- Click glycoconjugation of per-azido- and alkynyl-functionalized β-peptides built from aspartic acid
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Azide- and alkynyl-containing homo-β3-peptides, of up to six residues in length, were synthesised in solution from aspartic acid. Their subsequent conjugation with monosaccharides bearing an azide or a terminal alkyne function was efficiently achieved by copper-mediated cycloadditions leading to two novel families of small glycoclusters. These compounds represent ideal tools to explore carbohydrate-mediated multivalent interactions.
- Barra, Marielle,Roy, Olivier,Traikia, Mounir,Taillefumier, Claude
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Read Online
- Access to 2,6-Disubstituted 4-Oxopiperidines Using a 6-Endo-trig Cyclization: Stereoselective Synthesis of Spruce Alkaloid and (+)-241D
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A synthetic route to cis-2-methyl-4-oxo-6-alkylpiperidines has been developed using a 6-endo-trig cyclization of (E)-enones. The base-mediated intramolecular cyclization was found to be general for both alkyl- and aryl-substituted enones, providing the corresponding 4-oxopiperidines in high yields (80-89%). Stereoselective reduction of the 2,6-cis-disubstituted 4-oxopiperidines then gave the 2,4,6-cis,cis-trisubstituted 4-hydroxypiperidines in high diastereoselectivity. The general nature of this approach was demonstrated with the synthesis of the natural products, spruce alkaloid and (+)-241D.
- Harkiss, Alexander H.,Sutherland, Andrew
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Read Online
- Synthesis of a chiral β-amino acid derivative by a cobalt-catalysed coupling reaction
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A chiral β-amino acid derivative was synthesised by a cobalt-catalysed alkylation of 2,4,5-trifluorophenyl magnesium bromide with the alkyl halide derivative of L-aspartic acid, using an efficient catalytic reagent: CoCl 2/TMEDA. The halide der
- Pan, Xianhua,Yu, Wansheng,Ou, Wenhua,Tao, Xiaohu,Wan, Jiaomei,Liu, Feng
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Read Online
- 5-MEMBERED HETEROARYL COMPOUNDS CONTAINING A HYDROXAMATE MOIETY AND THEIR USE
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The present invention is directed to 5-membered heteroaryl compounds containing a hydroxamate moiety of Formula I, pharmaceutically acceptable salts or solvates thereof, and their use as sensitizers for chemotherapy of malignant tumors.
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Page/Page column 76-78
(2020/07/31)
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- Method for producing pyrazole derivative
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PROBLEM TO BE SOLVED: To provide a method for producing a pyrazole derivative. SOLUTION: There is provided the method for producing a pyrazole derivative by using a compound represented by formula (IIC), (IID) or (III) and a compound represented by formula (IV). SELECTED DRAWING: None COPYRIGHT: (C)2018,JPOandINPIT
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Paragraph 0252
(2018/08/30)
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- Stereoselective synthesis of 2,6-: Trans -4-oxopiperidines using an acid-mediated 6- endo-trig cyclisation
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An acid-mediated 6-endo-trig cyclisation of amine-substituted enones has been developed for the stereoselective synthesis of trans-6-alkyl-2-methyl-4-oxopiperidines. Performed under conditions that prevent removal of the Boc-protecting group or acetal formation, the key cyclisation was found to generate cleanly the 4-oxopiperidine products in high overall yields from a wide range of alkyl substituted enones. The synthetic utility of the trans-6-alkyl-2-methyl-4-oxopiperidines formed from this process was demonstrated with the total synthesis of the quinolizidine alkaloid, (+)-myrtine and the piperidine alkaloid, (-)-solenopsin A.
- Bell, Jonathan D.,Harkiss, Alexander H.,Wellaway, Christopher R.,Sutherland, Andrew
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p. 6410 - 6422
(2018/10/02)
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- PYRAZOLE DERIVATIVE, OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF
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[Problem] The present invention is to provide a novel pyrazole derivative, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the same, and a pharmaceutical use thereof. [Solution] The present invention provides a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, which has TRPM8 inhibitory effects: wherein ring A is C6-10 aryl or the like; X is CR4a or the like; R1 and R2 are a hydrogen atom or the like; R3 is a hydrogen atom or the like; R4 is a hydrogen atom or the like; ring B is C6-10 aryl or the like; R5 is a hydrogen atom or the like; R6a is a hydrogen atom or the like; R7a is a hydrogen atom or the like; R7b is a hydrogen atom or the like; R6b is a hydrogen atom or the like; R8 is a hydrogen atom or the like; n is 0, 1 or 2. Therefore, the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof is useful as an agent for treating or preventing diseases or symptoms caused by hyperexcitability or disorder of afferent neurons.
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Paragraph 0235
(2018/05/16)
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- Selective caspase inhibitors and uses thereof
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The present invention relates to compounds of Formula I, IA, II, HA, III, or IHA and their pharmaceutical uses. Particular aspects of the invention relate to the use of those compounds for the selective inhibition of one or more caspases. Also described are methods where the compounds of Formula I, IA, II, IIA, III, or IIIA are used in the prevention and/or treatment of various diseases and conditions in subjects, including caspase-mediated diseases such as sepsis, myocardial infarction, ischemic stroke, spinal cord injury (SCI), traumatic brain injury (TBI) and neurodegenerative disease (e.g. multiple sclerosis (MS) and Alzheimer's, Parkinson's, and Huntington's diseases).
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Page/Page column 98
(2017/02/28)
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- NOVEL QUINOLINE -SUBSTITUTED COMPOUND
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An object to be achieved by the present invention is to provide a novel compound having EGFR inhibitory effects and cell growth inhibitory effects, as well as a medication useful for the prevention and/or treatment of cancer based on the EGFR inhibitory effects. The present invention provides a compound represented by Formula (I) below, or a salt thereof.
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Paragraph 0396; 0397
(2016/08/10)
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- Synthesis of a novel series of 2,3,4-trisubstituted oxazolidines designed by isosteric replacement or rigidification of the structure and cytotoxic evaluation
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We have previously reported on a study of the structure-activity relationship in a series of 2,3,4-substituted oxazolidines recently discovered by our group varying the substituent at the ring or stereochemistry of the oxazolidine ring. We discovered the cytotoxic and pro-apoptotic potential of compounds 1 and 2 with good selectivity against cancer cell lines. In the present study we describe the synthesis and cytotoxic evaluation against cancer cell lines (HL60, JURKAT, MDA-MB-231 and LNCaP) of a series of oxazolidines designed by isosteric replacement or rigidification of the oxymethylene spacer of compounds 1 and 2. Alkenes 3 and 4 retained the activity against MDA-MB-231 cells and they were more active on HL60, JURKAT and LNCaP cells. Considering LNCaP cells, E-isomer 4 was at least 7 times and about 3 times more potent than lead 1 and Z-isomer 3, respectively. Compound 4 exerted significant activity against LNCaP with IC50 in the low micromolar range (11 μM) without affecting VERO cells and PBMC proliferation (IC50 > 100 μM) indicating its low toxicity to normal cells.
- Andrade, Saulo F.,Teixeira, Claudia S.,Ramos, Jonas P.,Lopes, Marcela S.,Pdua, Rodrigo M.,Oliveira, Mnica C.,Souza-Fagundes, Elaine M.,Alves, Ricardo J.
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p. 1693 - 1699
(2014/12/11)
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- METHOD FOR MANUFACTURING DIPEPTIDYL PEPTIDASE-IV INHIBITOR AND INTERMEDIATE
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The present invention relates to an improved method for manufacturing dipeptidyl peptidase-IV inhibitor and intermediate. The present invention allows reduction of production costs by reacting low cost reagents, improves yield and is adaptable for mass production.
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Page/Page column 8
(2012/02/01)
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- Design, synthesis and SAR of novel ethylenediamine and phenylenediamine derivatives as factor Xa inhibitors
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We previously reported on a series of cyclohexanediamine derivatives as highly potent factor Xa inhibitors. Herein, we describe the modification of the spacer moiety to discover an alternative scaffold. Ethylenediamine derivatives possessing a substituent at the C1 position in S configuration and phenylenediamine derivatives possessing a substituent at the C5 position demonstrated moderate to strong anti-fXa activity. Further SAR studies led to the identification of compound 30h which showed both good in vitro activity (fXa IC50 = 2.2 nM, PTCT2 = 3.9 μM) and in vivo antithrombotic efficacy.
- Yoshikawa, Kenji,Yoshino, Toshiharu,Yokomizo, Yoshihiro,Uoto, Kouichi,Naito, Hiroyuki,Kawakami, Katsuhiro,Mochizuki, Akiyoshi,Nagata, Tsutomu,Suzuki, Makoto,Kanno, Hideyuki,Takemura, Makoto,Ohta, Toshiharu
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scheme or table
p. 2133 - 2140
(2011/04/24)
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- An entry to 1,6-dioxaspiro[4.6]undecanes and 1,7-dioxaspiro[5.6]dodecanes
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Ketones 11a-c obtained by iterative alkylation of acetone N,N-dimethylhydrazone with iodides 6 and 8a,b or epoxide 9 followed by SiO2/H2O-induced cleavage of the hydrazone were quantitatively transformed into 1,6-dioxaspiro[4.6]undec
- Ollivier, Anthony,Sinibaldi, Marie-Eve,Toupet, Lo?c,Tra?kia, Mounir,Canet, Isabelle
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scheme or table
p. 4147 - 4149
(2010/08/20)
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- Orthogonally protected glycerols and 2-aminodiols: Useful building blocks in heterocyclic chemistry
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The efficient synthesis of orthogonally protected glycerols, 2-aminopropane-1,3-diols and 2-aminobutane-1,4-diols that can constitute useful tools in heterocyclic chemistry, is reported. These interesting tri-functionalized small synthons were easily prepared from serine or aspartic acid. In addition, these substrates can be readily transformed into their iodide derivatives in very good yields. ARKAT USA, Inc.
- Ollivier, Anthony,Goubert, Marlene,Tursun, Ahmatjan,Canet, Isabelle,Sinibaldia, Marie-Eve
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experimental part
p. 108 - 126
(2010/10/03)
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- From rigid cyclic templates to conformationally stabilized acyclic scaffolds. Part I: The discovery of CCR3 antagonist development candidate BMS-639623 with picomolar inhibition potency against eosinophil chemotaxis
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Conformational analysis of trans-1,2-disubstituted cyclohexane CCR3 antagonist 2 revealed that the cyclohexane linker could be replaced by an acyclic syn-α-methyl-β-hydroxypropyl linker. Synthesis and biological evaluation of mono- and disubstituted propyl linkers support this conformational correlation. It was also found that the α-methyl group to the urea lowered protein binding and that the β-hydroxyl group lowered affinity for CYP2D6. Ab initio calculations show that the α-methyl group governs the spatial orientation of three key functionalities within the molecule. α-Methyl-β-hydroxypropyl urea 31 with a chemotaxis IC50 = 38 pM for eosinophils was chosen to enter clinical development for the treatment of asthma.
- Santella III, Joseph B.,Gardner, Daniel S.,Yao, Wenqing,Shi, Chongsheng,Reddy, Prabhakar,Tebben, Andrew J.,DeLucca, George V.,Wacker, Dean A.,Watson, Paul S.,Welch, Patricia K.,Wadman, Eric A.,Davies, Paul,Solomon, Kimberly A.,Graden, Dani M.,Yeleswaram, Swamy,Mandlekar, Sandhya,Kariv, Ilona,Decicco, Carl P.,Ko, Soo S.,Carter, Percy H.,Duncia, John V.
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p. 576 - 585
(2008/09/19)
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- PROCESS FOR PRODUCTION OF NONNATURAL AMINO ACIDS AND INTERMEDIATES THEREFOR
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A process for the preparation of a nonnatural amino acid represented by the following formula (C): which is characterized by reacting a compound represented by the following formula (A1), a compound represented by the following formula (A2) and a compoun
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Page/Page column 8
(2010/11/25)
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- A rapid access to the spiroaminoketal framework
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A convergent and stereoselective synthesis of 1-oxa-7-azaspiro[5.5]undecane is described. This functional new spiroheterocycle is readily available from acetone N,N-dimethylhydrazone via a double alkylation and subsequent spiroannulation process. Georg Thieme Verlag Stuttgart.
- Tursun, Ahmatjan,Aboab, Bettina,Martin, Anne-Sophie,Sinibaldi, Marie-Eve,Canet, Isabelle
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p. 2397 - 2399
(2007/10/03)
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- NEW HETEROCYCLIC AMIDE COMPOUNDS USEFUL FOR THE TREATMENT OF INFLAMMATORY AND ALLERGIC DISORDERS: PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
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The present invention relates to novel heterocyclic compounds that inhibit phosphodiesterase type 4 (PDE 4). The compounds are useful for treating inflammatory conditions, diseases of the central nervous systems and insulin resistant diabetes.
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- Synthesis of enantiomerically pure β- and γ-amino acid derivatives using functionalized organozinc reagents
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β-Amido zinc reagents 4 and 5 readily undergo β-elimination when prepared in THF, but when a polar aprotic solvent such as DMF is employed, β-elimination is suppressed. Using DMF, reaction of 4 with aryl iodides provides β-homophenylalanine derivatives (12 examples, 20-89% yield), and analogous reactions of 5 give γ-bishomophenylalanine derivatives (7 examples, 34-80% yield). The related zinc/copper reagents 17 and 18 are also useful intermediates that undergo subsequent cross-coupling reactions with a wide range of electrophiles (9 examples, 28-87% yield).
- Dexter, Charles S.,Jackson, Richard F. W.,Elliott, Jason
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p. 7579 - 7585
(2007/10/03)
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- Efficient synthesis of β- and γ-amino acid derivatives using new functionalised zinc reagents: Enhanced stability and reactivity of β-amido zinc reagents in dimethylformamide
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The new zinc reagents 3 and 4 are not sufficiently stable to be prepared efficiently in THF, but they can be prepared in DMF under mild and convenient conditions; subsequent palladium- catalysed coupling with aromatic iodides gives protected β- and γ-amin
- Dexter, Charles S.,Jackson, Richard F. W.
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- Novel route to the synthesis of hydroxylated pyrrolidine derivatives via the intramolecular reaction of γ-aminoallylstannane with aldehyde. Total synthesis of (+)-preussin
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The thermal cyclization of γ-aminoallylstannane (8) having an aldehyde group gave β-hydroxypyrrolidine derivative (9a) as a sole product. This methodology was applied successfully to the total synthesis of (+)-preussin.
- Kadota, Isao,Saya, Shioko,Yamamoto, Yoshinori
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p. 335 - 348
(2007/10/03)
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- Diastereoselective reactions of Grignard reagents with chiral amino lactols derived from L-aspartic acid
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Nucleophilic additions to chiral amino lactols obtained from L-aspartic acid containing a chiral α-silyloxymethyl function by simple Grignard reagents exhibited high stereoselectivity to provide the corresponding optically active amino alcohols containing three contiguous stereogenic centers. The mechanistic origin of the asymmetric induction is rationalized based on chelation controlled models.
- Yoda,Nakagami,Takabe
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p. 169 - 172
(2007/10/02)
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