- PYRAZOLO[1,5-a]PYRIMIDIN-7(4H)-ONE INHIBITORS OF DYNEIN
-
Pyrazolo[1,5-a]pyrimidin-7(4H)-ones of formula (I) inhibit intraflagellar transport and are useful as anticancer agents and as probes of the function of dynein-dependent systems.
- -
-
-
- MONOACYLGLYCEROL LIPASE INHIBITORS
-
Provided are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof: Also provided are compositions comprising compounds of formula (I). The compounds and compositions are also provided for use as medicaments, for example as medicaments useful in the treatment of a condition modulated by monoacylglycerol lipase (MAGL). Also provided are the use of compounds and compositions for the inhibition of monoacylglycerol lipase (MAGL).
- -
-
Paragraph 0111-0112; 0141; 0153-0154; 0189
(2021/09/09)
-
- Design, synthesis, and biological evaluation of aryl piperazines with potential as antidiabetic agents via the stimulation of glucose uptake and inhibition of NADH:ubiquinone oxidoreductase
-
The management of blood glucose levels and the avoidance of diabetic hyperglycemia are common objectives of many therapies in the treatment of diabetes. An aryl piperazine compound 3a (RTC1) has been described as a promoter of glucose uptake, in part through a cellular mechanism that involves inhibition of NADH:ubiquinone oxidoreductase. We report herein the synthesis of 41 derivatives of 3a (RTC1) and a systematic structure-activity-relationship study where a number of compounds were shown to effectively stimulate glucose uptake in vitro and inhibit NADH:ubiquinone oxidoreductase. The hit compound 3a (RTC1) remained the most efficacious with a 2.57 fold increase in glucose uptake compared to vehicle control and micromolar inhibition of NADH:ubiquinone oxidoreductase (IC50 = 27 μM). In vitro DMPK and in vivo PK studies are also described, where results suggest that 3a (RTC1) would not be expected to provoke adverse drug-drug interactions, yet be readily metabolised, avoid rapid excretion, with a short half-life, and have good tissue distribution. The overall results indicate that aryl piperazines, and 3a (RTC1) in particular, have potential as effective agents for the treatment of diabetes.
- Breen, C. J.,Devine, R.,Driver, R. B.,Findlay, J. B. C.,Kelada, M.,Kinsella, G. K.,Leonard, S.,Martin, D. S. D.,Stephens, J. C.,Walsh, J. M. D.
-
-
- METHODS FOR FORMING ARYL CARBON-NITROGEN BONDS USING LIGHT AND PHOTOREACTORS USEFUL FOR CONDUCTING SUCH REACTIONS
-
The disclosure relates to a method for forming aryl carbon-nitrogen bonds and to photoreactors useful in these and other light-driven reactions. The method comprises contacting an aryl halide with an amine in the presence of a Ni salt catalyst solution and an optional base, thereby forming a reaction mixture; exposing the reaction mixture to light under reaction condition sufficient to produce the aryl carbon-nitrogen bonds. In certain embodiments, the amine may be present in a molar excess to the aryl halide. In certain embodiments, the Ni salt catalyst solution includes a Ni(II) salt and a polar solvent, wherein the Ni(II) salt is dissolved in the polar solvent. In certain embodiments, the reactions conditions include holding the reaction mixture at between about room temperature and about 80° C. for between about 1 hour and about 20 hours such that at least about 50% yield is obtained.
- -
-
Paragraph 0097-0098; 0124-0125
(2019/11/22)
-
- Energy Transfer to Ni-Amine Complexes in Dual Catalytic, Light-Driven C-N Cross-Coupling Reactions
-
Dual catalytic light-driven cross-coupling methodologies utilizing a Ni(II) salt with a photocatalyst (PC) have emerged as promising methodologies to forge aryl C-N bonds under mild conditions. The recent discovery that the PC can be omitted and the Ni(II) complex directly photoexcited suggests that the PC may perform energy transfer (EnT) to the Ni(II) complex, a mechanistic possibility that has recently been proposed in other systems across dual Ni photocatalysis. Here, we report the first studies in this field capable of distinguishing EnT from electron transfer (ET), and the results are consistent with F?rster-type EnT from the excited state [Ru(bpy)3]Cl2 PC to Ni-amine complexes. The structure and speciation of Ni-amine complexes that are the proposed EnT acceptors were elucidated by crystallography and spectroscopic binding studies. With the acceptors known, quantitative F?rster theory was utilized to predict the ratio of quenching rate constants upon changing the PC, enabling selection of an organic phenoxazine PC that proved to be more effective in catalyzing C-N cross-coupling reactions with a diverse selection of amines and aryl halides.
- Kudisch, Max,Lim, Chern-Hooi,Thordarson, Pall,Miyake, Garret M.
-
supporting information
p. 19479 - 19486
(2019/12/25)
-
- Heteroaromatic acetamide derivative, preparation and applications thereof
-
The present invention provides a heteroaromatic acetamide derivative, a preparation and applications thereof, wherein the derivative comprises a pharmaceutically acceptable salt and/or a solvate thereof. According to the present invention, the experiment results prove that the heteroaromatic acetamide derivative can specifically bind to transient receptor potential ankyrin 1 (TRPA1) and inhibit orreduce the activity of TRPA1, and can be used for treating diseases mediated by TRPA1; and the inhibitor of the present invention further comprises a pharmaceutical composition of the compound, and amethods for preparing the compounds. The derivative has a general formula defined in the specification.
- -
-
Paragraph 0030
(2019/11/04)
-
- C-N Cross-Coupling via Photoexcitation of Nickel-Amine Complexes
-
C-N cross-coupling is an important class of reactions with far-reaching impacts across chemistry, materials science, biology, and medicine. Transition metal complexes can elegantly orchestrate diverse aminations but typically require demanding reaction conditions, precious metal catalysts, or oxygen-sensitive procedures. Here, we introduce a mild nickel-catalyzed C-N cross-coupling methodology that operates at room temperature using an inexpensive nickel source (NiBr2·3H2O), is oxygen tolerant, and proceeds through direct irradiation of the nickel-amine complex. This operationally robust process was employed for the synthesis of diverse C-N-coupled products (40 examples) by irradiating a solution containing an amine, an aryl halide, and a catalytic amount of NiBr2·3H2O with a commercially available 365 nm LED at room temperature without added photoredox catalyst and the amine substrate serving additional roles as the ligands and base. Density functional theory calculations and kinetic isotope effect experiments were performed to elucidate the observed C-N cross-coupling reactivity.
- Lim, Chern-Hooi,Kudisch, Max,Liu, Bin,Miyake, Garret M.
-
supporting information
p. 7667 - 7673
(2018/05/31)
-
- Noble diamine compounds, and polyamic acid and polyamide therefrom
-
The present invention refers to a diamine compound represented by [formula 1] and manufacturing method and. is directed at the application of. Wherein, A1 to A5 said substituent, said substituent R1 to R5 defined in the detailed description of the invention is. (by machine translation)
- -
-
Paragraph 0098-0102
(2016/10/17)
-
- Pd-Catalyzed Synthesis of Piperazine Scaffolds under Aerobic and Solvent-Free Conditions
-
A facile Pd-catalyzed methodology providing an efficient synthetic route to biologically relevant arylpiperazines under aerobic conditions is reported. Electron donating and sterically hindered aryl chlorides were aminated to afford yields up to 97%, with examples using piperazine as solvent, illustrating an ecofriendly, cost-effective synthesis of these privileged structures.
- Reilly, Sean W.,Mach, Robert H.
-
supporting information
p. 5272 - 5275
(2016/10/31)
-
- Chrysin-piperazine conjugates as antioxidant and anticancer agents
-
Synthesis of 7-(4-bromobutoxy)-5-hydroxy-2-phenyl-4H-chromen-4-one intermediate treating chrysin with 1,4-dibromobutane facilitated combination of chrysin with a wide range of piperazine moieties which were equipped via reacting the corresponding amines with bis(2-chloroethyl)amine hydrochloride in diethylene glycol monomethyl ether solvent. Free radical scavenging potential of prepared products was analyzed in vitro adopting DPPH and ABTS bioassay in addition to the evaluation of in vitro anticancer efficacies against cervical cancer cell lines (HeLa and CaSki) and an ovarian cancer cell line SK-OV-3 using SRB assay. Bearable toxicity of 7a-w was examined employing Madin-Darby canine kidney (MDCK) cell line. In addition, cytotoxic nature of the presented compounds was inspected utilizing Human bone marrow derived mesenchymal stem cells (hBM-MSCs). Overall, 7a-w indicated remarkable antioxidant power in scavenging DPPH+ and ABTS++, particularly analogs 7f, 7j, 7k, 7l, 7n, 7q, 7v, 7w have shown promising free radical scavenging activity. Analogs 7j and 7o are identified to be highly active candidates against HeLa and CaSki cell lines, whereas 7h and 7l along with 7j proved to be very sensitive towards ovarian cancer cell line SKOV-3. None of the newly prepared scaffolds showed cytotoxic nature toward hBM-MSCs cells. From the structure-activity point of view, nature and position of the electron withdrawing and electron donating functional groups on the piperazine core may contribute to the anticipated antioxidant and anticancer action. Different spectroscopic techniques (FT-IR, 1H NMR, 13C NMR, Mass) and elemental analysis (CHN) were utilized to confirm the desired structure of final compounds.
- Patel, Rahul V.,Mistry, Bhupendra,Syed, Riyaz,Rathi, Anuj K.,Lee, Yoo-Jung,Sung, Jung-Suk,Shinf, Han-Seung,Keum, Young-Soo
-
p. 166 - 177
(2016/05/24)
-
- ANTHELMINTIC COMPOUNDS AND COMPOSITIONS AND METHOD OF USING THEREOF
-
The present invention relates to novel anthelmintic compounds of formula (I) below: wherein Y and Z are independently a bicyclic carbocyclic or a bicyclic heterocyclic group, or one of Y or Z is a bicyclic carbocyclic or a bicyclic heterocyclic group and the other of Y or Z is alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclyl or heteroaryl, and variables X1, X2, X3, X4, X5, X6, X7 and X8 are as defined herein. The invention also provides for veterinary compositions comprising the anthelmintic compounds of the invention, and their uses for the treatment and prevention of parasitic infections in animals.
- -
-
Paragraph 0704; 0705
(2014/05/25)
-
- Two analogues of fenarimol show curative activity in an experimental model of chagas disease
-
Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), is an increasing threat to global health. Available medicines were introduced over 40 years ago, have undesirable side effects, and give equivocal results of cure in the chronic stage of the disease. We report the development of two compounds, 6 and (S)-7, with PCR-confirmed curative activity in a mouse model of established T. cruzi infection after once daily oral dosing for 20 days at 20 mg/kg 6 and 10 mg/kg (S)-7. Compounds 6 and (S)-7 have potent in vitro activity, are noncytotoxic, show no adverse effects in vivo following repeat dosing, are prepared by a short synthetic route, and have druglike properties suitable for preclinical development.
- Keenan, Martine,Chaplin, Jason H.,Alexander, Paul W.,Abbott, Michael J.,Best, Wayne M.,Khong, Andrea,Botero, Adriana,Perez, Catherine,Cornwall, Scott,Thompson, R. Andrew,White, Karen L.,Shackleford, David M.,Koltun, Maria,Chiu, Francis C. K.,Morizzi, Julia,Ryan, Eileen,Campbell, Michael,Von Geldern, Thomas W.,Scandale, Ivan,Chatelain, Eric,Charman, Susan A.
-
p. 10158 - 10170
(2014/01/17)
-
- HETEROCYCLIC COMPOUNDS FOR THE INHIBITION OF PASK
-
Disclosed herein are new heterocyclic compounds and compositions and their application as pharmaceuticals for the treatment of disease. Methods of inhibiting PAS Kinase (PASK) activity in a human or animal subject are also provided for the treatment of diseases such as diabetes mellitus.
- -
-
Page/Page column 48-49
(2011/04/14)
-
- Industrial-scale palladium-catalyzed coupling of aryl halides and amines - A personal account
-
The palladium-catalyzed coupling of amines and aryl halides or aryl alcohol derivatives has matured from an exotic small-scale transformation into a very general, efficient and robust reaction during the last ten years. This article reports several applications of this method from an industrial vantage point, including ligand synthesis, synthesis of arylpiperazines, arylhydrazines and diarylamines. Much emphasis in placed on issues of scale-up and safety to underline the potential of C-N couplings as solutions for industrial-scale synthetic problems.
- Buchwald, Stephen L.,Mauger, Christelle,Mignani, Gerard,Scholz, Ulrich
-
-
- Process for preparing monoarylpiperazines
-
The invention provides a process for preparing arylpiperazines from the corresponding aryl chlorides or bromides and piperazine using a base and a catalyst consisting of a palladium salt and a bisaryldialkylphosphine.
- -
-
Page/Page column 4
(2008/06/13)
-
- 1-ARYL-4-SUBSTITUTED PIPERAZINES DERIVATIVES FOR USE AS CCR1 ANTAGONISTS FOR THE TREATMENT OF INFLAMMATION AND IMMUNE DISORDERS
-
Compounds are provided that act as potent antagonists of the CCR1 receptor, and which have been further confirmed in animal testing for inflammation, one of the hallmark disease states for CCR1. The compounds are generally aryl piperazine derivatives and are useful in pharmaceutical compositions, methods for the treatment of CCR1-mediated diseases, and as controls in assays for the identification of competitive CCR1 antagonists.
- -
-
-
- Nickel-catalysed selective N-arylation or N,N′-diarylation of secondary diamines
-
The selective synthesis of N-aryl or N,N′-diaryl piperazines and trimethylene(bis)piperidines from the corresponding diamines and aryl chlorides using a catalyst combination of Ni(0) associated to 2,2′-bipyridine is described. The Ni/2,2′-bipyridine catalyst is also effective for the sequential arylation of piperazine. The preparation of novel and unsymmetrical 1,4-diaryl piperazines is reported.
- Brenner, Eric,Schneider, Rapha?l,Fort, Yves
-
p. 6913 - 6924
(2007/10/03)
-
- Synthesis of potent and selective dopamine D4 antagonists as candidate radioligands
-
A series of dopamine D4 antagonists was synthesized and evaluated as potential candidates for development as positron emission tomography (PET) radioligands. All new compounds display high affinity and selectivity for the D4 receptors and compounds 5b, 5d, and 5e were identified as candidates for radioligand development.
- Huang, Yiyun,Kegeles, Lawrence S.,Bae, Sung-A,Hwang, Dah-ren,Roth, Bryan L.,Savage, Jason E.,Laruelle, Marc
-
p. 1375 - 1377
(2007/10/03)
-
- Nickel-mediated amination chemistry. Part 2: Selective N-arylation or N,N'-diarylation of piperazine
-
The 2,2'-bipyridine liganded Ni catalyst has revealed a good selectivity in the mono arylation of piperazine starting from aryl chlorides allowing a selective and efficient synthesis of N-arylpiperazines using stoichiometric amounts of reagents. The preparation of N,N'-diaryl substituted piperazines is also described. (C) 2000 Elsevier Science Ltd.
- Brenner, Eric,Schneider, Rapha?l,Fort, Yves
-
p. 2881 - 2884
(2007/10/03)
-
- Antiviral agents
-
Antiviral compounds (I): the symbols being as defined in the specification, are efficacious against infections caused by a variety of DNA viruses, RNA viruses and retroviruses. Other specified compounds also exhibit activity. The compounds have a wider spectrum of activity than known antiviral substances.
- -
-
-
- Synthesis and Insecticidal Activity of N4-Aryl-N1-(O,O-dialkyl thiophosphoryl)Piperazines
-
Eleven new N4-aryl-N1-(O,O-dialkyl thiophosphoryl) piperazines have been synthesised as possible insecticides by the condensation of N-aryl piperazines with O,O-dialkyl chloro-tiophosphates and tested against Periplanata americana.
- Agarwal, Kamlesh C.
-
p. 1170 - 1171
(2007/10/02)
-
