cas 16554-45-3, 2-METHOXY-6-NITRO-PHENYLAMINE

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Deconstructing Noncovalent Kelch-like ECH-Associated Protein 1 (Keap1) Inhibitors into Fragments to Reconstruct New Potent Compounds
Targeting the protein-protein interaction (PPI) between nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) is a potential therapeutic strategy to control diseases involving oxidative stress. Here, six classes of known small-molecule Keap1-Nrf2 PPI inhibitors were dissected into 77 fragments in a fragment-based deconstruction reconstruction (FBDR) study and tested in four orthogonal assays. This gave 17 fragment hits of which six were shown by X-ray crystallography to bind in the Keap1 Kelch binding pocket. Two hits were merged into compound 8 with a 220-380-fold stronger affinity (Ki = 16 μM) relative to the parent fragments. Systematic optimization resulted in several novel analogues with Ki values of 0.04-0.5 μM, binding modes determined by X-ray crystallography, and enhanced microsomal stability. This demonstrates how FBDR can be used to find new fragment hits, elucidate important ligand-protein interactions, and identify new potent inhibitors of the Keap1-Nrf2 PPI.
Pallesen, Jakob S.,Narayanan, Dilip,Tran, Kim T.,Solbak, Sara M. ?.,Marseglia, Giuseppe,S?rensen, Louis M. E.,H?j, Lars J.,Munafò, Federico,Carmona, Rosa M. C.,Garcia, Anthony D.,Desu, Haritha L.,Brambilla, Roberta,Johansen, Tommy N.,Popowicz, Grzegorz M.,Sattler, Michael,Gajhede, Michael,Bach, Anders
p. 4623 - 4661
(2021/05/07)

Overcoming imatinib resistance in chronic myelogenous leukemia cells using non-cytotoxic cell death modulators
Recent studies examined the possibility to overcome imatinib resistance in chronic myeloid leukemia (CML) patients by combination therapy with peroxisome proliferator-activated receptor gamma (PPARγ) ligands. Pioglitazone, a full PPARγ agonist, improved the survival of patients by the gradual elimination of the residual CML stem cell pool. To evaluate the importance of the pharmacological profile of PPARγ agonists on the ability to circumvent resistance, the partial PPARγ agonist 4‘-((2-propyl-1H-benzo[d]imidazol-1-yl)methyl)-[1,1’-biphenyl]-2-carboxylic acid, derived from telmisartan, and other related derivatives were investigated. The 4-substituted benzimidazole derivatives bearing a [1,1′-biphenyl]-2-carboxamide moiety sensitized K562-resistant cells to imatinib treatment. Especially the derivatives 18a-f, which did not activate PPARγ to more than 40% at 10 μM, retrieved the cytotoxicity of imatinib in these cells. The cell death modulating properties were higher than that of pioglitazone. It is of interest to note that all novel compounds were not cytotoxic neither on non-resistant nor on resistant cells. They exerted antitumor potency only in combination with imatinib.
Schoepf, Anna M.,Salcher, Stefan,Obexer, Petra,Gust, Ronald
supporting information

(2019/10/22)

A Comparative Assessment Study of Known Small-Molecule Keap1-Nrf2 Protein-Protein Interaction Inhibitors: Chemical Synthesis, Binding Properties, and Cellular Activity
Inhibiting the protein-protein interaction (PPI) between the transcription factor Nrf2 and its repressor protein Keap1 has emerged as a promising strategy to target oxidative stress in diseases, including central nervous system (CNS) disorders. Numerous non-covalent small-molecule Keap1-Nrf2 PPI inhibitors have been reported to date, but many feature suboptimal physicochemical properties for permeating the blood-brain barrier, while others contain problematic structural moieties. Here, we present the first side-by-side assessment of all reported Keap1-Nrf2 PPI inhibitor classes using fluorescence polarization, thermal shift assay, and surface plasmon resonance - and further evaluate the compounds in an NQO1 induction cell assay and in counter tests for nonspecific activities. Surprisingly, half of the compounds were inactive or deviated substantially from reported activities, while we confirm the cross-assay activities for others. Through this study, we have identified the most promising Keap1-Nrf2 inhibitors that can serve as pharmacological probes or starting points for developing CNS-active Keap1 inhibitors.
Tran, Kim T.,Pallesen, Jakob S.,Solbak, Sara M.,Narayanan, Dilip,Baig, Amina,Zang, Jie,Aguayo-Orozco, Alejandro,Carmona, Rosa M. C.,Garcia, Anthony D.,Bach, Anders
supporting information
p. 8028 - 8052
(2019/10/11)

PIPERIDINE DERIVATIVE
The purpose of the present invention is to provide a compound having excellent antibacterial activity against mycobacterium tuberculosis, multidrug-resistant tuberculosis bacteria, and/or non-tuberculous acid-fast bacteria. A compound represented by formula [I]: (in the formula, each symbol is as described in the attached specification), or a salt thereof can be used to diagnose, prevent, and/or treat tuberculosis.
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Paragraph 0496; 0513

(2019/02/19)

3-(2,3-DIHYDRO-1H-INDEN-5-YL)PROPANOIC ACID DERIVATIVES AND THEIR USE AS NRF2 REGULATORS
The present invention relates to compounds of Formula (I), and Formula (II), wherein B is benzotriazolyl, phenyl, triazolopyridinyl, or -(CH2)2-triazolyl each of which may be unsubstituted or substituted by 1, 2, or 3 substituents independently chosen from -C1-3 alkyl, -O-C1-3 alkyl, CN, - (CH2)2-O-(CH2)2-OR4 and halo; and D is -C(O)OH, -C(O)NHSO2CH3, -SO2NHC(O)CH3, 5-(trifluoromethyl)-4H-1,2,4-triazol-2-yl, or tetrazolyl; and their use as NRF2 regulators.
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Page/Page column 102

(2018/06/30)

HETEROCYCLIC COMPOUND
The present invention relates to a compound which can be useful for the treatment or prevention of SPT-related diseases including cancer and congenital diseases associated with sphingolipid accumulation (including Niemann-Pick disease).
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Paragraph 0490

(2018/03/25)

Exploration of SAR for novel 2-benzylbenzimidazole analogs as inhibitor of transcription factor NF-κB
A novel series of 2-benzylbenzimidazole analogs was designed, synthesized and investigated for their in vitro activities against LPS induced NF-κB inhibition in RAW 264.7 cells using the SEAP assay. Among them, 4-((4-(cyclohexylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)phenol (6e, >100% inhibition at 30?μM, IC50?=?3.0?μM), 4-((5-(cyclohexylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)phenol (6j, 96% inhibition at 30?μM, IC50?=?4.0?μM) and 2-((4-(cyclohexylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)phenol (6k, 95% inhibition at 30?μM, IC50?=?5.0?μM) showed strong inhibitory activity. The structure activity relationship confirmed that the substitution on benzimidazole ring A with hydrophobic cyclohexylmethoxy group at position 4 or 5 markedly enhances the activity. In addition, the hydrophilic hydrogen bonding donor group (OH) at position 2 or 4 on phenyl ring B connected with one methylene spacer to the benzimidazole ring is favorable for the inhibitory activity. However, hydrophobic (–OCH3 and –Cl) groups on phenyl ring B decrease the activity.
Boggu, Pulla Reddy,Venkateswararao, Eeda,Manickam, Manoj,Kim, Youngsoo,Jung, Sang-Hun
p. 469 - 479
(2017/04/13)

Monoacidic Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear Factor Erythroid 2-Related Factor 2 (KEAP1:NRF2) Protein-Protein Interaction with High Cell Potency Identified by Fragment-Based Discovery
KEAP1 is the key regulator of the NRF2-mediated cytoprotective response, and increasingly recognized as a target for diseases involving oxidative stress. Pharmacological intervention has focused on molecules that decrease NRF2-ubiquitination through covalent modification of KEAP1 cysteine residues, but such electrophilic compounds lack selectivity and may be associated with off-target toxicity. We report here the first use of a fragment-based approach to directly target the KEAP1 Kelch-NRF2 interaction. X-ray crystallographic screening identified three distinct "hot-spots" for fragment binding within the NRF2 binding pocket of KEAP1, allowing progression of a weak fragment hit to molecules with nanomolar affinity for KEAP1 while maintaining drug-like properties. This work resulted in a promising lead compound which exhibits tight and selective binding to KEAP1, and activates the NRF2 antioxidant response in cellular and in vivo models, thereby providing a high quality chemical probe to explore the therapeutic potential of disrupting the KEAP1-NRF2 interaction.
Davies, Thomas G.,Wixted, William E.,Coyle, Joseph E.,Griffiths-Jones, Charlotte,Hearn, Keisha,McMenamin, Rachel,Norton, David,Rich, Sharna J.,Richardson, Caroline,Saxty, Gordon,Willems, Henri?tte M. G.,Woolford, Alison J.-A.,Cottom, Joshua E.,Kou, Jen-Pyng,Yonchuk, John G.,Feldser, Heidi G.,Sanchez, Yolanda,Foley, Joseph P.,Bolognese, Brian J.,Logan, Gregory,Podolin, Patricia L.,Yan, Hongxing,Callahan, James F.,Heightman, Tom D.,Kerns, Jeffrey K.
p. 3991 - 4006
(2016/05/19)

NRF2 REGULATORS
The present invention relates to aryl analogs Formula (I), pharmaceutical compositions containing them and their use as Nrf2 regulators.
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Page/Page column 45; 46

(2017/01/02)

NRF2 REGULATORS
The present invention relates to aryl analogs, pharmaceutical compositions containing them and their use as Nrf2 regulators.
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Page/Page column 102

(2017/01/02)

NRF2 REGULATORS
Provided are aryl analogs，pharmaceutical compositions containing them and their use as NRF2 regulators.
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Page/Page column 129

(2017/01/02)

Palladium(II)-catalyzed, heteroatom-directed, regioselective C-H nitration of anilines using pyrimidine as a removable directing group
A new palladium-catalyzed, heteroatom-directed strategy for C-H nitration of anilines is described. This C-H functionalization reaction is highly ortho-selective and results in very good yields. The highlight of the work is the use of pyrimidine as the removable directing group. This approach constitutes one of the rare methods of ortho-nitration of anilines, a reaction that is normally very difficult to achieve via traditional approaches.
Pawar, Govind Goroba,Brahmanandan, Abhilashamole,Kapur, Manmohan
supporting information
p. 448 - 451
(2016/02/18)

NRF2 REGULATORS
The present invention relates to bis aryl analogs, pharmaceutical compositions containing them and their use as Nrf2 regulators.
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Page/Page column 69; 154; 155

(2015/07/07)

Synthesis and antiproliferative evaluation of novel benzoimidazole- contained oxazole-bridged analogs of combretastatin A-4
A series of novel oxazole-bridged analogs of combretastatin A-4 bearing a benzo[d]-imidazole as B ring were synthesized and evaluated for antiproliferative activities against five human cancer cell lines. Among all the synthesized compounds, the N-unsubstituted benzoimidazole analog 5 and the analogs 6b, 7a and 7b with a small hydrophobic group on nitrogen atom of benzoimidazole ring were identified as the most potent inhibitors of tumor cell growth with IC50 values at nanomolar levels (5, IC50 = 8.4 nM, HT29; 6b, 7a, 7b, IC50 = 9.6 nM, 3.8 nM, 3.0 nM, A549). In a murine H22 tumor xenograft model, compound 5 exhibited significant antitumor activity. The binding mode of compound 5 in the colchicine binding site of tubulin was probed.
Zhou, Jie,Jin, Jing,Zhang, Yi,Yin, Yuwen,Chen, Xiaoguang,Xu, Bailing
p. 222 - 232
(2013/10/01)

TRIAZOLOPYRAZINE DERIVATIVES AND THEIR USE FOR TREATING NEUROLOGICAL AND PSYCHIATRIC DISORDERS
The present invention is directed to triazolopyrazine compounds of Formula (I). Separate aspects of the invention are directed to pharmaceutical compositions comprising said compounds and uses of the compounds as therapeutic agents treating neurological and psychiatric disorders.
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Page/Page column 26

(2013/03/26)

SUBSTITUTED TRIAZOLOPYRAZINES AND USES THEREOF
The present invention is directed to substituted triazolopyrazine compounds of Formula (I). Separate aspects of the invention are directed to pharmaceutical compositions comprising said compounds and uses of the compounds as therapeutic agents treating neurological and psychiatric disorders.
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Page/Page column 19

(2013/03/26)

Design, synthesis and anticancer activity evaluation of diazepinomicin derivatives
A series of diazepinomicin derivatives were synthesized and evaluated in vitro for their growth inhibitory activity against the human carcinoma cell lines. The results indicated the anticancer selectivity of this kind of compounds. Based on the results, preliminary structure-activity relationships were discussed.
Yu, Yongguo,Wu, Jianbo,Lei, Fan,Chen, Lei,Wan, Weili,Hai, Li,Guan, Mei,Wu, Yong
p. 369 - 373
(2013/07/26)

HCV NS3 PROTEASE INHIBITORS
The present invention relates to macro-cyclic compounds of formula I that are useful as inhibitors of the hepatitis C virus (HCV) NS3 protease, their synthesis, and their use for treating or preventing HCV infections
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Page/Page column 47-48

(2012/04/10)

BENZIMIDAZOLE DERIVATIVES AS PI3 KINASE INHIBITORS
This invention relates to the use of benzimidazole derivatives for the modulation, notably the inhibition of the activity or function of the phosphoinositide 3′ OH kinase family (hereinafter PI3 kinases), suitably, PI3Kα, PI3Kβ, PI3Kβ, and/or PI3Kγ. Suitably, the present invention relates to the use of benzimidazoles in the treatment of one or more disease states selected from: autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection and lung injuries. More suitably, the present invention relates to PI3Kβ selective benzimidazoles compounds for treating cancer.
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Page/Page column 16; 22

(2012/04/18)

Synthesis and cytotoxic evaluation of N-(4-methoxy-1H-benzo[d]imidazol-7- yl)-arylsulfonamide and N-aryl-(4-methoxy-1H-benzo[d]imidazol)-7-sulfonamide analogs of combretastatin A-4
Two series of novel benzoimidazole sulfonamides as combretastatin A-4 analogs were synthesized. The cytotoxicities of the title compounds were evaluated against five different cancer cell lines. Among the tested compounds, four compounds displayed cytotoxicities against the HCT8 cell line. Compound 6a has shown the strongest potency against the tested human tumor cell lines with an IC50 value ranging from submicromolar to micromolar level.
Zhou, Jie,Zhang, Yi,Cui, Yi-Wen,Li, Zhan-Mei,Song, Hong-Rui,Dong, Jin-Hua,Chen, Xiao-Guang,Xu, Bai-Ling
scheme or table
p. 330 - 340
(2011/06/19)

Penta-substituted benzimidazoles as potent antagonists of the calcium-sensing receptor (CaSR-antagonists)
A series of novel benzimidazole derivatives has been designed via a scaffold morphing approach based on known calcilytics chemotypes. Subsequent lead optimisation led to the discovery of penta-substituted benzimidazoles that exhibit attractive in vitro and in vivo calcium-sensing receptor (CaSR) inhibitory profiles. In addition, synthesis and structure-activity relationship data are provided.
Gerspacher, Marc,Altmann, Eva,Beerli, René,Buhl, Thomas,Endres, Ralf,Gamse, Rainer,Kameni-Tcheudji, Jacques,Kneissel, Michaela,Krawinkler, Karl Heinz,Missbach, Martin,Schmidt, Alfred,Seuwen, Klaus,Weiler, Sven,Widler, Leo
scheme or table
p. 5161 - 5164
(2010/10/02)

Sensitized lanthanide-ion luminescence with aryl-substituted N-(2-nitrophenyl)acetamide-derived chromophores
The syntheses of the two tetraazamacrocyclic ligands L1 and L2 bearing a [(methoxy-2-nitrophenyl)amino]carbonyl chromophore, i.e., an N-(methoxy-2-nitrophenyl)acetamide moiety, together with their corresponding lanthanide-ion complexes are described. A combined spectroscopic (UV/VIS, 1H-NMR), structural (X-ray), and theoretical (DFT) investigation revealed that the absorption properties of the chromophores were dictated by the extent of electronic delocalisation, which in turn was determined by the position of the MeO substituent at the aromatic ring. X-Ray crystallographic studies showed that when attached to the macrocycle, both isomeric forms of the N-(methoxy-2-nitrophenyl)acetamide unit can participate in coordination, via the C=O, to an encapsulated potassium cation. Luminescence measurements confirmed that such a binding mode also exists in solution for the corresponding lanthanide complexes (q ca. ≤1), with the para-MeO derivative allowing longer wavelength sensitization (λex 330 nm).
Andrews, Michael,Ward, Benjamin D.,Laye, Rebecca H.,Kariuki, Benson M.,Pope, Simon J. A.
scheme or table
p. 2159 - 2172
(2010/03/26)

HETEROCYCLYC SULFONAMIDES HAVING EDG-I ANTAGONISTIC ACTIVITY
The invention relates to chemical compounds of formula (I), (Ia) and (Ib) or pharmaceutically acceptable salts thereof, which possess Edg-1 antagonistic activity and are accordingly useful for their anti-cancer activity and thus in methods of treatment of the human or animal body. The invention also relates to processes for the manufacture of said chemical compounds, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments for use in the production of an anti-cancer effect in a warm-blooded animal, such as man.
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Page/Page column 180

(2008/12/05)

JAK-2 MODULATORS AND METHODS OF USE
This invention relates to the field of protein tyrosine kinases and inhibitors thereof. In particular, the invention relates to inhibitors of JAK-2, pharmaceutical compositions of the compounds for inhibiting JAK-2, methods of inhibiting JAK-2 in a cell, comprising contacting a cell in which inhibition of JAK-2 is desired with a compound or pharmaceutical composition comprising a compound according to the invention. The also comprises methods of treating a disease or condition that involves JAK-2 comprising administering to a patient a pharmaceutical composition comprising a compound according to the invention
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Page/Page column 131

(2008/06/13)

PYRIMIDINE DERIVATIVES
The invention concerns pyrimidine derivatives of Formula (I), wherein each of p, R1, R2, q, R3, r, R4, X1 and Q1 have any of the meanings defined in the description; processes for their preparation, pharmaceutical compositions containing them and their use in a method for producing an anti-proliferative effect in a warm blooded animal such as man.
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Page/Page column 100

(2010/11/30)

Novel vanilloid receptor-1 antagonists: 2. Structure-activity relationships of 4-oxopyrimidines leading to the selection of a clinical candidate
A series of novel 4-oxopyrimidine TRPV1 antagonists was evaluated in assays measuring the blockade of capsaicin or acid-induced influx of calcium into CHO cells expressing TRPV1. The investigation of the structure-activity relationships in the heterocyclic A-region revealed the optimum pharmacophoric elements required for activity in this series and resulted in the identification of subnanomolar TRPV1 antagonists. The most potent of these antagonists were thoroughly profiled in pharmacokinetic assays. Optimization of the heterocyclic A-region led to the design and synthesis of 23, a compound that potently blocked multiple modes of TRPV1 activation. Compound 23 was shown to be effective in a rodent "on-target" biochemical challenge model (capsaicin-induced flinch, ED50 = 0.33 mg/kg p.o.) and was antihyperalgesic in a model of inflammatory pain (CFA-induced thermal hyperalgesia, MED = 0.83 mg/kg, p.o.). Based on its in vivo efficacy and pharmacokinetic profile, compound 23 (N-{4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl} -acetamide; AMG 517) was selected for further evaluation in human clinical trials.
Doherty, Elizabeth M.,Fotsch, Christopher,Bannon, Anthony W.,Bo, Yunxin,Chen, Ning,Dominguez, Celia,Falsey, James,Gavva, Narender R.,Katon, Jodie,Nixey, Thomas,Ognyanov, Vassil I.,Pettus, Liping,Rzasa, Robert M.,Stec, Markian,Surapaneni, Sekhar,Tamir, Rami,Zhu, Jiawang,Treanor, James J. S.,Norman, Mark H.
p. 3515 - 3527
(2008/02/08)

Novel Enantiomeric Pure Beta Agonists, Manufacturing and Use as a Medicament Thereof
The present invention relates to enantiomerically pure compounds of formula 1 wherein the groups m, n, B, X, R1, m and Ym- may have the meanings given in the claims and specification, methods for preparing them and their use as pharmaceutical compositions, particularly as pharmaceutical compositions for the treatment of respiratory complaints.
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Page/Page column 8-9

(2008/06/13)

Medicament Combinations for the Treatment of Respiratory Diseases
The present invention relates to new medicament combinations which contain in addition to one or more, preferably one compound of general formula 1 wherein A, B, R1, X, n and m may have the meanings given in the claims and in the specification, at least one other active substance 2, processes for preparing them and their use as pharmaceutical compositions.
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Page/Page column 35

(2010/11/28)

Synthesis, biological activity, and crystal structure of potent nonnucleoside inhibitors of HIV-1 reverse transcriptase that retain activity against mutant forms of the enzyme
In an ongoing effort to develop novel and potent nonnucleoside HIV-1 reverse transcriptase (RT) inhibitors that are effective against the wild type (WT) virus and clinically observed mutants, 1,2-bis-substituted benzimidazoles were synthesized and tested. Optimization of the N1 and C2 positions of benzimidazole led to the development of 1-(2,6-difluorobenzyl)-2-(2,6- difluorophenyl)-4-methylbenzimidazole (1) (IC50 = 0.2 μM, EC 50 = 0.44 μM, and TC50 ≥ 100 against WT). This paper describes how substitution on the benzimidazole ring profoundly affects activity. Substituents at the benzimidazole C4 dramatically enhanced potency, while at C5 or C6 substituents were generally detrimental or neutral to activity, respectively. A 7-methyl analogue did not inhibit HIV-1 RT. Determination of the crystal structure of 1 bound to RT provided the basis for accurate modeling of additional analogues, which were synthesized and tested. Several derivatives were nanomolar inhibitors of wild-type virus and were effective against clinically relevant HIV-1 mutants.
Morningstar, Marshall L.,Roth, Thomas,Farnsworth, David W.,Smith, Marilyn Kroeger,Watson, Karen,Buckheit Jr., Robert W.,Das, Kalyan,Zhang, Wanyi,Arnold, Eddy,Julias, John G.,Hughes, Stephen H.,Michejda, Christopher J.
p. 4003 - 4015
(2008/02/11)

Indazoles, benzothiazoles, benzoisothiazoles, benzisoxazoles, pyrazolopyridines, isothiazolopyridines, and preparation and uses thereof
The present invention relates generally to the field of ligands for nicotinic acetylcholine receptors (nACh receptors), activation of nACh receptors, and the treatment of disease conditions associated with defective or malfunctioning nicotinic acetylcholine receptors, especially of the brain. Further, this invention relates to novel compounds (e.g., indazoles and benzothiazoles), which act as ligands for the α7 nACh receptor subtype, methods of preparing such compounds, compositions containing such compounds, and methods of use thereof.
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Page/Page column 67

(2010/11/26)

7′-Substituted benzothiazolothio- and pyridinothiazolothio-purines as potent heat shock protein 90 inhibitors
We report on the discovery of benzo- and pyridinothiazolothiopurines as potent heat shock protein 90 inhibitors. The benzothiazole moiety is exceptionally sensitive to substitutions on the aromatic ring with a 7′-substituent essential for activity. Some of these compounds exhibit low nanomolar inhibition activity in a Her-2 degradation assay (28-150 nM), good aqueous solubility, and oral bioavailability profiles in mice. In vivo efficacy experiments demonstrate that compounds of this class inhibit tumor growth in an N87 human colon cancer xenograft model via oral administration as shown with compound 37 (8-(7-chloro-benzothiazol-2-ylsulfanyl)-9-(2-cyclopropylamino-ethyl) -9H-purin-6-ylamine).
Zhang, Lin,Fan, Junhua,Vu, Khang,Hong, Kevin,Le Brazidec, Jean-Yves,Shi, Jiandong,Biamonte, Marco,Busch, David J.,Lough, Rachel E.,Grecko, Roy,Ran, Yingqing,Sensintaffar, John L.,Kamal, Adeela,Lundgren, Karen,Burrows, Francis J.,Mansfield, Robert,Timony, Gregg A.,Ulm, Edgar H.,Kasibhatla, Srinivas R.,Boehm, Marcus F.
p. 5352 - 5362
(2007/10/03)

New betamimetics for the treatment of respiratory complaints
The present invention relates to compounds of formula 1 wherein the groups n, m, B, X and R1 may have the meanings given in the claims and specification, processes for preparing them and their use as pharmaceutical compositions, particularly as pharmaceutical compositions for the treatment of respiratory complaints.
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Page/Page column 12

(2010/10/20)

Pyridine, pyrimidine, quinoline, quinazoline, and naphthalene urotensin-II receptor antagonists
The present invention relates to urotensin II receptor antagonists, pharmaceutical compositions containing them and their use.
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(2008/06/13)

ORGANIC COMPOUNDS
Compounds of formula (I) in free or salt form, where Y, R1, R2, R3, R4 and R5 have the meanings as indicated in the specification, are useful for treating conditions that are mediated by the CXCR2 receptor. Pharmaceutical compositions that contain the compounds and a process for preparing the compounds are also described.
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Page/Page column 21

(2008/06/13)

CYCLIC GUANIDINES, COMPOSITIONS CONTAINING SUCH COMPOUNDS AND METHODS OF USE
The present invention relates to cyclic guanidines, compositions containing such compounds and methods of treatment. The compounds are glucagon receptor antagonists and thus are useful for treating, preventing or delaying the onset of type 2 diabetes mellitus.
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Page/Page column 79

(2010/02/12)

BENZIMIDAZOLE DERIVATIVES
A compound of formula (I) or a pharmaceutically acceptable salt or prodrug ester thereof; wherein R1-R7 are as disclosed in the specification and pharmaceutical uses thereof.
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Page/Page column 38

(2008/06/13)

Chemokine receptor binding heterocyclic compounds with enhanced efficacy
The invention relates to heterocyclic compounds consisting of a core nitrogen atom surrounded by three pendant groups, wherein two of the three pendant groups are preferably benzimidazolyl methyl and tetrahydroquinolyl, and the third pendant group contains N and optionally contains additional rings. The compounds bind to chemokine receptors, including CXCR4 and CCR5, and demonstrate protective effects against infection of target cells by a human immunodeficiency virus (HIV).
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(2008/06/13)

Substituted benzimidazoles, and methods of use thereof, for the inhibition of HIV reverse transcription and for the treatment of HIV infection
The present invention provides compositions and methods for the treatment of HIV infection. In particular, the present invention provides non-nucleoside inhibitors of reverse transcriptase (RT), as well as methods to treat HIV infection using these non-nucleoside inhibitors of RT. In preferred embodiments, the present invention provides a novel class of substituted benzimidazoles, effective in the inhibition of human immunodeficiency virus (HIV) RT.
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Example 46

(2008/06/13)

Bicyclic aryl carboxamides and their therapeutic use
Compounds of the formula (i) have therapeutic utility via inhibition of TNF or phosphodiesterase.
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Page column 9

(2010/02/05)

Construction of interconnected acidity functions based on ortho substituted anilines and N-methylanilines as indicators
The log I values of 15 mainly ortho substituted derivatives of aniline and N-methylaniline have been measured spectrophotometrically in sulfuric, perchloric, and methanesulfonic acids. A new algorithm has been suggested for construction of acidity functions enabling simultaneous and independent construction of acidity functions in various media under the condition of equal values of pKa of the same indicators in the given media. The so-called interconnected acidity functions have been constructed with using this algorithm and the log I values measured in the above media, and the pKa values have been calculated. The resulting acidity functions and pKa values agree well with the corresponding literature data.
Pytela, Oldrich,Kulhanek, Jiri,Jiraskova, Eva,Nevecna, Tatjana
p. 1638 - 1658
(2007/10/03)

A convenient copper-catalyzed direct animation of nitroarenes with 9-alkylhydroxylamines
O-Alkylhydroxylamines, particularly O-methylhydroxylamine, aminate nitroarenes in the presence of a strong base and a copper catalyst to give aminonitroarenes in good yields, ortho- or para-Animation with respect to the nitro group takes place, and in some cases the ortho-aminated product is preferentially obtained. With 3-substituted nitrobenzenes where the substituent has a lone pair of electrons, preferential amination occurs at the 2-position to give the sterically most congested 3c-f, 14 and 22g.
Seko, Shinzo,Miyake, Kunihito,Kavvamura, Norio
p. 1437 - 1444
(2007/10/03)

Nitroarylamines via the Vicarious Nucleophilic Substitution of Hydrogen: Amination, Alkylamination, and Arylamination of Nitroarenes with Sulfenamides
A new reaction of sulfenamides with electrophilic arenes under basic conditions is described. The σ adducts formed from nitroarenes and the anions of sulfenamides undergo elimination of thiol to produce the corresponding o- and/or p-nitroanilines. This reaction is analogous to the known alkylation and hydroxylation of nitroarenes via the vicarious nucleophilic substitution of hydrogen (VNS). The reaction gives access to a wide range of substituted nitroanilines, nitronaphthylamines, and aminoheterocycles. By means of the reaction with N-alkyl- and N-arylsulfenamides, it is possible to obtain N-alkylnitroanilines and nitrodiarylamines. By varying the structure of sulfenamide and the reaction conditions, particularly the nature and concentration of the base, it is possible to control the orientation of animation.
Makosza, Mieczyslaw,Bialecki, Maciej
p. 4878 - 4888
(2007/10/03)

1,1,1-trimethylhydrazinium iodide: A novel, highly reactive reagent for aromatic amination via vicarious nucleophilic substitution of hydrogen
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Pagoria, Philip F.,Mitchell, Alexander R.,Schmidt, Robert D.
p. 2934 - 2935
(2007/10/03)

Copper-catalyzed direct amination of nitrobenzenes with O-alkylhydroxylamines
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Seko, Shinzo,Kawamura, Norio
p. 442 - 443
(2007/10/02)

Process for preparing nitroaniline derivatives
A process for preparing a nitroaniline derivative comprising a step of reacting an aromatic nitro compound with an O-alkylhydroxylamine or a salt thereof in the presence of a base and optionally a metallic catalyst, which process is industrially advantageous since it provides the nitroaniline derivative from the aromatic nitro compound in a high yield in one step, and the aminating agent used can be obtained from hydroxylamine at a relatively low cost.
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(2008/06/13)

Nonpeptide angiotensin II receptor antagonists. Synthesis and biological activity of benzimidazoles
A series of substituted 2-butylbenzimidazoles bearing a biphenylylmethyl moiety at the 1-position was prepared via three synthetic routes and evaluated for angiotensin II (AII) receptor antagonistic activity (in vitro and in vivo). Binding affinity was determined using bovine adrenal cortical membrane. Substitution at the 4-, 5-, or 6-position reduced the affinity relative to that of the unsubstituted compound (13a). However, most of the compounds with a substituent at the 7-position showed binding affinity comparable to that of DuP 753 (losartan). In functional studies, a carboxyl group was found to be very important for antagonistic activity against AII. Comparison of 2-butyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H- benzimidazole-4-,-5-,-6-, and -7-carboxylic acids (15a-d) in an AII-induced rabbit aortic ring contraction assay clearly demonstrated the importance of the substitutional position of the carboxyl group. In an in vivo assay, oral administration of benzimidazole-7-carboxylic acids caused long-lasting inhibition of the AII-induced pressor response in rats. The optimum substituent at the 7-position of the benzimidazole ring was found to be a carboxyl or an ester group. The representative compound, 2-butyl-1-[[2'-(1H- tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (15d, CV-11194), inhibited the specific binding of [125I]AII to bovine adrenal cortical membrane with an IC50 value of 5.5 x 10-7 M. The AII-induced contraction of rabbit aortic strips was antagonized by CV-11194 (IC50 value, 5.5 x 10-11 M), while the compound had no effect on the contraction induced by norepinephrine or KCl. Orally administered CV-11194 at doses of 0.3-10 mg/kg dose-dependently inhibited the AII-induced pressor response in rats and dogs. CV-11194 at 1 mg/kg po reduced blood pressure in spontaneously hypertensive rats (SHR). The three-dimensional molecular structure of CV- 11194 was determined by X-ray diffraction.
Kubo,Inada,Kohara,Sugiura,Ojima,Itoh,Furukawa,Nishikawa,Naka
p. 1772 - 1784
(2007/10/02)

Benzimidazole derivatives and their use
Novel imidazole derivatives of the formula (I): STR1 wherein R1 is an optionally substituted alkyl group, R2 and R3 are independently a group capable of forming an anion or a group which can be changed thereinto, ring A is a benzene ring optionally having, besides the group shown by R2, further substituents, and X shows linkage of phenylene group and phenyl group directly or through a spacer whose atomic length is not more than 2 and a salt thereof, show antagonistic actions to angiotensin II, thus being useful as therapeutics for cardiovascular diseases.
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(2008/06/13)

New Herbicides
Benzimidazolyl derivatives of formula wherein Y represents:-, an optionally substituted alkyl, alkenyl or alkynyl group; or an optionally substituted cycloalkyl group; or a group -SR, -OR, halogen, aryl or aralkyl; or 2 groups Y form a fused phenyl ring;, R2represents a group -OH, -NR7R8or -XM;, A represents a group -SO2NR7R8;, Y1represents an optionally substituted alkyl, alkenyl or alkynyl group; or an optionally substituted cycloalkyl group; or a group such as -SR, -OR, halogen, aryl, aralkyl, -O-aryl or -NR7R8;, n represents one or two;, m represents an integer from 1 to 4;, R represents an optionally substituted alkyl group; or an optionally substituted cycloalkyl group;, R7and R8represent independently a group such as hydrogen, R, aryl or aralkyl; X represents oxygen or sulphur;, M represents an optionally substituted alkyl group; or an optionally substituted cycloalkyl group; or an aryl, aralkyl, alkenyl, alkynyl, or an imine group; agriculturally acceptable salts thereof;, the herbicidal compositions comprising these compounds and their application to crop protection is described.
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(2008/06/13)