- NOVEL HETEROAROMATIC AMIDE DERIVATIVE AND MEDICINE CONTAINING SAME
-
A compound selectively inhibiting Nav1.7 over Nav1.5 is provided. A heteroaromatic amide derivative or salt thereof showing high efficacy for various diseases associated with Nav1.7 such as pain, represented by the general formula (I) [wherein, X1-X2 is N-C or C-N, Y1 , Y2, Y3 and Y4 are -CH2-, -CR4aH- or -O- and so on, Z1 is-O- and so on, ring A is a 3- to 7-membered monocyclic aromatic ring and so on, R1a and R1b are a hydrogen atom or a halogen atom and so on, R2 is a hydrogen atom and so on, R3a, R3b and R3c are a hydrogen atom or an optionally substituted C1-C6 haloalkyl group and so on, R4a, R4b and R4c are, an optionally substituted C1-C6 haloalkyl group or C1-C6 haloalkoxy group and so on, R5a is a hydrogen atom and so on, R5a and R5b together form -CH2O- and so on, R6a and R6b are a hydrogen atom and so on, n is 1 or 2.].
- -
-
Paragraph 0394; 0397
(2021/07/24)
-
- NOVEL PHARMACEUTICAL COMPRISING HETEROAROMATIC AMIDE DERIVATIVE OR SALT THEREOF
-
PROBLEM TO BE SOLVED: To provide a compound useful for treating or preventing disease associated with voltage-dependent sodium channel (Nav1.7) such as disease involving a pain, disease involving an itch, autonomic nerve-associated disease, or a pharmaceutical composition thereof. SOLUTION: The present disclosure provides a compound illustrated by the following formula, and a pharmaceutical composition containing the same. SELECTED DRAWING: None COPYRIGHT: (C)2021,JPOandINPIT
- -
-
Paragraph 0680-0681; 0684
(2021/09/17)
-
- Synthesis of N-Alkyl Anilines from Arenes via Iron-Promoted Aromatic C-H Amination
-
We report both an intermolecular C-H amination of arenes to access N-methylanilines and an intramolecular variant for the synthesis of tetrahydroquinolines. A newly developed, highly electrophilic aminating reagent was key for the direct synthesis of unprotected N-methylanilines from simple arenes. The reactions display a broad functional group tolerance and employ catalytic amounts of a benign iron salt under mild reaction conditions.
- Falk, Eric,Gasser, Valentina C. M.,Morandi, Bill
-
supporting information
p. 1422 - 1426
(2021/03/08)
-
- Umpolung Strategy for Arene C?H Etherification Leading to Functionalized Chromanes Enabled by I(III) N-Ligated Hypervalent Iodine Reagents
-
The direct formation of aryl C?O bonds via the intramolecular dehydrogenative coupling of a C?H bond and a pendant alcohol represents a powerful synthetic transformation. Herein, we report a method for intramolecular arene C?H etherification via an umpoled alcohol cyclization mediated by an I(III) N-HVI reagent. This approach provides access to functionalized chromane scaffolds from primary, secondary and tertiary alcohols via a cascade cyclization-iodonium salt formation, the latter providing a versatile functional handle for downstream derivatization. Computational studies support initial formation of an umpoled O-intermediate via I(III) ligand exchange, followed by competitive direct and spirocyclization/1,2-shift pathways. (Figure presented.).
- Mikhael, Myriam,Guo, Wentao,Tantillo, Dean J.,Wengryniuk, Sarah E.
-
supporting information
p. 4867 - 4875
(2021/09/14)
-
- Access to Trisubstituted Fluoroalkenes by Ruthenium-Catalyzed Cross-Metathesis
-
Although the olefin metathesis reaction is a well-known and powerful strategy to get alkenes, this reaction remained highly challenging with fluororalkenes, especially the Cross-Metathesis (CM) process. Our thought was to find an easy accessible, convenient, reactive and post-functionalizable source of fluoroalkene, that we found as the methyl 2-fluoroacrylate. We reported herein the efficient ruthenium-catalyzed CM reaction of various terminal and internal alkenes with methyl 2-fluoroacrylate giving access, for the first time, to trisubstituted fluoroalkenes stereoselectively. Unprecedent TON for CM involving fluoroalkene, up to 175, have been obtained and the reaction proved to be tolerant and effective with a large range of olefin partners giving fair to high yields in metathesis products. (Figure presented.).
- Nouaille, Augustin,Pannecoucke, Xavier,Poisson, Thomas,Couve-Bonnaire, Samuel
-
supporting information
p. 2140 - 2147
(2021/03/06)
-
- Synthesis and inhibitory studies of phosphonic acid analogues of homophenylalanine and phenylalanine towards alanyl aminopeptidases
-
A library of novel phosphonic acid analogues of homophenylalanine and phenylalanine, containing fluorine and bromine atoms in the phenyl ring, have been synthesized. Their inhibitory properties against two important alanine aminopeptidases, of human (hAPN, CD13) and porcine (pAPN) origin, were evaluated. Enzymatic studies and comparison with literature data indicated the higher inhibitory potential of the homophenylalanine over phenylalanine derivatives towards both enzymes. Their inhibition constants were in the submicromolar range for hAPN and the micromolar range for pAPN, with 1-amino-3-(3-fluorophenyl) propylphosphonic acid (compound 15c) being one of the best low-molecular inhibitors of both enzymes. To the best of our knowledge, P1 homophenylalanine analogues are the most active inhibitors of the APN among phosphonic and phosphinic derivatives described in the literature. Therefore, they constitute interesting building blocks for the further design of chemically more complex inhibitors. Based on molecular modeling simulations and SAR (structure-activity relationship) analysis, the optimal architecture of enzyme-inhibitor complexes for hAPN and pAPN were determined.
- Wanat, Weronika,Talma, Micha?,Dziuk, B?a?ej,Kafarski, Pawe?
-
-
- Site-Selective C(sp3)–H Functionalization of Fluorinated Alkanes Driven by Polar Effects Using a Tungstate Photocatalyst
-
The TBADT-catalyzed C(sp3)–H functionalization of perfluorophenyl- and perfluoroalkyl-substituted alkanes was studied to determine how the fluorous substituents affect site-selectivity. Alkylation of alkyl-substituted perfluorobenzene avoids α-C–H bonds, unlike their alkylbenzene counterparts, allowing site-selective functionalization of C–H bonds remote to the aromatic ring. Alkylation of alkanes having a perfluoroalkyl group also avoided α-C–H bonds. Radical polar effects in the SH2 transition states could explain this avoidance of α-C–H functionalization.
- Fukuyama, Takahide,Nishikawa, Tomohiro,Ryu, Ilhyong
-
supporting information
p. 1424 - 1428
(2019/09/12)
-
- Carbene-Catalyzed α-Carbon Amination of Chloroaldehydes for Enantioselective Access to Dihydroquinoxaline Derivatives
-
An NHC-catalyzed α-carbon amination of chloroaldehydes was developed. Cyclohexadiene-1,2-diimines are used as amination reagents and four-atom synthons. Our reaction affords optically enriched dihydroquinoxalines that are core structures in natural products and synthetic bioactive molecules.
- Huang, Ruoyan,Chen, Xingkuan,Mou, Chengli,Luo, Guoyong,Li, Yongjia,Li, Xiangyang,Xue, Wei,Jin, Zhichao,Chi, Yonggui Robin
-
supporting information
p. 4340 - 4344
(2019/06/14)
-
- Salt-Free Strategy for the Insertion of CO2 into C?H Bonds: Catalytic Hydroxymethylation of Alkynes
-
A copper(I) catalyst enables the insertion of carbon dioxide into alkyne C?H bonds by using a suitable organic base with which hydrogenation of the resulting carboxylate salt with regeneration of the base becomes thermodynamically feasible. In the presence of catalytic copper(I) chloride/4,7-diphenyl-1,10-phenanthroline, polymer-bound triphenylphosphine, and 2,2,6,6-tetramethylpiperidine as the base, terminal alkynes undergo carboxylation at 15 bar CO2 and room temperature. After filtration, the ammonium alkynecarboxylate can be hydrogenated to the primary alcohol and water at a rhodium/molybdenum catalyst, regenerating the amine base. This demonstrates the feasibility of a salt-free overall process, in which carbon dioxide serves as a C1 building block in a C?H functionalization.
- Wendling, Timo,Risto, Eugen,Krause, Thilo,Goo?en, Lukas J.
-
supporting information
p. 6019 - 6024
(2018/03/27)
-
- Remote migratory cross-electrophile coupling and olefin hydroarylation reactions enabled by in situ generation of nih
-
A highly efficient strategy for remote reductive cross-electrophile coupling has been developed through the ligand-controlled nickel migration/arylation. This general protocol allows the use of abundant and bench-stable alkyl bromides and aryl bromides for the synthesis of a wide range of structurally diverse 1, 1-diarylalkanes in excellent yields and high regioselectivities under mild conditions. We also demonstrated that alkyl bromide could be replaced by the proposed olefin intermediate while using n-propyl bromide/Mn0 as a potential hydride source.
- Chen, Fenglin,Chen, Ke,Zhang, Yao,He, Yuli,Wang, Yi-Ming,Zhu, Shaolin
-
supporting information
p. 13929 - 13935
(2017/11/07)
-
- Structure-activity relationship studies of S1P agonists with a dihydronaphthalene scaffold
-
Structure-activity relationship (SAR) of sphingosine-1-phosphate receptor agonists with a dihydronaphthalene scaffold was investigated. Compound 1 was modified to improve S1P1 agonistic activity and in vivo peripheral lymphocyte lowering (PLL) activity without impairing selectivity over S1P 3 agonistic activity. A detailed SAR study of the terminal lipophilic part revealed that the introduction of substituents on the propylene linker and the terminal benzene ring influences in vitro and PLL activities. Compound 6n bearing a (S)-methyl group at the 2-position on the propylene linker and chlorine at the para-position on the terminal benzene ring showed potent hS1P1 agonistic activity with excellent selectivity over hS1P 3 and in vivo PLL activity in mice.
- Kurata, Haruto,Kusumi, Kensuke,Otsuki, Kazuhiro,Suzuki, Ryo,Kurono, Masakuni,Tokuda, Natsuko,Takada, Yuka,Shioya, Hiroki,Mizuno, Hirotaka,Komiya, Takaki,Ono, Takeji,Hagiya, Hiroshi,Minami, Masashi,Nakade, Shinji,Habashita, Hiromu
-
scheme or table
p. 144 - 148
(2012/02/16)
-
- Synthesis of optically active 4-substituted 2-cyclohexenones
-
Recently, Nicolaou and Baran independently synthesized optically active 4-substituted 2-cyclohexenones via an efficient LiOH-mediated intramolecular aldol condensation. Thus far, application of their cyclization approach has been limited to ketoaldehydes where the R-group is branched. It is demonstrated that the LiOH-mediated cyclization, when applied to substrates containing unbranched R-groups, results in significant erosion of optical purity. A mechanistic justification is provided, and a set of neutral, organocatalyzed conditions is identified that enables cyclization with little loss in optical purity.
- Houjeiry, Tania I.,Poe, Sarah L.,McQuade, D. Tyler
-
supporting information
p. 4394 - 4397
(2012/10/29)
-
- AMINE COMPOUND AND PHARMACEUTICAL USE THEREOF
-
Provided is a novel amine compound represented by the following formula (I) having a superior peripheral blood lymphocyte decreasing action and superior in the immunosuppressive action, rejection suppressive action and the like, which shows decreased side effects of, for example, bradycardia and the like, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate thereof, or a solvate thereof. wherein each symbol is as defined in the specification.
- -
-
Page/Page column 65
(2010/04/25)
-
- SUBSTITUTED FLUOROETHYL UREAS AS ALPHA 2 ADRENERGIC AGENTS
-
Therapeutic compounds, and methods, compositions, and medicaments related thereto are disclosed herein.
- -
-
Page/Page column 39
(2008/12/04)
-
- THERAPEUTIC FLUOROETHYLCYANO GUANIDINES
-
Disclosed herein is compound having a formula as described herein. Therapeutic methods, compositions, and medicaments related thereto are also disclosed.
- -
-
Page/Page column 19-20
(2008/12/04)
-
- Synthesis of N-glyoxyl prolyl and pipecolyl amides and thioesters and evaluation of their in vitro and in vivo nerve regenerative effects
-
The recent discovery that small molecule ligands for the peptidyl-prolyl isomerase (PPIase) FKBP12 possess powerful neuroprotective and neuroregenerative properties in vitro and in vivo suggests therapeutic utility for such compounds in neurodegenerative disease. The neurotrophic effects of these compounds are independent of the immunosuppressive pathways by which drugs such as FK506 and rapamycin operate. Previous work by ourselves and other groups exploring the structure-activity relationships (SAR) of small molecules that mimic only the FKBP binding domain portion of FK506 has focused on esters of proline and pipecolic acid. We have explored amide and thioester analogues of these earlier structures and found that they too are extremely potent in promoting recovery of lesioned dopaminergic pathways in a mouse model of Parkinson's disease. Several compounds were shown to be highly effective upon oral administration after lesioning of the dopaminergic pathway, providing further evidence of the potential clinical utility of a variety of structural classes of FKBP12 ligands.
- Hamilton, Gregory S.,Wu, Yong-Qian,Limburg, David C.,Wilkinson, Douglas E.,Vaal, Mark J.,Li, Jia-He,Thomas, Christine,Huang, Wei,Sauer, Hansjorg,Ross, Douglas T.,Soni, Raj,Chen, Yi,Guo, Hongshi,Howorth, Pamela,Valentine, Heather,Liang, Shi,Spicer, Dawn,Fuller, Mike,Steiner, Joseph P.
-
p. 3549 - 3557
(2007/10/03)
-
- Hexa-cyclic compound
-
A novel hexa-cyclic compound, a derivative of camptothecin, of the general formula: STR1 The compound is prepared from an aminoketone compound and a pyranoindolizine compound by the condensation-ring closing reaction. It is abundantly water-soluble, and has an excellent antitumour activity and a high degree of safety, and can be applied as an antitumour medicine for curing tumors of various kinds.
- -
-
-
- Substituted (arylalkoxybenzyl)aminopropanamide derivatives and process for their preparation
-
The invention provides new compounds of formula (I) STR1 wherein, subject to a proviso, n is zero or an integer of 1 to 3; each of R and R1, which may be the same or different, is hydrogen, halogen, trifluoromethyl or C1 -C4/su
- -
-
-
- REACTIONS OF COORDINATED LIGANDS. IX. CHROMIUM(O)-PROMOTED INTRAMOLECULAR NUCLEOPHILIC SUBSTITUTION OF AN ARYL HALIDE: A PREPARATION OF CHROMAN
-
When treated with potassium t-butoxide in dimethyl sulphoxide the chromium tricarbonyl complex of 3-(2-fluorophenyl)propan-1-ol underwent a rapid intramolecular nucleophilic substitution to give the corresponding complex of chroman, from which the heteroc
- Houghton, Roy P.,Voyle, Martyn,Price, Raymond
-
p. 183 - 188
(2007/10/02)
-