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Orally-effective, long-acting sorbitol dehydrogenase inhibitors: Synthesis, structure – Activity relationships, and in vivo evaluations of novel heterocycle-substituted piperazino-pyrimidines

Optimization of a previously disclosed sorbitol dehydrogenase inhibitor (SDI, II) for potency and duration of action was achieved by replacing the metabolically labile N,N-dimethylsulfamoyl group with a variety of heterocycles. Specifically, this effort led to a series of novel, in vitro potent SDIs with longer serum half-lives and acceptable in vivo activity in acutely diabetic rats (e.g., 62, 67, and 69). However, the desired in vivo potency in chronically diabetic rats, ED90 ? 5 mg/kg/day, was achieved only through further modification of the piperazine linker. Several members of this family, including 86, showed better than the targeted potency with ED90 values of 1-2 mg/kg/day. Compound 86 was further profiled and found to be a selective inhibitor of sorbitol dehydrogenase, with excellent pharmacodynamic/pharmacokinetic properties, demonstrating normalization of sciatic nerve fructose in a chronically diabetic rat model for ?17 h, when administered orally at a single dose of 2 mg/kg/day.

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A process for the preparation of intermediates […] (by machine translation)

The invention relates to a process for the preparation of intermediates […], the intermediate body is (3aR, 7aR) – 4 ? – (1,2-benzisothiazol-3-yl) eight hydrogen spiral [2H-isoindole -2,1 ?-piperazine] a sulfonate. The (1R, 2R) – 1,2-cyclohexane dimethanol as raw materials, dialkyltinacetal after armor is a sulfonic acid ester, with the 3 – (1-piperazinyl) – 1,2 benzothiazin hydrochloride reaction to obtain the required intermediate. (by machine translation)

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[1,3,4] OXADIAZOLE DERIVATIVE AND APPLICATION THEREOF

The present invention belongs to the medicinal chemistry field, and specifically discloses a [1,3,4]oxadiazole derivative with the structure of general formula (I) and pharmaceutically acceptable salt thereof. The compound can be used to prepare a medicine for preventing or treating a disease of the central nervous system.

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1,2,4-TRIAZOL-3-ONE ANTIDEPRESSANTS

Phenoxyalkyl substituted-1,2,4-triazolones having anti-depressant properties typified by 2-3-4-(3-chlorophenyl)-1-piperazinyl!propyl!-5-ethyl-4-(2-phenoxyethyl)-2H-1,2, 4-triazol-3(4H)-one are disclosed.

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PROCESS FOR PREPARING ZIPRASIDONE

The present invention concerns a process for the preparation of 5-(2-(4-(1,2- 5 benzisothiazol-3-yl)-1-piperazinyl)ethyl)-6-chloro-1,3-dihydro-2H-indol-2-one of the formula (I), or a pharmaceutically acceptable acid addition salt, solvate, hydrates or clathrate thereof, said process comprising reacting a compound of formula (II) wherein X is a halogen atom, with a compound of formula (III), said compound of formula (III) being the free base or an addition salt with an organic or inorganic acid, wherein said process is characterized in that said compounds according to formulas (II) and (III) are reacted in the presence of a neutralizing agent, and are reacted in a solvent comprising acetonitrile.

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Ureas/thioureas of benzo[d]isothiazole analog conjugated glutamic acid: Synthesis and biological evaluation

A series of urea and thiourea derivatives of glutamic acid conjugated to 3-(1-piperazinyl)-1,2-benzisothiazole were synthesized, spectroscopically characterized, and evaluated for their in vitro antiglycation and urease inhibitory activities. Preliminary screening of the synthesized compounds 1-35 showed significant results. Amongst these, compounds 17-21 and 30-35 bearing fluoro and methoxy substituents, respectively, exhibited inhibitory potency greater than the reference standards. Hence, they may serve as new lead compounds for further development. Urea and thiourea derivatives of glutamic acid conjugated to 3-(1-piperazinyl)-1,2-benzisothiazole were evaluated for their in vitro antiglycation and urease inhibitory activities. Compounds 17-21 and 30-35 bearing fluoro and methoxy substituents, respectively, exhibited inhibitory potency greater than the reference compounds. Copyright

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BENZOPYRONE DERIVATIVE AND USE THEREOF

The present invention relates to the field of pharmaceutical chemistry, and in particular, to a benzopyrone derivative and a use thereof. The benzopyrone derivative is compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof. It has been found by experiments that, this type of compounds is useful in prevention or treatment of neuropsychical diseases.

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Synthesis and biological evaluation of 1-(1,2-benzisothiazol-3-yl)- and (1,2-benzisoxazol-3-yl)piperazine derivatives as potential antipsychotic agents

Members of the series of title compounds were tested for potential antipsychotic activity in relevant receptor binding assays and behavioral screens. Structure-activity relationships within the series are discussed. Compound 24 (BMY 13859-1), a (1,2-benzisothiazol-3-yl)piperazine derivative, was selected for further study because of its potent and selective profile in primary CNS tests. It was active in the Sidman avoidance paradigm and blocked amphetamine-induced stereotyped behavior in dogs for up to 7 h. The compound’s lack of typical neuroleptic-like effects in the rat catalepsy test and its failure to produce dopamine receptor supersensitivity following chronic administration indicate that it should not cause the movement disorders commonly associated with antipsychotic therapy. Although 24 has potent affinity for dopaminergic binding sites, its even greater affinity for serotonin receptors suggests that a serotonergic component may be relevant to its atypical profile. Compound 24 is currently undergoing clinical evaluation in schizophrenic patients.

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HETEROCYCLIC SUBSTITUTED PIPERAZINES FOR THE TREATMENT OF SCHIZOPHRENIA

This invention relates to compounds of the formula 1 wherein X, Y, Z, A, R’, R2, R3, R4, R9, W’ and W2 are defined as in the specification, pharmaceutical compositions containing them and their use in the treatment of central nervous system and other disorders.

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Pro-drugs of 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)ethyl)-6-chloro-1,3-dihydro-2h-indol-2-one

The present invention relates to a pro-drug of ziprasidone or pharmaceutically acceptable salts thereof, processes for its preparation, and pharmaceutical compositions and methods of treatment comprising said pro-drug.

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