- Compound based on benzimidazole substituted phenyl n-butylamide and preparation method of compound
-
The invention relates to a compound based on benzimidazole substituted phenyl n-butylamide and a preparation method of the compound. According to the method disclosed by the invention, nitrification and polyphosphoric acid cyclization reactions are avoided, and the generation of a large amount of waste acid reaction liquid is avoided from the source. The synthesis method disclosed by the inventionhas the advantages of simplicity, high efficiency, mild conditions, less pollutants and the like, and is suitable for being developed into a green sustainable production process.
- -
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Paragraph 0203-0206
(2021/03/06)
-
- Ester group-containing aromatic diamine monomer and preparation method thereof
-
The invention discloses an ester group-containing aromatic diamine monomer and a preparation method thereof. The chemical structural formula of the ester group-containing aromatic diamine monomer is shown in the specification. The synthesis reaction of the ester group-containing aromatic diamine monomer comprises the following three steps: step 1, in the presence of a catalyst DMF, reacting a nitrobenzoic acid derivative with thionyl chloride to generate a nitrobenzoyl chloride derivative; 2, reacting the obtained nitrobenzoyl chloride derivative with a dihydric phenol and triethylamine at room temperature to generate an ester group-containing binitro compound intermediate; and 3, by taking stannous chloride dihydrate as a reducing agent, adding the ester group-containing binitro compoundintermediate, and reacting to obtain the novel ester group-containing aromatic diamine monomer. The ester-group-containing aromatic diamine monomer disclosed by the invention is simple in synthetic route, high in yield and suitable for industrial production, and the generated ester-group-containing aromatic diamine monomer can be used for preparing colorless, transparent and low-thermal-expansion-coefficient polyimide.
- -
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Paragraph 0033-0036; 0048-0051
(2021/03/18)
-
- Spiro-bis-benzoxazole diamine and preparation method and application thereof, polyimide and preparation method and application thereof
-
The invention belongs to the technical field of macromolecules, and particularly relates to spirobibenzoxazole diamine, a preparation method and application thereof, polyimide and a preparation method and application thereof. According to the present invention, the spiro-bis-benzoxazole diamine is adopted as the monomer to prepare the polyimide, and the spiro structure is introduced into the diamine structure, such that the obtained polyimide has excellent solubility and excellent processability; meanwhile, the polyimide forms a microporous structure, so that the gas permeability of the polyimide is improved.
- -
-
Paragraph 0065-0066; 0202-0204
(2021/09/04)
-
- Synthetic method of 3-methyl-4-amino-N-(4-amino-2-methyl-phenyl)-benzamide
-
The invention discloses a synthetic method of 3-methyl-4-amino-N-(4-amino-2-methyl-phenyl)-benzamide. The synthetic method comprises the following steps: (1) carrying out a chlorination reaction on 3-methyl-4-nitrobenzoic acid to prepare 3-methyl-4-nitrobenzoyl chloride; (2) carrying out a condensation reaction on 3-methyl-4-nitrobenzoyl chloride and 2-methyl-4-nitroaniline to prepare 3-methyl-4-nitro-N-(4-nitro-2-methyl-phenyl)-benzamide; and (3) carrying out catalytic hydrogenation on the 3-methyl-4-nitro-N-(4-nitro-2-methyl-phenyl)-benzamide to prepare the 3-methyl-4-amino-N-(4-amino-2-methyl-phenyl)-benzamide. The method is short in synthetic route, low in production cost, small in environmental pollution, suitable for industrial production, particularly capable of obtaining a pure white and high-purity target product through an optimization technical means, higher in use value and wider in application range.
- -
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Paragraph 0032; 0033; 0040; 0041; 0048-0049
(2020/05/05)
-
- Novel commercial scale synthetic approach for 5-cyanoindole: A potential intermediate for vilazodone hydrochloride, an antidepressant drug
-
Present work describes the synthesis of 5-cyanoindole, a common intermediate used in various synthetic route of the antidepressant vilazodone hydrochloride. The protocol is both robust and commercially viable, utilizing readily available and low-cost materials and the isomers are environmental friendly than previously reported routes through its evading use of cyanide reagents and heavy metals.
- VENKATANARAYANA,NUCHU, RAVI,SHARATH BABU,GARREPALLI, GANGA SRAVANTHI,TANGALLAPALL, SUDHAKAR
-
p. 2460 - 2462
(2020/10/22)
-
- Production method of 3-methyl-4-nitrobenzoate trichloronitrile butyl ester
-
The invention belongs to the technical field of fine chemistry, and relates to a production method of 3-methyl-4-nitrobenzoate trichloronitrile butyl ester. The production method comprises following steps: (1), cuprous chloride is taken as a catalyst, trichloroacetaldehyde and acrylonitrile are reacted at 65 to 95 DEG C to prepare 2, 4, 4-trichloro-4-formaldehyde butyronitrile; (2), formaldehyde,calcium hydrate, and 2, 4, 4-trichloro-4-formaldehyde butyronitrile are reacted at 30 to 70 DEG C so as to prepare 2, 4, 4-trichlorocyanbutanol; (3), 3-methyl-4 nitrobenzoic acid, pyridine, and thionyl chloride are reacted at 30 to 120 DEG C to prepare 3-methyl-4-nitro benzoyl chloride; and (4), 2, 4, 4-trichlorocyanbutanol and 3-methyl-4-nitro benzoyl chloride are reacted at 30 to 50 DEG C so asto obtain a finished product. The production method is capable of increasing the entire reaction yield, and reducing production cost; and is suitable for industrialized production.
- -
-
Paragraph 0029; 0041-0046
(2019/10/01)
-
- Compound with antidepressant activity and preparation method thereof
-
The present invention provides compounds with antidepressant activity and a preparation method thereof. The molecular formula of the compound is C13H17NO2Cl, the molecular weight is 252.5, the meltingpoint is 207 DEG C, and the structural formula is shown in the specification. The preparation method comprises the following steps: adding 3-methyl-4-nitrobenzoic acid and thionyl chloride into a first reaction container, stirring, dissolving and uniformly mixing the mixture, and condensing and refluxing the mixture at the temperature of 80 +/-3 DEG C to obtain acyl chloride A1; dropwise adding the acyl chloride A1, cooled to 0 DEG C, into a second reaction container to obtain an intermediate product A2; dissolving A2 in DMF, and adding the solution into a third reaction container to obtain an intermediate product A3; adding the obtained intermediate product A3 into a fourth reaction container to obtain a crude product, and treating the crude product in a chromatographic column to obtainan intermediate product A4; and adding the obtained intermediate product A4 into a sixth reaction container to obtain a powdery solid A5, which is the compound with the antidepressant activity.
- -
-
Paragraph 0012
(2019/07/04)
-
- Diamine and polyimide, and use thereof
-
PROBLEM TO BE SOLVED: To provide a polyimide having excellent solution processability. SOLUTION: The present invention provides a diamine and a polyimide having structures represented by formula (1) and formula (3) (R1's independently represent a C1-4 alkyl group or alkoxy group; n is an integer of 1-4; X1 is at least one of a tetravalent aromatic group and aliphatic group). SELECTED DRAWING: None COPYRIGHT: (C)2019,JPOandINPIT
- -
-
Paragraph 0121; 0122
(2019/01/25)
-
- Dopamine D3/D2 Receptor Antagonist PF-4363467 Attenuates Opioid Drug-Seeking Behavior without Concomitant D2 Side Effects
-
Dopamine receptor antagonism is a compelling molecular target for the treatment of a range of psychiatric disorders, including substance use disorders. From our corporate compound file, we identified a structurally unique D3 receptor (D3R) antagonist scaffold, 1. Through a hybrid approach, we merged key pharmacophore elements from 1 and D3 agonist 2 to yield the novel D3R/D2R antagonist PF-4363467 (3). Compound 3 was designed to possess CNS drug-like properties as defined by its CNS MPO desirability score (≥4/6). In addition to good physicochemical properties, 3 exhibited low nanomolar affinity for the D3R (D3 Ki = 3.1 nM), good subtype selectivity over D2R (D2 Ki = 692 nM), and high selectivity for D3R versus other biogenic amine receptors. In vivo, 3 dose-dependently attenuated opioid self-administration and opioid drug-seeking behavior in a rat operant reinstatement model using animals trained to self-administer fentanyl. Further, traditional extrapyramidal symptoms (EPS), adverse side effects arising from D2R antagonism, were not observed despite high D2 receptor occupancy (RO) in rodents, suggesting that compound 3 has a unique in vivo profile. Collectively, our data support further investigation of dual D3R and D2R antagonists for the treatment of drug addiction.
- Wager, Travis T.,Chappie, Thomas,Horton, David,Chandrasekaran, Ramalakshmi Y.,Samas, Brian,Dunn-Sims, Elizabeth R.,Hsu, Cathleen,Nawreen, Nawshaba,Vanase-Frawley, Michelle A.,O’Connor, Rebecca E.,Schmidt, Christopher J.,Dlugolenski, Keith,Stratman, Nancy C.,Majchrzak, Mark J.,Kormos, Bethany L.,Nguyen, David P.,Sawant-Basak, Aarti,Mead, Andy N.
-
p. 165 - 177
(2017/03/08)
-
- Crystal engineering of hand-twisted helical crystals
-
A strategy is outlined for the design of hand-twisted helical crystals. The starting point in the exercise is the one-dimensional (1D) plastic crystal, 1,4-dibromobenzene, which is then changed to a 1D elastic crystal, exemplified by 4-bromophenyl 4'-chlorobenzoate, by introduction of a molecular synthon -O-CO-in lieu of the supramolecular synthon Br···Br in the precursor. The 1D elastic crystals are next modified to two-dimensional (2D) elastic crystals, of the type 4-bromophenyl 4'-nitrobenzoate where the halogen bonding and C-H· · ·O hydrogen bonding are well-matched. Finally, varying the interaction strengths in these 2D elastic crystals gives plastic crystals with two pairs of bendable faces but without slip planes. Typical examples are 4-chlorophenyl and 4-bromophenyl 4'-nitrobenzoate. This type of 2D plasticity represents a new type of bendable crystals in which plastic behavior is seen with a fair degree of isotropic character in the crystal packing. The presence of two sets of bendable faces, generally orthogonal to each other, allows for the possibility of hand-twisting of the crystals to give grossly helical morphologies. Accordingly, we propose the name hand-twisted helical crystals for these substances.
- Saha, Subhankar,Desiraju, Gautam R.
-
supporting information
p. 1975 - 1983
(2017/02/15)
-
- Synthesis and biological evaluation of 1,2,4-triazole-3-thione and 1,3,4-oxadiazole-2-thione as antimycobacterial agents
-
Resistance among dormant mycobacteria leading to multidrug-resistant and extremely drug-resistant tuberculosis is one of the major threats. Hence, a series of 1,2,4-triazole-3-thione and 1,3,4-oxadiazole-2-thione derivatives (4a–5c) have been synthesized and screened for their antitubercular activity against Mycobacterium tuberculosis H37Ra (H37Ra). The triazolethiones 4b and 4v showed high antitubercular activity (both MIC and IC50) against the dormant H37Ra by in vitro and ex vivo. They were shown to have more specificity toward mycobacteria than other Gram-negative and Gram-positive pathogenic bacteria. The cytotoxicity was almost insignificant up to 100?μg/ml against THP-1, A549, and PANC-1 human cancer cell lines, and solubility was high in aqueous solution, indicating the potential of developing these compounds further as novel therapeutics against tuberculosis infection.
- Sonawane, Amol D.,Rode, Navnath D.,Nawale, Laxman,Joshi, Rohini R.,Joshi, Ramesh A.,Likhite, Anjali P.,Sarkar, Dhiman
-
p. 200 - 209
(2017/07/13)
-
- 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)
-
- Intramolecular electron transfer reactions in meso-(4-nitrophenyl)-substituted subporphyrins
-
A2B-type meso-(4-nitrophenyl)-substituted subporphyrins have been synthesized and shown to undergo very fast photoinduced intramolecular charge separation (CS) and charge recombination (CR) between the subporphyrin core and the meso-4-nitrophenyl group in CH2Cl2 as probed by femtosecond time-resolved transient absorption spectroscopy. Red-shifted emissions were detected from charge-separated states as a rare case for porphyrinoids.
- Copley, Graeme,Oh, Juwon,Yoshida, Kota,Shimizu, Daiki,Kim, Dongho,Osuka, Atsuhiro
-
supporting information
p. 1424 - 1427
(2016/01/25)
-
- Antitumour benzothiazoles. Part 32: DNA adducts and double strand breaks correlate with activity; Synthesis of 5F203 hydrogels for local delivery
-
Potent, selective antitumour AhR ligands 5F 203 and GW 610 are bioactivated by CYPs 1A1 and 2W1. Herein we reason that DNA adducts' generation resulting in lethal DNA double strand breaks (DSBs) underlies benzothiazoles' activity. Treatment of sensitive carcinoma cell lines with GW 610 generated co-eluting DNA adducts (R2 > 0.7). Time-dependent appearance of γ-H2AX foci revealed subsequent DNA double strand breaks. Propensity for systemic toxicity of benzothiazoles steered development of prodrugs' hydrogels for localised delivery. Clinical applications of targeted therapies include prevention or treatment of recurrent disease after surgical resection of solid tumours. In vitro evaluation of 5F 203 prodrugs' activity demonstrated nanomolar potency against MCF-7 breast and IGROV-1 ovarian carcinoma cell lines.
- Stone, Erica L.,Citossi, Francesca,Singh, Rajinder,Kaur, Balvinder,Gaskell, Margaret,Farmer, Peter B.,Monks, Anne,Hose, Curtis,Stevens, Malcolm F.G.,Leong, Chee-Onn,Stocks, Michael,Kellam, Barrie,Marlow, Maria,Bradshaw, Tracey D.
-
supporting information
p. 6891 - 6899
(2015/11/11)
-
- Use of compound binding to mSin3B that specifically binds to neuron restrictive silencer factor (NRSF)
-
The present invention identifies a compound which binds to the PAH1 domain of mSin3B that specifically binds to neural restrictive silencer factor NRSF, and uses the compound as a prophylactic and/or a therapeutic for diseases associated with abnormal expression of neural restrictive silencer factor NRSF/REST or abnormal expression of genes targeted by NRSF/REST, such as Huntington's disease, medulloblastoma and neuropathic pain. The present invention provides a pharmaceutical composition comprising a substance capable of binding to the PAH1 domain of mSin3B, e.g., a compound represented by the following formula (1), a pharmacologically acceptable salt thereof, or a pharmacologically acceptable ester thereof: wherein n represents 0 or 1; R1, R2, R3, R4 and R5 each independently represent a hydrogen atom, a hydrocarbon group or a functional group; Y represents a single bond, a carbonyl group, —CONH—, —NHCO— or a sulfonyl group; and Z represents a nitrogen-containing heterocyclic group which may have a substituent, an amino group which may have a hydrocarbon group or an aromatic hydrocarbon group, or a nitrogen and oxygen-containing heterocyclic group which may have a substituent.
- -
-
Paragraph 98
(2015/12/25)
-
- DIHYDROBENZOFURAN DERIVATIVES AS INSECTICIDAL COMPOUNDS
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The present invention relates to compounds of formula (I) wherein Q is (Q1) or (Q2) G1 is oxygen or sulfur; Y1 is oxygen, sulfur or CH2; Y2, Y3 and Y4 are each independently C-H, C-R5 or nitrogen, wherein no more than one of Y2, Y3 and Y4 is C-R5; Y5 is hydrogen, halogen, C1-C8alkyl, C1-C8haloalkyl or C3-C8cycloalkyl; Y6 is hydrogen, halogen, cyano, C1-C8alkyl, C1-C8haloalkyl or C3-C8cycloalkyl; R1a is hydrogen, C1-C8alkyl, C1-C8alkoxy, C1-C8alkylcarbonyl or C1-C8alkoxycarbonyl; R1b is hydrogen, C1-C8alkyl, C1-C8alkylcarbonyl or C1-C8alkoxycarbonyl; R3 is C1-C8haloalkyl; R4 is aryl or aryl substituted by one to five R10, or heteroaryl or heteroaryl substituted by one to five R10; R6a is hydrogen, cyano, C1-C8alkyl, C1-C8haloalkyl or C3-C8cycloalkyl; R6b is hydrogen, cyano, C1-C8alkyl, C1-C8haloalkyl or C3-C8cycloalkyl; or R6a and R6b together with the carbon atom to which they are attached may form a 3 to 6-membered carbocyclic ring; and R2a, R2b, R and R are as defined in the claims. The invention also relates to methods of controlling insects, acarines, nematodes or molluscs which comprises applying to a pest, to a locus of a pest, or to a plant susceptible to attack by a pest an insecticidally, acaricidally, nematicidally or molluscicidally effective amount of a compound of formula I.
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-
Page/Page column 88
(2014/11/13)
-
- Mild rhodium(III)-catalyzed C-H allylation with 4-vinyl-1,3-dioxolan-2-ones: Direct and stereoselective synthesis of (E)-allylic alcohols
-
A rhodium(III)-catalyzed C-H direct allylation reaction with 4-vinyl-1,3-dioxolan-2-ones has been developed. The reaction provides a facile and stereoselective access to substituted-(E)-allylic alcohols under mild and redox-neutral reaction conditions. Olefinic C-H activation is applicable, giving multifunctionalized skipped dienes in good yields. Minimal double-bond migration was observed.
- Zhang, Shang-Shi,Wu, Jia-Qiang,Lao, Ye-Xing,Liu, Xu-Ge,Liu, Yao,Lv, Wen-Xin,Tan, Dong-Hang,Zeng, Yao-Fu,Wang, Honggen
-
supporting information
p. 6412 - 6415
(2015/01/09)
-
- Synthesis of 2-(4-aminophenyl) benzothiazole derivatives and use thereof
-
The present invention provides a method of preparing a compound of formula 6 comprising: (a) reacting a compound of formula 1 with a compound of formula 2 to form a compound of formula 3 wherein X of formula 2 is Cl or OH; (b) treating the compound formula 3 with Lawesson's reagent to form a compound of formula 4 (c) reacting a compound of formula 4 with potassium ferricyanide to produce a compound of formula 5 and (d) performing catalytic reduction of nitro group of the compound of formula 5 with palladium on charcoal to generate the compound of formula 6, wherein R1 of formulae 1-6 is H, C1-10 alkyl, C1-10 alkoxy or C1-10 haloalkyl, and R2 of formulae 1-6 is H or C1-10 alkyl. The present invention also provides a photodynamic therapy to a patient having at least one tumor comprising the steps of: administering a compound of formula 6 (wherein R1 and R2 are defined as the above) in a pharmaceutically acceptable carrier to the patient; waiting for a sufficient time to allow the administered compound to be taken up by a target tissue having the at least one tumor; and irradiating a region of the patient containing the target tissue; wherein growth of the tumor is inhibited.
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Page/Page column 8
(2013/12/03)
-
- PYRAZOLE COMPOUNDS AND THIAZOLE COMPOUNDS AS PROTEIN KINASES INHIBITORS
-
A compound of formula (I): wherein A, B, D, X, Y, R1, R2, R3, m, p, and q are defined herein. Also disclosed is a method for inhibiting FMS-like tyrosine kinase 3, aurora kinase, or vascular endothelial growth factor receptor.
- -
-
Paragraph 0046; 0047
(2013/03/26)
-
- Bioactivation of fluorinated 2-aryl-benzothiazole antitumor molecules by human cytochrome P450s 1A1 and 2W1 and deactivation by cytochrome P450 2S1
-
Both 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203) and 5-fluoro-2-(3,4-dimethoxyphenyl)-benzothiazole (GW 610) contain the benzothiazole pharmacophore and possess potent and selective in vitro antitumor properties. Prior studies suggested the involvement of cytochrome P450 (P450) 1A1 and 2W1-mediated bioactivation in the antitumor activities and P450 2S1-mediated deactivation of 5F 203 and GW 610. In the present study, the biotransformation pathways of 5F 203 and GW 610 by P450s 1A1, 2W1, and 2S1 were investigated, and the catalytic parameters of P450 1A1- and 2W1-catalyzed oxidation were determined in steady-state kinetic studies. The oxidations of 5F 203 catalyzed by P450s 1A1 and 2W1 yielded different products, and the formation of a hydroxylamine was observed for the first time in the latter process. Liquid chromatography-mass spectrometry (LC-MS) analysis with the synthetic hydroxylamine and also a P450 2W1/5F 203 incubation mixture indicated the formation of dGuo adduct via a putative nitrenium intermediate. P450 2W1-catalyzed oxidation of GW 610 was 5-fold more efficient than the P450 1A1-catalyzed reaction. GW 610 underwent a two-step oxidation process catalyzed by P450 1A1 or 2W1: a regiospecific O-demethylation and a further hydroxylation. Glutathione (GSH) conjugates of 5F 203 and GW 610, presumably through a quninoneimine and a 1,2-quinone intermediate, respectively, were detected. These results demonstrate that human P450s 1A1 and 2W1 mediate 5F 203 and GW 610 bioactivation to reactive intermediates and lead to GSH conjugates and a dGuo adduct, which may account for the antitumor activities of 5F 203 and GW 610 and also be involved in cell toxicity. P450 2S1 can catalyze the reduction of the hydroxylamine to the amine 5F 203 under anaerobic conditions and, to a lesser extent, under aerobic conditions, thus attenuating the anticancer activity.
- Wang, Kai,Guengerich, F. Peter
-
p. 1740 - 1751
(2012/11/07)
-
- Discovery of phosphoric acid mono-{2-[(E/Z)-4-(3,3-dimethyl-butyrylamino)- 3,5-difluorobenzoylimino]-thiazol-3-ylmethyl} Ester (Lu AA47070): A phosphonooxymethylene prodrug of a potent and selective hA2A receptor antagonist
-
The discovery and structure-activity relationship of a series of hA 2A receptor antagonists is described. Compound 28 was selected from the series as a potent and selective compound and was shown to be efficacious in an in vivo model of Parkinson's disease. It had acceptableADME properties; however, the low intrinsic solubility of this compound was limiting for its developability, because the oral bioavailability from dosing in suspension was significantly lower than the oral bioavailability from solution dosage. As a consequence, prodrugs of 28 were prepared with dramatically increased aqueous solubility. The prodrugs efficiently delivered 28 into systemic circulation, with no detectable levels of prodrug in plasma samples. From this investigation, we selected 32 (Lu AA47070), a phosphonooxymethylene prodrug of 28, as a drug candidate.
- Sams, Anette G.,Mikkelsen, Gitte K.,Larsen, Mogens,Langg?rd, Morten,Howell?, Mark E.,Schr?der, Tenna J.,Brennum, Lise T.,Torup, Lars,J?rgensen, Erling B.,Bundgaard, Christoffer,Kreilg?rd, Mads,Bang-Andersen, Benny
-
supporting information; experimental part
p. 751 - 764
(2011/04/18)
-
- Subtlety of the Structure-Affinity and Structure-Efficacy Relationships around a Nonpeptide Oxytocin Receptor Agonist
-
Very few nonpeptide oxytocin agonists have currently been reported, and none of them seem suitable for the in vivo investigation of the oxytocin mediated functions. In an attempt to rationalize the design of better tools, we have systematically studied the structural determinants of the affinity and efficacy of representative ligands of the V1a, V2, and OT receptor subtypes. Despite apparently obvious similarity between the ligand structures on one hand, and between the receptor subtypes on the other hand, the binding affinity and the functional activity profiles of truncated and hybrid ligands highlight the subtlety of ligand-receptor interactions for obtaining nonpeptide OT receptor agonists.
- Frantz, Marie-Céline,Rodrigo, Jordi,Boudier, Laure,Durroux, Thierry,Mouillac, Bernard,Hibert, Marcel
-
experimental part
p. 1546 - 1562
(2010/08/05)
-
- Synthesis, and biological evaluation of 2-(4-aminophenyl)benzothiazole derivatives as photosensitizing agents
-
Photodynamic therapy (PDT) employing exogenous photosensitizers is currently being approved for treatment of basal cell carcinoma (BCC). 2-(4-Aminophenyl)benzothiazoles (6) consist of chromophoric structure and absorb light in the UVA (315-400 nm). These results encouraged us to design and synthesize a diversity of 2-phenylbenzothiazoles (6). Studies on the apoptotic mechanism involved in photosensitive effects induced by UVA-activated 6 in BCC cells are carried out in the present article. 6-UVA-treated cells displayed several features of apoptosis, including an increase in the sub-G1 population, a significantly increased annexin V binding, and activation of caspase-3. 6-UVA induced a decrease in mitochondrial membrane potential (Δψ mt) and ATP via enhanced ROS generation and promoted phosphorylation of extracellular signal-regulated kinase (ERK) and p38 MAPK expression. These results suggest that 6-UVA elicits photosensitive effects in mitochondria processes which involve ERK and p38 activation, and ultimately lead to BCC cell apoptosis.
- Hu, Wan-Ping,Chen, Yin-Kai,Liao, Chao-Cheng,Yu, Hsin-Su,Tsai, Yi-Min,Huang, Shu-Mei,Tsai, Feng-Yuan,Shen, Ho-Chuan,Chang, Long-Sen,Wang, Jeh-Jeng
-
experimental part
p. 6197 - 6207
(2010/10/02)
-
- 5-(HETEROCYCLYL)ALKYL-N-(ARYLSULFONYL)INDOLE COMPOUNDS AND THEIR USE AS 5-HT6 LIGANDS
-
The present invention relates to novel 5-(Heterocyclyl)alkyl-N- (arylsulfonyl)indole compounds of the formula (I), their derivatives, their stereoisomers, their pharmaceutically acceptable salts and pharmaceutically acceptable compositions containing them. The present invention also relates to a process for the preparation of above said novel compounds, their derivatives, their stereoisomers, their pharmaceutically acceptable salts and pharmaceutically acceptable compositions containing them. These compounds are useful in the treatment of various disorders that are related to 5-HT6 receptor functions. Specifically, the compounds of this invention are also useful in the treatment of various CNS disorders, hematological disorders, eating disorders, diseases associated with pain, respiratory diseases, genito-urological disorders, cardiovascular diseases and cancer.
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Page/Page column 21
(2008/12/07)
-
- Design, synthesis and structure-activity relationship studies of 6-phenyl-4,5-dihydro-3(2H)-pyridazinone derivatives as cardiotonic agents
-
Based on our previous study, a variety of 12 novel 6-phenyl-4,5-dihydro- 3(2H)-pyridazinone derivatives were synthesized. The structures attributed to the compounds were elucidated using IR, 1H-NMR and mass spectra. The cardiotonic activities of these compounds were assessed by Straub's perfusion method and a clear cardiotonic effect was shown for compounds 1c (2,3-dichloro-N-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl) benzamide), 1d (4-amino-3-methyl-N-(4-(4-methyl-6-oxo-1,4,5,6- tetrahydropyridazin-3-yl)phenyl)benzamide), 2a (3-methyl-4-nitro-N-(4-(6-oxo-1, 4,5,6-tetrahydropyridazin-3-yl)phenyl)benzamide) and 2d (4-amino-3-methyl -N-(4-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)benzamide) when compared to another 3(2H)-pyridazinone derivative, levosimendan (CAS 141505-33-1). The structure-activity relationships of the compounds were studied using the rough sets theory. ECV Editio Cantor Verlag.
- Wang, Teng,Dong, Ying,Wang, Li-Chen,Xiang, Bing-Ren,Chen, Zhen,Qu, Ling-Bo
-
experimental part
p. 569 - 573
(2009/04/06)
-
- PHARMACEUTICALS, COMPOSITIONS AND METHODS OF MAKING AND USING THE SAME
-
Compounds that are capable of acting as purine receptor antagonists, pharmaceutical compositions including the compounds, and methods of making the compounds, are disclosed. The compounds and compositions can be used in treating or preventing disorders related to purine receptor hyperfunctioning.
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-
Page/Page column 26-27
(2008/12/07)
-
- Synthesis and biological evaluation of benzoic acid derivatives as potent, orally active VLA-4 antagonists
-
A series of benzoic acid derivatives was synthesized as VLA-4 antagonists. Introduction of chlorine or bromine into the 3-position on the central benzene of the diphenylurea portion as in lead compound 2 led to improvement in the pharmacokinetic properties. In particular, 12l demonstrated an acceptable plasma clearance and bioavailability in mice and rats as well as dogs (mice, CL = 18.5 ml/min/kg, F = 28 %; rats, CL = 5.2 ml/min/kg, F = 36 %; dogs, CL = 3.6 ml/min/kg, F = 55 %). Additionally, 12l exhibited potent activity with an IC50 value of 0.51 nM and efficacy by oral administration at a dosage of 10 mg/kg in a rat pleurisy model.
- Chiba, Jun,Iimura, Shin,Yoneda, Yoshiyuki,Watanabe, Toshiyuki,Muro, Fumito,Tsubokawa, Masao,Iigou, Yutaka,Satoh, Atsushi,Takayama, Gensuke,Yokoyama, Mika,Takashi, Tohru,Nakayama, Atsushi,Machinaga, Nobuo
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p. 1679 - 1693
(2008/02/03)
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- PRO-DRUGS OF N-THIAZOL-2YL-BENZAMIDE DERIVATIVES
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The invention relates to compounds of the formula I wherein the variables are as defined in the claims. The compounds are pro-drugs of A2A-receptor ligands with improved aqueous solubility, and are useful in the treatment of neurological and psychiatric disorders where an A2A-receptor is implicated.
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Page/Page column 35
(2010/11/24)
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- Non-nucleoside reverse transcriptase inhibitors
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The present invention provides compounds for treating or preventing an HIV infection, or treating AIDS or ARC comprising administering a compound according to formula I where Ar, R1-R5, R7a, R7b, R7c, R8-R10, X1, X2 m, n, o and p are as defined herein.
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Page/Page column 34
(2008/06/13)
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- Novel heteroaryl alkylamide derivatives useful as bradykinin receptor modulators
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This invention is directed towards novel alkylamide derivatives as bradykinin receptor antagonists useful for the treatment of bradykinin modulated disorders such as pain, inflammation, asthma and allergy. Furthermore, the present invention is directed to novel alkylamide derivatives as bradykinin receptor agonists useful for the treatment of bradykinin modulated disorders such as hypertension and the like.
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- Synthesis and Structure-Activity Relationship of Aminobenzophenones. A Novel Class of p38 MAP Kinase Inhibitors with High Antiinflammatory Activity
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We wish to report the synthesis and structure-activity relationship (SAR) of a series of 4-aminobenzophenones, as a novel compound class with high antiinflammatory activity. Our initial lead, {4-[(2-aminophenyl)amino]phenyl}(phenyl)methanone (3), was systematically optimized and resulted in compounds that potently inhibited the release of the proinflammatory cytokines IL-1β and TNF-α in human peripheral blood mononuclear cells stimulated by LPS. One of the most potent compounds, among others, was {4-[(2-aminophenyl)amino]-2-chlorophenyl}(2-methylphenyl)methanone (45) with IC50 values of 14 and 6 nM for the inhibition of IL-1β and TNF-α, respectively. Furthermore, we found these types of compounds to be potent and selective p38 MAP kinase inhibitors, e.g. 45 had an IC50 value of 10 nM. Molecular modeling was used to rationalize our SAR data and to propose a model for the interaction of compound 45 with the p38 MAP kinase. The model involved a favorable hydrogen bond between the carbonyl group of the benzophenone and the NH of Met-109, positioning ring A in the hydrophobic pocket I of the enzyme. Good antiinflammatory effects were demonstrated in two murine models of dermatitis after topical application (oxazolone and TPA model).
- Ottosen, Erik Rytter,S?rensen, Morten Dahl,Bj?rkling, Fredrik,Skak-Nielsen, Tine,Fjording, Marianne Scheel,Aaes, Helle,Binderup, Lise
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p. 5651 - 5662
(2007/10/03)
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- NOVEL HETEROARYL ALKYLAMIDE DERIVATIVES USEFUL AS BRADYKININ RECEPTOR MODULATORS
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This invention is directed towards novel alkylamide derivatives as bradykinin receptor antagonists useful for the treatment of bradykinin modulated disorders such as pain, inflammation, asthma and allergy. Furthermore, the present invention is directed to novel alkylamide derivatives as bradykinin receptor agonists useful for the treatment of bradykinin modulated disorders such as hypertension and the like.
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Page/Page column 57-58
(2010/02/07)
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- Antirheumatic agents. II. Novel methotrexate derivatives bearing an alkyl-substituted benzene ring
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Novel methotrexate (MTX) derivatives with either a mono- or dialkyl- substituted benzene ring were synthesized and initially tested for in vitro anti-proliferative activities using human peripheral blood mononuclear cells (hPBMC) derived from healthy volunteers and synovial cells (hSC) derived from patients with rheumatoid arthritis (RA). Compounds with potent activities were further evaluated in an in vivo adjuvant arthritis model. In comparison with MTX, a glutamate derivative 3a was more potent as a suppressor of the in vitro cell proliferation and the in vivo experimental arthritis, and a homoglutamate derivative, 3e, exhibited fairly good activities in vitro and considerable activity in vivo in a dose-dependent manner. As expected, 3e did not act as a substrate of folylpolyglutamate synthetase (FPGS), and thus did not undergo polyglutamation, which is thought to be responsible for side-effects that occur during MTX therapy.
- Matsuoka, Hiroharu,Maruyama, Noriaki,Suzuki, Hiroshi,Kuroki, Toshio,Tsuji, Keiichiro,Kato, Nobuaki,Ohi, Nobuhiro,Mihara, Masahiko,Takeda, Yasuhisa,Yano, Keiichi
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p. 2287 - 2293
(2007/10/03)
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- Technetium-99m labeled p-aminohippuric acid analogues: renal function agents.
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A number of p-aminohippuric acid analogues were synthesized in order to develop clinically useful 99mTc-labeled radiopharmaceuticals for evaluation of renal function measurements. Stable 99mTc-labeled complexes were formed at pH 5.7 using a Sn(II) reduction method with all derivatives. The newly synthesized complexes were screened utilizing biodistribution studies in small animals. All complexes were excreted via the GU tract within 60 min post iv administration, with no significant activity in GI tract and liver. The [99mTc]methyl-PAHIDA complex showed optimal biodistribution among these analogues. Further investigation is needed to determine if these derivatives may be used to replace [131I]o-iodohippuric acid for the evaluation of renal function.
- Zhang,Bhargava,Chun,Blaufox,Chervu
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p. 829 - 832
(2007/10/02)
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- Electrophysiologic and antiarrhythmic activities of 4-amino-N-[2-(diethylamino)ethyl]-3,5-dimethylbenzamide, a sterically hindered procainamide analogue
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Procainamide is a widely used antiarrhythmic that is fraught with therapeutic limitations such as a short half-life, production of autoimmune antibodies and a lupus-like syndrome, and complex pharmacokinetics. We synthesized the congeners of procainamide possessing one or two methyl substituents ortho to the 4-amino moiety (compounds 4 and 5, respectively), in order to sterically encumber the 4-amino substituent and prevent or diminish the rate of metabolic N-acetylation. Moreover, we anticipated that this structural alteration might eliminate the autoimmune toxicities associated with procainamide. Like procainamide, the two methylated analogues significantly reduced the rate of rise and amplitude of the action potential when studied in isolated canine Purkinje fibers. Whereas procainamide caused no significant change in action potential duration (APD), both methylated congeners significantly reduced APD at 70% and 95% repolarization. Moreover, the dimethylated congener was significantly more efficacious than procainamide in reducing ERP (effective refractory period) and increasing the ERP/APD70. The ability of these compounds to block ouabain-induced arrhythmias was studied in anesthetized dogs. Addition of two methyl groups ortho to the amine produced an increase in potency: The conversion doses for procainamide and the monomethyl and dimethyl congeners were 19.0, 18.3, and 14.3 mg/kg, respectively, following iv administration. After iv administration to rats, procainamide was extensively metabolized to N-acetylprocainamide and displayed a half-life of 0.4 h. In contrast, dimethylprocainamide was not metabolized by N-acetylation, had a half-life of 1.4 h, and provided greater peak plasma concentrations. Thus, addition of methyl substituents ortho to the 4-amino group of procainamide alters the electrophysiological characteristics of the compound, increases its potency against ouabain-induced arrhythmias in vivo, increases its plasma half-life, and prevents N-acetylation.
- Robertson,Beedle,Wilson,Parli,Smallwood,Steinberg
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p. 1290 - 1295
(2007/10/02)
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- Discovery and anticonvulsant activity of the potent metabolic inhibitor 4-amino-N-(2,6-dimethylphenyl)-3,5-dimethylbenzamide
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Compound 2 [4-amino-N(2,6-dimethylphenyl)benzamide] is an effective anticonvulsant in several animal models. For example, following oral administration to mice, it antagonized maximal electroshock (MES) induced seizures with an ED50 of 1.7 mg/kg. During drug disposition studies with 2, we found that it was rapidly metabolized by N-acetylation. Thirty minutes after oral administration of 1.7 mg/kg of 2 to mice, plasma concentrations of parent drug and the N-acetyl metabolite 5 were 1.09 and 0.41 μg/mL, respectively. Six hours postadministration the concentrations were 0.23 and 0.22 μg/mL, respectively. In order to sterically preclude or diminish the rate of metabolic N-acetylation, we synthesized analogues of 2 possessing either one (3) or two (4) methyl groups ortho to the 4-amino substituent. Both compounds antagonized MES-induced seizures after administration to mice; oral ED50 values for 3 and 4 were 3.5 and 5.6 mg/kg, respectively. Compound 3 was rapidly metabolized by N-acetylation. However, 4 provided exceptionally high and long-lived plasma concentrations of parent drug; no N-acetyl metabolite could be detected. While 2 and 3 had no pharmacologically relevant effects on hexobarbital-induced sleeping time in mice, 4 was a potent, dose-dependent potentiator of sleeping time. Oral administration of 375 μg/kg led to a 61% increase in sleeping time relative to control values. Thus, 4 represents one of the most potent potentiators of hexobarbital-induced sleeping time described to date.
- Robertson,Leander,Lawson,Beedle,Clark,Potts,Parli
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p. 1742 - 1746
(2007/10/02)
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- Complement inhibitors
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Substituted-hydroxy-naphthalenedisulfonic acids, acid ureides and salts thereof useful as complement inhibitors.
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- Substituted-hydroxy-naphthalenedisulfonic acid compounds
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Substituted-hydroxy-naphthalenedisulfonic acids, acid ureides and salts thereof useful as complement inhibitors.
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