- Synthesis of benzoisoxazole derivatives and evaluation of inhibitory potency against cholinesterase for Alzheimer's disease therapeutics
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To improve Alzheimer's disease (AD) therapeutics, we have designed and synthesized new benzoisoxazole derivatives that are potent inhibitors of cholinesterase (acetylcholinesterase [AChE] and butyrylcholinesterase [BuChE]). Since inhibition of cholinesterase (ChE) is still considered to be one of the most effective ways of treating AD patients, many new classes of ChE inhibitors have been synthesized. To identify a new type of cholinergic drug, the benzoisoxazole moiety which is the pharmacophore moiety of Risperidone was coupled with natural antioxidants. Some benzoisoxazole derivatives (26-28 and 30) were found to effectively inhibit BuChE (IC50 50 = 8.4 ±0.1 μM). The new benzoisoxazole derivatives showing BuChE inhibitory activity represent a new class of ChE inhibitor and can be used to create novel compound derivative drugs for treating AD patients.
- Park, Jung-Youl,Shin, Sujeong,Kim, Jae-Kwan,Park, Kyoung Chan,Park, Jeong Ho
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- 1,3- and 1,4-Benzdiyne equivalents for regioselective synthesis of polycyclic heterocycles
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We have devised a novel 1,3-benzdiyne equivalent, capable of quadruple functionalization by sequential benzyne generation and reaction with arynophiles. The key features of this method include the chemoselective generation of two triple bonds in a single benzene ring under fluoride-mediated mild conditions, and the regiocontrol of each benzyne reaction by the substituent next to the triple bond. This method produced various benzo-fused heteroaromatic compounds via reactions with arynophiles, such as furans, azides, and diazo compounds. A validation of the method is given in the convergent synthesis of the antipsychotic drug risperidone. A similar strategy has also been applied to a 1,4-benzdiyne equivalent to construct linearly benzo-fused heteroaromatics.
- Ikawa, Takashi,Masuda, Shigeaki,Takagi, Akira,Akai, Shuji
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- In silico docking studies and synthesis of new phosphoramidate derivatives of 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole as potential antimicrobial agents
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A new class of phosphoramidate derivatives of 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole were synthesized in good to excellent yields (78–96%) by an in situ, three-step process. All the synthesized molecules were evaluated for anti-bacterial and anti-fungal activities using in?vitro and in silico methods. The results revealed that the compounds 4b, 4d, 4h, 4i, and 4j exhibited the most promising anti-bacterial activity against S. aureus, B. subtilis, K. pneumoniae, S. typhi and P. mirabilis and anti-fungal activity against A. niger and A. flavus when compared with the standard drugs Norfloxacin and Nystatin at concentrations of 25, 50, 75 and 100 μg/mL. The rest of the title compounds have shown moderate activity against all the bacterial and fungal strains. Molecular docking studies revealed that the synthesized compounds have exhibited significant binding modes with high dock scores ranging from ?7.2 to ?9.5 against 3V2B protein when compared with the standard drugs Norfloxacin (?5.8) and Nystatin (?6.6) respectively. Hence, it is suggested that the synthesized phosphoramidate derivatives of 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole will stand as the promising antimicrobial drug candidates in future.
- Sivala, Munichandra Reddy,Chintha, Venkataramaiah,Potla, Krishna Murthy,Chinnam, Sampath,Chamarthi, Naga Raju
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- Synthesis and characterization of new thiourea and urea derivatives of 6-fluoro-3-(piperidin-4-yl)benzo[d] isoxazole: In vitro Antimicrobial and Antioxidant activity
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A new class of antimicrobial and antioxidant agents, based on thiourea and urea derivatives of 6-fluoro-3-(piperidin-4-yl)benzo[d] isoxazole were synthesized by adopting a simple and efficient method. Synthesized compounds were characterized by spectral data of IR, 1H, 13C NMR and mass spectra. The compounds were evaluated for their efficacy as antimicrobial and antioxidant agents. A few compounds showed good antibacterial, antifungal and antioxidant activity when compared to standard drugs and thus represent a new class of promising lead compounds.
- Sudhamani, Hasti,Basha, Sk Thaslim,Venkateswarlu, Nagam,Vijaya, Tartte,Raju, Chamarthi Naga
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- Purification method of 6-fluoro-3-(4-piperidyl)-1,2-benzoisoxazole hydrochloride
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The invention discloses a purification method of a risperidone intermediate 6-fluoro-3-(4-piperidyl)-1,2-benzoisoxazole hydrochloride as shown in a formula II, which is characterized by comprising the following steps: adding 6-fluoro-3-(4-piperidyl)-1,2-benzoisoxazole hydrochloride into ethanol, adding a certain amount of water, and carrying out heating reflux until the solution is clear to obtain the risperidone intermediate 6-fluoro-3-(4-piperidyl)-1,2-benzoisoxazole hydrochloride; and cooling the compound to a certain temperature for crystal growing, then cooling the mixture to -5 to 10 DEG C, and filtering and drying the mixture to obtain the crystal. According to the purification method of the 6-fluoro-3-(4-piperidyl)-1,2-benzoisoxazole hydrochloride, the dimer shown as the formula V can be effectively separated out, the purification yield is 85% or above, the chemical purity of a finished product can reach 99.9% or above, an amplification effect cannot be generated in large-scale production, and the process is stable.
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Paragraph 0029; 0034; 0035
(2021/04/10)
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- Flow Synthesis in Hot Water: Synthesis of the Atypical Antipsychotic Iloperidone
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Inductively heated steel reactors continuously perform organic transformations in water under high temperature conditions, utilizing the unique physiochemical properties of water at subcritical conditions. We demonstrated the power of this set-up in the continuous synthesis of the atypical antipsychotic drug iloperidone, in which we performed four out of five steps under aqueous conditions.
- Hartwig, Jan,Kirschning, Andreas
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supporting information
p. 3044 - 3052
(2016/03/23)
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- Reformulating a Pharmacophore for 5-HT2A Serotonin Receptor Antagonists
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Several pharmacophore models have been proposed for 5-HT2A serotonin receptor antagonists. These typically consist of two aromatic/hydrophobic moieties separated by a given distance from each other, and from a basic amine. Although specified distances might vary, the models are relatively similar in their general construction. Because our preliminary data indicated that two aromatic (hydrophobic) moieties might not be required for such action, we deconstructed the serotonin-dopamine antipsychotic agent risperidone (1) into four smaller structural fragments that were thoroughly examined in 5-HT2A receptor binding and functional (i.e., two-electrode voltage clamp (TEVC) and intracellular calcium release) assays. It was apparent that truncated risperidone analogues behaved as antagonists. In particular, 6-fluoro-3-(1-methylpiperidin-4-yl)benzisoxazole (4) displayed high affinity for 5-HT2A receptors (Ki of ca. 12 nM) relative to risperidone (Ki of ca. 5 nM) and behaved as a potent 5-HT2A serotonin receptor antagonist. These results suggest that multiple aromatic (hydrophobic) moieties are not essential for high-affinity 5-HT2A receptor binding and antagonist activity and that current pharmacophore models for such agents are very much in need of revision.
- Younkin, Jason,Gaitonde, Supriya A.,Ellaithy, Amr,Vekariya, Rakesh,Baki, Lia,Moreno, José L.,Shah, Sneha,Drossopoulos, Peter,Hideshima, Kelsey S.,Eltit, Jose Miguel,González-Maeso, Javier,Logothetis, Diomedes E.,Dukat, Malgorzata,Glennon, Richard A.
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p. 1292 - 1299
(2016/09/28)
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- Aralkylpiperidine (or piperazinecarboxylic) and its derivatives used for treating hypercalcemia schinzopherenia
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PROBLEM TO BE SOLVED: To provide an agent for treating schizophrenia and related neuropsychiatric diseases.SOLUTION: This invention provides an aralkylpiperidine (or piperazine) derivative represented by formula (1), where A ring is a 5-7 membered heterocycle including N, with the heterocycle including a hetero atom arbitrarily selected from O, S, N; X is O, an amino group or a substituted amino group; Z is CH, N or C; Y is O, N or S; n is an integer of 1-5; and R1-R6 are H, a C1-C4 alkyl group or the like.
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Paragraph 0089
(2018/12/01)
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- Palladium-catalyzed benzo[d]isoxazole synthesis by C-H activation/[4 + 1] annulation
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We report a palladium-catalyzed intermolecular [4 + 1] annulation pathway for N-phenoxyacetamides with aldehydes to form 1,2-benzisoxazoles. By activating the C-H bonds ortho to phenol-derived O-N bonds, the method enables the simultaneous construction of C-C and CN bonds in 1,2-benzisoxazoles with the O-N bonds intact. The method has been successfully applied to the synthesis of active pharmaceutical intermediates, such as risperidone.
- Duan, Pingping,Yang, Yunfang,Ben, Rong,Yan, Yiyong,Dai, Lu,Hong, Mei,Wu, Yun-Dong,Wang, Dongqi,Zhang, Xinhao,Zhao, Jing
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p. 1574 - 1578
(2014/03/21)
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- Processes for the preparation of paliperidone
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The present invention relates to a novel process for the preparation of paliperidone and its intermediates and also relates to an improved process for the preparation of paliperidone compound of formula (I).
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Paragraph 22
(2013/07/25)
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- ARALKYL SUBSTITUTED PIPERIDINE OR PIPERAZINE DERIVATIVES AND THEIR USE FOR TREATING SCHIZOPHRENIA
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The present invention discloses an aralkyl substituted piperidine or piperazine derivative and the use of the derivative in preparation of medicaments for treating schizophrenia and correlative psychoneuroses. It is shown by pharmacological tests that the derivative of the present invention has better antischizophrenic effect and less toxicity. Said derivative is a free base or salt of the compound having the following general formula.
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- NOVEL AND IMPROVED PROCESSES FOR THE PREPARATION OF PALIPERIDONE
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The present invention relates to a novel process for the preparation of paliperidone and its intermediates and also relates to an improved process for the preparation of paliperidone compound of formula (I).
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- A PROCESS FOR THE PREPARATION OF RISPERIDONE
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The present invention relates to an improved process for the preparation of Risperidone of formula (I) by condensing 6-fluoro-3- (4-piperidinyl)-l, 2- benzisoxazole with 3-(2-chloroethyl)-6, 7, 8, 9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one in water and water immiscible solvents under basic conditions in the presence of a catalyst. This invention also relates to a method for purification of crude Risperidone by removing an impurity specifically named as 9-hydroxy Risperidone to undetectable level using acid chlorides and an organic base in a suitable solvent.
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Page/Page column 7-9
(2008/06/13)
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- METHOD FOR PREPARING RISPERIDONE
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Risperidone is prepared in a high yield by reacting 2,4-difluorophenyl(4-piperidinyl)methanone oxime hydrochloride and 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one in an aqueous alkali hydroxide solution having an alkali hydroxide concentration in the range of 20 to 40%.
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- A simple and efficient method for the synthesis of 1,2-benzisoxazoles: A series of its potent acetylcholinesterase inhibitors
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A simple and efficient method for the synthesis of 6-fluoro-3-(4- piperidinyl)-1,2-benzisoxazole hydrochloride is achieved. This reaction involves hydroxylamine sulfate/KOH mediated, in situ generated oxime formation and its subsequent internal cyclisation followed by alkaline hydrolysis of N-protected ketone in one step. Synthesis of 1,2-benzisoxazole analogues is described and they are found to be potent acetylcholinesterase inhibitors.
- Basappa,Mantelingu,Sadashiva,Rangappa
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p. 1954 - 1957
(2007/10/03)
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- Process improvements for the preparation of kilo quantities of a series of isoindoline compounds
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A series of isoindoline analogues with either an indazole (HMR 2934, HMR 2651) or benzisoxazole (HMR 2543) appendage were prepared for the proposed treatment of psychiatric disorders such as obsessive compulsive disorder and attention deficit disorder. The isoindoline compounds were prepared by reduction of the corresponding phthalimides with LiAlH4. One compound was not chiral, and the other two required an enantioselective synthesis. The key step for these optically active analogues involved the coupling by an SN2 process of either a piperazynyl intermediate or a piperdinyl intermediate with methyl 3-benzyloxy-2-trifluoromethansulfonatopropionate. The products for these two analogues had >98% ee. Process improvements led to the multi-kilogram syntheses of each of these compounds.
- Watson, Timothy J.,Ayers, Timothy A.,Shah, Nik,Wenstrup, David,Webster, Mark,Freund, David,Horgan, Stephen,Carey, James P.
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p. 521 - 532
(2013/09/05)
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- Fused heterocyclic compounds and pharmaceutical applications thereof
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The present invention relates to a fused heterocyclic compound of the formula (I) wherein each symbol is as defined in the specification, an optical isomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing a compound of the formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive, and a medicament containing a compound of the formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof. The compound of the present invention is a useful antipsychotic agent effective not only for positive symptoms centering on hallucination and delusion characteristic of the acute stage of schizophrenia, but also negative symptoms of apathy, abulia and autism. The inventive compound is expected to make a highly safe antipsychotic agent associated with less side effects, such as extrapyramidal symptoms and endocrine disturbance, which are observed when a conventional antipsychotic agent having a D2receptor blocking action is administered. Therefore, the inventive compound can be used as a therapeutic agent for the diseases such as schizophrenia.
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- Dipeptides which promote release of growth hormone
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Compounds of formula (I) are growth hormone releasing peptide mimetics which are useful for the treatment and prevention of osteoporosis. STR1
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- 1,2-benzisoxazole compounds
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Compounds of formula I STR1 in which m represents an integer from 0 to 5, n represents an integer from 1 to 2, p is equal to 0, 1 or 2, X, Y and Z, which may be identical or different, each represent a hydrogen atom, a halogen atom, a linear or branched alkyl radical, a trifluoromethyl radical, an alkoxy radical, an alkylthio radical or a hydroxyl radical, and R represents a 2-benzofuranyl or 2,3-dihydro-2-benzofuranyl radical (it being possible for each to be substituted on the benzene ring), a 2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b']difuran-2-yl radical, a 4-oxo-4H-chromen-2-yl radical (optionally substituted on the benzene ring), a benzocyclobutenyl radical of formula A or an indanyl radical of formula B: STR2 (in which: R1 and R2, which may be identical or different, each represent a hydrogen atom, a halogen atom, a trifluoromethyl radical, an alkyl radical, an alkoxy radical, a hydroxyl radical, a hydroxyalkyl radical or an alkylthio radical, or together form a methylenedioxy radical or an ethylenedioxy radical, and R3 represents a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms), or a radical of formula C: STR3 (in which R4, R5 and R6, which may be identical or different, each represent a hydrogen atom, a halogen atom, a trifluoromethyl radical, a hydroxyl radical, an alkyl radical, an alkoxy radical or an alkylthio radical, their optical isomers and their addition salts with a pharmaceutically acceptable organic or inorganic acid.
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- 3-piperidinyl-substituted 1,2-benzisoxazoles and 1,2-benzisothiazoles
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3-Piperdinyl-1,2-benzisothiazoles and 3-piperidinyl-1,2-benzisoxazoles and their pharmaceutically acceptable acid addition salts having useful antipsychotic properties and being useful in the treatment of a variety of complaints in which serotonin release is of predominant importance.
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