- 5-aryl substituted 2-aminobenzoxazole derivative and preparation method and application thereof
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The invention discloses a 5-aryl substituted 2-aminobenzoxazole derivative and a preparation method and application thereof, and belongs to the technical field of pesticides, the 5-aryl substituted 2-aminobenzoxazole derivative is characterized in that th
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Paragraph 0038-0041
(2021/01/24)
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- In vitro anti-Candida activity and action mode of benzoxazole derivatives
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A newly synthetized series of N-phenacyl derivatives of 2-mercaptobenzoxazole, including analogues of 5-bromo- and 5,7-dibromobenzoxazole, were screened against Candida strains and the action mechanism was evaluated. 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(4-b
- ?ukowska-Chojnacka, Edyta,Baran, Joanna,Gryciuk, Aleksander,Kawalec, Joanna,Kowalkowska, Anna,Kuryk, ?ukasz,Rogalska, Marta,Staniszewska, Monika
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- (±)-trans-2-phenyl-2,3-dihydrobenzofurans as leishmanicidal agents: Synthesis, in vitro evaluation and SAR analysis
-
Leishmaniasis, a neglected tropical disease caused by parasites of the genus Leishmania, causes a serious burden of disease around the world, represents a threat to the life of millions of people, and therefore is a major public health problem. More effective and non-toxic new treatments are required, especially for visceral leishmaniasis, the most severe form of the disease. On the backdrop that dihydrobenzofurans have previously shown antileishmanial activity, we present here the synthesis of a set of seventy trans-2-phenyl-2,3-dihydrobenzofurans and evaluation of their in vitro activity against Leishmania donovani as well as a discussion of structure-activity relationships. Compounds 8m-o and 8r displayed the highest potency (IC50 4.6). Nonetheless, structural optimization as further requirement was inferred from the high clearance of the most potent compound (8m) observed during determination in vitro of its metabolic stability. On the other hand, chiral separation of 8m and subsequent biological evaluation of its enantiomers demonstrated no effect of chirality on activity and cytotoxicity. Holistic analysis of in silico ADME-like properties and ligand efficiency metrics by a simple scoring function estimating druglikeness highlighted compounds 16c, 18 and 23 as promising candidates for further development. Overall, the potential of trans-2-phenyl-2,3-dihydrobenzofurans as leishmanicidal agents was confirmed.
- Bernal, Freddy A.,Gerhards, Marcel,Kaiser, Marcel,Wünsch, Bernhard,Schmidt, Thomas J.
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- Synthesis, docking, 3-D-qsar, and biological assays of novel indole derivatives targeting serotonin transporter, dopamine D2 receptor, and mao-a enzyme: In the pursuit for potential multitarget directed ligands
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A series of 27 compounds of general structure 2,3-dihydro-benzo[1,4]oxazin-4-yl)-2-{4-[3-(1H-3indolyl)-propyl]-1-piperazinyl}-ethanamides, Series I: 7(a-o) and (2-{4-[3-(1H-3-indolyl) -propyl]-1-piperazinyl}-acetylamine)-N-(2-morfolin-4-yl-ethyl)-fluorinated benzamides Series II: 13(a-l) were synthesized and evaluated as novel multitarget ligands towards dopamine D2 receptor, serotonin transporter (SERT), and monoamine oxidase-A (MAO-A) directed to the management of major depressive disorder (MDD). All the assayed compounds showed affinity for SERT in the nanomolar range, with five of them displaying Ki values from 5 to 10 nM. Compounds 7k, Ki = 5.63 ± 0.82 nM, and 13c, Ki = 6.85 ± 0.19 nM, showed the highest potencies. The affinities for D2 ranged from micro to nanomolar, while MAO-A inhibition was more discrete. Nevertheless, compounds 7m and 7n showed affinities for the D2 receptor in the nanomolar range (7n: Ki = 307 ± 6 nM and 7m: Ki = 593 ± 62 nM). Compound 7n was the only derivative displaying comparable affinities for SERT and D2 receptor (D2/SERT ratio = 3.6) and could be considered as a multitarget lead for further optimization. In addition, docking studies aimed to rationalize the molecular interactions and binding modes of the designed compounds in the most relevant protein targets were carried out. Furthermore, in order to obtain information on the structure-activity relationship of the synthesized series, a 3-D-QSAR CoMFA and CoMSIA study was conducted and validated internally and externally (q2 = 0.625, 0.523 for CoMFA and CoMSIA and r2ncv = 0.967, 0.959 for CoMFA and CoMSIA, respectively).
- Alarcón-Espósito, Jazmín,Araya-Maturana, Ramiro,Cabezas, David,Cerda-Cavieres, Christopher,Chung, Hery,Iturriaga-Vásquez, Patricio,Mella-Raipán, Jaime,Ojeda-Gómez, Claudia,Pessoa-Mahana, Carlos D.,Pessoa-Mahana, Hernán,Quiroz, Gabriel,Reyes-Parada, Miguel,Rodríguez-Lavado, Julio,Saitz, Claudio
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- HETEROCYCLIC COMPOUNDS AS ADENOSINE ANTAGONISTS
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Aminopyrazine compounds as modulators of an adenosine receptor are provided. The compounds may find use as therapeutic agents for the treatment of diseases mediated through a G-protein-coupled receptor signaling pathway and may find particular use in oncology.
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Paragraph 0389; 0391
(2019/02/05)
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- 1,8-NAPHTHYRIDINONE COMPOUNDS AND USES THEREOF
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1,8-naphthyridinone compounds as modulators of an adenosine receptor are provided. The compounds may find use as therapeutic agents for the treatment of diseases mediated through a G-protein-coupled receptor signaling pathway and may find particular use in oncology.
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Paragraph 0350; 0353; 0354
(2019/02/05)
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- ANDROGEN RECEPTOR ANTAGONISTS
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Compounds that inhibit the androgen receptor, pharmaceutical compositions comprising one or more of the compounds, as well as methods of treating cancer using such compounds are described.
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Paragraph 0336-0338
(2019/08/26)
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- Synthesis of benzoxazoles via the copper-catalyzed hydroamination of alkynones with 2-aminophenols
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We describe herein the synthetic method to benzoxazole derivatives via the copper-catalyzed hydroamination of alkynones with 2-aminophenols. The method produced a wide variety of functionalized benzoxazole derivatives in good yields. Preliminary mechanistic experiments revealed that the reaction would proceed through the copper-catalyzed hydroamination of alkynones and the sequential intramolecular cyclization of β-iminoketones/elimination of acetophenone promoted by the copper catalyst.
- Oshimoto, Kohei,Tsuji, Hiroaki,Kawatsura, Motoi
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supporting information
p. 4225 - 4229
(2019/05/10)
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- Directed Structural Transformations of Coordination Polymers Supported Single-Site Cu(II) Catalysts to Control the Site Selectivity of C-H Halogenation
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A main difficulty in C-H bond functionalization is to undertake the catalyst control accurately where the reaction takes place. In this work, to achieve highly effective and regioselective single-site catalysts, a three-dimensional (3D) rhombus-like framework of {[Mn(Hidbt)DMF]·H2O}n (1) [H3idbt = 5,5′-(1H-imidazole-4,5-diyl)-bis(2H-tetrazole)] containing coordinated DMF molecules was constructed. For the dissolution-recrystallization structural transformation process, attractive structural transformations proceeded from 1 to a new crystalline species formulated as {[Mn3(idbt)2(H2O)2]·3H2O}n (2) with a 3D windowlike architecture, and then the Mn ions in 2 could be exchanged with Cu ions through cation exchange in a single-crystal to single-crystal fashion to produce the Cu-exchanged product {[Mn2Cu(idbt)2(H2O)2]·3H2O}n (2a), which had a windowlike framework like that of 2. Furthermore, 2 and 2a were used as heterogeneous catalysts for the regioselective C-H halogenation of phenols with N-halosuccinimides (NCS and NBS) to produce the site selective single monohalogenated products. It was found that the catalytic activity and site selectivity of 2a were much higher than those of 2, because the unique structural features of 2a with the uniformly dispersed CuII active centers served as a single-site catalyst with a site-isolated and well-defined platform to promote the C-H halogenation reaction in regiocontrol and guide an orientation that favored the para selectivity during the reaction process.
- Huang, Chao,Zhu, Kaifang,Zhang, Yingying,Shao, Zhichao,Wang, Dandan,Mi, Liwei,Hou, Hongwei
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supporting information
p. 12933 - 12942
(2019/10/11)
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- 5 - Pyridyl -2 - amino - benzo [d] oxazole derivative and its preparation and use (by machine translation)
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The present invention discloses the general formula (I) indicated by the 5 - pyridyl - 2 - amino - benzo [d] oxazole derivative or its pharmaceutically acceptable salt, its preparation method, pharmaceutical composition and use: According to the compounds of this invention can be used for preparing the treatment of cervical cancer, breast cancer, stomach cancer, liver cancer, renal carcinomas of the drug. (by machine translation)
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Paragraph 0053; 0059-0061
(2018/05/16)
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- Synthesis and biological evaluation of potential acetylcholinesterase inhibitors based on a benzoxazine core
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With the purpose of expanding the structural variety of chemical compounds available as pharmacological tools for the treatment of Alzheimer's disease, we synthesized and evaluated a novel series of indole-benzoxazinones (Family I) and benzoxazine-arylpiperazine derivatives (Family II) for potential human acetylcholinesterase (hAChE) inhibitory properties. The most active compounds 7a and 7d demonstrated effective inhibitory profiles with Ki values of 20.3 ± 0.9 μM and 20.2 ± 0.9 μM, respectively. Kinetic inhibition assays showed non-competitive inhibition of AChE by the tested compounds. According to our docking studies, the most active compounds from both series (Families I and II) showed a binding mode similar to donepezil and interact with the same residues.
- Méndez-Rojas, Claudio,Quiroz, Gabriel,Faúndez, Mario,Gallardo-Garrido, Carlos,Pessoa-Mahana, C. David,Chung, Hery,Gallardo-Toledo, Eduardo,Saitz-Barría, Claudio,Araya-Maturana, Ramiro,Kogan, Marcelo J.,Zú?iga-López, María C.,Iturriaga-Vásquez, Patricio,Valenzuela-Gutiérrez, Carla,Pessoa-Mahana, Hernán
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- PHOSPHOINOSITIDE 3-KINASE INHIBITORS WITH ZINC BINDING MOIETY
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PROBLEM TO BE SOLVED: To provide phosphoinositide 3-kinase inhibitors with a zinc binding moiety. SOLUTION: There is provided a compound represented by formula (I) in the figure. (X is S, O or the like; Y is CH, N or the like; G1 is optionally substituted N or the like; R1 and R2 are each independently H or the like; C is a substituted heterocycle or the like; B is a linear alkyl or the like; Ra and Rb together with the nitrogen atom coupled to them are morpholino or the like; G2 is an indazole ring or the like; q, r and s are independently from 0 to 1, provided that at least one of them is 1; t is from 0 to 1; n is from 0 to 4; and p is from 0 to 2.) COPYRIGHT: (C)2016,JPOandINPIT
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Paragraph 0485
(2016/10/07)
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- NOVEL BICYCLIC BROMODOMAIN INHIBITORS
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The invention relates to substituted bicyclic compounds, which are useful for inhibition of BET protein function by binding to bromodomains, pharmaceutical compositions comprising these compounds, and use of the compounds and compositions in therapy.
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Paragraph 0197
(2015/01/16)
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- Enhanced treatment regimens using mTor inhibitors
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The present invention provides for methods and pharmaceutical compositions comprising inhibitors of mTorC1 and/or mTorC2. In some aspects, the invention provides for treatment regimens resulting in enhanced treatment efficacy and better tolerability.
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Page/Page column 114
(2015/11/27)
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- COMBINATION OF KINASE INHIBITORS AND USES THEREOF
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The present invention provides for a method for treating a disease condition associated with PI3-kinase a and/or mTOR in a subject. In another aspect, the invention provides for a method for treating a disease condition associated with PI3-kinase a and/or mTOR in a subject. In yet another aspect, a method of inhibiting phosphorylation of both Akt (S473) and Akt (T308) in a cell is set forth. The present invention also provides a pharmaceutical kit effective for treating a disease condition associated with PI3 -kinase α and/or mTOR in a subject.
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Paragraph 00502
(2014/10/04)
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- COMBINATION PHARMACEUTICAL COMPOSITIONS AND USES THEREOF
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The present invention provides for methods and pharmaceutical compositions for treating proliferative disorders. In one aspect, the method comprises administration of two cell-cycle suppressors having a synergistic effect. In another aspect, two cell-cycle suppressors having a synergistic effect are provided in a pharmaceutical composition.
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Paragraph 0485
(2014/12/09)
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- Identification of a novel benzoxazolone derivative as a selective, orally active 18 kDa translocator protein (TSPO) ligand
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Optimization of the pharmacokinetic properties for a series of benzoxazolone derivatives led to the identification of 9b, which showed anxiolytic effect in a rat model. However, 9b, like known benzodiazepines, induced motor impairment. Investigation into
- Fukaya, Takayuki,Ishiyama, Takeo,Baba, Satoko,Masumoto, Shuji
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supporting information
p. 8191 - 8195
(2013/11/06)
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- Convenient synthesis of benzoxazolone derivatives by cross-coupling of benzoxazolone boronates with aryl halides
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Benzoxazolone derivatives with various substituents at the C-5 position were synthesized efficiently via benzoxazolone boronates as the key intermediate. The target compounds were also synthesized from (het)aryl halides in a one-pot process. These methods permitted efficient exploratory syntheses of a series of benzoxazolone derivatives. Georg Thieme Verlag Stuttgart New York.
- Fukaya, Takayuki,Masumoto, Shuji
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p. 3269 - 3275
(2013/12/04)
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- TREATMENT OF CANCERS HAVING K-RAS MUTATIONS
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The present invention provides a method of treating a cancer associated with a K-ras mutation in a subject in need thereof. The method comprises the steps of: (1) identifying a subject with a cancer associated with a K-ras mutation; and (2) administering to the subject (i) an inhibitor of PI3 kinase and (ii) an HDAC inhibitor, wherein the PI3 kinase inhibitor and the HDAC inhibitor are administered in amounts which together are therapeutically effective.
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Paragraph 0571; 0572
(2013/05/08)
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- Design, synthesis and structure-activity relationships of novel benzoxazolone derivatives as 18 kDa translocator protein (TSPO) ligands
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Selective 18 kDa translocator protein (TSPO) ligands are expected to be therapeutic agents with a wide spectrum of action on psychiatric disorders and fewer side effects. We designed novel benzoxazolone derivatives and examined the structure-activity rela
- Fukaya, Takayuki,Kodo, Toru,Ishiyama, Takeo,Kakuyama, Hiroyoshi,Nishikawa, Hiroyuki,Baba, Satoko,Masumoto, Shuji
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p. 5568 - 5582
(2012/10/29)
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- Synthesis and in vitro antimycobacterial and isocitrate lyase inhibition properties of novel 2-methoxy-2′-hydroxybenzanilides, their thioxo analogues and benzoxazoles
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A new series of 2-methoxy-2′-hydroxybenzanilide derivatives and their thioxo analogues have been synthesised and characterised by IR, NMR and elemental analysis. These compounds were investigated for their in vitro antimycobacterial activities against Mycobacterium tuberculosis 331/88, Mycobacterium avium 330/88, Mycobacterium kansasii 235/80, clinically isolated M. kansasii 6509/96 and the ability to act as in vitro isocitrate lyase inhibitors. The best ICL inhibitors were two compounds from the thiobenzanilide group (8f, 8m), which exhibited an inhibition potential that was equal to the standard compound, 3-nitropropionic acid. In addition, the best antimycobacterial properties were exhibited by benzanilide derivatives 6h, 6k and 6l with 5-Cl and 4′ or 5′ Cl/Br substitution. For all the thiobenzanilide derivatives tested, two conformers were observed in the NMR spectra, which is most likely due to the hindered rotation of the C-N bond.
- Kozic, Ján,Novotná, Eva,Volková, Marie,Stola?íková, Ji?ina,Trejtnar, Franti?ek,Wsól, Vladimír,Vin?ová, Jarmila
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p. 108 - 119
(2013/01/15)
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- Identification and development of an efficient route to SB-649915
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The discovery and development of an efficient manufacturing route to the SSRI-5-HT1A receptor antagonist 6-[(1-{2-[(2-methyl-5-quinolinyl)oxy]ethyl}-4- piperidinyl)methyl]-2H-1,4-benzoxazin-3(4H)-one (SB-649915) 1 is described. The existing route to 1 involved coupling quinoline 6 with piperidine 5 and was considered lengthy as a consequence of the nine synthetic steps required to prepare 5. Two new routes to the key piperidine intermediate 5 are identified which deliver this compound in five and two steps respectively, from readily available materials using novel lithiation and Friedel-Crafts methodology respectively. The latter of these two routes was successfully demonstrated at 5 L scale to deliver 700 g of 5. Development to the methanesulfonate 34, an alternative to quinoline 6, is also described as is the final alkylation of piperidine 5 with this methanesulfonate 34 to deliver SB-649915 1.
- Armitage, Mark,Bret, Guillaume,Choudary, Bernie M.,Kingswood, Mike,Loft, Mike,Moore, Steve,Smith, Steve,Urquhart, Michael W. J.
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p. 1626 - 1634
(2013/02/22)
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- TREATMENT OF CANCERS HAVING K-RAS MUTATIONS
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The present invention provides a method of treating a cancer associated with a K- ras mutation in a subject in need thereof. The method comprises the steps of (1) identifying a subject with a cancer associated with a K-ras mutation; and (2) adminsiterign to the subject (i) an inhibitor of PI3 kinase and (ii) an HDAC inhibitor, wherein the PI3 kinase inhibitor and the HDAC inhibitor are administered in amounts which together are therapeutically effective.
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Page/Page column 226
(2011/11/01)
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- Regioselective and high-yielding bromination of phenols and anilins using N-bromosaccharin and amberlyst-15
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A regioselective and facile conversion method for bromination of anilines and phenols using N-bromosaccharine in the presence of a catalytic amount of Amberlyst-15 lead to enhancement of the reaction rate and yielded brominated products in good to excellent yields and short reaction times.
- Baharfar,Alinezhad,Azimi,Salehian
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experimental part
p. 863 - 865
(2012/04/23)
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- Synthesis and biological evaluation of oxadiazole derivatives as inhibitors of soluble guanylyl cyclase
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Soluble guanylyl cyclase (sGC) is an ubiquitously expressed enzyme that generates the second messenger cGMP and hence, leads to a number of physiological responses including vasodilation, inhibition of platelet aggregation and neurotransmission. Whilst ma
- von Wantoch Rekowski, Margarete,Pyriochou, Anastasia,Papapetropoulos, Nektarios,St??el, Anne,Papapetropoulos, Andreas,Giannis, Athanassios
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experimental part
p. 1288 - 1296
(2010/04/26)
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- BENZOXAZOLE KINASE INHIBITORS AND METHODS OF USE
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The present invention provides chemical entities or compounds and pharmaceutical compositions thereof that are capable of modulating certain protein kinases such as mTor, tyrosine kinases, and/or lipid kinases such as PI3 kinase. Also provided in the present invention are methods of using these compositions to modulate activities of one or more of these kinases, especially for therapeutic applications.
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Page/Page column 133
(2010/05/14)
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- Regiospecific oxyhalogenation of aromatics over SBA-15-supported nanoparticle group IV-VI metal oxides
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TiOx, VOx, MoOx and WOx supported on SBA-15 exhibit efficient catalytic activity for oxyhalogenation of aromatics with the H2O2-halide ion system. Unlike the hitherto known solid catalysts, these reusable catalysts yield the para-halogenated product with 100% selectivity at 298 K and moderate acidic pH (3-5). The catalytic activity was enhanced by five orders of magnitude when supported on SBA-15. Springer Science+Business Media, LLC 2010.
- Saikia,Rajesh,Srinivas,Ratnasamy
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scheme or table
p. 190 - 201
(2010/11/05)
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- Novel Phosphinic Acid-Containing Thyromimetics
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The present invention relates to compounds of phosphonic acid-containing T3 mimetics and monoesters thereof, stereoisomers, pharmaceutically acceptable salts, co-crystals, and prodrugs thereof and pharmaceutically acceptable salts and co-crystals of the prodrugs, as well as their preparation and uses for preventing and/or treating metabolic diseases such as obesity, NASH, hypercholesterolemia and hyperlipidemia, as well as associated conditions such as atherosclerosis, coronary heart disease, impaired glucose tolerance, metabolic syndrome x and diabetes.
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Page/Page column 159
(2009/02/11)
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- Regulatory molecules for the 5-HT3 receptor ion channel gating system
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Substituted benzoxazole derivatives which possess a nitrogen-containing heterocycle at C2 are selective partial agonists of the 5-HT3 receptor. Alteration of substituents on the benzoxazole nucleus affords both agonist-like and antagonist-like compounds, and uniquely modifies the function of the 5-HT3 receptor ion channel gating system. SAR and corroborative computational docking study for these partial agonists successfully explained structure and function of the 5-HT3 receptor.
- Yoshida, Satoshi,Watanabe, Takashi,Sato, Yasuo
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p. 3515 - 3523
(2008/02/07)
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- CETP INHIBITORS
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Compounds of Formula I, including pharmaceutically acceptable salts of the compounds, are CETP inhibitors, and are useful for raising HDL-cholesterol, reducing LDL-cholesterol, and for treating or preventing atherosclerosis. I
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Page/Page column 95-96
(2008/06/13)
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- NOVEL HETEROCYCLIC COMPOUND
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A drug having a high affinity for benzodiazepine ω3 receptors and showing curative and preventive effects for anxiety and depression, which comprises as the active ingredient, for example, a compound of the formula (1): wherein R1 an
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Page/Page column 26
(2010/11/24)
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- NOVEL PHOSPHORUS-CONTAINING THYROMIMETICS
-
The present invention relates to compounds of phosphonic acid containing T3 mimetics, stereoisomers, pharmaceutically acceptable salts, co-crystals, and prodrugs thereof and pharmaceutically acceptable salts and co-crystals of the prodrugs, as well as their preparation and uses for preventing and/or treating metabolic diseases such as obesity, NASH, hypercholesterolemia and hyperlipidemia, as well as associated conditions such as atherosclerosis, coronary heart disease, impaired glucose tolerance, metabolic syndromex and diabetes.
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Page/Page column 332
(2008/06/13)
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- Reduction of nitrophenols by zinc and ammonium chloride in aqueous medium
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A simple reduction procedure involving zinc and ammonium chloride in aqueous medium has been employed for the reduction of nitrophenols to aminophenols.
- Sridharan,Karpagavalli,Muthusubramanian,Sivasubramanian
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p. 2243 - 2244
(2007/10/03)
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- BENZOXAZINES AND DERIVATIVES THEREOF AS INHIBITORS OF PI3KS
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The present invention provides compounds of Formula (I) wherein W, Q, E, D, A, L, R6, R7, R8, Y, K, R9, R10,G, the dashed bond between D and E, and the double bond denoted "*" have any of the values defined therefore in the specification, and pharmaceutically acceptable salts thereof, that are useful as agents in the treatment of diseases and conditions, including inflammatory diseases, cardiovascular diseases, and cancers. Also provided are pharmaceutical compositions comprising one or more compounds of Formula (I).
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-
-
- Fused bicyclic-substituted amines as histamine-3 receptor ligands
-
Compounds of formula (I) are useful in treating conditions or disorders prevented by or ameliorated by histamine-3 receptor ligands. Also disclosed are pharmaceutical compositions comprising the histamine-3 receptor ligands and methods for using such compounds and compositions.
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-
-
- Fused bicyclic-substituted amines as histamine-3 receptor ligands
-
Compounds of formula (I) are useful in treating conditions or disorders prevented by or ameliorated by histamine-3 receptor ligands. Also disclosed are pharmaceutical compositions comprising the histamine-3 receptor ligands and methods for using such compounds and compositions.
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-
-
- CALCIUM RECEPTOR MODULATING ARYLALKYLAMINES
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The compounds of the invention are represented by the following general structure (I) or a pharmaceutically acceptable salt thereof, and compositions containing them, wherein the variables are defined herein, and their use to reduce or inhibit PTH secretion, including methods for reducing or inhibiting PTH secretion and methods for treatment or prophylaxis of diseases associated with bone disorders, such as osteoporosis, or associated with excessive secretion of PTH, such as hyperparathyroidism. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.
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-
-
- Pharmaceutical compositions for CNS and other disorders
-
The present invention relates to a method of treating disorders of the Central Nervous System (CNS) and other disorders in a mammal, including a human, by administering to the mammal a CNS-penetrant α7 nicotinic receptor agonist. It also relates to pharmaceutical compositions containing a pharmaceutically acceptable carrier and a CNS-penetrant α7 nicotinic receptor agonist.
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-
-
- Pharmaceutical composition for the treatment of CNS and other disorders
-
The present invention relates to a method of treating disorders of the Central Nervous System (CNS) and other disorders in a mammal, including a human, by administering to the mammal a CNS-penetrant α7 nicotinic receptor agonist. It also relates to pharma
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-
-
- Benzoxazole derivatives as novel 5-HT3 receptor partial agonists in the gut
-
A series of benzoxazoles with a nitrogen-containing heterocyclic substituent at the 2-position was prepared and evaluated for 5-HT3 partial agonist activity on isolated guinea pig ileum. The nature of the substituent at the 5-position of the benzoxazole ring affected the potency for the 5-HTs receptor, and the 5-chloro derivatives showed increased potency and lowered intrinsic activity. 5-Chloro-7-methyl-2-(4-methyl-1- homopiperazinyl)benzoxazole (6v) exhibited a high binding affinity in the same range as that of the 5-HT3 antagonist granisetron, and its intrinsic activity was 12% of that of 5-HT. Compound 6v inhibited 5-HT-evoked diarrhea but did not prolong the transition time of glass beads in the normal distal colon even at a dose of 100 times the ED50 for diarrhea inhibition in mice. Compounds of this type are expected to be effective for the treatment of irritable bowel syndrome without the side effect of constipation.
- Sato, Yasuo,Yamada, Megumi,Yoshida, Satoshi,Soneda, Tomoko,Ishikawa, Midori,Nizato, Tetsutaro,Suzuki, Kokichi,Konno, Fukio
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p. 3015 - 3021
(2007/10/03)
-
- Improved P1/P1' substituents for cyclic urea based HIV-1 protease inhibitors: Synthesis, structure-activity relationship, and X-ray crystal structure analysis
-
We present several novel P1/P1' substituents that can replace the characteristic benzyl P1/P1' moiety of the cyclic urea based HIV protease inhibitor series. These substituents typically provide 5-10-fold improvements in binding affinity compared to the unsubstituted benzyl analogs. The best substituent was the 3,4-(ethylenedioxy)benzyl group. Proper balancing of the molecule's lipophilicity facilitated the transfer of this improved binding affinity into a superior cellular antiviral activity profile. Several analogs were evaluated further for protein binding and resistance liabilities. Compound 18 (IC90 = 8.7 nM) was chosen for oral bioavailability studies based on its log P and solubility profile. A 10 mg/kg dose in dogs provided modest bioavailability with C(max) = 0.22 μg/mL. X-ray crystallographic analysis of two analogs revealed several interesting features responsible for the 3,4-(ethylenedioxy)benzyl-substituted analog's potency: (1) Comparing the two complexes revealed two distinct binding modes for each P1/P1' substituent; (2) The ethylenedioxy moieties are within 3.6 A? of Pro 81 providing additional van der Waals contacts missing from the parent structure; (3) The enzyme's Arg 8 side chain moves away from the P1 substituent to accommodate the increased steric volume while maintaining a favorable hydrogen bond distance between the para oxygen substituent and the guanidine NH.
- Nugiel, David A.,Jacobs, Kim,Cornelius, Lyndon,Chang, Chong-Hwan,Jadhav, Prabhakar K.,Holler, Edward R.,Klabe, Ronald M.,Bacheler, Lee T.,Cordova, Beverly,Garber, Sena,Reid, Carol,Logue, Kelly A.,Gorey-Feret, Lorraine J.,Lam, Gilbert N.,Erickson-Viitanen, Susan,Seitz, Steven P.
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p. 1465 - 1474
(2007/10/03)
-
- POLAROGRAPHIC AND CYCLIC VOLTAMMETRIC BEHAVIOUR OF SOME AZO COMPOUNDS DERIVED FROM SULFONAMIDE IN DMF-AQUEOUS SOLUTIONS
-
The polarographic and cyclic voltammetric behaviour of (2-hydroxyphenylazo)-4-benzenesulfonamide and some of its derivatives have been studied in Britton-Robinson buffer series containing 30 vol.percent of DMF.Over the entire pH range (2-12), the reduction pathway occurs through an irreversible 4-electron step corresponding to the reduction of N=N center to the amine stage.The voltammograms recorded in acidic and alkaline solution at different scan rates exhibit one or two cathodic peaks depending on the substituent and the pH of the medium.The electrode reaction mechanism was suggested, also the kinetic parameters were calculated.
- Mabrouk, El-Sayed M.,Killa, Hamada M.,Fattah, Abdel Fattah A. Abdel,Yasen, Shalaby A.
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p. 268 - 275
(2007/10/02)
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- Synthesis of Mercapturic Acid Derivatives of Putative Toxic Metabolites of Bromobenzene
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The synthesis and characterization of nine isomerically defined S-arylmercapturic acids of interest in connection with the metabolism of the model hepatotoxin bromobenzene is described.Included are three S-(bromophenyl)-, two S-(bromohydroxyphenyl)-, and three S-(bromodihydroxyphenyl)mercapturic acids of defined substitution pattern.In addition, several related compounds with two or no bromine atoms are described.These syntheses depend on two basic methods, 1,4-addition of various arene thiols to acetamidoacrylic acid or the 1,4-addition of N-acetyl-L-cysteine to various benzoquinone derivatives.In addition, we describe a method for efficient conversion of the mercapturic acids to thioanisole derivatives, regioisomers of which can be separed and detected at low levels by capillary gas-liquid chromatography.
- Hanzlik, Robert P.,Weller, Paul E.,Desai, Jayant,Zheng, Jiang,Hall, Larry R.,Slaughter, Donald E.
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p. 2736 - 2742
(2007/10/02)
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- Acid-base equilibria of hydrophilic indicators in water-in-oil microemulsions
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The apparent pKa values of the positively charged, hydrophilic indicators 2-hydroxy-5-bromo-trimethylanilinium chloride (HBTC) and 2-hydroxy-5-nitro-trimethylanilinium chloride (HNTC) in the presence of water-in-oil microemulsion of the surfactants benzylcetyldimethyl ammonium chloride (BCDC) in benzene and polyoxyethylene (4) dodecyl ether (Brij-30) in heptane were determined spectrophotometrically. The experimental variables were the type of buffer (benzimidazole, phosphate, and tris) and the ratios [water]/[surfactant] and [buffer]/[surfactant]. It is shown that: a) the indicators are confined within the second hydration shell of the nanodroplet, i.e. are not adsorbed at the water/oil interface; b) the use of the starting pH values of the buffer solutions, i.e., those measured outside the micellar domain, to calculate the micellar pKa values of the indicators is inadequate; c) buffer-independent micellar pKa values can be obtained if the starting pHs of the buffer solutions were corrected for ion exchange with the counter-ion of the positively charged surfactant, and for the lower polarity of the micelle-solubilized water (relative to bulk water).
- Chinelatto,Fonseca,Kiyan,El Seoud
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p. 882 - 887
(2007/10/02)
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- Hydrolysis and Fe2+-induced Reduction of N-Aryl -O-pivaloylhydroxylamines: Aqueous Solution Chemistry of Model Carcinogens.
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The N-aryl-O-pivaloylhydroxylamines, 1a-d, which serve as models for the carcinogenic metabolites of aromatic amines, decompose in aqueous media by heterolysis of the N-O bond.Substituent effects on rates of reaction and products of the decomposition of 1a-c are entirely consistent with the intermediacy of a singlet nitrenium ion.The least reactive compound in the series N-(4-nitrophenyl)-O-pivaloylhydroxylamine (1d) yields 4-nitroaniline (2d) as its major decomposition product.This material may be formed through H radical abstraction by a triplet ion, but a nitrene reaction appears to be more likely.In the presence of Fe2+ 1a-d undergo rapid reduction to the corresponding anilines 2a-d.This reaction requires complexation of the ester with Fe2+ and proceeds with heterolysis of the N-O bond since nearly quantitative yields of pivalic acid are isolated.The radical cations 25a-d appear to be the most likely precursors to the reduction products.
- Novak, Michael,Lagerman, Robert K.
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p. 4762 - 4769
(2007/10/02)
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- Acid- and Base-Dependent Hydrolysis of N-(Sulfonatooxy)-3-bromoacetanilide: Involvement of N-(3-Bromophenyl)hydroxylamine-O-sulfonate
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N-(Sulfonatooxy)-3-bromoacetanilide (1e) undergoes hydrolysis at 80 deg C in the range pH 1.0-8.0 by acid- and base-dependent processes and by an uncatalyzed path.The uncatalyzed reaction exhibits the same characteristics as the uncatalyzed N-O bond-cleavage reactions of the more reactive N-(sulfonatooxy)acetanilides.The pH-dependent pathways involve the hydrolysis of 1e to form N-(3-bromophenyl)hydroxylamine-O-sulfonate (2).This material cannot be directly detected under the conditions of this study, but its existence can be inferred from product study and trapping data.Although 2 undergoes decomposition entirely by heterolytic N-O bond cleavage to yield nitrenium ion intermediate 14, a less reactive analogue of 2, N-(3-bromophenyl)-O-pivaloylhydroxylamine (4), apparently undergoes competitive homolytic and heterolytic N-O bond cleavage to yield both the arylamino radical 17 and the nitrenium ion 14.Both 2 and 4 serve as models for certain suspected carcinogenic metabolites of polycyclic aromatic amines and amides.
- Novak, Michael,Rovin, Lise H.,Pelecanou, Maria,Mulero, Julio J.,Lagerman, Robert K.
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p. 2002 - 2010
(2007/10/02)
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- Thieno[3,4-b][1,5]benzoxazepin-10-ones and thieno[3,4-b][1,5]benzothiazepin-10-ones
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This disclosure describes novel substituted thieno[3,4-b][1,5]benzoxazepin-10 (9H)-ones and thieno[3,4-b][1,5]benzothiazepin-10(9H)-ones which are useful as intermediates for the preparation of 10-[4-(substituted)-1-piperazinyl]thieno[3,4-b][1,5]benzoxaze
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- 10-(Piperazinyl)thieno[3,4-b][1,5]benzoxazepines and 10-(piperazinyl)thieno[3,4-b][1,5]benzothiazepines
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This disclosure describes 10-[4-(substituted)-1-piperazinyl]thieno[3,4-b][1,5]benzoxazepines and 10-[4-(substituted-1-piperazinyl]thieno[3,4-b][1,5]benzothiazepines useful as anti-psychotic or neuroleptic agents.
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