Piperazine-substituted benzothiophene derivatives as antipsychotic agents

Patent metadata

Field	Value
Publication number	US-9260420-B2
Application number	US-201214343579-A
Country	US
Kind code	B2
Filing date	Sep 7, 2012
Priority date	Sep 8, 2011
Publication date	Feb 16, 2016
Grant date	Feb 16, 2016

Abstract

Provided is a superior, novel heterocyclic compound with improved solubility in oil such as sesame oil and benzyl benzoate, which has a broader treatment spectrum, causes less side effects, and is superior in tolerability and safety, and use thereof. A heterocyclic compound represented by the formula (I) wherein each symbol is as defined in the specification, or a salt thereof.

First claim

The invention claimed is:

1. A heterocyclic compound represented by the formula

wherein
A is a lower alkylene group;

in the monocyclic heterocycle containing Q is

wherein
R 2′ is the following group

wherein
Y 1′ is a lower alkylene group,
R 3′ is
(1) an alkyl group,
(2) a cycloalkyl group optionally substituted by a lower alkyl group,
(3) a phenyl group,
(4) a phenyl lower alkyl group
(5) a lower alkoxy group,
(6) a cycloaikyloxy group,
(7) an amino group optionally having 1 or 2 substituents selected from the group consisting of an alkyl group and a phenyl lower alkyl group, or
(8) a piperidyl group optionally haying a piperidyl group;
at the 3-position and the 4-position of the bicyclic heterocycle skeleton containing Z and W is —CH═CH— or

wherein R 6 and R 7 are the same or different and each is a hydrogen or a lower alkyl group;

wherein
R 2 is a hydrogen or
the following group

wherein
Y 1 is a lower alkylene group optionally substituted by
(1) a lower alkoxycarbonyl group or
(2) a lower alkyl group,
Y 2 is a lower alkylene group,
Y 3 is a single bond or a lower alkylene group optionally substituted by a lower alkyl group,
R3 is
(1) an alkyl group,
(2) a halogen-substituted lower alkyl group,
(3) an alkenyl group,
(4) an amino lower alkyl group,
(5) a cycloalkyl group,
(6) a phenyl group,
(7) a phenyl lower alkyl group,
(8) a piperidyl group optionally having 1or 2substituents selected from the group consisting of a lower alkyl group and a piperidyl group,
(9) a halogen-substituted piperidyl group,
(10) a morpholinyl group,
(11) a pyrrolidinyl group,
(12) a tetrahydropyranyl group,
(13) a furyl group,
(14) a thienyl group,
(15) a pyridyl group,
(16) a pyrimidinyl group,
(17) a pyridazinyl group,
(18) a benzofuryl group,
(19) a quinolyl group,
(20) a lower alkoxycarbonyl lower alkyl group,
(21) a lower alkoxy lower alkoxy lower alkyl group,
(22) a lower alkoxy lower alkoxy lower alkoxy lower alkyl group,
(23) an amino group optionally having 1 or 2 substituents selected from the group consisting of an alkyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, a lower alkenyl group, a halogen-substituted lower alkyl group, a lower alkoxy group, a lower alkoxy lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a phenyl lower alkyl group, a phenyl lower alkoxy group, a furyl lower alkyl group, a pyridyl lower alkyl group, a hydroxy-substituted lower alkyl group,
(24) an amino lower alkyl group optionally having a lower alkylcarbonyl group,
(25) a piperazinyl group optionally having a lower alkyl group, or
(26) the following group

wherein Ac is an alkylene group, and other symbols are defined above,
R 4 is
(1) an alkyl group,
(2) a phenyl group,
(3) a phenyl lower alkyl group,
(4) a halogen-substituted lower alkyl group, or
(5) a cycloalkyl group,
R 5 is
(1) a hydrogen,
(2) a lower alkyl group,
(3) a halogen-substituted lower alkyl group,
(4) a phenyl lower alkyl group,
(5) a phenyl lower alkoxy lower alkyl group,
(6) a tri-lower alkylsilyl group,
(7) a tetrahydropyranyl group, or
(8) a phosphono group,
R 10 is
(1) an alkenyl group,
(2) a phenyl lower alkyl group,
(3) a hydroxy-substituted lower alkyl group,
(4) a cycloalkyl group,
(5) an amino lower alkyl group optionally having 1 or 2 substituents selected from the group consisting of an amino lower alkylcarbonyl group and a lower alkylcarbonyl group,
(6) a pyrrolidinyl group optionally having an amino lower alkylcarbonyl group,
(7) an alkoxy group,
(8) a lower alkoxy lower alkoxy lower alkyl group,
(9) a lower alkoxy lower alkoxy lower alkoxy lower alkyl group,
(10) a phenyl lower alkoxy group,
(11) an amino group optionally having 1 or 2 substituents selected from the group consisting of an alkyl group, a hydroxy-substituted lower alkyl group and a phenyl lower alkyl group,
(12) a morpholino group,
(13) a piperazinyl group optionally having a lower alkyl group,
(14) a piperidyl group optionally having a piperidyl group, or
(15) a cycloalkyloxy group;
provided when

then
R 2 is not a hydrogen, or a salt thereof.

2. The heterocyclic compound according to claim 1 , which is represented by the formula (II)

wherein each symbol is as defined in claim 1 , or a salt thereof.

3. The heterocyclic compound according to claim 1 , which is represented by the formula (III)

wherein
R 2a is
the following group

wherein
Y 1a is a lower alkylene group,
Y 2a is a lower alkylene group,
R 3a is
(1) an alkyl group,
(2) a cycloalkyl group,
(3) a piperidyl group optionally having 1 or 2 substituents selected from the group consisting of a lower alkyl group,
(4) a tetrahydropyranyl group,
(5) a lower alkoxycarbonyl lower alkyl group,
(6) a lower alkoxy lower aikoxy lower alkyl group
(7) an amino lower alkyl group optionally having a lower alkylcarbonyl group, or
(8) the following group

wherein Ac′ is an alkylene group, Y 1a is a lower alkylene group and other symbols are as defined in claim 1 ,
R 4a is
(1) an alkyl group, or
(2) a cycloalkyl group; and
A is a lower alkylene group,
or a salt thereof.

4. The heterocyclic compound according to claim 2 ,
wherein
R 2 is
the following group

wherein
Y 1a is a lower alkylene group,
Y 2a is a lower alkylene group,
R 3a′ is
(1) an alkyl group,
(2) a cycloalkyl group
(3) a piperidyl group optionally having 1 or 2 substituents selected from the group consisting of a lower alkyl group,
(4) a tetrahydropyranyl group,
(5) a lower alkoxycarbonyl lower alkyl group,
(6) a lower alkoxy lower alkoxy lower alkyl group
(7) an amino lower alkyl group optionally having a lower alkylcarbonyl group,
R 4a is
(1) an alkyl group, or
(2) a cycloalkyl group;
or a salt thereof.

5. A method of producing a heterocyclic compound represented by the formula (I)

wherein each symbol is as defined in claim 1 ,
or a salt thereof, comprising reacting a compound represented by the formula

Assignees

• Yamashita Hiroshi
• Sakurai Yohji
• Miyamoto Motoyuki
• Nakamura Yuichi
• Kuroda Hideaki
• Minowa Takuya
• Otsuka Pharma Co Ltd

Inventors

• Yamashita Hiroshi
• Sakurai Yohji
• Miyamoto Motoyuki
• Nakamura Yuichi
• Kuroda Hideaki
• Minowa Takuya

Classifications

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P25/22

  Anxiolytics · CPC title

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61P25/24

  Antidepressants · CPC title