Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/10—Spiro-condensed systems

Definitions

• the present invention relates to the field of chemical medicine, in particular to 1,5-dihydro-2,4-benzodiazepine -3-ketone derivatives and their applications.
• Schizophrenia (Schizophrenia) has a hidden onset, low admission rate, and high lifetime prevalence. At present, about 0.3-0.7% of the world's population are affected by schizophrenia in their lifetime. In 2016, it is estimated that there were more than 21 million schizophrenic patients worldwide.
• the current anti-schizophrenia drugs mainly include typical anti-schizophrenia drugs and atypical anti-schizophrenia drugs.
• the current schizophrenia treatment drugs strongly block dopamine receptors, which lead to extrapyramidal reactions (EPS) and delays.
• EPS extrapyramidal reactions
• Adverse reactions such as primary dyskinesia and increased prolactin.
• adverse reactions such as addiction, drug resistance, and aftereffects are still unresolved problems.
• antipsychotics that exert pharmacological effects by blocking dopamine D 2 receptors are called first-generation antipsychotics, that is, "typical” antipsychotics (such as haloperidol), which treat positive symptoms of schizophrenia A breakthrough, but failed to treat negative symptoms and cognitive impairment.
• Typical antipsychotic drugs generally have severe EPS side effects and are ineffective in one-third of patients with schizophrenia.
• the serotonin system plays an important role in regulating the functions of the prefrontal cortex (PFC), including emotional control, cognitive behavior, and working memory.
• PFC prefrontal cortex
• the pyramidal neurons and GABA interneurons of PFC contain several 5-HT 1A and 5-HT 2A subtypes with particularly high-density serotonin receptors. It has recently been proved that PFC and NMDA receptor channels are the targets of 5-HT 1AR . These two receptors modulate excitatory neurons in the cerebral cortex, thereby affecting cognitive function. In fact, various preclinical data indicate that 5-HT 1AR may be a new target for the development of antipsychotic drugs.
• 5-HT 1A R The high affinity of atypical antipsychotics (such as olanzapine, aripiprazole, etc.) to 5-HT 1A R and their low EPS side effects indicate that the serotonin system plays an important role in regulating the function of the prefrontal cortex (PFC). Including emotional control, cognitive behavior, and working memory.
• the pyramidal neurons and GABA interneurons of PFC contain several 5-HT 1A and 5-HT 2A subtypes with particularly high density of serotonin receptors. Recent studies have shown that 5-HT 1A agonists are associated with atypical antipsychotic treatment and can improve negative symptoms and cognitive impairment.
• 5-HT 2A plays an important role in it, involving various aspects of perception, emotion regulation and movement control. Blocking the 5-HT 2A receptor can normalize the release of dopamine and play an anti-psychotic effect. In addition, 5-HT 2C receptors are closely related to weight gain.
• Piperserin is an inverse agonist with high affinity for 5-HT 2A and 5-HT 2C .
• the drug was approved by the U.S. Food and Drug Administration in April 2016 under the trade name NuplazidTM. It is mainly used for the treatment of Parkinson's symptoms such as hallucinations and delusions.
• an anti-schizophrenic drug that is effective for both positive and negative symptoms, can improve cognitive impairment, and can prevent extrapyramidal side effects, including tardive dyskinesia, Parkinson's disease, and reduce weight gain. .
• an object of the present invention is to provide a compound represented by formula I:
• n1, n2 are integers from 1 to 3;
• R1 is selected from C1-C8 linear or branched alkyl, C2-C8 alkenyl and C2-C8 alkynyl, the alkyl, alkenyl and alkynyl groups are each independently and optionally selected from halogen and C1- Substituent substitution of C8 haloalkyl;
• R2 is selected from hydrogen, halogen and C1-C8 haloalkyl
• R3, R4, R5, and R6 are each independently selected from hydrogen, halogen and C1-C8 haloalkyl
• R7 is selected from C1-C5 linear or branched alkyl
• cycloalkyl and R8 and R9 are each independently selected from C1-C8 linear or branched alkyl groups, and the alkyl groups and cycloalkyl groups are optionally substituted with substituents selected from halogen and C1-C8 haloalkyl groups;
• Z is selected from C, O, N;
• Q and W are selected from C and N respectively;
• n2, R1, R3, R7, W, and Z are as defined above; or
• n1 and n2 are integers from 1 to 3;
• R1 is selected from C1-C8 linear or branched alkyl, C2-C8 alkenyl and C2-C8 alkynyl, the alkyl, alkenyl and alkynyl are optionally selected from halogen and C1-C8 haloalkyl Substituent substitution;
• R2 is selected from hydrogen, halogen
• R3, R4, R5, and R6 are each independently selected from hydrogen, halogen and haloalkyl
• R7 is selected from C1-8 linear or branched alkyl, cycloalkyl, R8 and R9 are each independently selected from C1-C8 linear or branched alkyl groups, and the alkyl groups and cycloalkyl groups are optionally substituted with substituents selected from halogen and C1-C8 haloalkyl groups;
• Z is selected from C, O, N;
• Q and W are selected from C and N respectively.
• the C1-C8 linear or branched alkyl group is selected from the group consisting of C1-C5 linear or branched alkyl and C1-C3 linear or branched alkyl; and/or the C2-C8 Alkenyl is C2-C5 alkenyl; and/or said C2-C8 alkynyl is C2-C5 alkynyl; and/or said haloalkyl is C1-C5 haloalkyl; and/or said cycloalkyl is C3 -C10 cycloalkyl, preferably C3-C6 cycloalkyl.
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a therapeutically effective amount of the compound represented by formula I as described above, optionally further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or Their combination.
• the present invention provides an application of the compound of formula I and its pharmaceutical composition in the preparation of drugs for the treatment of mental diseases.
• the mental illness is schizophrenia or psychosis.
• the mental illness is Parkinson's disease, dementia-related behavioral disorders, and psychosis.
• the compounds of the present invention may be optionally substituted with one or more substituents, such as the above formula compounds or specific examples or subclasses in the examples.
• substituents such as the above formula compounds or specific examples or subclasses in the examples.
• substituents such as the above formula compounds or specific examples or subclasses in the examples.
• substituents such as the above formula compounds or specific examples or subclasses in the examples.
• substituents such as the above formula compounds or specific examples or subclasses in the examples.
• substituents such as the above formula compounds or specific examples or subclasses in the examples.
• substituent may be one or more hydrogen atoms, provided that the structure can make the compound reach a stable state.
• an optionally substituted group can be substituted at each substitutable position of the group.
• substituents selected from a specific group then the substituents can be substituted at each position with the same or different substitutions.
• the point of attachment of a substituent can be from any suitable position of the substituent.
• a bond of a substituent is shown as a bond connecting two atoms through a ring, then such a substituent may be bonded to any ring-forming atom in the substitutable ring.
• any numerical value and any included range falling within the range are specifically disclosed.
• each value range of the value disclosed herein should be understood to mean each value and range covered in a wider range.
• any variable such as R
• a variable with a label such as R1, R2, R3, R4, R5, R6, R7, etc.
• R1, R2, R3, R4, R5, R6, R7, etc. occurs more than once in the composition or structure of a compound, it is in each occurrence
• the definition in each case is independent. For example, if a group is substituted with 0, 1, 2, 3, or 4 R substituents, the group may optionally be substituted with up to four R substituents, and each The options for the R substituents are all independent of each other.
• the substituents of the compounds disclosed in the present invention are disclosed according to the group type or scope.
• the present invention includes each independent sub-combination of each member of these group types and ranges.
• mn used herein refers to the range from m to n and the sub-range composed of each point value therein and each point value.
• C1-C5 alkyl specifically refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl.
• alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), iso Propyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH(CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2- Butyl (-C(CH 3 ) 2
• C2-C8 or “C2-8” covers the range of 2-8 carbon atoms, and should be understood to also cover any subrange and each point value, such as C2-C5, C3-C4, C2-C6, C3-C6, C4-C6, C4-C7, C4-C8, C2-C5, etc., and C2, C3, C4, C5, C6, C7, C8, etc.
• C3-C10 or “C3-10” should also be understood in a similar manner, for example, it can cover any subrange and point value contained therein, such as C3-C9, C6-C9, C6-C8, C6 -C7, C7-C10, C7-C9, C7-C8, C8-C9, etc. and C3, C4, C5, C6, C7, C8, C9, C10, etc.
• C1-C5" or “C1-5" covers the range of 1-5 carbon atoms, and should be understood to also cover any subrange and each point value, such as C2-C5, C3-C4 , C1-C2, C1-C3, C1-C4, C1-C5, etc., and C1, C2, C3, C4, C5, etc.
• the expression “C2-C5" or “C2-5" covers the range of 2-5 carbon atoms, and should be understood to also cover any sub-range and each point value, such as C2-C5, C3-C4 , C2-C3, C2-C4, C3-C5, C4-C5, etc., and C2, C3, C4, C5, etc.
• C3-C6 covers the range of 3-6 carbon atoms, and should be understood to also cover any sub-range and each point value, such as C3-C5, C3-C4 , C3-C6, C5-C6, C4-C6, C4-C5, etc., and C3, C4, C5, C6, etc.
• C1-C8 covers the range of 1-8 carbon atoms, and should be understood to also cover any sub-range therein, as well as each point value, such as C2-C5, C3- C4, C2-C6, C3-C6, C4-C6, C4-C7, C4-C8, C2-C5, etc., and C1, C2, C3, C4, C5, C6, C7, C8, etc.
• the expression "three yuan to ten yuan” should be understood as covering any sub-range and each point value, such as three yuan to five yuan, three yuan to six yuan, three yuan to seven yuan, three yuan to eight yuan , Four yuan to five yuan, four yuan to six yuan, four yuan to seven yuan, four yuan to eight yuan, five yuan to seven yuan, five yuan to eight yuan, six yuan to seven yuan, six yuan to eight yuan, nine Yuan to ten Yuan, etc., and three, four, five, six, seven, eight, nine, ten Yuan, etc.
• Other similar expressions in this article should also be understood in a similar way.
• n 2 is any integer between 0-3
• n 2 includes any integer from 0-2, any integer from 2-3, etc., such as 1, 2, 3.
• one (species) or more (species) can mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 (species) Or more (species).
• selected from refers to one or more elements in the group listed below, independently selected, and may include a combination of two or more elements.
• each carbon atom in a group can be optionally replaced by a heteroatom, the condition is that the normal valence of all atoms in the group under the current situation is not exceeded, and a stable compound is formed.
• hydrogen (H) means a single hydrogen atom. Such atomic groups can be connected with other groups, for example, with oxygen atoms to form a hydroxyl group.
• halogen or "halo” should be understood to mean fluorine (F), chlorine (Cl), bromine (Br) or iodine (I), preferably fluorine, chlorine, bromine atoms, more preferably fluorine atoms.
• alkyl refers to a linear or branched saturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms, which is connected to the rest of the molecule by a single bond.
• Alkyl can have 1-5 carbon atoms, that is, “C1-C5 alkyl”, such as C1-4 alkyl, C1-3 alkyl, C1-2 alkyl, C3 alkyl, C4 alkyl, C1 -5 alkyl, C3-5 alkyl. It can also have 1-3 carbon atoms, that is, "C1-C3 alkyl", such as C1-3 alkyl, C1-2 alkyl, C3 alkyl.
• C1-C5 alkyl specifically refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, and C5 alkyl.
• alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), iso Propyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH(CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 3 ), 2-pentyl
• alkenyl refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond.
• the alkenyl group may have 2-5 carbon atoms, that is, "C 2-5 alkenyl", for example, C 2-4 alkenyl, C 3-4 alkenyl.
• Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl , (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, etc.
• cycloalkyl refers to a saturated cyclic hydrocarbon group composed of carbon atoms and hydrogen atoms, preferably containing 1 or 2 rings.
• the cycloalkyl group may be a monocyclic ring, a fused polycyclic ring, a bridged ring or a spiro ring structure.
• the cycloalkyl group may have 3-6 carbon atoms, that is, "C 3 -C 6 cycloalkyl", such as C 6 cycloalkyl, C 5 cycloalkyl, C 4 cycloalkyl, C 3 cycloalkyl.
• Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
• alkynyl refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one triple bond.
• the alkynyl group may have 2-5 carbon atoms, that is, "C 2-5 alkynyl", such as C 2-3 alkynyl, C 2-4 alkynyl.
• Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, and the like.
• the key "---" is either a single key "—” or nonexistent.
• pharmaceutically acceptable refers to a substance that, within the scope of normal medical judgment, is suitable for contact with the patient's tissue without undue toxicity, irritation, allergic reactions, etc., and has a reasonable ratio of advantages and disadvantages. And can be effectively used for its purpose.
• pharmaceutically acceptable carrier refers to those substances that have no obvious stimulating effect on the organism and do not impair the biological activity and performance of the active compound.
• “Pharmaceutically acceptable carriers” include but are not limited to glidants, sweeteners, diluents, preservatives, dyes/colorants, flavors, surfactants, wetting agents, dispersants, disintegrants, Stabilizer, solvent or emulsifier.
• administration refers to a method that enables the compound or composition to be delivered to a desired site of biological action. These methods include, but are not limited to, oral or parenteral (including intracerebroventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical, rectal administration and the like. Especially injection or oral administration.
• treatment includes alleviation, alleviation or amelioration of diseases or symptoms, prevention of other symptoms, amelioration or prevention of underlying metabolic factors of symptoms, inhibition of diseases or symptoms, for example, preventing the development of diseases or symptoms, alleviating diseases or symptoms, and promoting Remission of disease or symptoms, or cessation of symptoms of disease or symptoms, and extension to include prevention.
• Treatment also includes realizing therapeutic benefits and/or preventive benefits.
• Therapeutic benefit refers to eradicating or improving the condition being treated.
• the therapeutic benefit is achieved by eradicating or improving one or more physical symptoms related to the underlying disease. Although the patient may still have the underlying disease, the improvement of the patient's disease can be observed.
• Preventive benefit means that the patient uses the composition to prevent the risk of a certain disease, or when the patient has one or more physiological conditions of the disease, even though the disease has not been diagnosed.
• active ingredient refers to a chemical entity that can effectively treat or prevent the target disorder, disease or condition.
• mental disease is a disorder of the nervous system.
• the terms "effective amount”, “therapeutically effective amount” or “prophylactically effective amount” refer to a sufficient amount of a drug or medicament that has acceptable side effects but can achieve the desired effect.
• the determination of the effective amount varies from person to person, depends on the age and general condition of the individual, and also depends on the specific active substance. The appropriate effective amount in a case can be determined by a person skilled in the art according to routine experiments.
• “Individual” as used herein includes human or non-human animals.
• Exemplary human individuals include human individuals (referred to as patients) or normal individuals suffering from diseases such as those described herein.
• non-human animals include all vertebrates, such as non-mammals (such as birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (such as sheep, dogs). , Cats, cows, pigs, etc.).
• the present invention provides a compound represented by formula I:
• n1, n2 are integers from 1 to 3;
• R1 is selected from C1-C8 linear or branched alkyl, C2-C8 alkenyl and C2-C8 alkynyl, the alkyl, alkenyl and alkynyl groups are each independently and optionally selected from halogen and C1- Substituent substitution of C8 haloalkyl;
• R2 is selected from hydrogen, halogen and C1-C8 haloalkyl
• R3, R4, R5, and R6 are each independently selected from hydrogen, halogen and C1-C8 haloalkyl
• R7 is selected from C1-C8 linear or branched alkyl
• cycloalkyl and R8 and R9 are each independently selected from C1-C8 linear or branched alkyl groups, and the alkyl groups and cycloalkyl groups are optionally substituted with substituents selected from halogen and C1-C8 haloalkyl groups;
• Z is selected from C, O, N;
• Q and W are selected from C and N respectively;
• n2, R1, R3, R7, W, and Z are as defined above; or
• n1 and n2 are integers from 1 to 3;
• R1 is selected from C1-C8 linear or branched alkyl, C2-C8 alkenyl and C2-C8 alkynyl, the alkyl, alkenyl and alkynyl are optionally selected from halogen and C1-C8 haloalkyl Substituent substitution;
• R2 is selected from hydrogen, halogen and C1-C8 haloalkyl
• R3, R4, R5, and R6 are each independently selected from hydrogen, halogen and haloalkyl
• R7 is selected from C1-8 linear or branched alkyl
• cycloalkyl and R8 and R9 are each independently selected from C1-C8 linear or branched alkyl groups, and the alkyl groups and cycloalkyl groups are optionally substituted with substituents selected from halogen and C1-C8 haloalkyl groups;
• Z is selected from C, O, N;
• Q and W are selected from C and N respectively.
• n1 and n2 are integers selected from 1-3.
• n1 and n2 are independently selected from 1, 2 and 3, such as 1, 2 or 3, respectively.
• n1 is selected from 2 and 3.
• n1 is 1.
• n2 is 1.
• n1 is 2.
• n2 is 2.
• n1 is 3.
• n2 is 3.
• n1 is 2 and n2 is 1.
• R1 is selected from C1-C8 linear or branched alkyl, C2-C8 alkenyl and C2-C8 alkynyl, each of which is independently and optionally Substituents selected from halogen and C1-C8 haloalkyl are substituted.
• R1 is a C1-C8 linear or branched alkyl group, wherein the alkyl group is optionally substituted with a substituent selected from halogen and C1-C8 haloalkyl.
• R1 is a C1-C8 linear or linear alkyl group.
• R1 is a C1-C5 linear or branched alkyl group.
• R1 is a C1-C3 linear or branched alkyl group.
• R1 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and isopentyl.
• R1 is selected from methyl, ethyl and propyl.
• R1 is methyl.
• R1 is ethyl.
• R1 is propyl.
• R2 is selected from hydrogen, halogen, and C1-C8 haloalkyl. In a preferred embodiment, R2 is selected from hydrogen and halogen. In a more preferred embodiment, R2 is hydrogen. In another more preferred embodiment, R2 is halogen. In a specific embodiment, R2 is selected from hydrogen, fluorine, chlorine, bromine, and iodine. In a more specific embodiment, R2 is selected from hydrogen, fluorine, chlorine, and bromine. In a more specific embodiment, R2 is fluorine. In another more specific embodiment, R2 is chlorine. In yet another more specific embodiment, R2 is bromo.
• R3, R4, R5, and R6 are each independently selected from hydrogen, halogen, and C1-C8 haloalkyl.
• R3 is selected from hydrogen and halogen. In a more preferred embodiment, R3 is hydrogen. In another more preferred embodiment, R3 is halogen. In a particularly preferred embodiment, R3 is selected from fluorine, chlorine, bromine and iodine. In a more preferred embodiment, R3 is selected from fluorine, chlorine and bromine. In a specific embodiment, R3 is selected from hydrogen, fluorine, chlorine and bromine. In a more specific embodiment, R3 is selected from hydrogen, fluorine and chlorine. In a particularly specific embodiment, R3 is fluorine. In another particularly specific embodiment, R3 is chlorine.
• R4 is selected from hydrogen and halogen. In a more preferred embodiment, R4 is hydrogen. In another more preferred embodiment, R4 is halogen. In a particularly preferred embodiment, R4 is selected from fluorine, chlorine, bromine and iodine. In a more preferred embodiment, R4 is selected from fluorine, chlorine and bromine. In a specific embodiment, R4 is selected from hydrogen, fluorine, chlorine and bromine. In a more specific embodiment, R4 is selected from hydrogen, fluorine and chlorine. In a particularly specific embodiment, R4 is fluorine. In another particularly specific embodiment, R4 is chlorine.
• R5 is selected from hydrogen and halogen. In a more preferred embodiment, R5 is hydrogen. In another more preferred embodiment, R5 is halogen. In a particularly preferred embodiment, R5 is selected from fluorine, chlorine, bromine and iodine. In a more preferred embodiment, R5 is selected from fluorine, chlorine and bromine. In a specific embodiment, R5 is selected from hydrogen, fluorine, chlorine and bromine. In a more specific embodiment, R5 is selected from hydrogen, fluorine and chlorine. In a particularly specific embodiment, R5 is fluorine. In another particularly specific embodiment, R5 is chlorine.
• R6 is selected from hydrogen and halogen. In a more preferred embodiment, R6 is hydrogen. In another more preferred embodiment, R6 is halogen. In a particularly preferred embodiment, R6 is selected from fluorine, chlorine, bromine and iodine. In a more preferred embodiment, R6 is selected from fluorine, chlorine and bromine. In a specific embodiment, R6 is selected from hydrogen, fluorine, chlorine and bromine. In a more specific embodiment, R6 is selected from hydrogen, fluorine and chlorine. In a particularly specific embodiment, R6 is fluorine. In another particularly specific embodiment, R6 is chlorine.
• R7 is selected from C1-C8 linear or branched alkyl
• cycloalkyl and R8 and R9 are each independently selected from C1-C8 linear or branched alkyl groups, and the alkyl groups and cycloalkyl groups are optionally substituted with substituents selected from halogen and C1-C8 haloalkyl groups.
• R7 is a C1-C8 linear or branched alkyl group. In a more preferred embodiment, R7 is a C1-C5 linear or branched alkyl group. In a particularly preferred embodiment, R7 is a C1-C3 linear or branched alkyl group. In a specific embodiment, R7 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl. In a more specific embodiment, R7 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl. For example, methyl, ethyl, propyl, isopropyl, butyl or isobutyl. In a particularly specific embodiment, R7 is isopropyl.
• R7 is cycloalkyl. In a more preferred embodiment, R7 is C3-C10 cycloalkyl. In a particularly preferred embodiment, R7 is C3-C6 cycloalkyl. In a specific embodiment, R7 is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In a more specific embodiment, R7 is selected from cyclopropyl, cyclobutyl and cyclopentyl. For example, cyclopropyl, cyclobutyl or cyclopentyl.
• R7 is Wherein R8 and R9 are each independently selected from C1-C8 linear or branched alkyl groups. In a preferred embodiment, R7 is Wherein R8 and R9 are independently selected from C1-C3 linear or branched chain alkyl groups. In a specific embodiment, R7 is Wherein R8 and R9 are each independently selected from methyl, ethyl, propyl, butyl and pentyl. In a more specific embodiment, R7 is Wherein R8 and R9 are each independently selected from methyl, ethyl and propyl. For example, methyl, ethyl, n-propyl, and isopropyl. In a particularly specific embodiment, R8 and R9 are methyl.
• Z is selected from C, O, N. In a preferred embodiment, Z is C. In another preferred embodiment, Z is O. In yet another preferred embodiment, Z is N.
• Q and W are selected from C and N respectively.
• Q is N.
• Q is C.
• W is C.
• W is N.
• the C1-C8 linear or branched alkyl group is selected from the group consisting of C1-C5 linear or branched alkyl and C1-C3 linear or branched alkyl.
• C1-C8 linear or branched alkyl, C1-C5 linear or branched alkyl, and C1-C3 linear or branched alkyl are each independently selected from methyl, ethyl , Propyl, butyl, pentyl and isopentyl.
• C1-C8 linear or branched alkyl, C1-C5 linear or branched alkyl, and C1-C3 linear or branched alkyl are each independently selected from methyl, ethyl Group, propyl and butyl.
• the propyl group includes, but is not limited to, n-propyl (n-Pr, -CH 2 CH 2 CH 3 ) or isopropyl (i-Pr, -CH(CH 3 ) 2 ).
• the butyl group includes but is not limited to n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH(CH 3 ) 2 ), sec-butyl ( s-Bu, -CH(CH 3 )CH 2 CH 3 ) or tert-butyl (t-Bu, -C(CH 3 ) 3 ).
• the pentyl group includes, but is not limited to, n-pentyl (-CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (- CH(CH 2 CH 3 ) 2 ), 2-methyl-2-butyl(-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl(-CH(CH 3 )CH (CH 3 ) 2 ), 3-methyl-1-butyl (-CH 2 CH 2 CH(CH 3 ) 2 ) or 2-methyl-1-butyl (-CH 2 CH(CH 3 )CH 2 CH 3 ).
• the C2-C8 alkenyl group is a C2-C5 alkenyl group.
• C2-C8 alkenyl and C2-C5 alkenyl are each independently selected from vinyl, propenyl, butenyl, and pentenyl.
• C2-C8 alkenyl and C2-C5 alkenyl are each independently selected from vinyl, propenyl and butenyl.
• C2-C8 alkynyl is C2-C5 alkynyl.
• C2-C8 alkynyl and C2-C5 alkynyl are each independently selected from ethynyl, propynyl, butynyl, and pentynyl.
• C2-C8 alkynyl and C2-C5 alkynyl are each independently selected from ethynyl, propynyl, and butynyl.
• the propynyl group includes but is not limited to -H 2 CC ⁇ CH, -C ⁇ C-CH 3 .
• the butynyl including but not limited to -H 2 C-CH 2 -C ⁇ CH, -H 2 CC ⁇ C-CH 3, H 3 C-CH 2 -C ⁇ C-.
• the pentynyl including but not limited to H 3 CH 2 C-CH 2 -C ⁇ C -, - H 2 CH 2 CC ⁇ C-CH 3, H 3 CH 2 CC ⁇ C-CH 2 -, (H 3 C) 2 CC ⁇ C-.
• the C1-C8 haloalkyl group is a C1-C5 haloalkyl group.
• the C1-C8 alkyl group or the C1-C5 alkyl group is substituted with 1, 2, 3, or 4 halogens.
• C1-C8 alkyl or C1-C5 alkyl is -(CH 2 ) a CX 3 , wherein a is selected from 1, 2, 3, 4, 5, 6 and 7, and X represents halogen .
• the halogen is selected from fluorine, chlorine, bromine, and iodine.
• a is selected from 1, 2, 3, and 4.
• the halogen is fluorine.
• the C1-C8 haloalkyl or C1-C5 haloalkyl includes but is not limited to -CF 3 , -CCl 3 , -CBr 3 , -CI 3 , -CH 2 CF 3 , -CH 2 CCl 3 , -CH 2 CBr 3 , -CH 2 CI 3 , -(CH 2 ) 2 CF 3 , -(CH 2 ) 2 CCl 3 , -(CH 2 ) 2 CBr 3 , -(CH 2 ) 2 CI 3 and so on.
• halogen is selected from fluorine, chlorine, bromine and iodine. In a preferred embodiment, halogen is selected from fluorine, chlorine and bromine. For example, fluorine, chlorine, bromine or iodine. In a specific embodiment, halogen is fluorine.
• Z is O, and R1, R2, R3, R4, R5, R6, R7, n1, n2, Q and ------ bonds are as defined above.
• Z is O;
• R1 is a C1-C5 linear or branched alkyl group;
• R2 is selected from hydrogen and halogen;
• R3, R4, R5, and R6 are each independently selected from hydrogen and halogen;
• R7 is selected from C1-C5 linear or branched alkyl and C3-C6 cycloalkyl.
• Z is O;
• R1 is selected from methyl, ethyl, propyl, isopropyl, butyl and isobutyl;
• R2 is selected from hydrogen, fluorine, chlorine, bromine and iodine;
• R3, R4, R5, R6 are each independently selected from hydrogen, fluorine, chlorine, bromine and iodine;
• R7 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclobutyl And cyclopentyl.
• Z is O
• the bond is a single bond
• the compound of formula I is a compound represented by formula I-1:
• R1, R2, R3, R4, R5, R6, R7, n1, n2 and Q are as defined above.
• Z is O
• the bond is a single bond
• the compound of formula I is a compound represented by formula I-1
• R1 is a C1-C5 linear or branched alkyl group
• R2 is selected from hydrogen and halogen
• R3, R4, R5, and R6 are independently selected from hydrogen and halogen
• R7 is selected from C1-C5 linear or branched alkyl and C3-C6 cycloalkyl
• Q is N.
• Z is O
• the bond is a single bond
• the compound of formula I is a compound represented by formula I-1
• R1 is selected from methyl, ethyl, propyl, iso Propyl, butyl and isobutyl
• R2 is selected from hydrogen, fluorine, chlorine, bromine and iodine
• R3, R4, R5, and R6 are each independently selected from hydrogen, fluorine, chlorine, bromine and iodine
• R7 is selected from methyl , Ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclobutyl and cyclopentyl.
• the compound of formula I is a compound of formula IV:
• n1, n2 are integers from 1 to 3;
• R1 is selected from methyl, ethyl, propyl, butyl;
• R2 is selected from hydrogen, fluorine, chlorine, bromine, and iodine;
• R3, R4, R5, and R6 are selected from Hydrogen, fluorine, chlorine;
• R7 is selected from isopropyl, isobutyl, ethyl, propyl, methyl, cyclopropyl, cyclobutyl, Z is selected from C, O, and N;
• Q and W are selected from C and N respectively;
• the bond means that it does not exist or exists in the form of a single bond.
• n2 is an integer of 1-2;
• R1 is selected from methyl, ethyl, propyl, butyl;
• R3 is selected from hydrogen, fluorine, and chlorine;
• R7 is selected from isopropyl, isobutyl, ethyl, and propyl , Methyl, cyclopropyl, cyclobutyl,
• the bond in the compound of formula I is a single bond
• the compound of formula I is a compound represented by formula VI:
• n1 and n2 are integers from 1 to 3;
• R1 is methyl;
• R2 is selected from fluorine and hydrogen;
• R3, R4, R5, and R6 are selected from hydrogen, fluorine, and chlorine respectively;
• R7 is selected from isopropyl and cyclopropyl , Isobutyl, methyl,
• Z is selected from C, O, and N;
• Q and W are selected from C and N, respectively.
• the compound represented by formula I is selected from any one of the following compounds:
• the present invention provides a method for preparing a compound of formula I, which comprises:
• the substituted o-carboxybenzylamine and the primary amine undergo a condensation reaction to obtain intermediate Ia, wherein the amino group of the o-carboxybenzylamine is protected by Boc; then hydrochloric acid is added to the intermediate Ia to remove the Boc protection to obtain intermediate Ib; Ib then Reductive amination reaction with substituted aryl aldehydes to obtain intermediate Ic; then Ic reacts with borane to reduce the amide moiety to obtain intermediate Id; Id performs cyclization reaction with triphosgene to obtain intermediate Ie; Finally, Ie undergoes an alkylation reaction to obtain the compound represented by formula I.
• compositions and pharmaceutical preparations are provided.
• Another object of the present invention is to provide a pharmaceutical composition
• a pharmaceutical composition comprising a therapeutically effective amount of the compound of the present invention, and optionally a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or a combination thereof.
• the pharmaceutically acceptable carriers that can be used in the pharmaceutical composition of the present invention include, but are not limited to, sterile liquids such as water and oil.
• the composition may also contain small amounts of wetting agents, emulsifiers, lubricants, Stabilizer or pH buffer, etc.
• Oral formulations may contain standard carriers.
• the pharmaceutical composition can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Therefore, the active compound of the present invention can be formulated into a dosage form for oral, buccal administration, intranasal, parenteral (for example, intravenous, intramuscular or subcutaneous) or rectal administration, or suitable for administration by inhalation or insufflation.
• the dosage form of the medicine can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Therefore, the active compound of the present invention can be formulated into a dosage form for oral, buccal administration, intranasal, parenteral (for example, intravenous, intramuscular or subcutaneous) or rectal administration, or suitable for administration by inhalation or insufflation.
• the dosage form of the medicine can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Therefore, the active compound of the present invention can be formulated into a dosage form for oral, buccal administration, intranasal, parenteral (for example, intravenous, intramuscular
• the pharmaceutical composition of the present invention can be administered in any manner as long as it achieves the effect of preventing, alleviating, preventing or curing the symptoms of human or animal patients.
• various suitable dosage forms can be prepared according to the route of administration, especially injections, such as lyophilized powder for injection, injection or sterile powder for injection.
• an effective dose of the compound of the present invention can be taken orally together with, for example, an inert diluent or a certain carrier.
• the compound of the present invention can be encapsulated in a gelatin capsule or compressed into tablets.
• the compound of the present invention can be used together with excipients and used in the form of tablets, lozenges, capsules, suspensions, syrups and the like.
• the above formulation should contain at least 0.5% (w/w) of the active compound of the present invention, but it can vary according to specific dosage forms, and it is convenient to account for 4% to about 70% of the unit weight. The amount of active compound in such a pharmaceutical composition should reach an appropriate dose.
• the active compound of the present invention can be formulated into tablets or capsules by conventional means and pharmaceutically acceptable excipients, such as binders and fillers. , Lubricant, disintegrant or wetting agent.
• the tablets can be coated by methods well known in the art.
• Liquid preparations for oral administration such as solutions, syrups or suspensions, or volatilized into dry products, can be regenerated with water or other suitable carriers before use.
• Such liquid preparations can be prepared by conventional means using pharmaceutical additives, such as suspending agents, emulsifiers, non-aqueous carriers and preservatives.
• the active compound of the present invention when used for parenteral administration, can be combined with sterile water or an organic medium to form an injectable solution or suspension.
• the active compound of the present invention may be formulated into rectal compositions, such as suppositories or retention enemas, for example containing conventional suppository bases such as cocoa butter or other glycerides.
• the present invention also provides the use of the compound of formula I in the preparation of drugs for the treatment of mental diseases.
• the present invention also provides a method for treating mental diseases, which comprises administering a compound represented by Formula I or a pharmaceutical composition thereof to an individual in need.
• the method also optionally includes administering another active agent for the treatment of mental illness.
• the present invention also provides the compound of formula I or a pharmaceutical composition thereof for the treatment of mental diseases.
• the mental illness is selected from schizophrenia and psychosis.
• the mental illness is selected from Parkinson's disease, dementia-related behavioral disorders, and psychosis.
• n1, n2 are integers from 1 to 3;
• R1 is a C1-C5 linear or branched alkyl group
• R2 is selected from hydrogen, halogen
• R3, R4, R5, and R6 are each independently selected from hydrogen and halogen
• R7 is selected from C1-C5 linear or branched alkyl, cycloalkyl, R8 and R9 are independently selected from C1-C3 linear or branched alkyl groups;
• Z is selected from C, O, N;
• Q and W are selected from C and N respectively;
• n2, R1, R3, R7, W, and Z are as defined above;
• n1 and n2 are integers from 1 to 3;
• R1 is a C1-C5 linear or branched alkyl group
• R2 is selected from hydrogen, halogen
• R3, R4, R5, and R6 are each independently selected from hydrogen and halogen
• R7 is selected from C1-5 linear or branched alkyl, cycloalkyl, R8 and R9 are independently selected from C1-C3 linear or branched alkyl groups;
• Z is selected from C, O, N;
• Q and W are selected from C and N respectively.
• n1, n2 are integers of 1-3;
• R1 is selected from methyl, ethyl, propyl, butyl;
• R2 is selected from hydrogen, fluorine, chlorine, bromine, and iodine
• R3, R4, R5, and R6 are respectively selected from hydrogen, fluorine, and chlorine;
• R7 is selected from isopropyl, isobutyl, ethyl, propyl, methyl, cyclopropyl, cyclobutyl,
• Z is selected from C, O, N;
• Q and W are selected from C and N respectively;
• n2 is an integer of 1-2;
• R1 is selected from methyl, ethyl, propyl, butyl;
• R3 is selected from hydrogen, fluorine, and chlorine
• R7 is selected from isopropyl, isobutyl, ethyl, propyl, methyl, cyclopropyl, cyclobutyl,
• n1 and n2 are integers from 1 to 3;
• R1 is methyl
• R2 is selected from fluorine and hydrogen
• R3, R4, R5, and R6 are respectively selected from hydrogen, fluorine, and chlorine;
• R7 is selected from isopropyl, cyclopropyl, isobutyl, methyl,
• Z is selected from C, O, N;
• Q and W are selected from C and N respectively.
• a pharmaceutical composition characterized by containing the compound described in any one of items 1 to 7, optionally further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle, or a combination thereof .
• the application according to item 9 characterized in that the mental illness is Parkinson's disease, behavior disorder related to dementia, and psychosis.
• the compound provided by the present invention acts on 5-HT 2A and 5-HT 2C receptors, and has better selectivity to 5-HT 2A than or similar to pimoserin.
• the compound provided by the present invention is used to treat schizophrenia or Parkinson's disease, dementia-related behavioral disorders and psychosis.
• the antipsychotic activity of the compound of the present invention is comparable to that of piperserin, the side effects of sedation and the worsening of exercise are less than piperserin, and the cardiotoxicity is less than that of piperserin.
• Methyl 2-cyano-5-fluorobenzoate (1.8g, 10.05mmol), Raney-Ni (0.5mg), Boc 2 O (2.63g, 12.06mmol), NaHCO 3 (1.69g, 20.1mmol), THF (20mL) was added to a 50mL three-necked round-bottomed flask, and hydrogen was introduced and stirred at 50°C for 48h, then the reaction solution was filtered, and the filtrate was directly concentrated to obtain 2g (70.26%) of solid.
• Example 16 7,8-Difluoro-2-(4-isobutoxybenzyl)-4-(1-methylpiperidin-4-yl)-1,2,4,5-tetrahydro- Preparation of 3H-benzo[e][1,3]diazepine-3-one (A20001):
• benzyl-4-(8-fluoro-4-[[4-(2-hydroxypropyl)phenyl]methyl]-3-oxo-1,5-dihydro- 2,4-Benzodiazepine-2-yl)piperidine-1-carboxylate (200.00mg, 0.367mmol) and dichloromethane (20.00mL), protected by nitrogen, cooled to 0°C and stirred for 5 minutes, then DMP (310.92 mg, 0.733 mmol) was added, and the reaction was stirred at 25°C for 3 hours.
• the CHO-5-HT 2A cells were taken out from the refrigerator at -80°C and thawed naturally, and centrifuged at 2000g for 15 minutes at 4°C. Take the precipitate and discard the supernatant. Add B solution to precipitation. The cells were mixed for 20-30 seconds, and then centrifuged at 50,000g at 4°C for 25min. Carefully discard the supernatant, add again B solution to mix, and centrifuge at 50,000g at 4°C for 25min. Precipitate stored at -80°C.
• Cell CHO-D 2 was taken out from the refrigerator at -80°C and thawed naturally, centrifuged at 2000g for 15min, added the precipitate to homogenate C, mixed with a vortex mixer, centrifuged at 50,000g, 4°C for 25min, discarded the supernatant, took the precipitate, and added again Wash and resuspend in buffer C and centrifuge. After centrifugation, discard the supernatant and store the pellet at -80°C for later use.
• the first step first make the prepared membrane homogenate B into a 10 mg/mL membrane suspension for later use.
• Step 2 Add 100 ⁇ L of membrane preparation to each reaction tube.
• Step 3 Add 100 ⁇ L of B solution to the total binding tube (TB), add 100 ⁇ L of Methysergide (final concentration 1.0 ⁇ 10 -5 M) to the non-specific binding tube (NB), and add 100 ⁇ L of the test compound to each test compound tube (CB).
• Step 4 Add 10 ⁇ L of radioligand 3 H-Ketanserin to each reaction tube, with a final concentration of 2.98 nM.
• Step 5 Incubate each reaction tube at 37°C for 25min. After the reaction is complete, the bound ligand is quickly filtered under reduced pressure. Whatman test paper GF/C plate is soaked in 0.5% PEI for more than 1 hour in advance, and the filter membrane is dried at 60°C after filtration. , After attaching the base film, add 40 ⁇ L of scintillation fluid, seal the film and let it stand.
• Step 6 Put the scintillation cup into the liquid scintillation counter to count.
• the first step first make the prepared membrane homogenate B into a 210mg/mL membrane suspension for later use.
• Step 2 Add 100 ⁇ L of membrane preparation to each reaction tube.
• the third step add 100 ⁇ L of B solution to the total binding tube (TB), add 100 ⁇ L of Ketanserin (final concentration 1.0 ⁇ 10 -5 M) to the non-specific binding tube (NB), and add 100 ⁇ L of the test compound to each test compound tube (CB).
• Step 4 Add 10 ⁇ L of radioligand 3 H-Mesulergine to each reaction tube, with a final concentration of 3nM.
• Step 5 Incubate each reaction tube at 37°C for 25 minutes. After the reaction is complete, the bound ligands are quickly filtered under reduced pressure. Whatman test paper GF/C is saturated with 0.5% PEI solution 1 hour in advance, and washed thoroughly with ice-cold Tris buffer. Take the filter out and put it in a 4mL scintillation cup, add 1mL of toluene scintillation fluid and mix well.
• Step 6 Put the scintillation cup into the liquid scintillation counter to count.
• the first step first prepare the prepared membrane homogenate C into a suspension of 8 mg/mL membrane for later use.
• Step 2 Add 100 ⁇ L of membrane preparation to each reaction tube.
• Step 3 Add 100 ⁇ L of C solution to the total binding tube (TB), add 100 ⁇ L of Haloperidol to the non-specific binding tube (NB) (final concentration 1.0 ⁇ 10 -5 M), and add 100 ⁇ L of test compound to each test compound binding tube (CB) .
• Step 4 Add 10 ⁇ L of radioligand 3 H-Spiperone to each reaction tube, with a final concentration of 1.176 nM.
• Step 5 Incubate each reaction tube at 37°C for 25min. After the reaction is complete, the bound ligand is quickly filtered under reduced pressure. Whatman test paper GF/B plate is soaked in 0.5% PEI for more than 1 hour in advance, and the filter membrane is dried at 60°C after filtration. , After attaching the base film, add 40 ⁇ L of scintillation fluid, seal the film and let it stand.
• Step 6 Put the suction filter plate into the liquid scintillation counter to count.
• Piperidine do mianserin 5-HT 2A, 5-HT 2C receptor Ki values were 0.036,2.94nM, the compound NH-K-A19016-OA of the 5-HT 2A, 5-HT 2C receptor Ki values were 0.002, 26.1 nM, which is better than pimoserin; the 5-HT 2A and 5-HT 2C receptor Ki values of compound NH-K-A19001 are 0.028 and 2.4 nM, respectively, which are better than pimoserin; compound NH-K-A19005
• the Ki values with 5-HT 2A and 5-HT 2C receptors are 0.429 and 3.39 nM, respectively, which are at the same level as pimoserin. See the table below for details.
• test compound stock solution 0.3mM, 1mM and 3mM dilutions with DMSO.
• DMSO dimethyl sulfoxide
• the final working solution concentration of cisapride is 1nM, 10nM, 100nM and 1000nM.
• the HEK-293 cell line stably expressing the hERG potassium channel was cultured in DMEM medium containing 10% fetal bovine serum and 0.8 mg/mL G418 at a culture temperature of 37°C and a carbon dioxide concentration of 5%.
• Cell passage Remove the old medium and wash once with PBS, then add 0.5mL TrypLE TM Express solution, and incubate at 37°C for 1 minute. When the cells detach from the bottom of the dish, add 3 mL of complete medium pre-warmed at 37°C. The cell suspension was gently pipetted to separate the aggregated cells. Transfer the cell suspension to a sterile centrifuge tube, and centrifuge at 300G for 5 minutes to collect the cells. The cells are seeded in a 6 cm cell culture dish, and the inoculation amount of each cell culture dish is 1*10 5 cells (final volume: 5 mL), which is used for expansion or maintenance culture.
• the cell density In order to maintain the electrophysiological activity of the cells, the cell density must not exceed 80%.
• the voltage stimulation scheme of the cell hERG potassium current is as follows: the cell membrane clamp voltage is -80mV, then it is depolarized from -80mV to +30mV for 2.5 seconds, and then quickly maintained at -50mV for 4 seconds to stimulate the tail current of the hERG channel. Collect data repeatedly every 10 seconds. Use -50mV as leakage current detection.
• C represents the concentration of the test compound, IC 50 inhibition concentration representatives, h for Hill coefficient. Curve fit and IC calculated using GraphPad Prism 5.0 software to complete 50.
• the IC50 of the hERG experiment of piperserin was 208nM, and the IC50 of the hERG experiment of NH-K-A19001, NH-K-A19005, and NH-K-A19006 were 206, 3173, and 1194nM respectively.
• the cardiotoxicity of these three compounds is less than that of piperserin, suggesting that Compared with pimoserin, the compound of the present invention has lower cardiotoxicity.
• the results are shown in the table below.
• Animals receive intraperitoneal injections of different doses of MPTP every morning for 5 consecutive days. In the morning of the 5th day, after injection of MPTP, an interval of 1.5 hours, then intraperitoneal injection of piperoserin or NS, and an interval of 0.5 hours, then intraperitoneal injection of MK-801 0.3 mg/kg (or NS), after another 0.25h, put the mouse into an autonomous activity box (a black polyethylene box with a size of 29cm ⁇ 29cm ⁇ 30cm) for recording. The recording time is 20min. After the recording, video analysis is performed. Evaluate the activity of the mice.
• an autonomous activity box a black polyethylene box with a size of 29cm ⁇ 29cm ⁇ 30cm
• the scoring criteria are: four feet on the floor score 0; two forefoot scores on the net cage; four feet score 2 on the net cage.
• Qualified SPF grade C57BL/6j mice were randomly divided into 13 groups, each with 8 mice: blank group, pimoserin, NH-K-A1900, NH-K-A19005, NH-K-A19006. According to the different doses of each group, different concentration solutions were prepared for intraperitoneal injection administration, and the final administration volume was 10ml/kg.
• the ED50 of PDP efficacy, sedation, and exercise deterioration of pimoserin are 0.37 mg/kg, 6.79 mg/kg, and >30 mg/kg, respectively, and its sedation/PDP efficacy ratio is 18.35, exercise deterioration/PDP drug
• the efficacy ratio is >81.08;
• the efficacy and sedative ED50 of NH-K-A19001PDP are 0.33mg/kg and 3.74mg/kg, respectively, and the sedative/PDP efficacy ratio is 11.33.
• the efficacy of NH-K-A19005PDP is 1.85mg/kg.
• the efficacy and sedative ED50 of NH-K-A19006PDP were 0.31mg/kg and 11.9mg/kg, respectively. It can be seen that the efficacy of NH-K-A19001 and NH-K-A19006 is equivalent to that of pimoserin.
• the effective dose of NH-K-A19005PDP is slightly higher than that of pimoserin.
• the compounds of the present invention (such as NH-K-A19001, NH-K-A19005, and NH-K-A190016) do not have a DA mechanism of action, and no deterioration in exercise was observed.
• Example 23 In vivo and in vitro experimental methods and data of A01 series compounds of the Pymethrin project
• mice After stratified by body weight, the mice were randomly divided into a model control group, a blank control group and each administration group. One hour after the animal was given the vehicle or drug by intragastric administration, the animal was put into a beaker with fresh bedding (13cm in diameter, 19cm in height), and the model drug DOI(( ⁇ )-1-) was injected intraperitoneally at a dose of 1mg/kg.
• DOI(( ⁇ )-1-) (2,5-Dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride, ( ⁇ )-2,5-dimethoxy-4-iodoamphetamine hydrochloride), record small
• the head shaking behavior is defined as the rapid rotational twitching or wet dog-like shaking of the mouse's head, which is different from normal grooming or exploring behavior.
• mice The results of this experiment showed that the ED50 of pimoserin inhibiting DOI-induced head shaking in mice was 0.39 mg/kg, and NH-K-A19001, NH-K-A19005, NH-K-A19006, NH-K-A19012 inhibited
• the ED50 of MK-801 induced high activity behavior in mice was 0.06, 0.15, 0.012, and 0.30 mg/kg, respectively, indicating that the compound of the present invention has a better anti-psychiatric effect and a better drug effect.
• the detailed results are shown in the table below.
• ED50 is half the effective amount.
• mice After stratified by body weight, the mice were randomly divided into a model control group, a blank control group, and each administration group. After the test product (or reference product) was given, the mice were put into an autonomous activity box (specification 29cm ⁇ 29cm ⁇ 30cm). The black polyethylene box) adapts to the intraperitoneal injection of 0.3mg/kg of MK-801 1h after intragastric administration, and then put the mouse into the autonomous activity box for recording. The recording time is 60min. After the recording, the video analysis is performed for evaluation. Mouse activity.
• an autonomous activity box specifically 29cm ⁇ 29cm ⁇ 30cm.
• the black polyethylene box adapts to the intraperitoneal injection of 0.3mg/kg of MK-801 1h after intragastric administration, and then put the mouse into the autonomous activity box for recording.
• the recording time is 60min. After the recording, the video analysis is performed for evaluation. Mouse activity.
• mice The results of this experiment show that the ED50 of pimoserin inhibiting MK-801-induced hyperactive behavior in mice is 3.288 mg/kg, and NH-K-A19005, NH-K-A19006, and NH-K-A19012 inhibit MK-801 induction
• the ED50 of the high activity behavior of the mice were 1.01, 0.2648, and 3.728 mg/kg, respectively, indicating that the compound of the present invention has a better anti-psychiatric effect and a better drug effect.
• the detailed results are shown in the table below.
• ED50 is half the effective amount.
• the test method is carried out with reference to the literature and preliminary experiments.
• the specific process is as follows: first, 5 minutes of adaptation time (62dB of background sound), and 5 separate shock reflex stimuli (block1, the results are not included in the analysis) after the adaptation period.
• the initial response of the animal is reduced to a plateau level), and then 4 different types of trials (block2) are presented, which appear in a pseudo-random manner, namely: 1) Separate shock reflex stimulation (pulse-alone, 120dB, duration 20ms) 2) Prepulse-alone stimulation (75dB, 20ms duration) higher than the background sound by 13dB; 3) Combined test of prepulse stimulation and shock reflex stimulation (prepulse+pulse, each lasting 20ms, the interval between the two is 100ms) ); 4) No stimulus with background sound only, each trial is presented 5 times, and the average interval between each trial is 20s (10-30s).
• shock reflex stimulation alone or the pre-pulse combined shock reflex stimulation response amplitude is expressed in AVG (special unit of the instrument) value.
• AVG value indirectly reflects the shrinking response of the rat body.
• Evaluation index: PPI% (1-prepulse combined shock reflex stimulus response amplitude/single shock reflex stimulus response amplitude) ⁇ 100. The larger the value, the deeper the degree of inhibition.
• PPI refers to the inhibitory effect of the weak stimulus (30-500ms) before the strong shock reflex stimulus on the shock reflex. Studies have shown that the nerve nuclei and pharmacological mechanisms that regulate PPI in humans and rodents are very similar, so it is a cross-species behavioral indicator. Clinical studies have also found that patients with schizophrenia have PPI damage, and some antipsychotics can improve this. Based on the above characteristics, this model is widely used to study the pathogenesis of schizophrenia and the pharmacological effects of antipsychotics. It is also used as a tool for screening antipsychotics, especially for predicting negative symptoms and cognitive deficits in schizophrenia. Curative effect.
• rats given DOI 0.5mg/kg can significantly destroy PPI (P ⁇ 0.05), NH-K-A190060.3mg/kg, NH-K-A19005 3mg/kg, pimoserin 3mg/kg can Significantly reverse the DOI-induced PPI injury in rats (P ⁇ 0.05), see the table below for details.
• MEAN means average
• SD means standard deviation
• P means P value.
• the values in the table indicate reversal damage, where the larger the value, the more symptom reduction is compared with the model group.
• Model group vs. blank group; each administration group vs. model group.
• Model group vs. blank group; each administration group vs. model group.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Neurosurgery (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Psychiatry (AREA)
• Psychology (AREA)
• Epidemiology (AREA)
• Hospice & Palliative Care (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Priority Applications (8)

Applications Claiming Priority (4)

Related Child Applications (1)

Publications (1)

Family

ID=78374068

Family Applications (1)

Country Status (9)

Cited By (4)

Citations (8)

Family Cites Families (5)

• 2021
  • 2021-04-25 JP JP2022563189A patent/JP7693709B2/ja active Active
  • 2021-04-25 CA CA3172692A patent/CA3172692C/en active Active
  • 2021-04-25 BR BR112022021228A patent/BR112022021228A2/pt unknown
  • 2021-04-25 KR KR1020227040086A patent/KR102832951B1/ko active Active
  • 2021-04-25 EP EP21796540.9A patent/EP4144725B1/en active Active
  • 2021-04-25 WO PCT/CN2021/089660 patent/WO2021218863A1/zh not_active Ceased
  • 2021-04-25 CN CN202180029971.7A patent/CN115667236B/zh active Active
  • 2021-04-25 AU AU2021262281A patent/AU2021262281B2/en active Active
• 2022
  • 2022-10-20 US US18/048,340 patent/US12559471B2/en active Active

Patent Citations (8)

Non-Patent Citations (2)

Also Published As

Similar Documents

Legal Events