Pharmaceutical composition for treating, preventing or managing bilirubin-induced neurological dysfunction, psychiatric diseases with jaundice and psychiatric diseases caused by mutation of bilirubin UDP-glucuronyl transferase gene

Abstract

The inventors found that BIND, psychiatric diseases with jaundice and psychiatric diseases caused by UGT1A1 gene mutation of a subject can be treated, prevented or controlled by administering a 5-HT1A / 1B receptor agonist to the subject. Therefore, the present disclosure provides a pharmaceutical composition, including a 5-HT1A / 1B receptor agonist, for the treatment, prevention or control of BIND, psychiatric disorders with jaundice, and psychiatric disorders caused by UGT1A1 gene mutation.

Description

[Technical Field]

[0001] This invention relates to pharmaceutical compositions and methods for treating, preventing, or managing bilirubin-induced neurological dysfunction (BIND) (also known as bilirubin encephalopathy). Furthermore, this invention also relates to pharmaceutical compositions and methods for treating, preventing, or managing mental illnesses with jaundice and mental illnesses caused by mutations in the bilirubin UDP-glucuronyl transferase (UGT1A1) gene. [Background Technology]

[0002] Constitutional jaundice is a condition characterized by yellowing of the skin and whites of the eyes due to abnormal function of UDP-glucuronyl transferase (UGT1A1) in liver cells, leading to impaired metabolism of indirect bilirubin and elevated serum bilirubin levels. The prevalence of this condition is approximately 2% to 7% in the general population, and recent studies have found it to be frequently accompanied by symptoms of mental disorders. Currently, the academic community believes that UGT1A1 gene mutations and related jaundice reactions may be important pathogenic factors for schizophrenia and attention deficit hyperactivity disorder (ADHD). It is estimated that approximately 200,000 people in Japan (representing 20% ​​of all schizophrenia patients) suffer from both constitutional jaundice and schizophrenia. However, compared to individuals with schizophrenia alone, these patients with both conditions experience more pronounced extrapyramidal side effects due to the dopamine receptor blocking effect of antipsychotic drugs, exhibiting severe clinical symptoms in both the acute and stable phases, making treatment more challenging (Non-Patent Literature 1 and 2).

[0003] Bilirubin encephalopathy (BIND), also known as kernicterus, is caused by elevated levels of unconjugated bilirubin in the blood, which leads to neurotoxicity and brain damage, potentially resulting in intellectual disability and motor dysfunction. Recent studies have revealed a significant increase in BIND cases among premature infants, a phenomenon that has become a major challenge in neonatal medicine.

[0004] For neurodegenerative diseases, therapeutic drugs utilizing serotonin receptor antagonists and other similar agents are currently under development. However, existing studies have indicated that these drugs have side effects such as QT interval prolongation and limited efficacy, and related issues remain to be resolved (Patent Literature 1-3 and Non-Patent Literature 3-5). On the other hand, research cases aimed at treating mental illnesses and neurological dysfunctions caused by elevated serum bilirubin are almost non-existent, and the development of related therapeutic drugs has yet to achieve a breakthrough. [Existing Technical Documents] [Patent Documents]

[0005] [Patent Document 1] Patent Publication No. 2008-500325 [Patent Document 2] Patent Publication No. 2003-531829 [Patent Document 3] Patent Publication No. 2006-516284 [Non-patent documents]

[0006] [Non-Patent Literature 1] Tsuyoshi Miyaoka, “Improvement of Quality of Life from the Perspective of Heterogeneity in Schizophrenia - The Influence of Abnormal Bilirubin Metabolism”, Journal of Psychiatry and Neurology, Vol. 113, No. 4, 2011, pp. 361-367 [Non-Patent Literature 2] Takahashi H. et al., “The role of extrastriatal dopamine D2 receptors in schizophrenia”, Biological psychiatry Volume 59, Issue 10, May 2006, Pages 919-28. [Non-patent document 3] Q Tang et a1., "The 5-HT2 antagonist ketanserin is anopen channel blocker of human cardiac ether-a-go-go-related gene(hERG)potassium channels", British Journal ofPharmacology (2008) 155, 365-3373 [Non-patent document 4] Cummings J.et a1., "Pimavanserin for patients with Parkinson's disease psychosis: a randomized, placebo-controlled phase 3trial", Lancet 2014; 383: 533-40 [Non-patent document 5] McFarland K. et al., "Pimavanserin, a 5-HT2A inverseagonist, reverses psychosis-like behaviors in a rodent model of Parkinson's disease", Behav Pharmacol. 2011 Oct; 22(7): 681-92 [Non-patent document 6] Hayashida M. et al., "Hyperbilirubinemia-related behavioral and neuropathological changes in rats: A possible schizophreniaanimal model", Progress in Neuropsychopharmacology&Biological Psychiatry, 33 (2009) 581-588 [Non-patent document 7] Tsuchie K. et al., "The effects of antipsychotics on behavioral abnormalities of the Gunn rat (unconjugated hyperbilirubinemiarat), a rat model of schizophrenia", Asian Journal of Psychiatry, Volume 6, Issue 2, April 2013, Pages 119-123 [Non-patent document 8] Takeuchi K. et al., "Genetic polymorphisms ofbilirubinuridine diphosphate-glucuronosyltransferase gene in Japanese patients with Crigler-Najjar syndrome or Gilbert's syndrome as well as in healthy Japanese subjects", Journal of Gastroenterology and Hepatology (2004) 19, 1023-1028 [Non-patent document 9] Kimura K. et al., "Structures of the 5-HT2A receptor incomplex with the antipsychotics risperidone and zotepine", Nature Structural & Molecular Biology, volume 26, pages 121-128 (2019) [Summary of the Invention] [The technical problem this invention aims to solve]

[0007] This disclosure aims to provide pharmaceutical compositions and methods for treating, preventing, or managing bilirubin encephalopathy (BIND), mental illness with jaundice, and mental illness caused by UGT1A1 gene mutation. [Technical Solution to the Problem]

[0008] In developing drugs for the treatment of mental illnesses, the inventors focused on jaundice model rats (Gunn rats) carrying a mutation in the UGT1A1 gene. These rats have been shown to induce cognitive and behavioral disorders associated with schizophrenia (see Non-Patent Literature 6 and 7). Gunn rats can serve as model animals for studying BIND, jaundice-associated mental illness, and mental illnesses induced by the UGT1A1 gene mutation. By injecting Gunn rats with 5-HT... 1A / 1B The inventors discovered that receptor agonists significantly improve cognitive and behavioral disorders, and thus successfully developed this patented invention.

[0009] Therefore, this disclosure provides inventions of the following types. (Option 1) A pharmaceutical composition for the treatment, prevention, or management of bilirubin-induced neurological dysfunction, mental illness with jaundice, and mental illness caused by mutations in the bilirubin UDP-glucuronide transferase gene, comprising 5-HT 1A / 1B Receptor agonists. (Option 2) A pharmaceutical composition for treating, preventing, or managing bilirubin-induced neurological dysfunction in patients, comprising 5-HT 1A / 1B This drug composition is indicated for patients whose biological samples show higher bilirubin concentrations than healthy individuals or who have jaundice. (Option 3) A pharmaceutical composition for treating, preventing, or managing bilirubin-induced neurological dysfunction in patients, comprising 5-HT 1A / 1B This drug composition is indicated for patients who carry a mutation in the bilirubin UDP-glucuronide transferase gene. (Option 4) A pharmaceutical composition comprising 5-HT for use in a method of treating, preventing or managing bilirubin-induced neurological dysfunction in patients. 1A / 1B receptor agonists, The method includes: (a) The steps for obtaining biological samples from the patient; (b) The step of determining the bilirubin concentration in the biological sample obtained in step (a); and (c) If the bilirubin concentration measured in step (b) is higher than that of healthy individuals, or if the patient is determined to have jaundice based on the bilirubin concentration measured in step (b), then 5-HT is administered to the patient. 1A / 1B The steps of receptor agonist. (Option 5) A pharmaceutical composition comprising 5-HT for use in a method of treating, preventing or managing bilirubin-induced neurological dysfunction in patients. 1 / / 1B receptor agonists, The method includes: (a) Steps to determine whether the patient carries a bilirubin UDP-glucuronide transferase gene mutation; (b) If step (a) determines that the patient carries a bilirubin UDP-glucuronide transferase gene mutation, then administer 5-HT to the patient. 1A / 1B The steps of receptor agonist. (Option 6) A pharmaceutical composition for treating, preventing, or managing a patient's mental illness, comprising 5-HT 1A / 1B This drug composition is indicated for patients whose biological samples show higher bilirubin concentrations than healthy individuals or who have jaundice. (Option 7) A pharmaceutical composition for treating, preventing, or managing a patient's mental illness, comprising 5-HT 1A / 1B This drug composition is indicated for patients who carry a mutation in the bilirubin UDP-glucuronide transferase gene. (Option 8) A pharmaceutical composition for use in a method of treating, preventing, or managing a patient's mental illness, comprising 5-HT 1A / 1B Receptor agonist, the method comprising: (a) The steps for obtaining biological samples from the patient; (b) The steps for determining the bilirubin concentration in the biological samples obtained in process (a); and (c) If the bilirubin concentration measured in step (b) is higher than that of healthy individuals, or if the patient is determined to have jaundice based on the bilirubin concentration measured in step (b), then 5-HT is administered to the patient. 1A / 1B The steps of receptor agonist. (Option 9) A pharmaceutical composition for use in a method of treating, preventing, or managing a patient's mental illness, comprising 5-HT 1A / 1B Receptor agonist, the method comprising: (a) Steps to determine whether the patient carries a bilirubin UDP-glucuronide transferase gene mutation; (b) If step (a) determines that the subject carries a bilirubin UDP-glucuronide transferase gene mutation, then administer 5-HT to the patient. 1A / 1B The steps of receptor agonist. (Option 10) The pharmaceutical composition of any one of schemes 1 to 9, wherein the 5-HT 1A / 1B The receptor agonist is a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, or deuterated compound thereof:

Chemistry 1

[0010] In addition, this disclosure also provides inventions with the following solutions. (Option 19) A method for treating, preventing, or managing bilirubin-induced neurological dysfunction, mental illness with jaundice, and mental illness caused by mutations in the bilirubin UDP-glucuronide transferase gene in patients requiring intervention, comprising administering a therapeutically effective dose of 5-HT to the patient. 1A / 1B The steps of receptor agonist. (Option 20) A method for treating, preventing, or managing bilirubin-induced neurological dysfunction in a patient requiring intervention, wherein the patient has a higher bilirubin concentration in their biosample than healthy individuals or the patient has jaundice, the method comprising administering a therapeutically effective dose of 5-HT to the patient. 1A / 1B The steps of receptor agonist. (Option 21) A method for treating, preventing, or managing bilirubin-induced neurological dysfunction in a patient requiring intervention, wherein the patient carries a mutation in the bilirubin UDP-glucuronide transferase gene, the method comprising administering a therapeutically effective dose of 5-HT to the patient. 1A / 1B The steps of receptor agonist. (Option 22) A method for treating, preventing, or managing bilirubin-induced neurological dysfunction in patients requiring intervention, comprising: (a) The steps for obtaining biological samples from the patient; (b) The step of determining the bilirubin concentration in the biological sample obtained in step (a); and (c) If the bilirubin concentration measured in step (b) is higher than that of healthy individuals, or if the patient is determined to have jaundice based on the bilirubin concentration measured in step (b), then administer a therapeutically effective dose of 5-HT to the patient. 1A / 1B The steps of receptor agonist. (Option 23) A method for treating, preventing, or managing bilirubin-induced neurological dysfunction in a patient, comprising: (a) Steps to determine whether the patient carries a bilirubin UDP-glucuronide transferase gene mutation; (b) If step (a) determines that the patient carries a bilirubin UDP-glucuronide transferase gene mutation, then administer a therapeutically effective dose of 5-HT to the patient. 1A / 1B The steps of receptor agonist. (Option 24) A method for treating, preventing, or managing a mental illness in a patient requiring intervention, wherein the patient's biological sample shows a higher concentration of bilirubin than healthy individuals or the patient has jaundice, the method comprising administering a therapeutically effective dose of 5-HT to the patient. 1A / 1B The steps of receptor agonist. (Option 25) A method for treating, preventing, or managing a mental illness in a patient requiring intervention, wherein the patient carries a mutation in the bilirubin UDP-glucuronide transferase gene, the method comprising administering a therapeutically effective dose of 5-HT to the patient. 1A / 1B The steps of receptor agonist. (Option 26) A method for treating, preventing, or managing mental illness in patients requiring intervention, comprising: (a) The steps for obtaining biological samples from the patient; (b) The step of determining the bilirubin concentration in the biological sample obtained in step (a); and (c) If the bilirubin concentration measured in step (b) is higher than the level in healthy individuals, or if the patient is determined to have a disease based on the bilirubin concentration measured in step (b), If jaundice is present, administer a therapeutically effective dose of 5-HT to the patient. 1A / 1B The steps involved in receptor agonist administration; (Option 27) A method for treating, preventing, or managing mental illness in patients requiring intervention, comprising: (a) Steps to determine whether the patient carries a bilirubin UDP-glucuronide transferase gene mutation; (b) If step (a) determines that the subject carries a bilirubin UDP-glucuronide transferase gene mutation, then administer a therapeutically effective dose of 5-HT to the patient. 1A / 1B The steps of receptor agonist. (Option 28) The method of any one of schemes 19 to 27, wherein the 5-HT 1A / 1B The receptor agonist is a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, or deuterated compound thereof:

Chemistry 2

[0011] In addition, this disclosure also provides inventions with the following solutions. (Option 37) A 5-HT protein for the treatment, prevention, or management of bilirubin-induced neurological dysfunction, mental illness with jaundice, and mental illness caused by mutations in the bilirubin UDP-glucuronide transferase gene. 1A / 1B Receptor agonists. (Option 38) A 5-HT for the treatment, prevention, or management of bilirubin-induced neurological dysfunction in patients. 1A / 1B Receptor agonists, the patient's biological sample showed a higher concentration of bilirubin than healthy individuals, or the patient had jaundice. (Option 39) A 5-HT for the treatment, prevention, or management of bilirubin-induced neurological dysfunction in patients. 1A / 1B The patient carries a mutation in the bilirubin UDP-glucuronide transferase gene. (Option 40) 5-HT used in a method for treating, preventing, or managing bilirubin-induced neurological dysfunction in patients 1A / 1B Receptor agonist, the method comprising: (a) The steps for obtaining biological samples from the patient; (b) The step of determining the bilirubin concentration in the biological sample obtained in step (a); and (c) If the bilirubin concentration measured in step (b) is higher than that of healthy individuals, or if the patient is determined to have jaundice based on the bilirubin concentration measured in step (b), then 5-HT is administered to the patient. 1A / 1B The steps of receptor agonist. (Option 41) 5-HT used in a method for treating, preventing, or managing bilirubin-induced neurological dysfunction in patients 1A / 1B Receptor agonist, the method comprising: (a) Steps to determine whether the patient carries a bilirubin UDP-glucuronide transferase gene mutation; (b) If step (a) determines that the subject carries a bilirubin UDP-glucuronide transferase gene mutation, then administer 5-HT to the patient. 1A / 1B The steps of receptor agonist. (Option 42) A 5-HT for the treatment, prevention, or management of mental illness in patients 1A / 1B Receptor agonists, the patient's biological sample showed a higher concentration of bilirubin than healthy individuals, or the patient had jaundice. (Option 43) A 5-HT for the treatment, prevention, or management of mental illness in patients 1A / 1BThe patient carries a mutation in the bilirubin UDP-glucuronide transferase gene. (Option 44) 5-HT used in a method for treating, preventing, or managing a patient's mental illness 1A / 1B Receptor agonist, the method comprising: (a) The steps for obtaining biological samples from the patient; (b) The step of determining the bilirubin concentration in the biological sample obtained in step (a); and (c) If the bilirubin concentration measured in step (b) is higher than that of a healthy person, or if the patient is determined to have jaundice based on the bilirubin concentration measured in step (b), then 5-HT is administered to the patient. 1A / 1B The steps of receptor agonist. (Option 45) 5-HT used in a method for treating, preventing, or managing a patient's mental illness 1A / 1B Receptor agonist, the method comprising: (a) Steps to determine whether the patient carries a bilirubin UDP-glucuronide transferase gene mutation; (b) If step (a) determines that the subject carries a bilirubin UDP-glucuronide transferase gene mutation, then administer 5-HT to the patient. 1A / 1B The steps of receptor agonist. (Option 46) The 5-HT used in any one of schemes 37 to 45 1A / 1B Receptor agonist, wherein the 5-HT 1A / 1B The receptor agonist is a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, or deuterated compound thereof:

Transformation 3

[0012] It can be used to treat, prevent or manage BIND, mental illness with jaundice, and mental illness caused by UGT1A1 gene mutation. [Attached Image Description]

[0013]

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Detailed Implementation Methods

[0014] (1. Definition) The term "mental illness" as used in this specification has the broadest meaning within the technical field of this disclosure. Mental illness is a broad concept encompassing a variety of syndromes that are typically caused by significant distress or functional impairment resulting from a mental state that deviates from average or value standards. For example, while the term "mental illness" is not limited in scope, the DMS-IV Diagnostic and Statistical Manual of Mental Disorders classification includes delirium, dementia, amnesiac disorders, other cognitive impairments, mental disorders caused by general illnesses, substance use-related disorders, schizophrenia and other psychotic disorders, affective disorders, anxiety disorders, somatic symptom disorders, affective disorders, dissociative disorders, sexual disorders and gender identity disorders, eating disorders, sleep disorders, various unclassified impulse control disorders, adjustment disorders, and personality disorders. In addition to the above, the following types also exist: Attention Deficit Hyperactivity Disorder (ADHD), Autism, Alzheimer's Disease, Cognitive Abnormalities, Depression, Bipolar Disorder (Manic-Depressive Disorder), Neurodevelopmental Disorders, Cognitive Impairment Due to Neurological Disorders Caused by Infections During Pregnancy, Mental Disorders Caused by Immune System Disorders, Epilepsy, Organic Mental Disorders, Toxic Mental Disorders, Intellectual Disability (Intellectual Disability), Psychosis, Neurosis, etc. Mental disorders caused by syphilis, senile mental disorders, cerebrovascular mental disorders, mental disorders caused by head trauma, atypical endogenous psychosis, mental disorders caused by endocrine diseases, and exogenous reactive and degenerative mental disorders.

[0015] The term "bilirubin-induced neurological dysfunction" (BIND) as used in this specification has the broadest meaning within the technical field of this disclosure, generally referring to brain damage caused by bilirubin neurotoxicity. In this specification, "bilirubin-induced neurological dysfunction" is abbreviated as BIND. Specifically, unbound bilirubin (UB-Bil) is neurotoxic and can selectively damage the globus pallidus, subthalamic nucleus, hippocampus, oculomotor nucleus, ventral cochlear nucleus, Purkinje cells of the cerebellum, and dentate nucleus of the cerebellum. In premature infants, even mild hyperbilirubinemia can induce BIND. This "bilirubin-induced neurological dysfunction" is also known as "kernicterus" or "bilirubin encephalopathy."

[0016] As used in this instruction manual, the term "bilirubin UDP-glucuronide transferase" refers to the enzyme that converts unconjugated bilirubin (indirect bilirubin) into conjugated bilirubin (direct bilirubin). In this instruction manual, bilirubin UDP-glucuronide transferase is also referred to as... UGT1A1.

[0017] The terms "bilirubin UDP glucuronide transferase gene" or "UGT1A1 gene" used in this specification refer to the gene encoding bilirubin UDP glucuronide transferase (UGT1A1). Mutations in this gene are known to cause constitutional jaundice.

[0018] The term "bilirubin" as used in this specification has the broadest meaning within the technical field of this disclosure, generally referring to the conventional catabolism of yellow heme. The term "bilirubin" as used in this specification includes total bilirubin, indirect bilirubin, and direct bilirubin. Indirect bilirubin refers to bilirubin before it is transported to the liver, while direct bilirubin refers to bilirubin after processing by the liver. Total bilirubin is a collective term for both indirect and direct bilirubin.

[0019] The term "gene mutation" as used in this specification has the broadest meaning within the technical field of this disclosure. It generally refers to the presence of high-frequency abnormalities in a gene (such as base deletions, substitutions, insertions, etc.) that lead to a decline or complete loss of gene function.

[0020] As used in this specification, the term "jaundice" has the broadest meaning within the technical field of this disclosure. It generally refers to an abnormal increase in bile pigment (bilirubin) in the blood or tissues, resulting in yellowing of the skin, mucous membranes, and other tissues. "Jaundice" is particularly characterized by elevated concentrations of unconjugated bilirubin in the blood or urine. "Jaundice" includes latent jaundice (e.g., blood bilirubin concentration of approximately 1 mg / dL to 2 mg / dL), mild jaundice (e.g., blood bilirubin concentration of approximately 2 mg / dL to 10 mg / dL), moderate jaundice (e.g., blood bilirubin concentration of approximately 10 mg / dL to 20 mg / dL), and severe jaundice (e.g., blood bilirubin concentration of approximately 20 mg / dL to...). For specific examples, "jaundice" includes, but is not limited to, physiological jaundice and pathological jaundice, such as direct bilirubin jaundice, obstructive jaundice, hepatocellular jaundice, indirect bilirubin jaundice, hemolytic jaundice, constitutional jaundice, and neonatal jaundice.

[0021] As used in this specification, the term "constitutional jaundice" has the broadest meaning within the technical field of this disclosure, generally referring to a state of congenital impairment in bilirubin breakdown. "Constitutional jaundice" is characterized by elevated concentrations of unconjugated bilirubin in the blood or urine. Types of "constitutional jaundice" include Gilbert syndrome, Crigler-Najjar syndrome, Dubin-Johnson syndrome, and Rotor syndrome.

[0022] The term "5-HT" as used in this specification 1A / 1B"Receptor" has the broadest meaning in the technical field of this disclosure, and generally refers to the two subtypes of the serotonin (5-HT) receptor -5-HT 1A receptors and 5-HT 1B Receptors.

[0023] As used in this specification, the term "agonist" has the broadest meaning in the technical field of this disclosure and generally refers to a compound that enhances receptor activity when it binds to a receptor.

[0024] As used in this specification, the term "antagonist" has the broadest meaning within the technical field of this disclosure, generally referring to a compound that, upon binding to a receptor, forms a competitive antagonistic or inverse agonist effect, thereby blocking the action of the antagonist or inverse agonist in the receptor. However, it should be noted that antagonists (also known as "neutral" antagonists) do not affect intrinsic activity.

[0025] The term "5-HT" as used in this specification 1A / 1B "Receptor agonist" refers to a substance that belongs to both 5-HT receptors and 5-HT receptors. 1A Receptor agonists, also belonging to the 5-HT family. 1B Receptor agonists.

[0026] The term "biological sample" as used in this specification has the broadest meaning within the technical field of this invention. For example, the term "biological sample" refers to bodily fluids such as blood or urine. This term includes serum, plasma, and whole blood.

[0027] The term "brain" as used in this specification has the broadest meaning within the technical field of this disclosure. The brain referred to herein means the brain of an object, such as the human brain. For example, the brain includes, but is not limited to: the cerebrum, cerebral cortex, diencephalon, cerebellum, and brainstem. For further examples, the brain includes, but is not limited to: the parietal lobe, frontal lobe, temporal lobe, occipital lobe, midbrain, striatum, hippocampus, nucleus origin, raphe nuclei (e.g., dorsal raphe nucleus, greater raphe nucleus, and lateral part of the dorsal raphe nucleus), forebrain, medulla oblongata, pons, thalamus, hypothalamus, pituitary gland, globus pallidus, oculomotor nucleus, ventral cochlear nucleus, Purkinje cells of the cerebellum, dentate nucleus of the cerebellum, and basal ganglia of the cerebrum.

[0028] As used in this specification, the term "alkyl" is a monovalent group formed by the loss of one hydrogen atom from an aliphatic saturated hydrocarbon. For example, an "alkyl" may contain 1 to 10, 1 to 8, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 2 to 6 carbon atoms. An "alkyl" may have either a straight-chain structure or a branched structure. Taking "alkyl" as an example, it includes, but is not limited to: methyl, ethyl, propyl, isopropyl, 2,2-dimethylethyl, 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, tert-butyl, methylbutyl, pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

[0029] As used in this specification, the term "alkenyl" refers to a monovalent group formed by the loss of one hydrogen atom from an aliphatic unsaturated hydrocarbon containing at least one double bond. For example, an "alkenyl" may contain 2 to 10, 2 to 8, 2 to 6, 2 to 5, 2 to 4, 2 to 3, 3 to 6, 3 to 8, 4 to 6, 4 to 7, or 4 to 8 carbon atoms. An "alkenyl" can be either a straight-chain or branched structure. Examples of "alkenyl" include, but are not limited to: vinyl, propenyl, allyl, butenyl, methylbutenyl, butadienyl, pentenyl, pentadienyl, hexenyl, and hexadienyl.

[0030] As used in this specification, the term "alkynyl" refers to a monovalent group formed by the loss of one hydrogen atom from an aliphatic unsaturated hydrocarbon containing at least one triple bond. For example, an "alkynyl" group can contain 2–10, 2–8, 2–6, 2–5, 2–4, 2–3, 3–6, 4–6, 4–7, or 4–8 carbon atoms. An "alkynyl" group can have either a straight-chain or branched structure. Examples of "alkynyl" groups include, but are not limited to: ethynyl, propynyl, butynyl, methylbutynyl, pentyynyl, and hexynyl.

[0031] As used in this specification, the term "hydroxyalkyl" refers to an alkyl group containing a hydroxyl group. Examples of "hydroxyalkyl" include, but are not limited to, hydroxymethyl, hydroxyethyl, 2-hydroxy-2-propyl, and hydroxypentyl. As used in this specification, the term "aminoalkyl" refers to an alkyl group containing an amino group. Examples of "aminoalkyl" include, but are not limited to, aminomethyl and aminoethyl.

[0032] As used in this specification, the term "halogen" or "halogen" refers to fluorine (-F), chlorine (-Cl), bromine (-Br), and iodine (-I). The term "hydroxyl group" as used in this specification refers to -OH. The term "amino" as used in this specification refers to -NH2.

[0033] The term "salt" as used in this specification has the broadest meaning within the technical field of this disclosure. Salts are typically formed by acids or bases, including inorganic acids or inorganic bases, or organic acids or organic bases. Examples of salts include, but are not limited to: alkali metal salts (including, but not limited to: lithium, potassium, sodium), alkaline earth metal salts (including, but not limited to: barium, calcium, magnesium), transition metal salts (including, but not limited to: zinc), and other metal salts (including, but not limited to: sodium hydrogen phosphate, disodium phosphate), inorganic salts (including, but not limited to: hydrochlorides, sulfates), and organic acid salts (including, but not limited to: acetates, lactates, maleates, malates, tartrates, citrates, ascorbic acid salts, succinates, butyrates, valerates, fumarates). And organic sulfonates, amine salts (including but not limited to: lysine, N,N′-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, meglumine, procaine, N-benzylphenethylamine, 1-p-chlorobenzyl-2-(pyrrolidone-1-ylmethyl)benzimidazole, diethylamine and other alkylamines, piperazines, and tris(hydroxymethyl)aminomethane. In addition, the salts may include acid addition salts such as carboxylic acid addition salts or dicarboxylic acid addition salts (e.g., maleic acid addition salts or fumaric acid addition salts) and base addition salts.

[0034] The term "can be used as a medicine" as used in this instruction manual means that it is harmless to the intended recipient (e.g., mammals, including humans, especially humans).

[0035] The term "solvent" as used in this specification has the broadest meaning within the technical field of this disclosure, generally referring to a solvate-containing compound formed by the combination of one or more solvent molecules with a compound. Examples of solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, and acetic acid. Solvents include monosolvents, disolvents, trisolvents, and tetrasolvents. Furthermore, when the solvent is water, the solvate is a hydrate.

[0036] The term "stereoisomer" as used in this specification has the broadest meaning within the technical field of this disclosure. It encompasses both diastereomers (such as cis-trans isomers) and mirror-image isomers. The term "tautomer" as used in this specification has the broadest meaning within the technical field of this disclosure. Specifically, it refers to compounds exhibiting keto-enol tautomerism. As used in this specification, the term "deuterium-labeled compound" refers to a compound in which at least one hydrogen atom is replaced by deuterium in its structure.

[0037] As used in this specification, the term "subject" refers to an animal, which generally includes humans and non-human mammals. Examples of non-human animals include rats, mice, guinea pigs, rabbits, monkeys, dogs, cats, or miniature pigs. When the subject is a human, the subject is also referred to as a "subject" or "patient." The subject can be male or female. There is no particular age limit for the subject, and it can include newborns, infants, toddlers, children (adolescents), young adults, adults, middle-aged, or elderly individuals.

[0038] The term "about" as used in this specification has the broadest meaning within the technical field of this disclosure and generally refers to the permissible range of error for a given value. For example, the term may indicate 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% for a given value or its range.

[0039] The term “treatment” as used in this specification has the broadest meaning in the technical field of this disclosure and generally refers to the relief, reduction, improvement or eradication of symptoms associated with a particular disease or disorder.

[0040] The term “prevention” as used in this specification has the broadest meaning in the technical field of this disclosure, and generally refers to the preventive treatment of symptoms associated with a specific disease or disorder, such as administering medication to a patient at risk of mental illness before symptoms appear.

[0041] The term “management” as used in the context of a specific disease or disorder in this specification has the broadest meaning in the technical field of this disclosure and includes: preventing recurrence of a specific disease or disorder; prolonging the time a patient with a specific disease or disorder is in remission; and / or maintaining a reduction in the severity of symptoms associated with a specific disease or disorder or preventing its worsening.

[0042] The terms “carrier” and “excipient” as used in this specification have the broadest meaning in the technical field of this disclosure, and generally refer to non-toxic and inactivated solid, semi-solid or liquid substances that are conventionally used according to dosage forms, etc.

[0043] As used in this specification, the terms "effective amount" or "effective dose" refer to the amount of a compound or composition that is sufficient to achieve the intended therapeutic effect. In some embodiments, "therapeutic effective amount" specifically refers to the amount of a compound or pharmaceutical composition that is sufficient for the treatment, prevention, or management of a disease or disorder.

[0044] In this specification, especially in contexts related to concentration, the terms "high," "increased," and "excessive" specifically refer to the following: higher or increased compared to healthy individuals; higher or improved compared to previous data; statistically significantly higher or statistically significant increase; or greater than the median of the normal control group. The terms "high," "increased," or "greater than the median" refer to, for example, approximately 1.2 times, 1.5 times, 2 times, 3 times, 4 times, 5 times, 10 times, 15 times, 20 times, 30 times, 50 times, 100 times, or more than the median. "No effect," "no change," and "no change" specifically refer to the following: same as healthy individuals, same as subjects without the UGT1A1 gene mutation, same as previous data, no statistically significant difference, or same as the median of the normal control group. The terms "same" and "no significant difference" refer to p-values ​​not greater than 0.05 or 0.01, or differences of approximately 0%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 20%, or 30%.

[0045] (2. Diseases and Target Groups) The treatable, preventable, or manageable diseases according to this disclosure include: BIND, mental illness with jaundice, and mental illness caused by mutations in the UGT1A1 gene. In one embodiment, the treatable, preventable, or manageable diseases are selected from BIND, mental illness with jaundice, and mental illness caused by mutations in the UGT1A1 gene. The disease refers to one or more (e.g., one, two, or three) of the group consisting of mental illnesses caused by UGT1A1 gene mutations. In one embodiment, the treatable, preventable, or manageable disease specifically refers to BIND. In one embodiment, the treatable, preventable, or manageable disease specifically refers to mental illness with jaundice. In one embodiment, the treatable, preventable, or manageable disease specifically refers to mental illness caused by a UGT1A1 gene mutation.

[0046] "Mental illness with jaundice" includes situations where jaundice and mental illness coexist. Specifically, this includes cases where jaundice appears first and then develops into mental illness, or where mental illness occurs first and then jaundice appears, or where both occur simultaneously. In certain implementation plans, BIND may be... Mental illnesses caused by UGT1A1 gene mutations are often accompanied by jaundice. In some specific implementation plans, the jaundice is constitutional jaundice. "Mental illness caused by UGT1A1 gene mutation" specifically refers to mental illness caused by mutation of the UGT1A1 gene.

[0047] Specific examples of diseases that can be treated, prevented, or managed according to this disclosure are provided, including but not limited to delirium, dementia, amnesia, other cognitive impairments, mental disorders caused by general illnesses, substance use disorders, schizophrenia and other psychotic disorders, affective disorders, anxiety disorders, somatic symptom disorders, affective disorders, dissociative disorders, sexual disorders and gender identity disorders, eating disorders, sleep disorders, impulse control disorders that cannot be classified into any of the above categories, adjustment disorders, personality disorders, or attention deficit hyperactivity disorder (ADHD). The mental illnesses that can be treated, prevented, or managed according to this disclosure are preferably schizophrenia caused by UGT1A1 gene mutations and attention deficit hyperactivity disorder (ADHD) caused by UGT1A1 gene mutations.

[0048] Other specific examples of diseases that can be treated, prevented, or managed according to this disclosure include, but are not limited to, delirium with jaundice, dementia, amnesia, other cognitive impairments, mental disorders caused by general illnesses, substance use disorders, schizophrenia and other psychotic disorders, affective disorders, anxiety disorders, somatic symptom disorders, affective disorders, dissociative disorders, sexual disorders and gender identity disorders, eating disorders, sleep disorders, impulse control disorders that cannot be classified into any of the above categories, adjustment disorders, personality disorders, or attention deficit hyperactivity disorder (ADHD). Schizophrenia with jaundice and attention deficit hyperactivity disorder (ADHD) with jaundice are preferred mental illnesses that can be treated, prevented, or managed according to this disclosure.

[0049] UGT1A1 gene mutations are well known to those skilled in the art (see, for example, non-patent literature 8). A “UGT1A1 gene mutation” refers to a mutation in one, part, or more bases of the gene, resulting in a reduction (e.g., a reduction of approximately 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more than 95%) or complete loss of activity compared to the normal gene. Examples of UGT1A1 gene mutations include promoter region mutations, coding region mutations, and frameshift mutations. Specifically, such mutations include: frameshift mutations caused by a single base (G) deletion; homozygous Y486D; homozygous insertion of TA in the TATA box of the promoter region (TA7 / 7); homozygous... G71R; combinations of TA7 / 6 and heterozygous G71R; homozygous or heterozygous Y486D and P229Q; heterozygous P364L; homozygous or heterozygous TA7, G71R and heterozygous Y486D, and any combination of one or more of the above.

[0050] According to this disclosure, the treatable, preventable, or manageable BIND and mental illness may be caused by excessive serotonin transmission in the brain. UGT1A1 gene mutations may cause excessive serotonin transmission in the brain without affecting dopamine neurons and their transmission and / or concentration. Therefore, in a particular embodiment, the treatable, preventable, or manageable mental illness is accompanied by excessive serotonin transmission in the brain, but its dopamine transmission remains unchanged. UGT1A1 gene mutations may cause elevated serotonin concentrations in the brain and / or an increase in serotonin neurons. Therefore, in a particular embodiment, the treatable, preventable, or manageable mental illness is caused by the aforementioned elevated serotonin concentrations and / or increased neurons. UGT1A1 gene mutations can lead to elevated blood / urine bilirubin concentrations, which may cause jaundice. Therefore, in a particular embodiment, the treatable, preventable, or manageable mental illness is accompanied by elevated blood or urine bilirubin concentrations. In a particular embodiment, the treatable, preventable, or manageable mental illness is accompanied by jaundice.

[0051] In one embodiment, the treatable, preventable, or manageable subjects according to this disclosure include BIND, jaundice-associated mental illness, and mental illness caused by a mutation in the UGT1A1 gene. In one embodiment, the treatable, preventable, or manageable subjects suffer from one or more (e.g., one, two, or three) diseases selected from the group consisting of BIND, jaundice-associated mental illness, and mental illness caused by a mutation in the UGT1A1 gene.

[0052] In some embodiments, the subject is treatable, preventable, or manageable according to this disclosure and suffers from BIND. In some embodiments, the treatable, preventable, or manageable subject carries a UGT1A1 gene mutation. In some embodiments, the treatable, preventable, or manageable subject suffers from jaundice. In some embodiments, the biological sample of the treatable, preventable, or manageable subject has a high concentration of bilirubin, for example, a higher concentration than in healthy individuals.

[0053] In some embodiments, the subject is a treatable, preventable, or manageable individual with BIND and jaundice according to this disclosure. In some embodiments, the treatable, preventable, or manageable individual has BIND and carries a UGT1A1 gene mutation. In some embodiments, the treatable, preventable, or manageable individual has BIND, carries a UGT1A1 gene mutation, and has jaundice. In some embodiments, the treatable, preventable, or manageable individual carries a UGT1A1 gene mutation and has jaundice.

[0054] In some specific implementations, the subject is a person who is treatable, preventable or manageable under this disclosure and has BIND and whose biological sample has a higher concentration of bilirubin than that of healthy individuals, or who has jaundice.

[0055] In some embodiments, the subject is a treatable, preventable, or manageable mental illness according to this disclosure. In some embodiments, the treatable, preventable, or manageable subject has both a mental illness and carries a UGT1A1 gene mutation. In some embodiments, the treatable, preventable, or manageable subject has both a mental illness and jaundice. In some embodiments, the treatable, preventable, or manageable subject has a mental illness, carries a UGT1A1 gene mutation, and has jaundice.

[0056] In some specific implementations, the subject can be treated, prevented, or managed according to this disclosure if he / she suffers from a mental illness and has a higher concentration of bilirubin in his / her biological sample than that of a healthy person, or suffers from jaundice.

[0057] In some embodiments, the subject of treatment, prevention, or management according to this disclosure has one or more (e.g., one, two, three, four, or five) states selected from the group consisting of: mental illness, BIND, jaundice, UGT1A1 gene mutation, and high bilirubin concentrations in biological samples (e.g., higher than in healthy individuals). The mental illness includes mental illness with jaundice, and / or mental illness caused by UGT1A1 gene mutation.

[0058] In some specific implementations, the jaundice is constitutional jaundice. In some specific implementations, the biological sample is blood or urine.

[0059] Whether a subject has BIND can be determined using methods known to those skilled in the art. For example, it can be determined by examining the bilirubin concentration (total bilirubin concentration, direct bilirubin concentration, or indirect bilirubin) in the subject's biological sample, or by UGT1A1 gene mutation, or by a combination of two, three, or four of the above. For instance, if the subject's serum bilirubin is elevated (e.g., the subject's blood bilirubin concentration is higher than that of healthy individuals), it can be determined that they have BIND.

[0060] Whether a subject has jaundice can be determined using methods known to those skilled in the art. For example, constitutional jaundice is typically diagnosed using blood tests, which measure the concentration of intermediate bilirubin in the blood. For instance, if the subject's intermediate bilirubin concentration is elevated (e.g., the subject's blood bilirubin concentration is higher than that of healthy individuals), then the subject can be diagnosed with jaundice.

[0061] Total bilirubin concentration and direct bilirubin concentration can be measured using, for example, the CicaLiquid D-BIL reagent kit for blood testing (Kanto Chemical Co., Ltd.), the method using vanadate (see Clinical Chemistry, Vol. 22, 1993, pp. 116-122, which has been incorporated into this instruction manual by reference), the Aqua-autoKainos D-BIL reagent kit for direct bilirubin (KAINOS Co., Ltd.), or the serotec T-BIL reagent kit for total bilirubin determination (serotec Co., Ltd.). Since indirect bilirubin concentration often cannot be measured directly, it must be calculated by subtracting the direct bilirubin concentration from the total bilirubin concentration.

[0062] Whether a person suffers from a mental illness can be determined using methods known to those skilled in the art. For example, it can be determined through various diagnostic tests for mental illness, medical history taking, electroencephalography (EEG), CT scans, or one or more combinations of the above methods.

[0063] Whether a subject carries a UGT1A1 gene mutation can be determined by methods known to those skilled in the art. For example, the Invader (registered trademark) UGT1A1 test kit (Sekisui Medical Co., Ltd.) can be used as a method for detecting UGT1A1 genetic polymorphism.

[0064] UGT1A1 gene mutations may cause excessive serotonin transmission in the brain. Therefore, in certain embodiments, the subject being treated, prevented, or managed according to this disclosure exhibits excessive serotonin transmission in the brain. UGT1A1 gene mutations may cause excessive serotonin transmission in the brain without affecting dopamine neurons in the brain, their transmission, and / or concentration. Therefore, in certain embodiments, the dopamine neurons in the brain of the subject being treated, prevented, or managed are unchanged, and their transmission and / or concentration remain unchanged. In certain embodiments, the subject being treated, prevented, or managed exhibits excessive serotonin transmission in the brain, but dopamine transmission in the brain remains unchanged. UGT1A1 gene mutations may cause elevated serotonin concentrations in the brain and / or an increase in serotonin neurons in the brain. Therefore, in certain embodiments, the subject being treated, prevented, or managed exhibits elevated serotonin concentrations in the brain and / or an increase in serotonin neurons in the brain. UGT1A1 gene mutations can lead to elevated blood / urine bilirubin concentrations, potentially causing jaundice. Therefore, in certain embodiments, the subject being treated, prevented, or managed exhibits elevated blood / urine bilirubin concentrations. In a particular implementation, the blood / urine bilirubin concentration of the treatable, preventable, or manageable subject is significantly higher than that of a healthy individual.

[0065] The brain region is selected from one or more (e.g., one, two, three, or four) of the group consisting of, for example, the brainstem, frontal lobe, striatum, hippocampus, and origin nuclei (especially raphe nuclei, such as the dorsal raphe nucleus). Regarding serotonin, the brain region is preferably the frontal lobe and hippocampus; regarding dopamine, the brain region is preferably the frontal lobe, striatum, and hippocampus.

[0066] (3.5-HT 1A / 1B (receptor agonists) 5-HT 1A / 1B 5-HT receptor agonists may be used to treat, prevent, or manage the diseases listed in this product information. 1A / 1B Receptor agonists can be used in the manufacture of medicines for the treatment, prevention, or management of the diseases listed in this product information. 5-HT 1A / 1B Receptor agonists may be used for the treatment, prevention, or management of the conditions listed in this product information. 5-HT 1A / 1B Receptor agonists may be used in the manufacture of medicines for the treatment, prevention or administration of the subjects listed in this instruction manual. 5-HT 1A / 1B Receptor agonists may be used for the treatment, prevention or management methods listed in this instruction manual.

[0067] In one implementation, 5-HT 1A / 1B Receptor agonists are used to treat, prevent, or manage BIND, jaundice-associated mental illness, and mental illness caused by mutations in the UGT1A1 gene. In one embodiment, 5-HT 1A / 1B Receptor agonists are used in the production of medicines for the treatment, prevention, or management of the aforementioned diseases.

[0068] In one implementation, 5-HT 1A / 1B The receptor agonist is used to treat one or more (e.g., one, two, or three) disorders selected from the group consisting of BIND, jaundice-associated mental illness, and mental illness caused by mutations in the UGT1A1 gene. In one embodiment, 5-HT 1A / 1B Receptor agonists are used to prevent one or more (e.g., one, two, or three) disorders selected from the group consisting of BIND, jaundice-associated mental illness, and mental illness caused by UGT1A1 gene mutations. In one embodiment, 5-HT 1A / 1B Receptor agonists are used to manage one or more (e.g., one, two, or three) disorders selected from the group consisting of BIND, jaundice-associated mental disorders, and mental disorders caused by mutations in the UGT1A1 gene.

[0069] In one implementation, 5-HT 1A / 1B Receptor agonists are used to treat, prevent, or manage BIND in subjects. In one implementation, 5-HT... 1A / 1BReceptor agonists are used to treat, prevent, or manage mental illnesses accompanied by jaundice in subjects. In one implementation, 5-HT... 1A / 1B Receptor agonists are used to treat, prevent, or manage mental illnesses caused by mutations in the UGT1A1 gene.

[0070] In some implementation schemes, 5-HT 1A / 1B Receptor agonists are used to treat, prevent, or manage mental illnesses in subjects.

[0071] 5-HT 1A / 1B Receptor agonists can be used for the treatment, prevention, or management of a subject. In some embodiments, the subject has a mental illness; in some embodiments, the subject has BIND; in some embodiments, the subject has jaundice; in some embodiments, the subject carries a UGT1A1 gene mutation; in some embodiments, the subject's biological sample has a high concentration of bilirubin. In some embodiments, the subject's biological sample has a higher concentration of bilirubin than that of healthy individuals. In some embodiments, the subject has one or more (e.g., one, two, three, four, or five) states selected from the group consisting of mental illness, BIND, jaundice, UGT1A1 gene mutation, and high concentration of bilirubin in the biological sample.

[0072] In one implementation, 5-HT 1A / 1B The receptor agonist is a compound of formula (I) below, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, deuterated compound, crystal, polymorph or prodrug thereof.

Chemistry 4

[0073] In one implementation, R 1 Hydrogen, halogen, hydroxyl, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Hydroxyalkyl or C 1-6 Aminoalkyl, preferably hydrogen. In one embodiment, R 2 and R 3 Each time it appears, it is independently a halogen, hydroxyl, amino, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Hydroxyalkyl or C 1-6 Aminoalkyl. R 2 A bondable site that can be bonded to the piperazine ring. In one embodiment, R 2 Bondable sites (excluding the N site) that can bond to the piperazine ring. R 3 Can be bonded to fused rings (including X) 1 and X 2 Except for X, the fused ring formed by the ring and the benzene ring 1 and X 2 Other binding sites besides X. In one implementation, X 1 and X 2 Each independently is oxygen, sulfur, or -CR a R b Group, preferably oxygen, more preferably X 1 and X 2 All are oxygen. In one implementation, R a and R b Each is independently hydrogen, halogen, hydroxyl, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Hydroxyalkyl or C 1-6 Aminoalkyl. In one embodiment, n is an integer of 0, 1, 2, 3, or 4, preferably 0. In one embodiment, m is an integer of 0, 1, 2, 3, 4, or 5, preferably 0.

[0074] In a specific embodiment, the compound represented by formula (I) is eltoprazine (5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin). In a specific embodiment, 5-HT 1A / 1B The receptor agonist is etoprazine (5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin), or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, deuterated compound, crystal, polymorph, or prodrug thereof. Etoprazine has the following structure:

Transformation 5

[0075] In the specific implementation plan, 5-HT 1A / 1B The receptor agonist or the compound represented by formula (I) should be selected from compounds in the group consisting of, or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, deuterated compounds, crystals, polymorphs, or prodrugs thereof: 5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2-chloropiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(3-chloropiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(4-chloropiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2-Fluoroperizin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(3-Fluoroperpiezin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(4-Fluoroperizin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(3-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(4-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2-aminopiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(3-aminopiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(4-aminopiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(3-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(4-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2-Ethylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(3-Ethylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(4-ethylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2-(hydroxymethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(3-(hydroxymethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(4-(hydroxymethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2-(1-hydroxyethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(3-(1-hydroxyethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(4-(1-hydroxyethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2-(2-hydroxyethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(3-(2-hydroxyethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(4-(2-hydroxyethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2-(aminomethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(3-(aminomethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(4-(aminomethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2-(1-aminoethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(3-(1-aminoethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(4-(1-aminoethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2-(2-aminoethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(3-(2-aminoethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(4-(2-aminoethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-Chloro-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-Chloro-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-Chloro-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-Chloro-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-Chloro-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-Fluoro-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-Fluoro-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-Fluoro-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-Fluoro-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-Fluoro-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-Hydroxy-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-Hydroxy-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-Hydroxy-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-Hydroxy-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-Hydroxy-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-Amino-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-Amino-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-Amino-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-Amino-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-Amino-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-Methyl-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-Methyl-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-Methyl-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-Methyl-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-Methyl-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-Ethyl-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-Ethyl-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-Ethyl-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-Ethyl-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-Ethyl-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-(hydroxymethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-(hydroxymethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-(hydroxymethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-(hydroxymethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-(hydroxymethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-(1-hydroxyethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-(1-hydroxyethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-(1-hydroxyethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-(1-hydroxyethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-(1-hydroxyethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-(2-hydroxyethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-(2-hydroxyethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-(2-hydroxyethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-(2-hydroxyethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-(2-hydroxyethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-(aminomethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-(aminomethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-(aminomethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-(aminomethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-(aminomethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-(1-Aminoethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-(1-Aminoethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-(1-Aminoethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-(1-Aminoethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-(1-Aminoethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-(2-Aminoethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-(2-Aminoethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-(2-Aminoethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-(2-Aminoethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-(2-Aminoethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2,2-dichloropiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2,3-dichloropiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2,4-Dichloropiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2,5-dichloropiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2,6-Dichloropiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(3,3-dichloropiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(3,4-Dichloropiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(3,5-dichloropiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2,2-difluoropiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2,3-difluoropiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2,4-difluoropiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2,5-difluoropiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2,6-difluoropiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(3,3-difluoropiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(3,4-difluoropiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(3,5-difluoropiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2,2-dihydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2,3-dihydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2,4-dihydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2,5-dihydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2,6-dihydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(3,3-dihydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(3,4-dihydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(3,5-dihydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2,2-diaminopiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2,3-diaminopiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2,4-Diaminopiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2,5-diaminopiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2,6-Diaminopiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(3,3-diaminopiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(3,4-Diaminopiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(3,5-diaminopiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2,2-dimethylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2,3-dimethylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2,4-dimethylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2,5-dimethylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2,6-dimethylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(3,3-dimethylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(3,4-dimethylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(3,5-dimethylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2,2-Diethylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2,3-Diethylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2,4-Diethylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2,5-Diethylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2,6-Diethylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(3,3-diethylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(3,4-Diethylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(3,5-diethylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2,2-bis(hydroxymethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2,3-bis(hydroxymethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2,4-bis(hydroxymethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2,5-bis(hydroxymethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2,6-bis(hydroxymethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(3,3-bis(hydroxymethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(3,4-bis(hydroxymethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(3,5-bis(hydroxymethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2,2-bis(aminomethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2,3-bis(aminomethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2,4-bis(aminomethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2,5-bis(aminomethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2,6-bis(aminomethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(3,3-bis(aminomethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(3,4-bis(aminomethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(3,5-bis(aminomethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2,2-Dichloro-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2,3-Dichloro-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2,6-Dichloro-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2,7-Dichloro-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2,8-Dichloro-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3,3-Dichloro-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3,6-Dichloro-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3,7-Dichloro-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3,8-Dichloro-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6,7-Dichloro-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6,8-Dichloro-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7,8-Dichloro-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2,2-Difluoro-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2,3-Difluoro-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2,6-Difluoro-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2,7-Difluoro-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2,8-Difluoro-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3,3-Difluoro-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3,6-Difluoro-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3,7-Difluoro-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3,8-Difluoro-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6,7-Difluoro-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6,8-Difluoro-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7,8-Difluoro-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2,2-Dihydroxy-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2,3-Dihydroxy-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2,6-Dihydroxy-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2,7-Dihydroxy-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2,8-Dihydroxy-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3,3-Dihydroxy-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3,6-Dihydroxy-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3,7-Dihydroxy-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3,8-Dihydroxy-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6,7-Dihydroxy-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6,8-Dihydroxy-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7,8-Dihydroxy-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2,2-Diamino-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2,3-Diamino-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2,6-Diamino-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2,7-Diamino-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2,8-Diamino-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3,3-Diamino-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3,6-Diamino-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3,7-Diamino-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3,8-Diamino-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6,7-Diamino-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6,8-Diamino-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7,8-Diamino-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2,2-Dimethyl-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2,3-Dimethyl-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2,6-Dimethyl-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2,7-Dimethyl-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2,8-Dimethyl-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3,3-Dimethyl-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3,6-Dimethyl-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3,7-Dimethyl-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3,8-Dimethyl-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6,7-Dimethyl-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6,8-Dimethyl-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7,8-Dimethyl-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2,2-Diethyl-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2,3-Diethyl-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2,6-Diethyl-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2,7-Diethyl-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2,8-Diethyl-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3,3-Diethyl-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3,6-Diethyl-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3,7-Diethyl-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3,8-Diethyl-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6,7-Diethyl-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6,8-Diethyl-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7,8-Diethyl-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2,2-Bis(hydroxymethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2,3-Bis(hydroxymethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2,6-Bis(hydroxymethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2,7-Bis(hydroxymethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2,8-Bis(hydroxymethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3,3-Bis(hydroxymethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3,6-Bis(hydroxymethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3,7-Bis(hydroxymethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3,8-Bis(hydroxymethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6,7-Bis(hydroxymethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6,8-Bis(hydroxymethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7,8-Bis(hydroxymethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2,2-bis(aminomethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2,3-Bis(aminomethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2,6-bis(aminomethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2,7-bis(aminomethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2,8-bis(aminomethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3,3-bis(aminomethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3,6-bis(aminomethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3,7-bis(aminomethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3,8-bis(aminomethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6,7-bis(aminomethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6,8-bis(aminomethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7,8-bis(aminomethyl)-5-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-Chloro-5-(2-chloropiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-Chloro-5-(2-chloropiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-Chloro-5-(2-chloropiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-Chloro-5-(2-chloropiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-Chloro-5-(2-chloropiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-Chloro-5-(3-chloropiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-Chloro-5-(3-chloropiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-Chloro-5-(3-chloropiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-Chloro-5-(3-chloropiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-Chloro-5-(3-chloropiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-Chloro-5-(4-chloropiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-Chloro-5-(4-chloropiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-Chloro-5-(4-chloropiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-Chloro-5-(4-chloropiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-Chloro-5-(4-chloropiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-Fluoro-5-(2-Fluoroperizin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-Fluoro-5-(2-Fluoroperizin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-Fluoro-5-(2-Fluoroperizin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-Fluoro-5-(2-Fluoroperizin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-Fluoro-5-(2-Fluoroperizin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-Fluoro-5-(3-Fluoroperizin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-Fluoro-5-(3-Fluoroperizin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-Fluoro-5-(3-Fluoroperizin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-Fluoro-5-(3-Fluoroperpiezin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-Fluoro-5-(3-Fluoroperizin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-Fluoro-5-(4-Fluoroperpiezin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-Fluoro-5-(4-Fluoroperpiezin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-Fluoro-5-(4-Fluoroperizin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-Fluoro-5-(4-Fluoroperizin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-Fluoro-5-(4-Fluoroperizin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-Hydroxy-5-(2-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-Hydroxy-5-(2-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-Hydroxy-5-(2-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-Hydroxy-5-(2-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-Hydroxy-5-(2-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-Hydroxy-5-(3-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-Hydroxy-5-(3-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-Hydroxy-5-(3-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-Hydroxy-5-(3-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-Hydroxy-5-(3-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-Hydroxy-5-(4-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-Hydroxy-5-(4-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-Hydroxy-5-(4-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-Hydroxy-5-(4-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-Hydroxy-5-(4-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-Amino-5-(2-aminopiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-Amino-5-(2-aminopiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-Amino-5-(2-aminopiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-Amino-5-(2-aminopiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-Amino-5-(2-aminopiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-Amino-5-(3-aminopiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-Amino-5-(3-aminopiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-Amino-5-(3-aminopiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-Amino-5-(3-aminopiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-Amino-5-(3-aminopiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-Amino-5-(4-aminopiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-Amino-5-(4-aminopiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-Amino-5-(4-aminopiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-Amino-5-(4-aminopiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-Amino-5-(4-aminopiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-Methyl-5-(2-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-Methyl-5-(2-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-Methyl-5-(2-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-Methyl-5-(2-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-Methyl-5-(2-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-Methyl-5-(3-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-Methyl-5-(3-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-Methyl-5-(3-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-Methyl-5-(3-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-Methyl-5-(3-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-Methyl-5-(4-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-Methyl-5-(4-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-Methyl-5-(4-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-Methyl-5-(4-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-Methyl-5-(4-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-Ethyl-5-(2-ethylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-Ethyl-5-(2-ethylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-Ethyl-5-(2-ethylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-Ethyl-5-(2-Ethylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-Ethyl-5-(2-ethylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-Ethyl-5-(3-ethylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-Ethyl-5-(3-ethylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-Ethyl-5-(3-ethylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-Ethyl-5-(3-ethylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-Ethyl-5-(3-ethylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-Ethyl-5-(4-ethylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-Ethyl-5-(4-ethylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-Ethyl-5-(4-ethylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-Ethyl-5-(4-ethylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-Ethyl-5-(4-ethylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-(hydroxymethyl)-5-(2-(hydroxymethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-(hydroxymethyl)-5-(2-(hydroxymethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-(hydroxymethyl)-5-(2-(hydroxymethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-(hydroxymethyl)-5-(2-(hydroxymethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-(hydroxymethyl)-5-(2-(hydroxymethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-(hydroxymethyl)-5-(3-(hydroxymethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-(hydroxymethyl)-5-(3-(hydroxymethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-(hydroxymethyl)-5-(3-(hydroxymethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-(hydroxymethyl)-5-(3-(hydroxymethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-(hydroxymethyl)-5-(3-(hydroxymethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-(hydroxymethyl)-5-(4-(hydroxymethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-(hydroxymethyl)-5-(4-(hydroxymethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-(hydroxymethyl)-5-(4-(hydroxymethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-(hydroxymethyl)-5-(4-(hydroxymethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-(hydroxymethyl)-5-(4-(hydroxymethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-(aminomethyl)-5-(2-(aminomethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-(aminomethyl)-5-(2-(aminomethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-(aminomethyl)-5-(2-(aminomethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-(aminomethyl)-5-(2-(aminomethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-(aminomethyl)-5-(2-(aminomethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-(aminomethyl)-5-(3-(aminomethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-(aminomethyl)-5-(3-(aminomethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-(aminomethyl)-5-(3-(aminomethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-(aminomethyl)-5-(3-(aminomethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-(aminomethyl)-5-(3-(aminomethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-(aminomethyl)-5-(4-(aminomethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-(aminomethyl)-5-(4-(aminomethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-(aminomethyl)-5-(4-(aminomethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-(aminomethyl)-5-(4-(aminomethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-(aminomethyl)-5-(4-(aminomethyl)piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-Ethyl-5-(2-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-Ethyl-5-(2-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-Ethyl-5-(2-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-Ethyl-5-(2-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-Ethyl-5-(2-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-Ethyl-5-(3-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-Ethyl-5-(3-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-Ethyl-5-(3-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-Ethyl-5-(3-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-Ethyl-5-(3-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-Ethyl-5-(4-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-Ethyl-5-(4-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-Ethyl-5-(4-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-Ethyl-5-(4-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-Ethyl-5-(4-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2-Ethylpiperazin-1-yl)-2-methyl-2,3-dihydro-1,4-benzodioxin; 5-(2-Ethylpiperazin-1-yl)-3-methyl-2,3-dihydro-1,4-benzodioxin; 5-(2-Ethylpiperazin-1-yl)-6-methyl-2,3-dihydro-1,4-benzodioxin; 5-(2-Ethylpiperazin-1-yl)-7-methyl-2,3-dihydro-1,4-benzodioxin; 5-(2-Ethylpiperazin-1-yl)-8-methyl-2,3-dihydro-1,4-benzodioxin; 5-(3-Ethylpiperazin-1-yl)-2-methyl-2,3-dihydro-1,4-benzodioxin; 5-(3-Ethylpiperazin-1-yl)-3-methyl-2,3-dihydro-1,4-benzodioxin; 5-(3-Ethylpiperazin-1-yl)-6-methyl-2,3-dihydro-1,4-benzodioxin; 5-(3-Ethylpiperazin-1-yl)-7-methyl-2,3-dihydro-1,4-benzodioxin; 5-(3-ethylpiperazin-1-yl)-8-methyl-2,3-dihydro-1,4-benzodioxin; 5-(4-ethylpiperazin-1-yl)-2-methyl-2,3-dihydro-1,4-benzodioxin; 5-(4-ethylpiperazin-1-yl)-3-methyl-2,3-dihydro-1,4-benzodioxin; 5-(4-ethylpiperazin-1-yl)-6-methyl-2,3-dihydro-1,4-benzodioxin; 5-(4-ethylpiperazin-1-yl)-7-methyl-2,3-dihydro-1,4-benzodioxin; 5-(4-ethylpiperazin-1-yl)-8-methyl-2,3-dihydro-1,4-benzodioxin; 2-Chloro-5-(2-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-Chloro-5-(2-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-Chloro-5-(2-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-Chloro-5-(2-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-Chloro-5-(2-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-Chloro-5-(3-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-Chloro-5-(3-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-Chloro-5-(3-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-Chloro-5-(3-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-Chloro-5-(3-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-Chloro-5-(4-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-Chloro-5-(4-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-Chloro-5-(4-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-Chloro-5-(4-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-Chloro-5-(4-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2-chloropiperazin-1-yl)-2-methyl-2,3-dihydro-1,4-benzodioxin; 5-(2-chloropiperazin-1-yl)-3-methyl-2,3-dihydro-1,4-benzodioxin; 5-(2-chloropiperazin-1-yl)-6-methyl-2,3-dihydro-1,4-benzodioxin; 5-(2-chloropiperazin-1-yl)-7-methyl-2,3-dihydro-1,4-benzodioxin; 5-(2-chloropiperazin-1-yl)-8-methyl-2,3-dihydro-1,4-benzodioxin; 5-(3-chloropiperazin-1-yl)-2-methyl-2,3-dihydro-1,4-benzodioxin; 5-(3-chloropiperazin-1-yl)-3-methyl-2,3-dihydro-1,4-benzodioxin; 5-(3-chloropiperazin-1-yl)-6-methyl-2,3-dihydro-1,4-benzodioxin; 5-(3-chloropiperazin-1-yl)-7-methyl-2,3-dihydro-1,4-benzodioxin; 5-(3-chloropiperazin-1-yl)-8-methyl-2,3-dihydro-1,4-benzodioxin; 5-(4-chloropiperazin-1-yl)-2-methyl-2,3-dihydro-1,4-benzodioxin; 5-(4-chloropiperazin-1-yl)-3-methyl-2,3-dihydro-1,4-benzodioxin; 5-(4-chloropiperazin-1-yl)-6-methyl-2,3-dihydro-1,4-benzodioxin; 5-(4-chloropiperazin-1-yl)-7-methyl-2,3-dihydro-1,4-benzodioxin; 5-(4-chloropiperazin-1-yl)-8-methyl-2,3-dihydro-1,4-benzodioxin; 2-Hydroxy-5-(2-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-Hydroxy-5-(2-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-Hydroxy-5-(2-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-Hydroxy-5-(2-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-Hydroxy-5-(2-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-Hydroxy-5-(3-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-Hydroxy-5-(3-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-Hydroxy-5-(3-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-Hydroxy-5-(3-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-Hydroxy-5-(3-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-Hydroxy-5-(4-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-Hydroxy-5-(4-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-Hydroxy-5-(4-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-Hydroxy-5-(4-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-Hydroxy-5-(4-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2-hydroxypiperazin-1-yl)-2-methyl-2,3-dihydro-1,4-benzodioxin; 5-(2-hydroxypiperazin-1-yl)-3-methyl-2,3-dihydro-1,4-benzodioxin; 5-(2-hydroxypiperazin-1-yl)-6-methyl-2,3-dihydro-1,4-benzodioxin; 5-(2-hydroxypiperazin-1-yl)-7-methyl-2,3-dihydro-1,4-benzodioxin; 5-(2-hydroxypiperazin-1-yl)-8-methyl-2,3-dihydro-1,4-benzodioxin; 5-(3-hydroxypiperazin-1-yl)-2-methyl-2,3-dihydro-1,4-benzodioxin; 5-(3-hydroxypiperazin-1-yl)-3-methyl-2,3-dihydro-1,4-benzodioxin; 5-(3-hydroxypiperazin-1-yl)-6-methyl-2,3-dihydro-1,4-benzodioxin; 5-(3-hydroxypiperazin-1-yl)-7-methyl-2,3-dihydro-1,4-benzodioxin; 5-(3-hydroxypiperazin-1-yl)-8-methyl-2,3-dihydro-1,4-benzodioxin; 5-(4-hydroxypiperazin-1-yl)-2-methyl-2,3-dihydro-1,4-benzodioxin; 5-(4-hydroxypiperazin-1-yl)-3-methyl-2,3-dihydro-1,4-benzodioxin; 5-(4-hydroxypiperazin-1-yl)-6-methyl-2,3-dihydro-1,4-benzodioxin; 5-(4-hydroxypiperazin-1-yl)-7-methyl-2,3-dihydro-1,4-benzodioxin; 5-(4-hydroxypiperazin-1-yl)-8-methyl-2,3-dihydro-1,4-benzodioxin; 2-Amino-5-(2-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-Amino-5-(2-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-Amino-5-(2-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-Amino-5-(2-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-Amino-5-(2-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-Amino-5-(3-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-Amino-5-(3-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-Amino-5-(3-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-Amino-5-(3-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-Amino-5-(3-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-Amino-5-(4-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-Amino-5-(4-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-Amino-5-(4-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-Amino-5-(4-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-Amino-5-(4-methylpiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2-aminopiperazin-1-yl)-2-methyl-2,3-dihydro-1,4-benzodioxin; 5-(2-aminopiperazin-1-yl)-3-methyl-2,3-dihydro-1,4-benzodioxin; 5-(2-aminopiperazin-1-yl)-6-methyl-2,3-dihydro-1,4-benzodioxin; 5-(2-aminopiperazin-1-yl)-7-methyl-2,3-dihydro-1,4-benzodioxin; 5-(2-aminopiperazin-1-yl)-8-methyl-2,3-dihydro-1,4-benzodioxin; 5-(3-aminopiperazin-1-yl)-2-methyl-2,3-dihydro-1,4-benzodioxin; 5-(3-aminopiperazin-1-yl)-3-methyl-2,3-dihydro-1,4-benzodioxin; 5-(3-aminopiperazin-1-yl)-6-methyl-2,3-dihydro-1,4-benzodioxin; 5-(3-aminopiperazin-1-yl)-7-methyl-2,3-dihydro-1,4-benzodioxin; 5-(3-aminopiperazin-1-yl)-8-methyl-2,3-dihydro-1,4-benzodioxin; 5-(4-aminopiperazin-1-yl)-2-methyl-2,3-dihydro-1,4-benzodioxin; 5-(4-aminopiperazin-1-yl)-3-methyl-2,3-dihydro-1,4-benzodioxin; 5-(4-aminopiperazin-1-yl)-6-methyl-2,3-dihydro-1,4-benzodioxin; 5-(4-aminopiperazin-1-yl)-7-methyl-2,3-dihydro-1,4-benzodioxin; 5-(4-aminopiperazin-1-yl)-8-methyl-2,3-dihydro-1,4-benzodioxin; 5-(2-chloropiperazin-1-yl)-2-hydroxy-2,3-dihydro-1,4-benzodioxin; 5-(2-chloropiperazin-1-yl)-3-hydroxy-2,3-dihydro-1,4-benzodioxin; 5-(2-chloropiperazin-1-yl)-6-hydroxy-2,3-dihydro-1,4-benzodioxin; 5-(2-chloropiperazin-1-yl)-7-hydroxy-2,3-dihydro-1,4-benzodioxin; 5-(2-chloropiperazin-1-yl)-8-hydroxy-2,3-dihydro-1,4-benzodioxin; 5-(3-chloropiperazin-1-yl)-2-hydroxy-2,3-dihydro-1,4-benzodioxin; 5-(3-chloropiperazin-1-yl)-3-hydroxy-2,3-dihydro-1,4-benzodioxin; 5-(3-chloropiperazin-1-yl)-6-hydroxy-2,3-dihydro-1,4-benzodioxin; 5-(3-chloropiperazin-1-yl)-7-hydroxy-2,3-dihydro-1,4-benzodioxin; 5-(3-chloropiperazin-1-yl)-8-hydroxy-2,3-dihydro-1,4-benzodioxin; 5-(4-chloropiperazin-1-yl)-2-hydroxy-2,3-dihydro-1,4-benzodioxin; 5-(4-chloropiperazin-1-yl)-3-hydroxy-2,3-dihydro-1,4-benzodioxin; 5-(4-chloropiperazin-1-yl)-6-hydroxy-2,3-dihydro-1,4-benzodioxin; 5-(4-chloropiperazin-1-yl)-7-hydroxy-2,3-dihydro-1,4-benzodioxin; 5-(4-chloropiperazin-1-yl)-8-hydroxy-2,3-dihydro-1,4-benzodioxin; 2-Chloro-5-(2-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-Chloro-5-(2-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-Chloro-5-(2-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-Chloro-5-(2-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-Chloro-5-(2-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-Chloro-5-(3-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-Chloro-5-(3-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-Chloro-5-(3-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-Chloro-5-(3-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-Chloro-5-(3-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-Chloro-5-(4-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-Chloro-5-(4-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-Chloro-5-(4-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-Chloro-5-(4-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-Chloro-5-(4-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 5-(2-aminopiperazin-1-yl)-2-hydroxy-2,3-dihydro-1,4-benzodioxin; 5-(2-aminopiperazin-1-yl)-3-hydroxy-2,3-dihydro-1,4-benzodioxin; 5-(2-aminopiperazin-1-yl)-6-hydroxy-2,3-dihydro-1,4-benzodioxin; 5-(2-aminopiperazin-1-yl)-7-hydroxy-2,3-dihydro-1,4-benzodioxin; 5-(2-aminopiperazin-1-yl)-8-hydroxy-2,3-dihydro-1,4-benzodioxin; 5-(3-aminopiperazin-1-yl)-2-hydroxy-2,3-dihydro-1,4-benzodioxin; 5-(3-aminopiperazin-1-yl)-3-hydroxy-2,3-dihydro-1,4-benzodioxin; 5-(3-aminopiperazin-1-yl)-6-hydroxy-2,3-dihydro-1,4-benzodioxin; 5-(3-aminopiperazin-1-yl)-7-hydroxy-2,3-dihydro-1,4-benzodioxin; 5-(3-aminopiperazin-1-yl)-8-hydroxy-2,3-dihydro-1,4-benzodioxin; 5-(4-aminopiperazin-1-yl)-2-hydroxy-2,3-dihydro-1,4-benzodioxin; 5-(4-aminopiperazin-1-yl)-3-hydroxy-2,3-dihydro-1,4-benzodioxin; 5-(4-aminopiperazin-1-yl)-6-hydroxy-2,3-dihydro-1,4-benzodioxin; 5-(4-aminopiperazin-1-yl)-7-hydroxy-2,3-dihydro-1,4-benzodioxin; 5-(4-aminopiperazin-1-yl)-8-hydroxy-2,3-dihydro-1,4-benzodioxin; 2-Amino-5-(2-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-Amino-5-(2-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-Amino-5-(2-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-Amino-5-(2-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-Amino-5-(2-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-Amino-5-(3-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-Amino-5-(3-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-Amino-5-(3-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-Amino-5-(3-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 8-Amino-5-(3-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 2-Amino-5-(4-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 3-Amino-5-(4-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 6-Amino-5-(4-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; 7-Amino-5-(4-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin; and 8-Amino-5-(4-hydroxypiperazin-1-yl)-2,3-dihydro-1,4-benzodioxin

[0076] Pharmaceutically acceptable salts include, but are not limited to: 5-HT 1A / 1B A solution of a receptor agonist or a compound of formula (I); an acid solution selected from the group consisting of phosphoric acid, sulfuric acid, nitric acid, pyrophosphate, bicarbonate, carbonic acid, clavulanic acid, isothiocyanate, boric acid, halides, hydrogen halides, nitric acid, acetic acid, succinic acid, lactic acid, tartaric acid, lactobionic acid, lauric acid, mandelic acid, malic acid, citric acid, fumaric acid, maleic acid, oleic acid, oxalic acid, ascorbic acid, nicotinic acid, benzoic acid, methanesulfonic acid, salicylic acid, stearic acid, tannic acid, toluenesulfonic acid, valeric acid, methanesulfonic acid, ethylsulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 2-ethanedisulfonic acid, and naphthalenesulfonic acid; a salt or acidic additional salt prepared by mixing the above.

[0077] Furthermore, for 5-HT with an acidic structure 1A / 1B Receptor agonists or compounds of formula (I), whose pharmaceutically acceptable salts include, but are not limited to, alkali metal salts (such as sodium or potassium salts), alkaline earth metal salts (such as calcium or magnesium salts), and salts prepared by appropriate organic ligands (such as quaternary ammonium salts). Pharmaceutically acceptable salts of the above compounds include, but are not limited to: acetates, benzenesulfonates, benzoates, bicarbonates, bisulfates, tartrates, borates, bromides, calcium salts, carbonates, chlorides, clavulanates, citrates, dihydrochlorides, fumarates, gluconates, glutamates, hydrobromide, hydrochloride, hydroxynaphthylcarbamates, iodides, isothiocyanates, lactates, lactobionates, laurates, maleates, mandelates, methanesulfonates, methyl bromides, methyl nitrates, methyl sulfates, nitrates, N-methylglucosamine salts, oleates, oxalates, phosphates / bisphosphates, salicylates, stearates, sulfates, succinates, tannins, tartrates, toluenesulfonates, triethyliodide, and valerates.

[0078] The scope of this disclosure includes 5-HT 1A / 1BA prodrug of a receptor agonist or a compound of formula (I). The prodrug is an inactive derivative of the aforementioned compound that can be readily converted into the target compound in vivo. For information on the selection of appropriate prodrug derivatives and conventional methods of production, please refer to professional literature such as *Prodrug Design* (edited by H. Bundgaard, Elsevier, 1985). The content of this literature has been incorporated into this specification by quotation.

[0079] When 5-HT 1A / 1B When the receptor agonist or compound of formula (I) contains at least one chiral center, it may exist in racemic mixtures or enantiomers. Such isomers and mixtures thereof are within the scope of this disclosure. Furthermore, if 5-HT is present... 1A / 1B The crystal forms, crystals, crystalline solids, and polymorphs of receptor agonists or compounds of formula (I) are also included within the scope of this disclosure. Additionally, 5-HT 1A / 1B Receptor agonists or solvates and hydrates of compounds of formula (I) are also within the scope of this disclosure. 5-HT 1A / 1B The crystal form, crystal, crystalline solid and polymorph of the receptor agonist or the compound of formula (I) can be prepared by, for example by the methods described in International Publication No. 2006 / 037043 and International Publication No. 2006 / 036874 cited in this specification.

[0080] 5-HT 1A / 1B Receptor agonists are commercially available products. Whether a compound belongs to the 5-HT family can be easily determined using industry-known methods. 1A / 1B Receptor agonists. Compounds of formula (I) are also commercially available and can be prepared by organic synthetic chemistry. For details, please refer to Japanese Patent Application Publication No. 61-152655 and US Patent No. 5424313. The contents of the above documents are incorporated herein by reference.

[0081] 5-HT 1A and 5-HT 1B The receptor belongs to the G protein-coupled receptor (GPCR) category, and its ligand screening methods have formed a mature system and achieved commercial application (e.g., "Application of Active Learning in GPCR Ligand Screening" presented by Ryo Shimizu et al. at the 29th Niigata Conference on Information Chemistry JL1, Proceedings of the Cheminformatics Conference, and page 64 of "Insights into GPCR Drug Development and Research—Study on GPCR-Ligand Interactions and Signaling Pathways through Experimental and Functional Detection" in the 2022 issue of DiscoverX. These references are included in this specification by way of citation). Furthermore, several companies, including Cosmo Biotech Co., Ltd., provide GPCR profiling and screening services. Therefore, industry professionals can easily screen 5-HT... 1A / 1B The ligand of the receptor.

[0082] (4. Pharmaceutical Composition) This disclosure provides 5-HT 1A / 1B A pharmaceutical composition of a receptor agonist. In one embodiment, the pharmaceutical composition contains a therapeutically effective dose of 5-HT. 1A / 1B Receptor agonists. The pharmaceutical composition may also contain pharmaceutically acceptable carriers or excipients. No specific limitations are made regarding parameters such as dosage, route of administration, frequency of administration, dosing interval, order of administration, and timing of administration; these can be adjusted by physicians or other professionals based on clinical judgment and the patient's specific condition.

[0083] The pharmaceutical compositions disclosed herein can be used to treat, prevent, or manage the diseases described in this specification. The compositions can also be used to manufacture medicaments for treating, preventing, or managing the diseases described in this specification. Furthermore, the pharmaceutical compositions disclosed herein are suitable for treating, preventing, or managing the objects described in this specification. Simultaneously, the compositions can also be used to manufacture medicaments for treating, preventing, or managing the objects described in this specification. The pharmaceutical compositions disclosed herein may be used in the treatment, prevention or administration methods described in the specification.

[0084] In one embodiment, the pharmaceutical composition of this disclosure is used to treat, prevent, or manage a target BIND, a mental illness with jaundice, or a mental illness caused by a mutation in the UGT1A1 gene. In another embodiment, the pharmaceutical composition of this disclosure is used to manufacture a medicament for treating, preventing, or managing a target BIND, a mental illness with jaundice, or a mental illness caused by a mutation in the UGT1A1 gene.

[0085] In one embodiment, the pharmaceutical composition of this disclosure is used to treat one or more (e.g., one, two, or three) of a group consisting of a target BIND, jaundice-associated mental illness, and mental illness caused by a UGT1A1 gene mutation. In one embodiment, the pharmaceutical composition of this disclosure is used to prevent one or more (e.g., one, two, or three) of a group consisting of a target BIND, jaundice-associated mental illness, and mental illness caused by a UGT1A1 gene mutation. In one embodiment, the pharmaceutical composition of this disclosure can be used to treat one or more (e.g., one, two, or three) of a group consisting of a target BIND, jaundice-associated mental illness, and mental illness caused by a UGT1A1 gene mutation.

[0086] In one embodiment, the pharmaceutical composition of this disclosure is used to treat, prevent, or manage a target BIND. In one embodiment, the pharmaceutical composition of this disclosure is used to treat, prevent, or manage a mental illness accompanied by jaundice. In one embodiment, the pharmaceutical composition of this disclosure is used to treat, prevent, or manage a mental illness caused by a mutation in the UGT1A1 gene.

[0087] In some embodiments, the pharmaceutical compositions disclosed herein are used in methods of treating, preventing, or managing a target mental illness.

[0088] The pharmaceutical compositions disclosed herein can be used to treat, prevent, or manage a subject. In some embodiments, the subject has a high bilirubin concentration in its biological sample. In some embodiments, the subject has a higher bilirubin concentration in its biological sample than in healthy individuals. In some embodiments, the subject has BIND. In some embodiments, the subject has jaundice. In some embodiments, the subject has a UGT1A1 gene mutation. In some embodiments, the subject has one or more (e.g., 1, 2, 3, 4, or 5) states selected from the group consisting of mental illness, BIND, UGT1A1 gene mutation, jaundice, and a high bilirubin concentration in its biological sample (e.g., higher than in healthy individuals).

[0089] The pharmaceutical compositions disclosed herein can be formulated into oral, non-oral (e.g., intravenous, intramuscular, or subcutaneous), nasal, sublingual, or rectal formulations, as well as inhaled or aerosol formulations. For example, the pharmaceutical compositions can be in the form of tablets, pills, capsules (sustained-release or slow-acting formulations, etc.), powders, granules, elixirs, tinctures, syrups, emulsions, sterile non-oral liquids or suspensions, aerosols or liquid sprays, drops, ampoules, self-administered subcutaneous syringes, or suppositories. The pharmaceutical compositions disclosed herein can be formulated using conventional methods, such as those described in Remington Pharmaceutical Sciences (edited by Gennaro, Mack Publishing, Easton, PA, 1990), cited in this specification.

[0090] Pharmaceutically acceptable carriers or excipients are non-toxic and inactive solid, semi-solid, or liquid substances. Pharmaceutically acceptable carriers or excipients include: stabilizers, inert diluents, fillers, swelling agents, disintegrants, disintegration inhibitors, suspending agents, buffers, osmotic pressure regulators, chelating agents, pH adjusters, surfactants, capsule coatings, binders, preservatives, antioxidants, lubricants, humectants, adsorbents, slip agents, and any other formulation adjuvants. Specific examples of pharmaceutically acceptable carriers or excipients include, but are not limited to: water, alcohols (such as ethanol), solvents (such as dimethyl sulfoxide), saline solutions (such as physiological saline), or mixtures thereof; inorganic salts, such as sodium chloride; boric acid, phosphoric acid, acetic acid, citric acid, ε-aminocaproic acid, glutamic acid, ethylenediaminetetraacetic acid, or their corresponding salts, such as alkali metal salts or alkaline earth metal salts like sodium, potassium, calcium, or magnesium salts; monosaccharides such as glucose (dextrose), mannose, galactose, or fructose; sugar alcohols such as mannitol, inositol, or xylitol; disaccharides such as sucrose, lactulose, lactose, maltose, trehalose, or cellobiose; polysaccharides such as dextrin, dextran, cellulose, hyaluronic acid, or chondroitin sulfate; starches such as corn starch and potato starch; cellulose, methyl... Cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, cellulose acetate or their derivatives, etc.; human serum albumin; L-amino acids such as glycine, lysine, asparagine, arginine, glutamine, cysteine, aspartic acid or glutamic acid, etc.; tragacanth gum; gelatin; talc; cocoa butter or synthetic wax; natural wax or beeswax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, soybean oil or hydrogenated oil, etc.; glycols such as ethylene glycol or propylene glycol; esters such as ethyl oleate or ethyl laurate, etc.; agar; potassium hydroxide, sodium hydroxide, magnesium hydroxide or aluminum hydroxide; alginic acid; isotonic saline; Ringer's solution; ethanol; phosphate buffer; sodium dodecyl sulfate or magnesium stearate, etc. Pharmaceutically acceptable carriers or excipients can be flexibly selected according to the type of dosage form and the characteristics of the compounds used.

[0091] The 5-HT contained in the pharmaceutical composition disclosed herein 1A / 1B There are no particular limitations on the content of the receptor agonist, the second drug, and the pharmaceutically acceptable carrier or excipient, as long as an effective dose is achieved for the treatment, prevention, or management of the disease. In one embodiment, the pharmaceutical composition contains 5-HT 1A / 1B The content of the receptor agonist is the therapeutically effective dose. The pharmaceutical composition disclosed herein contains 5-HT... 1A / 1BThe content of the receptor agonist, the second drug, and the pharmaceutically acceptable carrier or excipient can be adjusted based on various factors such as the type of compound used, the age, weight, health status, sex, and diet of the mammal receiving the drug, the frequency and route of administration, the duration of treatment, and other drugs used concurrently. The pharmaceutical composition disclosed herein contains 5-HT... 1A / 1B Receptor agonists, for example, may comprise about 0.01 mg to about 100 mg, about 0.1 mg to about 50 mg, about 0.5 mg to about 50 mg, about 1 mg to about 25 mg, about 2.5 mg to about 25 mg, about 5 mg to about 25 mg, or about 10 mg to about 20 mg. In some embodiments, when the pharmaceutical composition of this disclosure is used on a subject, a daily or once-daily administration of 5-HT... 1A / 1B The receptor agonists are: approximately 0.0001 mg / kg (body weight) to approximately 50 mg / kg (body weight), approximately 0.001 mg / kg (body weight) to approximately 50 mg / kg (body weight), approximately 0.01 mg / kg (body weight) to approximately 50 mg / kg (body weight), approximately 0.1 mg / kg (body weight) to approximately 50 mg / kg (body weight), approximately 0.1 mg / kg (body weight) to approximately 40 mg / kg (body weight), approximately 0.1 mg / kg (body weight) to < approximately 34 mg / kg (body weight), approximately 0.1 mg / kg (body weight) to approximately 30 mg / kg (body weight), approximately 0.1 mg / kg (body weight) to approximately 20 mg / kg (body weight), approximately 0.5 mg / kg (body weight) to approximately 10 mg / kg (body weight), or approximately 1 mg / kg (body weight) to approximately 10 mg / kg (body weight). The amount of a pharmaceutically acceptable carrier or excipient contained in the pharmaceutical composition of this disclosure may be about 1 to about 99% by weight, about 5 to about 90% by weight, about 10 to about 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. 5-HT 1A / 1B Receptor agonists can be administered as a single daily dose or the entire daily dose can be divided into multiple doses, such as 2, 3 or 4 doses per day.

[0092] The pharmaceutical compositions disclosed herein can be formulated into oral or non-oral formulations, for example, via intravenous injection, subcutaneous injection, enteral administration, intraperitoneal injection, or intramuscular injection. The formulations may contain 5-HT. 1A / 1B Receptor agonists and selectively added carriers or excipients. In the formulation, 5-HT 1A / 1BThe receptor agonist can be uniformly distributed. Formulations include solid dosage forms such as tablets, pills, powders, granules, or capsules, as well as liquid dosage forms such as sterile aqueous solutions, sterile non-aqueous solutions, suspensions, emulsions, syrups, or elixirs. Dosage form is not particularly limited and can be flexibly selected according to the route of administration. The pharmaceutical compositions disclosed herein can be administered in different forms: for example, as solid dosage forms via oral tablets, or as liquid dosage forms via intravenous injection using syringes, catheters, or other devices.

[0093] Solid dosage forms can be prepared using traditional pharmaceutical techniques. Their active ingredients are formulated in combination with one or more of the following substances: excipients, binders, disintegrants, surfactants, disintegration inhibitors, absorption promoters, humectants, adsorbents, and lubricants. Binders include, but are not limited to: natural sugars (such as starch, gelatin, glucose, or β-lactose), natural and synthetic rubbers (such as gum arabic, tragacanth, or sodium alginate), carboxymethyl cellulose, polyethylene glycol, and natural waxes. Disintegrants include, but are not limited to: starch, methyl cellulose, agar, bentonite, and xanthan gum. Lubricants include, but are not limited to: sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, and sodium chloride. Depending on the specific requirements, colorants, preservatives, flavorings, flavorings, or sweeteners may also be added to solid dosage forms. Furthermore, solid dosage forms can be in the form of sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, or film-coated tablets, and can be made into double-layer or multi-layer tablets. Capsules are prepared by mixing the active ingredient with various pharmaceutically acceptable carriers using conventional methods, and then filling them into hard gelatin capsules or soft capsules. There are no particular limitations on the concentration of the active ingredient in solid dosage forms; for example, it can be controlled within the range of approximately 1% to approximately 99% by weight, approximately 20% to approximately 80% by weight, approximately 30% to approximately 60% by weight, or approximately 40% to approximately 50% by weight. Solid dosage forms may contain single or multiple doses of the active ingredient.

[0094] Liquid formulations are prepared by mixing the active ingredient with inactive diluents using conventional pharmaceutical techniques. Furthermore, one or more substances such as solubilizers, buffers, osmotic regulators, suspending agents, surfactants, antioxidants, and preservatives can be added as needed. Liquid formulations can also be pre-prepared as lyophilized powders and then reconstituted by dissolving or suspending them in inactive diluents or other substances before use. Colorants, preservatives, flavorings, tasters, or sweeteners can be added to liquid formulations as needed. There are no particular limitations on the concentration of the active ingredient in liquid formulations; for example, it can be controlled within the range of approximately 1% to approximately 99% by weight, approximately 20% to approximately 80% by weight, approximately 30% to approximately 60% by weight, or approximately 40% to approximately 50% by weight. Liquid formulations can contain single or multiple doses of the active ingredient.

[0095] The pharmaceutical compositions disclosed herein may further comprise a second drug. This composition can be used to deliver 5-HT 1A / 1B The receptor agonist and the second drug are administered to the subject concurrently, in combination, or sequentially. In the case of sequential administration, 5-HT can be administered first. 1A / 1B Receptor agonists can also be given as a second medication. The second medication is a drug for treating, preventing, or managing mental illness, such as well-known antipsychotics, antipsychotics, or anti-attention deficit hyperactivity disorder (ADHD) medications. In some implementations, the second drug is selected from the group consisting of cholinesterase inhibitors, acetylcholinesterase inhibitors, butyrylcholinesterase inhibitors, muscarinic receptor agonists, glutamatergic antagonists, cholinergic drugs, carnitine acetyltransferase agonists, acetylcholine release promoters, choline uptake promoters, nicotine-type acetylcholine receptor agonists, 5-HT6 receptor antagonists, 5-HT6 inverse agonists, anti-movement disorder drugs, anti-dystonia drugs, anti-myoclonus drugs, anti-tremor drugs, selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), antipsychotics, norepinephrine reuptake inhibitors, dopamine agonists, antisleep drugs, antimanic drugs, and antipharmacological drugs. In some implementation schemes, the second drug is one or more drugs selected from the group consisting of SB-742457, SB-271046, SB-399885, SB-357134, SB-258585, RO-436854, RO-0406790, and RO-65-7674. In some dosing regimens, the second drug is one or more drugs selected from the group consisting of levodopa, bromocriptine, pergolide, ephedrine sulfate, pemoline, masindole, d,1-α-methylphenidate, methylphenidate, pramipexole, modafinil, and ropinirole. There are no particular restrictions on the dosage, method of administration, route of administration, frequency of administration, dosing interval, order of administration, and timing of administration of the second drug; these can be determined by the physician based on the patient's condition. The dosage of the second drug can be a dose that is effective in treating, preventing, or managing mental illness.

[0096] (5. Treatment, prevention or management methods) This disclosure provides a method for treating, preventing, or managing a disease or condition, the method comprising administering 5-HT 1A / 1B The steps involve using a receptor agonist or the pharmaceutical composition described in this disclosure. In some embodiments, the method of this disclosure includes administering an effective therapeutic dose of 5-HT to a subject. 1A / 1B The steps of receptor agonist.

[0097] The methods disclosed herein can be used to treat, prevent, or manage the diseases described in this specification. The methods disclosed herein can be used to treat, prevent, or manage the subjects described in this specification.

[0098] In one embodiment, this disclosure provides a method for treating, preventing, or managing BIND, jaundice-associated mental illness, or mental illness caused by a UGT1A1 gene mutation in a subject with such a need, the method comprising administering an effective therapeutic dose of 5-HT to the subject. 1A / 1B The steps of using a receptor agonist or an effective therapeutic dose of the pharmaceutical composition described in this disclosure.

[0099] In one embodiment, the method of this disclosure is used to treat one or more (e.g., one, two, or three) diseases selected from the group consisting of BIND, jaundice-associated mental illness, and mental illness caused by UGT1A1 gene mutation in a subject with such need, the method comprising administering an effective therapeutic dose of 5-HT to the subject. 1A / 1B The steps of the receptor agonist. In one embodiment, the method of this disclosure is used to prevent one or more diseases (e.g., one, two, or three) selected from the group consisting of BIND, jaundice-associated mental illness, and mental illness caused by UGT1A1 gene mutation in a subject with such need, the method comprising administering an effective therapeutic dose of 5-HT to said subject. 1A / 1B The steps of using a receptor agonist. In one embodiment, the method of this disclosure is used to manage one or more (e.g., one, two, or three) diseases selected from the group consisting of BIND, jaundice-associated mental illness, and mental illness caused by a mutation in the UGT1A1 gene in a subject with such need, the method comprising administering an effective therapeutic dose of 5-HT to the subject. 1A / iB The steps of receptor agonist.

[0100] In one embodiment, the method of this disclosure is used to treat, prevent, or manage BIND in a subject with such a need, the method comprising administering an effective therapeutic dose of 5-HT to the subject. 1A / 1B The steps of using a receptor agonist. In one embodiment, the method of this disclosure is used to treat, prevent, or manage a subject with a mental illness accompanied by jaundice, the method comprising administering to the subject an effective therapeutic dose of 5-HT. 1A / 1B The steps of using a receptor agonist. In one embodiment, the method of this disclosure is used to treat, prevent, or manage a mental illness in a subject caused by a mutation in the UGT1A1 gene, the method comprising administering to the subject an effective therapeutic dose of 5-HT. 1A / 1B The steps of receptor agonist.

[0101] In some embodiments, the method of this disclosure is used to treat, prevent, or manage a mental illness in a subject with such a need, the method comprising administering an effective therapeutic dose of 5-HT to the subject. 1A / 1B The steps of receptor agonist.

[0102] In some embodiments, the method of this disclosure further includes the step of collecting a biological sample from the subject. The method for collecting the biological sample can be a method known in the art. For example, blood can be drawn from the subject using tools such as a syringe. Preferably, the biological sample is blood or urine.

[0103] In some embodiments, the method of this disclosure further includes the step of determining the bilirubin concentration in a biological sample collected from the subject. This concentration determination can be performed using methods known in the art. For example, using a total bilirubin assay kit for blood tests, such as CicaLiquid D-BIL (Kanto Chemical Co., Ltd.), vanadate (see Clinical Chemistry, Vol. 22, 1993, pp. 116-122, which is incorporated herein by reference); using a direct bilirubin assay kit, such as the Aqua-autoKainos D-BIL reagent (KAINOS Co., Ltd.), or a "serotec" T-BIL kit for total bilirubin determination (serotec Co., Ltd.).

[0104] In some embodiments, the method of this disclosure includes a step of determining whether a subject has BIND. The determination of whether a subject has BIND can be performed using methods known in the art. For example, BIND can be determined by detecting bilirubin concentration (total bilirubin concentration, direct bilirubin concentration, or indirect bilirubin concentration), UGT1A1 gene mutation, or combinations of two or more, three or more, or even four of these in a biological sample from which the subject is derived. For example, when a subject's blood bilirubin concentration is elevated (above the level of a healthy person, etc.), the subject can be determined to have BIND.

[0105] In some embodiments, the method of this disclosure includes a step of determining whether a subject has jaundice. Determining whether a subject has jaundice can be done using methods known in the art. For example, constitutional jaundice can be determined by measuring the concentration of indirect bilirubin in the blood through a blood test. For example, when a subject's indirect bilirubin concentration is elevated (higher than the level of a healthy person, etc.), the subject can be determined to have jaundice.

[0106] In some embodiments, the method disclosed herein includes a step of determining whether a subject has a UGT1A1 gene mutation. Determining whether a subject has a UGT1A1 gene mutation can be performed using methods known in the industry. For example, the Invader (registered trademark) UGT1A1 detection reagent (Sekisui Medical Co., Ltd.) can be used as a UGT1A1 gene polymorphism detection reagent.

[0107] In some implementations, the method of this disclosure includes a step of determining whether a subject suffers from a mental illness. The determination of whether a subject suffers from a mental illness can be performed using methods known in the art. For example, it can be done through various diagnostic tests for mental illness, medical history taking, electroencephalography (EEG), CT scans, or a combination thereof.

[0108] The methods disclosed herein can be used for the treatment, prevention, or control of a target subject. In some embodiments, the subject suffers from a mental illness; in some embodiments, the subject carries a BIND gene mutation; in some embodiments, the subject suffers from jaundice; in some embodiments, the subject carries a UGT1A1 gene mutation; in some embodiments, the subject's biological sample contains a high concentration of bilirubin. In some embodiments, the bilirubin concentration in the subject's biological sample is higher than that of a healthy person. In some embodiments, the subject has one or more states selected from categories (e.g., 1, 2, 3, 4, or 5) comprising mental illness, BIND, jaundice, UGT1A1 gene mutation, and elevated bilirubin concentration in the biological sample (e.g., bilirubin concentration higher than that of a healthy person).

[0109] In a specific implementation plan, the method disclosed herein is a method for treating, preventing, or controlling BIND or mental illness in target individuals, including: (a) Steps for obtaining biological samples from the object; (b) The step of determining the bilirubin concentration in the biological sample obtained in step (a); and (c) When the bilirubin concentration measured in step (b) is higher than that of a healthy person, or when the subject is determined to have jaundice based on the bilirubin concentration measured in step (b), administer an effective therapeutic dose of 5-HT to the subject. 1A / 1B The steps involve using a receptor agonist or an effective therapeutic dose of the pharmaceutical composition disclosed herein. The mental illness may include mental illness with jaundice and / or mental illness caused by a mutation in the UGT1A1 gene.

[0110] In a specific implementation, the method of this disclosure provides a pharmaceutical composition for treating, preventing, or controlling BIND or mental illness in a target individual, comprising: (a) Steps for determining whether the object carries a UGT1A1 gene mutation; (b) If the subject is determined to carry the UGT1A1 gene mutation in step (a), administer an effective therapeutic dose of 5-HT to the subject. 1A / 1B receptor agonist The steps of administering a dose or effective therapeutic dose of the pharmaceutical composition disclosed herein. The mental illness may include mental illness with jaundice, and / or mental illness caused by a mutation in the UGT1A1 gene.

[0111] In some embodiments, the method of this disclosure further includes a step of determining whether a subject suffers from or is likely to suffer from the disease or condition described in this specification. Specifically, the method of this disclosure further includes a step of determining whether a subject suffers from a mental illness, BIND, mental illness with jaundice, or a mental illness caused by a UGT1A1 gene mutation, or is likely to suffer from a mental illness, BIND, mental illness with jaundice, or a mental illness caused by a UGT1A1 gene mutation. In some embodiments, the method of this disclosure further includes a step of diagnosing the target mental symptoms or mental state.

[0112] 5-HT 1A / 1B There are no particular restrictions on the dosage, method of administration, route of administration, frequency of administration, dosing interval, order of administration, and timing of administration of the receptor agonist or the pharmaceutical composition disclosed herein; these can be determined by a physician or other appropriate authority based on the condition of the target individual. 1A / 1B The dosage of the receptor agonist or the pharmaceutical composition disclosed herein can be a dose effective for treating, preventing, or controlling BIND, mental illness with jaundice, or mental illness caused by a UGT1A1 gene mutation. For example, the dosage may be about 0.01 mg to about 100 mg, about 0.1 mg to about 50 mg, about 0.5 mg to about 50 mg, about 1 mg to about 25 mg, about 2.5 mg to about 25 mg, about 5 mg to about 25 mg, or about 10 mg to about 20 mg per dose daily or per administration. In some implementations, the target subjects receive 5-HT at doses of approximately 0.0001 mg / kg (body weight) to approximately 50 mg / kg (body weight), approximately 0.001 mg / kg (body weight) to approximately 50 mg / kg (body weight), approximately 0.01 mg / kg (body weight) to approximately 50 mg / kg (body weight), approximately 0.1 mg / kg (body weight) to approximately 50 mg / kg (body weight), approximately 0.1 mg / kg (body weight) to approximately 40 mg / kg (body weight), approximately 0.1 mg / kg (body weight) to less than approximately 34 mg / kg (body weight), approximately 0.1 mg / kg (body weight) to approximately 30 mg / kg (body weight), approximately 0.1 mg / kg (body weight) to approximately 20 mg / kg (body weight), approximately 0.5 mg / kg (body weight) to approximately 10 mg / kg (body weight), or approximately 1 mg / kg (body weight) to approximately 10 mg / kg (body weight) per day or per dose. 1A / 1BReceptor agonist administration. While there are no restrictions on the route of administration, it can be administered orally or non-orally, such as intravenously, subcutaneously, enterally, intraperitoneally, or intramuscularly. Dosage frequency can be once daily, twice daily, three times daily, or once every two days. Dosage intervals are 6 hours, 8 hours, 12 hours, 18 hours, 24 hours, 2 days, 3 days, 4 days, or 5 days.

[0113] The treatment, prevention, or control methods of this disclosure may further include the step of administering an effective therapeutic dose of a second drug to the subject. For example, the second drug may be a medication used to treat, prevent, or control mental illness, such as known antipsychotics, antipsychotics, or anti-attention deficit hyperactivity disorder (ADHD) medications. In one embodiment, the treatment, prevention, or control methods of this disclosure include administering 5-HT... 1A / 1B The procedure involves administering a receptor agonist concurrently, in combination, or sequentially with a second drug. In some embodiments, the second drug is one or more drugs selected from the following categories: cholinesterase inhibitors, acetylcholinesterase inhibitors, butyrylcholinesterase inhibitors, muscarinic receptor agonists, glutamatergic antagonists, cholinergic drugs, carnitine acetyltransferase agonists, acetylcholine release promoters, choline uptake promoters, nicotinic acetylcholine receptor agonists, 5-HT6 antagonists, 5-HT6 inverse agonists, anti-movement disorder agents, anti-dystonia agents, anti-myoclonus agents, anti-tremor agents, selective serotonin reuptake inhibitors (SSRIs), serotonin / norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), antipsychotics, norepinephrine reuptake inhibitors, dopaminergic drugs, anti-insomnia drugs, antimanic drugs, and antipharmacological drugs. In some implementations, the second drug is one or more drugs selected from the categories SB-742457, SB-271046, SB-399885, SB-357134, SB-258585, RO-436854, RO-0406790, and RO-65-7674. In some implementations, the second drug is one or more drugs selected from the categories levodopa, bromocriptine, pergolide, ephedrine sulfate, pemoline, masindole, d,1-α-methylphenidate, methylphenidate, pramipexole, modafinil, and ropinirole. There are no restrictions on the dosage, method of administration, route of administration, frequency of administration, dosing interval, order of administration, and timing of administration of the second drug; these can be determined by a physician or other physician based on the target individual's condition. The dosage of the second drug can be a dose effective in treating, preventing, or controlling mental illness.

[0114] In one embodiment, the treatment, prevention, or control methods of this disclosure further include a step of identifying whether the target subject suffers from BIND, mental illness with jaundice, or mental illness caused by a UGT1A1 gene mutation. In other embodiments, the treatment, prevention, or control methods of this disclosure further include a step of identifying whether the target subject suffers from jaundice and / or carries a UGT1A1 gene mutation.

[0115] (6. Reagent kit) This disclosure provides a 5-HT 1A / 1B A kit for a receptor agonist or a pharmaceutical composition disclosed herein. In some embodiments, the kit comprises an effective therapeutic dose of 5-HT. 1A / 1B The disclosed pharmaceutical composition comprises a receptor agonist or an effective therapeutic dose.

[0116] The kit disclosed herein may also include reagents for determining the concentration of bilirubin in biological samples, and / or reagents for detecting mutations in the bilirubin UDP-glucuronyl transferase gene. In some embodiments, the bilirubin concentration is a total bilirubin concentration, an indirect bilirubin concentration, or a direct bilirubin concentration. In some embodiments, the bilirubin concentration is selected from one or more (e.g., one, two, or three) of the categories of total bilirubin concentration, indirect bilirubin concentration, and direct bilirubin concentration.

[0117] While there are no limitations on the examples of reagents used to determine the concentration of bilirubin in biological samples, commonly used reagents include: the D-BIL reagent kit for total bilirubin detection in blood tests (Kanto Chemical Co., Ltd.), the method using vanadate (see Clinical Chemistry, 1993, Vol. 22, pp. 116-122. This literature has been cited and incorporated into the text of this instruction manual.), and the AquaAuto Kainos D-BIL reagent kit for direct bilirubin detection (Co., Ltd.). Kainos, or the "Serotec" T-BIL (Serotec Co., Ltd.) reagent for total bilirubin determination. Specific examples of this reagent include, but are not limited to, bilirubin oxidase, vanadate, or sodium metavanadate. Since indirect bilirubin concentration cannot usually be measured directly, the indirect bilirubin concentration must be calculated by subtracting the direct bilirubin concentration from the total bilirubin concentration.

[0118] Examples of reagents for determining bilirubin UDP-glucuronide transferase gene mutations include, although there are no limitations, the Invader (registered trademark) UGT1A1 detection reagent (Sekisui Medical Co., Ltd.) for determining UGT1A1 gene polymorphism.

[0119] In some implementation schemes, 5-HT 1A / 1BThe receptor agonist or the pharmaceutical composition of this disclosure is packaged in a container such as an ampoule or vial. Therefore, in some embodiments, the kit of this disclosure contains 5-HT. 1A / 1B A container for a receptor agonist or a pharmaceutical composition disclosed herein.

[0120] The kits disclosed herein can be used to treat, prevent, or control the diseases described in this specification. The kits disclosed herein can be used to treat, prevent, or control the target subjects described in this specification. The kits disclosed herein can also be used in the treatment, prevention, or control methods described in this specification. In specific embodiments, the kits disclosed herein will be used to treat, prevent, or control BIND, jaundice-associated mental illness, or mental illness caused by UGT1A1 gene mutations in target subjects.

[0121] In some embodiments, the kit of this disclosure may contain 5-HT 1A / 1B The kit includes instructions for using receptor agonists or pharmaceutical compositions disclosed herein. In some embodiments, the kit includes instructions describing methods for treating, preventing, or controlling the condition as described herein. In specific embodiments, the kit includes instructions describing methods for treating, preventing, or controlling BIND, mental illness with jaundice, or mental illness caused by a mutation in the UGT1A1 gene. In some embodiments, the kit also includes information on bilirubin concentration data in biological samples from healthy individuals. In some embodiments, the kit includes instruments for collecting biological samples from a target subject, such as containers like urine cups or syringes.

[0122] In one embodiment, the kit of this disclosure is used to treat one or more (e.g., one, two, or three) diseases in a target subject selected from the categories of BIND, jaundice-associated mental illness, and mental illness caused by UGT1A1 gene mutation. In one embodiment, the kit of this disclosure is used to prevent one or more (e.g., one, two, or three) diseases in a target subject selected from the categories of BIND, jaundice-associated mental illness, and mental illness caused by UGT1A1 gene mutation. In one embodiment, the kit of this disclosure is used to control one or more (e.g., one, two, or three) diseases in a target subject selected from the categories of BIND, jaundice-associated mental illness, and mental illness caused by UGT1A1 gene mutation.

[0123] In one embodiment, the kit of this disclosure is used to treat, prevent, or control BIND in a target subject. In one embodiment, the kit of this disclosure is used to treat, prevent, or control mental illness with jaundice in a target subject. In one embodiment, the kit of this disclosure is used to treat, prevent, or control mental illness caused by a mutation in the UGT1A1 gene in a target subject.

[0124] In some implementations, the kit disclosed herein can be used in methods for the treatment, prevention, or control of mental illness in target subjects.

[0125] The kit disclosed herein can be used for the treatment, prevention, or control of a target subject. In some embodiments, the subject has a mental illness; in some embodiments, the subject has BIND; in some embodiments, the subject has jaundice; in some embodiments, the subject carries a UGT1A1 gene mutation; in some embodiments, the subject's biological sample has a high concentration of bilirubin. In some embodiments, the bilirubin concentration in the subject's biological sample is higher than that of a healthy person. In some embodiments, the subject has one or more states selected from the following categories (e.g., 1, 2, 3, 4, or 5), which consist of mental illness, BIND, jaundice, UGT1A1 gene mutation, and elevated bilirubin concentration in the biological sample (e.g., bilirubin concentration higher than that of a healthy person).

Example

[0126] (7. Example) The following are examples. These examples are intended to help to better understand the present invention and are not intended to limit the invention.

[0127] (Example 1) (Confirmed through companion diagnostic drugs) Companion diagnostic drugs include reagents for measuring total bilirubin, indirect bilirubin, direct bilirubin concentrations, and UGT1A1 gene mutation detection. Therefore, the enzymatic method used in routine bilirubin detection was employed to investigate the plasma components of Gunn rats (9–10 weeks old), a BIND model mouse. The UGT1A1 gene mutation status in Gunn rats was further investigated. Normal Wistar rats (9–10 weeks old) were investigated using the same method as a comparative control.

[0128] Table 1 lists the concentrations of total bilirubin, direct bilirubin, and indirect bilirubin in the plasma of Gunn and Wistar rats. * indicates p < 0.05, ** indicates p < 0.01, and *** indicates p < 0.001 (Student-t test). Table 1 Table 1 Gunn rats Wistar rats Total bilirubin (mg / dL) 4.07±0.27*** 0.02±0.004 Direct bilirubin (mg / dL) 1.53±0.12*** ND (below detection range) Indirect bilirubin (mg / dL) 2.54±0.16*** 0.02±0.004 (mean ± standard error) A total of 6 Gunn rats and Wistar rats were used for testing.

[0129] It has been confirmed that the concentrations of various bilirubin types in the plasma of Gunn rats are significantly higher, and BIND can be identified by investigating the concentrations of various bilirubin types (total bilirubin, direct bilirubin, and indirect bilirubin).

[0130] The following paper reports that the UGT1A1 gene in Gunn rats has been mutated. Iyanagi T, Watanabe T, and Uchiyama Y, in their paper "Hyperbilirubinemia in Gunn rats," published in the Journal of Biochemistry, pointed out that the deficiency of 3-methylcholanthrene-inducible UDP-glucuronide transferase is caused by a -1 frameshift mutation. December 15, 1989, 264(35): 21302-7. Therefore, it can be concluded that the mutation of the UGT1A1 gene has a significant impact on the development of the UGT1A1 gene. BIND identification is also useful.

[0131] Furthermore, Gunn rats can also serve as model animals for mental illnesses with jaundice and those caused by UGT1A1 gene mutations (Non-Patent Literature 6 and 7). Therefore, by investigating the concentrations of various bilirubin types (total bilirubin, direct bilirubin, and indirect bilirubin), it is possible to differentiate between mental illnesses with jaundice and those caused by UGT1A1 gene mutations. Simultaneously, mutations in the UGT1A1 gene also contribute to the differentiation between mental illnesses with jaundice and those caused by UGT1A1 gene mutations.

[0132] (Example 2) (Open-box test) 5-HT 1A / 1B Etoprazine (E1357, manufactured by TCI), one of the receptor agonists, was dissolved in any solvent. Etoprazine was administered subcutaneously at a dose of 0.3 mg / kg to 9–10 week old Gunn rats (jaundice model rats). Simultaneously, 9–10 week old Gunn rats and Wistar rats were administered the solvent subcutaneously only as a control group. In addition, 5-HT... iA One of the receptor agonists, 8OH-DPAT (O415005, Fujifilm and Koichi Pharmaceutical), was dissolved in any solvent and administered subcutaneously to Gunn rats at a dose of 1 mg / kg as a control group. After each rat was placed in its cage for 60 minutes, a 60-minute open-box test was conducted using a ScanetMV-40 (Melquest). Spontaneous activity and standing frequency were measured by counting the number of times each rat crossed equally spaced central areas. The number of grooming sessions was visually counted. Results are shown in Tables 2-4 and... Figures 1-3 As shown.

[0133] Table 2 and Figure 1Spontaneous activity levels are listed for Wistar rats given solvent only (Vehicle(+ / +)), Gunn rats given solvent only (Vehicle(j / j)), Gunn rats given 0.3 mg / kg etorazine (Elto(j / j)), and Gunn rats given 1 mg / kg 8OH-DPAT (8OH-DPAT(j / j)). ** in the figure indicates p < 0.01 (Dunnett's test for each group relative to Wistar rats given solvent only). Table 2 Table 2. Autonomous Activity Level Average (total) Standard error Vehicle(+ / +) 5920 633 Vehicle(j / j) 11727 2102 Elto(j / j) 4640 522 8OH-DPAT(j / j) 2681 153

[0134] Table 3 and Figure 2 The number of standing episodes is listed for Wistar rats given solvent only (Vehicle(+ / +)), Gunn rats given solvent only (Vehicle(j / j)), Gunn rats given 0.3 mg / kg etorazine (Elto(j / j)), and Gunn rats given 1 mg / kg 8OH-DPAT (8OH-DPAT(j / j)). ** in the figure indicates p < 0.01 (Dunnett's test for each group relative to Wistar rats given solvent only). Table 3 Table 3 Number of Standing Times Average (number of times) Standard error Vehicle(+ / +) 72,3 8.7 Vehicle(j / j) 119.1 11.5 Elto(j / j) 61.5 9.6 8OH-DPAT(j / j) 0.3 0.3

[0135] Table 4 and Figure 3 The number of grooming events is listed for Wistar rats treated with solvent only (Vehicle(+ / +)), Gunn rats treated with solvent only (Vehicle(j / j)), Gunn rats treated with 0.3 mg / kg etoraprazine (Elto(j / j)), and Gunn rats treated with 1 mg / kg 8OH-DPAT (8OH-DPAT(j / j)). ** in the figure indicates p < 0.01 (Dunnett's test for each group relative to Wistar rats treated with solvent only). Table 4 Table 4 Number of grooming sessions Average (number of times) Standard error Vehicle(+ / +) 9.5 0.8 Vehicle(j / j) 21.8 5.3 Elto(j / j) 8.5 1 8OH-DPAT(j / j) 5.5 0.8

[0136] As shown in Tables 2-4 and Figures 1-3 As shown, after administration of etoraprazine, Gunn rats recovered to normal levels in terms of spontaneous activity, number of standing up, and number of grooming activities. In contrast, administration of 8OH-DPAT(5-HT) significantly reduced these levels. 1A After administration of receptor agonists, although the amount of spontaneous activity and grooming frequency returned to the level of normal rats, the number of times they stood up was abnormal.

[0137] (Example 3) (Open-box test) 5-HT 1A / 1B Etoprazine (E1357, manufactured by TCI), one of the receptor agonists, was dissolved in any solvent. Etoprazine was administered subcutaneously at a dose of 0.3 mg / kg to 9–10 week old Gunn rats (jaundice model rats). Simultaneously, 9–10 week old Gunn rats and Wistar rats were administered the solvent subcutaneously only as a control group. 5-HT... 1B CGS12066A (Sigma-Aldrich), one of the receptor agonists, was dissolved in any solvent and administered subcutaneously to Gunn rats at a dose of 1 mg / kg. Each rat was placed in a cage and left for 60 minutes, followed by a 60-minute open-box test using a ScanetMV-40 (Melquest). Spontaneous activity and standing frequency were measured by counting the number of times each rat crossed equally spaced central areas. The number of grooming sessions was visually counted. Results are shown in Tables 5–7. Figures 4-6 As shown.

[0138] Table 5 and Figure 4 Spontaneous activity levels are listed for Wistar rats administered solvent only (Vehicle(+ / +)), Gunn rats administered solvent only (Vehicle(j / j)), Gunn rats administered 0.3 mg / kg etorazine (Elto(j / j)), and Gunn rats administered CGS12066A1 mg / kg (CGS(j / j)). ** in the figure indicates p < 0.01 (Dunnett's test for each group relative to Wistar rats administered solvent only). Table 5 Table 5. Autonomous Activity Level Average (total) Standard error Vehicle(+ / +) 5920 633 Vehicle(j / j) 11727 2102 Elto(j / j) 4640 522 CGS(j / j) 4030 101

[0139] Table 6 and Figure 5 The number of standing episodes is listed for Wistar rats (Vehicle(+ / +)) given solvent only, Gunn rats (Vehicle(j / j)) given solvent only, Gunn rats given 0.3 mg / kg etorazine (Elto(j / j)), and Gunn rats given 1 mg / kg CGS12066A (CGS(j / j)). ** in the figure indicates p < 0.01 (Dunnett's test for each group relative to Wistar rats given solvent only). Table 6 Table 6 Number of Standing Times Average (number of times) Standard error Vehicle(+ / +) 72,3 8.7 Vehicle(j / j) 119.1 11.5 Elto(j / j) 61.5 9.6 CGS(j / j) 47 9.5

[0140] Table 7 and Figure 6 The number of grooming events is listed for Wistar rats (Vehicle(+ / +)) given solvent only, Gunn rats (Vehicle(j / j)) given solvent only, Gunn rats given 0.3 mg / kg etorazine (Elto(j / j)), and Gunn rats given 1 mg / kg CGS12066A (CGS(j / j)). * in the figure indicates p < 0.05 (Dunnett's test for each group relative to Wistar rats given solvent only). Table 7 Table 7 Number of grooming sessions Average (number of times) Standard error Vehicle(+ / +) 9.5 0.8 Vehicle(j / j) 21.8 5.3 Elto(j / j) 8.5 1 CGS(j / j) 19.6 6.9

[0141] As shown in Tables 5-7 and Figures 4-6 As shown, after administration of etoraprazine, Gunn rats recovered to normal levels in terms of spontaneous activity, number of standing up, and number of grooming activities. In contrast, administration of CGS12006A (5-HT) significantly reduced these levels. 1B After administration of receptor agonists, spontaneous activity and the number of times the rats stood up returned to the levels of normal rats, but the number of times the rats groomed themselves did not improve.

[0142] (Example 4) (Social Interaction Experiment) 5-HT 1A / 1B Etoprazine (E1357, manufactured by TCI), one of the receptor agonists, was dissolved in physiological saline. Nine- to ten-week-old Gunn rats were administered the solution subcutaneously, or received 0.3 mg / kg or 1 mg / kg of etoprazine, respectively. As a control, normal Wistar rats were administered the solution only. One hour after administration, two rats of the same breed (using the same drug, at the same dosage, and with the same genotype) were placed in the same cage and video-recorded from above for 10 minutes. The video data was visually analyzed, and the frequency of chasing behavior, aggressive behavior, and the duration of sniffing and grooming of the rats were measured.

[0143] Table 8 and Figure 7 The number of companion chasing behaviors is listed for Wistar rats given solvent only (Vehicle(+ / +)), Gunn rats given solvent only (Vehicle(j / j)), Gunn rats given 0.3 mg / kg etorazine (Elto 0.3 mg(j / j)), and Gunn rats given 1 mg / kg etorazine (Elto 1 mg(j / j)). *** in the figure indicates p<0.001 (Dunnett's test for each group relative to Wistar rats given solvent only). Table 8 Table 8 Chasing Behavior Average (number of times) Standard error Vehicle(+ / +) 3.5 0.73 Vehicle(j / j) 15.3 1.57 Elto(j / j) 2.16 0.65 Elto 1mg (j / j) 3.83 0.79

[0144] After administration of etorazine, the following behavior, which is a type of hostile behavior, decreased to the level of normal rats.

[0145] Table 9 and Figure 8 The number of attacks on peers is listed for Wistar rats given solvent only (Vehicle(+ / +)), Gunn rats given solvent only (Vehicle(j / j)), Gunn rats given 0.3 mg / kg etorazine (Elto 0.3 mg(j / j)), and Gunn rats given 1 mg / kg etorazine (Elto 1 mg(j / j)). *** in the figure indicates p<0.001 (Dunnett's test for each group relative to Wistar rats given solvent only). Table 9 Table 9 Attack Behaviors Average (number of times) Standard error Vehicle(+ / +) 1.28 0.63 Vehicle(j / j) 28 2.35 Elto(j / j) 2 1.43 Elto 1mg (j / j) 0.16 0.16

[0146] After administration of etorazine, aggressive behavior, a type of hostile behavior, decreased to the level of normal rats.

[0147] Table 10 and Figure 9 The table lists the time (in seconds) of sniffing and grooming behaviors towards companions in Wistar rats given solvent only (Vehicle(+ / +)), Gunn rats given solvent only (Vehicle(j / j)), Gunn rats given 0.3 mg / kg etoposide (Elto 0.3 mg(j / j)), and Gunn rats given 1 mg / kg etoposide (Elto 1 mg(j / j)). *** in the figure indicates p < 0.001 (Dunnett's test for each group relative to Wistar rats given solvent only). Table 10 Table 10 Smell-taking behavior and grooming behavior

[0148] After administration of etorazine, the time spent sniffing and grooming (a friendly sexual behavior) with a partner increased to normal levels.

[0149] (Example 5) (PPI test) 5-HT 1A / 1BEtoprazine (E1357, manufactured by TCI), one of the receptor agonists, was dissolved in physiological saline. Nine- to ten-week-old Gunn rats were administered the solution subcutaneously, or 0.3 mg / kg or 1 mg / kg of etoprazine subcutaneously. Normal Wistar rats were administered the solution only as a control. One hour after administration, a pre-concussion impulse inhibition (PPI) test was performed. The PPI test could be performed using an SR-LAB concussion reflex measuring instrument (manufactured by the San Diego Institute, USA). The rats were placed in the testing chamber and underwent 5 minutes of acclimatization training with 65 dB of background white noise before the stimulation began. The concussion reflex to a 120 dB auditory stimulus was measured using a piezoelectric sensor mounted at the bottom of the chamber. Regarding the experimental phase, a total of 50 trials were conducted, with randomized allocation of stimulation conditions: no stimulation (white noise only), a 120dB pulse stimulus lasting 20ms, and a 70dB or 80dB pulse lasting 20ms inserted before the 120dB pulse (interval 100ms). The interval between each trial was 20-60 seconds (average 40 seconds). The PPI percentage was calculated as follows: 100 - [(pre-pulse - startle reflex in pulsed stimulation trial - no stimulation trial) / (single pulse trial - no stimulation trial) × 100]

[0150] Table 11 and Figure 10 The percentage of PPI in Wistar rats (Vehicle(+ / +)) administered solvent only, Gunn rats (Vehicle(j / j)) administered solvent only, and Gunn rats administered 0.3 mg / kg etorazine (Elto 0.3 mg(j / j)) under the pre-80 dB pulse condition is listed. ** in the figure indicates p < 0.01, and *** indicates p < 0.001 (Dunnett's test for each group relative to Wistar rats administered solvent only). Table 11 Table 11 Percentage PPI average(%) Standard error Vehicle(+ / +) 82.8 1.7 Vehicle(j / j) 72.6 8.3 Elto 0.3 mg (j / j) 63.6 4.9

[0151] After administration of etoraprazine, the percentage of PPI, one of the indicators for evaluating cognitive function, showed an improving trend.

[0152] (Example 6) (Open-box test) The 5-HT described in this application specification 1A / 1B The receptor agonist is dissolved in any solvent. 0.3 mg / kg of 5-HT was administered subcutaneously to 9–10 week old jaundice model rats (Gunn rats). 1A / 1BReceptor agonists. Additionally, 9–10 week old Gunn and Wistar rats were administered the solvent subcutaneously as a control group. If necessary, 5-HT... 1A One of the receptor agonists, 8OH-DPAT (O415005 Fujifilm and Koichi Pharmaceutical), was dissolved in any solvent and administered subcutaneously to Gunn rats at a dose of 1 mg / kg as a control group. After each rat was placed in its cage for 60 minutes, a 60-minute open-box test was conducted using a Scanet MV-40 (Melquest) and other instruments. Spontaneous activity and the number of times each rat crossed equally spaced central areas were measured. The number of grooming sessions was visually counted.

[0153] (Example 7) (Open-box test) The 5-HT described in this application specification 1A / 1B The receptor agonist is dissolved in any solvent. 0.3 mg / kg of 5-HT was administered subcutaneously to 9–10 week old jaundice model rats (Gunn rats). 1A / 1B Receptor agonists. Additionally, 9–10 week old Gunn and Wistar rats were administered the solvent subcutaneously as a control group. If necessary, 5-HT... 1B CGS12066A (Sigma-Aldrich), one of the receptor agonists, was dissolved in any solvent and administered subcutaneously to Gunn rats at a dose of 1 mg / kg as a control group. Each rat was placed in a cage and, after 60 minutes, underwent a 60-minute open-box test using ScanetMV-40 (Melquest) and other methods. Spontaneous activity and the number of times each rat crossed equally spaced central areas were measured. The number of grooming sessions was visually counted.

[0154] (Example 8) (Social Interaction Experiment) The 5-HT described in this application specification 1A / 1B The receptor agonist was dissolved in physiological saline and administered subcutaneously to 9- to 10-week-old Gunn rats, along with an injection of 0.3 mg / kg of 5-HT. 1A / 1B Receptor agonists, or 5-HT administered by injection at a dose of 1 mg / kg. 1A / 1B Receptor agonist. Normal Wistar rats were administered the solvent only as a control. One hour after administration, two rats of the same breed (same drug, same dosage, and same genotype) were placed in the same cage and video-recorded from above for 10 minutes. The video data was visually analyzed, and the number of times the rats chased each other, aggressive behavior, and the time spent sniffing and grooming each other were measured.

[0155] (Example 9) (PPI test) The 5-HT described in this application specification 1A / 1B The receptor agonist was dissolved in physiological saline and administered subcutaneously to 9- to 10-week-old Gunn rats either as the solvent or as 0.3 mg / kg of 5-HT. 1A / 1B receptor agonists, or 1 mg / kg of 5-HT 1A / 1B Receptor agonist. Normal Wistar rats were administered the solvent only as a control. One hour after administration, a pre-pulse inhibition (PPI) test was performed. The PPI test was measured using an SR-LAB pre-pulse assay instrument (manufactured by the San Diego Institute, USA). Rats were placed in the testing chamber and underwent 5 minutes of acclimatization training with 65 dB white noise background before stimulation began. Pre-pulse reflexes to 120 dB auditory stimuli were measured using piezoelectric sensors mounted at the bottom of the chamber. A total of 50 tests were conducted, randomly assigned to no stimulation (white noise only), a 20 ms 120 dB pulse stimulus, and a 20 ms 70 dB or 80 dB pulse inserted before the 120 dB pulse (100 ms interval). The interval between tests was 20–60 seconds (average 40 seconds). The PPI percentage was calculated as follows: 100 - [(pre-pulse - pre-pulse stimulation test pre-pre-pulse reflex - no stimulation test) / (pre-pulse test - no stimulation test) × 100].

Claims

1. A pharmaceutical composition comprising 5-HT 1A / 1B Including receptor agonists, it is used to treat, prevent or control bilirubin-induced neurological dysfunction, mental illness with jaundice, or mental illness caused by mutations in the bilirubin UDP-glucuronide transferase gene.

2. A pharmaceutical composition comprising 5-HT 1a / 1B Including receptor agonists, used to treat, prevent or control bilirubin-induced neurological dysfunction in the user, applicable in the following situations: the user's biological sample contains bilirubin concentrations higher than those of healthy individuals, or the user has jaundice.

3. A pharmaceutical composition comprising 5-HT 1A / 1B Including receptor agonists, used to treat, prevent or control bilirubin-induced neurological dysfunction in the recipient, and applicable to recipients with bilirubin UDP-glucuronide transferase gene mutations.

4. A pharmaceutical composition comprising 5-HT 1A / 1B Including receptor agonists, used in methods for treating, preventing, or controlling bilirubin-induced neurological dysfunction in users. The method includes: (a) The process of obtaining biological samples from the user; (b) The process of determining the bilirubin concentration in the biological sample obtained in process (a); as well as (c) When the bilirubin concentration measured in procedure (b) is higher than that of healthy individuals, or when the bilirubin concentration measured in procedure (b) indicates that the user has jaundice, the user shall be given 5-HT. 1A / 1B The process of receptor agonists.

5. A pharmaceutical composition comprising 5-HT 1A / 1B Including receptor agonists, used in methods for treating, preventing, or controlling bilirubin-induced neurological dysfunction in users. The method includes: (a) The process of determining whether the user has a bilirubin UDP-glucuronide transferase gene mutation; (b) If the user has a bilirubin UDP-glucuronide transferase gene mutation during the determination process (a), the user shall be given 5-HT. 1A / 1B The process of receptor agonists.

6. A pharmaceutical composition comprising 5-HT 1A / 1B Including receptor agonists, used to treat, prevent or control mental illness in the user, applicable in the following situations: the user's biological sample has a higher concentration of bilirubin than healthy individuals, or the user has jaundice.

7. A pharmaceutical composition comprising 5-HT 1A / 1B Including receptor agonists, used to treat, prevent or control mental illness in the user, and applicable to users with bilirubin UDP-glucuronide transferase gene mutations.

8. A pharmaceutical composition comprising 5-HT 1A / 1B Receptor agonists, among others, are used in methods for treating, preventing, or controlling mental illness in the recipient. The method includes: (a) The process of obtaining biological samples from the user; (b) The process of determining the bilirubin concentration in the biological sample obtained in process (a); as well as (c) When the bilirubin concentration measured in procedure (b) is higher than that of healthy individuals, or when the bilirubin concentration measured in procedure (b) indicates that the user has jaundice, the user shall be given 5-HT. 1A / 1B The process of receptor agonists.

9. A pharmaceutical composition comprising 5-HT 1A / 1B Receptor agonists, among others, are used in methods for treating, preventing, or controlling mental illness in the recipient. The method includes: (a) The process of determining whether the user has a bilirubin UDP-glucuronide transferase gene mutation. (b) If the user has a bilirubin UDP-glucuronide transferase gene mutation during the determination process (a), the user shall be given 5-HT. IA / 1B The process of receptor agonists.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein, The above 5-HT 1A / 1B The receptor agonist is a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, or deuterated compound thereof. (where R is in the formula) 1 Hydrogen, halogen, hydroxyl, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Hydroxyalkyl or C 1-6 aminoalkyl; R 2 and R 3 When they appear individually, they are each independently selected from halogens, hydroxyl groups, amino groups, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Hydroxyalkyl or C 1-6 aminoalkyl; X 1 and X 2 Each is independently selected from oxygen, sulfur, or -CR a R b ; R a and R b Each is independently selected from hydrogen, halogen, hydroxyl, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Hydroxyalkyl or C 1-6 aminoalkyl; n is an integer from 0 to 4; m is an integer from 0 to 5.

11. The pharmaceutical composition of claim 10, wherein, In the compound of formula (I), X 1 and X 2 It is oxygen.

12. The pharmaceutical composition of claim 10, wherein, In the compound of formula (I), R 1 It is hydrogen.

13. The pharmaceutical composition of claim 10, wherein, In the compound of formula (I), n is 0 and m is 0.

14. The pharmaceutical composition of claim 10, wherein, In the compound of formula (I), R 1 The hydrogen is 0, n is 0, and m is 0.

15. The pharmaceutical composition of claim 10, wherein, The compound of formula (I) is etorazide.

16. The pharmaceutical composition according to any one of claims 1 to 9, wherein, The aforementioned mental illnesses are schizophrenia or attention deficit hyperactivity disorder.

17. A pharmaceutical composition for treating, preventing, or controlling bilirubin-induced neurological dysfunction, mental illness with jaundice, or mental illness caused by bilirubin UDP-glucuronide transferase gene mutation, wherein the kit comprises 5-HT 1A / 1B Receptor agonists.

18. The kit of claim 17, comprising reagents for determining the concentration of bilirubin in a biological sample and / or reagents for determining bilirubin UDP-glucuronide transferase gene mutations.

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