WO1997047601A1 - Composes heterocycliques fusionnes et leurs utilisations medicinales - Google Patents

Composes heterocycliques fusionnes et leurs utilisations medicinales Download PDF

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Publication number
WO1997047601A1
WO1997047601A1 PCT/JP1997/001993 JP9701993W WO9747601A1 WO 1997047601 A1 WO1997047601 A1 WO 1997047601A1 JP 9701993 W JP9701993 W JP 9701993W WO 9747601 A1 WO9747601 A1 WO 9747601A1
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Prior art keywords
alkyl
quinazoline
substituent
piperazine
carbon atoms
Prior art date
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PCT/JP1997/001993
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English (en)
Japanese (ja)
Inventor
Takanobu Kuroita
Yoshifumi Togo
Seigo Ishibuchi
Masakazu Fujio
Takashi Futamura
Original Assignee
Yoshitomi Pharmaceutical Industries, Ltd.
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.)
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Application filed by Yoshitomi Pharmaceutical Industries, Ltd. filed Critical Yoshitomi Pharmaceutical Industries, Ltd.
Priority to AU29807/97A priority Critical patent/AU2980797A/en
Priority to JP50143598A priority patent/JP3531169B2/ja
Publication of WO1997047601A1 publication Critical patent/WO1997047601A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07—ORGANIC CHEMISTRY
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C07D215/44—Nitrogen atoms attached in position 4 with aryl radicals attached to said nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
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    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/30—Phthalazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/74—Quinazolines; Hydrogenated quinazolines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/93—Sulfur atoms
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    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
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    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention has a higher affinity for the Eh receptor than for the dopamine D 2 (hereinafter referred to as D 2, a dopamine receptor subtype described below.) 1VL, serotonin one 2 (5-HT 2), a Dorenari Nhi relates to novel heterocyclic compounds condensation with high affinity for «2 receptor.
  • D 2 dopamine D 2
  • 5-HT 2 serotonin one 2
  • Dorenari Nhi relates to novel heterocyclic compounds condensation with high affinity for «2 receptor.
  • the compound of the present invention is used in the medical field as a central nervous agent, particularly as an antipsychotic.
  • Ndoru derivatives having affinity for the receptor is disclosed in International Patent application Publication WO 9 4/2 0 4 5 9 No., the WO 9 4/2 0 4 9 7 No., affinity D 4 receptor is such pyrrolidine derivative conductor disclosed with International Patent application Publication WO 9 4Z2 1 6 1 5 No., the WO 9 4Z2 2 8 3 No. 9, etc. Benzui imidazole derivatives having affinity for D 4 receptor disclosed Have been.
  • International Patent Application Publication Nos. WO940415 and WO94Z24771 disclose pyrazole derivatives and quinoline derivatives each having an affinity for an Eh receptor. ing.
  • Japanese Patent Application Laid-Open No. 6-507716 describes piperidine, piperazine, and 1,2,3,6-tetrahydropyridine having a condensed heterocyclic structure. derivatives are disclosed, serotonin (5- ⁇ 2) have an antagonistic effect O
  • Japanese Patent Application Laid-Open No. 50-37779 discloses a purine derivative having a piperazine structure, which has the effect of releasing histamine and serotonin and inhibiting the action thereof.
  • DE-2139082 discloses a 41- (omega-1 (4-aryl-1-piperazinyl) alkoxy) pyrimidine derivative having an antihypertensive action and an analgesic action.
  • DE-21313983 discloses a 41- (omega-1 (41- (orthomethoxyphenyl) -11-piperazinyl) alkylamino) pyrimidine derivative having an antihypertensive action and an analgesic action.
  • DE- 2 143 780 discloses piperazinyl alkylaminopyridine derivatives having an antihypertensive action and an analgesic action.
  • EP-254,623 discloses a triazolopyridine derivative having an analgesic action.
  • JP-A-7-304474 discloses a tetrahydroquinoxaline derivative having strong affinity for serotonin-11A (5- HT1A ) receptor.
  • dopamine receptors are conventionally classified into two receptor subtypes by pharmacological methods based on their ligand-binding properties and their association with adenylate cyclase [Nature (Nature) Vol. 27, p. 93 (19779)].
  • D a receptor that activates adenylate cyclase via a promoting G protein to produce cyclic AMP, and a receptor type, and inhibits adenylate cyclase via an inhibitory G protein, and Tsu c but is suppresses D 2 receptor type production click AMP
  • Dopami emissions receptors are five different genes are cloned, D, family Lee and Di, D 5 receptors belonging to, D 2 belonging to the D 2 family Lee, D 3, D, is clearly a ivy be classified into receptor [Bok lens Inn 'Famako port radical' Sciences (T rendsi n Pharma col. S ci. :) Vol. 15, p. 264 (1994)].
  • the Haroperi Dole a typical antipsychotic exhibits a high affinity to D 2 receptors than D 4 receptor, the effective clozapine also less negative symptoms extrapyramidal side effects D 2 receptors than D 4 receptor (Nature), Vol. 350, pp. 691 (1991), Trends in Pharmaceuticals' Sciences (T rendsin Pharma col. Sci.), Vol. 15, p. 264 (1994)]. Moreover, effective therapeutic blood seminal plasma concentration D 4 to correlate with the affinity constant of the receptor has also been reported [train's' in 'Pharmacol Logical' Saienshizu (T rendsin P clozapine har ma co 1. S ci ) Vol.15, p.264 (1994)].
  • D 4 receptors in the cerebral cortex frontal lobe which governs the emotional function It is clear that it is most abundant. Therefore, D 4 receptor in schizophrenia etiology, Oh Rui is considered likely involved in the site of action of the therapeutic agent.
  • clozapine ratio Bemusukarin receptor antagonizing D 2 receptor antagonism in the linear body and the cerebellum in rats predominates [Life Saienshizu (L ife S ciences) 5 Volume 8, 5 8 P. 5 (1996)]
  • muscarinic receptor antagonism is also considered to be one of the mechanisms of action of clozapine's atypical antipsychotic effect.
  • extrapyramidal side effects which are one of the side effects caused by the administration of typical antipsychotic drugs, tricholinergic trihexifidine, procyclidine, biperiden, etc. Of Parkinson's drugs have been used.
  • Cerro to typical antipsychotics in clinical phosphatonin one 2 (- HT 2)
  • an antagonist improves the affective disorders, such as negative symptoms and anxiety, appearing during typical antipsychotics alone extrapyramidal et al or the side effects are reduced which have been, 5-HT 2 antagonism that has been known to compensate for the shortcomings of conventional typical antipsychotic.
  • 5-HT 2 antagonist is raised in Haroperi Doll It is known to attenuate catalepsy.
  • the present invention is a muscarinic not only receptors, 5 -HT 2, add Renarin has a high affinity for alpha 2 receptor, negative symptoms as compared with the conventional typical antipsychotics And for positive symptoms Also effective, and to provide a fewer side effects compounds.
  • the novel condensed heterocyclic compound represented by the following general formula (I), its optical isomer or its pharmaceutically acceptable salt is more effective than the D 2 acceptor. not only has a strong blocking action on D 4 receptor, Dopami emissions other than receptor receptor e.g. muscarinic M,, serotonin one 2 (5- HT 2), Adore Nari emissions, alpha 2 receptor to It has been found that they also have high affinity. Therefore, the compound of the present invention exerts its effects not only on the positive symptoms centered on hallucinations and delusions which are characteristic in the acute phase, but also on the negative symptoms such as dullness, inactivity, and autism.
  • the present inventors have found that the present invention can be a useful antipsychotic drug in which side effects such as extrapyramidal symptoms and abnormal endocrine disorders observed when an antipsychotic drug is administered can be reduced, thereby completing the present invention.
  • R 1 and R 2 are the same or different and represent hydrogen, alkyl, hydroxy, amino, arylalkyl, or aryl or heteroaryl which may have a substituent.
  • A is a straight-chain or branched chain having 1 to 4 carbon atoms which can have a substituent R 3 at any position (R 3 represents hydrogen, alkyl, hydroquinine, alkoxy, amino or alkylamino). Shows a chain alkylene.
  • Y represents absent or oxygen atom, a sulfur atom, SO, S0 2 or N IT (R 4 is hydrogen, alkyl, Ariru, Heteroariru. Showing a ⁇ reel alkyl or Ashiru) a.
  • Substituents R 3 a an arbitrary position B (R 3 a is hydrogen, alkyl, human Dorokishi, an alkoxy, shows the Amino or alkylamino.) Straight or having 1 to 4 carbon atoms which may have a Shows a branched alkylene.
  • D represents a linear or branched alkylene chain having 1 to 8 carbon atoms.
  • R represents a group selected from the group of formulas (1), (2), (3), (4), (5), (6), (7), (8), and (9).
  • Q—T represents CH 2 —N, CH 2 CH or CH 2 C.
  • R 7 represents hydrogen or alkyl.
  • R B represents an aromatic hydrocarbon group or a heterocyclic group which may have a substituent.
  • R 9 is a hydrogen atom, an alkyl, human Dorokishi, alkoxy, provided that c a cycloalkyl or optionally ⁇ Li may have a substituent Ichiru or to Teroari Ichiru, having 3 to 8 carbon atoms, in the formula (2)
  • Q—T is CH 2 —N
  • R 9 is a hydrogen atom, alkyl, cycloalkyl having 3 to 8 carbon atoms, or aryl which may have a substituent. Or heterogeneous.
  • R 1 Represents alkyl, cycloalkyl having 3 to 8 carbon atoms, or aryl or heteroaryl which may have a substituent.
  • the bond represented by a dotted line and a solid line indicates a single bond or a double bond.
  • R 12 represents alkyl, cycloalkyl having 3 to 8 carbon atoms, or aryl or heteroaryl which may have a substituent.
  • W represents an oxygen atom, a sulfur atom or N—R ′ 3 (R 13 represents a hydrogen atom, an alkyl, or an aryl or heteroaryl which may have a substituent).
  • R 14 represents a hydrogen atom, alkyl, alkoxy, trifluoromethyl, alkylthio, alkylsulfinyl, alkylamino, hydroxy, halogen, cyano or nitro.
  • Ar represents an aromatic ring or an aromatic heterocyclic ring.
  • R 1 and R 2 are the same or different and represent hydrogen or alkyl.
  • A represents a linear or branched alkylene having 1 to 4 carbon atoms which can have a substituent R 3 (R 3 represents hydrogen or alkyl.) At an arbitrary position.
  • R 3 represents hydrogen or alkyl.
  • Y is absent or represents an oxygen or sulfur atom.
  • ⁇ is (are R 3 a. Represents a hydrogen or alkyl) substituents R 3 a to an arbitrary position denotes a straight or branched alkylene having four 1 carbon atoms which can have.
  • Z represents an oxygen atom, N—R 5 (R 5 represents hydrogen or alkyl.) Or CH 2 .
  • D represents a linear or branched alkylene chain having 1 to 8 carbon atoms.
  • R represents a group selected from the group of formulas (1), (2), (3), (4), (5), (6), (7), (8), and (9).
  • R 7 represents hydrogen or alkyl.
  • R 8 represents an aromatic hydrocarbon group or a heterocyclic group which may have a substituent.
  • R 9 is a hydrogen atom, an alkyl, a hydroquine, an alkoxy, a C 3-8 cyclo C represents alkyl or aryl or heteroaryl which may have a substituent, provided that when Q—T is CH 2 —N in the formula (2), R 9 is a hydrogen atom, alkyl, or carbon number; 3 to 8 cycloalkyl, or aryl or heteroaryl which may have a substituent.
  • R '° represents alkyl, cycloalkyl having 3 to 8 carbon atoms, or aryl or heteroaryl which may have a substituent.
  • the bond represented by a dotted line and a solid line indicates a single bond or a double bond.
  • R 1 ′ represents a hydrogen atom, alkyl, cycloalkyl having 3 to 8 carbon atoms, or aryl or heteroaryl which may have a substituent.
  • R ′ 2 represents alkyl, cycloalkyl having 3 to 8 carbon atoms, or aryl or heteroaryl which may have a substituent.
  • W represents an oxygen atom, a sulfur atom or N—R 13 (R 13 represents a hydrogen atom, an alkyl, or an aryl or heteroaryl which may have a substituent).
  • R represents a hydrogen atom, alkyl, alkoxy, trifluoromethyl, alkylthio, alkylsulfinyl, alkylamino, hydroxy, halogen, cyano or nitro.
  • Ar represents an aromatic ring or an aromatic heterocyclic ring.
  • R 1 and R 2 are the same or different and represent hydrogen or alkyl.
  • A represents a linear alkylene having 1 to 4 carbon atoms which can have a substituent R 3 (R 3 represents hydrogen or alkyl) at any position.
  • Y is absent or represents an oxygen or sulfur atom.
  • R 3 a (are R 3 a. Represents a hydrogen or alkyl) substituents R 3 a at any position a straight chain alkylene having from 4 to several atoms which can have.
  • Z represents an oxygen atom, N—R 5 (R 5 represents hydrogen or alkyl.) Or CH 2 .
  • D represents a linear or branched alkylene chain having 1 to 8 carbon atoms.
  • R represents a group selected from the group of formulas (1), (2), (3), (4), (5), (6), (7), (8), and (9).
  • R 7 represents hydrogen or alkyl.
  • R 8 represents an aromatic hydrocarbon group or a heterocyclic group which may have a substituent.
  • R 9 is a hydrogen atom, an alkyl, human Dorokin, alkoxy, provided that c shows a Teroariru cycloalkyl having 3 to 8 carbon atoms or a substituent to good ⁇ Li Ichiru or have a, in equation (2) Q- When T is CH 2 —N, R 9 represents a hydrogen atom, alkyl, cycloalkyl having 3 to 8 carbon atoms, or aryl or heteroaryl which may have a substituent.
  • R ′ ° represents alkyl, cycloalkyl having 3 to 8 carbon atoms, or optionally substituted aryl or heteroaryl.
  • the bond represented by a dotted line and a solid line indicates a single bond or a double bond.
  • R 11 represents a hydrogen atom, alkyl, cycloalkyl having 3 to 8 carbon atoms, or aryl or heteroaryl which may have a substituent.
  • R 12 represents alkyl, cycloalkyl having 3 to 8 carbon atoms, or optionally substituted aryl or heteroaryl.
  • W represents an oxygen atom, a sulfur atom or N—R 13 (R 13 represents an alkyl or an aryl or heteroaryl which may have a substituent).
  • R 14 represents a hydrogen atom, alkyl, trifluoromethyl, hydroxy, halogen, cyano or nitro.
  • Ar represents an aromatic ring or an aromatic heterocyclic ring.
  • R ′ represents hydrogen or alkyl.
  • A represents a linear alkylene having 1 to 4 carbon atoms.
  • Y is absent or represents an oxygen atom.
  • B represents a linear alkylene having 1 to 4 carbon atoms.
  • Z represents an oxygen atom, N—R 5 (R 5 represents hydrogen or alkyl.) Or CH 2 .
  • D represents a linear or branched alkylene chain having 1 to 8 carbon atoms.
  • R represents a group selected from the group of formulas (1), (2), (3), (4), (5), (6), (7), and (8).
  • R 7 represents hydrogen or alkyl.
  • R 8 represents an aromatic hydrocarbon group or a heterocyclic group which may have a substituent.
  • R 9 represents alkyl, cycloalkyl having 3 to 8 carbon atoms, or optionally substituted aryl or heteroaryl.
  • R 1 U represents aryl or heteroaryl which may have a substituent.
  • the bond represented by a dotted line and a solid line indicates a single bond or a double bond.
  • R u represents an Teroariru alkyl, cycloalkyl of 3 to 8 carbon atoms or good I Ariru may have a substituent group to the properly.
  • R '2 represents a Teroariru also good Ariru or to have a substituent.
  • W represents N—R ′ 3 (R ′′ represents aryl or heteroaryl which may have a substituent.)
  • R 14 represents a hydrogen atom, alkyl, trifluoromethyl, halogen or cyano.
  • the condensed heterocyclic compound according to the above item 2 which is selected from the following compound group, an optical isomer, or a pharmaceutically acceptable salt thereof.
  • ⁇ A pharmaceutical composition comprising the condensed heterocyclic compound or the optical isomer thereof or the pharmaceutically acceptable salt thereof described in the above item 1 and a pharmaceutically acceptable additive.
  • ⁇ A medicament comprising the fused heterocyclic compound according to the above ⁇ , an optical isomer thereof or a pharmaceutically acceptable salt thereof.
  • the medicament according to the above ⁇ 2 ⁇ which is an antipsychotic.
  • the fused heterocyclic compound of the general formula (I) includes the following five embodiments.
  • Alkyl in R 1 and R 2 is a group having 1 to 18 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, heptyl, octyl, decyl, hexadecyl and octadecyl.
  • Represents alkyl Preferred is an alkyl having a prime number of 1 to 4.
  • Arylalkyl means benzyl, 2-phenylethyl, 3-phenylpropyl, 2-methyl-2-phenylethyl, 3-methyl-3-phenylpropyl, 4-chlorobenzyl, 2- (4-chlorophenyl) ethyl, 3- (4 —Chlorophenyl) propyl, 2-methyl-2- (4-chlorophenyl) ethyl, 3-methyl-1- (4-chlorophenyl) propyl, etc.
  • the aryl or heteroaryl which may have a substituent may have one or two substituents such as halogen, methyl, ethyl, trifluoromethyl, methoxy, hydroxy, amino and nitro.
  • substituents such as halogen, methyl, ethyl, trifluoromethyl, methoxy, hydroxy, amino and nitro.
  • a linear or branched chain having 1 to 4 carbon atoms which can have a substituent R 3 at any position in A (R 3 represents hydrogen, alkyl, hydroquinine, alkyne, amino or alkylamino).
  • R 3 represents hydrogen, alkyl, hydroquinine, alkyne, amino or alkylamino).
  • a chain alkylene is of the formula
  • alkyl for R 3 those similar to the alkyls for R 1 and R 2 can be mentioned.
  • Alkoxy means methoxy, ethoxy, propoquine, isopropoxy, butokin, Shows alkoxy with 1 to 8 carbon atoms such as isobutoxy, tertiary butoxy, pentyloxy, hexyloxy, heptyloxy, and octyloxy. Preferred is 44 alkoxy.
  • Alkylamino refers to methylamino, dimethylamino, ethylamino, getylamino, propylamino, dipropylamino and the like.
  • R 3 is preferably hydrogen or alkyl, and particularly preferably hydrogen.
  • N-is alkyl of R 4 in R 4 can be exemplified R], something like the alkyl of R 2.
  • Aryl includes phenyl and naphthyl, and heteroaryl includes chenyl, furyl and pyridyl.
  • arylalkyl examples include those similar to arylalkyl for R 1 and R 2 .
  • acyl examples include formyl, acetyl, propionyl, benzoyl, and benzylcarbonyl.
  • Substituents R 3 a (R 3 a is hydrogen, alkyl, human Dorokin, ⁇ Rukokin shows Amino or alkylamino.) In an arbitrary position in the B linear or having four number 1 carbon which can have As the branched alkylene, the same alkylene as A can be mentioned. Alkyl in R 3 a, Arukokin, alkylamino include the same ones as R 3.
  • N-alkyl R 5 in R 5 are as ⁇ reel alkyl may include those similar to the alkyl, ⁇ reel alkyl R 'R 2.
  • the linear or branched alkylene having 1 to 8 carbon atoms in D is methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, octamethylene, methylmethylene, dimethylmethylene, 1-methylethylene, 2-Methylethylene, 1, 1-Dimethylethylene, 2,2-Dimethylethylene, Ethylmethylene, Jethylmethylene, 1-Ethylethylene, 2-Ethyleethylene, 1-methyltrimethylene, 1, 1-Dimethyltrimethylene, 2- Methyltrimethylene, 2,2-dimethyltrimethylene, 3-methyltrimethylene, 3,3 -Dimethyltrimethylene, 1-ethyltrimethylene, 2-ethylethylmethylene, 31-ethyltrimethylene, etc.
  • each symbol in the groups represented by R in formulas (1) to (9) is as follows.
  • the alkyl for R 7 those similar to R 1 and R 2 can be mentioned.
  • the aromatic hydrocarbon group for R 8 include aromatic hydrocarbons such as phenyl, naphthyl, indenyl, anthracenyl, and fluorenyl (11-fluorenyl, 9-fluorenyl, etc.), and 5, 6, 7, 8—tetrahydro.
  • Draw refers to partially saturated aromatic hydrocarbons such as draw 1-naphthyl, indane-4-yl, and indane-5-yl.
  • 1,2,3,4-tetrahide mouth 1 nophthyl
  • 1,2,3,4-tetrahide mouth 2 nophthyl
  • indane-1 yl
  • indane1-2 yl
  • the moiety may be an aromatic hydrocarbon present on a saturated ring.
  • the heterocyclic group represented by R 8 is a substituent derived from pyridine, furan, thiophene, pyrimidine, imidazole, pyridazine, thiazole, oxazole, isothiazol, isoxazole, etc., and a benzene ring.
  • 1,2-benzoisoxazole, 1,2-benzoisothiazole, indole, 1-benzozofuran, 1-benzothiophene, quinoline, isoquinoline, cinnoline, quinoxaline, quinazoline Derived substituents are shown, and 4, 5, 6, 7—tetrahydro 1,2—benzisoxazole, 4,5,6,7—tetrahydride 1,2—benzisothiazole, 4 , 5,6,7—Tetrahydrid mouth Indol, 4,5,6,7—Tetrahydrid 1 1 Benzofuran, 4,5,6,7—Tetrahydrid mouth 1 — benzothiophene, 5, 6, 7, 8 — tetrahydroquinoline, 5, 6, 7, 8 — tetraquinoline isoquinoline, 5, 6, 7, 8 — tetranoide cinnoline , 5,6,7,8—Tetrahydrid quinazoline, 3,4—Dihidro 2 H—
  • Rings containing nitrogen atoms are saturated such as 2,3,4-tetrahydridoquinoline, 1,2,3,4-tetrahydroisoquinoline, and 2,3-dihydro 1H-indole
  • the binding site may be on the nitrogen atom.
  • substituents include halogens such as fluorine, chlorine and bromine; haloalkyls such as trifluoromethyl; alkyls having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tertiary butyl; C1-C8 alkoxy, hydroxy, nitro, amino, methylamino, dimethylamino, etc., such as ethoxy, ethoxyquin, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, etc. 1 to 3 may be present on an aromatic ring or a saturated ring.
  • halogens such as fluorine, chlorine and bromine
  • haloalkyls such as trifluoromethyl
  • alkyls having 1 to 4 carbon atoms such as methyl
  • Examples of the alkyl for R 9 , R ′, and R 1 R 12 include the same as those for the alkyl for R ′, R 2 .
  • Cycloalkyl having 3 to 8 carbon atoms means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Examples of the aryl or heteroaryl which may have a substituent include those similar to R 1 R 2 .
  • alkyl for R 14 examples include the same as those for R ′ and R 2 .
  • Alkoxy is the same as defined for R 3 .
  • Alkyl in alkylthio, alkylsulfinyl and alkylamino means alkyl having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isoptyl and tertiary butyl.
  • Halogen refers to fluorine, chlorine, bromine, and iodine.
  • aromatic ring or aromatic heterocyclic ring in Ar examples include benzene, naphthalene, thiophene, furan, pyridine and the like.
  • preferred groups are as follows.
  • X 1 —X 2 -X 3 is preferably N—C (R 1 ) —N.
  • R ' as R 2 is hydrogen, alkyl or phenyl are preferred, especially hydrogen is not good.
  • A is preferably a straight-chain alkylene having 1 to 4 carbon atoms, particularly, ethylene, trimethylene, and tetramethylene.
  • Y is not present or is preferably an oxygen atom, and is preferably not present.
  • B is preferably methylene.
  • A—Y—B— one CH 2 CH 2 CH 2 CH 2 — is preferable.
  • Z is preferably an oxygen atom, N—R 5 or CH 2 , particularly preferably N—R 5 or CH 2 .
  • R 5 is preferably hydrogen or alkyl, and particularly preferably hydrogen.
  • D is preferably ethylene or trimethylene.
  • the formulas (1) to (8) are preferable, and (1), (2), (3), (5) and (6) are particularly preferable.
  • R 7 is preferably hydrogen.
  • R 8 is preferably aryl, heteroaryl or condensed heteroaryl which may have a substituent.
  • R 9 and R ′ ° are preferably an aromatic hydrocarbon group or a heterocyclic group which may have a substituent.
  • R ′ R 12 is preferably aryl or heteroaryl which may have a substituent.
  • W is preferably an oxygen atom, a sulfur atom or N—R ′ 3 , particularly preferably N—R ′ 3 .
  • R ' is preferably aryl or heteroaryl which may have a substituent.
  • R is preferably methyl, halogen, cyano or trifluoromethyl.
  • Compounds of general formula (I) and pharmaceutically acceptable salts thereof include inorganic acids (hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.) and organic acids (acetic acid, propionic acid, succinic acid, glycolic acid) , Lactic acid, lingic acid, tartaric acid, citric acid, maleic acid, fumaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, and ascorbic acid).
  • inorganic acids hydroochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.
  • organic acids acetic acid, propionic acid, succinic acid, glycolic acid
  • Lactic acid, lingic acid tartaric acid, citric acid, maleic acid, fumaric acid, methanesulfonic acid, benzenesulfonic acid, p
  • optical isomers There are two types of optical isomers. These optical isomers and their racemates are included in the present invention.
  • a compound of the general formula (14) is obtained.
  • a suitable reducing agent such as borane or aluminum hydride
  • a solvent that does not hinder the reaction of the compound of general formula (14) eg, tetrahydrofuran, getyl ether, diisopropyl ether.
  • the compound of the general formula (15) can be obtained by reacting at a temperature of 8 ° C to the reflux temperature of the solvent for 1 to 24 hours.
  • a solvent such as dimethylformamide, dimethylimidazole, and acetonitrile
  • carbonated sodium, sodium hydroxide By reacting with a base such as potassium tertiary butoxide, triethylamine, pyridine, or dimethylaminoviridine at a temperature of 100 ° C. for 1 to 24 hours, a compound of the general formula (17) is obtained.
  • a base such as potassium tertiary butoxide, triethylamine, pyridine, or dimethylaminoviridine
  • the compound of the general formula (19) and the compound of the general formula (24) are reacted with a solvent (dimethylformamide, dimethylimidazole, acetonitrile, etc.) in a solvent such as potassium carbonate, sodium hydroxide,
  • a solvent such as potassium carbonate, sodium hydroxide
  • the compound of general formula (25) is reacted with a base such as potassium tertiary butoxide, triethylamine, pyridine, dimethylaminopyridine at room temperature at 100 ° C for 1 to 24 hours. obtain.
  • a compound of the general formula (13) in a suitable solvent such as tetrahydrofuran, dichloromethane, dimethylformamide, or any mixed solvent thereof
  • a suitable solvent such as tetrahydrofuran, dichloromethane, dimethylformamide, or any mixed solvent thereof
  • tertiary amines such as triethylamine
  • condensing agents such as 1,3-zinclohexylcarpoimide, 1-ethyl-3- (3-dimethylaminopropyl) carpoimide, and getyl cyanophosphonate, and ice.
  • the reaction is allowed to proceed under cooling or at room temperature for 1 to 24 hours to give a compound of the general formula (31).
  • an appropriate solvent that does not inhibit the progress of the reaction tetrahydrofuran, dichloromethane, chloroform, benzene
  • the reaction proceeds in the presence of a tertiary amine such as triethylamine or pyridine in ice or at room temperature for 1 to 24 hours.
  • An appropriate reducing agent lithium aluminum hydride, borane
  • a suitable solvent such as tetrahydrofuran, getyl ether, toluene, or any mixed solvent thereof
  • a compound of the general formula (33) (wherein E is as defined above) is reacted with a suitable solvent (tetrahydrofuran, getyl ether, benzene, toluene, or By using an appropriate reducing agent (such as borane (BH 3 ) or lithium aluminum hydride) in a mixed solvent thereof, the compound of the general formula (34) can be obtained.
  • the compound of the general formula (34) is dissolved in a solvent free or in a suitable solvent that does not hinder the progress of the reaction (such as chloroform, methylene dichloride, benzenetoluene, tetrahydrofuran or a mixed solvent thereof).
  • the reaction is carried out at 0 ° C to the reflux temperature of the solvent in the presence of a halogenating agent (thionyl chloride, phosphorus oxychloride, phosphorus pentachloride thionyl bromide, phosphorus tribromide, etc.), or the reaction proceeds.
  • a halogenating agent thionyl chloride, phosphorus oxychloride, phosphorus pentachloride thionyl bromide, phosphorus tribromide, etc.
  • Potassium carbonate, sodium carbonate, sodium hydroxide in a suitable non-inhibiting solvent dimethylformamide, 1,3-dimethyl-2-imidazolidinone (DMI), acetonitrile, water or any mixed solvent of these
  • a compound of the general formula (37) can be obtained.
  • a solvent such as dimethylformamide, dimethylimidazole, acetonitrile, etc.
  • carbon dioxide lime hydroxylation
  • the compound of the general formula (38) is reacted with a base such as sodium, potassium tert-butoxide, triethylamine, pyridine, dimethylaminopyridine at room temperature to 100 ° C. for 1 to 24 hours.
  • a base such as sodium, potassium tert-butoxide, triethylamine, pyridine, dimethylaminopyridine at room temperature to 100 ° C. for 1 to 24 hours.
  • the compound of the general formula (39) is reacted with hydrogen peroxide in glacial acetic acid, or in a solvent such as methylene dichloride or chloroform which does not hinder the progress of the reaction.
  • a solvent such as methylene dichloride or chloroform which does not hinder the progress of the reaction.
  • the compound of the general formula (40) is obtained.
  • the compound of the general formula (44) can be obtained by reducing the compound of the formula (43) with triethylsilane in trifluoroacetic acid.
  • An acid hydroochloric acid, sulfuric acid, etc.
  • an alkali sodium hydroxide, potassium hydroxide, sodium carbonate
  • a suitable solvent such as ethanol, methanol, water, or a mixture thereof
  • Potassium carbonate, etc. is dissolved in a suitable solvent.
  • the compound of the general formula (13) is treated with a compound of the general formula (45) in a suitable solvent (such as tetrahydrofuran, methylene dichloride, dimethylformamide, or any mixed solvent thereof) which does not inhibit the progress of the reaction.
  • a suitable solvent such as tetrahydrofuran, methylene dichloride, dimethylformamide, or any mixed solvent thereof
  • 1,3-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide getyl cyanophosphonate, etc. in the presence of a compound of formula
  • the compound of the formula (46) is obtained by reacting the agent with the agent under ice cooling or at room temperature for 1 to 24 hours.
  • a reactive derivative of the compound of the general formula (45) (acid chloride, acylimigazole, etc.)
  • a suitable solvent tetrahydrofuran, methylene dichloride, chloroform, benzene, Or an arbitrary mixed solvent thereof
  • a tertiary amine such as triethylamine or pyridin under ice-cooling or room temperature for 1 to 24 hours.
  • a suitable solvent such as tetrahydrofuran, getyl ether, toluene, or any mixed solvent thereof
  • a suitable reducing agent lithium aluminum hydride, Borane, etc.
  • the compound of the general formula (45) can also be obtained by the following method.
  • Diisobutylaluminum hydride, etc. in a suitable solvent such as tetrahydrofuran, methylene dichloride, chloroform, benzene, or any mixture thereof
  • a suitable solvent such as tetrahydrofuran, methylene dichloride, chloroform, benzene, or any mixture thereof
  • the reaction is carried out at 178 to room temperature for 1 to 24 hours using the reducing agent of formula (1) to obtain a compound of the general formula (48).
  • Malonic acid and a suitable base sodium hydride, potassium tertiary butoxide, sodium methoxide
  • a suitable solvent such as dimethylsulfoxide, dimethylformamide, benzene or any mixed solvent thereof
  • the compound of the general formula (48) can be obtained by reacting the compound of the general formula (48) with cooling or heating in the presence of toxide, sodium hydroxide, etc.).
  • the compound of the general formula (49) is reacted with a catalyst (palladium) in a suitable solvent (eg, ethyl acetate, acetic acid, methanol, ethanol, or any mixed solvent thereof) which does not inhibit the progress of the reaction.
  • a catalyst palladium
  • the compound of the general formula (45) is reduced by reducing with a reducing agent such as hydrogen or ammonium formate under normal pressure or pressure, at room temperature or under heating, in the presence of carbon, Raney nickel, platinum oxide, etc.). can get.
  • a reducing agent such as hydrogen or ammonium formate under normal pressure or pressure, at room temperature or under heating, in the presence of carbon, Raney nickel, platinum oxide, etc.
  • the compound of the general formula (47) can also be obtained by the following method.
  • a base lithium diisopropylamide, butyllithium, phenyllithium
  • a suitable solvent such as tetrahydrofuran, ether, liquid ammonia, or any mixed solvent thereof
  • the compound of the general formula (51) is obtained by adding an acid treatment and deprotecting.
  • the compound of the general formula (51) is reacted with a catalyst (palladium-carbon, lanthanum) in a suitable solvent (such as trifluoroacetic acid, ethyl acetate, acetic acid, methanol, ethanol or any mixed solvent thereof) which does not hinder the progress of the reaction. —Nitrogen, platinum oxide, etc.), under atmospheric pressure or under pressure, at room temperature or under heating, with a reducing agent such as hydrogen or ammonium formate to obtain a compound of the general formula (52).
  • a catalyst palladium-carbon, lanthanum
  • a suitable solvent such as trifluoroacetic acid, ethyl acetate, acetic acid, methanol, ethanol or any mixed solvent thereof
  • the compound of the general formula (52) is dissolved in a suitable solvent (eg, chloroform, methylene dichloride, benzenetoluene, tetrahydrofuran or any mixture thereof) in the absence of a solvent or a solvent which does not inhibit the progress of the reaction.
  • a suitable solvent eg, chloroform, methylene dichloride, benzenetoluene, tetrahydrofuran or any mixture thereof
  • Potassium carbonate, sodium carbonate, sodium hydroxide, and the like are prepared by adding a compound of the general formula (53) to a suitable solvent (such as dimethylformamide, DMI, acetonitrile, water or any mixture thereof) which does not inhibit the progress of the reaction.
  • a suitable solvent such as dimethylformamide, DMI, acetonitrile, water or any mixture thereof
  • a base such as triethylamine, pyridin, or dimethylaminopyridine
  • the compound of the general formula (13) is reacted at a temperature of 100 ° C. for 1 to 24 hours from room temperature to obtain a compound of the general formula (47).
  • a compound can be obtained.
  • a solvent methanol, ethanol, propyl alcohol, acetic acid
  • the compound of general formula (55) is obtained by hydrogenation in an arbitrary mixed solvent of the above.
  • the compound of the general formula (55) may be mixed with a solvent (methylene chloride, chloroform, benzene, toluene, etc.) which does not hinder the reaction and a supersaturated aqueous solution of sodium bicarbonate or an aqueous solution of carbon dioxide with an appropriate concentration.
  • the compound of the formula (56) is obtained.
  • the reaction between the compound of the general formula (56) and the compound of the general formula (13) in a solvent that does not hinder the reaction is carried out in the presence of potassium carbonate, sodium hydroxide, potassium hydroxide.
  • a base such as tertiary butoxide, triethylamine, pyridine, or dimethylaminopyridine at room temperature.
  • the compound of the general formula (59) is treated with a base (lithium diisopropylamide, butyllithium) in a suitable solvent (eg, tetrahydrofuran, ether, liquid ammonia, or any mixed solvent thereof) which does not hinder the progress of the reaction.
  • a suitable solvent eg, tetrahydrofuran, ether, liquid ammonia, or any mixed solvent thereof
  • 2-bromoethanol protected with an appropriate protecting group tetrahydropyran, methoxymethyl, trimethylnyl group, etc.
  • the compound is further deprotected with an acid or the like to obtain a compound of the general formula (60).
  • a compound of the general formula (60) is converted into a suitable solvent (trifluoroacetic acid, ethyl acetate, vinegar) which does not inhibit the progress of the reaction.
  • the compound of the general formula (61) is halogenated in a solvent free or in a suitable solvent that does not hinder the progress of the reaction (such as chloroform, methylene dichloride, benzenetoluene, tetrahydrofuran or a mixed solvent of any of these).
  • a suitable solvent such as chloroform, methylene dichloride, benzenetoluene, tetrahydrofuran or a mixed solvent of any of these.
  • thionyl chloride phosphorous oxychloride, phosphorous pentachloride, phosphorous tribromide, phosphorous tribromide, etc.
  • the compound of the general formula (62) is dissolved in a suitable solvent (such as dimethylformamide, DMI, acetonitrile, water or a mixed solvent of these) in a suitable solvent that does not inhibit the progress of the reaction.
  • a suitable solvent such as dimethylformamide, DMI, acetonitrile, water or a mixed solvent of these
  • a base such as sodium, triethylamine, pyridin, dimethylaminopyridine, or the like
  • the compound of the general formula (13) is reacted at room temperature for 1 to 24 hours at 100 ° C for 1 to 24 hours.
  • the compound of 3) can be obtained.
  • a compound of the general formula (64) is obtained.
  • a two-phase solvent such as a solvent that does not hinder the reaction of the compound of general formula (64) (methylene chloride, chloroform, benzene, toluene, etc.) and a supersaturated aqueous solution of sodium bicarbonate or an aqueous solution of potassium carbonate at an appropriate concentration.
  • a base such as triethylamine, pyridine or dimethylaminopyridine in a medium or a solvent that does not interfere with the above reaction
  • a base such as carbon dioxide, sodium hydroxide, potassium tertiary butoxide, triethylamine, pyridine, dimethylaminopyridine at room temperature to 100 ° C for 1 to 24 hours.
  • a compound of the formula (66) is obtained: a solvent that does not interfere with the reaction of the compound of the formula (66) (eg, tetrahydrofuran, getyl ether, diisopropyl ether).
  • the compound of the general formula (67) can be obtained by reacting with a suitable reducing agent (borane, lithium aluminum hydride, etc.) at ⁇ 78 ° C. for 1 to 24 hours at the reflux temperature of the solvent.
  • a base potassium carbonate acid, Toriwechiruamin, the presence or absence of pyridine, etc.
  • a base potassium carbonate acid, Toriwechiruamin, the presence or absence of pyridine, etc.
  • a base potassium carbonate acid, Toriwechiruamin, the presence or absence of pyridine, etc.
  • a base potassium carbonate acid, Toriwechiruamin, the presence or absence of pyridine, etc.
  • c formula compound is obtained in the (6-9)
  • the compound is used without solvent or in a suitable solvent that does not hinder the progress of the reaction (such as benzene, toluene, xylene, chloroform, methylene dichloride, or any mixture of these), phosphorus oxychloride, thionyl chloride, pentachloride
  • the compound of the general formula (70) is obtained by reacting phosphorus or the like at room temperature or under heating.
  • the compound of the general formula (71) is obtained. can get.
  • the compound of the general formula (71) is reacted in a suitable solvent (such as trifluoroacetic acid, ethyl acetate, acetic acid, methanol, ethanol or a mixed solvent thereof) in a suitable solvent that does not inhibit the progress of the reaction.
  • a suitable solvent such as trifluoroacetic acid, ethyl acetate, acetic acid, methanol, ethanol or a mixed solvent thereof
  • a suitable solvent such as trifluoroacetic acid, ethyl acetate, acetic acid, methanol, ethanol or a mixed solvent thereof
  • Reduction with a reducing agent such as hydrogen or ammonium formate under normal pressure or pressure, at room temperature or under heating, in the presence of nickel, platinum oxide, etc.
  • a mixture of the compound of the general formula (13) and an aqueous formaldehyde solution or a paraformaldehyde solution is heated and stirred in a solvent such as acetic acid that does not hinder the progress of the reaction, and then the compound of the general formula (72) is added. By reacting, a compound of the general formula (73) is obtained.
  • a reducing agent sodium borohydride, lithium aluminum hydride, diisopropyl aluminum
  • a suitable solvent such as methanol, ethanol or any mixed solvent thereof
  • the resulting product is a racemic form, it is separated into the desired optically active form, for example, by fractional recrystallization of a salt with an optically active acid or by passing through a column filled with an optically active carrier.
  • a column filled with an optically active carrier can be.
  • Individual diastereomers can be separated by such means as fractional crystallization, chromatography and the like. These can also be obtained by using optically active starting compounds and the like.
  • Stereoisomers can be isolated by a recrystallization method, a column chromatography method, or the like.
  • the compounds of the present invention are effective not only for positive symptoms such as hallucinations and delusions characteristic of the acute phase of schizophrenia, but also for negative symptoms such as insensitivity, inactivity, and autism.
  • useful as antipsychotic conventional antipsychotics side effects such as extrapyramidal symptoms and endocrine abnormalities seen when administered with only D 2 receptor antagonism has been reduced.
  • the compound of the present invention can be used as a therapeutic drug for diseases such as schizophrenia.
  • the compound of the present invention can be a pharmaceutically acceptable carrier (excipient, binder, disintegrant, flavoring agent)
  • a pharmaceutically acceptable carrier excipient, binder, disintegrant, flavoring agent
  • Pharmaceutical compositions or preparations tablettes, pills, capsules, granules, powders, syrups, emulsions, elixirs, suspensions, etc. obtained by mixing with water, flavoring agents, emulsifiers, diluents, solubilizing agents, etc. Suspensions, solutions, injections, infusions or suppositories) can be administered orally or parenterally.
  • the pharmaceutical composition can be formulated according to a usual method.
  • parenteral refers to subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, or infusion. And so on.
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be prepared according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as an aqueous solution.
  • acceptable vehicles or solvents that can be used include water, Ringer's solution, and isotonic saline solution.
  • sterile, fixed oils may be conventionally employed as a solvent or suspending medium.
  • any bland fixed oil or fatty acid can be used; natural L, synthetic ⁇ , semi-synthetic fatty oil or fatty acid, and natural or synthetic or semi-synthetic mono-, di- or triglyceride. And the like.
  • Suppositories for rectal administration are solid at room temperature, including the drug and suitable nonirritating excipients, for example, cocoa butter and polyethylene glycols, but liquid at intestinal temperature and Solid dosage forms for oral administration that can be produced by mixing with those that melt and release the drug include those mentioned above such as powders, granules, tablets, pills, capsules and the like.
  • the active ingredient compound may comprise at least one excipient such as sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starches, agar, alginate, chitin, chitosan, It can be mixed with pectins, tragacanth gums, gum arabic, gelatins, collagens, caseins, albumins, synthetic or semi-synthetic polymers or glycerides.
  • Such dosage forms may also contain, as usual, further additives, such as inert diluents, lubricants such as magnesium stearate, storage of parabens, sorbins and the like.
  • Tablets and pills can also be prepared with enteric coating.
  • Liquid preparations for oral administration include pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, and solutions, which are commonly used in the art. It may contain an inert diluent, for example, water.
  • Dosage will depend on age, weight, general health, gender, diet, time of administration, mode of administration, rate of excretion, drug combination, the extent of the condition being treated by the patient at the time, and other factors. Determined in consideration of factors.
  • the compound of the present invention, its optical isomer or its pharmaceutically acceptable salt can be used safely with low toxicity, and its daily dose depends on the condition and weight of the patient, the type of compound, and the route of administration.
  • N-Acetyl-l-l-l-l-l-l-A-l-l-h-heptane-3- l-one is used as the starting material and reacted in the same manner as in Synthesis example 1 of the starting material to give 8-H-acetyl-l-l-amino-l 6,7,8,9-tetrahedro 5H-azepino [3, 4 — d] Pyrimidine is obtained. Further, by reacting in the same manner as in Synthesis Example 2 of the starting material, 8-acetyl-4-hydroxy-1,6-, 7,8,9-tetrahydr-5H-azepino [3,4-1d] pyrimidine is obtained.
  • Example 4 4-amino-6,7-dihydro-5H-cyclopentapyrimidine is reacted as in Example 4 to give N- (6,7-dihydro-5H-cyclopentapyrimidine. Gin-1-4-) 1-2-Chloroacetamide is obtained.
  • N- (5,6,7,8-tetrahydrin quinazoline-141-yl) 1-2-chloroacetamide 3.4 g and N- (4-cyclo-phenyl) piperazine hydrochloride 3.5 g of the salt was dissolved in 30 ml of dimethylformamide, 4 g of potassium carbonate and 1 g of potassium iodide were added, and the mixture was stirred at room temperature for 24 hours. After evaporating the solvent under reduced pressure, water was added to the residue and extracted with chloroform. The extract was dried over magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure.
  • the reaction was carried out in the same manner as in Example 1, and N— (5, 6, 7, 8-tetraquinoline quinazoline-141-yl) -1-2- (4-(2-chlorophenyl) piperazine-1 1 yl) 1.2 g of acetoamide was obtained.
  • the compound was further reacted in the same manner as in Example 1 to obtain a compound of the formula (4— (4— (2-chlorophenyl) pyrazine-111-ethyl) ethyl) amino.
  • 0.6 g of, 7,8-tetrahide quinazoline was obtained. Melting point 1 1 4 1 1 1 6 ° C
  • N- (5,6,7,8-tetrahide quinazoline-141-yl) -1-chloroacetamide and N- (4-promophenyl) piperazine were prepared in the same manner as in Example 1. Reaction to obtain N- (5,6,7,8-tetrahydridoquinazoline-4-yl) —2— (4— (4-promophenyl) pirazin-1 1-yl) acetoamide . Further, this compound was reacted in the same manner as in Example 1 to give 4-((2- (4- (4-bromophenyl) piperazine-11-yl) ethyl) ami-5,6,7, Get 8-quinoline quinazoline.
  • the compound was further reacted in the same manner as in Example 1 to give 4-((4- (4- (4-chloro-1--2-methylphenyl) piperazine-11-yl) ethyl) amino, 15, 6,7,8—To obtain tetrahydroquinazoline.
  • Example 1 ⁇ - (5,6,7,8-tetraquinoline quinazoline-14-yl) -12-chloroacetamide and ⁇ - (4-trifluoromethylphenyl) piperazine as in Example 1 ⁇ ⁇ — (5,6,7,8-tetraquinoline quinazoline — 4 —yl) 1 2— (4 — (4—trifluoromethylphenyl) piperazine 1 1 Get the acetate amide. The compound was further reacted in the same manner as in Example 1. To give 4-((2- (4- (4-trifluoromethylphenyl) piperazine-1 1-yl) ethyl) amino) -5,6,7,8-tetrahydroquinazoline .
  • This compound was further reacted in the same manner as in Example 1 to give 4-((2- (4- (2-bromophenyl) piperazine-111-ethyl) ethyl) amino-5,6- , 7,8—Tetrahydrid quinazoline is obtained.
  • This compound was reacted in the same manner as in Example 1 to give 4-((2- (4- (3-promophenyl) pirazin-1-yl) ethyl) amino) —5, 6, 7 , 8-Tetrahydrid quinazoline is obtained.
  • the reaction was carried out in the same manner as in Example 1, and N— (5, 6, 7, 8 _ tetrahydrid quinazoline- 1-4-yl) 1-2-(4-(1-naphthyl) piperazine-1-yl ) 1.2 g of acetoamide were obtained.
  • N- (5,6,7,8-tetrahidoquinazoline-14-yl) -12-chloroacetamide and N- (3-fluorophenyl) piperazine were treated in the same manner as in Example 1.
  • the reaction is performed to obtain N- (5, 6, 7, 8-tetraquinoline quinazoline-4-yl)-2- (4- (3-fluorophenyl) piperazine-11-yl) acetamide.
  • the compound was further reacted in the same manner as in Example 1 to give 4-((2- (4- (3-fluorophenyl) piperazine-111-ethyl) ethyl) amino) -1,5,6 7,8—Tetrahydrid quinazoline is obtained.
  • the reaction was carried out in the same manner as in Example 1, and N- (5, 6, 7, 8-tetrahydroquinazoline-14-yl) -12- (4- (4-fluorophenyl) piperazine-11- Le) Acetamide 2.0 g was obtained. Further, 1.7 g of this compound was reacted in the same manner as in Example 1 to give 4-((2- (4- (4-fluorophenyl) piperazine-11-yl) ethyl) amino. , 6,7,8-tetragram hydroquinazoline 1.5 g was obtained. Melting point 1 1 4 1 1 1 5 ° C
  • N- (5,6,7,8-tetrahydroquinazoline-14-yl) -12-chloroacetamide and N- (2-fluorophenyl) piperazine in the same manner as in Example 1. And react with N- (5, 6, 7, 8-tetraquinoline quinazoline-141-yl) -2-(4- (2-fluorophenyl) piperazine-1-yl) ase Obtain toamide. Further, the compound was reacted in the same manner as in Example 1 to give 4-((2- (4- (2-fluorophenyl) piperazine-11-yl) ethyl) amino) -1,5,6,7 , 8—Tetrahydrid quinazoline is obtained.
  • N- (5, 6, 7, 8-tetraquinoline quinazoline-141-yl) -1-chloroacetamide and N- (3-methylphenyl) piperazine were treated in the same manner as in Example 1.
  • N- (5, 6, 7, 8-tetraquinoline quinazoline-141-yl) -1-2- (4- (3-methylphenyl) -piperazine-1-1-yl) acetoamide Obtain.
  • This compound was reacted in the same manner as in Example 1 to give 4-((2- (4-(3-methylphenyl) piperazine-11-yl) ethyl) amino) —5, 6, 7, 8 —Obtain quinazoline with tetrahide mouth.
  • N- (5, 6, 7, 8-tetraquinoline quinazoline-14-yl) -12-chloroacetamide was reacted with N- (2-methylphenyl) piperazine in the same manner as in Example 1.
  • N- (5, 6, 7, 8-tetraquinoline quinazoline-141-yl)-2- (4- (2-methylphenyl) piperazine-111-yl) acetoamide is obtained.
  • this compound was reacted in the same manner as in Example 1 to give 4-((2- (4- (2-methylphenyl) piperazine-11-yl) ethyl) amino).
  • 6, 7, 8-tetraquinone quinazoline is obtained.
  • the reaction is carried out using N- (5,6,7,8-tetraquinone quinazoline-1-yl) 1-2- (4-1 (2,3-dichlorophenyl) pirazazine-1-yl) Get the acetate amide.
  • N- (5,6,7,8-tetrahydrin quinazoline-14-yl) -12-chloroacetamide is reacted with 4_ (4-chlorophenyl) piperidine in the same manner as in Example 1.
  • This compound was further reacted in the same manner as in Example 1 to give 4-((2- (4- (4-chlorophenyl) piperidine-11-yl) ethyl) amino) -1,5,6,7 , 8-tetrahide quinazoline is obtained.
  • Example 24 The same procedure as in Example 24 was carried out using 2-chloro-1,2-methyl-5,6,7,8-tetrahydrido quinazoline and 2- (4- (4-chlorophenyl) piperidine-1 1-yl) ethylamine. By reacting by operation, 4 — ((2-(4-1 (4-phenyl) piperidine 1 1-yl) ethyl) amino) 1-2-methyl 1, 5,6,7,8-tetrahydro Obtain quinazoline.
  • 4 _ ((2— (4— (4-chlorophenyl) -1,3,6-dihydro-1 2H—pyridine-1 1 1) 2-methyl-5,6,7,8-tetrahydridoquinazoline is obtained.
  • the salt was reacted with N- (6,7,8,9-tetrahyd 5D-Hydroxyheptyl pyrimidine-14-yl) 1-2- (4- (4-chlorophenyl) piperazine-11-yl) acetoamide is obtained.
  • the salt was reacted with the salt in the same manner as in Example 1 to give N— (5,6,8,9-tetrahydroxoxepino [4,5—d] pyrimidine-14-yl) 12 — (4-(4-Chlorophenyl) piperazine) to obtain acetoamide.
  • N- (5,6,7,8-tetrahydridoisoquinolin-1-yl) -12-chloroacetamide and N- (4-chlorophenyl) piperazine hydrochloride were reacted in the same manner as in Example 1.
  • N- (5,6,7,8-tetrahide mouth isoquinoline-41-yl) -1-2- (4- (4-chlorophenyl) piperazine-11-yl) acetamide is obtained.
  • this compound was reacted in the same manner as in Example 1 to give 4-((2- (4- (4-chlorophenyl) piperazine-1 1-yl) ethyl) amino) -1,5,6 , 7,8-tetraquinone isoquinoline is obtained.
  • N- (5,6,7,8-tetrahydroquinoline-141-yl) -1-2-chloroacetoamide is reacted with N- (4-chlorophenyl) piperazine hydrochloride in the same manner as in Example 1.
  • N- (5, 6, 7, 8-tetraquinoline quinoline-41-yl) -2- (4- (4-chlorophenyl) piperazine-11-yl) acetoamide was reacted in the same manner as in Example 1 to give 4-((2- (4-(4-chlorophenyl) piperazine-11-yl) ethyl) amino) -5, 6, 7 , 8-tetraquinone quinoline.
  • N- (6,7-dihydro-5H-cyclopentapyrimidine-14-yl) -12-chloroacetamide and N- (4-chlorophenyl) pidazine hydrochloride were prepared in the same manner as in Example 1.
  • this compound was reacted in the same manner as in Example 1 to give 4- (4- (4- (4-chlorophenyl) piperazine-11-yl) ethyl) amino.
  • 7-Dihydro-5H-cyclopentapyrimidine 7-Dihydro-5H-cyclopentapyrimidine.
  • 5 g was reacted in the same manner as in Example 1 to give N— (5,6,7,8-tetrahydridoquinazoline-14-yl) -1-2- (4-(2,5-dichlorophenyl) ) Piperazine — 1 yl) Acetamide 1.4 g was obtained.
  • the reaction was carried out in the same manner as in 1, and N— (5, 6, 7, 8—tetrahydroquinazolin-1-yl) 1—2— (4— (4-chlorophenyl) 1-3—methylpidazine 1 1— 1.3 g of acetoamide was obtained.
  • the reaction was carried out in the same manner as in Example 1 and N- (5, 6, 7, 8-tetraquinoline quinazoline-4-yl) -12- (4-(2-naphthyl) piperazine-11-yl) acetamide 1.1 g were obtained.
  • the reaction was carried out in the same manner as in Example 1, and N- (5, 6, 7, 8-tetrahydrido-12-methylquinazoline-14-yl) -12- (4-diphenylmethylbiperazine-1 —Yl) 1.3 g of acetoamide were obtained.
  • Example 8 2—0.6 g of 1- (5,6,7,8-tetrahidoquinazoline-1-yl) propionic acid and 0.6 g of 1— (4-chlorophenyl) pidazine
  • the reaction was carried out in the same manner as described above, and 4- (3- (4- (4-chlorophenyl) piperazine-11-yl) propyl) -1,5,6,7,8-tetrahydridoquinazoline 0.3 got g ( 'H-NMR (CF 3 COOH) (5: l.
  • Example 8 The reaction was carried out in the same manner as in Example 2 to obtain 4- (3- (4- (3-trifluoromethylphenyl) piperazine-11-yl) propyl) -1,5,6,7,8- 0.3 g of quinazoline with tetrahide mouth was obtained.
  • 4- (3-chloropropyl) 1-5,6,7,8-Tetrahydrid quinazoline and 4-benzoylbiperidine are dissolved in dimethylformamide, and potassium carbonate and methyl iodide are added. React at 0 ° C. After the reaction is completed, the solvent is distilled off under reduced pressure, water is added to the residue, and the mixture is extracted with chloroform. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography to give 4- (3- (4-benzylbiperidine-1 1-yl) propyl) 1,5,6,7 , 8-tetrahydroquinazoline is obtained.
  • Examples of 3- (5,6,7,8-tetrahedral quinazoline-14-yl) propionic acid and 1- (1,2,3,4-tetrahedroid_1-naphthyl) pidazine 8 Perform the reaction in the same manner as 2 to obtain 4- (3- (4- (1,2,3,4-tetrahydro-1--1-naphthyl) piperazine-11-yl) propyl) -1,5,6,7 , 8—Tetrahai Droquinazoline was obtained.
  • the reaction mixture contains 4 1 (1-hydroxy 3-(4-(5, 6, 7, 8-tetrahydro 1-naphthyl) piperazine 1-1-yl) propyl) 1-5, 6, 7, 8 — Add cinnoline at the tetrahide port and heat to reflux. After completion of the reaction, add aqueous sodium thiosulfate and aqueous potassium carbonate, and extract with ethyl acetate.
  • Example 13 3 Using 1- (diphenylmethyl) piperazine hydrochloride and 4-acetyl-5,6,7,8-tetrahydrin cinnoline, the procedure of Example 13 3 was repeated to give 4— (3— (4— (diphenylmethyl). ) 1-Pyrazine-1 -yl) propionyl) 1, 5,6,7,8-tetrahydrocynnoline. Using this compound, in the same manner as in Example 13 33, 4- (1-hydroquinine-3- (4- (diphenylmethyl) piperazine-11-yl) propyl) -1,5,6,7,8 —Obtain tetrahide mouth cinnoline.
  • Example 13 3 Using this compound, the same procedure as in Example 13 3 was carried out to obtain 4- (3- (4- (diphenylmethyl) piperazine-111-yl) propyl) -1,5,6,7,8-tetrahydroxide. Obtain nonlin.
  • Example 12-23 The same procedure as in Example 12-23 using 4- (3-chloropropyl) -1,5,6,7,8-tetrahydridoquinoline and 1- (fluorene-19-yl) piperazine 4-(3-(4-(fluorene-1-1 yl) piperazine-1-1 -yl) propyl)-1, 5, 6, 7, 8-Tetrahydride quinoline was obtained. Melting point 1 5 1 — 15 3 ° C Example 1 3 6
  • Example 1 The same operation as in Example 12-23 using 4- (3-chloropropyl)-1,5,6,7,8-tetrahydridoquinoline and 1- (2,3-dimethylphenyl) piperazine This gives 4- (3- (4-(2,3-dimethylphenyl) pidazine-1 1-yl) -pyrazine) -1,5,6,7,8-tetrahide quinoline.
  • Example 1 3 8
  • Example 1 Using the same procedure as in Example 123, using 4- (dichloromethylene) piperidine and 4- (diphenylmethylene) piperidine. 1- (3- (4- (diphenylmethylene) piperidine-1 1-yl) propyl) 1 56,7,8-tetraquinone quinoline is obtained. Example 1 4 0
  • Example 4 4- (3-chloropropyl) 1,5,6,7,8-tetrahydroquinoline and 4- (1,2,3,4-tetraquinoquinone 1-yl) pi Using lysine and the same procedure as in Example 1 23, use the same procedure as in Example 4 (3- (4- (1,2,3,4-tetrahydroquinoline-1-yl) piperidine-11-yl) Propyl) 1,5,6,7,8-tetrahydroquinoline was obtained. Melting point 1 3 8— 1 40 ° C
  • the quinoline with tetrahide mouth was obtained.
  • Example 1 23 using 4 _ (3-chloro mouth propyl) 1, 5,6,7,8 -tetrahide quinoline and 1,2,3,4 -tetrahide mouth 1 -methyl-carboline In the same manner as above, obtain 4- (3- (1,2,3,4-tetrahydro-5-methyl- ⁇ -carboline-12-yl) propyl) -1,5,6,7,8-tetrahydroquinoline .
  • Example 1 Same as in Example 12 1 using 1,5-, 7,8-tetraquinone isoquinoline and 1,2,3,4-tetrahydr-5-methyl-carboline By the above operation, 1- (3— (1,2,3,4-tetrahydric port—5-methylmethylcarboline-12-yl) propyl) -1,5,6,7,8—tetrahydroisoquinoline is obtained.
  • Example 12 using 4 — (3 — chloropropyl)-1, 5, 6, 7, 8-tetrahydroquinoline and 1, 2, 3, 4-tetrahydric 9-methyl-S-carboline
  • 4- (3— (1,2,3,4—tetrahide mouth—9—methyl-1- ⁇ carboline—1-2—yl) propyl) —1,5,6,7,8—tetrahydroxyquino Get phosphorus.
  • Examples 1 2 1 and 1 _ (3-chloro mouth propyl) _ 5,6,7,8-tetraquinone isoquinoline and 1,2,3,4-tetrahide mouth 9-methyl-carboline
  • 1— (3— (1,2,3,4-tetrahedral port—9—methyl_; 9-carboline-12-yl) propyl) —1,5,6,7,8—tetrahydroisoquinoline Get.
  • Example 8 3-(5,6,7,8-tetrahide mouth quinazoline- 14-yl) propionic acid and 1,2,3,4-tetrahedro 9-f 12-loop / 5-carboline 4— (3— (1,2,3,4—tetrahide mouth 1—1—Fe—2—; S—carboline—2—yl) propyl) 1,5,6,7,8 —Get Tetra Hydroquinazoline.
  • Example 1 2 3 using 4 — (3-chloropropyl) 1, 5,6,7,8-tetrahidoquinoline and 1,2,3,4-tetrahydro 9-monophenyl) S-carboline In the same manner as above, use 4- (1,3- (1,2,3,4-tetrahedral—9-phenyl-2-S / S-carboline-12-yl) propyl) -5,6,7,8-tetrahyd Get Droquinoline.
  • Example 1 6 2 3 using 4 — (3-chloropropyl) 1, 5,6,7,8-tetrahidoquinoline and 1,2,3,4-tetrahydro 9-monophenyl) S-carboline In the same manner as above, use 4- (1,3- (1,2,3,4-tetrahedral—9-phenyl-2-S / S-carboline-12-yl) propyl) -5,6,7,8-tetrahyd Get Droquinoline.
  • Example 1 The same operation as in Example 122 using 1- (3-chloropropyl)-1,5,6,7,8-tetrahydridoisoquinoline and 4-((1-phenyl) ethylidene) piperidine This gives 1- (3- (4-((1-phenyl) ethylidene) piperidine-1_yl) propyl) -5,6,7,8-tetraquinone isoquinoline.
  • Example 1 (3-chloropropyl) 1-5,6,7,8-tetraquinone isoquinoline and 1— (1,2,3,4—tetrahydroquinone 1-naphthyl) piperazine Using the same procedure as in Example 12 1, use the same procedure as in Example 1 2 1 (3— (4 _ (1,2,3,4-tetrahydro 1-naphthyl) piperazine-1 1-yl) propyl) 1 5, 6, 7, 8 — Get tetrahydroisoquinoline.
  • Example 1 The compound of Example 1 (1.0 mg) and sodium chloride (9.0 mg) were dissolved in water for injection, filtered to remove pyrogens, and the filtrate was aseptically transferred to an ampoule, sterilized, and then sealed by melting. The active ingredient is obtained as an injection containing O mg.
  • Non-specific binding was determined in the presence of 100 M (sat) -sulpiride.
  • the 50% inhibitory concentration (IC 5 ) of the test compound was calculated by nonlinear regression, and the inhibition constant (K i value) was determined.
  • IC 5 50% inhibitory concentration
  • K i value the inhibition constant
  • D receptor expressing cell membrane specimen and 3 H- spiperone with the presence of the test compound 27.
  • C I incubated for 2 hours.
  • the solution was subjected to suction filtration with a Putman GF / B filter-(trade name), and the radioactivity on the filter was measured with a liquid scintillation counter. Non-specific binding was determined in the presence of 1% haloperidol.
  • the 50% inhibitory concentration (IC 5 ) of the test compound was calculated by nonlinear regression, and the inhibition constant (K i value) was determined.
  • the preparation and binding experiments of the crude synaptic membrane were carried out according to the method of Leysen JE et al. [Molecular 'Pharmaco Ji-ichi, Vol. 21, p. 301 (1 982)].
  • the crude synaptic membranes from rat cerebral cortex and cryopreserved were prepared and incubated film specimen and 3 H- ketanserin in the presence of a test compound 37 ° C, 20 min.
  • the solution was subjected to suction filtration with a Kettman GF7B filter (trade name), and the radioactivity on the filter was measured with a liquid scintillation counter. The amount of non-specific binding was determined in the presence of 10 // M mianserin.
  • the 50% inhibitory concentration (IC 5 ) of the test compound was calculated by nonlinear regression, and the inhibition constant (K i value) was determined.
  • the present compound showed strong affinity of 0. 1 ⁇ 1 00 nM in 5 -HT 2 receptor.
  • the compound of the present invention exhibited a strong affinity of 0.1 to 1 O OnM for the receptor.
  • the present compound showed 0. 1 ⁇ 1 0 0 nM strong affinity for Mus force phosphoric M 1 / Mz receptor.

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Abstract

La présente invention concerne des composés hétérocycliques fusionnés représentés par la formule générale (I), certains de leurs isomères optiques ou de leurs sels galéniques, des compositions médicinales comprenant ces composés, des adjuvants galéniques et des médicaments comprenant ces composés. Ces composés exercent des effets de blocage plus puissants sur les récepteurs D4 que sur les récepteurs D2. En outre, ils présentent des affinités importantes pour des récepteurs autres que les récepteurs de la dopamine, en l'occurrence des récepteurs tels que ceux de la muscarine M1, de la sérotonine-2 (5-HT2), et des adrénalines α1 et α2. De ce fait, ces composés sont efficaces, non seulement contre les symptômes positifs se caractérisant par des hallucinations et des délires spécifiques de la schizophrénie à l'état aigu, mais également contre les symptômes négatifs tels que la torpeur émotionnelle, l'aboulie et l'autisme. De plus, ces composés qui conviennent comme neuroleptiques, présentent moins d'effets secondaires (symptômes extrapyramidaux et sécrétions internes anormales notamment) que ce que l'on observe dans le cas d'administration de neuroleptiques conventionnels n'agissant que par antagonisme avec le récepteur D2. Ces composés conviennent comme médicaments contre des affections telles que la schizophrénie.
PCT/JP1997/001993 1996-06-11 1997-06-09 Composes heterocycliques fusionnes et leurs utilisations medicinales WO1997047601A1 (fr)

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