- PYRAZOLOTRIAZOLOPYRIMIDINE DERIVATIVES AS A2A RECEPTOR ANTAGONIST
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Disclosed herein is a pyrazolotriazolopyrimidine derivative or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof useful as an A2A receptor antagonist, and a pharmaceutical composition comprising the same. Also disclosed herein is a method of treating cancer using the pyrazolotriazolopyrimidine derivative or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an A2A receptor antagonist.
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- New derivatives of quinoline-4-carboxylic acid with antiplasmodial activity
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New analogues of the recently published compound DDD107498 were prepared. Their activities were examined in vitro against the chloroquine-sensitive NF54 strain. The most active were also tested against the multiresistant K1 strain of Plasmodium falciparum. A couple of the newly synthesized compounds showed promising antiplasmodial activity and selectivity. A single compound showed adequate reduction of parasitaemia (98.1%) in mice infected with Plasmodium berghei. Survival time was doubled compared to control. The results of the biological tests of the novel compounds were compared with the activities of drugs in use. Structure-activity relationships were discussed.
- Hochegger, Patrick,Faist, Johanna,Seebacher, Werner,Saf, Robert,M?ser, Pascal,Kaiser, Marcel,Weis, Robert
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p. 2251 - 2259
(2017/03/23)
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- CINNAMIC ACID AMIDE DERIVATIVE
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The present invention provides a cinnamic acid amide derivative having an excellent analgesic action. The cinnamic acid amide derivative of the present invention is a compound showing excellent analgesic actions to not only a nociceptive pain model animal but also a neuropathic pain model animal, which is very useful as an agent for treating various pain diseases showing acute or chronic pains or neuropathic pains.
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Paragraph 0028; 0044
(2015/11/24)
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- Binding kinetics of ZM241385 derivatives at the human adenosine A 2A receptor
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Classical drug design and development rely mostly on affinity- or potency-driven structure-activity relationships (SAR). Thus far, a given compound's binding kinetics have been largely ignored, the importance of which is now being increasingly recognized. In the present study, we performed an extensive structure-kinetics relationship (SKR) study in addition to a traditional SAR analysis at the adenosine A2A receptor (A 2AR). The ensemble of 24 A2AR compounds, all triazolotriazine derivatives resembling the prototypic antagonist ZM241385 (4-(2-((7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)amino) ethyl)phenol), displayed only minor differences in affinity, although they varied substantially in their dissociation rates from the receptor. We believe that such a combination of SKR and SAR analyses, as we have done with the A 2AR, will have general importance for the superfamily of G protein-coupled receptors, as it can serve as a new strategy to tailor the interaction between ligand and receptor. Above and beyond: Insight into the binding kinetics of ZM241385 derivatives at the human adenosine A2A receptor has provided additional information beyond a traditional structure-activity relationship (SAR) analysis. The strategy, combining a structure-kinetics relationship investigation and SAR, can serve as an important tool for more directed medicinal chemistry efforts in the future.
- Guo, Dong,Xia, Lizi,Van Veldhoven, Jacobus P. D.,Hazeu, Marc,Mocking, Tamara,Brussee, Johannes,Ijzerman, Adriaan P.,Heitman, Laura H.
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p. 752 - 761
(2014/05/06)
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- The design and synthesis of 1,4-substituted piperazine derivatives as triple reuptake inhibitors
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Novel 1,4-substituted piperazine derivatives 5, Series A and B were designed by fragment analysis and molecular modification of 4 selected piperazine-containing compounds which possess antidepressant activity. We synthesized new 39 analogues of Series A and 10 compounds of Series B, respectively. The antidepressant screening against DA, NE, and serotonin neurotransmitter uptake inhibition was carried out using the Neurotransmitter Transporter Uptake Assay Kit. The compounds in Series B showed relatively higher reuptake inhibitory activity for SERT, NET, and DAT than those in Series A. The length of spacer between the central piperazine core and the terminal phenyl ring substituted at the piperazine ring in Series B seems to exert an important role in the activity.
- Han, Minsoo,Han, Younghue,Song, Chiman,Hahn, Hoh-Gyu
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p. 2597 - 2602
(2012/10/29)
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- Synthesis, structure, and cholinergic effect of novel neuroprotective compounds bearing the tacrine pharmacophore
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Novel tacrine congeners with side ligands suitable for optimal interaction with the peripheral and catalytic sites of acetyl- and butyrylcholinesterase (AChE and BuChE) have been synthesized using either 9-isothiocyanato-1,2,3,4-tetrahyhroacridine or 9-chloro-1,2,3,4-tetrahydroacridine which represent convenient synthons by reaction with various substituted amines. The synthesized compounds were tested for their inhibition of AChE and BuChE whereby a morpholine and a furfuryl derivative were found to be the most potent AChE and BuChE inhibitors, respectively, with the latter compound comparable in activity to tacrine.
- Hamul'akova, Slavka,Kristian, Pavol,Jun, Daniel,Kuca, Kamil,Imrich, Jan,Danihel, Ivan,Boehm, Stanislav,Klika, Karel D.
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experimental part
p. 1219 - 1235
(2009/06/28)
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- Efficient and scalable method for the selective alkylation and acylation of secondary amines in the presence of primary amines
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Selective substitution of secondary amines in the presence of primary amines is performed by using the reaction solvent, methyl isobutylketone (MIBK), as a temporary protecting group for the primary amine. After acylation or alkylation of the secondary amine, the resulting imine intermediate is smoothly hydrolysed, leading to the free primary amine in high yield and purity. This procedure represents a cheap and scalable alternative to multistep methods requiring several protections and deprotections.
- Laduron, Frederic,Tamborowski, Vanessa,Moens, Luc,Horvath, Andras,De Smaele, Dirk,Leurs, Stef
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p. 102 - 104
(2012/12/24)
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- Piperazinyl-substituted pyridylalkane, alkene and alkine carboxamides
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The invention relates to new piperazinyl-substituted pyridylalkane, alkene, and alkine acid amides substituted with saturated or one or several-fold unsaturated hydrocarbon residue in the carboxylic acid group according to the general formula (I) as well as methods for the production of these compounds, medicaments containing these and their production as well as their therapeutic use, especially as cytostatic agents and immunosuppressive agents, for example in the treatment or prevention of various types of tumors and control of immune reactions such as autoimmune diseases.
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Page/Page column 167-168
(2010/02/11)
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- Malonic acid derivatives, processes for their preparation, for their use and pharmaceutical compositions containing them
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New compounds for the inhibition of blood clotting proteins, and more particularly, to malonic acid derivatives of the formula I, wherein R(1), R(2), R(3), R(4), R(5), and R(6) have the meanings indicated in the claims. The compounds of formula I are inhibitors of the blood clotting enzyme factor Xa. Processes for the preparation of the compounds of formula I, methods of inhibiting factor Xa activity and of inhibiting blood clotting, use of the compounds of formula I in the treatment and prophylaxis of diseases, which can be treated or prevented by the inhibition of factor Xa activity such as thromboembolic diseases, and use of the compounds of formula I in the preparation of medicaments to be applied in such diseases. Compositions containing a compound of formula I in admixture or otherwise in association with an inert carrier, in particular pharmaceutical compositions containing a compound of formula I together with pharmaceutically acceptable carrier substances and auxiliary substances.
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- N,N-SUBSTITUTED CYCLIC AMINE DERIVATIVES
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N,N-substituted cyclic amine derivatives represented by general formula (VIII) or pharmacologically acceptable salts thereof: wherein A represents aryl, etc.; E represents -CO- or -CHOH-; G represents oxygen, etc.; J represents optionally substituted aryl; R1 represents lower alkyl, etc.; Alk represents linear or branched lower alkylene; n, v, w, x and y independently represent each 0 or 1; and p represents 2 or 3. These compounds or salts thereof are efficacious in treating diseases against which calcium antagonism is efficacious. These diseases include cerebrovascular disorder at the acute stage, cerebral stroke, cerebral infarction, head injury, cerebral nerve cell death, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, brain circulatory disturbance, brain function disturbance, pain, convulsion, schizophrenia, hemicrania, epilepsy, circular psychosis, nerve degeneration diseases, brain ischemia, AIDS, complex dementia, edema, anxiety and diabetic nephropathy.
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- 1-[(aminoalkyl and aminoalkylamino)carbonyl and thiocarbonyl]-α,α-diarylpyrrolidine, piperidine and homopiperidineacetamides and acetonitriles
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Novel 1-[(aminoalkyl and aminoalkylamino)carbonyl and thiocarbonyl]-α,α-diaryl-pyrrolidine, piperidine and homopiperidineacetamides and acetonitriles having the formula: STR1 wherein; n is zero, one or two; X is oxygen or sulfur; Z is STR2 p is 0 to 5 inclusive with the proviso that when Z is STR3 p is at least one; Y is aminocarbonyl or cyano; Ar1 and Ar2 are 2, 3 or 4-pyrido, phenyl or substituted phenyl; R is hydrogen or loweralkyl; R1, R2 and R3 are hydrogen, cycloalkyl, loweralkyl, phenyl, substituted phenyl, phenylloweralkyl, and R2 and R3 taken with the adjacent nitrogen may form a heterocyclic residue, and diastereoisomers when possible and pharmaceutical salts; and the method and pharmaceutical compositions for treating cardiac arrhythmias therewith are disclosed.
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- Aryloxy-N-(aminoalkyl)-1-pyrrolidine and piperidine carboxamides and carbothioamides having antiarrhythmic activity
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Pharmaceutical compositions comprised of aryloxy-N-(aminoalkyl)-1-pyrrolidine and piperidine carboxamides and carbothioamides are provided of the formula: STR1 wherein Ar is selected from the group consisting of 1-naphthyl, 2-naphthyl, 2,3-dihydro-1H-inden-4-yl, 2,3-dihydro-1H-inden-5-yl, phenyl, substituted phenyl wherein the substituents are selected from lower alkyl of from 1 to 8 carbon atoms, lower alkyloxy of from 1 to 8 carbon atoms, halogen and trifluoromethyl; m and n are 1 or 2 but are never 2 at the same time; p is 1, 2, 3 or 4; R is selected from hydrogen or lower alkyl of from 1 to 3 carbon atoms; R1 and R2 are selected from hydrogen, lower alkyl of from 1 to 8 carbon atoms, phenyl, phenyl lower alkyl of from 7 to 9 carbon atoms, and cycloalkyl of from 3 to 8 carbon atoms, and R1 and R2 taken together with the adjacent atom may form a heterocyclic residue selected from 4-morpholino, 1-pyrrolidino, 1-piperidino, 1-piperazino and 4-lower alkyl piperazin-1-yl; X is oxygen or sulfur; and the pharmaceutically acceptable acid addition salts thereof having antiarrhythmic activity.
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