US2021052575A1PendingUtilityA1
Piperazine-substituted benzothiophene derivatives as antipsychotic agents
Est. expirySep 8, 2031(~5.1 yrs left)· nominal 20-yr term from priority
A61K 31/496A61K 31/5377A61K 31/695A61P 25/28C07D 409/14C07D 409/12A61K 31/541A61P 25/24A61P 25/20A61P 25/18A61K 31/675A61P 1/08C07F 7/1804A61P 25/06A61K 31/506A61P 3/04A61K 31/501A61P 25/00A61P 25/22A61P 25/16A61P 25/04
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Claims
Abstract
Provided is a superior, novel hetrocyclic compound with improved solubility in oil such as sesame oil and benzyl benzoate, which has a broader treatment spectrum, causes 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.
Claims
exact text as granted — not AI-modified1 . A heterocyclic compound represented by the formula (I)
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 cycloalkyloxy 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 having 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;
is
wherein
R 1 is
a lower alkoxy lower alkoxy group,
a phosphonooxy lower alkoxy group,
a phenyl lower alkoxy lower alkoxy group,
a phosphonooxy group optionally having 1 or 2 lower alkyl groups,
the following group
wherein
R 8 is
(1) an alkyl group,
(2) a hydroxy-substituted lower alkyl group,
(3) a cycloalkyl group,
(4) a phenyl group,
(5) a phenyl lower alkyl group,
(6) an alkenyl group,
(7) a lower alkoxy group,
(8) a cycloalkyloxy group,
(9) a lower alkoxy lower alkoxy group,
(10) an amino group optionally having 1 or 2 substituents selected from the group consisting of an alkyl group and a hydroxy-substituted lower alkyl group,
(11) a piperidyl group optionally having a piperidyl group,
(12) a piperazinyl group optionally having a lower alkyl group, or
(13) the following group
wherein Aa is an alkylene group, and other symbols are as defined above, or
the following group
wherein
R 9 is
(1) an alkyl group,
(2) a hydroxy-substituted lower alkyl group,
(3) a cycloalkyl group,
(4) a phenyl group,
(5) a phenyl lower alkyl group,
(6) an alkenyl group,
(7) a lower alkoxy group,
(8) a cycloalkyloxy group,
(9) a lower alkoxy lower alkoxy group,
(10) a phenyloxy group,
(11) an amino group optionally having 1 or 2 substituents selected from the group consisting of an alkyl group and a hydroxy-substituted lower alkyl group,
(12) a piperidyl group optionally having a piperidyl group,
(13) a piperazinyl group optionally having a lower alkyl group, or
(14) the following group
wherein Ab is an alkylene group, and other symbols are as defined above;
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,
R 3 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 1 or 2 substituents 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 as 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,
is (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 alkyl group,
(2) an alkenyl group,
(3) a phenyl group,
(4) a phenyl lower alkyl group,
(5) a hydroxy-substituted lower alkyl group,
(6) a cycloalkyl group,
(7) 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,
(8) a pyrrolidinyl group optionally having an amino lower alkylcarbonyl group,
(9) an alkoxy group,
(10) a lower alkoxy lower alkoxy lower alkyl group,
(11) a lower alkoxy lower alkoxy lower alkoxy lower alkyl group,
(12) a phenyl lower alkoxy group,
(13) 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,
(14) a morpholino group,
(15) a piperazinyl group optionally having a lower alkyl group,
(16) a piperidyl group optionally having a piperidyl group, or
(17) 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
is
wherein
R 1a is the following group
R 8a is
(1) an alkyl group,
(2) a cycloalkyl group,
(3) a lower alkoxy group,
(4) a cycloalkyloxy group,
(5) a lower alkoxy lower alkoxy group,
(6) an amino group optionally having 1 or 2 substituents selected from the group consisting of an alkyl group and a hydroxy-substituted lower alkyl group, or
(7) the following group
wherein Aa′ is an alkylene group, and other symbol is as defined in claim 1 , or
the following group
wherein
R 9a is
(1) an alkyl group,
(2) a hydroxy-substituted lower alkyl group,
(3) a cycloalkyl group,
(4) a lower alkoxy group,
(5) a cycloalkyloxy group,
(6) a lower alkoxy lower alkoxy group,
(7) a phenyloxy group,
(8) an amino group optionally having 1 or 2 substituents selected from the group consisting of an alkyl group,
(9) a piperidyl group optionally having a piperidyl group,
(10) a piperazinyl group optionally having a lower alkyl group, or
(11) the following group
wherein Ab′ is an alkylene group, and other symbol is as defined in claim 1 ;
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 alkoxy 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 1 is
the following group
wherein
R 8a′ is
(1) an alkyl group,
(2) a cycloalkyl group,
(3) a lower alkoxy group,
(4) a cycloalkyloxy group,
(5) a lower alkoxy lower alkoxy group, or
(6) an amino group optionally having 1 or 2 substituents selected from the group consisting of an alkyl group and a hydroxy-substituted lower alkyl group, or
the following group
wherein
R 9a′ is
(1) an alkyl group,
(2) a hydroxy-substituted lower alkyl group,
(3) a cycloalkyl group,
(4) a lower alkoxy group,
(5) a cycloalkyloxy group,
(6) a lower alkoxy lower alkoxy group,
(7) a phenyloxy group,
(8) an amino group optionally having 1 or 2 substituents selected from the group consisting of an alkyl group,
(9) a piperidyl group optionally having a piperidyl group, or
(10) a piperazinyl group optionally having a lower alkyl group;
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 pharmaceutical composition comprising the heterocyclic compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent and/or a carrier.
6 . A prophylactic and/or therapeutic agent for a central neurological disease, comprising the heterocyclic compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
7 . The agent according to claim 6 , wherein the central neurological disease is selected from the group consisting of schizophrenia, treatment-resistant, refractory or chronic schizophrenia, emotional disturbance, psychotic disorder, mood disorder, bipolar disorder, mania, depression, endogenous depression, major depression, melancholic and treatment-resistant depression, dysthymic disorder, cyclothymic disorder, anxiety disorder, somatoform disorder, factitious disorder, dissociative disorder, sexual disorder, eating disorder, sleep disorder, adjustment disorder, substance-related disorder, anhedonia, delirium, Alzheimer's disease, Parkinson disease, cognitive impairment, cognitive impairment associated with neurodegenerative diseases, cognitive impairment caused by neurodegenerative diseases, cognitive impairment in schizophrenia, cognitive impairment caused by treatment-resistant, refractory or chronic schizophrenia, vomiting, notion sickness, obesity, migraine, pain, mental retardation, autistic disorder, Tourette's disorder, tic disorder, attention deficit hyperactivity disorder, conduct disorder and Down's syndrome.
8 . Use of the heterocyclic compound according to claim 1 or a pharmaceutically acceptable salt thereof as a medicament.
9 . A method of preventing and/or treating a central neurological disease, comprising administering the heterocyclic compound according to claim 1 or a pharmaceutically acceptable salt thereof to a human or an animal.
10 . The method according to claim 9 , wherein the central neurological disease is selected from the group consisting of schizophrenia, treatment-resistant, refractory or chronic schizophrenia, emotional disturbance, psychotic disorder, mood disorder, bipolar disorder, mania, depression, endogenous depression, major depression, melancholic and treatment-resistant depression, dysthymic disorder, cyclothymic disorder, anxiety disorder, somatoform disorder, factitious disorder, dissociative disorder, sexual disorder, eating disorder, sleep disorder, adjustment disorder, substance-related disorder, anhedonia, delirium, Alzheimer's disease, Parkinson disease, cognitive impairment, cognitive impairment associated with neurodegenerative diseases, cognitive impairment caused by neurodegenerative diseases, cognitive impairment in schizophrenia, cognitive impairment caused by treatment-n) resistant, refractory or chronic schizophrenia, vomiting, motion sickness, obesity, migraine, pain, mental retardation, autistic disorder, Tourette's disorder, tic disorder, attention deficit hyperactivity disorder, conduct disorder and Down's syndrome.
11 . 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
wherein X 1 is a halogen atom or a group that causes a substitution reaction similar to that by a halogen atom, and other symbols are as defined in claim 1 , or a salt thereof, with a compound represented by
wherein Q is as defined in claim 1 , or a salt thereof.Join the waitlist — get patent alerts
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