WO2021214950A1

WO2021214950A1 - Pharmaceutical composition for treatment, prevention or management of mental disorder

Info

Publication number: WO2021214950A1
Application number: PCT/JP2020/017552
Authority: WO
Inventors: 新大西; 章子三浦
Original assignee: 国立大学法人島根大学
Priority date: 2020-04-23
Filing date: 2020-04-23
Publication date: 2021-10-28
Also published as: WO2021215478A1; JPWO2021214950A1; JP2021172655A; JP6833242B1

Abstract

The present invention provides: a pharmaceutical composition that includes a serotonin transmission inhibitor and that is for treating, preventing or managing a mental disorder attributed to bilirubin UDP-glucuronic acid transferase (UGT1A1) gene mutation or a mental disorder accompanied by jaundice; and a method for treating, preventing or managing said mental disorders, the method including administration of serotonin transmission inhibitor. Specific examples of the mental disorders include schizophrenia and attention-deficit hyperactivity disorder (ADHD).

Description

Pharmaceutical composition for treating, preventing or managing psychiatric disorders

The present invention provides a pharmaceutical composition for treating, preventing or managing a psychiatric disorder caused by a bilirubin UDP-glucuronosyltransferase (UGT1A1) gene mutation, or a psychiatric disorder associated with jaundice, and treating, preventing or controlling the psychiatric disorder. Regarding how to manage.

Constitutional jaundice is a well-known disease that affects 2 to 7% of the population, but in recent years it has become clear that it is also associated with mental illness, and jaundice is one of the causes of schizophrenia. The possibility has been pointed out. However, patients with constitutional jaundice and schizophrenia have more extrapyramidal side effects due to the dopamine receptor blocking action of antipsychotic drugs than patients without complications, and in the acute phase and It was difficult to treat because the clinical symptoms were severe even in the stable condition (Non-Patent Document 1). Almost all conventional antipsychotic drugs have some kind of dopamine receptor blocking action (Non-Patent Document 2). Although it is estimated that 20% (more than 200,000) of schizophrenia patients in Japan have both constitutional jaundice and schizophrenia, no therapeutic drug for the disease has been developed.

Gunn rats are Wistar rats with a frameshift mutation due to a 1-base (G) deficiency of the UGT1A1 gene, and show high blood unconjugated bilirubin concentrations, similar to jaundice patients. On the other hand, Gunn rats are known to cause cognitive behavioral disorders similar to schizophrenia. Attempts have been made to develop a drug for schizophrenia associated with jaundice using Gunn rats, but this has not yet been successful (Non-Patent Documents 3 and 4).

Japanese Patent Publication No. 2008-500325 discloses a method for treating central nervous system diseases including schizophrenia and other central nervous system diseases _{using a combination of atomoxetine and a 5-HT 1A} agonist (Patent Document 1). However, the publication does not describe the experimental results and does not show that such a combination can actually treat these diseases.

Special Table 2008-500325

The present invention provides a pharmaceutical composition for treating, preventing or managing a psychiatric disorder caused by a UGT1A1 gene mutation, or a psychiatric disorder associated with jaundice, and a method for treating, preventing or managing the psychiatric disorder. With the goal.

The present inventors focused on jaundice model rats (Gunn rats) having a UGT1A1 gene mutation in developing a therapeutic drug for psychiatric disorders. The model rat is known to cause cognitive behavioral disorders associated with schizophrenia (Non-Patent Document 3). The model rat can be a model rat for psychiatric disorders caused by mutations in the UGT1A1 gene and psychiatric disorders associated with jaundice. A detailed analysis of the model rat revealed that the present inventors have normal dopamine transmission in the frontal lobe, striatum, and hippocampus, which are brain regions important for cognitive function, in the model rat. We found that serotonin hypertransmission occurred in the frontal lobe and hippocampus, and that it was associated with cognitive-behavioral disorders. From these findings, it is presumed that "intracerebral serotonin overtransmission" is an important pathological condition for psychiatric disorders, rather than "intracerebral dopamine overtransmission", which is a conventional model of schizophrenia pathology. Therefore, it was found that when a serotonin transmission inhibitor having a dopamine receptor blocking action lower than that of risperidone was administered to the model rat, cognitive behavioral disorders were improved, and the present invention was developed.

The present inventors have obtained the finding that the UGT1A1 gene mutation causes serotonin overtransmission in the brain, thereby causing psychiatric disorders. At the same time, it was found that mutations in the UGT1A1 gene can increase unconjugated bilirubin levels in blood or urine, thereby causing jaundice.

The present invention provides a pharmaceutical composition for treating, preventing or managing a psychiatric disorder caused by a UGT1A1 gene mutation or a psychiatric disorder associated with jaundice, which comprises a serotonin transmission inhibitor. Risperidone can be excluded from the serotonin transmission inhibitor (because it has a strong dopamine receptor blocking effect). In one embodiment, the serotonin transfer inhibitor has a binding inhibition constant (K _i ) value _{greater than 3.57 nM for the D 2 receptor.} The serotonin transfer inhibitor may further have a _{K i} value greater than 3.6 nM for _{the D 3} _{receptor and a K i} value greater than 4.66 nM for the _{D 4 receptor.} In certain embodiments, the serotonin transfer inhibitors have a K _i value of greater than or equal to about 30 nM to D ₂ receptors. In certain embodiments, the serotonin transfer inhibitor has _{a binding affinity for 5-HT 2A} receptor that is more than 21-fold higher than the binding affinity for _{D 2 receptor.}

In certain embodiments, the serotonin transmission inhibitor is a 5-HT _{2A / 2c} receptor antagonist or a 5-HT _2A receptor antagonist. In a specific embodiment, the 5-HT _{2A / 2c} receptor antagonist or 5-HT _2A receptor antagonist may be acceptable as ketanserin, sarpogrelate hydrochloride, ritanserin, methysergide, cyproheptadine, or cyclobenzaprine, or a medicament thereof. It is a salt, a solvent product, a steric isomer, or a mutual mutant organism. In certain embodiments, the serotonin transmission inhibitor is a 5-HT _1A receptor agonist or a 5-HT _1B receptor agonist. In a specific embodiment, the 5-HT _1A receptor agonist is 8-OH-DPAT, 5-carboxamidottryptamine, tandospirone, ipsapilone, or buspirone, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. It is a body or a tandospirone. In a specific embodiment, the 5-HT _1B receptor agonist is a CGS-12066A, CP-93129, or triptan formulation (such as sumatriptan, zolmitriptan, eletriptan, lizatriptan, or naratriptan), or naratriptan thereof. A pharmaceutically acceptable salt, triptan, triptan or tally mutant.

In a particular embodiment, the serotonin transfer inhibitor is a compound represented by the following formula (I), or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof:

(During the ceremony,
X ¹ is CR ^a R ^b , CO, NR ^c , CR ^d or N;
X ² is CR ^e , N or C;
X ³ is CR ^f , N or C;
X ⁴ is CR ^g , N or C;
Are R ¹ and R ² independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, acyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, acyloxy, nitro, amino, alkylamino, halo or oxo? Or, R ¹ and R ² can form an aromatic carbocyclic ring or an aromatic heterocyclic ring that is ^{unsubstituted or substituted with one or more R s1s} together with the atoms to which they are attached;
R ^s1 is alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, acyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, acyloxy, nitro, amino, alkylamino or halo, respectively, independently on each appearance;
R ³ is an alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, acyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, acyloxy, nitro, amino, alkylamino, or halo, independently of each appearance;
R ^a , R ^b , R ^c , R ^d , R ^e , R ^f and R ^g are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, acyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, respectively. Acyloxy, nitro, amino, alkylamino, or halo;
Y ¹ and Y ² are hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, acyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, acyloxy, nitro, amino, alkylamino or halo, respectively, on each appearance. ;
Z is CH or N;
Whether B ¹ and B ² are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, acyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, acyloxy, nitro, amino, alkylamino, or halo, respectively. or B ¹ and B ^2, that together with the atoms to which they are attached, are unsubstituted or substituted by one or more R ^s2, to form a non-aromatic carbocyclic or non-aromatic heterocyclic saturated or unsaturated Can be;
R ^s2 is alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, acyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, acyloxy, nitro, amino, alkylamino or halo, respectively, independently on each appearance;
m is an integer from 0 to 4;
n is an integer from 0 to 6;

Represents a single bond or a double bond. ).

In a particular embodiment, in formula (I), X ¹ is CH ₂ , CO, or N; X ² is CH, N or C; X ³ is CH or C; X. ⁴ is CH or N; R ¹ is hydrogen or oxo and R ² is hydrogen, or R ¹ and R ² are unsubstituted aromatics, along with the atoms to which they are attached. Forming a heterocycle; R ³ is haloalkyl or hydroxy; Y ¹ and Y ² are hydrogen; Z is CH or N; B ¹ and B ² are independently alkyl, respectively. or B ¹ and B ² are, together with the atom to which they are attached, substituted with one R ^s2, to form a non-aromatic heterocyclic ring saturated; R ^s2 is alkyl or acyl; m is It is 0 or 1; and n is an integer of 0 to 2.

In a particular embodiment, the compound represented by the formula (I) is a compound represented by the following formula (IA):

(In the equation, R ³ , Y ¹ , Y ² , Z, B ¹ , B ² , m and n are as defined above).

In a particular embodiment, the compound represented by the formula (IA) is a compound represented by the following formula (Ia):

(Wherein, R ^3, R ^s2 and m are as defined above.). In a particular embodiment, in formula (Ia), R ^s2 is an acyl and m is 0.

In a particular embodiment, the compound represented by the formula (I) is a compound represented by the following formula (IB):

In a particular embodiment, the compound represented by the formula (IB) is a compound represented by the following formula (Ib):

(In the equation, R ³ and m are as defined above.) In a particular embodiment, in formula (Ib), R ³ is hydroxy and m is 1.

In a particular embodiment, the compound represented by the formula (I) is a compound represented by the following formula (IC):

In a particular embodiment, the compound represented by the formula (IC) is a compound represented by the following formula (Ic):

(Wherein, R ^3, R ^s2 and m are as defined above.). In certain embodiments, in the formula (Ic), R ³ is haloalkyl, R ^s2 is alkyl, and m is 1. In a further specific embodiment, the compound represented by formula (I) is ketanserin, 8-OH-DPAT or CGS-12066A.

In one embodiment, the psychiatric disorder is caused by serotonin hypertransmission in the brain. In certain embodiments, the psychiatric disorder is schizophrenia or attention deficit hyperactivity disorder. In certain embodiments, the jaundice is constitutional jaundice. The present invention also provides a kit for treating, preventing or managing a psychiatric disorder caused by a UGT1A1 gene mutation or a psychiatric disorder accompanied by jaundice, which contains a pharmaceutical composition containing a serotonin transmission inhibitor.

According to the present invention, it is possible to treat, prevent or manage a psychiatric disorder caused by a mutation in the UGT1A1 gene or a psychiatric disorder accompanied by jaundice.

The amount of serotonin nerves in the raphe nuclei of jaundice model rats (Gunn rats) and normal rats (Wistar rats) is shown. The amount of tryptophan hydroxylase (TPH2) contained specifically in serotonin nerve in the brain stem of jaundice model rat (Gunn rat) and normal rat (Wistar rat) is shown. The behavioral observation results of jaundice model rats (Gunn rats) and normal rats (Wistar rats) after ketanserin administration are shown. In FIG. 3, (+ / +) represents a Wistar rat and (j / j) represents a Gunn rat. 0, 1, and 3 on the horizontal axis represent administration of 0 mg / kg (ie, solvent administration), administration of 1 mg / kg, and administration of 3 mg / kg, respectively. * P <0.05, *** P <0.001 (Dunnett's test for Wistar rat solvent administration). The behavioral observation results of jaundice model rats (Gunn rats) and normal rats (Wistar rats) after administration of 8-OH-DPAT or CGS-12066A are shown. *** P <0.001 (Dunnett's test for Wistar rat solvent administration).

(1. Definition)
The term "mental illness" as used herein has the broadest meaning used in the art of the present invention. Examples of the term "mental illness" include, but are not limited to, schizophrenia, attention deficit hyperactivity disorder (ADHD), autism, Alzheimer's disease, cognitive dysfunction, depression, bipolar disorder (manic depression). , Cerebral neurodevelopment disorder, cognitive dysfunction caused by neuropathy due to infection during pregnancy, mental disorder caused by immune disorder, epilepsy, cerebral organic mental disorder, addictive mental disorder, intellectual disorder (mental retardation), mental illness Quality, neuropathy, plum toxic psychiatric disorder, senile psychiatric disorder, cerebrovascular psychiatric disorder, psychiatric disorder due to head trauma, atypical intrinsic psychiatric disorder, endocrine psychiatric disorder and extrinsic psychiatric disorder, and degenerative psychiatric disorder be.

The term "bilirubin UDP-glucuronosyltransferase" or "UGT1A1" used herein is an enzyme that converts the in vivo substance unconjugated bilirubin (indirect bilirubin) into conjugated bilirubin (direct bilirubin).

The term "bilirubin UDP glucuronosyltransferase gene" or "UGT1A1 gene" used in the present specification means a gene encoding bilirubin UDP glucuronosyltransferase (UGT1A1). It is known that mutations in this gene can cause constitutional jaundice.

As used herein, the term "gene mutation" or "gene mutation" has the broadest meaning used in the art of the invention and generally has a high frequency of abnormalities in the gene (deletion of base). , Substitution, insertion, etc.), and these abnormalities mean that the function of the gene is reduced or lost.

The term "jaundice" as used herein has the broadest meaning used in the art of the present invention, and generally, bile pigment (bilirubin) is abnormally increased in blood and tissues, and the skin. , Means a symptom of yellowing of mucous membranes and other tissues. "Jaundice" is particularly high in blood or urine unconjugated bilirubin levels. "Jaundice" includes latent jaundice (for example, blood bilirubin concentration of about 1 mg / dl to about 2 mg / dl), mild jaundice (for example, blood bilirubin concentration of about 2 mg / dl to about 10 mg / dl), Includes moderate jaundice (eg, blood bilirubin concentration of about 10 mg / dl to about 20 mg / dl) and severe jaundice (eg, blood bilirubin concentration of about 20 mg / dl to). Specific examples of "jaundice" include physiological and pathological jaundice, such as direct bilirubin-dominant jaundice, obstructive jaundice, hepatocellular jaundice, indirect bilirubin-dominant jaundice, hemolytic jaundice, and constitutional jaundice. And newborn jaundice.

The term "constitutional jaundice" used in the present specification has the broadest meaning used in the technical field of the present invention, and generally means a state in which there is a congenital disorder in the decomposition of bilirubin. "Constitutional jaundice" particularly shows high levels of unconjugated bilirubin in blood or urine. "Constitutional jaundice" includes Gilbert's syndrome, Crigler-Najjar syndrome, Dubin-Johnson syndrome, Rotor syndrome and the like.

The term "serotonin" used in this specification is one of the neurotransmitters existing in the brain, and is deeply involved in emotional and mood control and mental stability. "Serotonin" is 5-hydroxytryptamine (abbreviated as 5-HT). In the present specification, serotonin present in the brain is also referred to as serotonin in the brain. It is known that when serotonin is deficient, brain function declines, it becomes difficult to maintain mental balance, and it can cause stress disorders, depression, and sleep disorders. Excessive levels of serotonin in the brain are known to cause psychological symptoms such as anxiety, confusion, and irritability. A prominent example is serotonin syndrome.

The term "serotonin transmission" used in the present specification has the broadest meaning used in the technical field of the present invention, and generally, in serotonin nerves existing in the brain, by activation of serotonin receptors and the like. It means that serotonin is secreted from the origin nucleus (particularly the raphe nucleus) to various brain regions including the frontal lobe, striatum and hippocampus, and information is transmitted via serotonin. "Serotonin transmission" is also referred to as serotonin transmission in the brain. There are 11 types of serotonin receptors (5-HT receptors) (5-HT _1A receptor, 5-HT _1B receptor, 5-HT _1D receptor, 5-HT _2A receptor, 5-HT _2B receptor, 5-HT _2C receptor, 5-HT ₃ receptor, 5-HT ₄ receptor, 5-HT ₅ receptor, 5-HT ₆ receptor, and 5-HT ₇ receptor) are known to exist. There is.

The term "serotonin overtransmission" as used herein has the broadest meaning used in the art of the present invention and generally means that serotonin transduction in the brain is excessive. .. "Serotonin overtransmission" is also referred to as intracerebral serotonin overtransmission. "Serotonin hypertransmission" involves increasing serotonin levels in the brain.

The term "inhibition of serotonin transmission" as used herein has the broadest meaning used in the art of the present invention and generally means to inhibit serotonin transmission in the brain. "Inhibition of serotonin transmission" includes inhibiting the secretion of serotonin from serotonin nerves present in the brain. "Inhibition of serotonin transmission" is also referred to as inhibition of serotonin transmission in the brain. "Inhibition of serotonin transmission" is also referred to as inhibition of serotonin secretion.

As used herein, the term "serotonin transmission inhibitor" has the broadest meaning used in the art of the present invention and generally means a substance capable of inhibiting serotonin transmission in the brain. .. "Serotonin transmission inhibitor" includes substances capable of binding to serotonin receptors in the brain and inhibiting serotonin secretion. The "serotonin transmission inhibitor" is also referred to as a serotonin transmission inhibitor in the brain.

The term "dopamine" used in the present specification is one of the neurotransmitters existing in the brain, and is a substance deeply involved in motor regulation and hormone regulation. In the present specification, dopamine present in the brain is also referred to as intracerebral dopamine in particular.

The term "dopamine transmission" as used herein has the broadest meaning used in the art of the present invention, and is generally derived from dopaminergic nerves present in the origin nucleus (particularly the substantia nigra). It is secreted to various brain regions including the frontal lobe, striatum and hippocampus, and means that information is transmitted via dopamine. "Dopamine transmission" is also referred to as intracerebral dopamine transmission. It is known that there are about 5 types of dopamine receptors (D ₁ receptor, D _{2 (S, L)} receptor, D ₃ receptor, D ₄ receptor, and D _{5 receptor).}

The term "inhibition of dopamine transmission" as used herein has the broadest meaning used in the art of the present invention and generally means to inhibit dopamine transmission in the brain. "Inhibition of dopamine transmission" includes inhibiting the secretion of dopamine from dopaminergic nerves present in the brain. "Inhibition of dopamine transmission" can be caused by dopamine receptor blocking action. "Inhibition of dopamine transmission" is also referred to as inhibition of dopamine transmission in the brain. "Inhibition of dopamine transmission" is also referred to as "inhibition of dopamine secretion".

As used herein, the term "dopamine transmission inhibitor" has the broadest meaning used in the art of the present invention and generally means a substance capable of inhibiting dopamine transmission in the brain. .. "Dopamine transmission inhibitors" include substances that can bind to dopamine receptors in the brain and inhibit dopamine secretion. The "dopamine transmission inhibitor" is also referred to as a dopamine transmission inhibitor in the brain.

The term "brain" as used herein has the broadest meaning used in the technical field of the present invention. The brain is the target brain, eg, the human brain. Specific examples of the brain include the cerebrum, cerebral cortex, diencephalon, cerebellum and brain stem. More specific examples of the brain include parietal lobe, frontal lobe, temporal lobe, occipital lobe, midbrain, striatum, hippocampus, raphe nuclei, raphe nuclei (eg, dorsal raphe nuclei, basal ganglia). The lateral part of the raphe nuclei and dorsal raphe nuclei), the anterior brain, medulla oblongata, pons, thorax, hypothalamus, parietal lobe, and basal ganglia.

As used herein, the term "alkyl" means a monovalent group produced by the loss of one hydrogen atom in an aliphatic saturated hydrocarbon. Alkyl is, for example, 1 to 20 carbon atoms, typically 1 to 10, 1 to 8, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 1. It has 2 or 2 to 6 carbon atoms. The alkyl may be linear or branched. Examples of alkyl are, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1. -Butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2 -Pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl , T-Butyl, Pentyl, Isopentyl, Neopentyl, n-Hexyl, n-Heptyl, n-octyl, n-Nonyl, n-decyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, and n-octadecyl. .. Alkyl may be substituted with one or more substituents (eg, one, two, three, four, five or more) which may be the same or different.

As used herein, the term "cycloalkane" means an alicyclic compound. Cycloalkanes are, for example, 3 to 10 carbon atoms, typically 3 to 8, 3 to 6, 3 to 5, 3 to 4, 4 to 5, 4 to 6, or It has 4 to 8 carbon atoms. Examples of cycloalkanes include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane. Cycloalkanes may be substituted with one or more substituents (eg, one, two, three, four, five or more) which may be the same or different.
As used herein, the term "cycloalkyl" means a monovalent group resulting from the loss of one hydrogen atom in a cycloalkane.

As used herein, the term "alkenyl" means a monovalent group resulting from the loss of one hydrogen atom in an aliphatic unsaturated hydrocarbon having at least one double bond. Alkenyl is, for example, 2 to 20 carbon atoms, typically 2 to 10, 2 to 8, 2 to 6, 2 to 5, 2 to 4, 2 to 3, 3 to. It has 6, 3-8, 4-6, 4-7, or 4-8 carbon atoms. The alkenyl may be linear or branched. Examples of alkenyl are, but are not limited to, vinyl (-CH = CH ₂ ), allyl (-CH ₂ CH = CH ₂ ), -CH = CH (CH ₃ ), -CH = C (CH ₃ ) ₂ , -C (CH ₃ ) = CH ₂ , -C (CH ₃ ) = CH (CH ₃ ), -C (CH ₂ CH ₃ ) = CH ₂ , 1,3-Butadienyl (-CH = CH-CH = CH ₂₎ ), And hepta-1,6-diene-4-yl (-CH _2- (CH ₂ CH = CH ₂ ) ₂ ). Alkenyl may be substituted with one or more substituents (eg, one, two, three, four, five or more) which may be the same or different.

As used herein, the term "alkynyl" means a monovalent group resulting from the loss of one hydrogen atom in an aliphatic unsaturated hydrocarbon having at least one triple bond. Alkynes are, for example, 2 to 20 carbon atoms, typically 2 to 10, 2 to 8, 2 to 6, 2 to 5, 2 to 4, 2 to 3, 3 to. It has 6, 4-6, 4-7, or 4-8 carbon atoms. The alkynyl may be linear or branched. Examples of alkynyl include, but are not limited to, ethynyl (-C≡CH), - C≡C (CH 3), - C≡C (CH 2 CH 3), - CH 2 C≡CH, -CH 2 C There are ≡ C (CH ₃ ) and -CH ₂ _{C ≡ C (CH 2} CH ₃ ). The alkynyl may be substituted with one or more substituents (eg, one, two, three, four, five or more) which may be the same or different.

The term "alkoxy" used herein means -OR. R is, for example, an alkyl substituted with one or more substituents (eg, one, two, three, four, five or more) which may be identical or different. Alkenyl, alkynyl, non-aromatic carbocyclic group, non-aromatic heterocyclic group, aromatic carbocyclic group, aromatic heterocyclic group and the like. Examples of alkoxy include, but are not limited to, methoxy (-O-methyl), ethoxy (-O-ethyl), propoxy (-O-propyl), -O-isopropyl, -O-2-methyl-1-propyl. , -O-2-methyl-2-propyl, -O-2-methyl-1-butyl, -O-3-methyl-1-butyl, -O-2-methyl-3-butyl, -O-2, 2-Dimethyl-1-propyl, -O-2-methyl-1-pentyl, 3-O-methyl-1-pentyl, -O-4-methyl-1-pentyl, -O-2-methyl-2-pentyl , -O-3-methyl-2-pentyl, -O-4-methyl-2-pentyl, -O-2,2-dimethyl-1-butyl, -O-3,3-dimethyl-1-butyl,- There are O-2-ethyl-1-butyl, -O-butyl, -O-isobutyl, -Ot-butyl, -O-pentyl, -O-isopentyl, -O-neopentyl, and -O-hexyl. Alkoxy may be substituted with one or more substituents (eg, one, two, three, four, five or more) which may be the same or different.

The term "haloalkyl" means an alkyl substituted with at least one (eg, one, two or three) halogens. Haloalkyl includes fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl. Fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl can each have at least one (eg, one, two, or three) fluorine, chlorine, bromine, and iodine atoms. Examples of haloalkyl include, but are not limited to, fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, dichloromethyl, dibromomethyl, diiodomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, triiodomethyl, fluoroethyl, Chloroethyl, bromoethyl, iodoethyl, fluoropropyl, chloropropyl, bromopropyl, iodopropyl, fluorobutyl, chlorobutyl, bromobutyl, iodobutyl, fluoropentyl, chloropentyl, bromopentyl, iodopentyl, fluorohexyl, chlorohexyl, bromohexyl, iodohexyl , Fluoroheptyl, chloroheptyl, bromoheptyl, iodoheptyl, fluorooctyl, chlorooctyl, bromooctyl, iodooctyl and the like. Haloalkyl may be substituted with one or more substituents (eg, one, two, three, four, five or more) which may be the same or different.

As used herein, the term "acyl" means a group represented by -CO-R'. R'is, for example, an alkyl substituted with one or more substituents (eg, one, two, three, four, five or more) which may be identical or different. , Alkenyl, alkynyl, non-aromatic carbocyclic group, non-aromatic heterocyclic group, aromatic carbocyclic group, aromatic heterocyclic group and the like. Examples of acyls include, but are not limited to, acetyl (-COCH ₃ ), ethylcarbonyl, propylcarbonyl, pentylcarbonyl, cyclohexylcarbonyl, octylcarbonyl, 2-ethylhexylcarbonyl, dodecylcarbonyl, benzoyl (-CO-Ph), halogens. There are benzoyl compounds (eg 4-fluorobenzoyl (-CO-Ph-F)), benzylcarbonyl, naphthylcarbonyl, and pyridylcarbonyl. Acyls may be substituted with one or more substituents (eg, one, two, three, four, five or more) which may be the same or different.

As used herein, the term "alkoxycarbonyl" means -CO-alkoxy, ie-COOR. R is described in the section "Alkoxy".
As used herein, the term "hydroxy" or "hydroxyl" means -OH.
As used herein, the term "hydroxyalkyl" refers to at least one (eg, one, two, three, four or more) hydrogen atoms of an alkyl substituted with an -OH group. means. Examples of hydroxyalkyl include, but are not limited to, 1-hydroxyethyl, 2-hydroxyethyl, 1,1-dihydroxyethyl, 1,2-dihydroxyethyl, 2,2-dihydroxyethyl, 1,1,2-tri There are hydroxyethyl, 1,2,2-trihydroxyethyl, 2,2,2-trihydroxyethyl, and 1,2,3-trihydroxypropyl.

As used herein, the term "carboxy" means -COOH.
As used herein, the term "acyloxy" means -O-acyl, i.e. -O-CO-R'. R'is explained in the item of "acyl". Examples of acyloxy include, but are not limited to, acetoxy (-OCOCH ₃ ), _{-OCO-nC 15} H ₃₁ , and -OCO-nC ₁₇ H ₃₅ .
As used herein, the term "carbonyl" means-(C = O)-.
The term "oxo" as used herein means = O.
The term "nitro" as used herein means _{-NO 2.}
As used herein, the term "amino" means _{-NH 2.}
As used herein, the term "alkylamino" means an amino group substituted with one or two alkyl groups. When clarifying the number of alkyl groups, it is described as "monoalkylamino" or "dialkylamino".
The term "halogen" or "halo" means fluoro (-F), chloro (-Cl), bromo (-Br), and iodine (-I).

As used herein, the term "non-aromatic carbocyclic ring" means a cyclic saturated hydrocarbon or a cyclic non-aromatic unsaturated hydrocarbon. When the non-aromatic carbocyclic ring is a cyclic saturated hydrocarbon, it is particularly referred to as "saturated non-aromatic carbocyclic ring". When the non-aromatic carbocycle is a cyclic non-aromatic unsaturated hydrocarbon, it is particularly referred to as an "unsaturated non-aromatic carbocycle". Unsaturated non-aromatic carbocycles are one or more (eg, one, two, three or four) double bonds, one or more (eg, one, two, three or four). ) Can have a triple bond or a combination thereof. The non-aromatic carbocyclic ring may be a monocyclic ring or a condensed ring such as a bicyclic ring or a tricyclic ring. One ring of a non-aromatic carbon ring is, for example, a 3-10 membered ring, typically a 3-8 membered ring, a 3-6 membered ring, a 4-6 membered ring, a 5-6 membered ring, a 5-membered ring. It is a ring or a 6-membered ring. Examples of non-aromatic carbocycles include, but are not limited to, cycloalkanes and cycloalkenes, but more specifically cyclopropane, cyclobutane, cyclopentane, which are unsubstituted or substituted with one or more substituents. Cyclopentene, cyclopentadiene, cyclohexane, and cyclohexene and the like. The non-aromatic carbocycles may be substituted with one or more substituents (eg, one, two, three, four, five or more) which may be the same or different.
As used herein, the term "non-aromatic carbocyclic group" means a monovalent group resulting from the loss of one hydrogen atom in the non-aromatic carbocyclic ring.

As used herein, the term "non-aromatic heterocycle" is a saturated or unsaturated non-aromatic ring having one or more identical or different heteroatoms arbitrarily selected from O, S and N in the ring. It means a ring. When the non-aromatic heterocycle is a saturated non-aromatic ring, it is particularly referred to as a "saturated non-aromatic heterocycle". When the non-aromatic heterocycle is an unsaturated non-aromatic ring, it is particularly referred to as an "unsaturated non-aromatic heterocycle". Unsaturated non-aromatic heterocycles are one or more (eg, one, two or three) double bonds, one or more (eg, one, two or three) triple bonds, or You can have a combination of them. The non-aromatic heterocycle may be a monocyclic ring or a condensed ring such as a bicyclic ring or a tricyclic ring. One ring of a non-aromatic heterocycle is, for example, a 3-10 membered ring, typically a 3-8 membered ring, a 3-6 membered ring, a 4-6 membered ring, a 5-6 membered ring, a 5-membered ring. It is a ring or a 6-membered ring. Examples of non-aromatic heterocycles are, but are not limited to, tetrahydrofuran, dihydrofuran (2,5-dihydrofuran, or 2,3-dihydrofuran) unsubstituted or substituted with one or more substituents. , Tetrahydropyran, dihydropyran (eg, 3,4-dihydro-2H-pyran), pyrrolidine, pyrrolin, piperazine, and piperazine. Non-aromatic heterocycles may be substituted with one or more substituents (eg, one, two, three, four, five or more) which may be the same or different. The non-aromatic heterocycle may contain a lactone.
As used herein, the term "non-aromatic heterocyclic group" means a monovalent group resulting from the loss of one hydrogen atom in a non-aromatic heterocycle.

As used herein, the term "aromatic carbocycle" means a cyclic aromatic hydrocarbon. The aromatic carbocycle may be a monocyclic ring or a condensed ring such as a bicyclic ring or a tricyclic ring. One ring of an aromatic carbon ring is, for example, a 3 to 10-membered ring, typically a 3- to 8-membered ring, a 3- to 6-membered ring, a 4- to 6-membered ring, a 5- to 6-membered ring, or a 5-membered ring. Or it is a 6-membered ring. Examples of aromatic carbocycles include, but are not limited to, benzene, naphthalene, and anthracene, which are unsubstituted or substituted with one or more substituents. The aromatic carbocycles may be substituted with one or more substituents (eg, one, two, three, four, five or more) which may be the same or different.
As used herein, the term "aromatic carbocyclic group" means a monovalent group resulting from the loss of one hydrogen atom in the aromatic carbocycle.

As used herein, the term "aromatic heterocycle" means an aromatic ring having one or more identical or different heteroatoms arbitrarily selected from O, S and N in the ring. The aromatic heterocycle may be a monocyclic ring or a condensed ring such as a bicyclic ring or a tricyclic ring. One ring of an aromatic heterocycle is, for example, a 3-10 membered ring, typically a 3-8 membered ring, a 3-6 membered ring, a 4-6 membered ring, a 5-6 membered ring, a 5-membered ring. Or it is a 6-membered ring. Examples of aromatic heterocycles include, but are not limited to, furan, pyrrole, pyrazole, pyridine, pyridazine, pyrimidine, pyrazine, and oxazole, which are unsubstituted or substituted with one or more substituents. Aromatic heterocycles may be substituted with one or more substituents (eg, one, two, three, four, five or more) which may be the same or different.
As used herein, the term "aromatic heterocyclic group" means a monovalent group resulting from the loss of one hydrogen atom in an aromatic heterocycle.

As used herein, the term "substituent" is one or more (eg, one, two, three, four, five or more) that can be introduced in a chemical structural formula. ) Means the group. When a plurality of substituents are introduced, the substituents may be the same or different. Examples of substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, acyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, acyloxy, nitro, amino, alkylamino, halo, oxo, alkylidene, non-. There are aromatic carbocyclic groups, non-aromatic heterocyclic groups, aromatic carbocyclic groups, aromatic heterocyclic groups and the like.

As used herein, the term "salt" has the broadest meaning used in the art of the invention and generally includes an inorganic acid or an inorganic base, or an organic acid or an organic base, an acid or It can be formed using bases. Examples of salts include, but are not limited to alkali metal salts, such as, but not limited to, lithium, potassium, and sodium; alkaline earth metal salts, such as, but not limited to, barium, calcium, and magnesium; transition metal salts. , For example, but not limited to zinc; and other metal salts, such as, but not limited to, sodium hydrogen phosphate and disodium phosphate; salts of mineral acids, such as, but not limited to, hydrochlorides and sulfates; organic acids. Salts such as, but not limited to, acetate, lactate, maleate, malate, tartrate, citrate, ascorbate, succinate, butyrate, valerate, fumarate, and Organic sulfonates; and amine salts such as, but not limited to, lysine, N, N'-dibenzylethylenediamine, chloroprocine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, prokine. , N-benzylphenethylamine, 1-para-chlorobenzyl-2-pyrrolidin-1'-ylmethyl-benzimidazole, diethylamine and other alkylamines, piperazine and tris (hydroxymethyl) aminomethane. Further, the salt may include an acid addition salt such as a carboxylic acid addition salt or a dicarboxylic acid addition salt (for example, a maleic acid addition salt or a fumaric acid addition salt), and a base addition salt.

The term "pharmaceutically acceptable" as used herein means that it is not harmful to a subject, eg, a mammal, including humans, especially humans.

As used herein, the term "solvate" has the broadest meaning used in the art of the invention and generally includes the association of one or more solvent molecules with a compound. Means a solvent compound. Examples of the solvent include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, acetic acid and the like. Solvates include, for example, monosolvates, disolvates, trisolvates, and tetrasolvates. When the solvent is water, the solvate is a hydrate.

The term "stereoisomer" as used herein has the broadest meaning used in the art of the present invention. Stereoisomers include diastereomers (such as cis-trans isomers) and enantiomers.
The term "tautomer" as used herein has the broadest meaning used in the art of the present invention. Tautomers include keto-enol tautomers.

As used herein, the term "subject" means an animal, typically a mammal, including human and non-human animals. Non-human animals include, for example, non-human mammals such as rats, mice, guinea pigs, rabbits, monkeys, dogs, cats, or mini pigs. When a subject is a human, the subject is also referred to as a "subject" or "patient". When the subject is a human, the subject may be male or female. When the subject is a human, the age of the subject is not particularly limited, and is, for example, a newborn baby, an infant, an infant, a child (boy), an adolescent, a middle-aged person, a middle-aged person, or an old person. The race of the subject is not particularly limited, but is, for example, Japanese.

As used herein, the term "about" has the broadest meaning used in the art of the present invention and generally means the tolerable degree of error in the numbers shown. The term "about" means, for example, a variation of ± 0.1 to 20%, ± 0.1 to 10%, ± 0.1 to 5%, ± 0.1 to 1.0%, or ± 0.1 to 0.5% over a given value or range of values. Means that there is.

The term "treatment" as used herein has the broadest meaning used in the art of the present invention and generally alleviates or reduces symptoms associated with a particular illness or disorder (eg, psychiatric illness). Means to improve or eradicate.

As used herein, the term "prevention" has the broadest meaning used in the art of the invention and generally pre-occurs symptoms associated with a particular illness or disorder (eg, psychiatric illness). Preventing, for example, giving the drug to a patient at risk for a mental illness before the onset of the symptom.

As used herein in the context of a particular illness or disorder (eg, a psychiatric disorder), the term "management" has the broadest meaning used in the art of the invention and is a recurrence of a particular illness or disorder. To prevent patients with a particular disease or disorder from staying in remission, and / or to maintain a reduction or avoidance of the severity of symptoms associated with a particular disease or disorder. Contains.

As used herein, the terms "carrier" and "injector" have the broadest meaning used in the art of the present invention and are generally commonly used depending on the dosage form and the like. Means a toxic, inert solid, semi-solid or liquid substance.

As used herein, the term "effective amount" or "effective amount" means the amount of compound or composition that can achieve the desired effect. In some embodiments, "effective amount" or "effective amount" means the amount of a compound or pharmaceutical composition capable of treating, preventing or managing a psychiatric disorder.

(2. Mental illness treated, prevented or controlled by the present invention)
In one embodiment, the psychiatric disorder treated, prevented or controlled by the present invention is a psychiatric disorder resulting from a mutation in the UGT1A1 gene. In another embodiment, the psychiatric disorder treated, prevented or controlled by the present invention is a psychiatric disorder with jaundice. "Mental illness with jaundice" includes the co-occurrence of jaundice and psychiatric illness. Jaundice may develop first, followed by a mental illness, mental illness may develop first, then jaundice may develop, or jaundice and mental illness may develop at the same time. In certain embodiments, psychiatric disorders resulting from UGT1A1 gene mutations are associated with jaundice. In a specific embodiment, jaundice is constitutional jaundice.

Specific examples of psychiatric disorders treated, prevented or controlled by the present invention include, but are not limited to, schizophrenia, attention deficit hyperactivity disorder (ADHD), due to UGT1A1 gene mutation or with jaundice. Autism, Alzheimer's disease, cognitive dysfunction, depression, bipolar disorder (manic depression), cerebral neurodevelopment disorder, cognitive dysfunction due to neuropathy due to infection during pregnancy, psychiatric disorder due to immune disorder, epilepsy , Cerebral organic psychiatric disorder, addictive psychiatric disorder, intellectual disorder (mental retardation), psychiatric disorder, neuropathy, plum toxic psychiatric disorder, senile psychiatric disorder, cerebrovascular psychiatric disorder, psychiatric disorder due to head trauma, non- There are typical intrinsic psychiatric disorders, endocrine psychiatric disorders and extrinsic psychiatric disorders, and degenerative psychiatric disorders. Preferably, the psychiatric disorders treated, prevented or controlled by the present invention are schizophrenia or attention deficit hyperactivity disorder (ADHD) due to UGT1A1 gene mutation, or schizophrenia or attention deficit hyperactivity disorder with constitutional jaundice. It is schizophrenia (ADHD).

The UGT1A1 gene mutation is known to those skilled in the art (see, for example, Non-Patent Document 5). In "UGT1A1 gene mutation", for example, one, a part or a plurality of bases of the UGT1A1 gene are mutated, and the activity of the UGT1A1 gene is reduced as compared with normal (for example, about 5%, about 10%, about 20%, It can mean a decrease of about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% or about 95% or more) or disappear. Examples of UGT1A1 gene mutations include mutations in the promoter region, mutations in the coding region, frame-shift mutations, specifically, frame-shift mutations due to 1-base (G) deletion, homozygous Y486D, to the TATA box in the promoter region. TA homozygous insertion (TA7 / 7), homozygous G71R, combination of TA7 / 6 and heterozygous G71R, homozygous or heterozygous Y486D and P229Q, heterozygous P364L, homozygous Alternatively, there are heterozygous TA7, G71R, and heterozygous Y486D, and any combination of one or more of these.

Psychiatric disorders treated, prevented or controlled by the present invention can be caused by serotonin hypertransmission in the brain. Mutations in the UGT1A1 gene can cause serotonin hypertransmission in the brain without affecting dopaminergic nerves, transmission and / or concentration in the brain. Thus, in certain embodiments, the psychiatric disorders treated, prevented or controlled by the present invention are associated with serotonin hypertransmission in the brain, but dopamine transmission in the brain is unchanged. Mutations in the UGT1A1 gene can cause increased levels of serotonin in the brain and / or increased serotonin nerves in the brain. Thus, in certain embodiments, the psychiatric disorders treated, prevented or controlled by the present invention are caused by increased levels of serotonin in the brain and / or increased serotonin nerves in the brain. Mutations in the UGT1A1 gene can increase bilirubin levels in blood or urine, resulting in jaundice. Thus, in certain embodiments, the psychiatric disorders treated, prevented or controlled by the present invention are associated with increased levels of bilirubin in blood or urine. In certain embodiments, the psychiatric disorders treated, prevented or controlled by the present invention are associated with jaundice.

In one embodiment, the subject treated, prevented or controlled by the present invention has a psychiatric disorder resulting from a mutation in the UGT1A1 gene. In another embodiment, the subject treated, prevented or controlled by the present invention has a psychiatric disorder and jaundice. In certain embodiments, the subject treated, prevented or controlled by the present invention has a psychiatric disorder and jaundice due to a mutation in the UGT1A1 gene. In a specific embodiment, jaundice is constitutional jaundice. In one embodiment, the subject treated, prevented or controlled by the present invention has a UGT1A1 gene mutation. Whether or not the subject has the UGT1A1 gene mutation can be easily determined by a method known to those skilled in the art. Mutations in the UGT1A1 gene can cause serotonin overtransmission in the brain. Thus, in certain embodiments, the subject treated, prevented or controlled by the present invention results in serotonin hypertransmission in the brain. Mutations in the UGT1A1 gene can cause serotonin hypertransmission in the brain without affecting dopaminergic nerves, transmission and / or concentration in the brain. Thus, in certain embodiments, the subject treated, prevented or controlled by the present invention has no changes in dopaminergic nerves, transmission and / or concentration in the brain. In certain embodiments, the subject treated, prevented or controlled by the present invention has serotonin hypertransmission in the brain but no change in dopamine transmission in the brain. Mutations in the UGT1A1 gene can cause increased levels of serotonin in the brain and / or increased serotonin nerves in the brain. Thus, in certain embodiments, the subject treated, prevented or controlled by the present invention has increased serotonin levels in the brain and / or serotonin nerves in the brain. UGT1A1 mutations increase bilirubin levels in blood or urine, and as a result, UGT1A1 mutations can cause jaundice. Thus, in certain embodiments, the subject treated, prevented or controlled by the present invention has an increased concentration of bilirubin in blood or urine. In certain embodiments, the subject treated, prevented or controlled by the present invention has jaundice.

The brain is selected from the group consisting of, for example, the brain stem, frontal lobe, striatum, hippocampus, and origin nuclei (particularly raphe nuclei, eg dorsal raphe nuclei) (eg, one, two). One, three, or four) or more parts. With respect to serotonin, the brain is preferably the frontal lobe and hippocampus. With respect to dopamine, the brain is preferably the frontal lobe, striatum, and hippocampus.

"Increase" and "excess" are increased compared to healthy subjects, increased compared to oneself in the past, statistically significantly increased, or in the normal control group. It can mean greater than the median. "Increasing" or "greater than the median" means, for example, about 1.2 times, about 1.5 times, about 2 times, about 3 times, about 4 times, about 5 times, about 10 times, about 15 times, It can mean about 20 times, about 30 times, about 50 times, about 100 times or more, increasing or greater than the median. "No effect", "no change", and "no change" are, for example, the same as those of healthy subjects, the same as those of subjects without UGT1A1 gene mutation, and the past. It can mean that it is the same as itself, that there is no statistically significant difference, or that it is the same as the median of the normal control group. “Same” and “no significant difference” mean, for example, that the p value is 0.05 or less or 0.01 or less, or the difference is about 0%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about. It can mean about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 10%, about 20%, or about 30%.

(3. Serotonin transmission inhibitor)
The pharmaceutical composition of the present invention contains a serotonin transmission inhibitor. Serotonin transmission inhibitors can be used to treat, prevent or manage psychiatric disorders. Serotonin transmission inhibitors can be used as therapeutic, prophylactic or controlled agents for psychiatric disorders. Serotonin transmission inhibitors can be used in the treatment, prevention or management of psychiatric disorders. Serotonin transmission inhibitors can be used in methods of treating, preventing or managing psychiatric disorders. Serotonin transmission inhibitors can be used in the manufacture of pharmaceuticals for the treatment, prevention or control of psychiatric disorders. Serotonin transmission inhibitors can inhibit serotonin transmission and / or secretion. Here, the mental illness may be described in the above-mentioned "2. Mental illness treated, prevented or managed by the present invention".

In one embodiment, risperidone (3- [2- [4- (6-fluoro-1,2-benzoisoxazole-3-yl) -1-piperidinyl] ethyl]-because it has a strong blocking effect on dopamine receptors. 6,7,8,9-Tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one) is excluded. In one embodiment, serotonin transmission inhibitors target serotonin receptors (5-HT receptors). In one embodiment, the serotonin transmission inhibitor binds to serotonin receptors (5-HT receptors). In one embodiment, the serotonin transmission inhibitor targets only serotonin receptors (5-HT receptors). In one embodiment, the serotonin transmission inhibitor binds only to serotonin receptors (5-HT receptors). The serotonin receptor (5-HT receptor) is preferably a 5-HT _2A receptor, a 5-HT _2c receptor, a 5-HT _1A receptor, a 5-HT _1B receptor, or a 5-HT _1D receptor. The body.

In one embodiment, the serotonin transmission inhibitor is selected from the group consisting of _{5-HT 2A} receptor, 5-HT _2c receptor, 5-HT _1A receptor, 5-HT _1B receptor and 5-HT _{1D receptor.} A substance that binds to one or more (eg, one, two, three, four, or five). In a preferred embodiment, the serotonin transmission inhibitor _{binds to a 5-HT 2A} receptor-binding substance, a 5-HT _2c receptor-binding substance, a 5-HT _2A receptor and a 5-HT _2c receptor. A substance, a substance that binds to a 5-HT _1A receptor, a substance that binds to a 5-HT _1B receptor, or a substance that binds to a 5-HT _1B receptor and a 5-HT _1D receptor.

In certain embodiments, the serotonin transmission inhibitor is an agonist or antagonist of serotonin receptors (5-HT receptors). For example, cellotonin transmission inhibitors include 5-HT _2A receptor antagonist, 5-HT _2c receptor antagonist, 5-HT _{2A / 2c} receptor antagonist, 5-HT _1A receptor agonist, 5-HT _1B receptor agonist, It is a 5-HT _1D receptor agonist or a 5-HT _{1B / 1D} receptor agonist. "5-HT _{2A / 2c} receptor antagonist" means that it is both a 5-HT _2A receptor antagonist and a 5-HT _2c receptor antagonist. "5-HT _{1B / 1D} receptor agonist" means that it is both a 5-HT _1B receptor agonist and a 5-HT _1D receptor agonist.

The present inventors have found that there is no change in dopamine concentration in the brain in psychiatric disorders caused by UGT1A1 gene mutation (see Example 1). Therefore, in a preferred embodiment, the serotonin transmission inhibitor does not affect the dopamine concentration in the brain. In one embodiment, the serotonin transmission inhibitor inhibits only serotonin transmission in the brain. In one embodiment, the serotonin transmission inhibitor is not a serotonin dopamine antagonist (SDA). In one embodiment, the serotonin transmission inhibitor is not a dopamine transmission inhibitor. In one embodiment, the serotonin transmission inhibitor does not target dopamine receptors in the brain. In one embodiment, serotonin transmission inhibitors do not inhibit or activate dopamine transmission in the brain. The brain is one (eg, one, two) selected from the group consisting of, for example, the brain stem, frontal lobe, striatum, hippocampus, and origin nucleus (particularly raphe nuclei, eg dorsal raphe nuclei). , 3 or 4) or more.

In one embodiment, the serotonin transmission inhibitor is a substance having a low binding affinity to a dopamine receptor, a substance having a high binding affinity to a dopamine receptor as compared to a binding affinity to a dopamine receptor, or a dopamine receptor. It is a substance that does not bind to the body. In one embodiment, the serotonin transmission inhibitor is not a dopamine receptor antagonist or agonist. In a specific embodiment, the serotonin transmission inhibitor comprises a 5-HT _2A receptor, a 5-HT _2c receptor, a 5-HT _1A receptor, a 5-HT _1B receptor, and a 5-HT _1D receptor. Dopamine receptor, a substance that binds to at least one (eg, 1, 2, 3, 4, or 5) receptors selected from the group but has a low binding affinity to the dopamine receptor. A substance having a high binding affinity for these serotonin receptors as compared with a binding affinity for the dopamine receptor, or a substance that does not bind to the dopamine receptor. In a specific embodiment, the serotonin transmission inhibitor is a 5-HT _2A receptor antagonist, a 5-HT _2c receptor antagonist, a 5-HT _{2A / 2c} receptor antagonist, a 5-HT _1A receptor agonist, 5- HT _1B receptor agonist or 5-HT _{1B / 1D} receptor agonist, but with low binding affinity for dopamine receptor, binding to these serotonin receptors compared to binding affinity for dopamine receptor An antagonist or agonist that has a high affinity or does not bind to the dopamine receptor.

Dopamine receptors are at least one (eg, one, two, etc.) selected from the group consisting of _{D 1} receptor, D ₂ receptor, D ₃ receptor, D ₄ receptor, and D _{5 receptor.} It can be 3, 4 or 5). Dopamine D ₁ receptor, dopamine D ₂ receptor, dopamine D ₃ receptor, dopamine D ₄ receptor, and dopamine D ₅ receptor are D ₁ receptor, D ₂ receptor, D ₃ receptor, D, respectively. Also called ₄ receptor and D _{5 receptor.} The serotonin transmission inhibitor is, for example, at least one (eg, one) selected from the group consisting of _{D 1} receptor, D ₂ receptor, D ₃ receptor, D ₄ receptor, and D _{5 receptor.} Substances with low binding affinity for 2, 3, 4 or 5), substances with high binding affinity for serotonin receptors compared to their binding affinity for dopamine receptors, or these It can be a substance that does not bind to the dopamine receptor. In a specific embodiment, the serotonin transfer inhibitors, have high binding affinity to D ₂ binding affinity substance having low to the receptor, as compared to the binding affinity for D ₂ receptors serotonin receptor material or D ₂ does not bind to the receptor substance, or D ₂ receptors and D ₃ receptors and D ₄ binding low affinity substance to the receptor, D ₂ receptors and D ₃ receptors and D ₄ receptors It is a substance that has a high binding affinity to the serotonin receptor as compared with the binding affinity to and, or a substance that does not bind to the _{D 2} receptor, the D ₃ receptor, and the D _{4 receptor.}

Examples of 5-HT _{2A / 2c} receptor antagonists include:
Ketanserin (3- [2- [4- (4-fluorobenzoyl) piperidine-1-yl] ethyl] quinazoline-2,4 (1H, 3H) -dione);
Sarpogrelate hydrochloride (1- [1-dimethylaminomethyl-2- [2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] hydrochloride);
Methysergide ((6aR) -4,7-dimethyl-9α-[[[(S) -1- (hydroxymethyl) propyl] amino] carbonyl] -4,6,6a, 7,8,9-hexahydroindro [4,3-fg] Quinoline);
Cyproheptadine (4- [5H-dibenzo [a, d] cycloheptene-5-iriden] -1-methylpiperidine); or cyclobenzaprine (3- (5H-dibenzo [a, d] cycloheptene-5-iriden) -N , N-Dimethyl-1-propanamine); or pharmaceutically acceptable salts, solvates, stereoisomers or tethered organisms thereof.
Examples of 5-HT _2A receptor antagonists include:
Ritanserin (6- [2- [4- (4,4'-difluorobenzhydrylidene) piperidino] ethyl] -7-methyl-5H-thiazolo [3,2-a] pyrimidin-5-one); or its drug Acceptable salts, solvates, stereoisomers or tautomers.

Examples of 5-HT _1A receptor agonists include:
8-OH-DPAT (7- (dipropylamino) -5,6,7,8-tetrahydronaphthalene-1-ol);
5-Carboxamide Tryptamine (5-CT) (3- (2-Aminoethyl) -1H-Indole-5-Carboxamide);
Tandospirone ((1β, 2β, 3β, 4β) -N- [4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl] -2,3-bicyclo [2.2.1] heptane dicarboimide);
Ipsapilone (2- [4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl] -1,2-benzoisothiazole-3 (2H) -one 1,1-dioxide); or buspirone (8-{ 4- [4- (Pyrimidine-2-yl) piperazin-1-yl] butyl} -8-azaspiro [4.5] decane-7,9-dione); or a pharmaceutically acceptable salt, solvate, steric Isomer or tethered organism.

Examples of 5-HT _1B receptor agonists include:
CGS-12066A (4- (4-methylpiperazin-1-yl) -7- (trifluoromethyl) pyrolo [1,2-a] quinoxaline);
CP-93129 (1,4-dihydro-3-[(1,2,3,6-tetrahydropyridine) -4-yl] -5H-pyrrolo [3,2-b] pyridine-5-one); or triptan Pharmaceuticals; or pharmaceutically acceptable salts, solvates, stereoisomers or tautomers thereof.
Triptan preparations can also be 5-HT _{1B / 1D receptor agonists.}

Examples of triptan preparations include:
Sumatriptan (N-methyl- [3- [2- (dimethylamino) ethyl] -1H-indole-5-yl] methanesulfotanamide);
Zolmitriptan ((4S) -4β-[[3- [2- (dimethylamino) ethyl] -1H-indole-5-yl] methyl] oxazolidine-2-one);
Eletriptan (3-[[(2R) -1-methyl-2-pyrrolidinyl] methyl] -5- [2- (phenylsulfonyl) ethyl] -1H-indole);
Rizatriptan (N, N-dimethyl-2- [5- (1H-1,2,4-triazole-1-ylmethyl) -1H-indole-3-yl] ethaneamine); or naratriptan (N-methyl-3) -(1-Methyl-4-piperidyl) -1H-indol-5- (etanesulfonamide)); or a pharmaceutically acceptable salt, solvate, steric isomer or tautomer thereof.

In one embodiment, the serotonin transmission inhibitor is a compound represented by the following formula (I), or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

(During the ceremony,
X ¹ is CR ^a R ^b , CO, NR ^c , CR ^d or N;
X ² is CR ^e , N or C;
X ³ is CR ^f , N or C;
X ⁴ is CR ^g , N or C;
Are R ¹ and R ² independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, acyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, acyloxy, nitro, amino, alkylamino, halo or oxo? , or R ¹ and R ² are atoms to which they are attached (i.e., X ³ and X ⁴⁾ with substituted with unsubstituted or one or more R ^s1, an aromatic carbocyclic or aromatic heterocyclic Can be formed;
R ^s1 is alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, acyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, acyloxy, nitro, amino, alkylamino or halo, respectively, independently on each appearance;
R ³ is an alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, acyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, acyloxy, nitro, amino, alkylamino, or halo, independently of each appearance;
R ^a , R ^b , R ^c , R ^d , R ^e , R ^f and R ^g are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, acyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, respectively. Acyloxy, nitro, amino, alkylamino, or halo;
Y ¹ and Y ² are hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, acyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, acyloxy, nitro, amino, alkylamino or halo, respectively, on each appearance. ;
Z is CH or N;
Whether B ¹ and B ² are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, acyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, acyloxy, nitro, amino, alkylamino, or halo, respectively. or B ¹ and B ^2, atom to which they are attached (i.e., Z) together, which is unsubstituted or substituted by one or more R ^s2, non-aromatic carbocyclic ring saturated or unsaturated or non-aromatic heterocyclic Can form a ring;
R ^s2 is alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, acyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, acyloxy, nitro, amino, alkylamino or halo, respectively, independently on each appearance;
m is an integer from 0 to 4;
n is an integer from 0 to 6;

Represents a single bond or a double bond. ).

The aromatic carbocycle is preferably a monocyclic ring. The aromatic carbocycle is preferably a 5- or 6-membered ring.
The aromatic heterocycle is preferably a monocycle. The aromatic heterocycle is preferably a 5- or 6-membered ring. Aromatic heterocycles preferably have one N. The aromatic heterocycle is more preferably an unsubstituted or one or more R ^s2 substituted pyrroles.

The non-aromatic carbocyclic ring is preferably a monocyclic ring. The non-aromatic carbocycle is preferably a 5- or 6-membered ring. More preferably, the non-aromatic carbocycle is saturated. Even more preferably, the non-aromatic carbocycle is cycloalkyl, eg, cyclohexane, ^{unsubstituted or substituted with one or more Rs2.}
The non-aromatic heterocycle is preferably a monocycle. More preferably, the non-aromatic heterocycle is a 5- or 6-membered ring. More preferably, the non-aromatic heterocycle is saturated. Even more preferably, the non-aromatic heterocycle has one N. Even more preferably, the non-aromatic heterocycle is piperidine or piperazine, ^{unsubstituted or substituted with one or more Rs2.}

In the equation, if n is 0,-(C (Y ¹ ) (Y ² )) _n- does not exist and X ² and Z are directly combined. When n is 1, 2, 3, 4, 5, and 6,-(C (Y ¹ ) (Y ² )) _n -is methylene chain, ethylene chain, propylene chain, butylene chain, pentylene chain, respectively. And has a hexylene chain. When n is 2-6, each Y ¹ and each Y ^{2 present} may be the same or different and are independently defined above: hydrogen, alkyl, alkenyl, alkynyl, alkoxy, Haloalkyl, acyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, acyloxy, nitro, amino, alkylamino or halo.

If ^{the bond between X 1} and X ² is a single bond, then X ¹ can represent CR ^a R ^b , CO, or NR ^c. If ^{the bond between X 1} and X ² is a double bond, then X ¹ can represent CR ^{d or N.} If ^{the bond between X 1} and X ² is a single bond, then X ² can represent CR ^{e or N.} If ^{the bond between X 1} and X ² is a double bond, then X ² can represent C.

If ^{the bond between X 3} and R ¹ is a single bond, then X ³ can represent CR ^{f or N.} If ^{the bond between X 3} and R ¹ is a double bond, then X ³ can represent C. When ^{the bond between X 3} and R ¹ is a single bond, R ¹ is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, acyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, acyloxy, nitro, amino, It can represent alkylamino or halo. If ^{the bond between X 3} and R ¹ is a double bond, then R ¹ can represent oxo (= O).

If ^{the bond between X 4} and R ² is a single bond, then X ⁴ can represent CR ^{g or N.} If ^{the bond between X 4} and R ² is a double bond, then X ⁴ can represent C. When ^{the bond between X 4} and R ² is a single bond, R ² is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, acyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, acyloxy, nitro, amino, It can represent alkylamino or halo. If ^{the bond between X 4} and R ² is a double bond, then R ² can represent oxo (= O).

Preferably, in formula (I), X ¹ is CH ₂ , CO, or N; X ² is CH, N or C; X ³ is CH or C; X ⁴ is. CH or N; R ¹ is hydrogen or oxo and R ² is hydrogen, or R ¹ and R ² form an unsubstituted aromatic heterocycle with the atoms to which they are attached. Formed; R ³ is haloalkyl or hydroxy; Y ¹ and Y ² are hydrogen; Z is CH or N; B ¹ and B ² are independently alkyl or alkyl, respectively. B ¹ and B ² are, together with the atom to which they are attached, substituted with one R ^s2, to form a non-aromatic heterocyclic ring saturated; R ^s2 is alkyl or acyl; m is 0 or 1 And n is an integer from 0 to 2.

In a specific embodiment, the serotonin transmission inhibitor is a compound represented by the following formula (IA), or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

In a more specific embodiment, the serotonin transmission inhibitor is a compound represented by the following formula (Ia), or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

(Wherein, R ^3, R ^s2 and m are as defined above.).
In certain embodiments, in formula (Ia), R ³ is haloalkyl or hydroxy. Preferably, the haloalkyl is a fluoroalkyl. Preferably, the fluoroalkyl is fluoromethyl, difluoromethyl, or trifluoromethyl, more preferably trifluoromethyl. In certain embodiments, in formula (Ia), m is 0 or 1, preferably 0. In certain embodiments, in formula (Ia), R ^s2 is alkyl or acyl, preferably acyl. Preferably, the alkyl is methyl. Preferably, the acyl is a benzoyl unsubstituted or substituted with one or more substituents. More preferably, the acyl is a halo-substituted benzoyl. More preferably, the acyl is a fluoro-substituted benzoyl. Even more preferably, the acyl is 4-fluorobenzoyl.

In a specific embodiment, the serotonin transmission inhibitor is a compound represented by the following formula (IB), or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

In a more specific embodiment, the serotonin transmission inhibitor is a compound represented by the following formula (Ib), or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

(Wherein, R ^3, R ^s2 and m are as defined above.).
In certain embodiments, in formula (Ib), R ³ is haloalkyl or hydroxy. Preferably, the haloalkyl is trifluoromethyl. Preferably, in formula (Ib), R ³ is hydroxy. In certain embodiments, in formula (Ib), m is 0 or 1. Preferably, in equation (Ib), m is 1. More preferably, m is 1 and R ³ is attached to the 1-position of the 5,6,7,8-tetrahydronaphthalene ring of formula (Ib).

In a specific embodiment, the serotonin transmission inhibitor is a compound represented by the following formula (IC), or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

In a more specific embodiment, the serotonin transmission inhibitor is a compound represented by the following formula (Ic), or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

(Wherein, R ^3, R ^s2 and m are as defined above.).
In certain embodiments, in formula (Ic), R ³ is haloalkyl or hydroxy, preferably haloalkyl. Preferably, the haloalkyl is a fluoroalkyl. Preferably, the fluoroalkyl is fluoromethyl, difluoromethyl, or trifluoromethyl, more preferably trifluoromethyl. In certain embodiments, in formula (Ic), m is 0 or 1, preferably 1. More preferably, m is 1 and R ³ binds to the 7-position of the pyrrolo [1,2-a] quinoxaline ring of formula (Ic). In certain embodiments, in formula (Ic), R ^s2 is alkyl or acyl, preferably alkyl. Preferably, the alkyl is methyl. Preferably, the acyl is a benzoyl unsubstituted or substituted with one or more substituents. More preferably, the acyl is a halo-substituted benzoyl. More preferably, the acyl is a fluoro-substituted benzoyl. Even more preferably, the acyl is 4-fluorobenzoyl.

In equation (I), equation (IA), equation (IB), equation (IC), equation (Ia), equation (Ib) and equation (Ic), if m is an integer of 1 to 4. R ³ binds to any position on the benzene ring. R ³ can be bonded to the benzene ring, for example, as follows.

Each R ³ may be the same or different and independently defined above: alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, acyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, acyloxy, It is selected from nitro, amino, alkylamino, and halo.

In a more specific and preferred embodiment, the serotonin transmission inhibitor is ketanserin (3- [2- [4- (4-fluorobenzoyl) piperidine-1-yl] ethyl] quinazoline-2,4 (1H) having the following structure: , 3H) -dione), or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

In a more specific and preferred embodiment, the serotonin transfer inhibitor is 8-OH-DPAT (7- (dipropylamino) -5,6,7,8-tetrahydronaphthalene-1-ol) having the following structure, or The pharmaceutically acceptable salt, solvate, stereoisomer or tautomer.

In a more specific and preferred embodiment, the compound represented by formula (I) is CGS-12066A (4- (4-methylpiperazin-1-yl) -7- (trifluoromethyl) pyrolo [ 1,2-a] quinoxaline), or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

In one embodiment, the compound of formula (IA) and the compound of formula (Ia) _{bind to 5-HT 2A / 2c} receptors (ie, 5-HT _2A receptor and 5-HT _2c receptor). In one embodiment, the compound of formula (IA) and the compound of formula (Ia) are 5-HT _{2A / 2c} receptor antagonists. In one embodiment, compounds and compounds of formula (Ia) of the formula (IA) is less binding affinity for D ₂ receptors, as compared to the binding affinity for D ₂ receptors to serotonin receptors High binding affinity or does not bind to _{D 2 receptor.} In one embodiment, the compound of formula (IA) and the compound of formula (Ia) have a low binding affinity for _{the D 2} receptor, the D ₃ receptor and the D ₄ _{receptor, the D 2} receptor and the D _{3 receptor.} compared to binding affinity to the receptor and D ₄ receptor is higher binding affinity to serotonin receptors, or D ₂ receptors and D ₃ does not bind to the receptor and D ₄ receptors. In one embodiment, the compound of formula (IA) and the compound of formula (Ia) have a low binding affinity for the dopamine receptor, a binding affinity for the serotonin receptor as compared to a binding affinity for the dopamine receptor. Does not bind to highly potent substances or dopamine receptors.

In one embodiment, the compound of formula (IB) and the compound of formula (Ib) bind to the _{5-HT 1A receptor.} In one embodiment, the compound of formula (IB) and the compound of formula (Ib) are 5-HT _1A receptor agonists. In one embodiment, compounds and compounds of formula (Ib) of the formula (IB) has a low binding affinity for D ₂ receptors, as compared to the binding affinity for D ₂ receptors to serotonin receptors High binding affinity or does not bind to _{D 2 receptor.} In one embodiment, the compound of formula (IB) and the compound of formula (Ib) have a low binding affinity for _{the D 2} receptor, the D ₃ receptor and the D ₄ _{receptor, the D 2} receptor and the D _{3 receptor.} compared to binding affinity to the receptor and D ₄ receptor is higher binding affinity to serotonin receptors, or D ₂ receptors and D ₃ does not bind to the receptor and D ₄ receptors. In one embodiment, the compound of formula (IB) and the compound of formula (Ib) have a low binding affinity for the dopamine receptor, a binding affinity for the serotonin receptor as compared to a binding affinity for the dopamine receptor. Highly sexual or does not bind to dopamine receptors.

In one embodiment, the compound of formula (IC) and the compound of formula (Ic) bind to the _{5-HT 1B receptor.} In one embodiment, the compound of formula (IC) and the compound of formula (Ic) are 5-HT _1B receptor agonists. In one embodiment, compounds and compounds of formula (Ic) of formula (IC) is less binding affinity for D ₂ receptors, as compared to the binding affinity for D ₂ receptors to serotonin receptors High binding affinity or does not bind to _{D 2 receptor.} In one embodiment, the compound of formula (IC) and the compound of formula (Ic) have a low binding affinity for _{the D 2} receptor, the D ₃ receptor and the D ₄ _{receptor, the D 2} receptor and the D _{3 receptor.} compared to binding affinity to the receptor and D ₄ receptor is higher binding affinity to serotonin receptors, or D ₂ receptors and D ₃ does not bind to the receptor and D ₄ receptors. In one embodiment, the compound of formula (IC) and the compound of formula (Ic) have a low binding affinity for the dopamine receptor, a binding affinity for the serotonin receptor as compared to a binding affinity for the dopamine receptor. Highly sexual or does not bind to dopamine receptors.

"K _i " means a binding inhibition constant. K _i value is high binding affinity to a small extent receptors, low binding affinity to as K _i value is greater receptor. In the context of receptors, "low binding affinity" is greater K _i values, for example, K _i values greater than K _i value for the dopamine receptors with risperidone, specifically, 3.57 nM larger K _i value, 3.6 nM larger K _i value, 4.66 nM larger K _i values of about 5 nM or K _i values of, K _i value of greater than about 7.5 nM, K _i value of greater than about 10 nM, about 15 nM or K _i of value, K _i values of at least about 20 nM, K _i values of at least about 30 nM, K _i value of greater than about 40 nM, K _i values of at least about 50 nM, about 75 nM or K _i values of, or about 100 It can mean having _{a K i} value greater than or equal to nM. Risperidone has D ₂ receptor with respect to K _i values of 3.57 nM, K _i values of 3.6 nM to D ₃ receptors, and D ₄ receptors relative to K _i values 4.66 nM. Serotonin transmission inhibitors with high _Ki values may not have dopamine receptor blocking activity.

In the context of binding affinity comparisons, "high binding affinity", eg, "high binding affinity for serotonin receptors compared to binding affinity for dopamine receptors", "to D ₂ receptors" Higher binding affinity for serotonin receptors compared to binding affinity for serotonin receptors "and" binding affinity for D ₂ receptors, D ₃ receptors and D ₄ receptors compared to serotonin receptors "High binding affinity" means that the binding affinity for serotonin receptors is about 10 times higher, about 15 times higher, about 20 times higher, and about 20 times higher than the binding affinity for dopamine receptors. 21 times higher, about 21 times higher, about 22 times higher, about 25 times higher, about 30 times higher, about 35 times higher, about 40 times higher, about 50 times higher, about 60 times higher Higher than, about 70 times higher, about 80 times higher, about 90 times higher, or about 100 times higher, for example, the ratio of _{K i} to dopamine receptor to _{K i to serotonin receptor} Values (ie, _Ki (dopamine receptor) / (K _i (serotonin receptor)) are about 10 or more, about 15 or more, about 20 or more, about 21 or more, about 21 or more, about 22 or more, about 25 or more. , About 30 or more, about 35 or more, about 40 or more, about 50 or more, about 60 or more, about 70 or more, about 80 or more, about 90 or more, or about 100 or more. The body is at least one (eg, one, two, three) selected from the group consisting of _{D 1} receptor, D ₂ receptor, D ₃ receptor, D ₄ receptor, and D _{5 receptor.} , 4 or 5), preferably D ₂ receptors, where the serotonin receptors are 5-HT receptors, such as 5-HT _2A receptors, 5-HT _2c receptors, 5 One or more (eg, one, two, three, four or five) selected from the group consisting of -HT _1A receptor, 5-HT _1B receptor and 5-HT _{1D receptor, preferably.} , 5-HT _2A receptor.

In the context of receptors, "binding" means, for example, that the _Ki value is about 40 nM or less, about 30 nM or less, about 20 nM or less, about 10 nM or less, about 5 nM or less, about 3 nM or less, or It can mean less than about 1 nM. In the context of the receptor, "non-binding" means, for example, that the _Ki value is about 50 nM or more, about 75 nM or more, about 100 nM or more, about 200 nM or more, about 300 nM or more, about 400 nM or more, or It can mean that it is about 500 nM or more.

Serotonin receptors and dopamine receptors are present in the brain. The brain is selected from the group consisting of, for example, the brain stem, frontal lobe, striatum, hippocampus, and origin nucleus (particularly raphe nuclei, eg, dorsal raphe nucleus) (eg, one or two). , 3 or 4) or more.

Whether or not a compound is a serotonin transmission inhibitor can be easily determined by a method known to those skilled in the art. For example, it is possible to determine whether a specific compound inhibits serotonin transmission by a microdialysis method that can measure the serotonin concentration in the brain in a timely manner. In addition, it can be determined whether or not a specific compound binds to a serotonin receptor (5-HT receptor) in the brain. _{The Ki} value of a compound can also be easily determined by a method known to those skilled in the art. Whether or not a compound is a serotonin transmission inhibitor that does not inhibit dopamine transmission in the brain or has a higher binding affinity for serotonin receptors than that for dopamine receptors is also described above. It can be easily determined by the microdialysis method.

Serotonin transmission inhibitors are commercially available. The serotonin transfer inhibitor can be synthesized by an organic chemical synthesis means known to those skilled in the art.

(4. Pharmaceutical composition)
The pharmaceutical composition of the present invention contains a serotonin transmission inhibitor. The pharmaceutical composition of the present invention contains an effective amount of a serotonin transmission inhibitor. The pharmaceutical composition of the present invention may be a therapeutic agent, a preventive agent or a management agent for the mental illness. The pharmaceutical composition of the present invention can be used for treating, preventing or managing the mental illness. The pharmaceutical composition of the present invention can be used in the treatment, prevention or management of the mental illness. The pharmaceutical composition of the present invention can be used in a method for treating, preventing or managing the mental illness. The pharmaceutical composition of the present invention can be used in the manufacture of a pharmaceutical product for treating, preventing or controlling the mental illness. Here, the mental illness may be described in the above-mentioned "2. Mental illness treated, prevented or managed by the present invention". The serotonin transmission inhibitor may be those described in "3. Serotonin transmission inhibitor". The dose, administration method, administration route, administration frequency, administration interval, administration order, administration time, etc. of the pharmaceutical composition of the present invention are not particularly limited and can be determined by a doctor or the like based on the condition of the subject. ..

The pharmaceutical composition of the present invention can further contain a second agent. The second agent may be, for example, another agent for treating, preventing or managing a psychiatric disorder, such as a known antipsychotic agent, an antischizophrenia agent, or an attention deficit hyperactivity disorder (ADHD) agent. Is.

The pharmaceutical composition of the present invention can contain a plurality of (for example, two, three, or more) serotonin transmission inhibitors. The pharmaceutical composition of the present invention may contain, for example, at least one selected from the group consisting of ketanserin, 8-OH-DPAT, and CGS-12066A (eg, one, two, or three). can. In a specific embodiment, the pharmaceutical composition of the present invention comprises ketanserin and 8-OH-DPAT. In another specific embodiment, the pharmaceutical composition of the present invention comprises ketanserin and CGS-12066A. In yet another specific embodiment, the pharmaceutical composition of the present invention comprises 8-OH-DPAT and CGS-12066A. In yet another specific embodiment, the pharmaceutical composition of the present invention comprises ketanserin, 8-OH-DPAT and CGS-12066A.

The pharmaceutical composition of the present invention may be a combination of a plurality of (for example, two, three, or more) pharmaceutical compositions. In certain embodiments, the pharmaceutical composition of the present invention is a combination of a pharmaceutical composition comprising a serotonin transmission inhibitor and a pharmaceutical composition comprising a second agent. The second agent may be, for example, another agent for treating, preventing or managing a psychiatric disorder, such as a known antipsychotic agent, an antischizophrenia agent, or an attention deficit hyperactivity disorder (ADHD) agent. Is. In certain embodiments, the pharmaceutical composition of the present invention is a combination of a first pharmaceutical composition comprising a serotonin transmission inhibitor and a second pharmaceutical composition comprising another serotonin transmission inhibitor. It is a combination of a first pharmaceutical composition containing ketanserin and a second pharmaceutical composition containing 8-OH-DPAT. In a specific embodiment, the pharmaceutical composition of the present invention is a combination of a first pharmaceutical composition comprising ketanserin and a second pharmaceutical composition comprising 8-OH-DPAT. In another specific embodiment, the pharmaceutical composition of the present invention is a combination of a first pharmaceutical composition comprising ketanserin and a second pharmaceutical composition comprising CGS-12066A. In yet another specific embodiment, the pharmaceutical composition of the present invention is a combination of a first pharmaceutical composition comprising 8-OH-DPAT and a second pharmaceutical composition comprising CGS-12066A. In yet another specific embodiment, the pharmaceutical composition of the present invention comprises a first pharmaceutical composition comprising ketanserin, a second pharmaceutical composition comprising 8-OH-DPAT and a third pharmaceutical composition comprising CGS-12066A. It is a combination with. When the pharmaceutical composition of the present invention is a combination of a plurality of (eg, 2, 3 or more) pharmaceutical compositions, they are co-administered, co-administered or sequentially administered. The dose, administration method, administration route, administration frequency, administration interval, administration order, administration time, etc. of each pharmaceutical composition are not particularly limited, and can be determined by a doctor or the like based on the condition of the subject.

The pharmaceutical composition of the present invention may contain one or more pharmaceutically acceptable carriers or excipients in addition to the serotonin transmission inhibitor. When the pharmaceutical composition of the present invention is a combination of a plurality of (for example, two, three, or more) pharmaceutical compositions, each pharmaceutical composition may be independently the same or different. The above pharmaceutically acceptable carriers or excipients can be included.

A pharmaceutically acceptable carrier or excipient is a non-toxic, inert solid, semi-solid or liquid substance. Examples of pharmaceutically acceptable carriers or excipients include, for example, stabilizers, inert diluents, fillers, bulking agents, disintegrants, disintegrant inhibitors, suspending agents, buffers, isotonic. Agents, chelating agents, pH regulators, surfactants, capsule encapsulants, binders, preservatives, antioxidants, lubricants, moisturizers, adsorbents, lubricants or any other pharmaceutical aids, etc. be. Specific examples of pharmaceutically acceptable carriers or excipients include, but are not limited to: water, alcohols (such as ethanol), solvents (such as dimethylsulfoxide), salt water (such as physiological saline). , Or a mixed solution thereof; inorganic salts such as sodium chloride; boric acid, phosphoric acid, acetic acid, citric acid, ε-aminocaproic acid, glutamate, edetic acid, or their corresponding salts, such as sodium salt, potassium salt, Alkali metal salts or alkaline earth metal salts such as calcium salt or magnesium salt; monosaccharides such as glucose (dextrose), mannose, galactose, or fructose; sugar alcohols such as mannitol, inositol, or xylitol; sucrose, lactulose, lactose , Disaccharides such as maltose, trehalose, or cellobiose; polysaccharides such as dextrin, dextran, cellulose, hyaluronic acid, or chondroitin sulfate; starches such as corn starch and potato starch; cellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl Cellulose such as cellulose, hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose acetate, cellulose acetate, or derivatives thereof; human serum albumin; L-amino acids such as glycine, lysine, asparagine, arginine, glutamine, cysteine, aspartic acid, or glutamate; tragacant Gelatin; talc; cocoa butter or wax; wax or beeswax; peanut oil, cotton seed oil, Benibana oil, sesame oil, olive oil, corn oil, soybean oil, or hardened oils; glycols such as ethylene glycol or propylene glycol; Esters such as ethyl oleate or ethyl laurate; agar; potassium hydroxide, sodium hydroxide, magnesium hydroxide or aluminum hydroxide; alginic acid; isotonic salt solution; Ringer's solution; ethyl alcohol; phosphate buffer; lauryl Such as sodium sulfate or magnesium stearate. The pharmaceutically acceptable carrier or excipient can be appropriately selected depending on the type of dosage form, the compound used, and the like.

The amount of the serotonin transmission inhibitor, the second agent, and / or the pharmaceutically acceptable carrier or excipient contained in the pharmaceutical composition of the present invention is not particularly limited, and the psychiatric disorder is treated, prevented or controlled. Any amount that is effective for this is sufficient. The amount of serotonin transmission inhibitor, second agent, and / or pharmaceutically acceptable carrier or excipient contained in the pharmaceutical composition of the present invention is the type of compound used; the mammalian to which it is administered. It is determined by various factors such as age, weight, health condition, gender and dietary content; frequency of administration and route of administration; duration of treatment; other drugs used at the same time. The amount of the serotonin transmission inhibitor contained in the pharmaceutical composition of the present invention is, for example, about 0.01 mg / kg to about 20 mg / kg, about 0.05 mg / kg to about 10 mg / kg, and about 0.1 mg / kg to about. The amount of the serotonin transmission inhibitor can be administered in an amount of 5 mg / kg, about 0.5 mg / kg to about 3 mg / kg or about 1 mg / kg to about 2 mg / kg. The amount of the carrier or excipient contained in the pharmaceutical composition of the present invention that is acceptable as a medicine is about 1 to about 99% by weight, about 5 to about 90% by weight, and about 10 to about 10 to about 10 to about 10 to about 10 to about 99% by weight. The amount can be 80% by weight, about 20 to about 70% by weight, about 30 to about 60% by weight, or about 40 to about 50% by weight.

The pharmaceutical composition of the present invention can be formulated for oral administration or parenteral administration, for example, for intravenous, subcutaneous, enteral, intraperitoneal, or intramuscular administration. The pharmaceutical product can contain a serotonin transmission inhibitor and optionally a carrier or an excipient. In the pharmaceutical product, the serotonin transmission inhibitor can be uniformly present. The formulation is, for example, a solid formulation such as a tablet, a pill, a powder, a powder, a granule, or a capsule, or a liquid such as a sterile aqueous solution, a sterile non-aqueous solution, a suspending agent, an emulsion, a syrup, an emulsion, or an elixir. There is a formulation. The type of dosage form is not particularly limited and is appropriately selected according to the administration route. The pharmaceutical composition of the present invention is administered, for example, as a solid dosage form by oral administration by tablets, or as a liquid dosage form by intravenous administration by a syringe, a catheter or the like.

A solid preparation is a group consisting of an excipient, a binder, a disintegrant, a surfactant, a disintegration inhibitor, an absorption promoter, a moisturizer, an adsorbent, and a lubricant according to a conventional pharmaceutical compounding technique. It can be prepared by combining with one or more substances selected from. The solid preparation may further contain a coloring agent, a preservative, a flavoring agent, a flavoring agent, a sweetening agent and the like, if necessary. Further, the solid preparation can be, for example, a sugar-coated tablet, a gelatin-encapsulated tablet, an enteric-coated tablet, or a film-coated tablet, and can also be a double tablet or a multi-layer tablet. Capsules can be prepared by mixing the active ingredient with various pharmaceutically acceptable carriers and filling them in hard gelatin capsules, soft capsules, or the like according to a conventional method. The concentration of the active ingredient in the solid preparation is not particularly limited, and is, for example, about 1% by weight to about 99% by weight, about 20% by weight to about 80% by weight, about 30% by weight to about 60% by weight, or about 40% by weight. It can be from% by weight to about 50% by weight. The solid formulation can contain a single or divided dose of the active ingredient.

The liquid preparation can be prepared by mixing the active ingredient with an inert diluent or the like according to a conventional pharmaceutical compounding technique. Further, optionally, one or more substances selected from the group consisting of solubilizers, buffers, isotonic agents, suspending agents, surfactants, antioxidants, preservatives and the like are added. You can also. In addition, the liquid preparation may be prepared by first preparing and storing the pharmaceutical composition of the present invention as a lyophilized powder, and then dissolving or suspending it in an inert diluent or the like immediately before use. The liquid preparation may further contain a colorant, a preservative, a flavoring agent, a flavoring agent, a sweetening agent, or the like, if necessary. The concentration of the active ingredient in the liquid preparation is not particularly limited, and is, for example, about 1% by weight to about 99% by weight, about 20% by weight to about 80% by weight, about 30% by weight to about 60% by weight, or about 40% by weight. It can be from% by weight to about 50% by weight. The liquid formulation can contain a single or divided dose of the active ingredient.

(5. Treatment, prevention or management method)
The serotonin transmission inhibitor or the pharmaceutical composition of the present invention can be used to treat, prevent or manage the psychiatric disorder. The method of treatment, prevention or management of the present invention comprises administering to a subject a serotonin transmission inhibitor or a pharmaceutical composition comprising a serotonin transmission inhibitor. The method of treatment, prevention or management of the present invention comprises administering to a subject an effective amount of a serotonin transmission inhibitor or a pharmaceutical composition comprising an effective amount of a serotonin transmission inhibitor. Here, the mental illness and the subject may be those described in "2. Mental illness treated, prevented or controlled by the present invention". The serotonin transmission inhibitor may be those described in "3. Serotonin transmission inhibitor". The pharmaceutical composition may be as described in "4. Pharmaceutical Composition".

The dose, administration method, administration route, number of administrations, administration interval, administration order, administration timing, etc. of the serotonin transmission inhibitor or the pharmaceutical composition containing the serotonin transmission inhibitor are not particularly limited and are based on the condition of the subject. , Can be judged by a doctor or the like. The dose of the serotonin transmission inhibitor, or the pharmaceutical composition comprising the serotonin transmission inhibitor, can be an effective amount for treating, preventing or managing a psychiatric disorder. The doses are, for example, about 0.01 mg / kg to about 20 mg / kg, about 0.05 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 5 mg / kg, and about 0.5 mg / kg to about 3. It is mg / kg or about 1 mg / kg to about 2 mg / kg. The route of administration is, for example, oral or parenteral administration, such as intravenous, subcutaneous, enteral, intraperitoneal, or intramuscular administration. The number of administrations is, for example, once a day, twice a day, three times a day, or once every two days. The dosing interval is 6 hours, 8 hours, 12 hours, 18 hours, 24 hours, 2 days, 3 days, 4 days, or 5 days.

The treatment, prevention or management method of the present invention can further include administering to the subject a second agent. The second agent may be, for example, another agent for treating, preventing or managing a psychiatric disorder, such as a known antipsychotic agent, an antischizophrenia agent, or an attention deficit hyperactivity disorder (ADHD) agent. Is. The dose, administration method, administration route, administration frequency, administration interval, administration order, administration time, etc. of the second drug are not particularly limited, and can be determined by a doctor or the like based on the condition of the subject. The dose of the second agent can be an effective amount for treating, preventing or managing a psychiatric disorder.

In one embodiment, the therapeutic, prophylactic or management method of the present invention administers to a subject a pharmaceutical composition comprising a plurality of (eg, two, three, or more) serotonin transmission inhibitors or serotonin transmission inhibitors. Including doing. In a specific embodiment, the therapeutic, prophylactic or management method of the present invention comprises administering ketanserin and 8-OH-DPAT to a subject. In another specific embodiment, the therapeutic, prophylactic or management method of the present invention comprises administering ketanserin and CGS-12066A to a subject. In yet another specific embodiment, the pharmaceutical composition of the present invention comprises administering 8-OH-DPAT and CGS-12066A to a subject. In yet another specific embodiment, the pharmaceutical composition of the present invention comprises administering ketanserin, 8-OH-DPAT and CGS-12066A to a subject.

In other embodiments, the therapeutic, prophylactic or management method of the present invention comprises administering to a subject a combination of a plurality of (eg, two, three, or more) pharmaceutical compositions. For example, the therapeutic, prophylactic or management method of the present invention comprises administering to a subject a pharmaceutical composition comprising a serotonin transmission inhibitor and a pharmaceutical composition comprising a second agent. The second agent may be, for example, another agent for treating, preventing or managing a psychiatric disorder, such as a known antipsychotic agent, an antischizophrenia agent, or an attention deficit hyperactivity disorder (ADHD) agent. Is. In a specific embodiment, the method of treatment, prevention or management of the present invention comprises administering to a subject a first pharmaceutical composition comprising ketanserin and a second pharmaceutical composition comprising 8-OH-DPAT. In another specific embodiment, the method of treatment, prevention or management of the present invention comprises administering to a subject a first pharmaceutical composition comprising ketanserin and a second pharmaceutical composition comprising CGS-12066A. In yet another specific embodiment, the therapeutic, prophylactic or controlled method of the invention is administered to a first pharmaceutical composition comprising 8-OH-DPAT and a second pharmaceutical composition comprising CGS-12066A. Including that. In yet another specific embodiment, the therapeutic, prophylactic or controlled method of the invention comprises a first pharmaceutical composition comprising ketanserin, a second pharmaceutical composition comprising 8-OH-DPAT and a third comprising CGS-12066A. Includes administration to a subject with a pharmaceutical composition. When a plurality of (eg, two, three, or more) pharmaceutical compositions are administered in combination, they are co-administered, co-administered or sequentially administered. When administered sequentially, the order of administration is not particularly limited and includes all combinations of orders. The dose, administration method, administration route, administration frequency, administration interval, administration order, administration time, etc. of each pharmaceutical composition are not particularly limited, and can be determined by a doctor or the like based on the condition of the subject.

(6. Kit)
The kit of the present invention contains a serotonin transmission inhibitor or a pharmaceutical composition containing a serotonin transmission inhibitor. The kit of the present invention contains an effective amount of a serotonin transmission inhibitor or a pharmaceutical composition containing an effective amount of a serotonin transmission inhibitor. The kit of the present invention can be used for treating, preventing or managing the mental illness. The kit of the present invention can be used in the treatment, prevention or management of the mental illness. The kit of the present invention can be used in a method for treating, preventing or managing the mental illness. The kit of the present invention can be used in the manufacture of pharmaceuticals for treating, preventing or managing said psychiatric disorders. Here, the mental illness may be described in the above-mentioned "2. Mental illness treated, prevented or managed by the present invention". The serotonin transmission inhibitor may be those described in "3. Serotonin transmission inhibitor". The pharmaceutical composition may be as described in "4. Pharmaceutical Composition".

The kit of the present invention is further selected from the group consisting of the dose, administration method, administration route, administration frequency, administration interval, administration order, administration time, etc. of the serotonin transmission inhibitor or the pharmaceutical composition containing the serotonin inhibitor. Can include instructions containing one or more instructions.

(7. Example)
Examples of the present invention will be described below. The following examples are described for deepening the understanding of the scope of claims of the present invention, and are not intended to limit the scope of claims of the present invention.

(Experimental animal)
A 9-week-old Gunn rat and its normal control rat, Wistar rat, were purchased from Nippon SLC Co., Ltd. Each rat was bred in a zoo at a temperature of 23 ± 2 ° C., a humidity of 55 ± 5%, and a 12-hour lighting cycle (lighting from 7:00 am to 7:00 pm) until 10 weeks of age. During that time, solid samples and water exclusively for rats were allowed to be freely ingested. 10-week-old Gunn and Wistar rats were used in the experiments shown below.
(Measurement of indirect bilirubin in blood and direct bilirubin)
Blood was collected from the tail veins of 9-week-old Gunn rats and Wistar rats, plasma was collected from the blood, and conjugated bilirubin and unconjugated bilirubin were measured by an enzymatic method. The results are shown in Table 1 below.

(Example 1: Measurement of serotonin concentration and dopamine concentration in the brain of Gunn rats)
Serotonin and dopamine are neurotransmitters that play important roles in cognitive function in the brain. Since Gunn rats expose cognitive dysfunction (Non-Patent Document 3), the brain serotonin concentration and dopamine concentration in Gunn rats were measured by HPLC.

(experimental method)
10-week-old Gunn rats and Wistar rats were deeply anesthetized, blood was removed by perfusing physiological saline containing heparin at 4 ° C from the heart, and the brain was promptly collected. The collected brain was divided into the frontal lobe, hippocampus, and striatum, and each brain region was added to 0.2 M perchloric acid (including isopropanol as an internal standard) to prepare a homogenate. The homogenate was allowed to stand on ice for 30 minutes, then centrifuged at 15000 × g at 4 ° C., and the supernatant was collected. The collected supernatant is filtered through a 0.22 um filter, and then adjusted to pH 3.5 with 1 M sodium acetate. HTEC-500 (column: reverse phase C18 column (SC-50DS Acom), column temperature: 25 ° C. , Working electrode: WE-3G (Acom), Applied voltage: + 750 mV vs Ag / AgCl, Mobile phase: 0.1 M acetate-quen containing 14% methanol, 140 mg / L sodium 1-octane sulfonate, and 5 mg / L EDTA The serotonin concentration and the dopamine concentration were measured with an acid buffer). The measurement results were tested using the Student t-test. The results are shown in Table 2.

Increased concentrations of serotonin and its metabolite, 5HIAA, in the frontal lobe and hippocampus of Gunn rats revealed that serotonin was overtransmitted in the brain.

(Example 2: Observation of serotonin nerve in Gunn rat)
Since the serotonin nerve is mainly localized in the raphe nuclei and projects from there to various brain regions including the frontal lobe, striatum and hippocampus, the serotonin nerve in the raphe nuclei of Gunn rats is a specific marker. (TPH2) was observed by immunostaining and Western blot.

(experimental method)
(Immunostaining of TPH2)
10-week-old Gunn and Wistar rats were deeply anesthetized and blood was removed by perfusing physiological saline containing heparin at 4 ° C from the heart. Then, 4% paraformaldehyde (PFA) was perfused and the brain was immediately collected. The collected brain was immersed in 4% PFA at 4 ° C. for 3 hours, and then immersed in 20% sucrose overnight.

The soaked brain was frozen and sliced with a microtome to a thickness of 20 μm. Incubate the sliced brain in 1% hydrogen peroxide for 30 minutes at room temperature, then block the non-specific binding of the antibody with 3% bovine serum albumin and use the anti-TPH2 antibody (1: 2000 Abcam Co., Ltd.). Combined. Brain slices to which the anti-TPH2 antibody was bound were colored with the ABC kit (Vector Laboratory). The results are shown in FIG. 1 and Table 3.

Color intensity was statistically significantly increased in Gunn rats.

(Western blot)
10-week-old Gunn and Wistar rats were deeply anesthetized and blood was removed by perfusing physiological saline containing heparin at 4 ° C from the heart. Then, the brain stem containing the raphe nuclei was collected, dissolved in RIPA buffer, and the protein was extracted. The extracted protein was quantified by the BCA method and separated by SDS-PAGE. The separated protein was transferred to a nitrocellulose membrane. In the transcribed membrane, non-specific binding was blocked with EzBlock chemi (ATTO), and an anti-TPH2 antibody (1: 2000 Abcam Co., Ltd.) was bound. The bound anti-TPH2 antibody was bound with HRP-anti-rabbit IgG antibody (abcam) and luminescence was emitted by ECL. The emission intensity was measured with Las-4000 (Fujifilm) and corrected with GAPDH. The results are shown in FIG. 2 and Table 4.

Color intensity was statistically significantly increased in Gunn rats.

(Example 3: Effect of administration of serotonin transmission inhibitor 1)
_{Ketanserin (TCI Chemicals. K0051), a 5-HT 2A / 2c} receptor antagonist, which is one of the serotonin transmission inhibitors, was dissolved in physiological saline containing 5% DMSO (Wako) and 5% Tween 80 for 10 weeks. It was administered subcutaneously in age Gunn and Wistar rats in an amount of 1 or 3 mg / kg. Only solvent was administered as a control. Each rat was placed in a home cage and 30 minutes later, a 60-minute open field test was performed using Scanet MV-40 (Melquest). In addition, the test was photographed with a video camera, and the number of times of hair styling was measured.

The results are shown in Fig. 3. In FIG. 3, (+ / +) represents a Wistar rat and (j / j) represents a Gunn rat. In addition, 0, 1, and 3 on the horizontal axis represent administration of 0 mg / kg (that is, solvent administration), administration of 1 mg / kg, and administration of 3 mg / kg, respectively. * P <0.05, *** P <0.001 (Dunnett's test for Wistar rat solvent administration). As shown in FIG. 3, administration of ketanserin was observed to improve behavioral disorders in Gunn rats.

(Example 4: Effect of administration of serotonin transmission inhibitor 2)
_{A 5-HT 1A} receptor agonist (8-OH-DPAT: Sigma) that inhibits the secretion of serotonin is dissolved in physiological saline containing 10% HPCD (2-hydroxypropyl-β-cyclodextrin: Wako), and 10 It was administered to the abdominal cavity of week-old Gunn rats and Wistar rats at an amount of 1 mg / kg. In addition, 5-HT _1B receptor agonist (CGS-12066A: Sigma) was dissolved in physiological saline containing 10% HPCD (2-hydroxypropyl-β-cyclodextrin: Wako), and 10-week-old Gunn rats and 10-week-old Gunn rats and It was administered to the abdominal cavity of Wistar rats at a dose of 5 mg / kg. Only solvent was administered as a control. Each rat was placed in a home cage and 20 minutes later, a 60-minute open field test was performed using Scanet MV-40 (Melquest). In addition, the test was photographed with a video camera, and the number of times of hair styling was measured.

The results are shown in Fig. 4. *** P <0.001 (Dunnett's test for Wistar rat solvent administration). Vehicle represents a control administered with solvent only. The vertical axis shows the ratio (%) to the control (100%). As shown in FIG. 4, administration of 8-OH-DPAT was observed to improve behavioral disorders in Gunn rats. In addition, administration of CGS-12066A was also observed to improve behavioral disorders in Gunn rats.

(Example 5: Effect of administration of serotonin transmission inhibitor 3)
_{A 5-HT 2A / 2c} receptor antagonist (sarpogrelate hydrochloride, methysergide, cyproheptadine, or cyclobenzaprine) or a 5-HT _2A receptor antagonist (ritanserin) that inhibits serotonin transmission is dissolved in physiological saline for 10 weeks. Administer to the abdominal cavity of young Gunn and Wistar rats. Administer only the solvent as a control. Each rat is placed in a home cage and 20 minutes later, a 60-minute open field test is performed using Scanet MV-40 (Melquest). In addition, the test is photographed with a video camera to measure the number of times of hair styling.

(Example 6: Effect of administration of serotonin transmission inhibitor 4)
_{5-HT 1A} receptor agonists that inhibit serotonin secretion (5-carboxamidotryptamine (5-CT), tandospirone, ipsapilone, or buspirone) were dissolved in saline and in 10-week-old Gunn and Wistar rats. Administer intraperitoneally. Administer only the solvent as a control. Each rat is placed in a home cage and 20 minutes later, a 60-minute open field test is performed using Scanet MV-40 (Melquest). In addition, the test is photographed with a video camera to measure the number of times of hair styling.

(Example 7: Effect of administration of serotonin transmission inhibitor 5)
_{A 5-HT 1B} receptor agonist (CP-93129 or triptan preparation (sumatriptan, solmitriptan, eletriptan, lizatriptan, or naratriptan)) that inhibits serotonin secretion was dissolved in physiological saline for 10 weeks. Administer to the abdominal cavity of aged Gunn and Wistar rats. Administer only the solvent as a control. Each rat is placed in a home cage and 20 minutes later, a 60-minute open field test is performed using Scanet MV-40 (Melquest). In addition, the test is photographed with a video camera to measure the number of times of hair styling.

Claims

A pharmaceutical composition for treating, preventing or managing psychiatric disorders caused by bilirubin UDP-glucuronosyltransferase (UGT1A1) gene mutation or psychiatric disorders associated with jaundice, excluding serotonin transmission inhibitors (excluding risperidone). ), The pharmaceutical composition.
The pharmaceutical composition according to claim 1, wherein the serotonin transmission inhibitor has a binding inhibition constant (K i ) value greater than 3.57 nM with respect to the D 2 receptor.
The pharmaceutical composition according to claim 2, wherein the serotonin transmission inhibitor further has a K i value greater than 3.6 nM for the D 3 receptor and a K i value greater than 4.66 nM for the D 4 receptor. thing.
The serotonin transmission inhibitor, D 2 receptors to have a K i value of greater than about 30 nM, pharmaceutical composition according to any one of claims 1-3.
The invention according to any one of claims 1 to 4, wherein the serotonin transmission inhibitor has a binding affinity for 5-HT 2A receptor that is more than 21 times higher than that for binding to the D 2 receptor. Pharmaceutical composition.
The pharmaceutical composition according to any one of claims 1 to 5, wherein the serotonin transmission inhibitor is a 5-HT 2A / 2c receptor antagonist or a 5-HT 2A receptor antagonist.
The 5-HT 2A / 2c receptor antagonist or the 5-HT 2A receptor antagonist is ketanserin, sarpogrelate hydrochloride, ritanserin, methiselgide, cyproheptadine, or cyclobenzaprine, or a pharmaceutically acceptable salt or solvent product thereof. The pharmaceutical composition according to claim 6, which is a steric isomer or a mutual mutant organism.
The pharmaceutical composition according to any one of claims 1 to 4, wherein the serotonin transmission inhibitor is a 5-HT 1A receptor agonist or a 5-HT 1B receptor agonist.
The 5-HT 1A receptor agonist is 8-OH-DPAT, 5-carboxamidottryptamine, tandospirone, ipsapilone, or buspirone, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautovariant organism thereof. , The pharmaceutical composition according to claim 8.
The 5-HT 1B receptor agonist according to claim 8, wherein the 5-HT 1B receptor agonist is a CGS-12066A, CP-93129, or triptan preparation, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer. Pharmaceutical composition.
Any one of claims 1 to 5, wherein the serotonin transmission inhibitor is a compound represented by the following formula (I), or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof. The pharmaceutical composition described in the section:

(During the ceremony,
X 1 is CR a R b , CO, NR c , CR d or N;
X 2 is CR e , N or C;
X 3 is CR f , N or C;
X 4 is CR g , N or C;
Are R 1 and R 2 independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, acyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, acyloxy, nitro, amino, alkylamino, halo or oxo? Or, R 1 and R 2 can form an aromatic carbocyclic ring or an aromatic heterocyclic ring that is unsubstituted or substituted with one or more R s1s together with the atoms to which they are attached;
R s1 is alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, acyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, acyloxy, nitro, amino, alkylamino or halo, respectively, independently on each appearance;
R 3 is an alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, acyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, acyloxy, nitro, amino, alkylamino, or halo, independently of each appearance;
R a , R b , R c , R d , R e , R f and R g are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, acyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, respectively. Acyloxy, nitro, amino, alkylamino, or halo;
Y 1 and Y 2 are hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, acyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, acyloxy, nitro, amino, alkylamino or halo, respectively, on each appearance. ;
Z is CH or N;
Whether B 1 and B 2 are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, acyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, acyloxy, nitro, amino, alkylamino, or halo, respectively. or B 1 and B 2, that together with the atoms to which they are attached, are unsubstituted or substituted by one or more R s2, to form a non-aromatic carbocyclic or non-aromatic heterocyclic saturated or unsaturated Can be;
R s2 is alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, acyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, acyloxy, nitro, amino, alkylamino or halo, respectively, independently on each appearance;
m is an integer from 0 to 4;
n is an integer from 0 to 6;

Represents a single bond or a double bond. ).
In the above formula,
X 1 is CH 2 , CO, or N;
X 2 is CH, N or C;
X 3 is CH or C;
X 4 is CH or N;
R 1 is hydrogen or oxo and R 2 is hydrogen or
R 1 and R 2 form an unsubstituted aromatic heterocycle with the atoms to which they bond;
R 3 is haloalkyl or hydroxy;
Y 1 and Y 2 are hydrogen;
Z is CH or N;
B 1 and B 2 are each independently alkyl, or B 1 and B 2 are, together with the atom to which they are attached, substituted with one R s2, to form a non-aromatic heterocyclic ring saturated ;
R s2 is alkyl or acyl;
The pharmaceutical composition according to claim 11, wherein m is 0 or 1; and n is an integer of 0 to 2.
The pharmaceutical composition according to claim 12, wherein the compound represented by the formula (I) is a compound represented by the following formula (IA):

(In the equation, R 3 , Y 1 , Y 2 , Z, B 1 , B 2 , m and n are as defined above).
The pharmaceutical composition according to claim 13, wherein the compound represented by the formula (IA) is a compound represented by the following formula (Ia):

(Wherein, R 3, R s2 and m are as defined above.).
The pharmaceutical composition according to claim 14, wherein R s2 is an acyl and m is 0 in the above formula.
The pharmaceutical composition according to claim 12, wherein the compound represented by the formula (I) is a compound represented by the following formula (IB):

(In the equation, R 3 , Y 1 , Y 2 , Z, B 1 , B 2 , m and n are as defined above).
The pharmaceutical composition according to claim 16, wherein the compound represented by the formula (IB) is a compound represented by the following formula (Ib):

(In the equation, R 3 and m are as defined above.)
The pharmaceutical composition according to claim 17, wherein R 3 is hydroxy and m is 1 in the above formula.
The pharmaceutical composition according to claim 12, wherein the compound represented by the formula (I) is a compound represented by the following formula (IC):

(In the equation, R 3 , Y 1 , Y 2 , Z, B 1 , B 2 , m and n are as defined above).
The pharmaceutical composition according to claim 19, wherein the compound represented by the formula (IC) is a compound represented by the following formula (Ic):

(Wherein, R 3, R s2 and m are as defined above.).
In the formula, R 3 is haloalkyl, R s2 is alkyl, and m is 1, claim 20 pharmaceutical composition.
The pharmaceutical composition according to any one of claims 11 to 21, wherein the compound represented by the formula (I) is ketanserin, 8-OH-DPAT or CGS-12066A.
The pharmaceutical composition according to any one of claims 1 to 22, wherein the psychiatric disorder is caused by serotonin overtransmission in the brain.
The pharmaceutical composition according to any one of claims 1 to 23, wherein the psychiatric disorder is schizophrenia or attention deficit hyperactivity disorder.
The pharmaceutical composition according to any one of claims 1 to 24, wherein the jaundice is constitutional jaundice.
A kit for treating, preventing or managing a psychiatric disorder caused by a UGT1A1 gene mutation or a psychiatric disorder accompanied by jaundice, which contains the pharmaceutical composition according to any one of claims 1 to 25.