- Synthesis and in Vitro Evaluation of 8-Pyridinyl-Substituted Benzo[e]imidazo[2,1-c][1,2,4]triazines as Phosphodiesterase 2A Inhibitors
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Phosphodiesterase 2A (PDE2A) is highly expressed in distinct areas of the brain, which are known to be related to neuropsychiatric diseases. The development of suitable PDE2A tracers for Positron Emission Tomography (PET) would permit the in vivo imaging of the PDE2A and evaluation of disease-mediated alterations of its expression. A series of novel fluorinated PDE2A inhibitors on the basis of a Benzoimidazotriazine (BIT) scaffold was prepared leading to a prospective inhibitor for further development of a PDE2A PET imaging agent. BIT derivatives (BIT1–9) were obtained by a seven-step synthesis route, and their inhibitory potency towards PDE2A and selectivity over other PDEs were evaluated. BIT1 demonstrated much higher inhibition than other BIT derivatives (82.9% inhibition of PDE2A at 10 nM). BIT1 displayed an IC50 for PDE2A of 3.33 nM with 16-fold selectivity over PDE10A. This finding revealed that a derivative bearing both a 2-fluoro-pyridin-4-yl and 2-chloro-5-methoxy-phenyl unit at the 8- and 1-position, respectively, appeared to be the most potent inhibitor. In vitro studies of BIT1 using mouse liver microsomes (MLM) disclosed BIT1 as a suitable ligand for 18F-labeling. Nevertheless, future in vivo metabolism studies are required.
- Ritawidya, Rien,Ludwig, Friedrich-Alexander,Briel, Detlef,Brust, Peter,Scheunemann, Matthias
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- Sulfide Analogues of Flupirtine and Retigabine with Nanomolar KV7.2/KV7.3 Channel Opening Activity
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The potassium channel openers flupirtine and retigabine have proven to be valuable analgesics or antiepileptics. Their recent withdrawal due to occasional hepatotoxicity and tissue discoloration, respectively, leaves a therapeutic niche unfilled. Metabolic oxidation of both drugs gives rise to the formation of electrophilic quinones. These elusive, highly reactive metabolites may induce liver injury in the case of flupirtine and blue tissue discoloration after prolonged intake of retigabine. We examined which structural features can be altered to avoid the detrimental oxidation of the aromatic ring and shift oxidation toward the formation of more benign metabolites. Structure–activity relationship studies were performed to evaluate the KV7.2/3 channel opening activity of 45 derivatives. Sulfide analogues were identified that are devoid of the risk of quinone formation, but possess potent KV7.2/3 opening activity. For example, flupirtine analogue 3-(3,5-difluorophenyl)-N-(6-(isobutylthio)-2-(pyrrolidin-1-yl)pyridin-3-yl)propanamide (48) has 100-fold enhanced activity (EC50=1.4 nm), a vastly improved toxicity/activity ratio, and the same efficacy as retigabine in vitro.
- Bock, Christian,Surur, Abdrrahman S.,Beirow, Kristin,Kindermann, Markus K.,Schulig, Lukas,Bodtke, Anja,Bednarski, Patrick J.,Link, Andreas
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supporting information
p. 952 - 964
(2019/04/10)
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- Synthesis and in vitro evaluation of diverse heterocyclic diphenolic compounds as inhibitors of DYRK1A
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Dual-specificity tyrosine phosphorylation-related kinase 1A (DYRK1A) is a dual-specificity protein kinase that catalyses phosphorylation and autophosphorylation. Higher DYRK1A expression correlates with cancer, in particular glioblastoma present within the brain. We report here the synthesis and biological evaluation of new heterocyclic diphenolic derivatives designed as novel DYRK1A inhibitors. The generation of these heterocycles such as benzimidazole, imidazole, naphthyridine, pyrazole-pyridines, bipyridine, and triazolopyrazines was made based on the structural modification of the lead DANDY and tested for their ability to inhibit DYRK1A. None of these derivatives showed significant DYRK1A inhibition but provide valuable knowledge around the importance of the 7-azaindole moiety. These data will be of use for developing further structure-activity relationship studies to improve the selective inhibition of DYRK1A.
- Zhou, Qingqing,Reekie, Tristan A.,Abbassi, Ramzi H.,Indurthi Venkata, Dinesh,Font, Josep S.,Ryan, Renae M.,Munoz, Lenka,Kassiou, Michael
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p. 5852 - 5869
(2018/11/10)
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- Oxidation of aromatic amines into nitroarenes with m-CPBA
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A versatile and highly efficient approach for the synthesis of nitroarenes from aromatic amine using m-CPBA has been developed. This oxidation reaction was operationally straightforward and proceeded to afford products in good isolated yields.
- Liu, Jia,Li, Jue,Ren, Jiangmeng,Zeng, Bu-Bing
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p. 1581 - 1584
(2014/03/21)
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- HOMOGENEOUS TIME RESOLVED FLUORESCENCE BASED TEST SYSTEM
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The present invention concerns a fluorescence resonance energy transfer based high throughput test system to measure the formation of the HIV gp41 six-helix bundle. In a first embodiment the current invention relates to a homogeneous time resolved fluorescence-based test system comprising a first helical polypeptide consisting essentially of the sequence of IQN36 (SEQ ID NO:1); a second helical polypeptide consisting essentially of the sequence of C34 (SEQ ID NO: 2) wherein said IQN36 is labeled with a light emitting fluorophore and said C34 is labeled with an ultra-violet excitable fluorophore.
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(2010/12/29)
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- BENZIMIDAZOLYL COMPOUNDS AS POTENTIATORS OF MGLUR2 SUBTYPE OF GLUTAMATE RECEPTOR
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Compounds and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula (I) as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.
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Page/Page column 60
(2010/11/30)
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- BENZIMIDAZOLYL COMPOUNDS
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Compounds and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of formula (I) or pharmaceutically acceptable salts thereof, wherein Y1, R17, R2, R4, R5, R6, R7, R8, X2 and n are as defined in the detailed description of the invention. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.
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Page/Page column 65
(2010/11/29)
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- Electrochemical fluorination of aromatic compounds in anhydrous HF
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Electrochemical fluorination of anisole furnished 2- and 4-fluoroanisoles in a 3:1 ratio, guaiacol, and 4,4′-dimethoxydiphenyl ether. Phenylacetonitrile alongside the fluorination in the ring suffered the transformation of the cyano group into a trifluoromethyl. 4-Bromobenzamide was fluorinated to a high conversion mostly in the ring to afford predominantly 4-bromo-3,3,6,6-tetrafluoro-1,4-cyclohexadienecarboxamide. 4-Bromonitrobenzene in a low yield gave 4-bromofluoronitrobenzene and 3,4-dibromofluoronitrobenzene. 3-Bromo-nitrobenzene and 1,4-dichlorobenzene did not undergo fluorination. In the course of the electrolysis of the 4-bromobenzamide and 4-bromonitrobenzene in anhydrous HF apart the fluorination occurred also the bromination of the substrates. Pleiades Publishing, Inc. 2006.
- Shainyan,Danilevich
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p. 214 - 219
(2007/10/03)
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- In search of simplicity and flexibility: A rational access to twelve fluoroindolecarboxylic acids
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All twelve indolecarboxylic acids 1-12 carrying both a fluorine substituent and a carboxy group at the benzo ring have been prepared either directly from the corresponding fluoroindoles 13-16 or from the chlorinated derivatives 22, 23 and 25 by hydrogen/metal permutation ("metalation"), or from the bromo- or iodofluoroindoles 17-20 and 26, 27, 29 and 30 by halogen/metal permutation, the organometallic intermediate being each time trapped with carbon dioxide. In most, though not all cases, the nitrogen atom in the five-membered ring had to be protected by a trialkylsilyl group. Some of the bromo- or iodofluoroindoles (26 and 27) were successfully subjected to a basicity gradient-driven selective migration of the heavy halogen. An unexpected finding on the way to the target compounds were the rigorously site-selective metalation of the 5-fluoro-N-(trialkylsilyl)indole (14b; exclusive deprotonation of the 4-position). The fluoroindoles 13-16, although previously known, were accessed more conveniently from suitably substituted nitrobenzenes using the Bartoli or the Leimgruber-Batcho method. A new and very attractive indole synthesis was elaborated consisting of the ortho-lithiation of an N-acyl-protected aniline followed by ortho-formylation, Wittig chloromethylenation and base-catalyzed cyclization accompanied by dehydrochlorination. These five consecutive steps can be contracted to a convenient one-pot protocol. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.
- Schlosser, Manfred,Ginanneschi, Assunta,Leroux, Frederic
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p. 2956 - 2969
(2007/10/03)
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- AROMATIC AMIDES AS INHIBITORS OF C-FMS KINASE
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The invention relates to compounds of Formula (I), wherein A, X, R2 and W are set forth in the specification, as well as solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof, that inhibit protein tyrosine kinases, especially c-fms kinase. Methods of treating autoimmune diseases; and diseases with an inflammatory component; treating metastasis from ovarian cancer, uterine cancer, breast cancer, colon cancer, stomach cancer, hairy cell leukemia and non-small lung carcinoma; and treating pain, including skeletal pain caused by tumor metastasis or osteoarthritis, or visceral, inflammatory, and neurogenic pain; as well as osteoporosis, Paget's disease, and other diseases in which bone resorption mediates morbidity including arthritis, prosthesis failure, osteolytic sarcoma, myeloma, and tumor metastasis to bone with the compounds of Formula (I), are also provided.
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Page/Page column 83
(2008/06/13)
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- C-fms kinase inhibitors
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The invention is directed to compounds of Formulae I: wherein A, R1, R2, R3, R4, X, and W are set forth in the specification, as well as solvates, hydrates, tautomers or pharmaceutically acceptable salts thereof, that inhibit protein tyrosine kinases, especially c-fms kinase.
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- Elucidation of the vicarious nucleophilic substitution of hydrogen mechanism via studies of competition between substitution of hydrogen, deuterium, and fluorine
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Relations of rates of the vicarious nucleophilic substitution of hydrogen (VNS) and SNAr substitution of fluorine in 2-fluoronitrobenzenes with chloroalkyl aryl sulfone carbanions were determined from competitive experiments carried out at various concentrations of base. The observed dependence of the VNS/SNAr rate ratio on the base concentration confirmed the two-step mechanism of the VNS, which consists of reversible formation of σH adducts of the α-chlorocarbanion to nitroarene, followed by base-induced β-elimination of HCl. It was also evidenced that both of these processes can be the rate-limiting steps: the β-elimination at low base concentration and the nucleophilic addition at high base concentration. Consistent with that conclusion is the finding that the kinetic isotope effect in the VNS reaction decreases from 4.2 (a value typical of a primary KIE) to 0.8 (a value typical of a secondary KIE) with increasing base concentration. Also reported is our discovery that the SNAr substitution of the 2-fluoronitrobenzenes studied in this work was subject to base catalysis under some of the experimental conditions employed in our competitive experiments.
- Makosza, Mieczyslaw,Lemek, Tadeusz,Kwast, Andrzej,Terrier, Francois
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p. 394 - 400
(2007/10/03)
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- Benzimidazolones and analogues
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The present invention provides compounds and pharmaceutical formulations useful as progesterone receptor agonists and antagonists and having the general formula: wherein: A is O, S, or NR4; B is a bond between A and C═Q, or the moiety CR5R6; R4, R5, R5are independently selected from H or optionally substituted C1to C6alkyl, C2to C6alkenyl, C2to C6alknyl, C3to C8cycloalkyl, substituted C3to C8cycloalkyl, aryl, or heterocyclic groups, or cyclic alkyl constructed by fusing R4and R5to from a 5 to 7 membered ring; R1is selected from H, OH, NH2, C1to C6alkyl, substituted C1to C6alkyl, C3to C6alkenyl, substituted C1to C6alkenyl, alkynyl, substituted alknyl, —COH, or optionally substituted —CO(C1to C3alkyl), —CO(aryl), —CO(C1to C3alkoxy), or —CO(C1to C3aminoalkyl) groups; R2is selected from H, halogen, CN, NO2, or optionally substituted C1to C6alkyl, C1to C6alkoxy, or C1to C6aminoalkyl groups; R3is selected from a trisubstituted benzene ring; or a 5- or 6-membered heteroaromatic ring containing 1 or 2 substituents; Q is O, S, NR8, or CR9R10; or a pharmaceutically acceptable salt thereof. The invention also includes methods of contraception and methods of treating or preventing maladies associated with the progesterone receptor.
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- Combination therapies using benzimidazolones
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This invention relates to cyclic combination therapies and regimens utilizing substituted indoline derivative compounds which are antagonists of the progesterone receptor having the general structure: wherein: A is O, S, or NR4; B is a bond between A and C═Q, or the moiety CR5R6; R4, R5, R6are independently selected from H or optionally substituted C1to C6alkyl, C2to C6alkenyl, C2to C6alkynyl, C3to C8cycloalkyl, substituted C3to C8cycloalkyl, aryl, or heterocyclic groups, or cyclic alkyl constructed by fusing R4and R5to from a 5 to 7 membered ring; R1is selected from H, OH, NH2, C1to C6alkyl, substituted C1to C6alkyl, C3to C6alkenyl, substituted C1to C6alkenyl, alkynyl, substituted alkynyl, —COH, or optionally substituted —CO(C1to C3alkyl), —CO(aryl), —CO(C1to C3alkoxy), or —CO(C1to C3aminoalkyl) groups; R2is selected from H, halogen, CN, NO2, or optionally substituted C1to C6alkyl C1to C6alkoxy, or C1to C6aminoalkyl groups; R3is selected from a trisubstituted benzene ring; or a 5- or 6-membered heteroaromnatic ring containing 1 or 2 substituents; or a pharmaceutically acceptable salt thereof, in combination with a progestational agent, an estrogen, or both or for the treatment and/or prevention of secondary amenorrhea, dysfunctional bleeding, uterine leiomyomata, endometriosis; polycystic ovary syndrome, carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, prostate. These combinations may also be used to in methods of contraception, to stimulate food intake or for minimization of side effects or cyclic menstrual bleeding.
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