- NOVEL NICOTINAMIDE DERIVATIVES OR SALTS THEREOF
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An object of the present invention is to provide to a compound and a pharmaceutical composition, which have excellent Syk-inhibitory activity. Th e present invention provides a nicotinamide derivative represented by the follo wing formula (I) (wherein R 1 represents a halogen atom; R 2 represents a C 1-12 alkyl group, a C 2-12 alkenyl group, a C 2-12 alkynyl group, a C 3-8 cycloalkyl g roup, an aryl group, an ar-C 1-6 alkyl group or a heterocyclic group, each opti onally having at least one substituent; R 3 represents an aryl group or a hetero cyclic group each optionally having at least one substituent; and R 4 and R 5 e ach independently represent a hydrogen atom; and R 2 and R 4 may form a cyc lic amino group optionally having at least one substituent together with the ni trogen atom to which they bind) or a salt thereof, and a pharmaceutical comp osition for use in the treatment of a Syk-related disease which comprises the nicotinamide derivative or a salt thereof.
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Paragraph 1232; 1235; 1236
(2018/09/08)
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- METALLO-BETA-LACTAMASE INHIBITORS
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The present invention relates to compounds of formula I that are metallo-β-lactamase inhibitors, the synthesis of such compounds, and the use of such compounds for use with β-lactam antibiotics for overcoming resistance.
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- CARBAZOLE-CONTAINING AMIDES, CARBAMATES, AND UREAS AS CRYPTOCHROME MODULATORS
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The subject matter herein is directed to carbazole-containing amide, carbamate, and urea derivatives and pharmaceutically acceptable salts or hydrates thereof of structural formula I wherein the variable R1, R2, R3, R4, R5, R6, R7, A, D, E, G, J, L, M, Q, a, and b are accordingly described. Also provided are pharmaceutical compositions containing the compounds of formula I to treat a Cry-mediated disease or disorder, such as diabetes, complications associated with diabetes, Cushing's syndrome, NASH, NAFLD, asthma, and COPD.
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- PEPTIDE-OLIGOUREA CHIMERIC COMPOUNDS AND METHODS OF THEIR USE
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The present description provides compositions and methods for producing therapeutic oligomeric compounds. In another aspect the description provides methods for administering the oligomeric compounds for the treatment and prevention of disease in a mammal. In particular, the invention relates to medicaments comprising various novel oligomeric compounds and pharmaceutically acceptable salts thereof. The compounds of the invention may optionally be administered with at least one of a pharmaceutically acceptable excipient, additional pharmacologically active agent or a combination thereof.
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- Discovery of AZ0108, an orally bioavailable phthalazinone PARP inhibitor that blocks centrosome clustering
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The propensity for cancer cells to accumulate additional centrosomes relative to normal cells could be exploited for therapeutic benefit in oncology. Following literature reports that suggested TNKS1 (tankyrase 1) and PARP16 may be involved with spindle s
- Johannes, Jeffrey W.,Almeida, Lynsie,Daly, Kevin,Ferguson, Andrew D.,Grosskurth, Shaun E.,Guan, Huiping,Howard, Tina,Ioannidis, Stephanos,Kazmirski, Steven,Lamb, Michelle L.,Larsen, Nicholas A.,Lyne, Paul D.,Mikule, Keith,Ogoe, Claude,Peng, Bo,Petteruti, Philip,Read, Jon A.,Su, Nancy,Sylvester, Mark,Throner, Scott,Wang, Wenxian,Wang, Xin,Wu, Jiaquan,Ye, Qing,Yu, Yan,Zheng, Xiaolan,Scott, David A.
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p. 5743 - 5747
(2015/11/24)
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- Novel methyl substituted 1-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanones are P2X7 antagonists
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Abstract The optimization efforts that led to a novel series of methyl substituted 1-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanones that are potent rat and human P2X7 antagonists are described. These efforts resulted in the discovery of co
- Rudolph, Dale A.,Alcazar, Jesus,Ameriks, Michael K.,Anton, Ana Belen,Ao, Hong,Bonaventure, Pascal,Carruthers, Nicholas I.,Chrovian, Christa C.,De Angelis, Meri,Lord, Brian,Rech, Jason C.,Wang, Qi,Bhattacharya, Anindya,Andres, Jose Ignacio,Letavic, Michael A.
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p. 3157 - 3163
(2015/07/08)
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- Novel Heterocyclic Compounds and Uses Thereof
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New substituted heterocyclic compounds, compositions containing them, and methods of using them for the inhibition of Raf kinase activity are provided. The new compounds and compositions may be used either alone or in combination with at least one additional agent for the treatment of a Raf kinase mediated disorder, such as cancer.
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Paragraph 0405
(2013/08/28)
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- Sequential enantiodivergent organocatalysis: Reversibility in enantioswitching controlled by a conformationally flexible guanidine/bisthiourea organocatalyst
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Here we describe our studies on solvent-dependent enantiodivergent Mannich-type reactions utilizing conformationally flexible guanidine/bisthiourea organocatalyst (S,S)-1. Our mechanistic investigations revealed that the stereo-determining steps in both t
- Sohtome, Yoshihiro,Yamaguchi, Takahisa,Tanaka, Shinji,Nagasawa, Kazuo
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supporting information
p. 2780 - 2786
(2013/05/09)
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- Discovery of a novel chemotype of potent human ENaC blockers using a bioisostere approach. Part 2: α-Branched quaternary amines
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We report the synthesis and biological evaluation of a series of novel α-branched pyrazinoyl quaternary amines for their ability to block ion transport via the epithelial sodium channel (ENaC) in human bronchial epithelial cells (HBECs). Compound 12g has an IC50 of 30 nM and is highly efficacious in the Guinea-pig tracheal potential difference (TPD) model of ENaC blockade with an ED50 of 1 μg kg-1 at 1 h. In addition the SAR results demonstrate for the first time the chiral nature of the binding site of human ENaC. As such, pyrazinoyl quaternary amines represent a promising new class of ENaC blockers for the treatment of cystic fibrosis that are structurally distinct from the pyrazinoyl guanidine chemotype found in prototypical ENaC blockers such as amiloride.
- Hunt, Thomas,Atherton-Watson, Hazel C.,Collingwood, Stephen P.,Coote, Kevin J.,Czarnecki, Sarah,Danahay, Henry,Howsham, Catherine,Hunt, Peter,Paisley, Derek,Young, Alice
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p. 2877 - 2879
(2012/05/20)
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- 1,3,4,8-Tetrahydro-2H-Pyrido[1,2-a]Pyradine Derivatives and Use Thereof as HIV Integrase Inhibitor
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[Problem] Provided is a novel 1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine derivative or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is useful as an anti-HIV agent. [Solving Means] The present invention provides a compound repre
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Page/Page column 32
(2012/05/07)
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- Synthesis of imidacloprid derivatives with a chiral alkylated imidazolidine ring and evaluation of their insecticidal activity and affinity to the nicotinic acetylcholine receptor
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A series of imidacloprid (IMI) derivatives with an alkylated imidazolidine ring were asymmetrically synthesized to evaluate their insecticidal activity against adult female housefly, Musca domestica, and affinity to the nicotinic acetylcholine receptor of the flies. The bulkier the alkyl group, the lower was the receptor affinity, but the derivatives methylated and ethylated at the R-5-position of the imidazolidine ring were equipotent to the unsubstituted compound. Quantitative structure-activity relationship (QSAR) analysis of the receptor affinity demonstrated that the introduction of a substituent into the imidazolidine ring was fundamentally disadvantageous, but the introduction of a substituent at the R-5-position was permissible in the case of its small size. The binding model of the synthesized derivatives with the receptor supported the QSAR analysis, indicating the existence of space for a short alkyl group around the R-5-position in the ligand-binding site. In addition, positive correlation was observed between the insecticidal activity and receptor affinity, suggesting that the receptor affinity was the primary factor in influencing the insecticidal activity even if the imidazolidine ring was modified.
- Nishiwaki, Hisashi,Kuriyama, Mituhiro,Nagaoka, Hikaru,Kato, Akira,Yamauchi, Satoshi,Shuto, Yoshihiro,Akamatsu, Miki
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p. 6305 - 6312,8
(2012/12/11)
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- COMPOUNDS AND COMPOSITIONS AS PROTEIN KINASE INHIBITORS
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The invention provides a novel class of compounds of formula 1, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly diseases or disorders that involve abnormal activation of B-Raf.
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Page/Page column 46
(2011/04/14)
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- Affinity to the nicotinic acetylcholine receptor and insecticidal activity of chiral imidacloprid derivatives with a methylated imidazolidine ring
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Four imidacloprid derivatives with an asymmetrically methylated imidazolidine ring were synthesized. Their affinity to the nicotinic acetylcholine receptor of housefly Musca domestica and insecticidal activity against the housefly were measured. The compound with a 5R-methylated imidazolidine ring demonstrated intrinsic activity comparable to that of the unsubstituted compound. Most of the compounds were synergized by oxygenase inhibitors.
- Nishiwaki, Hisashi,Nagaoka, Hikaru,Kuriyama, Mituhiro,Yamauchi, Satoshi,Shuto, Yoshihiro
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experimental part
p. 780 - 782
(2011/11/13)
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- HETEROARYL COMPOUNDS AND COMPOSITIONS AS PROTEIN KINASE INHIBITORS
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The present invention provides compounds of Formula (I): wherein R1, R2, R3, and X are as defined herein. The compounds of Formula (I) and pharmaceutical compositions thereof are useful for the treatment of cancer, and B-
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Page/Page column 36
(2012/01/13)
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- A nonpeptidic reverse-turn scaffold stabilized by urea-based dual intramolecular hydrogen bonding
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A novel nonpeptidic reverse-turn scaffold containing urea fragments that are connected by a conformationally constrained d-prolyl-cis-1,2- diaminocyclohexane (d-Pro-DACH) linker is reported. The scaffold adopts a well-defined reverse-turn conformation tha
- Medda, Amiya K.,Park, Chul Min,Jeon, Aram,Kim, Hyunwoo,Sohn, Jeong-Hun,Lee, Hee-Seung
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p. 3486 - 3489
(2011/09/12)
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- Parallel synthesis of an oligomeric imidazole-4, 5-dicarboxamide library
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A library of oligomeric compounds was synthesized based on the imidazole-4, 5-dicarboxylic acid scaffold along with amino acid esters and chiral diamines derived from amino acids. The final compounds incorporate nonpolar amino acids (Leu, Phe, Trp), polar amino acids (Ser, Asp, Arg), and neutral amino acids (Gly, Ala), and were designed to be useful in screening for inhibitors of protein-protein interactions. Many of the protected and deprotected oligomers show evidence of conformational isomers persistent at room temperature in aqueous solution. A total of 317 final oligomers, out of 441 targeted compounds, were obtained in high analytical purity and of sufficient quantity to submit them for high-throughput screening as part of the NIH Roadmap.
- Xu, Zhigang,DiCesare, John C.,Baures, Paul W.
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supporting information; experimental part
p. 248 - 254
(2010/08/19)
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- Benzothiophene inhibitors of MK2. Part 1: Structure-activity relationships, assessments of selectivity and cellular potency
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Identification of potent benzothiophene inhibitors of mitogen activated protein kinase-activated protein kinase 2 (MK2), structure-activity relationship (SAR) studies, selectivity assessments against CDK2, cellular potency and mechanism of action are pres
- Anderson, David R.,Meyers, Marvin J.,Kurumbail, Ravi G.,Caspers, Nicole,Poda, Gennadiy I.,Long, Scott A.,Pierce, Betsy S.,Mahoney, Matthew W.,Mourey, Robert J.
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scheme or table
p. 4878 - 4881
(2010/04/28)
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- NOVEL HETEROCYCLIC COMPOUNDS AND USES THEROF
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New substituted heterocyclic compounds, compositions containing them, and methods of using them for the inhibition of Raf kinase activity are provided. The new compounds and compositions may be used either alone or in combination with at least one additional agent for the treatment of a Raf kinase mediated disorder, such as cancer.
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Page/Page column 122
(2009/10/22)
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- HETEROCYCLIC SULFONAMIDE DERIVATIVES AS INHIBITORS OF FACTOR XA
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The invention relates to compounds of formula (I), wherein R1, R2 and R3 are independently selected from carbon and nitrogen, and where at least one of R1, R2 and R3 is nitrogen; A is a single bond or a double bond; n is 0, 1, 2 or 3; each R4 is independently selected from hydrogen, C1-3 alkyl, hydroxy, oxo and thioxo; R5 is hydrogen or oxo; m is 0, 1, 2 or 3; each R6 is independently selected from hydrogen, C1-5alkyl, oxo, carboxy, cyano, tetrazolyl, hydroxy C1-5 alkyl, carboxy C1-5 alkyl, C1-5 alkylcarboxy, C1-5alkoxyoxo C1-5 alkyl, carbamoyl, C1-5 alkylcarbamoyl, di(C1-5 alkyl) carbamoyl, -CONR80 (CH2)xS(O)pR9, -CONH(CH2)qNR10R11, -C1-5 alkyl-Y1, -COOCHR17R18 and -CON R17 R18; R7 is carbon or nitrogen; p1 is 0, 1 or 2; each R8 is independently selected from hydrogen and halogen; or a pharmaceutically acceptable salt thereof, said compounds possess antithrombotic and anticoagulant properties and are accordingly useful in methods of treatment of humans or animals. The invention also relates to processes for the preparation of the compounds, to their use, to pharmaceutical compositions comprising them, to their use in the manufacture of medicaments for use in the production of an antithrombotic or anticoagulant effect, and to combinations comprising them.
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Page/Page column 27
(2008/06/13)
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- HETEROCYCLIC SULFONAMIDE DERIVATIVES AS INHIBITORS OF FACTOR XA
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The invention relates to compounds of formula (I), Chemical formula should be inserted here. Please see paper copy wherein R1 is hydrogen, C1-3alkyl, R5R6 aminoC1-5alkyl, where R5 and R6 are each independently selected from hydrogen and C1-3alkyl, or R5 and R6 may, together with the nitrogen to which they are attached, form a five- or six-membered heterocyclic ring, where said heterocyclic ring has 0 or 1 additional heteroatom; n is 1 or 2; each R2 are independently selected from hydrogen, oxo and C1-3alkyl, R3 is an indolyl, and R4 a hydrogen or a halogen; or a pharmaceutically acceptable salt thereof, said compounds possess antithrombotic and anticoagulant properties and are accordingly useful in methods of treatment of humans or animals. The invention also relates to processes for the preparation of the compounds, to their use, to pharmaceutical compositions comprising them, to their use in the manufacture of medicaments for use in the production of an antithrombotic or anticoagulant effect, and to combinations comprising them.
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Page/Page column 17; 23-24
(2010/11/25)
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- Enantiomer-pure (4S,8S)- and (4R,8R)-4-p-nitrobenzyl-8-methyl-3,6,9-triaza-3N,6N,9N-tricarboxymethyl-1,11-undecanedioic acid and derivatives thereof, process for their production and use for the production of pharmaceutical agents
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Enantiomer-pure compounds of general formulas VIIa and VIIb in which A stands for a group —COO—, and Z and R have different meanings, as well as use thereof are described.
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- Modified Amino Acids and Peptides. Part 2. A Convenient Conversion of Amino and Peptide Alcohols into Amines.
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A convenient general method for the conversion of N-protected amino and peptide alcohols into amines is described.The hydroxyl group of the alcohols was replaced by an azido group and a substituted amino group after activation through mesylation.Hydrogenation of the N-protected amino azides afforded optically active monoprotected diamines or free 1,2-diamines depending on the N-protecting group.Selective reduction of the azido group in the presence of a benzyloxycarbonyl group was performed in high yield using sodium borohydride in the presence of 10percent palladium on charcoal.
- Kokotos, George,Constantinou-Kokotou, Violetta
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p. 3117 - 3132
(2007/10/02)
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