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WO2001017993A1 - Derives d'alkypiperidi nylbenzo [d] isoxazole presentant une activite psychotrope, compositions pharmaceutiques contenant ces derniers, et procede de preparation de l'ingredient actif - Google Patents

Derives d'alkypiperidi nylbenzo [d] isoxazole presentant une activite psychotrope, compositions pharmaceutiques contenant ces derniers, et procede de preparation de l'ingredient actif Download PDF

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Publication number
WO2001017993A1
WO2001017993A1 PCT/HU2000/000096 HU0000096W WO0117993A1 WO 2001017993 A1 WO2001017993 A1 WO 2001017993A1 HU 0000096 W HU0000096 W HU 0000096W WO 0117993 A1 WO0117993 A1 WO 0117993A1
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WO
WIPO (PCT)
Prior art keywords
ιsoxazole
formula
hydrogen atom
derivative
mmoles
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/HU2000/000096
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English (en)
Inventor
József Barkóczy
István Gacsályi
László BALÁZS
György Lévay
Gyula Simig
Éva SCHMIDT
Katalin Pallagi
Gábor SZÉNÁSI
Imre Domán
Zoltán Greff
Péter KÓTAY-NAGY
Zoltán RÁTKAI
Péter SERES
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Egyt Gyogyszervegyeszeti Gyar
Egis Pharmaceuticals PLC
Original Assignee
Egyt Gyogyszervegyeszeti Gyar
Egis Pharmaceuticals PLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from HU9903042A external-priority patent/HUP9903042A2/hu
Priority claimed from HU9903043A external-priority patent/HUP9903043A2/hu
Application filed by Egyt Gyogyszervegyeszeti Gyar, Egis Pharmaceuticals PLC filed Critical Egyt Gyogyszervegyeszeti Gyar
Priority to AU75471/00A priority Critical patent/AU7547100A/en
Publication of WO2001017993A1 publication Critical patent/WO2001017993A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the invention refers to novel alkylp ⁇ pe ⁇ d ⁇ nylbenzo[d] ⁇ soxazole derivatives, pharmaceutical compositions containing the same, and a process for the preparation of the active ingredient
  • the compounds of the invention exert action on the central nervous system and have primarily, psychotropic activity
  • the invention refers to novel alkylpipe ⁇ dinylbenzo- [d] ⁇ soxazole derivatives of the formula
  • Z represents a hydrogen atom or a hydroxy group
  • n has a value of 0 or 1
  • X and Y mean, independently, a hydrogen atom, and simultaneously R stands for a hydrogen atom a halo atom a C 1-6 alkyl group or a C ⁇ -6 alkoxy group, and
  • X' and Y' represent, independently, a hydrogen atom, a halo atom, a d -6 alkyl group or a C 1-6 alkoxy group, or
  • X' forms together with Y' a 5- to 7-membered aromatic or partially saturated isocyclic or heterocyclic ring that can be fused with one or more further 5- to 7-membered aromatic or partially saturated isocyclic or heterocyclic ring, wherein each heterocyclic ring may contain, independently, one or more oxygen atom(s) and/or nitrogen atom(s) and/or sulfur atom(s) as the heteroatom and each isocyclic or heterocyclic ring may be independently substituted by a halo atom, a C ⁇ - 6 alkyl group and/or a C 1-6 alkoxy group, or b)
  • R, X' and Y' represent, independently, a hydrogen atom
  • X forms together with Y a 5- to 7-membered aromatic or partially saturated isocyclic or heterocyclic ring that can be fused with one or more further 5- to 7-membered aromatic, partially saturated or saturated isocyclic or heterocyclic ring, wherein each heterocyclic ring may contain, independently, one or more oxygen atom(s) and/or nitrogen atom(s) and/or sulfur atom(s) as the heteroatom, and each isocyclic or heterocyclic ring may be independently substituted by a C ⁇ - 6 alkyl group or a C ⁇ -6 alkoxy group, and pharmaceutically suitable acid addition salts thereof
  • the psychiatric disorders including the affective clinical patterns (schizophrenia anxiety, depression) form a great challenge for the medical science
  • schizophrenia about 1 % of the entire population is involved
  • the medicinal therapy currently used is not thoroughly appropriate for the treatment of the disease
  • the so called conventional neuroleptics such as haloperidol i e 4-/4-(4-chlorophenyl)-4- hydroxy-1 -pipe ⁇ dinyl -(4-fluorophenyl)-1 -butanone, chlor- promazine i e 2-chloro-N,N-d ⁇ methyl-10H-phenoth ⁇ az ⁇ e-10- propanamine
  • These neuroleptics are primarily dopamine D 2 receptor antagonists, consequently, possess several disagreeable side-effects Furthermore they are ineffective in certain symptom complex of schizophrenia (negative symptoms) [Ellenbroek, B A , Pharmacol Ther , 57, 1 (1993)]
  • a C- ⁇ -6 alkyl group is, for example, a methyl, ethyl, n-propyi, isopropyl, n-butyl, sec -butyl, tert -butyl, isobutyl n-pentyl or n-hexyl group
  • a C 1 - 4 alkoxy group is a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec -butoxy, tert -butoxy or isobutoxy group
  • a C 1 . 6 alkoxy group can be, in addition to the ones listed in the definition of the C ⁇ - alkoxy group, e g also an n-pentyloxy or n- hexyloxy group
  • a halo atom is, for example, a fluoro, chloro, bromo or lodo atom
  • a ring consisting of only carbon atoms or containing in addition to the carbon atoms one or more heteroatom(s) and having 5, 6 or 7 members is meant, wherein the ring is either of aromatic structure, or partially saturated lf X forms together with Y such a ring, then this ring is naturally fused with the benzene ring to which X and Y are bound
  • the isocyclic or heterocyclic ring defined above may be fused with one or more further r ⁇ ng(s) that correspond(s) to the above definition or is/are completely saturated, wherein each heterocyclic ring may contain, independently, one or more oxygen atom(s) and/or one or more (nitrogen atom(s) and/or one or more sulfur atom(s)
  • Each isocyclic or heterocyclic ring of the ring system can be, independently substituted
  • each heterocyclic ring may contain, independently, one or more oxygen atom(s) and/or one or more (nitrogen atom(s)
  • Each isocyclic or heterocyclic ring of the ring system can be independently, substituted
  • X can form together with Y (or X' can form together with Y') a furan, pyrazole, imidazole, t ⁇ azole isoxazole oxazole, oxadiazole, cyclope ⁇ tene, benzene pyridine, pyridazine, pyrimidine, pyrazine, triazine oxazine, azepine diazepine, indene, benzofuran, indole, benzisoxazole, naphthalene ring etc
  • a pharmaceutically suitable acid addition salt is an acid addition salt formed with a pharmaceutically suitable inorganic acid such as hydrogen chloride hydrogen bromide, sulfuric acid, phosphoric acid etc , or with a pharmaceutically suitable organic acid such as formic acid acetic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, succinic acid, citric acid methanesulfomc acid etc
  • the invention includes any possible optical isomers of the alkylp ⁇ per ⁇ d ⁇ nylbenzo[d] ⁇ soxazole derivatives of the formula I and the mixtures thereof
  • a preferred subgroup of the compounds of the invention consists of the alkylp ⁇ per ⁇ d ⁇ nylbenzo[d] ⁇ soxazole derivatives and pharmaceutically suitable acid addition salts thereof, wherein in formula I
  • Z represents a hydrogen atom or a hydroxy group R
  • X' and Y' mean, independently, a hydrogen atom
  • X forms together with Y a 5- to 6-membered aromatic or partially saturated isocyclic or heterocyclic ring, said latter ring containing one or more oxygen atom(s) and/or nitrogen atom(s) and/or sulfur atom(s) as the heteroatom and the isocyclic or heterocyclic ring can be substituted by a Ci 4 alkyl group or a C ⁇ . alkoxy group
  • n has a value of 0 or 1
  • the especially preferred alkyl- p ⁇ pe ⁇ d ⁇ nylbenzo[d] ⁇ soxazole derivatives consist of the compounds of the formula I wherein Z represents a hydrogen atom or a hydroxy group, R, X' and Y' mean, independently, a hydrogen atom, X forms together with Y a benzene ring or a 5-membered aromatic or partially saturated heterocyclic ring containing two oxygen atoms or two nitrogen atoms and a sulfur atom as the heteroatom, n has a value of 0 or 1 , and pharmaceutically suitable acid addition salts thereof.
  • a further preferred subgroup of the compounds of the invention consists of alkylpiperidinylbe ⁇ zo[d]isoxazole derivatives of the formula wherein
  • Z represents a hydrogen atom or a hydroxy group
  • R stands for a hydrogen atom
  • X' and Y' mean, independently, a hydrogen atom or a C ⁇ -4 alkoxy group, or
  • X' forms together with Y' a 5- to 6-membered aromatic or partially saturated isocyclic or heterocyclic ring, said latter ring containing two oxygen atoms or a nitrogen atom as the heteroatom, and the isocyclic or heterocyclic ring is optionally fused with a benzene ring, n has a value of 0 or 1 , and pharmaceutically suitable acid addition salts thereof
  • the especially preferred alkyl- p ⁇ per ⁇ d ⁇ nylbenzo[d] ⁇ soxazole derivatives consist of the compounds of the formula la, wherein
  • Z represents a hydrogen atom or a hydroxy group
  • R stands for a hydrogen atom
  • X' and Y' mean, independently, a hydrogen atom or a methoxy group, or X' forms together with Y a benzene ring or pyrrol ring which latter is fused with a benzene ring, n has a value of 0 or 1 , and pharmaceutically suitable acid addition salts thereof
  • Z' stands for a hydrogen atom or a hydroxy group or Q forms together with Z' an oxygen atom X, Y, X', Y', R and n are as defined in connection with formula I, is reacted with 6-fluoro-3-(p ⁇ pe ⁇ d ⁇ ne-4-yl)benzo[d]- isoxazole, and, if desired, an obtained alkylp ⁇ per ⁇ d ⁇ ylbenzo[d] ⁇ soxazole derivative of the formula I is converted to a pharmaceutically suitable acid addition salt or the base is liberated from the salt
  • Processes a) and b) of the invention are carried out in an analogous way as the processes known from the literature [Houben-Weyl Methoden der Organischen Chemie, VI/3 54- 62, 465-468, Xl/L . 311 , XI/2, 407, 654, 656, Georg Thieme Verlag, Stuttgart]
  • the p ⁇ per ⁇ d ⁇ nylbe ⁇ zo[d] ⁇ soxazole derivative of the formula II used as starting compound in process a) of the invention can be prepared by the reaction of a compound of the formula wherein A and Q represent, independently, a leaving group, Z' stands for a hydrogen atom or a hydroxy group, or Z forms together with Q an oxygen atom, n is as defined in connection with formula I, with 6-fluoro-3-p ⁇ pe ⁇ d ⁇ ne-4-ylbenzo[d] ⁇ soxazole in an analogous way as the processes known from the literature [Houben-Weyl Methoden der Organischen Chemie, XI/2 407, 654, 656, Georg Thieme Verlag, Stuttgart]
  • the compound of the formula III used as the starting substance is prepared by the reaction of a phenol derivative of the formula IV with the compound of the formula V in an analogous way as the processes known from the literature [Houben-Weyl Methoden der Organischen Chemie, VI/3, 54-62, Georg Thieme Verlag Stuttgart]
  • the antipsychotic (neuroleptic) effect was evaluated by the assessment of inhibition of the learned conditioned avoidance response
  • the experiments were done on male Wistar rats weighing 120 to 150 g (at the beginning of conditioning)
  • the experimental apparatus (shuttle-box) consisted of two 24x24 5x23 cm compartments connected by a 6x9 cm passage way
  • the animals were conditioned to avoid punishment (electric shock) by passing from one compartment to the other after a neutral signal was delivered
  • the warning (conditioned) signal was given in the very compartment occupied by the animal in the moment of signaling
  • Blinking white light was used as conditioned signal (CS) for 15 sec 0 6 mA randomized electric foot shock started in the last 5 sec of the CS was employed as unconditioned signal (UCS)
  • UCS unconditioned signal
  • Passage of the animal through the gate from one compartment of the apparatus to the other during CS was considered as avoidance response, while passing during UCS was determined as escape response
  • Both responses stopped the existent signal, the trial was terminated
  • mice Male NMRI mice weighing 20 to 25 g were used in the experiments 30 mm after oral administration (20 ml/kg) of the test compound or vehicle, the animals were placed in a 12x12x12 cm wire mesh cage covered with plexiglass top for habituation After 30 mm, mice were treated subcutaneously with 1 mg/kg of apomorphine hydrochloride in 10 ml/kg volume Stereotyped behaviour was scored from 0 to 4 for 25 mm according to the following criteria
  • the novel compounds examined displayed significant anxiolytic activity in the lick conflict model With the exception of the compound according to Example 21 , all compounds examined showed effectiveness similar to that of diazepam, while the efficacy of the compound of Example 27 was remarkably higher than that of the reference compound
  • the arms of the plus-maze were 50 cm long and 15 cm wide, the walls of the closed arms were 40 cm high
  • the maze was elevated to 60 cm height from floor level
  • the behaviour of the animals in the maze was observed through a video camera in an adjacent room During the 5 minutes test period, the number of entries into the open and closed arms as well as the cumulative time spent by the rat in the open and closed arms were recorded
  • the compounds of the invention are effective in the treatment of various mental and mood disorders It is particularly remarkable that the compounds of the invention inhibit apomorphine induced climbing in a significantly lower dose than apomorphine induced stereotyped behaviour (Table 2) These results are particularly important as inhibition of apomorphine induced stereotypes is connected to the blockade of stnatal dopaminergic receptors, while inhibition of apomorphine induced climbing is associated with the blockade of dopamine receptors of the nucleus accumbens [Costall et al , Eur J Pharmacol , 50, 39 (1978)] Thus, compounds inhibiting apomorphine induced stereotypes and climbing in about the same dosage range are most likely to produce extrapyramidal side effects in the therapeutically effective doses
  • the so called atypical antipsychotics such as clozapine inhibit apomorhme induced climbing in a lower dose than stereotyped behaviour [Moore, N C and Gershon, S , Clin Neuropharmacol , 12, 167 (1989)]
  • the presence such as
  • novel alkylp ⁇ per ⁇ d ⁇ nylbenzo[d] ⁇ soxazole derivatives of the formula I and pharmaceutically suitable acid addition salts thereof can be used as active ingredients in pharmaceutical compositions.
  • compositions of the invention contain a therapeutically active amount of the compound of the formula I or a pharmaceutically suitable acid addition salt thereof and one or more conventional carr ⁇ er(s)
  • compositions of the invention are suitable for peroral, parenteral or rectal administration or for local treatment, and can be solid or liquid
  • the solid pharmaceutical compositions suitable for peroral administration may be powders capsules tablets, film-coated tablets, microcapsules etc , and can comprise binding agents such as gelatine, sorbitol, poly(v ⁇ nylpyrrol ⁇ done) etc , filling agents such as lactose, glucose, starch calcium phosphate etc , auxiliary substances for tablettmg such as magnesium stearate, talc, poly(ethyle ⁇ e glycol), silica etc , wetting agents such as sodium laurylsulfate etc as the carrier
  • the liquid pharmaceutical compositions suitable for peroral administration may be solutions, suspensions or emulsions and can comprise e g suspending agents such as gelatine, carboxymethylcellulose etc emulsifiers such as sorbitane monooleate etc , solvents such as water, oils, glycerol, propylene glycol ethanol etc , preservatives such as methyl p- hydroxybenzoate etc as the carrier
  • compositions suitable for parenteral administration consist of sterile solutions of the active ingredient, in general
  • compositions of the invention contain, in general, 0 1 to 95 0 per cent by mass of a compound of the formula I or a pharmaceutically suitable acid addition salt thereof
  • a typical dose for adult patients amounts to 0 1 to 1000 mg of the compound of the formula I or a pharmaceutically suitable acid addition salt thereof, daily
  • the above dose can be administered in one or more portions
  • the actual dosage depends on many factors and is determined by the doctor
  • compositions of the invention are prepared by admixing a compound of the formula I or a pharmaceutically suitable acid addition salt thereof to one or more car ⁇ er(s), and converting the mixture obtained to a pharmaceutical composition in a manner known per se Useful methods are known from the literature, e g Remington's Pharmaceutical Sciences mentioned above
  • One preferred subgroup of the pharmaceutical compositions of the invention contains an alkylp ⁇ per ⁇ d ⁇ nylbenzo[d] ⁇ soxazole derivative of the formula I, wherein Z represents a hydrogen atom or a hydroxy group R, X' and Y' mean, independently, a hydrogen atom, X forms together with Y a 5- to 6-membered aromatic or partially saturated isocyclic or heterocyclic ring, said latter ring containing one or more oxygen atom(s) and/or nitrogen atom(s) and/or sulfur atom(s) as the heteroatom and the isocyclic or heterocyclic ring can be substituted by a C ⁇ - alkyl group or a C
  • compositions of the invention contain an alkylp ⁇ per ⁇ d ⁇ nyi-be ⁇ zo[d] ⁇ soxazole derivative of the formula I, wherein
  • Z represents a hydrogen atom or a hydroxy group
  • R, X' and Y' mean, independently, a hydrogen atom
  • X forms together with Y a benzene ring or a 5-membered aromatic or partially saturated heterocyclic ring containing two oxygen atoms or two nitrogen atoms and a sulfur atom as the heteroatom
  • n has a value of 0 or 1
  • a pharmaceutically suitable acid addition salt thereof as the active ingredient
  • a further preferred subgroup of the pharmaceutical compositions of the invention contains an alkylpipe ⁇ dmyl- benzo[d] ⁇ soxazole derivative of the formula la, wherein
  • Z represents a hydrogen atom or a hydroxy group
  • R stands for a hydrogen atom
  • X' and Y' mean, independently, a hydrogen atom or a C ⁇ -4 alkoxy group, or
  • X' forms together with Y a 5- to 6-membered aromatic or partially saturated isocyclic or heterocyclic ring, said latter ring containing two oxygen atoms or a nitrogen atom as the heteroatom, and the isocyclic or heterocyclic ring is optionally fused with a benzene ring, n has a value of 0 or 1 , or a pharmaceutically suitable acid addition salt thereof as the active ingredient
  • compositions of the invention contain an alkylpipendinyl- benzo[d] ⁇ soxazole derivative of the formula la, wherein
  • Z represents a hydrogen atom or a hydroxy group
  • R stands for a hydrogen atom
  • X' and Y' mean, independently, a hydrogen atom or a methoxy group, or X' forms together with Y' a benzene ring or pyrrol ring which latter is fused with a benzene ring, n has a value of 0 or 1 , or a pharmaceutically suitable acid addition salt thereof as the active ingredient
  • the invention refers to a method of treatment in which a patient suffering from especially a disease of the central nervous system is treated with a non-toxic dose of an alkylp ⁇ per ⁇ d ⁇ nylbenzo[d] ⁇ soxazole derivative of the formula I or a pharmaceutically suitable acid addition salt thereof
  • the invention includes the use of an alkylpipe ⁇ dinyl- benzo[d] ⁇ soxazole derivative of the formula I or a pharmaceutically suitable acid addition salt thereof for the preparation of a pharmaceutical composition having psychotropic effect

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Psychiatry (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
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Abstract

L'invention concerne de nouveaux dérivés d'alkylpipéridinylbenzo[d]isoxazole présentant la formule (I). L'invention traite également de compositions pharmaceutiques contenant ces derniers et d'un nouveau procédé de préparation de la substance active. Les composés de la présente invention exercent une action sur le système nerveux central, et présentent essentiellement une activité psychotrope.
PCT/HU2000/000096 1999-09-09 2000-09-07 Derives d'alkypiperidi nylbenzo [d] isoxazole presentant une activite psychotrope, compositions pharmaceutiques contenant ces derniers, et procede de preparation de l'ingredient actif Ceased WO2001017993A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU75471/00A AU7547100A (en) 1999-09-09 2000-09-07 Alkylpiperidi nylbenzo [d] isoxazole derivatives having psychotropic activity, pharmaceutical compositions containing the same, and a process for the preparation of the active ingredient

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
HUP9903042 1999-09-09
HUP9903043 1999-09-09
HU9903042A HUP9903042A2 (hu) 1999-09-09 1999-09-09 Alkil-piperidinil-benzo[d]izoxazol-származékok, ilyen hatóanyagot tartalmazó gyógyászati készítmények, és eljárás a hatóanyag előállítására
HU9903043A HUP9903043A2 (hu) 1999-09-09 1999-09-09 Új benzo[d]izoxazol-származékok, ilyen hatóanyagot tartalmazó gyógyászati készítmények, és eljárás a hatóanyag előállítására

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WO2001017993A1 true WO2001017993A1 (fr) 2001-03-15

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005056540A1 (fr) * 2003-12-08 2005-06-23 Warner-Lambert Company Llc Derives d'indane heterocyclique substitue et composes apparentes pour le traitement de la schizophrenie
WO2008004013A3 (fr) * 2006-07-03 2008-04-03 Egyt Gyogyszervegyeszeti Gyar Médicament pour l'amélioration d'une fonction cognitive et la neuroprotection
CN102161658A (zh) * 2011-03-01 2011-08-24 浙江华海药业股份有限公司 一种n-(萘氧烷基)杂芳基哌啶化合物及其制备方法与应用
JP2011529090A (ja) * 2008-07-28 2011-12-01 江蘇国華投資有限公司 アラルキルピペリジン（又はピペラジン）誘導体及びその統合失調症治療のための使用
CN102718758A (zh) * 2011-03-31 2012-10-10 江苏恒谊药业有限公司 喹啉酮衍生物及其作为抗精神分裂症药物的应用
JP2014144964A (ja) * 2014-03-26 2014-08-14 Jiangsu guohua investment co ltd アラルキルピペリジン（又はピペラジン）誘導体及びその統合失調症治療のための使用
WO2023144764A1 (fr) 2022-01-29 2023-08-03 Suven Life Sciences Limited Composes de benzoisothiazole et de benzoisoxazole pour le traitement de troubles mentaux

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WO1995011680A1 (fr) * 1993-10-28 1995-05-04 Hoechst-Roussel Pharmaceuticals Inc. Heteroarylpiperidines, pyrrolidines et piperazines et leur utilisation comme antipsychotiques et analgesiques
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Title
STRUPCZEWSKI J T ET AL: "3-[[(Aryloxy)alkyl]piperidinyl]-1,2-Benzisoxazoles as D2/5-HT2 Antagonists with Potential Atypical Antipsychotic Activity: Antipsychotic Profile of Iloperidone (HP 873)", JOURNAL OF MEDICINAL CHEMISTRY., vol. 38, no. 7, 1995, AMERICAN CHEMICAL SOCIETY. WASHINGTON., US, pages 1119 - 1131, XP000941571, ISSN: 0022-2623 *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005056540A1 (fr) * 2003-12-08 2005-06-23 Warner-Lambert Company Llc Derives d'indane heterocyclique substitue et composes apparentes pour le traitement de la schizophrenie
JP2007513197A (ja) * 2003-12-08 2007-05-24 ワーナー−ランバート カンパニー リミテッド ライアビリティー カンパニー 統合失調症の治療のための複素環式置換インダン誘導体および関連化合物
WO2008004013A3 (fr) * 2006-07-03 2008-04-03 Egyt Gyogyszervegyeszeti Gyar Médicament pour l'amélioration d'une fonction cognitive et la neuroprotection
US8318743B2 (en) 2006-07-03 2012-11-27 Egis Gyogyszergyar Nyilvanosan Mukodo Reszvenytarsasag Medicament for the enhancement of cognitive function and neuroprotection
CN101516373B (zh) * 2006-07-03 2012-09-12 埃吉斯药物股份公开有限公司 用于增强认知功能和神经保护的药物
EA016142B1 (ru) * 2006-07-03 2012-02-28 Эгиш Дьёдьсердьяр Ньильваношан Мюкёдё Ресвеньтаршашаг ПРИМЕНЕНИЕ 4-ХЛОР-5-{2-[4-(6-ФТОР-1,2-БЕНЗ[d]ИЗОКСАЗОЛ-3-ИЛ)ПИПЕРИДИН-1-ИЛ]ЭТИЛАМИНО}-2-МЕТИЛ-3-(2H) ПИРИДАЗИНОНА ИЛИ ЕГО ФАРМАЦЕВТИЧЕСКИ ПРИЕМЛЕМЫХ СОЛЕЙ ДЛЯ НЕЙРОПРОТЕКЦИИ (ВАРИАНТЫ), ЛЕКАРСТВЕННЫЙ ПРЕПАРАТ (ВАРИАНТЫ) И СПОСОБ ЛЕЧЕНИЯ (ВАРИАНТЫ)
EP2322520A4 (fr) * 2008-07-28 2012-04-25 Jiangsu Guohua Invest Co Ltd Dérivés de pipéridine ou de pipérazine substitués par aralkyle et leurs utilisations pour le traitement de la schizophrénie
JP2011529090A (ja) * 2008-07-28 2011-12-01 江蘇国華投資有限公司 アラルキルピペリジン（又はピペラジン）誘導体及びその統合失調症治療のための使用
KR101457339B1 (ko) 2008-07-28 2014-11-03 지앙쑤 구오후아 인베스트먼트 컴퍼니 리미티드 아랄킬 치환된 피페리딘 또는 피페라진 유도체 및 정신분열증 치료를 위한 이의 용도
CN102161658A (zh) * 2011-03-01 2011-08-24 浙江华海药业股份有限公司 一种n-(萘氧烷基)杂芳基哌啶化合物及其制备方法与应用
CN102718758A (zh) * 2011-03-31 2012-10-10 江苏恒谊药业有限公司 喹啉酮衍生物及其作为抗精神分裂症药物的应用
JP2014144964A (ja) * 2014-03-26 2014-08-14 Jiangsu guohua investment co ltd アラルキルピペリジン（又はピペラジン）誘導体及びその統合失調症治療のための使用
WO2023144764A1 (fr) 2022-01-29 2023-08-03 Suven Life Sciences Limited Composes de benzoisothiazole et de benzoisoxazole pour le traitement de troubles mentaux
US12338236B2 (en) 2022-01-29 2025-06-24 Suven Life Sciences Limited Benzoisothiazole and benzoisoxazole compounds for the treatment of mental disorders

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