B. Satyanarayana, Y. Sumalatha,, Sythana Suresh Kumar
2005
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Heterocyclic Communications
Abstract
Aripiprazole is a recently developed anti-psychotic drug used for the treatment of schizophrenia. Aripiprazole and its N-oxides exhibit a strong activity for influencing the neurotransmission of dopamine receptors and are devoid of side effects induced by the known drugs useful for the treatment of schizophrenia. Further, Aripiprazole is metabolized by different biotransformation pathways as dehydrogenation, hydroxylation and N-dealkylation giving rise to different metabolites. The present work details the development of a simple and novel process for the preparation of Aripiprazole N-oxides as Aripiprazole-4-N-oxide, Aripiprazole-1-N-oxide and Aripiprazole-l,4-di-N-oxide and Aripiprazole metabolites such as dehydro Aripiprazole and Aripiprazole hydroxy metabolite. Introduction Aripiprazole 1 is an anti-psychotic drug used in the treatment of psychoses including schizophrenia. Schizophrenia is a most common type of psychosis caused by an excessive neurotransmission activity of the dopaminergic nervous system in the CNS. Aripiprazole, a carbostyril derivative, functions as a partial agonist'"' at the dopamine D2 and serotonin 5-HTIA receptors and as an antagonist at serotonin 5-HT2A receptor. Clinical studies have demonstrated that Aripiprazole and its N-oxides are well tolerated and do not significantly induce extra pyramidal syndromes, which are the side effects, found in the case of drugs having a strong activity for blocking neurotransmission of dopaminergic receptor. The N-oxides of Aripiprazole include Aripiprazole-4-N-oxide, Aripiprazole-1-N-oxide and Aripiprazole-1,4-di-N-oxide. Metabolism is often the major factor influencing the efficacy and side effect profile of drugs. An understanding of a drug's metabolism and recognition of potential drug-drug interactions is critical to successful drug development. Aripiprazole is metabolized primarily by three biotransformation pathways dehydrogenation, hydroxylation and N-dealkylation. 7-[4-[4-(2,3Dichlorophenyl)-l-piperazinyl] butoxy]-3,4-dehydro-2-(lH) quinolinone (Dehydro Aripiprazole, 9), is a major active metabolite formed by the dehydrogenation of Aripiprazole. The other important metabolite is 7-(4-hydroxy butoxy)-3,4-dihydro-2-(lH)-quinolinone. Discussions In this present article, we herewith disclose our work regarding the synthesis and characterization of the various N-oxides and metabolites of Aripiprazole. 7-[4-[4-(2,3-DichIorophenyI)-l-piperazinyl (4-N-oxo)] butoxy] 3, 4-dihydro-2-(lH) quinoiinone (Aripiprazole-4-N-oxide, 6) In the preparation of Aripiprazole-4-N-oxide 6, 2, 3-dichloro phenyl piperazine hydrochloride 2 was chosen as the starting material. The secondary nitrogen of 2 is highly reactive when compared to the tertiary nitrogen, having a possibility for N-oxide formation at the secondary nitrogen. Hence, in order to get the N-oxide at the tertiary nitrogen, the cyclic secondary amine 2 was protected using benzoyl chloride in the presence of dichloromethane as the solvent and triethyl amine as the base, to yield benzoyl protected dichloro phenyl piperazine 3. The EI mass spectrum of 3 showed the molecular ion at m/z 336. The presence of carbonyl group (1630 cm') was evident in the infrared spectrum. Reaction of piperazine derivative 3 with /w-chloro per benzoic acid in dichloromethane solvent resulted in benzoyl protected dichloro phenyl piperazine-N-oxide 4. The EI mass spectrum displayed the molecular ion of 4 at m/z 351. Deprotection by hydrolysis of 4 in the presence of aqueous Vol. 11, No. 6, 2005 Synthesis and characterization of η-oxides and metabolites of anti-psychotic drig, aripiprazole sulphuric acid yielded 4-N-oxide of dichloro phenyl piperazine 5. The EI mass spectrum of 5 displayed the molecular ion at m/z 247. Deprotection of secondary amine was evident from infrared spectral values showing NH at 3275 cm'. Finally, condensation of 4-N-oxide of dichlorophenyl piperazine 5 with 7-(4-bomobutoxy)-3,4-dihydro-2-(lH)-quinolinone furnished 7-[4-[4-(2,3dichlorophenyl)-l-piperazinyl (4-N-oxo)] butoxy]3,4-dihydro-2(lH) quinolinone 6 (Scheme-1). The molecular ion of 6 appeared as the base peak at m/z 465 in the EI mass spectrum. The presence of NH (3377 cm"), carbonyl (1679 cm") aryl alkyl ether (1272, 1048 cm") and aromatic C-Cl (1173 cm") groups was evident in the infrared spectrum. In the 'H NMR spectrum (δ ppm), the cyclic amide NH appeared as a singlet at 10.0, which disappeared on adding deuterium oxide. The O-CH2 protons appeared as a triplet at 3.95. The methylene protons of the free nitrogen of piperazine moiety appeared at 3.05 whereas those methylene protons attached to the oxo nitrogen appeared as a triplet at 4.6.