cas 38818-50-7, 4-Chloro-3-nitrobenzoyl chloride

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Hydrogen-bonded framework structures in 4-[(4-chloro-3-nitrobenzoyl)- hydrazinocarbonyl]pyridinium chloride and N-3,5-dinitrobenzoyl-N′- isonicotinoylhydrazine
In 4-[(4-chloro-3-nitrobenzoyl)hydrazinocarbonyl]pyridinium chloride, C13H10ClN4O4 -·Cl-, the component ions are linked into a three-dimensional framework structure by a combination of three N-H...Cl and five C-H...O hydrogen bonds. In N-3,5-dinitrobenzoyl-N′- isonicotinoylhydrazine, C13H9-N5O6, the molecules are linked into a three-dimensional framework structure by one N-H...O and three C-H...O hydrogen bonds, augmented by an aromatic π-π stacking interaction.
Vasconcelos, Thatyana R. A.,De Souza, Marcus V. N.,Wardell, Solange M. S. V.,Wardell, James L.,Low, John N.,Glidewell, Christopher
p. o222-o226
(2006)
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Synthesis and structure-activity relationship studies of n-monosubstituted aroylthioureas as urease inhibitors
Background: Thiourea is a classical urease inhibitor which is usually used as a positive control, and many N,N'-disubstituted thioureas have been determined as urease inhibitors. However, due to steric hindrance, N,N'-disubstituted thiourea motif could not bind urease as thiourea. On the contrary, N-monosubstituted thiourea with a tiny thiourea motif could theoretically bind into the active pocket as thiourea. Objective: A series of N-monosubstituted aroylthioureas were designed and synthesized for evaluation as urease inhibitors. Methods: Urease inhibition was determined by the indophenol method and IC50 values were calculated using computerized linear regression analysis of quantal log dose-probit functions. The kinetic parameters were estimated via surface plasmon resonance (SPR) and by nonlinear regression analysis based on the mixed type inhibition model derived from Michaelis-Menten kinetics. Results: Compounds b2, b11, and b19 reversibly inhibited urease with a mixed mechanism, and showed excellent potency against both cell-free urease and urease in the intact cell, with IC50 values being 90-to 450-fold and 5-to 50-fold lower than the positive control acetohydroxamic acid, respectively. The most potent compound b11 showed an IC50 value of 0.060 ± 0.004μM against cell-free urease, which bound to urea binding site with a very low KD value (0.420±0.003nM) and a very long residence time (6.7 min). Compound b11 was also demonstrated to have very low cytotoxicity to mammalian cells. Conclusion: The results revealed that N-monosubstituted aroylthioureas bound to the active site of urease as expected, and represent a new class of urease inhibitors for the development of potential therapeutics against infections caused by urease-containing pathogens.
Dawalamu,Fang, Hai-Lian,Fu, Zi-Juan,Li, Fang,Li, Ke,Li, Wei-Yi,Liu, Li,Ni, Wei-Wei,Ouyang, Hui,Xiao, Zhu-Ping,Ye, Ya-Xi,Zhu, Hai-Liang,Zhu, Wen-Yan,Zou, Xia
p. 1046 - 1059
(2021/11/30)

Synthesis, in silico study and antimicrobial activity of new piperine derivatives containing substituted δ-esters
A series of fifteen new piperine-derived diesters was synthesized through the substitution reaction between the salt of piperic acid, obtained through piperine basic hydrolysis, with the δ-chloro-esters, obtained through the cleavage of tetrahydrofuran (THF) with acyl chlorides in the presence of ZnCl2. The final compounds were obtained with yields ranging from 50 to 84% and were characterized by infrared (IR) and 1H and 13C nuclear magnetic resonance spectroscopy (NMR). The new compounds were evaluated in silico in regard to their ADME (absorption, distribution, metabolism, and excretion) properties, and in vitro for their antimicrobial activity against bacteria strains (Staphylococcus aureus and Pseudomonas aeruginosas), yeast fungi (Candida albicans and C. tropicalis) and filamentous fungi (Aspergillus fumigatus, A. flavus and A. niger). The results from the in silico studies of Lipinski's rule of five showed that most compounds present good pharmacological possibilities, and the results from in vitro antimicrobial activity showed that 8 of the 15 synthesized compounds displayed antimicrobial activity, inhibiting the growth of 40-80% of tested strains, with a minimum inhibitory concentration (MIC) interval ranging from 1024 to 256 μg mL-1
Barbosa-Filho, José M.,Brandao, Maria C. R.,De Athayde-Filho, Petr?nio F.,Dutra, Thalisson F.,Lima, Edeltrudes O.,Lira, Bruno F.,Neto, Hermes Diniz,Trindade, Emmely O.
p. 2590 - 2602
(2020/11/18)

HMOX1 inducers
The present invention is related to compounds of structure (I) as heme oxygenase 1 (HMOX 1) inducers. The present invention is also related a method of controlling the activity or the amount, or both the activity and the amount, of heme-oxygenase 1 in a mammalian subject. The definitions of the variables are provided herein.
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Page/Page column 89

(2020/09/18)

Preparation method of flubendazole
The invention relates to a preparation method of flubendazole. The preparation method comprises the following steps: dropwise adding thionyl chloride into a reaction system taking 4-chloro-3-nitrobenzoic acid and o-dichlorobenzene as solvents, wherein DMF (Dimethyl Formamide) is used as a reaction catalyst; then dropwise adding an acylated reaction solution into a fluorobenzene and aluminum trichloride system and carrying out Friedel-Crafts reaction; adding ammonia water, methane and a Friedel-Crafts product into a closed reactor for carrying out amination reaction; adding aminate, the methaneand a palladium carbon catalyst into a high-pressure hydrogenation reactor for reducing; adding a cyclization agent into a reduced reaction solution from which a catalyst is removed for cyclizing; finally, dropwise adding hydrogen peroxide into the cyclized reaction solution for oxidizing. The preparation method disclosed by the invention has the advantages that firstly, during cyclization reaction, an intermediate has an passivation action of carbonyl, so that the cyclization reaction is smoother and reaction time is greatly shortened; secondly, nitro is reduced by adopting a hydroreductionmethod which has better economic and environment-friendly properties compared with a traditional sulfuration alkaline method; thirdly, the cyclization agent adopts lower-price methyl cyanocarbamate,so that production cost is reduced.
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Paragraph 0035

(2018/03/26)

NOVEL CLASS OF QUINOLONE HETEROCYCLIC AROMATIC MOLECULES FOR CANCER TREATMENT
The invention is directed to new class of quinolone heterocyclic aromatic molecules (Renotinibs) and their use in the treatment of cancer, in particular, cancer that harbor abnormal human epidermal growth factor receptors (EGFRs).
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Paragraph 0107

(2018/05/24)

Design, synthesis and evaluation of derivatives based on pyrimidine scaffold as potent Pan-Raf inhibitors to overcome resistance
Simutaneous targeting all Raf isoforms offers the prospect of enhanced efficacy as well as reduced potential for resistance. Described herein is the discovery and characterization of a series of pyrimidine scaffold with DFG-out conformation as potent Pan-Raf inhibitors. Among them, I-41 with excellent Pan-Raf potency demonstrates inhibitory activity against BRafWTphenotypic melanoma and BRafV600Ephenotypic colon cells. The western blot results for the Erk inhibition in human melanoma SK-Mel-2?cell lines showed I-41 inhibited the proliferation of SK-Mel-2?cell lines without paradoxical activation of Erk, which supported I-41 may become a good candidate compound to overcome the resistance of melanoma against the current BRafV600Einhibitor therapy. I-41 also have a favorable pharmacokinetic profile in rat. Synthesis, SAR, lead selection, and evaluation of the key compounds studies are described.
Wang, Lu,Zhang, Qing,Zhu, Gaoyuan,Zhang, Zhimin,Zhi, Yanle,Zhang, Li,Mao, Tianxiao,Zhou, Xiang,Chen, Yadong,Lu, Tao,Tang, Weifang
supporting information
p. 86 - 106
(2017/03/02)

METHOD FOR PREPARING DABIGATRAN ETEXILATE INTERMEDIATE, AND INTERMEDIATE COMPOUND
Disclosed are a method for preparing a dabigatran etexilate intermediate, and an intermediate compound. The method for preparing a dabigatran etexilate intermediate 4 comprises; reacting a compound 3 with a C1-C3 alkyl alcohol solution of methylamine in an organic solvent, wherein, X=chlorine, bromine, or iodine. Also disclosed are an intermediate compound 3 and a preparation method thereof. The method for preparing a dabigatran etexilate intermediate of the present invention has the advantages of simple process, easy operation, high yield, and easy purification, thus being suitable for industrial production.
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Paragraph 0048-0049

(2017/08/01)

Synthetic method of 3-nitryl-4-chloro-benzophenone
The invention discloses a synthetic method of 3-nitryl-4-chloro-benzophenone. 3-nitryl-4-chlorobenzoic acid is converted into 3-nitryl-4-chloro-benzoyl chloride by selecting a new acylation reagent, and the 3-nitryl-4-chloro-benzoyl chloride and benzene perform Friedel-crafts reaction under the catalysis of Lewis acid to obtain the 3-nitryl-4-chloro-benzophenone. The method is simple in reaction path, easy to operate and suitable for large-scale production, and the middle process is easy to control.
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Paragraph 0033-0035

(2017/09/02)

Potent Pan-Raf and Receptor Tyrosine Kinase Inhibitors Based on a Cyclopropyl Formamide Fragment Overcome Resistance
While selective BRafV600E inhibitors have been proven effective clinically, acquired resistance rapidly develops through reactivation of the mitogen-activated protein kinase (MAPK) pathway. Simultaneous targeting of multiple nodes in the pathway offers the prospect of enhanced efficacy as well as reduced potential for acquired resistance. Replacement pyridine group of Y-1 by a cyclopropyl formamide group afforded I-01 as a novel multitargeted kinase inhibitor template. I-01 displayed enzyme potency against Pan-Raf and receptor tyrosine kinases (RTKs). Based on the binding mode of I-01, analogues I-02-I-18 were designed and synthesized. The most promising compound I-16 potently inhibits all subtypes of Rafs with IC50 values of 3.49 (BRafV600E), 8.86 (ARaf), 5.78 (BRafWT), and 1.65 nM (CRaf), respectively. I-16 not only exhibit comparable antiproliferative activities with positive control compounds against HepG2, SW579, MV4-11, and COLO205 cell lines, but also suppress the proliferation of melanoma SK-MEL-2 harboring overexpressed BRafWT with IC50 values of 0.93 μM. The Western blot results for the ERK inhibition in human melanoma SK-MEL-2 cell lines show that I-16 inhibits the proliferation of SK-MEL-2 cell lines without paradoxical activation of ERK, which support the hypothesis that the inhibition of Pan-Raf and RTKs might be a tractable strategy to overcome the resistance of melanoma induced by the therapy with the current selective BRafV600E inhibitors.
Zhang, Yanmin,Wang, Lu,Zhang, Qing,Zhu, Gaoyuan,Zhang, Zhimin,Zhou, Xiang,Chen, Yadong,Lu, Tao,Tang, Weifang
p. 1439 - 1452
(2017/06/30)

A darbey adds the group ester and process for the preparation of intermediates intermediate compound
The invention discloses a preparation method for a dabigatran etexilate intermediate and an intermediate compound. The preparation method of the dabigatran etexilate intermediate 4 comprises the following step: in a protic organic solvent, reacting a compound 3 with a C1-C3 alkanol solution of methylamine. In the formula of the compound 3, X is chlorine, bromine or iodine. The invention also discloses the intermediate compound 3 and a preparation method of the intermediate compound 3. The preparation method for the dabigatran etexilate intermediate is simple and easy to operate, the yield is high, the product is easy to purity, and the preparation method is suitable for industrial production. The formula of the preparation method for the dabigatran etexilate intermediate is shown in the specification.
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Paragraph 0054-0057; 0066-0069; 0074-0077

(2017/02/28)

BENZOIMIDAZOLE DERIVATIVES AS PAD4 INHIBITORS
Compounds of formula (I): wherein X, Y, R1 and R3-R11 are as herein defined, and salts thereof are PAD4 inhibitors and may be useful in the treatment of various disorders, for example rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosis, and psoriasis.
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Page/Page column 111; 112

(2016/12/07)

Structure-activity relationships for lipoprotein lipase agonists that lower plasma triglycerides in vivo
The risk of cardiovascular events increases in individuals with elevated plasma triglyceride (TG) levels, therefore advocating the need for efficient TG-lowering drugs. In the blood circulation, TG levels are regulated by lipoprotein lipase (LPL), an unstable enzyme that is only active as a non-covalently associated homodimer. We recently reported on a N-phenylphthalimide derivative (1) that stabilizes LPL in vitro, and moderately lowers triglycerides in vivo (Biochem. Biophys. Res. Commun. 2014, 450, 1063). Herein, we establish structure-activity relationships of 51 N-phenylphthalimide analogs of the screening hit 1. In vitro evaluation highlighted that modifications on the phthalimide moiety were not tolerated and that lipophilic substituents on the central phenyl ring were functionally essential. The substitution pattern on the central phenyl ring also proved important to stabilize LPL. However, in vitro testing demonstrated rapid degradation of the phthalimide fragment in plasma which was addressed by replacing the phthalimide scaffold with other heterocyclic fragments. The in vitro potency was retained or improved and substance 80 proved stable in plasma and efficiently lowered plasma TGs in vivo.
Caraballo, Rémi,Larsson, Mikael,Nilsson, Stefan K.,Ericsson, Madelene,Qian, Weixing,Tran, Nam Phuong Nguyen,Kindahl, Tomas,Svensson, Richard,Saar, Valeria,Artursson, Per,Olivecrona, Gunilla,Enquist, Per-Anders,Elofsson, Mikael
p. 191 - 209
(2015/09/15)

A novel one-pot synthesis of 3-[(3-Amino-4-methylaminobenzoyl pyridin-2-yl)amino]propionic acid ethyl ester
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Guo, Ya-Jun,Huang, Yu,Yuan, Zhe-Dong,Zhu, Xue-Yan
p. 376 - 380
(2014/08/05)

NOVEL COMPOUNDS
The present invention relates to substituted N-(phenyl-heteroaryl)-3-acetylamino-benzamides and N- [3-(acetylamino)phenyl]-phenyl-heteroaryl-carboxamides of general formula(I) as described and defined herein,to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease.
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Paragraph 184

(2014/10/03)

Design, synthesis and antiviral activity of 2-(3-amino-4-piperazinylphenyl) chromone derivatives
Previously, we have confirmed that the antiviral activities of the chromone derivatives were controlled by the type as well as the position of the substituents attached to the chromone core structure. In the course of our ongoing efforts to optimize the antiviral activity of the chromone derivatives, we have been attempting to derivatize the chromone scaffold via introduction of various substituents. In this proof-of-concept study, we introduced a 3-amino-4-piperazinylphenyl functionality to the chromone scaffold and evaluated the antiviral activities of the resulting chromone derivatives. The synthesized 2-(3-amino-4-piperazinylphenyl)- chromones showed severe acute respiratory syndrome-corona virus (SARS-CoV)-specific antiviral activity. In particular, the 2-pyridinylpiperazinylphenyl substituents provided the resulting chromone derivatives with selective antiviral activity. Taken together, this result indicates the possible pharmacophoric role of the 2-pyridinylpiperazine functionality attached to the chromone scaffold, which warrants further in-depth structure-activity relationship study.
Kim, Mi Kyoung,Yoon, Hyunjun,Barnard, Dale Lynn,Chong, Youhoon
p. 486 - 488
(2013/05/22)

Synthesis of B-ring substituted flavones and evaluation of their antitumor and antioxidant activities
A series of flavones, substituted at the ring B, were synthesized using either Claisen-Schimdt Condensation or Baker-Venkataraman rearrangement. The synthesized compounds were tested for in vitro cytotoxic activity by sulforhodamine B assay against three cell lines of different origin, viz. HepG2, MCF-7, and MOLT-4. The compounds were also tested for a possible antioxidant activity by determination of inhibition of lipid peroxidation. Quercetin was taken as a standard for antioxidant activity. Compound 1c showed the highest cytotoxic activity against MCF-7 (GI50 0.1 μM) and MOLT-4 (GI50 0.1 μM) cell lines and was comparable to adriamycin, the standard used. Compounds 1b, 1g, and 1h also showed promising activity against MCF-7 and MOLT-4 cell lines. In the absence of a hydroxyl group, one or more methoxy groups present on the B-ring (compounds 1c-1e) were major determinants of inhibition of lipid peroxidation.
Joshi, Akshada J.,Gadhwal, Manoj K.,Joshi, Urmila J.,D'Mello, Priscilla,Sinha, Ragini,Govil, Girjesh
p. 4293 - 4299
(2013/09/02)

Development and characterization of endocannabinoid hydrolases FAAH and MAGL inhibitors bearing a benzotriazol-1-yl carboxamide scaffold
A series of (1H-benzo[d][1,2,3]triazol-1-yl)(4-benzylpiperazin-1-yl) methanones and of (1H-benzo[d][1,2,3]triazol-1-yl)(4-phenylpiperazin-1-yl) methanones has been prepared and tested on human fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). In the benzylpiperazinyl series, compound 29 (ML30) exhibited an IC50 value of 0.54 nM on MAGL, combined with a 1000-fold selectivity versus FAAH, while compounds 11 and 16 acted as potent dual FAAH-MAGL inhibitors (IC50 50 values against MAGL in the nanomolar range, whilst being between one and two orders of magnitude less potent on the FAAH, while compounds 31 and 32 were potent FAAH inhibitors (IC50 20 nM) and over 12-fold selective versus MAGL. The key structural determinants driving the structure-activity relationships were explored by the minimization of the inhibitors inside the active site of both enzymes.
Morera, Ludovica,Labar, Geoffray,Ortar, Giorgio,Lambert, Didier M.
p. 6260 - 6275
(2012/11/13)

Synthesis and biological evaluation of analogues of AKT (protein kinase B) inhibitor-IV
Inhibitors of the PI3-kinase/AKT (protein kinase B) pathway are under investigation as anticancer and antiviral agents. The benzimidazole derivative AKT inhibitor-IV (ChemBridge 5233705) affects this pathway and exhibits potent anticancer and antiviral activity. To probe its biological activity, we synthesized AKT inhibitor-IV and 21 analogues using a novel six-step route based on ZrCl4-catalyzed cyclization of 1,2-arylenediamines with α,β-unsaturated aldehydes. We examined effects on viability of HeLa carcinoma cells, viability of normal human cells (NHBE), replication of recombinant parainfluenza virus 5 (PIV5) in HeLa cells, and replication of the intracellular bacterium Mycobacterium fortuitum in HeLa cells. Replacement of the benzimidazole N-ethyl substitutent of AKT inhibitor-IV with N-hexyl and N-dodecyl groups enhanced antiviral activity and cytotoxicity against the cancer cell line, but these compounds showed substantially lower toxicity (from 6-fold to >20-fold) against NHBE cells and no effect on M. fortuitum, suggesting inhibition of one or more host protein(s) required for proliferation of cancer cells and PIV5. The key structural elements identified here may facilitate identification of targets of this highly biologically active scaffold.
Sun, Qi,Wu, Runzhi,Cai, Sutang,Lin, Yuan,Sellers, Llewlyn,Sakamoto, Kaori,He, Biao,Peterson, Blake R.
experimental part
p. 1126 - 1139
(2011/04/25)

BENZIMIDAZOLES AS FATTY ACID SYNTHASE INHIBITORS
This invention relates to the use of benzimidazole derivatives for the modulation, notably the inhibition of the activity or function of fatty acid synthase (FAS). Suitably, the present invention relates to the use of benzimidazoles in the treatment of cancer.
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Page/Page column 145-146

(2011/06/11)

Synthesis and biological evaluation of some substituted amino thiazole derivatives
Condensation of acetophenone with thiourea in presence of halogen (Iodine) gives 2-amino-4-phenylthiazole (I). 2-Amino-4-phenyl-5-phenylazothizole (II) was prepared by coupling of phenyldiazonium chloride with 2-amino-4-phenylthiazole (I). A series of amide can be synthesized by treatment of appropriate substituted acid chlorides (III) with compound (II) using pyridine as solvent. All the synthesized compounds are characterized by the combination of elemental analysis and standard spectroscopic method. They are screened for anti-bacterial activity against Escherichia coli and Staphylococcus aureus as well as screened for antifungal activity against Aspergillus niger and Apergillus oryzae by cup plate method at 1μg/mL concentration in DMF. All the synthesized compounds showed moderate to good microbial activity.
Prajapati,Modi, Vishal P.
experimental part
p. 240 - 243
(2010/11/05)

Synthesis and in vitro antimicrobial activity of new 2-[p-substituted-benzyl]-5-[substituted-carbonylamino]benzoxazoles
Some new 2-(benzyl/p-chlorobenzyl)-5-[(substituted-thienyl/phenyl/phenylthiomethyl/benzyl)carbonylamino]benzoxazole derivatives have been synthesized by reacting 5-amino-2-(benzyl/p-chlorobenzyl)benzoxazoles with appropriate carboxylic acid chlorides. The structures of the synthesized compounds were confirmed by IR, 1H NMR and MASS spectral data. In vitro antimicrobial activities of the compounds were investigated using twofold serial dilution technique against different two Gram-positive, two Gram-negative bacteria and three Candida spp. in comparison with standard drugs. Microbiological results indicated that the newly synthesized 2-(benzyl/p-chlorobenzyl)-5-[(substituted-thienyl/phenyl/phenylthiomethyl/benzyl)carbonylamino]benzoxazole derivatives (3-12) possessed a broad spectrum of activity having MIC values of 6.25-100 μg/ml against the tested microorganisms. Especially, with an MIC value of 6.25 μg/ml, 2-(p-chlorophenyl)-5-[(2,5-dimethylphenyl)carbonylamino]benzoxazole 4 displayed the same activity against Candida albicans as the standard drug clotrimazole.
Tekiner-Gulbas, Betul,Temiz-Arpaci, Ozlem,Yildiz, Ilkay,Altanlar, Nurten
p. 1293 - 1299
(2008/03/28)

CONDENSED PYRIMIDINE DERIVATIVE AND XANTHINE OXIDASE INHIBITOR
The invention relates to compounds of the following formula (I) or their salts: in which R 1 is a group of phenyl, naphthyl, pyridyl or the like which may have a substituent such as an alkyl group having 1-8 carbon atoms, an alkoxy group having 1-8 carbon atoms, an alkoxycarbonyl group having 2-8 carbon atoms, carboxyl, halogen, hydroxyl, nitro, or cyano; R 2 is cyano, nitro, or the like; R 3 is hydroxyl or the like; X is oxygen, sulfur, or the like; and Y is oxygen or sulfur, and a xanthine oxidase inhibitor containing the compound.
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Page/Page column 15

(2008/06/13)

Synthesis and antibacterial activity of some N-(3-hydroxy-2-pyridyl) benzamides
N-(3-Hydroxy-2-pyridyl)benzamides 3(a-J) were synthesized under weak basic solution by reacting of 2-amino-3-pyridinol and an appropriate carboxylic acid chloride, obtained by reaction of carboxylic acids with thionyl chloride. The microbiological activity of these compounds was tested in vitro against Escherichia Coil (PTCC 1338), Pseudomonas aeruginosa (PTCC 1074), Entrococcus faecalis (PTCC 1237) and Staphylococcus aureus (PTCC 1119) bacteria. Compounds 3a, 3e and 3f were the active benzamide derivatives against the Ef and Sa bacteria with a MIC value of 128 μg/ml. Compound 3g was the active entry against Ec and Pa bacteria with a MIC value of 128 μg/.
Mobinikhaledi,Forughifar,Shariatzadeh,Fallah
p. 427 - 430
(2008/02/12)

3-Aminobenzamide compounds and inhibitors of vanilloid receptor subtype 1 (VR1) activity
The present invention relates to a novel 3-aminobenzamide compound represented by the following formula which effectively inhibits vanilloid receptor subtype 1 (VR1) activity (wherein, for example, R1 is a C1-6 alkyl group which may be substituted, R2 is a hydrogen atom, a C1-6 alkyl group or a C1-6 alkoxy group which may be substituted, R3 is a hydrogen atom or a C1-6 alkyl group, R4 is a C1-6 alkyl group, a C1-6 alkoxy group, or a halo C1-6 alkyl group, m is an integer of 1 to 5 and P is a carbon or hetero ring) or a pharmaceutically acceptable salt thereof. The pharmaceutical composition comprising as active ingredients the 3-aminobenzamide compound or a pharmaceutically acceptable salt thereof is useful for treating diseases involved in VR1 activity such as pain, acute pain, chronic pain, neuropathic pain, rheumatoid arthritis pain, and neuralgia.
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Page/Page column 27

(2010/10/19)

Synthesis and structure-activity relationships of suramin-derived P2Y 11 receptor antagonists with nanomolar potency
Selective and potent P2Y11 receptor antagonists have yet to be developed, thus impeding an evaluation of this G protein-coupled receptor mainly expressed on immune cells. Taking suramin with moderate inhibitory potency as a template, 18 ureas with variations of the methyl groups of suramin and their precursors were functionally tested at P2Y11, P2Y1, and P2Y2 receptors. Fluorine substitution of the methyl groups of suramin led to the first nanomolar P2Y11 antagonist (8f, NF157, pK i: 7.35). For selectivity, 8f was also tested at various P2X receptors. 8f displayed selectivity for P2Y11 over P2Y1 (> 650-fold), P2Y2 (> 650-fold), P2X2 (3-fold), P2X3 (8-fold), P2X4 (>22-fold), and P2X7 (>67-fold) but no selectivity over P2X1. QSAR studies confirm that residues with favored resonance and size parameters in the aromatic linker region can indeed lead to an increased potency as is the case for 8f. A symmetric structure linking two anionic clusters seems to be required for bioactivity. 8f may be helpful for studies evaluating the physiological role of P2Y11 receptors.
Ullmann, Heiko,Meis, Sabine,Hongwiset, Darunee,Marzian, Claudia,Wiese, Michael,Nickel, Peter,Communi, Didier,Boeynaems, Jean-Marie,Wolf, Christian,Hausmann, Ralf,Schmalzing, Günther,Kassack, Matthias U.
p. 7040 - 7048
(2007/10/03)

6-ALKENYL AND 6-PHENYLALKYL SUBSTITUTED 2-QUINOLINONES AND 2-QUINOXALINONES AS POLY(ADP-RIBOSE) POLYMERASE INHIBITORS
The present invention provides compounds of formula (I) and compounds of formula (I), (VII-a), as well as pharmaceutical compositions comprising said compounds and their use as PARP inhibitors wherein n, R1, R2, R3, R4, R5, R6, R7, Re, Rd and X have defined meanings.
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Page/Page column 49

(2010/02/12)

Computational study on hydroxybenzotriazoles as reagents for ester hydrolysis
1-Hydroxybenzotriazole (1) and several of its derivatives (2-5) demonstrate potent esterolytic activity toward activated esters such as p-nitrophenyl diphenyl phosphate (PNPDPP) and p-nitrophenyl hexanoate (PNPH) in cationic micelles at pH 8.2 and 25 °C. The deprotonated anionic forms of such reagents act as reactive species in the hydrolysis of ester. To rationalize the origin of their nucleophilic character, a detailed ab initio/DFT computational study has been performed on 1-5 along with additional hydroxybenzotriazole derivatives (6-13). The geometries of 1-hydroxybenzotriazoles (1-13) and their corresponding bases are discussed in detail. All calculations were carried out using different methods, i.e., restricted Hartree-Fock (RHF) and hybrid ab initio/DFT (B3LYP) using 6-31G* and 6-31+G* basis sets. Free energy of protonation ("fep") of the 1-hydroxybenzotriazoles (1-13), free energy of solvation ΔGaq, and the corresponding pKa values have been calculated, Solvation-free energies were calculated using density functional theory and the polarizable continuum model. In addition, to examine the reliability of calculated fep, benzaldehyde oxime (14) and 2-methyl propionaldehyde oxime (15) have been computed as reference systems using different methods and basis sets, the experimental feps of which are known. Our experimental finding shows that the compound 4 is the most effective catalyst for the hydrolytic cleavages of PNPDPP and PNPH, This has been predicted from our calculated fep, pKa, and natural charge analysis results as well. In general, the introduction of electron-withdrawing substituents on 1-hydroxybenzotriazoles facilitates the lowering of pKa and fep. As the pKa values are lowered, a greater percentage of such hydroxybenzotriazoles remain in their deprotonated, anionic forms at pH 8.2. Since the anionic forms are nucleophilic, pKa lowering should enhance their ester cleaving capacity. However, such substitution also decreases the charge density on the catalytically active oxido atom (O7). Taking these two factors together, the derivatives are only modestly better nucleophiles in comparison to the parent 1-hydroxybenzotriazole. Interestingly, the introduction of electron-donating groups does not significantly enhance the charge accumulation on the oxido atom (O7) of 1- hydroxybenzotriazoles.
Kumar, Praveen,Ganguly, Bishwajit,Bhattacharya, Santanu
p. 8634 - 8642
(2007/10/03)

Potential plant growth regulators: Synthesis and activity of new substituted N-(2-benzoyl-4-chlorophenyl)benzamides and N-[4-chloro-2-(α, α-hydroxyphenylmethyl)phenyl]benzamides
2-Amino-5-chlorobenzophenone 3 prepared in 2 steps from isatoic anhydride 1 on condensation with substituted benzoyl chlorides 6a-i in presence of Et 3N in 1,2-dichloroethane (DCE) affords substituted N-(2-benzoyl-4-chlorophenyl)-benzamides 7a-i which on reduction with NaBH 4 gives corresponding alcohols, N-[4-chloro-2-(α,α- hydroxyphenyl-methyl)phenyl]benzamides 8a-i. The structures of all the compounds are confirmed by 1H NMR spectra, and their cytokinin (plant growth promoting) activity is determined on seeds of Raphanus sativus, family Brassicaceae (common name white radish, variety Pusa Chetki), for concentrations varying between 0.1 to 10 mg/litre. Compounds 7c, 7d, 7g and 7h at all concentrations and 7i at 4 concentrations have been found to show higher plant growth promoting (PGP) activity than benzyladenine (standard). Compounds 8d and 8g also show moderate plant growth promoting (cytokinin) activity, while compounds 7a, 7b, 7e, 7f and 8a, 8b, 8c, 8e, 8f and 8i are found to have plant growth inhibiting (PGI) activity.
Hatim, Jaywant Govind,Joshi, Vidya
p. 2689 - 2695
(2007/10/03)

Low-temperature x-ray structural studies of the ester and ether derivatives of cis- and trans-4-tert-butyl cyclohexanol and 2-adamantanol: Application of the variable oxygen probe to determine the relative σ-donor ability of C-H and C-C bonds
Results of low-temperature X-ray structural studies for five cis-, and three trans-4-tert-butyl cyclohexanol, and six 2-adamantanol ester and ether derivatives are reported. Plots of C-OR bond distance against pKa(ROH) for derivatives of axial alcohol (5), equatorial alcohol (6) and 2-adamantanol derivatives (7) give slopes of -2.77 × 10-3, -2.86 × 10-3 and -3.05 × 10-3, respectively. Given that the relative differences in the slopes are modest, no clear distinction can be made about the relative σ-donor ability of a C-H bond and a C-C bond.
Spiniello, Marisa,White, Jonathan M.
p. 3094 - 3101
(2007/10/03)

Viral polymerase inhibitors
A compound of the formula I: wherein: X is CH or N; Y is O or S; Z is OH, NH2, NMeR3, NHR3; OR3 or 5- or 6-membered heterocycle, having 1 to 4 heteroatoms selected from 0, N and S, said heterocycle being optionally substituted with from 1 to 4 substituents; A is N, COR7 or CR5, wherein R5 is H, halogen, or (C1-6) alkyl and R7 is H or (C1-6 alkyl), with the proviso that X and A are not both N; R6 is H, halogen, (C1-6 alkyl) or OR7, wherein R7 is H or (C1-6 alkyl); R1 is selected from the group consisting of 5- or 6-membered heterocycle having 1 to 4 heteroatoms selected from O, N, and S, phenyl, phenyl(C1-3)alkyl, (C2-6)alkenyl, phenyl(C2-6)alkenyl, (C3-6)cycloalkyl, (C1-6)alkyl, CF3, 9- or 10-membered heterobicycle having 1 to 4 heteroatoms selected from O, N and S, wherein said heterocycle, phenyl, phenyl(C2-6)alkenyl and phenyl(C1-3)alkyl), alkenyl, cycloalkyl, (C1-6)alkyl, and heterobicycle are all optionally substituted with from 1 to 4 substituents R2 is selected from (C1-6)alkyl, (C3-7)cycloalkyl, (C3-7)cycloalkyl(C1-3)alkyl, (C6-10)bicycloalkyl, adamantyl, phenyl, and pyridyl, all of which is optionally substituted with from1 to 4 substituents; R3 is selected from H, (C1-6)alkyl, (C3-6)cycloalkyl, (C36)cycloalkyl(C1-6)alkyl, (C6-10)aryl, (C6-10)aryl(C1-6)alkyl, (C2-6)alkenyl, (C3-6)cycloalkyl(C2-6)alkenyl, (C6-10)aryl(C2-6)alkenyl, N{(C1-6)alkyl}2, NHCOO(C1-6)alkyl(C6-10)aryl, NHCO(C6-10)aryl, (C1-6)alkyl-5- or 10-atom heterocycle, having 1 to 4 heteroatoms selected from O, N and S, and 5- or 10-atom heterocycle having 1 to 4 heteroatoms selected from O, N and S; wherein said alkyl, cycloalkyl, aryl, alkenyl and heterocycle are all optionally substituted with from 1 to 4 substituents; n is zero or 1; or a detectable derivative or salt thereof. The compounds of the invention may be used as inhibitors of hepatitis C virus replication. The invention further provides a method for treating or preventing hepatitis C virus infection.
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(2008/06/13)

Bicyclic heterocycles, the preparation thereof, and their use as pharmaceuticals
The present invention relates to 5-membered heterocyclic condensed benzoderivatives of formula wherein Ra to Rc, A, X and Y are defined as in claim 1, the tautomers, stereoisomers, mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases which have valuable properties. The compounds of the above formula I wherein Rc denotes a cyano group are valuable intermediates for preparing the other compounds of formula I, and the compounds of the above formula I wherein Rc denotes one of the following amidino groups and the tautomers and stereoisomers thereof have valuable pharmacological properties, particularly an antithrombotic activity.
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(2008/06/13)

Synthesis of nitrogen and sulfur analogues of the seco-CI alkylating agent
Two complementary syntheses of amino seco-CI (CI = 1a,2,3,5-tetrahydro-1H-cycloprop[1,2-c]indol-5-one) alkylating agents starting from isomeric chloronitrobenzoic acids are reported. Further reactions of these compounds, including diazotisation to phenol and thiophenol derivatives, and alkylation and acylation reactions relevant to the preparation of pro-drug forms are also described.
Tercel, Moana,Denny, William A.
p. 509 - 519
(2007/10/03)

Utility of Complementary Molecular Reactivity and Molecular Recognition (CMR/R) Technology and Polymer-Supported Reagents in the Solution-Phase Synthesis of Heterocyclic Carboxamides
The use of our recently reported chemical library purification strategy in the development of a herbicidal lead, N-(3-benzoylphenyl)-3-(1,1-dimethylethyl)-1-methyl-1H-pyrazole-5-carboxamide (3), is described. The approach applying fundamental properties of complementary molecular reactivity and molecular recognition (CMR/R) as the basis for a general purification strategy was utilized. Polymeric reagents were used in the synthesis to generate reactive species involved in product formation, and complementary molecular reactivity/molecular recognition polymer 8 (CMR/R polymer 8) was used in the solution-phase syntheses of building blocks, primary libraries, and lead refinement libraries. An extension of the CMR/R methodology was applied, utilizing a sequestration enabling reagent (SER), transforming a reactant into an electrophilic species sequestrable by CMR/R polymer 8. This library purification strategy enabled rapid lead generation and lead refinement to afford herbicide 27o. The CMR/R solid-phase purification technique enabled a simple, general, and powerful protocol, eliminating the usual tedious and time-consuming methods required for solution-phase product purification. The result was the synthesis of hundreds of compounds, prepared in a relatively short time, leading to a compound with a 4-fold improvement in herbicidal activity over the initial lead.
Parlow, John J.,Mischke, Deborah A.,Woodard, Scott S.
p. 5908 - 5919
(2007/10/03)

Nucleophilic displacement at the benzoyl centre: A study of the change in geometry at the carbonyl carbon atom
The second-order rate constants for the reaction between hydroxide ion and phenoxide ion with 4-nitrophenyl esters of substituted benzoic acids in 10% acetonitrile-water (v/v) solution obey Hammett σ correlations. The values of the Hammett ρ of 1.67 (κArO) and 2.14 (κOH) are consistent with a large change in hybridization at the central carbon by comparison with the ρ value for a standard reaction where a full sp2 to sp3 change occurs. The transition state for the concerted reaction thus has a substantially tetrahedral geometry. The observation of the anti-Hammond effect whereby the ρ value for the hydroxide ion exceeds that of the less reactive phenoxide ion is consistent with a concerted, ANDN, mechanism for these reactions. A stepwise mechanism, AN + DN, is unlikely to yield a measurable break in the Hammett correlation for a change in the benzoyl substituent if the partitioning of the putative tetrahedral intermediate involves forward and reverse reactions with Hammett correlations possessing similar ρ values.
Colthurst, Matthew J.,Williams, Andrew
p. 1493 - 1497
(2007/10/03)

4-Substituted 1-chloro-2-nitrobenzenes: Structure-activity relationships and extension of the substrate model of rat glutathione S-transferase 4-4
In the present study, eleven 4-substituted 1-chloro-2-nitrobenzenes were tested for their GSH conjugation capacity when catalyzed by base or rat glutathione S-transferase (GST) 4-4. Kinetic parameters (k(s) and K(m), k(cat), and k(cat)/K(m)) were determined and subsequently used for the description of structure-activity relationships (SAR's). For this purpose, eight physicochemical parameters (electronic, steric, and lipophilic) of the substituents and five computer-calculated parameters of the substrates (charge distributions and several energy values) were used in regression analyses with the kinetic parameters. The obtained SAR's are compared with corresponding SAR's for the GSH conjugation of 2-substituted 1-chloro-4- nitrobenzenes, previously determined [Van der Aar et al. (1996) Chem. Res. Toxicol. 9, 527-534]. The kinetic parameters of the 4-substituted 1-chloro- 2-nitrobenzenes correlated well with the Hammett σ(p)- constant; the Hammett σ(p) constant corrected for 'through resonance', while the corresponding kinetic parameters of the 2-substituted 1-chloro-4- nitrobenzenes did not. The base-and GST 4-4-catalyzed GSH conjugation reactions of 2-substituted 1-chloro-4-nitrobenzenes depend to a different extent on the electronic properties of the ortho substituents, suggesting the involvement of different rate-limiting transition states. The base- and GST 4-4-catalyzed conjugation of 4-substituted 1-chloro-2-nitrobenzenes, however, showed a similar dependence on the electronic properties of the para substituents, indicating that these substrates are conjugated to GSH via a similar transition state. Multiple regression analyses revealed that, besides electronic interactions, also steric and lipophilic restrictions appeared to play an important role in the GST 4-4-catalyzed GSH conjugation of 4- substituted 1-chloro-2-nitrobenzenes. Finally, the 4-substituted 1-chloro-2- nitrobenzenes were also used to extend the previously described substrate model for GST 4-4 [De Groot et al. (1995) Chem. Res. Toxicol. 8, 649-658], by which a specific steric restriction of substrates for GST 4-4 became clear.
Van Der Aar, Ellen M.,De Groot, Marcel J.,Bouwman, Tialda,Bijloo, Greetje J.,Commandeur, Jan N. M.,Vermeulen, Nico P. E.
p. 439 - 449
(2007/10/03)

Disazo dyestuffs
Disazo dyestuffs have been found which, in the form of the free acid, correspond to the formula (I) STR1 represents H or an optionally substituted aliphatic or aromatic radical and R1 to R6 and A have the meaning given in the description, which are outstandingly suitable for inkjet printing.
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(2008/06/13)

Nitrogen and sulfur analogues of the seco-CI alkylating agent: Synthesis and cytotoxicity
The first synthesis of seco-CI alkylating agents bearing a nitrogen or sulfur substituent in place of the oxygen at C-6 is described. In comparison with a phenol, an amino substituent confers reduced but significant cytotoxicity, even when mono- or dimethylated, while sulfur analogues are considerably less potent.
Tercel,Denny,Wilson
p. 2735 - 2740
(2007/10/03)

Heterocyclic compounds
The invention provides compounds of formula (I) having nematicidal, insecticidal, acaricidal and fungicidal properties, compositions comprising them and processes and intermediates for their preparation: STR1 wherein: X is oxygen or sulphur; n is 0, 1 or 2; R1, R2, R3, and R4 are as described in the specification.
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(2008/06/13)

Antiparasitic agents: Part XVI - Synthesis of 5(6)-substituted benzimidazole-2-carbamates as anthelmintic agents
3-(β-N-Aroylaminoethyl)indoles (3-6), 3-aminoethyl>indole (7), 1-aryl-9H-pyridoindoles (9-11) and 1--9H-pyridoindole (12) have been synthesized and tested for their anthelmintic, antifilarial and antiamoebic activities against Ancylostoma ceylanicum, Nippostrongylus brasiliensis, Hymenolepis nana, Litomosoides carinii, Acanthocheilonema viteae, Brugia malayi and Entamoeba histolytica.However, none of the compounds shows any significant activityexcept 7, which exhibits reduction of adult worm by 79.4percent at 50 mg/kg (i.p.) and 44percent at 100 mg/kg (oral route) against Brugia malayi infection in Mastomys natalensis.
Agarwal, Alka,Agarwal, Shiv K.,Bhakuni, D. S.,Singh, Som Nath,Chatterjee, R. K.
p. 453 - 456
(2007/10/02)

Hydroxybenzotriazole supporte sur polymere: mise au point sur la synthese du PHBT
Due to some difficulties encountered in order to obtain a polystyrene supported hydroxybenzotriazole (PHBT) as described by Patchornik, a reexamination of its synthesis and reactivity in peptide chemistry was undertaken.Experimental conditions will be discussed, particularly the synthesis of the starting 4-chloro-3-nitro benzylic alcohol and the influence of the polymer loading.
Berrada, Amal,Cavelier, Florine,Jacquier, Robert,Verducci, Jean
p. 511 - 514
(2007/10/02)

Synthesis, Tubulin Binding, Antineoplastic Evalutaion, and Structure-Activity Relationship of Oncodazole Analogues
n an attempt to identify a soluble oncodazole analogue that could be easily formulated, a series of substituted oncodazoles was synthesized and evaluated for tubulin binding affinity, in vitro cyctotoxicity against cultured mouse B-16 cells, and ability to prolong lifespan at the maximally tolerated dose in the P388 mouse leukemia model.Biological evaluation of all the isomeric methyloncodazoles demonstrated the thiophene 4'-position to be the only site of significant bulk tolerance, although substitution of this position with polar or charged functional groups abolished biological activity.Simple esters of the 4'-carboxymethyloncodazole were shown to have enhanched antitumor activity and tubulin binding affinity relative to oncodazole.Despite a failure of this study to identify a water-soluble oncodazole with antitumor activity, the structure-activity relationship developed led to a derivative with enhanced activity in the P388 leukemia model and facilitated the preparation of a biologically active photolabile analogue.
Kruse, Lawrence I.,Ladd, David L.,Harrsch, Peter B.,McCabe, Francis L.,Mong, Shau-Ming,et al.
p. 409 - 417
(2007/10/02)

THE INVENTION OF RADICAL REACTIONS. PART XVI. RADICAL DECARBOXYLATIVE BROMINATION AND IODINATION OF AROMATIC ACIDS
Thiohydroxamic esters of aromatic carboxylic acids undergo clean decarboxylative bromination or iodination on treatment with bromotrichloromethane, iodoform or diiodomethane in the presence of a radical initiator.
Barton, Derek H.R.,Lacher, Brigitte,Zard, Samir Z.
p. 4321 - 4328
(2007/10/02)

Antiviral thiazolinyl or thiazinyl benzimidazole esters
Certain thiazolinyl or thiazinyl benzimidazole ester compounds are useful as antiviral agents.
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(2008/06/13)

3-Pyridinyl-5-isothiocyanophenyl oxadiazoles
Compounds are provided having the formula STR1 which compounds are useful as anthelmintics, and anti-fungal and anti-bacterial agents. In addition, methods for preparing such compounds, intermediates prepared in such methods, useful compositions containing such compounds and methods for employing such compounds and compositions containing the same are also provided.
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(2008/06/13)