- IMIDAZOPIPERAZINONE INHIBITORS OF TRANSCRIPTION ACTIVATING PROTEINS
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The present disclosure relates to heterocyclic compounds and methods which may be useful as inhibitors of transcription activating proteins such as CBP and P300 for the treatment or prevention of diseases such as proliferative diseases, inflammatory disorders, autoimmune diseases, and fibrotic diseases.
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Paragraph 0722; 0723
(2019/10/20)
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- IMIDAZOPIPERAZINE INHIBITORS OF TRANSCRIPTION ACTIVATING PROTEINS
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The present disclosure relates to heterocyclic compounds and methods which may be useful as inhibitors of transcription activating proteins such as CBP and P300 for the treatment or prevention of diseases such as proliferative diseases, inflammatory disorders, autoimmune diseases, and fibrotic diseases.
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Paragraph 0616-0617
(2019/10/17)
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- Discovery of β-Arrestin Biased, Orally Bioavailable, and CNS Penetrant Neurotensin Receptor 1 (NTR1) Allosteric Modulators
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Neurotensin receptor 1 (NTR1) is a G protein coupled receptor that is widely expressed throughout the central nervous system where it acts as a neuromodulator. Neurotensin receptors have been implicated in a wide variety of CNS disorders, but despite extensive efforts to develop small molecule ligands there are few reports of such compounds. Herein we describe the optimization of a quinazoline based lead to give 18 (SBI-553), a potent and brain penetrant NTR1 allosteric modulator.
- Pinkerton, Anthony B.,Peddibhotla, Satyamaheshwar,Yamamoto, Fusayo,Slosky, Lauren M.,Bai, Yushi,Maloney, Patrick,Hershberger, Paul,Hedrick, Michael P.,Falter, Bekhi,Ardecky, Robert J.,Smith, Layton H.,Chung, Thomas D. Y.,Jackson, Michael R.,Caron, Marc G.,Barak, Lawrence S.
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supporting information
p. 8357 - 8363
(2019/09/10)
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- Compound for inhibiting IDO and application of compound
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The invention discloses a compound for inhibiting IDO and application of the compound, in particular to application of a compound shown in formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prod
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Paragraph 0200; 0202-0205
(2019/12/25)
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- Iodine(III) Reagent-Mediated Intramolecular Amination of 2-Alkenylanilines to Prepare Indoles
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A variety of 3-substituted and 2,3-disubstituted indoles were synthesized efficiently in good yields through the intramolecular amination of 2-alkenylanilines promoted by readily available iodine(III) reagents in a short reaction time. Mechanistic studies showed that the reaction pathway went through a nitrenium ion and that 3-acetoxy indoline was the key intermediate in the indole formation. The indole product was easily prepared on a gram scale and amination also proceeded smoothly using catalytic 3,5-dimethylphenyl iodine in the presence of mCPBA. Furthermore, the indolo[3,2-a]carbazole scaffold was prepared in good yield in six steps from commercial ortho-iodoaniline. (Figure presented.).
- Zhao, Chun-Yang,Li, Kun,Pang, Yu,Li, Jia-Qing,Liang, Cui,Su, Gui-Fa,Mo, Dong-Liang
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supporting information
p. 1919 - 1925
(2018/03/28)
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- An Efficient Method for the Synthesis of Laquinimod
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Laquinimod, 5-chloro-1,2-dihydro-N-ethyl-4-hydroxy-1-methyl-2-oxo-N- phenyl-3-quinoline carboxamide, is an oral drug in clinical trials for the treatment of multiple sclerosis. An efficient synthetic method for laquinimod from 2-amino-6-chlorobenzoic acid via four steps was established. The overall yield of laquinimod is up to 82% as compared with 70% reported in literature. It has also been demonstrated that green reagent dimethyl carbonate is not suitable for the N-methylation of 5-chloroisatoic anhydride owing to the ring-cleavage reaction induced by the generated methanol. The ring-cleavage by-products were isolated and characterized by 1H-NMR and 13C-NMR. In addition, in the study of laquinimod derivatives, we found that 5-chloro-1,2-dihydro-N-ethyl-4-hydroxy-1-methyl-2-oxo-N-phenyl-3-quinoline carboxamide (laquinimod) was obtained in much higher yield than 7-chloro-1,2-dihydro-N-ethyl-4-hydroxy-1-methyl-2-oxo-N-phenyl-3-quinoline carboxamide under the same reaction conditions, and it is possibly attributed to a neighboring group effect.
- Huang, Yanyan,Feng, Ying,Gao, Wensheng,Zhang, Chao,Chen, Ligong
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p. 437 - 440
(2016/04/19)
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- QUINAZOLINE BASED RESPIRATORY SYNCYTIAL VIRUS INHIBITORS
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Compounds of Formula (I), wherein R1, R2, R3, R4 and n are defined herein, are useful as inhibitors of RSV.
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Page/Page column 54
(2015/05/19)
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- SMALL MOLECULE AGONISTS OF NEUROTENSIN RECEPTOR 1
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Provided herein are small molecule neurotensin receptor agonists, compositions comprising the compounds, and methods of using the compounds and compositions comprising the compounds.
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Paragraph 00435
(2016/04/26)
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- Zn-Catalyzed Enantio- and Diastereoselective Formal [4 + 2] Cycloaddition Involving Two Electron-Deficient Partners: Asymmetric Synthesis of Piperidines from 1-Azadienes and Nitro-Alkenes
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We report a catalytic asymmetric synthesis of piperidines through [4 + 2] cycloaddition of 1-azadienes and nitro-alkenes. The reaction uses earth abundant Zn as catalyst and is highly diastereo- and regioselective. A novel BOPA ligand (F-BOPA) confers high reactivity and enantioselectivity in the process. The presence of ortho substitution on the arenes adjacent to the bis(oxazolines) was found to be particularly impactful, due to limiting the undesired coordination of 1-azadiene to the Lewis acid and thus allowing the reaction to be carried out at lower temperature. A series of secondary kinetic isotope effect studies using a range of ligands implicates a stepwise mechanism for the transformation, involving an initial Michael-type addition of the imine to the nitro-alkene followed by a cyclization event. The stepwise mechanism obviates the electronic requirement inherent to a concerted mechanism, explaining the successful cycloaddition between two electron-deficient partners. (Chemical Equation Presented).
- Chu, John C. K.,Dalton, Derek M.,Rovis, Tomislav
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supporting information
p. 4445 - 4452
(2015/04/14)
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- Discovery of novel bacterial RNA polymerase inhibitors: Pharmacophore-based virtual screening and hit optimization
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The bacterial RNA polymerase (RNAP) is a validated target for broad spectrum antibiotics. However, the efficiency of drugs is reduced by resistance. To discover novel RNAP inhibitors, a pharmacophore based on the alignment of described inhibitors was used for virtual screening. In an optimization process of hit compounds, novel derivatives with improved in vitro potency were discovered. Investigations concerning the molecular mechanism of RNAP inhibition reveal that they prevent the protein-protein interaction (PPI) between σ70 and the RNAP core enzyme. Besides of reducing RNA formation, the inhibitors were shown to interfere with bacterial lipid biosynthesis. The compounds were active against Gram-positive pathogens and revealed significantly lower resistance frequencies compared to clinically used rifampicin.
- Hinsberger, Stefan,Hüsecken, Kristina,Groh, Matthias,Negri, Matthias,Haupenthal, J?rg,Hartmann, Rolf W.
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p. 8332 - 8338
(2013/12/04)
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- MINERALOCORTICOID RECEPTOR MODULATOR COMPOUNDS AND METHODS
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This invention relates to compounds that bind to mineralocorticoid receptors and/or modulate activity of mineralocorticoid receptors, and to methods for making and using such compounds.
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Page/Page column 65
(2008/06/13)
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- PYRIMIDINE DERIVATIVE
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This invention provides pyrimidine derivatives represented by a formula, in the formula, ring A stands for carbocyclic group or heterocyclic group, X 1 stands for hydrogen, lower alkyl, amino, etc., X 2 stands for hydrogen or lower alkyl, Y stands for a direct bond or sulfur or nitrogen, n stands for an integer of 0 - 4, and Ar stands for a group of the following formula, or a salt thereof, which concurrently exhibit 5-HT 1A agonistic activity and 5-HT 3 antagonistic activity and are useful for therapy and treatments of diseases such as IBS. The invention furthermore provides a therapeutic method of IBS, characterized by having 5-HT 1A agonistic activity and 5-HT 3 antagonistic activity work simultaneously and cooperatively in vivo, which comprises either administering 5-HT 3 antagonistic agent which concurrently exhibits 5-HT 1A agonistic activity, or administering 5-HT 1A agonistic agent and 5-HT 3 antagonistic agent simultaneously, in sequence or at an interval.
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Page/Page column 81
(2010/11/24)
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- THERAPEUTIC USE OF ARYL AMINO ACID DERIVATIVES
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The compounds of formula (I) are useful in the treatment of faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, neuropathic pain, neuropathological disorders and sleep disorders. Processes for the preparation of the final products and intermediates useful in the process are included. Pharmaceutical compositions containing one or more of the compounds are also included.
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Page/Page column 34-35
(2010/02/06)
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- Changes in the activity and selectivity of herbicides by selective fluorine substitution, taking bentranil and classic analogues as examples
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The introduction of fluorine atoms into 2-phenyl-4H-3,1-benzoxazin-4-one (bentranil) led to sweeping changes in its herbicidal properties in some cases, and 5-fluoro-2-phenyl-4H-3,1-benzoxazin-4-one ('fluorobentranil') was found to be the most active compound. It can be prepared from 2-amino-6-fluoro-benzoic acid or by direct halogen exchange of 5-chloro-2-phenyl-4H-3,1-benzoxazin-4-one. The latter reaction was investigated on a pilot scale, including a high-temperature (350°C) potassium fluoride halogen exchange without solvent. When sulfolane was used as a solvent, a side reaction at 220°C - partial decomposition to a diphenylether - could be prevented by addition of a small amount of a radical scavenger. Other intermediates with a pseudohalogen substitution were obtained by side-chain chlorination of suitable methylsulfanyl benzoic acid precursors and halogen exchange. 'Fluorobentranil' shows good broad-leaf activity and selectivity on rice, cereals and maize. In a second case study, the fluoro-substituted anthranilic acids mentioned above were also found to be appropriate for synthesizing herbicidal sulfonylurea (SU) compounds via Meerwein reaction of their aniline function. Methyl 2-[({[(4-chloro-6-methoxy-2- pyrimidinyl)-amino]carbonyl}amino)sulfonyl]-6-fluorobenzoate is an example of a SU that is compatible with maize, whereas the unsubstituted Classic analogue is not selective.
- Hamprecht, Gerhard,Würzer, Bruno,Witschel, Matthias
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p. 117 - 122
(2007/10/03)
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- N-aryl(thio)anthranilic acid amide derivatives, their preparation and their use as VEGF receptor tyrosine kinase inhibitors
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Described are compounds of formula (I), wherein W is O or S; X is NR8; Y is CR9R10-(CH2)n wherein R9 and R10 are independently of each other hydrogen or lower alkyl, and n is an integer of
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- 7-Chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5- tetrahydro-1H-1-benzazepine (OPC-41061): A potent, orally active nonpeptide arginine vasopressin V2 receptor antagonist
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We previously reported a series of benzazepine derivatives as orally active nonpeptide arginine vasopressin (AVP) V2 receptor antagonists. After the lead structure OPC-31260 was structurally evaluated and optimized, the introduction of the 7-Cl moiety on the benzazepine and 2-CH3 on the aminobenzoyl moiety enhanced its oral activity. The new AVP-V2 selective antagonist OPC-41061 was determined to be a potent and orally active agent. Copyright (C) 1999 Elsevier Science Ltd.
- Kondo, Kazumi,Ogawa, Hidenori,Yamashita, Hiroshi,Miyamoto, Hisashi,Tanaka, Michinori,Nakaya, Kenji,Kitano, Kazuyoshi,Yamamura, Yoshitaka,Nakamura, Shigeki,Onogawa, Toshiyuki,Mori, Toyoki,Tominaga, Michiaki
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p. 1743 - 1754
(2007/10/03)
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- Pyridazinedione compounds useful in treating neurological disorders
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The present invention relates to pyridazino[4,5-b]quinolines, and pharmaceutically useful salts thereof, which are excitatory amino acid antagonists and which are useful when such antagonism is desired such as in the treatment of neurological disorders. The invention further provides pharmaceutical compositions containing pyridazino[4,5-b]quinolines as active ingredient, and methods for the treatment of neurological disorders.
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- Synthesis and structure-activity relationships of 1,2,3,4- tetrahydroquinoline-2,3,4-trione 3-oximes: Novel and highly potent antagonists for NMDA receptor glycine site
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A series of 1,2,3,4-tetrahydroquinoline-2,3,4-trione 3-oximes (QTOs) was synthesized and evaluated for antagonism of NMDA receptor glycine site. Glycine site affinity was determined using a [3H]DCKA binding assay in rat brain membranes and electrophysiologically in Xenopus oocytes expressing 1a/2C subunits of cloned rat NMDA receptors. Selected compounds were also assayed for antagonism of AMPA receptors in Xenopus oocytes expressing rat brain poly-(A)+ RNA. QTOs were prepared by nitrosation of 2,4- quinolinediols. Structure-activity studies indicated that substitutions in the 5-, 6-, and 7-positions increase potency, whereas substitution in the 8- position causes a decrease in potency. Among the derivatives evaluated, 5,6,7-trichloro-QTO was the most potent antagonist with an IC50 of 7 nM in the [3H]DCKA binding assay and a K(b) of 1-2 nM for NMDA receptors expressed in Xenopus oocytes. 5,6,7-Trichloro-QTO also had a K(b) of 180 nM for AMPA receptors in electrophysiological assays. The SAR of QTOs was compared with the SAR of 1,4-dihydroquinoxaline-2,3-diones (QXs). For compounds with the same benzene ring substitution pattern, QTOs were generally 5-10 times more potent than the corresponding QXs. QTOs represent a new class of inhibitors of the NMDA receptor which, when appropriately substituted, are among the most potent glycine site antagonists known.
- Cai, Sui Xiong,Zhou, Zhang-Lin,Huang, Jin-Cheng,Whittemore, Edward R.,Egbuwoku, Zizi O.,Lü, Yixin,Hawkinson, Jon E.,Woodward, Richard M.,Weber, Eckard,Keana, John F. W.
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p. 3248 - 3255
(2007/10/03)
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- Saccharin derivatives useful as proteolytic enzyme inhibitors and compositions and method of use thereof
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Novel 2-substituted saccharins which inhibit the enzymatic activity of proteolytic enzymes, are useful in the treatment of degenerative diseases and have the formula STR1 wherein: L is --O--, --S--, --SO-- or --SO2 --; m and n are each independently 0 or 1; R1 is halo, lower-alkanoyl, 1-oxophenalenyl, phenyl or substituted phenyl, heterocyclyl or substituted heterocyclyl or, when L is --O-- and n is 1, cycloheptatrienon-2-yl or, when L is --S-- and n is 1, cyano or lower-alkoxythiocarbonyl or, when L is --SO2 -- and n is 1, lower-alkyl or trifluoromethyl; R2 is hydrogen, lower-alkoxycarbonyl, phenyl or phenylthio; and R3 and R4 are each hydrogen or various substituents and processes for preparation and pharmaceutical compositions and method of use thereof are disclosed.
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- Linear and Proximal Benzo-Separated Alkylated Xanthines as Adenosine-Receptor Antagonists
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The linear and proximal benzo-separated derivatives of 8-phenyltheophylline, 1,3-diethyl-8-phenylxanthine, 1,3-dipropylxanthine, 1,3-dibutylxanthine, 3-isobutyl-1-methylxanthine, theophylline, caffeine, and isocaffeine have been synthesized and evaluated for affinity at the A1 and A2 adenosine receptors.Although structure-activity relationships in the benzo-separated series differed from the relationships in simple xanthines, the most potent of the benzo-separated xanthines were about equal in affinity to the most potent of the corresponding xanthines.On the basis of the present results and the diverse structures reported in the literature as non-xanthine adenosine antagonists, it appears that the primary requirement for the adenosine-receptor affinity in nonnucelosides is a flat, neutral, fused-ring heterocycle and that once this requirement is met there are numerous potential binding modes.
- Schneller, Stewart W.,Ibay, Augusto C.,Christ, William J.,Bruns, Robert F.
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p. 2247 - 2254
(2007/10/02)
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- 4-Hydroxy-1,2-Benzisothiazol-3(2H)-one-1,1-dioxides and salts thereof
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Compounds of the formula STR1 wherein R1 is hydrogen or hydroxyl, and non-toxic, pharmacologically acceptable salts thereof formed with inorganic or organic bases. The compounds as well as their salts are useful as sweetening agents.
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- Preparation of a mixture of an alkyl 3-chloroanthranilate and an alkyl 6-chloroanthranilate
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A mixture of an alkyl 3-chloroanthranilate and an alkyl 6-chloroanthranilate, with a particular molar ratio of the components, is prepared by (a) reacting 3-chlorophthalic anhydride with ammonia, an alkali metal hydroxide and an alkali metal hypochlorite or (b) converting 3-chlorophthalic anhydride to 3-chlorophthalimide followed by reaction of the latter with an alkali metal hydroxide and an alkali metal hypochlorite, and, finally, esterifying the mixture of 5-chloroisatoic anhydride and 8-chloroisatoic anhydride, obtained by method (a) or method (b), with an alkanol. The compounds obtainable by the process of the invention are valuable starting materials for the preparation of dyes, crop protection agents and scents.
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