ChemInform Abstract: Novel Antipsychotic Agents with Dopamine Autoreceptor Agonist Properties: Synthesis and Pharmacology of 7‐[4‐(4‐Phenyl‐1‐piperazinyl)butoxy]‐3,4‐dihydro‐2(1H)‐quinolinone Derivatives.

Abstract

Novel Antipsychotic Agents with Dopamine Autoreceptor Agonist Properties:Synthesis and Pharmacology of 7-[4-(4-Phenyl-1piperazinyl)butoxy]-3,4-dihydro-2(1H)-quinolinone Derivatives.-A series of title compounds (39 examples) is synthesized and evaluated for their properties as an agonist of dopamine autoreceptors and an antagonist of postsynaptic DA receptors. The most active compounds are (Va) and (Vb), which may be potent agents for treatment of schizophrenia. -(OSHIRO, Y.; SATO, S.; KURAHASHI, N.; TANAKA, T.; KIKUCHI, T.; TOTTORI, K.; UWAHODO, Y.; NISHI, T.; J. Med. Chem. 41 (1998) 5, 658-667; Tokushima Inst. New Drugs Res.

Functionally Selective Dopamine D2, D3Receptor Partial Agonists

“…Introduction of a second H-bond-accepting functional group into the heteroarene moiety mimicking the lactam group of the lead structure 2a was also envisioned. Starting from 1,4-disubstituted phenylpiperazines (1,4-DAPs), known as privileged structural surrogates for biogenic amines, , we built our synthesis strategy in analogy to previously described routes leading to analogues of 2a (Scheme ). − Initially, pyrazolo[1,5- a ]pyridine scaffolds 4a – 4e were prepared in different regioisomeric forms. ,,− For the synthesis of the 5-substituted carboxylate 4f , we adopted our previously described protocol involving 1,3-dipolar cycloaddition of dimethylacetylene dicarboxylate and 4-methoxy- N -aminopyridinium ions under oxidative conditions, followed by simultaneous ester hydrolysis, decarboxylation, and ether cleavage by hydrobromic acid and subsequent re-esterification (for details, see the Supporting Information).…”

“…Alkylation of the phenolic hydroxyl group with 1,4-dibromobutane in analogy to a literature described protocol afforded the alkyl bromides 5a – f , which were subsequently reacted with 1-(2,3-dichlorophenyl)piperazine in the presence of sodium iodide to yield the target compounds 6a – f . To mimic the carboxamide moiety of the dihydroquinolin-2( 1H )-one substructure of 2a , we introduced a formyl group into position 3 of the pyrazolo[1,5- a ]pyridine ring by a protocol involving the Vilsmeyer reaction, resulting in formation of the test compounds 7a – e .…”

Classics in Chemical Neuroscience: Aripiprazole

“…74 In 1998, Otsuka scientists described a similar synthesis for the free base, but with slightly different conditions (Scheme 1). 75 The synthesis begins with the alkylation of 7-hydroxy-3,4-dihydro-2(1H)-quinolinone by stirring it with 1,4-dibromobutane (3 mol equiv) in the presence of potassium carbonate (1 mol equiv) in dimethylformamide at 60 °C for 4 h to give 7-(4bromobutoxy)-3,4-dihydro-2(1H)-quinolinone. The reaction mixture is then diluted with an equal volume of water, and the organic phase is extracted with ethyl acetate.…”

“…After rotary evaporation, the resulting product is recrystallized in ethyl alcohol. 74,75 The product is subsequently combined with sodium iodide (2 mol equiv) in acetonitrile and refluxed for 30 min before cooling to room temperature. Next, 1-(2,3dichlorophenyl)piperazine (1.5 mol equiv, prepared based on 76 ) and triethylamine (2 mol equiv) are added to the reaction mixture, and the mixture is refluxed for another 4 h. The resulting precipitate is filtered and discarded.…”

“…The powder may then be dissolved in ethyl alcohol with acid to yield a variety of salts. Other compounds, such as OPC-4392 (Figure 1), aripiprazole's predecessor, were prepared using similar procedures by condensing (4-bromobutoxy)-2(1H)-quinolinone (or a structural analog) with various phenylpiperizines; 74,75 the procedure has since been optimized. 77…”