- NOVEL COMPOUNDS FOR USE IN COGNITION IMPROVEMENT
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Novel compounds for use in cognition improvement It relates to certain compounds having a polycyclic structure and a -(C=O)NRaRb moiety, wherein the polycyclic structure comprises at least three ring systems, wherein one ring system is a polycyclic ring system comprising from 2 to 4 rings; at least one ring is an aromatic ring; and wherein the structure comprises at least 3 nitrogen atoms and 1 oxygen atom. It also relates to pharmaceutical compositions containing them, and to their use in medicine, in particular in the treatment and/or prevention of neurological disorders coursing with a cognition deficit or impairment, or neurodegenerative diseases.
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Page/Page column 49; 50
(2016/04/19)
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- PYRAZOLOPYRIMIDINONES FOR THE TREATMENT OF IMPOTENCE AND PROCESS FOR THE PREPARATION THEREOF
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The present invention relates to Pyrazolopyrimidinone compounds as PDE5 inhibitors with better IC50 value, good in vivo efficacy and PK profile and a process for the preparation thereof. The present invention covers the pyrazolo pyrimidinone based compounds that have been designed, synthesized and screened for PDE5 inhibitory activity and its PDE5 inhibitory potential is provided in this invention. These designer compounds have shown nanomolar potency when screened for PDE5 inhibitory activity and also shown better in vivo efficacy. These compounds can be used in the treatment of male erectile dysfunction or in the treatment of impotence.
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Page/Page column 45; 46
(2015/09/23)
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- Novel pyrazole-5-carboxamide and pyrazole-pyrimidine derivatives: Synthesis and anticancer activity
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A series of novel pyrazole-5-carboxamide and pyrazole-pyrimidine derivatives were designed and synthesized. All compounds have been screened for their antiproliferative activity against MGC-803, SGC-7901 and Bcap-37 cell lines in vitro. The results revealed that compounds 8a, 8c and 8e exhibited strong inhibitory activity against MGC-803 cell line. The flow cytometric analysis result showed that compound 8e could inhibit MGC-803 proliferation. Some title compounds were tested against telomerase, and compound 8e showed the most potent inhibitory activity with IC50 value at 1.02 ± 0.08 μM. The docking simulation of compound 8e was performed to get the probable binding model, among them, LYS 189, LYS 372, LYS 249 and ASP 254 may be the key residues for the telomerase activity.
- Shi, Jing Bo,Tang, Wen Jian,Qi, Xing Bao,Li, Rong,Liu, Xin Hua
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p. 889 - 896
(2015/06/02)
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- NOVEL COMPOUNDS AS DUAL INHIBITORS OF PHOSPHODIESTERASES AND HISTONE DEACETYLASES
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It relates to certain compounds having a polycyclic structure and a hydroxamic acid moiety, wherein the polycyclic structure comprises at least three ring systems, wherein one ring system is a polycyclic ring system comprising from 2 to 4 rings; at least one ring is an aromatic ring; and wherein the structure comprises at least 3 nitrogen atoms and 1 oxygen atom. It also relates to a process for their preparation, as well as to pharmaceutical compositions containing them, and to their use in medicine, in particular in the treatment and/or prevention of neurological disorders coursing with a cognition deficit or impairment, or neurodegenerative diseases. wherein B1 is a radical selected from the group consisting of formula (A"), formula (B"), formula (C"), and formula (D"):
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Page/Page column 80
(2014/09/16)
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- Cascade regioselective synthesis of pyrazoles from nitroallylic acetates and N-tosyl hydrazine
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A simple, practical, and regioselective synthetic protocol for the formation of pyrazoles was developed. Unlike all other previously reported reactions of nitroallylic acetates, this process was initiated by a S N2 reaction at the electrophilic γ site. A plausible mechanism for the cascade SN2-Michael synthesis is proposed.
- Shao, Nana,Chen, Tong,Zhang, Taotao,Zhu, Huajian,Zheng, Qunxiong,Zou, Hongbin
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p. 795 - 799
(2014/01/23)
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- Highly regioselective organocatalyzed synthesis of pyrazoles from diazoacetates and carbonyl compounds
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A general, organocatalytic inverse-electron-demand [3+2] cycloaddition reaction between a range of carbonyl compounds and diazoacetates has been developed. This reaction is catalyzed by secondary amines as a "green promoter" to generate substituted pyrazoles with high levels of regioselectivity. It is noteworthy that this [3+2] cycloaddition reaction proceeds efficiently at room temperature with a simple and inexpensive catalyst. Considering the large variety and ready availability of the starting materials (e.g. ketones, β-ketoesters, β-diketones, and aldehydes), as well as the operational simplicity of this process, a convenient, practical, and highly modular pyrazole synthesis has been developed. We believe that this work will arouse more research interest in the organocatalytic synthesis of other biologically active heterocycles. Such studies are currently underway in our laboratory. Dipoles apart: In situ formed enamines react with diazoacetates under mild conditions to afford the corresponding polysubstituted pyrazoles in good-to-excellent yields through an inverse-electron-demand 1,3-dipolar cycloaddition process (see scheme). Copyright
- Wang, Lei,Huang, Jiayao,Gong, Xiaojie,Wang, Jian
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supporting information
p. 7555 - 7560
(2013/07/05)
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- 1,3-Dipolar cycloaddition of diazoacetate compounds to terminal alkynes promoted by Zn(OTf)2: an efficient way to the preparation of pyrazoles
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A series of pyrazoles were prepared in good yields via 1,3-dipolar cycloaddition of diazoacetate compounds to terminal alkynes promoted by Zn(OTf)2 under mild conditions. It was supposed that the reaction was through the intermediate of Zn alky
- He, Sheng,Chen, Li,Niu, Yan-Ning,Wu, Lu-Yong,Liang, Yong-Min
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experimental part
p. 2443 - 2445
(2009/08/07)
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- HIGHLY SELECTIVE and LONG-ACTING PDE5 MODULATORS
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Disclosed herein are substituted phosphodiesterase type 5 enzyme modulators of Formula I, processes of preparation thereof, pharmaceutical compositions thereof, and methods of use thereof.
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Page/Page column 53; 56
(2008/12/07)
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- Synthesis of pyrazole-3-carboxylates and pyrazole-1,5-dicarboxylates by one-pot cyclization of hydrazone dianions with diethyl oxalate
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The one-pot cyclization of hydrazone dianions with diethyl oxalate allows a convenient synthesis of pyrazole-3-carboxylates and pyrazole-1,5-dicarboxylates.
- Dang, Tung T.,Dang, Tuan T.,Fischer, Christine,G?rls, Helmar,Langer, Peter
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p. 2207 - 2215
(2008/09/18)
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- Agonist lead identification for the high affinity niacin receptor GPR109a
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A strategy for lead identification of new agonists of GPR109a, starting from known compounds shown to activate the receptor, is described. Early compound triage led to the formulation of a binding hypothesis and eventually to our focus on a series of pyrazole acid derivatives. Further elaboration of these compounds provided a series of 5,5-fused pyrazoles to be used as lead compounds for further optimization.
- Gharbaoui, Tawfik,Skinner, Philip J.,Shin, Young-Jun,Averbuj, Claudia,Jung, Jae-Kyu,Johnson, Benjamin R.,Duong, Tracy,Decaire, Marc,Uy, Jane,Cherrier, Martin C.,Webb, Peter J.,Tamura, Susan Y.,Zou, Ning,Rodriguez, Nathalie,Boatman, P. Douglas,Sage, Carleton R.,Lindstrom, Andrew,Xu, Jerry,Schrader, Thomas O.,Smith, Brian M.,Chen, Ruoping,Richman, Jeremy G.,Connolly, Daniel T.,Colletti, Steven L.,Tata, James R.,Semple, Graeme
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p. 4914 - 4919
(2008/02/12)
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- Fluorinated pyrazole acids are agonists of the high affinity niacin receptor GPR109a
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A series of 5-alkyl pyrazole-3-carboxylic acids were prepared and found to act as potent and selective agonists of the human GPCR, GPR109a, the high affinity nicotinic acid receptor. No activity was observed at the highly homologous low affinity niacin receptor, GPR109b. A further series of 4-fluoro-5-alkyl pyrazole-3-carboxylic acids were shown to display similar potency. One example from the series was shown to have improved properties in vivo compared to niacin.
- Skinner, Philip J.,Cherrier, Martin C.,Webb, Peter J.,Shin, Young-Jun,Gharbaoui, Tawfik,Lindstrom, Andrew,Hong, Vu,Tamura, Susan Y.,Dang, Huong T.,Pride, Cameron C.,Chen, Ruoping,Richman, Jeremy G.,Connolly, Daniel T.,Semple, Graeme
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p. 5620 - 5623
(2008/04/02)
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- One-pot synthesis of pyrazole-5-carboxylates by cyclization of hydrazone 1,4-dianions with diethyl oxalate
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The cyclization of hydrazone dianions with diethyl oxalate afforded pyrazole-5-carboxylates.
- Dang, Tuan Thanh,Dang, Tung Thanh,Langer, Peter
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p. 3591 - 3593
(2008/02/02)
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- Pyrazole derivatives as partial agonists for the nicotinic acid receptor
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Nicotinic acid as a hypolipidemic agent appears unique due to its potential to increase HDL cholesterol levels to a greater extent than other drugs. However, it has some side effects, among which severe skin flushing is the most frequent and often limits patients' compliance. In a search for novel agonists for the recently identified and cloned G protein-coupled nicotinic acid receptor, we synthesized a series of substituted pyrazole-3-carboxylic acids that proved to have substantial affinity for this receptor. The affinities were measured by inhibition of [3H] nicotinic acid binding to rat spleen membranes. Potencies and intrinsic activities relative to nicotinic acid were determined by their effects on [35S]GTPγS binding to rat adipocyte and spleen membranes. Interestingly, most compounds were partial agonists. In particular, 2-diazabicyclo-[3,3,O 4,8]octa-3,8-diene-3-carboxylic acid (4c) and 5-propylpyrazole-3-carboxylic acid (4f) proved active with Ki values of approximately 0.15 μM and EC50 values of approximately 6 μM, while their intrinsic activity was only ~50% when compared to nicotinic acid. Even slightly more active was 5-butylpyrazole-3-carboxylic acid (4g) with a Ki value of 0.072 μM, an EC50 value of 4.12 μM, and a relative intrinsic activity of 75%. Of the aralkyl derivatives, 4q (5-(3-chlorobenzyl)pyrazole-3-carboxylic acid) was the most active with a relatively low intrinsic activity of 39%. Partial agonism of the pyrazole derivatives was confirmed by inhibition of G protein activation in response to nicotinic acid by these compounds. The pyrazoles both inhibited the maximum effect elicited by 100 μM nicotinic acid and concentration dependently shifted nicotinic acid concentration-response curves to the right, pointing to a competive mechanism of action.
- Van Herk,Brussee,Van den Nieuwendijk,Van der Klein,IJzerman,Stannek,Burmeister,Lorenzen
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p. 3945 - 3951
(2007/10/03)
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- Fused 7-oxo-pyrimidinyl compounds, preparation, composition and use thereof
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The present invention relates to novel antiobesity and hypocholesterolemic compounds, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them. More particularly, the present invention relates to novel β-aryl-α-oxysubstituted alkylcarboxylic acids of the general formula (I), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them. The present invention also relates to a process for the preparation of the above said novel compounds, their analogs, their derivatives, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates and pharmaceutical compositions containing them. The present invention also relates to novel intermediates, processes for their preparation and their use in the preparation of compounds of formula (I).
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- Sildenafil (Viagra(TM)), a potent and selective inhibitor of type 5 CGMP phosphodiesterase with utility for the treatment of male erectile dysfunction
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5-(2'-Alkoxyphenyl)pyrazolo[4,3-d]pyrimidin-7-ones, and in particular our preferred compound, sildenafil (VIAGRA(TM)), discovered through a rational drug design programme, are potent and selective inhibitors of the type 5 cGMP phosphodiesterase from both rabbit platelets and human corpus cavernosum. Sildenafil is currently in the clinic for the oral treatment of male erectile dysfunction.
- Terrett, Nicholas K.,Bell, Andrew S.,Brown, David,Ellis, Peter
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p. 1819 - 1824
(2007/10/03)
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- Pyrazole derivative
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Novel pyrazole derivatives of the formula (I): STR1 wherein R is an alkyl group and D is an alkoxy group, a hydroxyl group, a halogen atom or an amino group which may be substituted, and salts thereof show strong antagonistic actions to angiotensin II, th
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