WO2024088109A1 - Composé hétérocyclique aryle, son procédé de préparation et son utilisation - Google Patents

Composé hétérocyclique aryle, son procédé de préparation et son utilisation Download PDF

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WO2024088109A1
WO2024088109A1 PCT/CN2023/124966 CN2023124966W WO2024088109A1 WO 2024088109 A1 WO2024088109 A1 WO 2024088109A1 CN 2023124966 W CN2023124966 W CN 2023124966W WO 2024088109 A1 WO2024088109 A1 WO 2024088109A1
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alkyl
hydrogen
membered
independently
optionally substituted
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PCT/CN2023/124966
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Chinese (zh)
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邵黎明
孔令辉
肖立
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复旦大学
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    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/453—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/76—Benzo[c]pyrans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/96—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings spiro-condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • C07D313/02—Seven-membered rings
    • C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
    • C07D313/08—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/10—Spiro-condensed systems

Definitions

  • the present invention relates to the fields of pharmaceutical chemistry and pharmacotherapy. Specifically, the present invention relates to a series of cyclopentadiene compounds represented by general formula I and stereoisomers, a preparation method thereof, a chiral separation method, a pharmaceutical composition comprising the compound and its use.
  • the compound represented by general formula I provided by the present invention has a high binding activity with monoamine transporters. Therefore, the cyclopentadiene compounds of the present invention can be used to prevent or treat mental diseases such as schizophrenia, depression, anxiety, etc.
  • Mental illness refers to a disease in which the brain of the human body is disturbed due to various biological, psychological and social environmental factors, resulting in varying degrees of disorders in mental activities such as cognition, emotion, will and behavior.
  • mental illnesses include schizophrenia, depression, anxiety, attention deficit disorder, avolition, autism, etc.
  • monoamine neurotransmitters such as norepinephrine and dopamine in the brain, which causes serious harm to both the patient and society.
  • depression Take depression as an example. Its prevalence among adults has reached 10% to 20%, making it the fourth largest disease affecting global public health security. According to the latest statistics, the number of depression patients in my country has reached more than 90 million, and the incidence rate is increasing year by year while showing a trend of younger age. Depression has the characteristics of complex mechanisms, many subtypes, difficult diagnosis and large individual differences among patients, which brings great challenges to the treatment of depression.
  • Existing antidepressants are mainly designed and developed based on the monoamine neurotransmitter hypothesis. The drugs work by increasing the level of monoamine transmitters in the synaptic cleft or enhancing related nervous system functions.
  • the first-line clinical antidepressants are mainly selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine dual reuptake inhibitors (SNRIs).
  • SSRIs serotonin reuptake inhibitors
  • SNRIs norepinephrine dual reuptake inhibitors
  • TRIs 5-hydroxytryptamine
  • NE norepinephrine
  • DA dopamine
  • TRIs triple reuptake inhibitors
  • TRIs are considered to be an important direction for developing new antidepressant drugs by optimizing monoamine strategies.
  • other receptors in the monoaminergic system such as 5-HT receptors or DA receptors, are regulated to balance neurotransmitters in the brain, which has a therapeutic effect on mental illness and other related diseases.
  • the first object of the present invention is to provide a cyclopentadiene compound having monoamine transporter protein binding activity, including stereoisomers or pharmaceutically acceptable salts, prodrugs or solvates thereof.
  • Such compounds can be used for preventing, diagnosing and treating central nervous system diseases such as schizophrenia, depression, anxiety, attention deficit disorder, pain, neurodegenerative diseases, as well as obesity and obesity-related diseases.
  • the second object of the present invention is to provide a method for preparing the above-mentioned annular compound.
  • the third object of the present invention is to provide a method for chiral separation of the above-mentioned cyclopentane compound.
  • the fourth object of the present invention is to provide a pharmaceutical composition of the annular compound represented by general formula I, its stereoisomers, and pharmaceutically acceptable salts, prodrugs or solvates thereof.
  • the present invention provides a compound as shown in formula (I),
  • Ring A is selected from 5-7 membered heteroaryl or aryl, wherein the 5-7 membered heteroaryl or aryl is optionally substituted by 1-3 halogen, amino, hydroxy, C 1 -C 4 alkyl, C 1 -C 3 alkoxy, C 2 -C 4 alkenyl or trifluoromethyl;
  • n 1, 2 or 3; preferably, m is 1 or 2;
  • n is 1, 2 or 3; preferably, n is 1 or 2;
  • R1 and R2 are each independently (i) hydrogen, C1 - C4 alkyl, C1 - C3 alkoxy, C2 - C4 alkenyl, C2 - C4 alkynyl, 3-5 membered cycloalkyl, C5 - C10 aryl or 5-10 membered aralkyl;
  • the C 1 -C 4 alkyl, C 1 -C 3 alkoxy, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, 3-5 membered cycloalkyl is optionally substituted by 1-3 halogens, amino, 3-5 membered cycloalkyl;
  • the C 5 -C 10 aryl or 5-10 membered aralkyl is optionally substituted by 1-3 halogens, amino, C 1 -C 4 alkyl, C 1 -C 3 alkoxy or trifluoromethyl;
  • R3 and R4 are each independently (i) hydrogen, C1 - C4 alkyl, C1 - C3 alkoxy, C2 - C4 alkenyl, C2 - C4 alkynyl, 3-5 membered cycloalkyl, 5-10 membered aryl or heteroaryl, 5-10 membered aralkyl or heteroaralkyl;
  • the C 1 -C 4 alkyl, C 1 -C 3 alkoxy, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, 3-5 membered cycloalkyl is optionally substituted by 1-3 halogens or amino groups, and the 5-10 membered aryl or heteroaryl, 5-10 membered aralkyl or heteroaralkyl is optionally substituted by 1-3 halogens, amino groups, C 1 -C 4 alkyl, C 1 -C 3 alkoxy, trifluoromethyl, or phenyl groups;
  • R 3 and R 4 together with the carbon atom to which they are attached form a 3-6 membered cycloalkyl group, wherein the 3-6 membered cycloalkyl group is optionally substituted by 1-3 halogen or amino groups.
  • Ring A is selected from thiophene, furan or benzene ring optionally substituted with 1-2 halogen, amino, hydroxy, C 1 -C 4 alkyl, C 1 -C 3 alkoxy, C 2 -C 4 alkenyl or trifluoromethyl.
  • the structural unit of Ring A dihydropyran has the following structure:
  • R 7 is hydrogen, halogen, C 1 -C 4 alkyl or C 1 -C 3 alkoxy
  • R 8 and R 9 are independently selected from hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 3 alkoxy or hydroxy.
  • the structural unit of ring A dihydropyran is selected from the following structures:
  • R1 and R2 are each independently (i) hydrogen, C1 - C4 alkyl, C1 - C3 alkoxy, 3-5-membered cycloalkyl or methylcyclopropyl; or (ii) R1 and R2 together with the nitrogen atom to which they are attached form a 5-7 membered heterocyclic group containing 1-2 nitrogen atoms, and the 5-7 membered heterocyclic group containing 1-2 nitrogen atoms may be optionally substituted by a benzyl group; the benzyl group is optionally substituted by 1-3 halogens, amino, nitro, hydroxyl, C1 - C4 alkyl; preferably, the 5-7 membered heterocyclic group containing 1-2 nitrogen atoms includes tetrahydropiperidine and tetrahydropiperazine.
  • R 1 and R 2 are each independently H, -CH 3 , -CH 2 CH 3 or -CH 2 CH 2 CH 3 ; or the structural unit is selected from since:
  • R 3 and R 4 are each independently (i) hydrogen, C 1 -C 4 alkyl, 3-5 membered cycloalkyl, phenyl or naphthyl; the phenyl or naphthyl may be optionally substituted with 1-3 halogens, amino, C 1 -C 4 alkyl, C 1 -C 3 alkoxy, trifluoromethyl or phenyl;
  • R 3 and R 4 are each independently (i) hydrogen, methyl, ethyl, isopropyl, methoxy, trifluoromethyl, or selected from the following structures:
  • formula (I) has the following structure:
  • R 5 and R 6 are each independently (i) hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 3 alkoxy, trifluoromethyl, trifluoromethoxy, phenyl or 5-10 membered aralkyl; or (ii) R 5 and R 6 together with the carbon atom to which they are attached form a 6-10 membered aryl group;
  • R7 is selected from hydrogen, halogen or C1 - C4 alkyl.
  • R1 and R2 are each independently (i) hydrogen, C1 - C4 alkyl or methylcyclopropyl; or (ii) R1 and R2 together with the nitrogen atom to which they are attached form a 5-7 membered heterocyclic group containing 1-2 nitrogen atoms, wherein the 5-7 membered heterocyclic group containing 1-2 nitrogen atoms may be optionally substituted by a benzyl group; and the benzyl group may be optionally substituted by 1-3 halogens, amino, nitro, hydroxyl or C1 - C4 alkyl;
  • the 5-7 membered heterocyclic group containing 1-2 nitrogen atoms includes tetrahydropiperidine and tetrahydropiperazine.
  • R 1 and R 2 are each independently hydrogen, methyl, ethyl, n-propyl or methylcyclopropyl; or the structural unit Selected from:
  • Structural units Selected from:
  • formula (I) has the following structure:
  • R1 and R2 are each independently (i) hydrogen, C1 - C4 alkyl; or (ii) R1 and R2 together with the nitrogen atom to which they are attached form a 5-7 membered heterocyclic group containing 1-2 nitrogen atoms, wherein the 5-7 membered heterocyclic group containing 1-2 nitrogen atoms may be optionally substituted by a benzyl group; the benzyl group may be optionally substituted by 1-3 halogens, amino, nitro, hydroxyl, or C1 - C4 alkyl;
  • the 5-7 membered heterocyclic group containing 1-2 nitrogen atoms includes tetrahydropiperidine and tetrahydropiperazine;
  • R 5 and R 6 are each independently (i) hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 3 alkoxy, trifluoromethyl, trifluoromethoxy, phenyl or 5-10 membered aralkyl; or (ii) R 5 and R 6 together with the carbon atom to which they are attached form a 6-10 membered aryl group;
  • R7 is selected from hydrogen, halogen, C1 - C4 alkyl.
  • Ic is selected from: R1 and R2 are each independently hydrogen, C1 - C4 alkyl; R5 and R6 are each independently (i) hydrogen, halogen, C1 - C4 alkyl, C1 - C3 alkoxy, trifluoromethyl, trifluoromethoxy, phenyl or 5-10 membered aralkyl; or (ii) R5 and R6 together with the carbon atom to which they are attached form a 6-10 membered aryl group; R7 is hydrogen.
  • Ic is selected from: R 1 and R 2 are each independently hydrogen, methyl, ethyl or n-propyl; R 5 and R 6 are each independently hydrogen, methyl, methoxy, trifluoromethyl or halogen; R 7 is hydrogen.
  • formula (I) has the following structure:
  • R1 and R2 are each independently (i) hydrogen, C1 - C4 alkyl; or (ii) R1 and R2 together with the nitrogen atom to which they are attached form a 5-7 membered heteroaromatic ring containing 1-2 nitrogen atoms, wherein the 5-7 membered heteroaromatic ring containing 1-2 nitrogen atoms may be optionally substituted by a benzyl group; the benzyl group may be optionally substituted by 1-3 halogens, amino, nitro, hydroxyl, or C1 - C4 alkyl;
  • the 5-7 membered heteroaromatic ring containing 1-2 nitrogen atoms includes tetrahydropiperidine and tetrahydropiperazine;
  • R3 and R4 are each independently (i) hydrogen, C1 - C4 alkyl, 3-5 membered cycloalkyl, said C1 - C4 alkyl, 3-5 membered cycloalkyl may be optionally substituted by 1-3 halogens, amino, C1 - C4 alkyl, C1 - C3 alkoxy, trifluoromethyl or phenyl; or (ii) R3 and R4 together with the carbon atom to which they are attached form a 3-6 membered cycloalkyl;
  • R7 is selected from hydrogen, halogen, C1 - C4 alkyl.
  • Id is selected from: R1 and R2 are each independently hydrogen, C1 - C4 alkyl; R3 and R4 are each independently (i) hydrogen, C1 - C4 alkyl or 3-5 membered cycloalkyl; or (ii) R3 and R4 together with the carbon atom to which they are attached form a 3-6 membered cycloalkyl; R7 is hydrogen.
  • Id is selected from: R 1 and R 2 are each independently hydrogen, methyl, ethyl or n-propyl; R 3 and R 4 are each independently (i) hydrogen, methyl, ethyl, isopropyl or cyclopropylmethyl; or (ii) R 3 and R 4 together with the carbon atoms to which they are attached form cyclopropyl, cyclobutyl or cyclopentyl; R 7 is hydrogen.
  • formula (I) has the following structure:
  • R1 and R2 are each independently (i) hydrogen, C1 - C4 alkyl; or (ii) R1 and R2 together with the nitrogen atom to which they are attached form a 5-7 membered heterocyclic group containing 1-2 nitrogen atoms, wherein the 5-7 membered heterocyclic group containing 1-2 nitrogen atoms may be optionally substituted by a benzyl group; the benzyl group may be optionally substituted by 1-3 halogens, amino, nitro, hydroxyl, or C1 - C4 alkyl;
  • the 5-7 membered heteroaromatic ring containing 1-2 nitrogen atoms includes tetrahydropiperidine and tetrahydropiperazine;
  • R 5 and R 6 are each independently (i) hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 3 alkoxy, trifluoromethyl, trifluoromethoxy, phenyl or 5-10 membered aralkyl; or (ii) R 5 and R 6 together with the carbon atom to which they are attached form a 6-10 membered aryl group;
  • R 8 and R 9 are each independently hydrogen, C 1 -C 4 alkyl, alkoxy or hydroxy.
  • Ie is selected from: R 1 and R 2 are each independently hydrogen or C 1 -C 4 alkyl; R 5 and R 6 are each independently (i) hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 3 alkoxy, trifluoromethyl, trifluoromethoxy, phenyl or 5-10 membered aralkyl; or (ii) R 5 and R 6 together with the carbon atom to which they are attached form a 6-10 membered aryl group; R 8 and R 9 are each independently hydrogen, C 1 -C 4 alkyl, alkoxy or hydroxy.
  • Ie is selected from: R 1 and R 2 are each independently hydrogen, methyl, ethyl or n-propyl; R 5 and R 6 are each independently hydrogen, methyl, methoxy, trifluoromethyl or halogen; R 8 and R 9 are each independently hydrogen, methyl, methoxy or hydroxyl.
  • formula (I) has the following structure:
  • R 1 and R 2 are each independently (i) hydrogen, C 1 -C 4 alkyl; or (ii) R 1 and R 2 together with the nitrogen atom to which they are attached form a 5-7 membered heterocyclic group containing 1-2 nitrogen atoms, including but not limited to tetrahydropiperidine, tetrahydropiperazine, etc., wherein the 5-7 membered heterocyclic group containing 1-2 nitrogen atoms may be optionally substituted by benzyl; the benzyl group may be optionally substituted by 1-3 halogens, amino, nitro, hydroxyl, C 1 -C 4 alkyl;
  • R3 and R4 are each independently (i) hydrogen, C1 - C4 alkyl, 3-5 membered cycloalkyl, said C1 - C4 alkyl, 3-5 membered cycloalkyl may be optionally substituted by 1-3 halogens, amino, C1 - C4 alkyl, C1 - C3 alkoxy, trifluoromethyl or phenyl; or (ii) R3 and R4 together with the carbon atom to which they are attached form a 3-6 membered cycloalkyl;
  • R 8 and R 9 are each independently hydrogen, C 1 -C 4 alkyl, alkoxy or hydroxy.
  • R 1 and R 2 are each independently hydrogen, methyl, ethyl, n-propyl; R 3 and R 4 are each independently (i) hydrogen, methyl, ethyl, isopropyl, cyclopropylmethyl; or (ii) R 3 and R 4 together with the carbon atoms to which they are attached form cyclopropyl, cyclobutyl or cyclopentyl; R 8 and R 9 are hydrogen, methyl, methoxy, hydroxyl.
  • the present invention discloses the use of the compound as shown in Formula I and its stereoisomers, and pharmaceutically acceptable salts in the preparation of drugs for preventing, treating and diagnosing depression, anxiety, schizophrenia, attention deficit disorder, obesity, neuropathic pain and neurodegenerative diseases.
  • the compound as shown in Formula I and its stereoisomers involved in the present invention have been proved by biological activity tests to have monoamine transporter proteins and GPCR receptor binding activity such as 5-hydroxytryptamine receptors and dopamine receptors, wherein the monoamine transporter is selected from one or more proteins of 5-hydroxytryptamine transporter (SERT), dopamine transporter (DAT), and norepinephrine transporter (NET).
  • SERT 5-hydroxytryptamine transporter
  • DAT dopamine transporter
  • NET norepinephrine transporter
  • the hydrogen described in the present invention includes various isotopes of hydrogen, such as deuterium and tritium;
  • hydrocarbon refers to any structure containing carbon atoms and hydrogen atoms
  • alkyl refers to a linear or branched saturated hydrocarbon group, wherein the alkyl group may be optionally substituted with one or more substituents, including but not limited to methyl, ethyl, propyl (including all isomeric forms), n-propyl, isopropyl, butyl (including all isomeric forms), n-butyl, isobutyl, tert-butyl;
  • cycloalkyl is used to refer to non-aromatic carbocyclic groups, including cyclized alkyl groups, which may include bicyclic or polycyclic ring systems; the cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decahydronaphthalene, and adamantyl;
  • heterocyclic group is used to represent a non-aromatic carbocyclic ring containing heteroatoms N, O, S, including but not limited to tetrahydropyrrole, tetrahydropyridine, tetrahydropyrazine;
  • alkoxy is used to denote an -O-alkoxy group
  • aryl refers to a monocyclic aromatic group and/or a polycyclic monovalent aromatic group containing at least one aromatic hydrocarbon ring; the aromatic group includes, but is not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl and biphenyl;
  • heteroaryl refers to a monocyclic heteroaryl containing heteroatoms N, O, S and/or a polycyclic monovalent heteroaryl containing at least one aromatic hydrocarbon ring; the heteroaryl includes but is not limited to thiophene, furan, pyrrole;
  • halogen is used to refer to fluorine, chlorine, bromine and iodine
  • pharmaceutically acceptable salt refers to a salt prepared from a pharmaceutically acceptable non-toxic acid, including inorganic and organic acids.
  • suitable non-toxic acids include inorganic and organic acids, but are not limited to, for example, acetic acid, alginic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, succinic acid, succinic acid, vinylsulfonic acid, formic acid, fumaric acid, furancarboxylic acid, gluconic acid, glutamic acid, glucuronic acid, galacturonic acid, epoxypropionic acid, hydrobromic acid, hydrochloric acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, galactaric acid, nitric acid, pamoic acid, pantothenic acid, phenylacetic acid, propionic acid, phosphoric acid, salicylic acid, stearic acid, succinic acid, sulfuric acid, tartaric
  • solvate refers to a compound or salt thereof provided by the present invention that further comprises a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces.
  • the solvent is water
  • the solvate is a hydrate.
  • stereoisomer includes all enantiomerically/stereomerically pure and enantiomerically/stereomerically enriched compounds of the invention.
  • Dashed and bold lines in chemical formulae are used to represent a chemical structure with one or more stereocenters and indicate the absolute stereochemistry of the stereocenter in the chemical structure.
  • bonds depicted in the structural formula do not represent preferred stereostructures; chemical structures containing one or more stereocenters include all possible stereoisomeric forms and mixtures thereof.
  • the compound of formula I is prepared by the following synthetic route, which is only an exemplary description of the present invention and is not intended to limit the present invention.
  • Compound 1 is used as a raw material and reacted with the corresponding halogenated aromatic hydrocarbon to generate compound 2.
  • Compound 27 is used as a raw material and reacted with the corresponding halogenated aliphatic hydrocarbon to obtain compound 28.
  • the compound as shown in formula I and its stereoisomers provided by the present invention have monoamine transporter protein binding activity, wherein the monoamine transporter is selected from one or more proteins of serotonin transporter (SERT), dopamine transporter (DAT), and norepinephrine transporter (NET), and can be used for the prevention, diagnosis and treatment of central nervous system diseases such as schizophrenia, depression, attention deficit disorder, neuropathic pain, neurodegenerative diseases, as well as obesity and obesity-related diseases.
  • SERT serotonin transporter
  • DAT dopamine transporter
  • NET norepinephrine transporter
  • Reagents and conditions (i) EtMgCl, (iPr) 2 NH, THF, 50°C, 3h; Pd(tBu 3 P) 2 , THF, 60°C, 3h; (ii) LiAlH 4 , THF, rt, 3h; (iii) CF 3 SO 3 H, 1,4-dioxane, 80°C, 3h.
  • step i-iii described in Example 1 bromobenzene in step i was replaced by 4-methylbromobenzene to obtain yellow oil 4-B with a total yield of 23.4%.
  • step i-iii described in Example 1 bromobenzene in step i was replaced by 4-trifluoromethylbromobenzene to obtain yellow oil 4-D with a total yield of 19.2%.
  • step i-iii described in Example 1 3,4-dichloroiodobenzene was used to replace bromobenzene in step i to obtain yellow oil 4-E, with a total yield of 14.5%.
  • ESI-MS (M+H) + 328.0.
  • HMRS calc. for C 15 H 15 Cl 2 NOS 328.0324, found 328.0329.
  • the solution was cooled to room temperature at a rate of 5°C/10 min.
  • the solid was filtered and weighed to 408 mg (yield: 65%) after drying.
  • the solid was added to 50 mL methanol and heated to 70°C.
  • the solid was completely dissolved, and the solution was cooled at a rate of 5°C/10min.
  • the supersaturation point of the solution was also observed. If a small amount of solid precipitated, the temperature was maintained and stirring was continued until the amount of precipitated solid no longer increased, and then the temperature was continued to be lowered to room temperature, filtered, and dried to obtain a solid.
  • the solid was added to a system of 30mL ethyl acetate and 20mL water, and 1N sodium hydroxide solution was added dropwise while stirring to adjust the pH of the aqueous phase to 11-12, and then stirred at room temperature for 20 minutes. After standing and stratification, the organic phase was obtained.
  • the aqueous phase was extracted with ethyl acetate (20mL x2), and the organic phases were combined and washed with saturated brine (20mL), dried, and concentrated to obtain 68mg of optically pure transparent oily substance 4-E-1A, with a total yield of 23%.
  • the solution was cooled to room temperature at a rate of 5°C/10 min.
  • the solid was filtered and weighed to 408 mg (yield: 65%) after drying.
  • the solid was added to 50 mL methanol and heated to 70°C to make the solid The solid was completely dissolved, and the solution was cooled at a rate of 5°C/10min. The supersaturation point of the solution was also observed. If a small amount of solid precipitated, the temperature was maintained and stirring was continued until the amount of precipitated solid no longer increased, and then the temperature was continued to be lowered to room temperature, filtered, and dried to obtain a solid.
  • the solid was added to a system of 30mL ethyl acetate and 20mL water, and 1N sodium hydroxide solution was added dropwise while stirring to adjust the pH of the aqueous phase to 11-12, and then stirred at room temperature for 20 minutes. After standing and stratification, an organic phase was obtained.
  • the aqueous phase was extracted with ethyl acetate (20mL x 2), and the organic phases were combined and washed with saturated brine (20mL), dried, and concentrated to obtain 54mg of optically pure transparent oily 4-E-1B with a total yield of 18%.
  • Example 11 Separation of cis and trans isomers of N-methyl-1-(4-(3-methylphenyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine (4-H)
  • Example 17 Separation of cis and trans isomers of N-methyl-N-ethyl-1-(4-phenyl-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine (5-A)
  • Example 19 Separation of cis and trans isomers of N-methyl-N-n-propyl-1-(4-phenyl-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine (5-B)
  • Reagents and conditions (vi) CF 3 SO 3 H, 1,4-dioxane, 80°C, 5h; (vii) K 2 CO 3 , KI, CH 3 CN, MW, 120°C, 1h.
  • Example 24 Separation of cis and trans isomers of 1-((4-phenyl-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methyl)azepane (8-C)
  • N-benzyl-bis-o-chloroethylamine was used to replace N-p-fluorobenzyl-bis-o-chloroethylamine hydrochloride to obtain yellow oil 9-B in a yield of 14.2%.
  • N-benzyl-bis-o-chloroethylamine was used to replace N-p-methoxybenzyl-bis-o-chloroethylamine hydrochloride to obtain yellow oil 9-C in a yield of 52.1%.
  • N-benzyl-bis-o-chloroethylamine was used to replace N-p-trifluoromethylbenzyl-bis-o-chloroethylamine hydrochloride to obtain yellow oil 9-D in a yield of 51.1%.
  • N-benzyl-bis-o-chloroethylamine was used to replace N-p-nitrobenzyl-bis-o-chloroethylamine hydrochloride to obtain yellow oil 9-E in a yield of 51.7%.
  • Reagents and conditions (ix) EtMgCl, (iPr) 2 NH, THF, 50°C, 3h; Pd(tBu 3 P) 2 , THF, 60°C, 3h; (x) LiAlH 4 , THF, rt, 3h; (xi) CF 3 SO 3 H, 1,4-dioxane, 80°C, 3h.
  • Reagents and conditions (xii) EtMgCl, (iPr) 2 NH, THF, 50°C, 3h; Pd(tBu 3 P) 2 , THF, 60°C, 3h; (xiii) LiAlH 4 , THF, rt, 3h; (xiv) CF 3 SO 3 H, 1,4-dioxane, 80°C, 3h.
  • Example 37 Separation of cis and trans isomers of N-methyl-1-(7-(3,4-dichlorophenyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methanamine (17-E)
  • 17-E-1A N-methyl-1-((4R,7R)-7-(3,4-dichlorophenyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)-methylamine
  • 17-E-1B N-methyl-1-((4S,7S)-7-(3,4-dichlorophenyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)-methylamine
  • step xii was replaced by 2-bromonaphthalene, and methylaminoacetaldehyde dimethyl acetal was replaced by aminoacetaldehyde dimethyl acetal to obtain a yellow oil 17-H with a total yield of 9.9%.
  • step xii was replaced by 2-bromonaphthalene
  • dimethylaminoacetaldehyde dimethyl acetal in step xiv was replaced by aminoacetaldehyde dimethyl acetal to obtain a yellow oil 17-I with a total yield of 11.3%.
  • step xii was replaced with 3,4-dichloroiodobenzene, and methylaminoacetaldehyde dimethyl acetal in step xiv was replaced with aminoacetaldehyde dimethyl acetal to obtain a yellow oil 17-J with a total yield of 11.1%.
  • step xii was replaced with 3,4-dichloroiodobenzene, and methylaminoacetaldehyde dimethyl acetal in step xiv was replaced with dimethylaminoacetaldehyde dimethyl acetal to obtain a yellow oil 17-K with a total yield of 8.7%.
  • step xvi was replaced by N-fluorobisbenzenesulfonamide (NFSI) to obtain yellow oil 20-B in an overall yield of 4.8%.
  • NFSI N-fluorobisbenzenesulfonamide
  • Reagents and conditions (xvii) EtMgCl, (iPr) 2 NH, THF, 50°C, 3h; Pd(tBu 3 P) 2 , THF, 60°C, 3h; (xix) LiAlH 4 , THF, rt, 3h; (xx) CF 3 SO 3 H, 1,4-dioxane, 80°C, 3h.
  • Reagents and conditions (xxi) EtMgCl, (iPr) 2 NH, THF, 50°C, 3h; Pd(tBu 3 P) 2 , THF, 60°C, 3h; (xxii) LiAlH 4 , THF, rt, 1h; (xxiii) CF 3 SO 3 H, 1,4-dioxane, 80°C, 3h.
  • Example 51 Separation of cis and trans isomers of N-methyl-1-(4-methyl-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine (26-A)
  • 26-A-1 trans-N-methyl-1-(4-methyl-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine
  • 26-A-2 cis-N-methyl-1-(4-methyl-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine
  • iodomethane was used to replace iodomethane in step xxi to obtain yellow oil 26-B, with a total yield of 5.7%.
  • ESI-MS (M+H) + 212.1.
  • HMRS calc. for C 11 H 17 NOS ([M+H] + ) 212.1104, found 212.1105.
  • Example 53 Separation of cis and trans isomers of N-methyl-1-(4-ethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine
  • 26-B was separated to give pale yellow oil 26-B-1 (yield: 24.7%) and pale yellow oil 26-B-2 (yield: 23.3%).
  • H-NMR confirmed that 26-B-1 was trans-configuration and 26-B-2 was cis-configuration.
  • 26-B-1 trans-N-methyl-1-(4-ethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine
  • 26-B-2 cis-N-methyl-1-(4-ethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine
  • Reagents and conditions (xxiv) NaH, DMSO, rt, 3h; (xxv) 4.0N LiOH (aq), 100°C, 15h; (xxvi) LiAlH 4 , THF, rt, 3h; (xxvii) CF 3 SO 3 H, 1,4-dioxane, 80°C, 3h.
  • HMRS calc.for C 11 H 17 NOS([M+H] + )212.1104,found 212.1105.
  • Example 59 1-(4-(3,4-dichlorophenyl)-8-methoxyisochroman-1-yl)-N-methylmethylamine (Compound 35-A), 1-(4-(3,4-dichlorophenyl)-6-methoxyisochroman-1-yl)-N-methylmethylamine (Compound 35-B)
  • Reagents and conditions (xxviii) EtMgCl, (iPr) 2 NH, THF, 50°C, 3h; Pd(tBu 3 P) 2 , THF, 60°C, 3h; (xxix) LiAlH 4 , THF, rt, 3h; (xxx) CF 3 SO 3 H, 1,4-dioxane, 100°C, 24h.
  • Reagents and conditions (xxxi) Ag 2 CO 3 , Pd(OAc) 2 , AcOH, 100°C, 6 ⁇ 30h; (xxxii) L-proline, CHCl 3 , rt, 16h; (xxxiiii) LiAlH 4 , 0°C, 2h; (xxxiv) CF 3 SO 3 H, 1,4-dioxane, 80°C, 16h.
  • xxxiv. 200 mg 39-A (0.83 mmol, 1.0 eq) was added to a 48 mL sealed tube, 10 mL of anhydrous 1,4-dioxane was added to dissolve it, and then 196 mg of methylaminoacetaldehyde dimethyl acetal (1.66 mmol, 2.0 eq) and 373 mg of trifluoromethanesulfonic acid (2.49 mmol, 3.0 eq) were added to the flask. After the sealed tube was sealed, it was heated and stirred at 100°C for 24 hours.
  • step xxxi 3,5-dimethyliodobenzene in step xxxi was replaced with 3-methoxyiodobenzene to obtain yellow oil 40-B with a total yield of 14.5%.
  • Example 66 1-((4,4-dimethyl)-8-methoxyisochroman-1-yl)-N-methylmethanamine (Compound 45-A), 1-((4,4-dimethyl)-6-methoxyisochroman-1-yl)-N-methylmethanamine (Compound 45-B)
  • the reference compound solutions with a maximum concentration of 2 ⁇ M were diluted in a 4-fold concentration gradient using assay buffer (20 mM HEPES in HBSS, containing 0.1% BSA), in duplicate; the test compound was diluted in a 3-fold concentration gradient to obtain 10 test compound solutions with a maximum concentration of 6 ⁇ M, in duplicate for each concentration sample.
  • the multi-mode plate reader reads the plate information and calculates the corresponding inhibition rate.
  • Example 80 Monoamine transporter binding protein binding activity test of aryl annular compounds (II):
  • Example 81 Monoamine transporter binding protein binding activity test of aryl annular compounds (III):

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Abstract

L'invention concerne un composé hétérocyclique aryle, son procédé de préparation et son utilisation, et la formule développée du composé hétérocyclique aryle est telle que représentée dans la formule (I). Le composé selon l'invention a un effet de régulation des systèmes monoaminergiques, et a une activité de liaison sur une protéine transporteur des monoamines et sur des récepteurs couplés aux protéines G, tels qu'un récepteur de 5-hydroxytryptamine, un récepteur de dopamine et un récepteur des amines à l'état de trace. Le composé peut être appliqué au traitement de différentes maladies, parmi lesquelles figurent, sans caractère restrictif, la dépression, l'anxiété, la schizophrénie, le trouble déficitaire de l'attention, l'obésité, la douleur, les maladies neurodégénératives et analogues.
PCT/CN2023/124966 2022-10-27 2023-10-17 Composé hétérocyclique aryle, son procédé de préparation et son utilisation WO2024088109A1 (fr)

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