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Process for the preparation of 6-(perfluoroalkyl) uracil compounds from 2-(N,N-disubstituted) amino-4-(perfluoroalkyl)-1,3-oxazin-6-one compounds

An improved process for the preparation of 6-(perfluoroalkyl)uracil compounds having the structural formula I STR1 from 2-(N,N-disubstituted)amino-4-(perfluoroalkyl)-1,3-oxazin-6-one compounds having the structural formula II STR2

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Discovery of isatin and 1H-indazol-3-ol derivatives as D-amino acid oxidase (DAAO) inhibitors

D-Amino acid oxidase (DAAO) is a potential target in the treatment of schizophrenia as its inhibition increases brain D-serine level and thus contributes to NMDA receptor activation. Inhibitors of DAAO were sought testing [6+5] type heterocycles and identified isatin derivatives as micromolar DAAO inhibitors. A pharmacophore and structure-activity relationship analysis of isatins and reported DAAO inhibitors led us to investigate 1H-indazol-3-ol derivatives and nanomolar inhibitors were identified. The series was further characterized by pKa and isothermal titration calorimetry measurements. Representative compounds exhibited beneficial properties in in vitro metabolic stability and PAMPA assays. 6-fluoro-1H-indazol-3-ol (37) significantly increased plasma D-serine level in an in vivo study on mice. These results show that the 1H-indazol-3-ol series represents a novel class of DAAO inhibitors with the potential to develop drug candidates.

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CASPASE INHIBITOR AND PHARMACEUTICAL COMPOSITION, USE AND THERAPEUTIC METHOD THEREOF

Disclosed are a class of compounds as a caspase inhibitor, and in particular the compound as shown in formula (I) or a pharmaceutically acceptable salt thereof, and the use of the compound in treating caspase-related diseases.

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Validation of tautomeric and protomeric binding modes by free energy calculations. A case study for the structure based optimization of d-amino acid oxidase inhibitors

Abstract: Optimization of fragment size d-amino acid oxidase (DAAO) inhibitors was investigated using a combination of computational and experimental methods. Retrospective free energy perturbation (FEP) calculations were performed for benzo[d]isoxazole derivatives, a series of known inhibitors with two potential binding modes derived from X-ray structures of other DAAO inhibitors. The good agreement between experimental and computed binding free energies in only one of the hypothesized binding modes strongly support this bioactive conformation. Then, a series of 1-H-indazol-3-ol derivatives formerly not described as DAAO inhibitors was investigated. Binding geometries could be reliably identified by structural similarity to benzo[d]isoxazole and other well characterized series and FEP calculations were performed for several tautomers of the deprotonated and protonated compounds since all these forms are potentially present owing to the experimental pKa values of representative compounds in the series. Deprotonated compounds are proposed to be the most important bound species owing to the significantly better agreement between their calculated and measured affinities compared to the protonated forms. FEP calculations were also used for the prediction of the affinities of compounds not previously tested as DAAO inhibitors and for a comparative structure?activity relationship study of the benzo[d]isoxazole and indazole series. Selected indazole derivatives were synthesized and their measured binding affinity towards DAAO was in good agreement with FEP predictions. Graphical Abstract: [Figure not available: see fulltext.].

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Muscarinic agonists

Compounds are provided which are useful in the treatment of disease conditions in which modification of cholinergic, especially muscarinic m1, m4 or both m1 and m4, receptor activity has a beneficial effect. Also a use is provided of the compounds in the manufacture of pharmaceutical compositions for treating such diseases and conditions.

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Ortho Effects in Shiff Bases of Diaminodicyanoethane

In the electron impact mass spectra of azomethines derived from various substituted aromatic aldehydes and diaminodicyanoethene the superposition of two ortho effects concurring with the azomethine group is apparent: one involving the amino group of the diaminodicyanoethene part accounts for the cyclization to + ions and the other involving ortho substituents of the benzylidene part which can interact with the azomethine moiety is responsible for specific fragment ions, suppressing the typical fragmentations of azomethines.The ortho effect was studied for the o-nitro derivative by labelling experiments, analysis of metastable transitions and collisional activation comparing model ions, demonstrating that the specific +. and +. ions are the result of cyclization processes.

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BENZISOXAZOLE COMPOUND AND USE THEREOF

A benzisoxazole compound represented by general formula (I) or a pharmaceutically acceptable salt thereof wherein, when the bond (a) between the 2- and 3-positions represents a single bond, Rarepresents the group (II) (wherein R represents hydrogen, alkyl, alkenyl, cycloalkylalkyl, cycloalkylalkenyl, phenylalkenyl, naphthylalkyl or naphthylalkenyl; A represents linear or branched alkylene; and n represents 1, 2 or 3) and Rbrepresents oxygen, or alternatively when the bond (a) between the 2- and 3-positions represents a double bond, Rais absent; Rbrepresents either the group (III), wherein each symbol is as defined above, or the group (IV), wherein E represents oxygen or sulfur, and R, A and n are each as defined above; and R1, R2, R3 and R4 are each as defined in the specification. This compound has a centroselective acetylcholine esterase inhibiting activity and/or a potent affinity for sigma receptor.

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Isoxazole derivatives

An isoxazole compound having the following formula: wherein R1 represents hydrogen, halogen, alkyl, alkoxy, hydroxyl, alkylthio, amino, alkanoyl, alkanoylamino, alkanoyloxy, alkoxycarbonyl, carboxy, (alkylthio)thiocarbonyl, carbamoyl, nitro or cyano; R2 represents an amino; m is 1; n is 1 to 6; ring A represents a phenyl ring or a naphthyl ring; and X represents oxygen or sulfur. The isoxazole compound has an excellent monoamine oxidase inhibitory activity, and is useful for treating Parkinson’s disease, depression and Alzheimer’s disease.

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Benzo[d]isoxazol-3-ol DAAO inhibitors

Methods for increasing D-Serine concentration and reducing concentration of the toxic products of D-Serine oxidation, for enhancing learning, memory and/or cognition, or for treating schizophrenia, Alzheimer”s disease, ataxia, or neuropathic pain, or preventing loss in neuronal function characteristic of neurodegenerative diseases involve administering to a subject in need of treatment a therapeutic amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof: wherein

  • Z1 is N or CR3;
  • Z2 is N or CR4;
  • Z3is O or S;
  • A is hydrogen, alkyl or M+; M is aluminum, calcium, lithium, magnesium, potassium, sodium, zinc or a mixture thereof;
  • R1, R2, R3 and R4 are independently selected from hydrogen, alkyl, hydroxy alkoxy, aryl, acyl, halo, cyano, haloalkyl, NHCOOR5 and SO2NH2;
  • R5 is aryl, arylalkyl, heteroaryl or heteroarylalkyl;
  • at least one of R1, R2, R3 and R4 is other than hydrogen; and
  • at least one of Z1 and Z2 is other than N.

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NOVEL PIPERAZINYL-PYRAZINONE DERIVATIVES FOR THE TREATMENT OF 5-HT2A RECEPTOR-RELATED DISORDERS

Compounds of the general formula (I): (I) wherein m, n, R1, R2, R3 and R4 are as described in the specification. Further included are pharmaceutical compositions comprising the compounds, processes for their preparation, as well as the use of the compounds for the preparation of a medicament for the treatment of 5-HT2A receptor-related disorders or medical conditions.

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