percent ethanol.This absorption increases in intensity on addition of base and disappears on acidification of the solutions.It is not observed in rigorously dried solvents like chloroform or methylene chloride.By 1H NMR spectroscopy it has been shown that a 1,2-dihydropyridine is formed reversibly by addition of hydroxide (or methoxide) to the 2-position of the pyridinium salts.Concurrently with the formation of these intermediates, proton-deuterium exchange (in deuterated solvents) occurs, possibly via betaines formed by base-induced deprotonation at the 2-position of the pyridinium salts.The corresponding derivatives of pyridine-2,5- and -3,5-dicarboxylic acids do not display this behavior.
- Speelman, Johanna C.,Kellogg, Richard M.
-
p. 647 - 653
(2007/10/02)
-
- Reaction of (E)-β-Enamino Amides with Dimethyl Acetylenecarboxylate (DMAD): Formation of Benzene Derivatives, Enamino Esters, and 2-Pyridones
-
An investigation of the additions of (E)-enamino amides (1a-d) with DMAD has shown that they are influenced by the stereochemistry of the intermediates and the amine component of the enamine system.In dry acetonitrile (E)- benzyl(methyl)amino- (1b), (E)-pyrrolidin-1-ylamino-(1c), and (E)-piperidin-1-ylamino-(1d) acrylamides, following a known mechanism, yielded tetramethyl benzene-1,2,3,4-tetracarboxylate (5), the (E)-aminobutenedioates (6a-d), and the 3,4-bismethoxycarbonylpyridin-2(1H)-one (8).Dimethylamino-(1a) and morpholin-1-ylamino-(1e)-acrylamides, owing to the different nucleophilicity of the β-carbon, formed a zwitterion (11) which eliminated propiolamide to give only the (E)-aminobutenedioates (6a,e).
- Nuvole, Antonio,Paglietti, Giuseppe
-
p. 1007 - 1011
(2007/10/02)
-
- Change of Orientation in Photoreaction by Oxygen. Effect of Oxygen on Photo-methoxylation of Dimethyl Ester of 2,4- and 3,4-Pyridinedicarboxylic Acid
-
The UV-irradiation of dimethyl 2,4- and 3,4-pyridinedicarboxylates in methanol in the presence of H2SO4 under O2 brings about methoxylation at the β-position of the pyridine ring, while under N2 methoxylation occurs at the α-position.
- Sugiyama, Toru,Kanai, Mitsuharu,Takenaka, Setsuko,Sugimori, Akira
-
p. 1331 - 1332
(2007/10/02)
-
- Heterocyclic Analogues of Phthalhydrazides: Cyclic Hydrazides of Pyridine 1-Oxide and Pyrazine 1,4-Dioxide Dicarboxylic Acids
-
The synthesis of N-oxides of the cyclic hydrazides of pyridine and pyrazine o-dicarboxylic acids is described.Pyridopyridazine-5,8-dione 1-oxide, pyridopyridazine-1,4-dione 6-oxide, and pyrazinopyridazine-5,8-dione 1,2-dioxide, were obtained by direct oxidation of the parent hydrazides with peracetic acid.The pyridopyridazine derivatives were also unambiguously synthesized by treating the anhydrides or diesters of the relevant carboxylic acid 1-oxides with hydrazine hydrate.
- Paul, D. Brenton
-
-
- INDUCTION OF CELL ARREST IN G2: STRUCTURAL SPECIFICITY OF TRIGONELLINE
-
Synthetic analogues of N-methyl nicotinic acid, trigonelline, were prepared to test the structural features necessary for the induction of cellular arrest in G2 in Pisum sativum.Analogues that (1) were regioisomers of trigonelline, (2) possessed different 1,3-substituents, ad (3) contained additional substituents on the pyridine ring were tested for their ability to induce cell arrest in G2 and to anatogize trigonelline induced arrest in G2.Only N-methyl-3-quinoline-carboxic acid and 1-methyl nicotinamide induced cell arrest in G2, and 1-methyl-4-pyridine carboxylic acid and 1-methyl-2-pyridine carboxylic acid were effective trigonelline antagonists.These data further support a specific role for trigonelline in the induction of cell arrest in G2.Key words: Pisum sativum; Leguminosae; pea; trigonelline; structural specificity; structural analogues; cell arrest; G2.
- Lynn, David G.,Lewis, David H.,Tramontano, William A.,Evans, Lance S.
-
p. 1225 - 1228
(2007/10/02)
-