WO2022002131A1 - 5-((1,2,3,4-四氢异喹啉-7-基)氨基)吡啶-2(1h)-酮衍生物及其应用 - Google Patents

5-((1,2,3,4-四氢异喹啉-7-基)氨基)吡啶-2(1h)-酮衍生物及其应用 Download PDF

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WO2022002131A1
WO2022002131A1 PCT/CN2021/103543 CN2021103543W WO2022002131A1 WO 2022002131 A1 WO2022002131 A1 WO 2022002131A1 CN 2021103543 W CN2021103543 W CN 2021103543W WO 2022002131 A1 WO2022002131 A1 WO 2022002131A1
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independently selected
cycloalkyl
hydrogen
compound
alkyl
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French (fr)
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陈科
蒋钰
张长青
季明华
罗欢
金雪梅
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苏州恩华生物医药科技有限公司
江苏恩华药业股份有限公司
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Priority to CN202180042136.7A priority Critical patent/CN115702146A/zh
Publication of WO2022002131A1 publication Critical patent/WO2022002131A1/zh

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    • 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
    • A61K31/435—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
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • 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
    • A61K31/435—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
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • 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
    • A61K31/435—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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • 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
    • A61P25/22—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
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/08—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with a hetero atom directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring

Definitions

  • the invention belongs to the medical field and relates to a 5-((1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyridine-2(1H)- Ketone derivatives, methods for their preparation and compositions containing the compounds, and their use in the field of medicine.
  • depression In psychiatry, depression is defined as an affective disorder. Depression is a chronic, highly relapsed, and highly disabling mental illness, and it is the first disease that causes people to lose their ability to work and live. Traditional antidepressants have delayed effects and slow onset of action, usually taking more than 2-3 weeks to take effect; in addition, traditional antidepressants have a low response rate, of which 30% of depressed patients have no response, and 30% have only partial In addition, traditional antidepressant drugs are prone to drug resistance, and once drug resistance occurs, the therapeutic effect is greatly reduced.
  • Anxiety disorder also known as anxiety disorder, is a mental disorder with anxiety symptoms as the main clinical phase, including panic disorder, generalized anxiety disorder and social anxiety disorder. Its clinical symptoms are often manifested as mental symptoms of nervousness, fear and anxiety, accompanied by somatic symptoms of autonomic hyperfunction. Anxiety disorders have a high comorbidity rate, and can share one or more mental disorders at the same time.
  • the treatment drugs include common antidepressants, benzodiazepines, and 5-HT1A agonists represented by buspirone. agent. Benzodiazepines have more side effects, other drugs have less improvement in anxiety, and the efficacy needs to be improved.
  • Sigma-1 receptor ( ⁇ 1 receptor) is an emerging drug target in recent years, and it is a binding protein for a variety of specific psychoactive drugs.
  • Sigma-1 receptor is a ligand-regulated protein chaperone, which exerts its role as a molecular chaperone by interacting with receptors such as NMDA: regulating NMDA, APMA and other ion channels and downstream receptors, thereby regulating mitochondrial function and 5- Release of neurotransmitters such as serotonin, dopamine, etc.
  • sigma-1 receptor agonists such as opiprazol, igmetacin, SA-4503, ANAVEX2-73, etc.
  • Compounds such as benzomorphanes (SKF10047, dextromethorphan), SSRI antidepressants (fluvoxamine, sertraline, fluoxetine, etc.) all have high affinity for the Sigma-1 binding site.
  • Opipramol is also a dopamine D2 receptor antagonist and a histamine H1 receptor antagonist.
  • the target effect also brings certain side effects.
  • Sigma-1 receptors in the field of depression, anxiety and other neuropsychiatric diseases, it is of great significance to find compounds with good selectivity for Sigma-1 receptors and good "pharmacological properties" for clinical applications.
  • the present invention aims to provide a series of structurally unique 5-((1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyridin-2(1H)-one derivatives, all of which have very high High sigma-1 receptor affinity and selectivity can be used for the treatment of mental diseases such as depression and anxiety.
  • the present invention provides a compound of general formula (I) or a pharmaceutically acceptable salt thereof:
  • R 1 is independently selected from any one of hydrogen, straight-chain or branched-chain alkyl, cycloalkyl, and alkyl substituted with at least one halogen;
  • R 2 and R 3 are each independently selected from any one of hydrogen, straight-chain or branched-chain alkyl, and cycloalkyl;
  • R 4 is independently selected from any one of hydrogen, straight-chain or branched-chain alkyl, alkyl substituted by at least one halogen, and cycloalkyl;
  • R 5 , R 6 , R 7 and R 8 are each independently hydrogen
  • n1, n2, n3 and n4 are each independently any integer between 0-3;
  • X is either O or CH 2 .
  • the present invention also provides a compound of general formula (I') or a pharmaceutically acceptable salt thereof:
  • R 1 is independently selected from any one of hydrogen, hydroxyl, straight or branched chain alkyl, cycloalkyl, and alkyl substituted with at least one halogen;
  • R 10 is hydrogen or
  • R 2 and R 3 are each independently selected from any one of hydrogen, straight-chain or branched-chain alkyl, and cycloalkyl;
  • R 4 is independently selected from any one of hydrogen, straight-chain or branched-chain alkyl, alkyl substituted by at least one halogen, and cycloalkyl;
  • R 5 and R 6 are each independently selected from hydrogen, halogen, amino, hydroxyl, straight or branched chain alkyl and cycloalkyl, wherein the alkyl and cycloalkyl are unsubstituted or at least one independently selected from Substituent substitution of R X;
  • R 7 and R 8 are each independently selected from hydrogen, halogen, amino, hydroxy, straight or branched chain alkyl and cycloalkyl, wherein said alkyl, cycloalkyl is unsubstituted or independently selected from at least one Substituent substitution of R X;
  • R 7 and R 8 together with the atoms to which they are attached form a three-ring or four-membered ring;
  • R X is independently selected from halogen, cyano, hydroxyl, amino, C 1-6 alkyl and C 3-6 cycloalkyl;
  • n1, n2, n3 and n4 are each independently any integer between 0-3;
  • X is any one of O, CH 2 or does not exist.
  • R 1 is cyclopropyl
  • X is CH 2 .
  • R 2 is methyl
  • R 3 is methyl
  • R 4 is methyl
  • R 5 , R 6 , R 7 and R 8 are each independently hydrogen.
  • the halogen is selected from any one of fluorine, chlorine, bromine or iodine.
  • the straight-chain or branched-chain alkyl group in the structure of the above formula (I') is selected from C1-C5 straight-chain or branched-chain alkyl groups; the cycloalkyl group is selected from C3-C6 cyclic alkyl groups Alkyl; the alkyl substituted with at least one halogen is selected from C1-C5 alkyl substituted with at least one halogen.
  • the straight-chain or branched-chain alkyl group of C1-C5 is any one of methyl, ethyl, propyl, butyl, and pentyl ;
  • the cycloalkyl of the C3-C6 is any one of cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
  • the alkyl of the C1-C5 substituted by at least one halogen is trifluoromethyl or Any of the difluoromethyl groups.
  • 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 groups include, but are 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(
  • the compound represented by the general formula (I') preferably has the structure represented by the following formula (i):
  • R 9 , R 10 ′ and R 11 are independently selected from hydrogen, C1-C5 straight or branched chain alkyl, cycloalkyl and C 1-6 alkyl-C 3-6 cycloalkyl, wherein Said alkyl and cycloalkyl are optionally substituted by at least one substituent independently selected from R X ; wherein said R X is independently selected from halogen, cyano, hydroxyl, amino, C 1-6 alkyl and C 3 -6cycloalkyl , preferably halogen and C3-6cycloalkyl .
  • R 9 , R 10 ′, and R 11 are each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isopropyl Butyl, hydroxyethyl, methoxyethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylmethoxyethyl, 3-trifluoropropyl, 2-difluoroethyl, trifluoromethyl and 2-trifluoroethyl.
  • R 9 is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclopropyl, cyclopropylmethyl, cyclobutylmethyl , cyclopentylmethyl, cyclohexylmethyl, trifluoromethyl, 3-trifluoropropyl, hydroxyethyl, 2-difluoroethyl, trifluoromethyl and 2-trifluoroethyl; more preferably , R 9 is independently selected from ethyl, n-propyl, isopropyl, n-butyl, 3-trifluoropropyl, hydroxyethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexyl methyl.
  • R 9 is cyclopropylmethyl.
  • R 10 ' is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclopropylmethyl, cyclobutylmethyl, 3- trifluoropropyl, and trifluoromethyl; more preferably, R 10 ' is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclopropylmethyl and cyclobutylmethyl;
  • R 10 ' is isopropyl
  • R 11 is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclopropyl, 3-trifluoropropyl, 2- Difluoroethyl, trifluoromethyl and cyclopropylmethyl; more preferably, R 11 is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, isobutyl, cyclopropyl, 2 -difluoroethyl and cyclopropylmethyl; further preferably, R 11 is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, isobutyl and cyclopropylmethyl.
  • R 11 is methyl
  • the compound represented by the general formula (I') preferably has the structure represented by the following formula (ii):
  • R 9 ', R 10 ', R 11 are independently selected from hydrogen, C1-C5 straight or branched chain alkyl, C3-C6 cycloalkyl and C 1-6 alkyl-C 3-6 cycloalkane wherein said alkyl, cycloalkyl is optionally substituted by at least one substituent independently selected from R X ; wherein said R X is independently selected from halogen, cyano, hydroxyl, amino, C 1-6 alkane and C 3-6 cycloalkyl, preferably halogen and C 3-6 cycloalkyl.
  • R 9 ' is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclopropyl, cyclopropyl propylmethyl, trifluoromethyl, 3-trifluoropropyl, 2-difluoroethyl, trifluoromethyl and 2-trifluoroethyl; more preferably, R 9 ' is independently selected from hydrogen, methyl , trifluoromethyl, cyclopropyl and cyclopropylmethyl; further preferably, R 9 ' is independently selected from hydrogen, methyl and cyclopropylmethyl.
  • R 10 ' is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclopropylmethyl, cyclobutylmethyl, 3-trifluoropropyl, and trifluoro methyl; more preferably, R 10 ' is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclopropylmethyl and cyclobutylmethyl.
  • R 11 is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclopropyl, 3-trifluoropropyl, 2-difluoroethyl, trifluoromethyl and cyclopropylmethyl; more preferably, R 11 is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, isobutyl, cyclopropyl, 2-difluoroethyl and cyclopropyl propylmethyl; further preferably, R 11 is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, isobutyl and cyclopropylmethyl.
  • n5 is an integer of 1 to 3, for example, 1, 2 or 3.
  • the compound of the present invention is selected from any one of the following compounds:
  • the present invention further provides the preparation method of general formula (I), comprising:
  • R 1 is independently selected from any one of hydrogen, straight-chain or branched-chain alkyl, cycloalkyl, and alkyl substituted with at least one halogen;
  • R 2 and R 3 are each independently selected from any one of hydrogen, straight-chain or branched-chain alkyl, and cycloalkyl;
  • R 4 is independently selected from any one of hydrogen, straight-chain or branched-chain alkyl, alkyl substituted by at least one halogen, and cycloalkyl;
  • R 5 , R 6 , R 7 and R 8 are each independently hydrogen
  • n1, n2, n3 and n4 are each independently any integer between 0-3;
  • X is either O or CH 2 .
  • the present invention further provides the preparation method of intermediate (III), comprising:
  • R 1 is independently selected from any one of hydrogen, straight-chain or branched-chain alkyl, cycloalkyl, and alkyl substituted with at least one halogen;
  • R 5 , R 6 , R 7 and R 8 are each independently hydrogen
  • n3 and n4 are each independently any integer between 0-3;
  • X is either O or CH 2 .
  • the present invention further provides the preparation method of general formula (I), comprising:
  • R 1 is independently selected from any one of hydrogen, hydroxyl, straight or branched chain alkyl, cycloalkyl, and alkyl substituted with at least one halogen;
  • R 2 and R 3 are each independently selected from any one of hydrogen, straight-chain or branched-chain alkyl, and cycloalkyl;
  • R 4 is independently selected from any one of hydrogen, straight-chain or branched-chain alkyl, alkyl substituted by at least one halogen, and cycloalkyl;
  • R 5 , R 6 each independently selected from hydrogen, halogen, amino, hydroxy, straight or branched chain alkyl and cycloalkyl, wherein said alkyl, cycloalkyl are unsubstituted or independently selected by at least one Substituted from a substituent of R X;
  • R 7 and R 8 are each independently selected from hydrogen, halogen, amino, hydroxy, straight or branched chain alkyl and cycloalkyl, wherein said alkyl, cycloalkyl is unsubstituted or independently selected from at least one Substituent substitution of R X;
  • R 7 and R 8 together with the atoms to which they are attached form a three- or four-membered ring; preferably, R 5 , R 6 , R 7 and R 8 are each independently hydrogen;
  • R X is independently selected from halogen, cyano, hydroxyl, amino, C 1-6 alkyl and C 3-6 cycloalkyl;
  • n1, n2, n3 and n4 are each independently any integer between 0-3;
  • X is any one of O, CH 2 or does not exist.
  • the present invention further provides the preparation method of general formula (I'), comprising:
  • R 1 is independently selected from any one of hydrogen, hydroxyl, straight or branched chain alkyl, cycloalkyl, and alkyl substituted with at least one halogen;
  • R 10 is hydrogen or
  • R 2 and R 3 are each independently selected from any one of hydrogen, straight-chain or branched-chain alkyl, and cycloalkyl;
  • R 4 is independently selected from any one of hydrogen, straight-chain or branched-chain alkyl, alkyl substituted by at least one halogen, and cycloalkyl;
  • R 5 , R 6 each independently selected from hydrogen, halogen, amino, hydroxy, straight or branched chain alkyl and cycloalkyl, wherein said alkyl, cycloalkyl are unsubstituted or independently selected by at least one Substituted from a substituent of R X;
  • R 7 and R 8 are each independently selected from hydrogen, halogen, amino, hydroxy, straight or branched chain alkyl and cycloalkyl, wherein said alkyl, cycloalkyl is unsubstituted or independently selected from at least one Substituent substitution of R X;
  • R 7 and R 8 together with the atoms to which they are attached form a three- or four-membered ring; preferably, R 5 , R 6 , R 7 and R 8 are each independently hydrogen;
  • R X is independently selected from halogen, cyano, hydroxyl, amino, C 1-6 alkyl and C 3-6 cycloalkyl;
  • n1, n2, n3 and n4 are each independently any integer between 0-3;
  • X is any one of O, CH 2 or does not exist.
  • the present invention further provides the preparation method of intermediate (III), comprising:
  • R 1 is independently selected from any one of hydrogen, hydroxyl, straight or branched chain alkyl, cycloalkyl, and alkyl substituted with at least one halogen;
  • R 5 and R 6 are each independently selected from hydrogen, halogen, amino, hydroxyl, C 1-6 alkyl and C 3-6 cycloalkyl, wherein the alkyl and cycloalkyl are unsubstituted or replaced by at least one Substituents independently selected from R X are substituted; preferably, R 5 and R 6 are each independently hydrogen;
  • R 7 and R 8 are each independently selected from hydrogen, halogen, amino, hydroxy, C 1-6 alkyl and C 3-6 cycloalkyl, wherein said alkyl, cycloalkyl is unsubstituted or is at least substituted with a substituent independently selected from R X;
  • R 7 and R 8 together with the atoms to which they are attached form a three-membered ring or a four-membered ring; preferably, R 7 and R 8 are each independently hydrogen;
  • R X is independently selected from halogen, cyano, hydroxyl, amino, C 1-6 alkyl and C 3-6 cycloalkyl;
  • R 5 , R 6 , R 7 and R 8 are each independently hydrogen;
  • n3 and n4 are each independently any integer between 0-3; X is any one of O, CH 2 or none.
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers.
  • the active compounds of the present invention may be formulated for oral, buccal, intranasal, parenteral (eg intravenous, intramuscular or subcutaneous) or rectal administration, or suitable for administration by inhalation or insufflation
  • the dosage form of the medicine may also be formulated in sustained release dosage forms.
  • an effective dose of a compound of the present invention or a pharmaceutically acceptable salt thereof may be administered orally together with, for example, an inert diluent or some carrier.
  • the compounds of the present invention may be encapsulated in gelatin capsules or compressed into tablets.
  • the compounds of the present invention can be used with excipients and in the form of tablets, troches, capsules, suspensions, syrups and the like.
  • the above formulations should contain at least 0.5% (w/w) of the active compound of the invention, but may vary depending on the particular dosage form, where from 4% to about 70% by weight per unit is convenient. The amount of active compound in such pharmaceutical compositions should result in an appropriate dosage.
  • the active compound of the present invention can be formulated into tablets or capsules by conventional means, for example, with pharmaceutically acceptable excipients, such as binders, fillers , lubricants, disintegrants or wetting agents. Tablets can be coated by methods well known in the art.
  • Liquid preparations for oral administration such as solutions, syrups or suspensions, or volatilized as dry products, can be reconstituted with water or other suitable carriers before use. Such liquid preparations can be prepared by conventional means using pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous carriers and preservatives.
  • the compounds provided herein can be combined with sterile aqueous or organic vehicles to form injectable solutions or suspensions.
  • the active compounds of the present invention may be formulated in rectal compositions such as suppositories or retention enemas, eg, containing conventional suppository bases such as cocoa butter or other glycerides.
  • the present invention also provides the use of a compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in the manufacture of a medicament for modulating sigma receptors, wherein the medicament optionally comprises another one or more modulating mammalian nervous system or active agents for the relief of mental illness.
  • the modulation includes, but is not limited to, agonistic activity on the receptor.
  • the present invention provides the use of a compound of the present invention or a pharmaceutical composition thereof in the manufacture of a medicament for the treatment and/or prevention of a sigma-1 receptor-related disease or disease state.
  • the present invention also provides a method of treating and/or preventing a sigma-1 receptor-related disease or disease state, comprising administering to an individual in need thereof a compound of the present invention and its pharmaceutical composition.
  • a compound of the present invention or a pharmaceutical composition thereof is used to treat and/or prevent a sigma-1 receptor related disease or disease state.
  • the sigma-1 receptor-related diseases are mental diseases such as depression, anxiety, Alzheimer's, etc., preferably depression.
  • compounds of the present invention may be optionally substituted with one or more substituents, such as compounds of the general formula above or as specific examples, subclasses in the Examples.
  • substituents such as compounds of the general formula above or as specific examples, subclasses in the Examples.
  • substituents such as compounds of the general formula above or as specific examples, subclasses in the Examples.
  • substituents such as compounds of the general formula above or as specific examples, subclasses in the Examples.
  • substituents such as compounds of the general formula above or as specific examples, subclasses in the Examples.
  • C 1 -C 6 alkyl refers particularly to the disclosure independently methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, C 6 alkyl group.
  • 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 CHCH
  • n 2 is any integer between 0 and 3
  • n 2 includes, for example, any integer from 0 to 2, any integer from 2 to 3, and the like, such as 1, 2, and 3.
  • hydrox (H) refers to a single hydrogen atom. Such radicals may be attached to other groups, such as oxygen atoms, to form hydroxyl groups.
  • halogen refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  • pharmaceutically acceptable salt refers to a salt of a compound of the present invention, which can be prepared from the free form of the compound with a relatively non-toxic acid or base.
  • base addition salts can be obtained by contacting the neutral forms of such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include nitric acid, carbonic acid, bicarbonate hydroiodic acid, phosphorous acid, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, succinic acid, suberic acid, Similar acids such as fumaric, lactic, mandelic, phthalic, citric, fumaric, tartaric, and methanesulfonic acids; also include salts of amino acids (eg, arginine, etc.), and salts such as glucose Salts of organic acids such as aldehydes.
  • pharmaceutically acceptable means compatibility with the other components of the formulation and without unacceptable toxicity to the user.
  • alkyl is used to refer to a straight or branched chain saturated hydrocarbon group, which in some embodiments is a C 1-12 alkyl; in other embodiments , the alkyl group is a C 1-6 alkyl group; in other embodiments, the alkyl group is a C 1-3 alkyl group.
  • alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl) and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl and the like.
  • C 1-6 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms.
  • the C 1-6 alkyl includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl and the like; it can be Is monovalent (eg methyl), divalent (eg methylene) or polyvalent (eg methine).
  • C 1-6 alkyl examples include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl , s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.
  • cycloalkyl includes any stable cyclic alkyl group, including monocyclic, bicyclic, or tricyclic ring systems, wherein bicyclic and tricyclic rings include spiro, paracyclic, and bridged rings.
  • the cycloalkyl is C 3-8 cycloalkyl; in other embodiments, the cycloalkyl is C 3-6 cycloalkyl; in other embodiments, the cycloalkyl Cycloalkyl is C 5-6 cycloalkyl. It may be mono- or polysubstituted, and may be monovalent, divalent or polyvalent.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0 ] Bicyclodecane, etc.
  • C 3-6 cycloalkyl means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which are monocyclic and bicyclic ring systems, said C 3-6 cycloalkyl including C 3-5 , C 4-5 and C 5-6 cycloalkyl and the like; it may be monovalent, divalent or polyvalent.
  • Example C 3- 6 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • R 7 and R 8 are both -CH 2 - and are attached to the tetrahydroisoquinoline 4 carbon by a single bond to form a cyclopropyl; or R 7 and R 8 are each -CH 2 - and -CH 2 -CH 2 -, and are connected with the 4-position carbon of tetrahydroisoquinoline through a single bond to form a cyclobutyl group.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
  • the compounds of the present invention may have a variety of uses or indications, including but not limited to the specific uses or indications recited in this application.
  • R 1 is independently selected from any one of hydrogen, straight-chain or branched-chain alkyl, cycloalkyl, and alkyl substituted with at least one halogen;
  • R 2 and R 3 are each independently selected from any one of hydrogen, straight-chain or branched-chain alkyl, and cycloalkyl;
  • R 4 is independently selected from any one of hydrogen, straight-chain or branched-chain alkyl, alkyl substituted by at least one halogen, and cycloalkyl;
  • R 5 , R 6 , R 7 and R 8 are each independently hydrogen
  • n1, n2, n3 and n4 are each independently any integer between 0-3;
  • X is either O or CH 2 .
  • a pharmaceutical composition characterized by comprising the compound described in any one of items 1-5, optionally further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or a combination thereof.
  • neuropsychiatric disease is selected from any one of depression and anxiety.
  • the 5-((1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyridin-2(1H)-one derivatives provided by the present invention are sigma-1 receptor agonists, 1 Receptor compounds with pharmacological activity and receptor selectivity, as well as preparation methods of these compounds, and uses in the treatment and prevention of central nervous system diseases.
  • Example 25 1-(Cyclopropylmethyl)-5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl )amino)pyridin-2(1H)-one
  • cell lines and related reagents used in the test examples of the present invention can be obtained from commercially available sources.
  • Test Example 1 In vitro sigma-1 receptor binding experiment
  • Test compound preparation all test products are dissolved in 1% DMSO. If the dissolution is not good or the suspension is uneven, add HCl (10%, 10 ⁇ L) appropriately, and the initial concentration is 1.0 ⁇ 10 -5 M (ie 10 ⁇ M). ), followed by 1 ⁇ M, 333nM, 100nM, 33nM, 10nM, 3.3nM, 1nM, 0.33nM, 0.1nM, 0.01nM, for use.
  • the bound ligands are quickly filtered under reduced pressure. Whatman GF/C test paper is soaked in 0.5% PEI for more than 1 h in advance, and the filter is fully washed with ice-cold test buffer. Take it out and put it into a 4 mL scintillation beaker, add 1 mL of toluene scintillation fluid and mix it. Finally, put the scintillation vial into a HIDEX liquid scintillation counter for counting.
  • Test Example 2 sigma-1 agonist functional test
  • phenytoin can change the configuration of sigma-1 receptors.
  • the Ki value of the agonist and the normal Ki value The Ki value of the inhibitor becomes larger than the normal Ki value.
  • the present invention also conducts target selective screening experiments on the compounds of the examples. Taking compound 4 as an example, according to the different types of receptor targets, the corresponding tests were carried out by enzymatic detection method, FLIPR test, nuclear receptor binding test, membrane receptor binding test and ion channel detection method.
  • Target LCK Prepare 50 mL of 1X buffer: 50 mM HEPES (pH 7.5), 1 mM EDTA, 0.01% Brij TM -35 and 10 mM MgCl 2 , store at 4°C for later use. Use Echo to transfer 100nL/well of compound to the test plate, add 5 ⁇ L of a mixture of 40nM enzyme and 0% phosphorylated Tyr2 (4 ⁇ M) to compound wells and DMSO vehicle wells, and add 100% inhibitor to the no-enzyme control group. 5 ⁇ L of 100% phosphorylated Tyr2 (4 ⁇ M) was added as a fully phosphorylated control. Centrifuge at 1000rpm for 30s.
  • Target MAO-A Use Echo to transfer 100nL/well of compound to assay plate, add 5 ⁇ L 2X 16 ⁇ M MAO substrate mix to assay plate, centrifuge at 1000rpm for 30s, add 5 ⁇ L 2X 0.25 ⁇ M MAO substrate mix to assay plate In the test plate, centrifuge at 1000rpm for 30s, seal the test plate with sealing film, and incubate at 23°C for 90min. Add 10 ⁇ L of detection solution to the test well, centrifuge at 1000rpm for 30s, seal the test plate with sealing film, incubate at 23°C for 60min, and read the plate on Envision.
  • Targets PDE3A, PDE4D2 Use Echo to transfer compounds into assay plates, 4-fold dilution series, 10 concentration gradients.
  • 1X reaction solution configuration 40 mM Tris-HCl (pH 7.5), 10 mM MgCl 2 , 0.1 mg/mL BSA.
  • the enzyme stock solution was diluted to 4.4nM with Tris buffer, and 50uL of the diluted enzyme solution was added to the 96-well plate. Add 2 ⁇ L of the reference substance or test compound, the maximum final concentration of the control substance is 100 ⁇ M, as the lower limit control, and 2% DMSO as the upper limit control.
  • the enzyme and compound were incubated for 5 min at room temperature on a shaker. Mix 100 mM iodothioacetylcholine with 10 mM DTNB and pipet 48 ⁇ L into the well plate. The final concentration of substrate was 400 ⁇ M and DTNB was 0.5 mM. Centrifuge at 1000rpm and incubate at 37°C for 1h. Plates were read on SpectraMax.
  • Target COX-1, COX-2 the reference substance was diluted 3-fold or 4-fold with 10% DMSO, and the final concentration of DMSO was 0.5%.
  • the test compound was diluted to 4 mM.
  • the test target is ETA.
  • the specific method use Eta/HEK293 cell line (provided by Shanghai WuXi PharmaTech Co., Ltd.), thaw the cells quickly in a 37°C water bath and transfer the cell suspension to a 50mL conical tube, add culture medium To the 45ml mark, centrifuge at room temperature and gently aspirate the supernatant, taking care not to aspirate the cells, resuspend the cells in 45ml medium, and suspend the cells by pipetting up and down with a sterile pipette; count the cell concentration with ViCell. Add 20 ⁇ L of cell suspension per well to a 384-well plate (20K cells per well), and incubate the cell plate in a 37°C 5% CO 2 incubator overnight.
  • Compound plate Use the Echo instrument to dilute the control compound at a ratio of 1:3 with 100% DMSO 8 points sequentially, and then transfer 900 nL of the compound to the target plate.
  • Compounds to be tested were diluted to 2 mM and then transferred 900 nL with ECHO starting at a final concentration of 10 ⁇ M.
  • AR and GR belong to nuclear receptors.
  • the specific test method dilute the cytosol and radioligand to a specific concentration with buffer, and transfer 1 ⁇ L of the compound to the test plate.
  • the reference substance was diluted by 4 times, with a total of 8 concentration points, the final concentration of the test compound was 10 ⁇ M, and there were two duplicate wells.
  • targets such as 5HT2B, 5HT3, 5HTT, DAT, op-kappa, op-mu, D1, 5HT1A, H1, 5HT2A, M1, M2, M3, D2, GABAA, etc. were detected by membrane receptor binding assay.
  • the specific methods are: The receptor membrane and radioligand were diluted to specific concentrations in buffer and 1 ⁇ L of the compound was transferred to the assay plate.
  • the reference substance was serially diluted 4 times, with a total of 8 concentration points, the final concentration of the test compound was 10 ⁇ M, and there were two duplicate wells.
  • 1 ⁇ L of non-specific binding compound was added to the test well according to the test pattern (prescribed non-specific binding, summary sum, reference substance, and the position pattern of the compound to be tested), and 1 ⁇ L of DMSO was added to the total binding tube.
  • the test pattern add a certain volume of receptor membrane stock solution. After adding a certain volume of radioligand, cover it, shake the test plate with an oscillator, and react for a period of time. The reaction time and temperature of different targets are different. Add the mixture to 96GF/C filter plate, add 50 ⁇ L of 0.3% PEI to each well, and leave to react at room temperature for at least 0.5 h.
  • the compounds to be tested and the reference substance are diluted with 100% DMSO and stored, diluted to the final concentration with extracellular fluid, and the final concentration of DMSO is less than or equal to 0.3% by visual inspection for precipitation.
  • the current signal was then recorded using manual patch clamp (clamp voltage -120mM, set 8s ramp up to -60mV to inactivate sodium channels, then set 20ms ramp down to -120mV, then set 20ms ramp up to -10mV to turn on sodium ions channel, and then down to a forced voltage of -120mV, a cycle of detection for 15s, continuous recording), and analyze the data.
  • manual patch clamp clamp voltage -120mM, set 8s ramp up to -60mV to inactivate sodium channels, then set 20ms ramp down to -120mV, then set 20ms ramp up to -10mV to turn on sodium ions channel, and then down to a forced voltage of -120mV, a cycle of detection for 15s, continuous recording
  • the current signal was then recorded using manual patch clamp (the pinning voltage was -80mV, set 2000ms to increase the voltage gradient to 40mV, then set 1000ms to decrease the voltage gradient to -50mV, and finally reduce the voltage gradient to the pinning voltage, repeating a cycle every 150000ms), analyze data.
  • the results are shown in Table 6 below:
  • mice forced swimming experiment Male ICR mice with a body weight of 18-22g were used and divided into vehicle control group, positive control group (duloxetine, 15mg/kg), test group (compounds 1-34, 30, 60, 90mg/kg). The test group, the vehicle group and the positive control group were all injected with the test substance or vehicle 30 minutes before the formal swimming, and then the mice were subjected to the forced swimming test. The mice were put into a transparent glass cylinder (water depth 15cm, water temperature 23-25°C) for 6 minutes, and the activity status of the mice was recorded by video. After the experiment, Forced Swim ScanTM 2.0 software was used to analyze the forced swimming of the mice in 6 minutes. Cumulative immobility time results for the last 4 minutes of the period.
  • the results of the FST test in Figure 2 show that in the forced swimming model of mice, the duloxetine group (positive control) showed extremely significant efficacy (p ⁇ 0.0001), and compound 4 was at 30 mg/kg. No effect, significant effect at 60mg/kg (p ⁇ 0.05), and extremely significant effect at 90mg/kg (p ⁇ 0.0001).
  • mice were placed on a rotarod with a diameter of 3 cm, the rotarod was activated, and if the mouse fell during the experiment, it was placed on the rod again. 5 minutes of training each time, 3 times of continuous training, and an interval of more than 20 minutes between two training sessions as fatigue recovery time. After the mice were placed on the rod for the third time, the time that the mice stayed on the rod was recorded, and the mice with the residence time less than 5 minutes, those who did not move on the axis, had poor jumping and physical coordination ability were excluded, and the qualified mice were regrouped after screening. .
  • mice were randomly divided into normal control group, high-dose drug group, drug-medium-dose group, and drug-low-dose group, with 10 mice in each group.
  • Each drug group was given the corresponding dose of the test drug by gavage, and the normal control group was given the same volume of vehicle by gavage (5 min interval for every 5 rats).
  • the drop latency within 4 minutes of 0.5h, 1h, and 2h after administration was measured for mice in each group.
  • the present invention provides a 5-((1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyridin-2(1H)-one with high affinity and selectivity for sigma-1 receptors
  • Derivatives can be used for the treatment of mental diseases such as depression and anxiety. Therefore, it can be made into a corresponding medicine, which is suitable for industrial application.

Abstract

一种5-((1,2,3,4-四氢异喹啉-7-基)氨基)吡啶-2(1H)-酮衍生物及其制备方法及应用，其具有如式(I')所示的化合物结构，该类化合物对sigma-1受体具有高药理活性以及高选择性，可用于中枢神经疾病的治疗和预防，特别是可用于制备抗抑郁、抗焦虑的药物。

Description

5-((1,2,3,4-四氢异喹啉-7-基)氨基)吡啶-2(1H)-酮衍生物及其应用
本申请要求2020年6月30日提交的题为“N-(2-吡啶酮)-1,2,3,4-四氢异喹啉衍生物及其应用”的202010616096.X号中国申请的优先权，其内容整体援引加入本文。
技术领域
本发明属于医疗领域，涉及一种对sigma-1受体具有高亲和力的5-((1,2,3,4-四氢异喹啉-7-基)氨基)吡啶-2(1H)-酮衍生物、其制备方法和包含该化合物的组合物，以及其在医药领域的应用。
技术背景
在精神病学上，抑郁被定义为情感障碍。抑郁症是一种慢性、高复发、高致残的精神性疾病，是导致人们丧失工作与生活能力的第一疾病。传统抗抑郁药物具有延迟作用，起效时间慢，通常需要2-3周以上时间起效；此外传统的抗抑郁药物其应答率不高，其中对30％的抑郁患者无反应，30％只有部分应答；另外传统的抗抑郁药物容易产生抗药性，一旦产生抗药性以后，其治疗效果大打折扣。
焦虑障碍又称焦虑症，是一种以焦虑症状为主要临床相的精神障碍，包括惊恐障碍、广泛性焦虑障碍和社交焦虑障碍。其临床症状常表现为紧张不安、恐惧忧虑的精神症状，伴随伴发的自主神经功能亢进的躯体症状。焦虑症的共病率较高，可以同时共一种或一种以上的精神障碍，其治疗药物包括常见的抗抑郁药、苯二氮卓类及以丁螺环酮为代表的5-HT1A激动剂。苯二氮卓类副作用较大，其他药物对焦虑改善程度较小，疗效有待提高。
Sigma-1受体(σ1受体)是近年来新兴的药物靶点，是多种特异性精神类药物的结合蛋白。Sigma-1受体是一种配体调节型蛋白分子伴侣，通过与NMDA等受体相互作用来发挥其分子伴侣的作用：调节NMDA、APMA等离子通道和下游受体，从而调节线粒体功能以及5-羟色胺，多巴胺等神经递质的释放等。
已知的sigma-1受体激动剂如奥匹哌醇、伊格美辛、SA-4503、ANAVEX2-73等在临床上显示了抗抑郁、抗焦虑方面的效果。诸如苯并***烷类化合物(SKF10047,右美沙芬)、SSRI抗抑郁剂(氟伏沙明、舍曲林、氟西汀等)等对Sigma-1结合位点均具有高亲和力。
当前，现有技术公开了不同的Sigma-1受体激动剂，如：Igmesine、Cutamesine、OPC-14523、Opipramol、PRE-084、SA-4503、ANAVEX2-73、ANAVEX1-41、ANAVEX3-71d等具有明显抗抑郁作用的配体分子；专利WO2017190109公开部分sigma受体激动剂的结构及CNS相关疾病用途。
然而临床进展最靠前的Igmesine已在临床3期实验中宣告失败，已上市的Opipramol除了针对sigma-1靶点，同时还是多巴胺D2受体拮抗剂及组胺H1受体拮抗剂，这种多靶点作用同时带来了一定的副作用。
考虑到Sigma-1受体在抑郁、焦虑等神经精神疾病领域的潜在应用，寻找对Sigma-1受体具有较好选择性并具有良好“可药用性”的化合物对临床应用具有重要意义。
发明内容
本发明旨在提供一系列结构独特的5-((1,2,3,4-四氢异喹啉-7-基)氨基)吡啶-2(1H)-酮衍生物，这些化合物均具有很高的sigma-1受体亲和力和选择性，可用于抑郁症、焦虑症等精神疾病的治疗。
本发明提供一种如通式(I)所示的化合物或其药学可接受的盐：
Figure PCTCN2021103543-appb-000001
其中：
R 1独立地选自氢、直链或支链烷基、环烷基、被至少一个卤素取代的烷基中的任意一种；
R 2、R 3各自独立地选自氢、直链或支链烷基、环烷基中的任意一种；
R 4独立地选自氢、直链或支链烷基、被至少一个卤素取代的烷基、环烷基中的任意一种；
R 5、R 6、R 7和R 8各自独立地为氢；
n1、n2、n3和n4各自独立地为0-3之间的任意一个整数；
X为O或CH 2中的任意一种。
本发明还提供一种如通式(I’)所示的化合物或其药学可接受的盐：
Figure PCTCN2021103543-appb-000002
其中：
R 1独立地选自氢、羟基、直链或支链烷基、环烷基、被至少一个卤素取代的烷基中的任意一种；
R 10为氢或
Figure PCTCN2021103543-appb-000003
R 2、R 3各自独立地选自氢、直链或支链烷基、环烷基中的任意一种；
R 4独立地选自氢、直链或支链烷基、被至少一个卤素取代的烷基、环烷基中的任意一种；
R 5、R 6各自独立地选自氢、卤素、氨基、羟基、直链或支链烷基和环烷基，其中所述的烷基、环烷基未被取代或被至少一个独立选自R X的取代基取代；
R 7和R 8各自独立地选自氢、卤素、氨基、羟基、直链或支链烷基和环烷基，其中所述的烷基、环烷基未被取代或被至少一个独立选自R X的取代基取代；
或R 7和R 8连同与它们相连的原子一起形成三元环或四元环；
R X独立选自卤素、氰基、羟基、氨基、C 1-6烷基和C 3-6环烷基；
n1、n2、n3和n4各自独立地为0-3之间的任意一个整数；
X为O、CH 2中的任意一种或不存在。
在本发明的一个实施例方案中，上述式(I’)结构中，R 1为环丙基，X为CH 2。
在本发明的一个实施例方案中，上述式(I’)结构中，R 2为甲基。
在本发明的一个实施例方案中，上述式(I’)结构中，R 3为甲基。
在本发明的一个实施例方案中，上述式(I’)结构中，R 4为甲基。
在本发明的一个实施例方案中，上述式(I’)结构中，R 5、R 6、R 7和R 8各自独立地为氢。
本发明的一个实施例方案中，上述式(I’)结构中，所述卤素选自氟、氯、溴或碘中的任意一种。
本发明的一个实施例方案中，上述式(I’)结构中直链或支链烷基选自C1-C5的直链或支链烷基；所述环烷基选自C3-C6的环烷基；所述被至少一个卤素取代的烷基选自被至少一个卤素取代的C1-C5的烷基。
本发明的一个实施例方案中，上述式(I’)结构中，所述C1-C5的直链或支链烷基为甲基、乙基、丙基、丁基、戊基中任意一种；所述C3-C6的环烷基为环丙基、环丁基、环戊基或环己基中任意一种；所述被至少一个卤素取代的C1-C5的烷基为三氟甲基或二氟甲基中任意一种。
本发明的一个实施例方案中，所述丙基包括但不限于正丙基(n-Pr、-CH 2CH 2CH 3)或异丙基((i-Pr、-CH(CH 3) 2)；所述丁基包括但不限于正丁基(n-Bu、-CH 2CH 2CH 2CH 3)、异丁基(i-Bu、-CH 2CH(CH 3) 2)、仲丁基(s-Bu、-CH(CH 3)CH 2CH 3)或叔丁基(t-Bu、-C(CH 3) 3)；所述戊基包括但不限于正戊基(-CH 2CH 2CH 2CH 2CH 3)、2-戊基(-CH(CH 3)CH 2CH 2CH 3)、3-戊基(-CH(CH 2CH 3) 2)、2-甲基-2-丁基(-C(CH 3) 2CH 2CH 3)、3-甲基-2-丁基(-CH(CH 3)CH(CH 3) 2)、3-甲基-1-丁基(-CH 2CH 2CH(CH 3) 2)或2-甲基-1-丁基(-CH 2CH(CH 3)CH 2CH 3)。
在本发明的另一个实施方案中，通式(I’)所示的化合物优选的具有如下式(i)所示的结构：
Figure PCTCN2021103543-appb-000004
其中R 9、R 10’、R 11分别独立的选自氢、C1-C5的直链或支链烷基、环烷基和C 1-6烷基-C 3-6环烷基，其中所述烷基、环烷基任选地被至少一个独立选自R X的取代基取代；其中所述的R X独立选自卤素、氰基、羟基、氨基、C 1-6烷基和C 3-6环烷基，优选卤素和C 3-6环烷基。
优选地，所述式(i)所示的结构，其中R 9、R 10’、R 11各自独立的选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、羟乙基、甲氧基乙基、环丙基甲基、环丁基甲基、环戊基甲基、环己基甲基、环丙基甲氧基乙基、3-三氟丙基、2-二氟乙基、三氟甲基和2-三氟乙基。
本发明的一个实施方案中，R 9独立选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、环丙基、环丙基甲基、环丁基甲基、环戊基甲基、环己基甲基、三氟甲基、3-三氟丙基、羟乙基、2-二氟乙基、三氟甲基和2-三氟乙基；更优选地，R 9独立选自乙基、正丙基、异丙基、正丁基、3-三氟丙基、羟乙基、环丙基甲基、环丁基甲基、环戊基甲基和环己基甲基。本发明的一个实施方案中，R 9为环丙基甲基。
本发明的一个实施方案中，R 10’独立选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、环丙基甲基、环丁基甲基、3-三氟丙基、和三氟甲基；更优选地，R 10’独立选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、环丙基甲基和环丁基甲基；
本发明的一个实施方案中，R 10’为异丙基。
本发明的一个实施方案中，R 11独立选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、环丙基、3-三氟丙基、2-二氟乙基、三氟甲基和环丙基甲基；更优选地，R 11独立选自氢、甲基、乙基、正丙基、异丙基、异丁基、环丙基、2-二氟乙基和环丙基甲基；进一步优选的，R 11独立选自氢、甲基、乙基、正丙基、异丙基、异丁基和环丙基甲基。
本发明的一个实施方案中，R 11为甲基。
在本发明的另一个实施方案中，通式(I’)所示的化合物优选的具有如下式(ii)所示的结构：
Figure PCTCN2021103543-appb-000005
其中R 9’、R 10’、R 11独立的选自氢、C1-C5的直链或支链烷基、C3-C6的环烷基和C 1-6烷基-C 3-6环烷基，其中所述烷基、环烷基任选地被至少一个独立选自R X的取代基取代；其中所述的R X独立选自卤素、氰基、羟基、氨基、C 1-6烷基和C 3-6环烷基，优选卤素和C 3-6环烷基。
优选地，所述式(ii)所示的结构，其中R 9’独立选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、环丙基、环丙基甲基、三氟甲基、3-三氟丙基、2-二氟乙基、三氟甲基和2-三氟乙基；更优选地，R 9’独立选自氢、甲基、三氟甲基、环丙基和环丙基甲基；进一步优选地，R 9’独立选自氢、甲基和环丙基甲基。
R 10’独立选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、环丙基甲基、环丁基甲基、3-三氟丙基、和三氟甲基；更优选地，R 10’独立选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、环丙基甲基和环丁基甲基。
R 11独立选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、环丙基、3-三氟丙基、2-二氟乙基、三氟甲基、和环丙基甲基；更优选地，R 11独立选自氢、甲基、乙基、正丙基、异丙基、异丁基、环丙基、2-二氟乙基和环丙基甲基；进一步优选地，R 11独立选自氢、甲基、乙基、正丙基、异丙基、异丁基和环丙基甲基。
n5为1～3的整数，例如为1、2或3。
具体的，本发明所述的化合物选自如下所示任意一个化合物：
表1通式(I)或通式(I’)所示化合物的示例化合物
Figure PCTCN2021103543-appb-000006
Figure PCTCN2021103543-appb-000007
Figure PCTCN2021103543-appb-000008
Figure PCTCN2021103543-appb-000009
本发明进一步提供通式(I)的制备方法，包括：
Figure PCTCN2021103543-appb-000010
方法一：中间体(III)与化合物Reagent-2经Buchwald–Hartwig偶联反应制备得到通式(I)；
或者
方法二：中间体(III)与化合物Reagent-3经Buchwald–Hartwig偶联反应制备得到中间体(IV)，中间体(IV)与化合物Reagent-4经取代反应制备得到通式(I)。
其中：
R 1独立地选自氢、直链或支链烷基、环烷基、被至少一个卤素取代的烷基中的任意一种；
R 2、R 3各自独立地选自氢、直链或支链烷基、环烷基中的任意一种；
R 4独立地选自氢、直链或支链烷基、被至少一个卤素取代的烷基、环烷基中的任意一种；
R 5、R 6、R 7和R 8各自独立地为氢；
n1、n2、n3和n4各自独立地为0-3之间的任意一个整数；
X为O或CH 2中的任意一种。
本发明进一步提供中间体(III)的制备方法，包括：
Figure PCTCN2021103543-appb-000011
将中间体(II)与化合物Reagent-1溶解在在有机溶剂中，以弱碱为催化剂，经取代反应制备得到中间体(III)。
其中：
R 1独立地选自氢、直链或支链烷基、环烷基、被至少一个卤素取代的烷基中的任意一种；
R 5、R 6、R 7和R 8各自独立地为氢；
n3和n4各自独立地为0-3之间的任意一个整数；
X为O或CH 2中的任意一种。
本发明进一步提供通式(I)的制备方法，包括：
Figure PCTCN2021103543-appb-000012
方法一：中间体(III)与化合物Reagent-2经Buchwald–Hartwig偶联反应制备得到通式(I)；
或者
方法二：中间体(III)与化合物Reagent-3经Buchwald–Hartwig偶联反应制备得到中间体(IV)，中间体(IV)与化合物Reagent-4经取代反应制备得到通式(I)。
其中：
R 1独立地选自氢、羟基、直链或支链烷基、环烷基、被至少一个卤素取代的烷基中的任意一种；
R 2、R 3各自独立地选自氢、直链或支链烷基、环烷基中的任意一种；
R 4独立地选自氢、直链或支链烷基、被至少一个卤素取代的烷基、环烷基中的任意一种；
R 5、R 6、各自独立地选自氢、卤素、氨基、羟基、直链或支链烷基和环烷基，其中所述的烷基、环烷基未被取代或被至少一个独立选自R X的取代基取代；
R 7和R 8各自独立地选自氢、卤素、氨基、羟基、直链或支链烷基和环烷基，其中所述的烷基、环烷基未被取代或被至少一个独立选自R X的取代基取代；
或R 7和R 8连同与它们相连的原子一起形成三元环或四元环；优选地，R 5、R 6、R 7和R 8各自独立地为氢；
R X独立选自卤素、氰基、羟基、氨基、C 1-6烷基和C 3-6环烷基；
n1、n2、n3和n4各自独立地为0-3之间的任意一个整数；
X为O、CH 2中的任意一种或不存在。
本发明进一步提供通式(I’)的制备方法，包括：
Figure PCTCN2021103543-appb-000013
方法一：中间体(III)与化合物Reagent-2经Buchwald–Hartwig偶联反应制备得到通式(I’)；
或者
方法二：中间体(III)与化合物Reagent-3经Buchwald–Hartwig偶联反应制备得到中间体(IV)，中间体(IV)与化合物Reagent-4经取代反应制备得到通式(I’)。
其中：
R 1独立地选自氢、羟基、直链或支链烷基、环烷基、被至少一个卤素取代的烷基中的任意一种；
R 10为氢或
Figure PCTCN2021103543-appb-000014
R 2、R 3各自独立地选自氢、直链或支链烷基、环烷基中的任意一种；
R 4独立地选自氢、直链或支链烷基、被至少一个卤素取代的烷基、环烷基中的任意一种；
R 5、R 6、各自独立地选自氢、卤素、氨基、羟基、直链或支链烷基和环烷基，其中所述的烷基、环烷基未被取代或被至少一个独立选自R X的取代基取代；
R 7和R 8各自独立地选自氢、卤素、氨基、羟基、直链或支链烷基和环烷基，其中所述的烷基、环烷基未被取代或被至少一个独立选自R X的取代基取代；
或R 7和R 8连同与它们相连的原子一起形成三元环或四元环；优选地，R 5、R 6、R 7和R 8各自独立地为氢；
R X独立选自卤素、氰基、羟基、氨基、C 1-6烷基和C 3-6环烷基；
n1、n2、n3和n4各自独立地为0-3之间的任意一个整数；
X为O、CH 2中的任意一种或不存在。
本发明进一步提供中间体(III)的制备方法，包括：
Figure PCTCN2021103543-appb-000015
将中间体(II)与化合物Reagent-1溶解在在有机溶剂中，以弱碱为催化剂，经取代反应制备得到中间体(III)。
其中：
R 1独立地选自氢、羟基、直链或支链烷基、环烷基、被至少一个卤素取代的烷基中的任意一种；
R 5、R 6各自独立地选自氢、卤素、氨基、羟基、C 1-6烷基和C 3-6环烷基，其中所述的烷基、环烷基未被取代或被至少一个独立选自R X的取代基取代；优选地，R 5和R 6各自独立地为氢；
R 7和R 8各自独立地选自氢，、卤素、氨基、羟基、C 1-6烷基和C 3-6环烷基，其中所述的烷基、环烷基未被取代或被至少一个独立选自R X的取代基取代；
或R 7和R 8连同与它们相连的原子一起形成三元环或四元环；优选地，R 7和R 8各自独立地为氢；
R X独立选自卤素、氰基、羟基、氨基、C 1-6烷基和C 3-6环烷基；
优选地，R 5、R 6、R 7和R 8各自独立地为氢；
n3和n4各自独立地为0-3之间的任意一个整数；X为O、CH 2中的任意一种或不存在。
本发明进一步提供一种药物组合物，包含治疗有效量的本发明的化合物或其可药用的盐和医学上可接受的载体。
本发明的一个实施例方案中，药物组合物可以利用一种或多种可药用的载体按照常规的方式加以配制。因此，本发明的活性化合物可以被配制成口服、口腔含化给药、鼻内、肠胃外(例如静脉内、肌内或皮下)或直肠给药的剂型，或者适用于通过吸入或吹入给药的剂型。本发明的化合物或其可药用的盐也可以被配制成持续释放的剂型。
本发明的一个实施例方案中，有效剂量的本发明的化合物或其可药用的盐可与如惰性稀释剂或某种载体一起口服。根据本发明的一些实施例，可将本发明的化合物包裹于明胶胶囊中或压制成片。为口服治疗的目的，本发明化合物可与赋形剂一起使用并以片剂、锭剂、胶囊、混悬剂、糖浆剂等形式使用。根据本发明的实施例，上述制剂应含有至少0.5％(w/w)的本发明的活性化合物，但可根据特定的剂型变化，其中占单位重量的4％至约70％是便利的。在这样的药物组合物中活性化合物的量应达到适当的剂量。
本发明的一个实施例方案中，关于口服给药，本发明的活性化合物例如可通过常规手段与可药用的赋形剂加以配制成片剂或胶囊，赋形剂例如粘合剂，填充剂，润滑剂，崩解剂或润湿剂。片剂可以通过本领域熟知的方法加以包衣。用于口服给药的液体制剂，如可以采用溶液、糖浆或悬液，或挥发为干燥产物，使用前用水或其他合适的载体再生。这类液体制剂可利用药用的添加剂通过常规手段加以制备，添加剂例如悬浮剂，乳化剂，非水性载体和防腐剂。
本发明的一个实施例方案中，当本发明的活性化合物用于胃肠外施用时，可将本发明提供的化合物与无菌水或有机介质组合形成可注射的溶液或悬液。
本发明的一个实施例方案中，本发明的活性化合物可以被配制成直肠组合物，例如栓剂或保留灌肠剂，例如含有常规的栓剂基质，例如可可脂或其他甘油酯。
本发明还提供本发明的化合物或其可药用的盐或其药物组合物在制备调控sigma受体的药物中的用途，其中所述药物任选包含另外一种或多种调节哺乳动物神经***或缓解精神疾病的活性剂。
本发明的一个实施例方案中，所述调控包括但不限于对受体的激动活性。
本发明的一个实施例方案中，本发明提供本发明的化合物或其药物组合物在制备治疗和/或预防sigma-1受体相关疾病或疾病状态中的药物的用途。在本发明的又一实施例方案中，本发明还提供一种治疗和/或预防sigma-1受体相关疾病或疾病状态的方法，其包括向有此需要的个体给药本发明的化合物及其药物组合物。在本发明的另一个实施例方案中，本发明的化合物或其药物组合物用于治疗和/或预防sigma-1受体相关疾病或疾病状态。进一步的，所述sigma-1受体相关疾病为抑郁、焦虑、阿尔茨海默等精神疾病，优选抑郁症。
术语解释
术语“任选”、“任选地”或“任选存在”是指随后描述的事件或情形可以但不一定出现，并且该描述包括其中所述事件或情形出现的情况和不出现的情况。例如，“任选存在的键”是指该键可以存在或可以不存在，并且该描述包括单键、双键或三键等。
术语“包含”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。应当理解，术语“包含”可以涵盖封闭式的含义，即“由…组成”。
像本发明所描述的，本发明的化合物可以任选地被一个或多个取代基所取代，如上面的通式化合物或者像实施例中特定的实例、子类。应了解术语“任选取代的”与术语“取代或未取代的”可以交换使用。一般而言，术语“取代的”表示所给结构中的一个或多个氢原子被特定取代基所取代。除非其他方面表明，任选取代的基团可以在该基团各个可取代的位置进行取代。当所给出的结构式中不只一个位置能被选自特定基团的一个或多个取代基所取代时，那么取代基可以相同或不同地在各个位置取代。
另外，需要说明的是，除非以其他方式明确指出，在本发明中所采用的描述方式“分别独立地为”应做广义理解，其既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。
在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C 1-C 6烷基”特别指独立公开的甲基、乙基、C 3烷基、C 4烷基、C 5烷基、C 6烷基。烷基基团的实例包括但不限于甲基(Me、-CH 3)、乙基(Et、-CH 2CH 3)、正丙基(n-Pr、-CH 2CH 2CH 3)、异丙基(i-Pr、-CH(CH 3) 2)、正丁基(n-Bu、-CH 2CH 2CH 2CH 3)、异丁基(i-Bu、-CH 2CH(CH 3) 2)、仲丁基(s-Bu、-CH(CH 3)CH 2CH 3)、叔丁基(t-Bu、-C(CH 3) 3)、正戊基(-CH 2CH 2CH 2CH 2CH 3)、2-戊基(-CH(CH 3)CH 2CH 2CH 3)、3-戊基(-CH(CH 2CH 3) 2)、2-甲基-2-丁基(-C(CH 3) 2CH 2CH 3)、3-甲基-2-丁基(-CH(CH 3)CH(CH 3) 2)、3-甲基-1-丁基(-CH 2CH 2CH(CH 3) 2)、2-甲基-1-丁基(-CH 2CH(CH 3)CH 2CH 3)等。
本文列举的范围(如数值范围)可以涵盖其范围中的每一个值以及由各个值形成的各个亚范围。因此，例如表述“n 2为0～3之间的任意一个整数”包括例如0～2的任意一个整数、2～3的任意一个整数等，例如1、2、3。
术语“氢(H)”表示单个氢原子。这样的原子团可以与其他基团连接，譬如与氧原子相连，形成羟基基团。
术语“卤素”是指氟(F)、氯(Cl)、溴(Br)或碘(I)。
术语“药学可接受的盐”是指本发明化合物的盐，可以由化合物的游离形式与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括硝酸、碳酸，碳酸氢根氢碘酸、亚磷酸、乙酸、丙酸、异丁酸、马来酸、丙二酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、柠檬酸、富马酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。
术语“药学可接受”是指与制剂中的其它组分相容，并且对使用者无不可接受的毒害。
除非另有规定，术语“烷基”用于表示直链或支链的饱和的碳氢基团，在一些实施方案中，所述烷基为C 1-12烷基；在另一些实施方案中，所述烷基为C 1-6烷基；在另一些实施方案中，所述烷基为C 1-3烷基。其可以是单取代(如-CH 2F)或多取代的(如-CF 3)，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。烷基的实例包括但不限于甲基(Me)，乙基(Et)，丙基(包括n-丙基和异丙基)，丁基(包括n-丁基，异丁基，s-丁基和t-丁基)，戊基(包括n-戊基，异戊基和新戊基)、己基等。
除非另有规定，术语“C 1-6烷基”用于表示直链或支链的由1至6个碳原子组成的饱和碳氢基团。所述C 1-6烷基包括C 1-5、C 1-4、C 1-3、C 1-2、C 2-6、C 2-4、C 6和C 5烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1-6烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)、丁基(包括n-丁基，异丁基，s-丁基和t-丁基)、戊基(包括n-戊基，异戊基和新戊基)、己基等。
除非另有规定，“环烷基”包括任何稳定的环状烷基，其包括单环、双环或者三环体系，其中双环和三环体系包括螺环、并环和桥环。在一些实施方案中，所述环烷基为C 3-8环烷基；在另一些实施方案中，所述环烷基为C 3-6环烷基；在另一些实施方案中，所述环烷基为C 5-6环烷基。其可以是单取代或多取代的，可以是一价、二价或者多价。这些环烷基的实例包括，但不限于，环丙基、环丁基、环戊基、环己基、环庚基、降冰片烷基、[2.2.2]二环辛烷、[4.4.0]二环癸烷等。
除非另有规定，“C 3-6环烷基”表示由3至6个碳原子组成的饱和环状碳氢基团，其为单环和双环体系，所述C 3-6环烷基包括C 3-5、C 4-5和C 5-6环烷基等；其可以是一价、二价或者多价。C 3- 6环烷基的实例包括，但不限于，环丙基、环丁基、环戊基、环己基等。
除非另有规定，“与相连的原子一起形成三元环或四元环”表示该原子作为三元环或四元环的一部分，与其他原子一起形成饱和的脂肪环。例如，在一些实施方案中，R 7和R 8均为-CH 2-， 并通过单键相连与四氢异喹啉4位碳一起形成环丙基；或R 7和R 8分别为-CH 2-和-CH 2-CH 2-，并通过单键相连与四氢异喹啉4位碳一起形成环丁基。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明的化合物可以有多种用途或适应症，包括但不限于本申请所列举的具体用途或适应症。
实施方案
1.一种如通式(I)所示的化合物或其药学可接受的盐：
Figure PCTCN2021103543-appb-000016
其中：
R 1独立地选自氢、直链或支链烷基、环烷基、被至少一个卤素取代的烷基中的任意一种；
R 2、R 3各自独立地选自氢、直链或支链烷基、环烷基中的任意一种；
R 4独立地选自氢、直链或支链烷基、被至少一个卤素取代的烷基、环烷基中的任意一种；
R 5、R 6、R 7和R 8各自独立地为氢；
n1、n2、n3和n4各自独立地为0-3之间的任意一个整数；
X为O或CH 2中的任意一种。
2.如第1项所述的通式(I)所示的化合物或其药学可接受的盐，其特征在于，所述卤素选自氟、氯、溴或碘中的任意一种。
3.如第1项所述的通式(I)所示的化合物或其药学可接受的盐，其特征在于，所述的直链或支链烷基选自C1-C5的直链或支链烷基；所述环烷基选自C3-C6的环烷基；所述被至少一个卤素取代的烷基选自被至少一个卤素取代的C1-C5的烷基。
4.如第3项所述的通式(I)所示的化合物或其药学可接受的盐，其特征在于，所述C1-C5的直链或支链烷基选自甲基、乙基、丙基、丁基、戊基中的至少一种；所述C3-C6的环烷基选自环丙基，环丁基，环戊基或环己基中的一种；所述被至少一个卤素取代的C1-C5的烷基选自三氟甲基、二氟甲基中的一种。
5.如第1-4任一项所述的通式(I)所示的化合物或其药学可接受的盐，其特征在于，选自如下任意一个化合物：
Figure PCTCN2021103543-appb-000017
Figure PCTCN2021103543-appb-000018
6.一种药物组合物，其特征在于包含第1-5任一项所述的化合物，任选地进一步包含药学上可接受的赋形剂、载体、佐剂、溶媒或它们的组合。
7.如第1-5中任一项所述的化合物或第6项所述的药物组合物在制备治疗神经精神类疾病药物中的应用。
8.如第7项所述的用途，其特征在于，所述神经精神类疾病选自抑郁、焦虑中的任意一种。
本发明有益的技术效果
本发明提供的5-((1,2,3,4-四氢异喹啉-7-基)氨基)吡啶-2(1H)-酮衍生物为sigma-1受体激动剂，对sigma-1受体具有药理活性以及受体选择性的化合物，以及这些化合物的制备方法、及其在中枢神经疾病治疗、预防之用途。
附图说明
图1.正常组与苯妥英组Ki值对比。
图2.度洛西汀组、溶媒组、化合物4组小鼠强迫游泳实验不动时间对比。
图3.化合物4各组小鼠4min内掉落潜伏期情况。
实施例
下面详细描述本发明的实施例。下面描述的实施例是示例性的，仅用于解释本发明，而不能理解为对本发明的限制。本领域的专业人员能够理解，在不背离本发明的精神和范围的前提下，可以对本发明进行各种变化和修饰。
实施例1:5-((2-(环丙基甲基)-1,2,3,4-四氢异喹啉-7-基)(甲基)氨基)-1-甲基吡啶-2(1H)-酮(1)的制备：
Figure PCTCN2021103543-appb-000019
1.1 7-溴-2-(环丙甲基)-1，2，3，4-四氢异喹啉的合成
将7-溴-1,2,3,4-四氢异喹啉(4.71g,22.2mmol)，溴甲基环丙烷(3.15g,23.13mmol)溶于150mL乙腈，磁力搅拌反应过夜，反应完毕，经硅胶柱层析纯化(PE/EA＝15/1)得7-溴-2-(环丙甲基)-1,2,3,4-四氢异喹啉5.8g(产率98.3％)。
1.2 5-((2-(环丙基甲基)-1,2,3,4-四氢异喹啉-7-基)(甲基)氨基)-1-甲基吡啶-2(1H)-酮的合成
将反应物7-溴-2-(环丙甲基)-1,2,3,4-四氢异喹啉(266mg，1.0mmol)，5-(甲氨基)-1-甲基吡啶-2(1H)-酮(152mg，1.1mmol)，2-二环己基膦-2',4',6'-三异丙基联苯(48mg，0.10mmol)，Pd 2(dba) 3(92mg，0.10mmol)，Cs 2CO 3(630mg，1.9mmol)和二甲苯(10ml)依次加入反应瓶中，氮气保护下于100℃反应16小时。反应结束后，应液冷却至室温，用硅藻土过滤，滤饼用EA(30ml x 2)和DCM(50ml x 2)洗涤，有机相合并，浓缩，柱层析分离(DCM/MeOH＝10:1)纯化得到油状物5-((2-(环丙基甲基)-1,2,3,4-四氢异喹啉-7-基)(甲基)氨基)-1-甲基吡啶-2(1H)-酮(159mg，收率：45.4％)。
1H NMR(400MHz,Methanol-d 4)δ7.79(d,J＝2.9Hz,1H),7.67(dd,J＝9.5,2.9Hz,1H),7.22(d,J＝8.4Hz,1H),6.97(dd,J＝8.4,2.5Hz,1H),6.91(d,J＝9.5Hz,1H),6.88(d,J＝2.5Hz,1H),4.62(d,J＝15.4Hz,1H),4.34(d,J＝15.5Hz,1H),3.88(q,J＝12.2,8.0Hz,1H),3.82(s,3H),3.41(td,J＝11.5,5.1Hz,1H),3.28(s,3H),3.26–3.07(m,4H),1.33–1.27(m,1H),0.85–0.79(m,2H),0.51(td,J＝4.7,2.3Hz,2H).MS(ESI)m/z 324.25([M+H] +).
实施例2:5-((2-(环丙基甲基)-1,2,3,4-四氢异喹啉-7-基)氨基)-1-甲基吡啶-2(1H)-酮
Figure PCTCN2021103543-appb-000020
将5-(甲氨基)-1-甲基吡啶-2(1H)-酮替换成5-氨基-1-甲基吡啶-2(1H)-酮，按实施例1方法制备得到目标化合物。
1H NMR(400MHz,Methanol-d 4)δ7.86(d,J＝9.6Hz,2H),7.19(d,J＝8.3Hz,1H),7.01(dd,J＝13.7,8.9Hz,2H),6.90(s,1H),4.63(d,J＝15.3Hz,1H),4.35(d,J＝15.5Hz,1H),3.86(s,4H),3.40(td,J＝11.7,5.1Hz,1H),3.23(dt,J＝14.8,7.8Hz,3H),3.14–3.04(m,1H),1.24(s,1H),0.82(d,J＝7.7Hz,2H),0.51(d,J＝4.6Hz,2H).MS(ESI)m/z 310.2([M+H] +).
实施例3:5-((2-(环丙基甲基)-1,2,3,4-四氢异喹啉-7-基)(乙基)氨基)-1-甲基吡啶-2(1H)-酮
Figure PCTCN2021103543-appb-000021
3.1 7-溴-2-(环丙甲基)-1,2,3,4-四氢异喹啉的合成
将7-溴-1,2,3,4-四氢异喹啉(4.71g,22.2mmol)，溴甲基环丙烷(3.15g,23.13mmol)溶于150mL乙腈，磁力搅拌反应过夜，反应完毕，经柱层析(PE/EA＝15/1)纯化得7-溴-2-(环丙甲基)-1,2,3,4-四氢异喹啉5.8g(产率98.3％)。
3.2 5-((2-(环丙基甲基)-1,2,3,4-四氢异喹啉-7-基)氨基)-1-甲基吡啶-2(1H)-酮的合成
将反应物7-溴-2-(环丙甲基)-1,2,3,4-四氢异喹啉(266mg，1.0mmol)，5-氨基-1-甲基吡啶-2(1H)-酮(136mg，1.1mmol)，2-二环己基膦-2',4',6'-三异丙基联苯(48mg，0.10mmol)，Pd 2(dba) 3(92mg，0.10mmol)，Cs 2CO 3(630mg，1.9mmol)和二甲苯(10ml)依次加入反应瓶中，氮气保护下于100℃反应16小时。反应结束后，应液冷却至室温，用硅藻土过滤，滤饼用EA(30ml x 2)和DCM(50ml x 2)洗涤，有机相合并浓缩，柱层析分离纯化(DCM/MeOH＝10:1)得到油状物5-((2-(环丙基甲基)-1,2,3,4-四氢异喹啉-7-基)氨基)-1-甲基吡啶-2(1H)-酮(145mg,收率：42.8％)。
3.3 5-((2-(环丙基甲基)-1,2,3,4-四氢异喹啉-7-基)(乙基)氨基)-1-甲基吡啶-2(1H)-酮(3)的合成
将5-((2-(环丙基甲基)-1,2,3,4-四氢异喹啉-7-基)氨基)-1-甲基吡啶-2(1H)-酮(145mg，0.47mmol)溶于DMF(10ml)中，0℃下分批加入NaH(60％,48mg,1.2mmol)，加入完毕后，缓慢升至室温，搅拌0.5小时后加入溴乙烷(85mg，0.78mmol)，室温搅拌2h。反应完毕后，加H 2O(50ml)淬灭，DCM(50mlx3)萃取，无水硫酸钠干燥、过滤、浓缩得粗品，经硅胶柱层析(DCM/PE/NH 3·H 2O＝16/1/0.1)纯化得到5-((2-(环丙基甲基)-1,2,3,4-四氢异喹啉-7-基)(乙基)氨基)-1-甲基吡啶-2(1H)-酮(84.0mg，收率：53％)。
1H NMR(400MHz,Methanol-d4)δ7.71(d,J＝2.8Hz,1H),7.54(d,J＝2.9Hz,0.5H),7.52(d,J＝2.9Hz,0.5H),7.17(d,J＝8.5Hz,1H),6.86(d,J＝10.9Hz,1H),6.79(d,J＝9.5Hz,1H),6.74(d,J＝2.3Hz,1H),4.59(d,J＝15.4Hz,1H),4.31(d,J＝15.4Hz,1H),3.86(d,J＝15.8Hz,1H),3.70(d,J＝12.7Hz,5H),3.44–3.34(m,1H),3.27–3.02(m,4H),1.21(t,J＝7.1Hz,4H),0.85–0.77(m,2H),0.53–0.47(m,2H).MS(ESI)m/z 338.3([M+H] +).
实施例4:5-((2-(环丙基甲基)-1,2,3,4-四氢异喹啉-7-基)(异丙基)氨基)-1-甲基吡啶-2(1H)-酮
将5-(甲氨基)-1-甲基吡啶-2(1H)-酮替换成5-(异丙基氨基)-1-甲基吡啶-2(1H)-酮，按实施例1方法制备得到目标化合物4。
Figure PCTCN2021103543-appb-000022
1H NMR(400MHz,Methanol-d4)δ7.65(d,J＝2.8Hz,1H),7.47(d,J＝2.8Hz,0.5H),7.44(d,J＝2.9Hz,0.5H),7.20(d,J＝8.5Hz,1H),6.85(d,J＝9.4Hz,2H),6.74(d,J＝2.1Hz,1H),4.60(d,J＝15.4Hz,1H),4.38–4.25(m,2H),3.86(d,J＝16.4Hz,1H),3.78(s,3H),3.42(d,J＝6.2Hz,1H),3.27–3.05(m,4H),1.24(s,1H),1.18(d,J＝6.5Hz,6H),0.81(d,J＝8.1Hz,2H),0.50(q,J＝4.8Hz,2H).MS(ESI)m/z 352.3([M+H] +).
实施例5:5-((2-(环丙基甲基)-1,2,3,4-四氢异喹啉-7-基)(丙基)氨基)-1-甲基吡啶-2(1H)-酮
将5-(甲氨基)-1-甲基吡啶-2(1H)-酮替换成5-(丙基氨基)-1-甲基吡啶-2(1H)-酮，按实施例1方法制备得到目标化合物5。
Figure PCTCN2021103543-appb-000023
1H NMR(400MHz,Methanol-d 4)δ7.80(d,J＝2.9Hz,1H),7.71(dd,J＝9.5,2.9Hz,1H),7.24(d,J＝8.4Hz,1H),7.00(dd,J＝8.8,2.4Hz,2H),6.92(d,J＝2.4Hz,1H),4.63(d,J＝15.5Hz,1H),4.35(d,J＝15.5Hz,1H),3.87(s,4H),3.69–3.60(m,2H),3.42(m,J＝11.6,5.1Hz,1H),3.22(m,J＝13.2,12.2,6.5Hz,3H),3.15–3.07(m,1H),1.67(q,J＝7.5Hz,2H),1.27–1.21(m,1H),0.97(t,J＝7.4Hz,3H),0.81(m,J＝10.3,3.2Hz,2H),0.51(q,J＝5.0Hz,2H).
参照实施例1或3的实验方法合成了以下实施例的化合物：
实施例6:5-((2-(环丙基甲基)-1,2,3,4-四氢异喹啉-7-基)(丁基)氨基)-1-甲基吡啶-2(1H)-酮
Figure PCTCN2021103543-appb-000024
1H NMR(400MHz,Methanol-d4)δ7.74(d,J＝2.9Hz,1H),7.66(dd,J＝9.5,3.0Hz,1H),7.19(d,J＝8.3Hz,1H),7.01–6.91(m,2H),6.87(d,J＝2.3Hz,1H),4.58(d,J＝15.4Hz,1H),4.31(d,J＝15.5Hz,1H),3.81(s,4H),3.68–3.56(m,2H),3.37(dt,J＝11.9,5.7Hz,1H),3.25–3.10(m,3H),3.10–3.00(m,1H),1.62–1.51(m,2H),1.41–1.28(m,2H),1.25–1.17(m,1H),0.89(t,J＝7.4Hz,3H),0.76(ddd,J＝7.8,5.6,3.7Hz,2H),0.51–0.41(m,2H).MS(ESI)m/z 366([M+H] +).
实施例7:5-((环丙基甲基)(2-环丙基甲基)-1,2,3,4-四氢异喹啉-7-基)氨基)-1-甲基吡啶-2(1H)-酮
Figure PCTCN2021103543-appb-000025
1H NMR(400MHz,DMSO-d 6)δ7.70(d,J＝2.9Hz,1H),7.27(dd,J＝9.6,3.0Hz,1H),7.02(d,J＝8.5Hz,1H),6.64(dd,J＝8.5,2.6Hz,1H),6.54(d,J＝2.6Hz,1H),6.46(d,J＝ 9.5Hz,1H),4.41(d,J＝3.1Hz,1H),4.23–4.16(m,1H),3.44(s,3H),3.37(d,J＝6.8Hz,2H),3.27–3.15(m,2H),3.07(m,3H),2.85(m,1H),1.22–1.16(m,1H),1.01(m,1H),0.70–0.63(m,2H),0.46–0.41(m,4H),0.13(dd,J＝4.9,1.6Hz,2H).MS(ESI)m/z 364([M+H] +).
实施例8:5-((环丁基甲基)(2-环丙基甲基)-1,2,3,4-四氢异喹啉-7-基)氨基)-1-甲基吡啶-2(1H)-酮
Figure PCTCN2021103543-appb-000026
1H NMR(400MHz,DMSO-d 6)δ7.64(d,J＝2.8Hz,1H),7.21(dd,J＝9.5,2.9Hz,1H),7.01(d,J＝8.6Hz,1H),6.60(dd,J＝8.4,2.6Hz,1H),6.50(d,J＝2.5Hz,1H),6.44(d,J＝9.5Hz,1H),4.47–4.39(m,1H),4.23–4.15(m,1H),3.65(m,4H),3.29–3.10(m,3H),3.06(m,2H),2.89–2.81(m,1H),2.56(m,1H),1.98–1.91(m,2H),1.78(m,2H),1.67(m,2H),1.21(m,2H),0.72–0.60(m,2H),0.43(m,2H).MS(ESI)m/z 378([M+H] +)。
实施例9:5-(异丙基(1,2,3,4-四氢异喹啉-7-基)氨基)-1-甲基吡啶-2(1H)-酮
Figure PCTCN2021103543-appb-000027
1H NMR(400MHz,Methanol-d4)δ7.66(d,J＝2.9Hz,1H),7.48(dd,J＝9.5,2.9Hz,1H),7.21(d,J＝8.3Hz,1H),6.93(d,J＝9.5Hz,1H),6.87(dd,J＝8.3,2.5Hz,1H),6.80(d,J＝2.3Hz,1H),4.31(s,2H),3.82(s,3H),3.48(t,J＝6.4Hz,2H),3.29(s,1H),3.08(t,J＝6.4Hz,2H),1.15(d,J＝6.5Hz,6H).MS(ESI)m/z 298([M+H] +).
实施例10:5-(异丙基(2-(甲基)-1,2,3,4-四氢异喹啉-7-基)氨基)-1-甲基吡啶-2(1H)-酮
Figure PCTCN2021103543-appb-000028
1H NMR(400MHz,Methanol-d4)δ7.67(d,J＝2.9Hz,1H),7.49(dd,J＝9.5,2.9Hz,1H),7.22(d,J＝8.4Hz,1H),6.93(d,J＝9.5Hz,1H),6.88(dd,J＝8.3,2.4Hz,1H),6.77(d,J＝2.4Hz,1H),4.54–4.45(m,1H),4.36–4.20(m,2H),3.82(s,3H),3.77–3.69(m,1H),3.40(td,J＝11.6,5.1Hz,1H),3.21(s,1H),3.04(s,1H),3.02(s,3H),1.15(d,J＝6.5Hz,6H).MS(ESI)m/z 312([M+H] +).
实施例11:5-((2-乙基-1,2,3,4-四氢异喹啉-7-基)(异丙基)氨基)-1-甲基吡啶-2(1H)-酮
Figure PCTCN2021103543-appb-000029
1H NMR(400MHz,Methanol-d4)δ7.68(d,J＝2.8Hz,1H),7.52(dd,J＝9.5,2.8Hz,1H),7.24(d,J＝8.3Hz,1H),6.97(d,J＝9.5Hz,1H),6.91(dd,J＝8.3,2.4Hz,1H),6.84(d,J＝2.4Hz,1H),4.54(d,J＝15.3Hz,1H),4.37–4.18(m,2H),3.85(s,3H),3.78(ddt,J＝11.6,4.8,2.0Hz,1H),3.43–3.30(m,3H),3.28–3.20(m,1H),3.09(dt,J＝17.5,3.3Hz,1H),1.43(t,J＝7.3Hz,3H),1.15(d,J＝6.6Hz,6H).
实施例12:5-((2-异丙基-1,2,3,4-四氢异喹啉-7-基)(异丙基)氨基)-1-甲基吡啶-2(1H)-酮
Figure PCTCN2021103543-appb-000030
1H NMR(400MHz,Methanol-d4)δ7.64(d,J＝2.9Hz,1H),7.43(dd,J＝9.5,2.9Hz,1H),7.18(d,J＝8.4Hz,1H),6.87–6.77(m,2H),6.72(d,J＝2.4Hz,1H),4.38(s,2H),4.30(p,J＝6.5Hz,1H),3.78–3.66(m,5H),3.41–3.33(m,1H),3.29–3.18(m,1H),3.09(ddd,J＝17.2,4.8,2.3Hz,1H),1.46(dd,J＝6.7,3.4Hz,6H),1.18(d,J＝6.5Hz,6H).MS(ESI)m/z340([M+H] +).
实施例13:5-((2-丙基-1,2,3,4-四氢异喹啉-7-基)(异丙基)氨基)-1-甲基吡啶-2(1H)-酮
Figure PCTCN2021103543-appb-000031
1H NMR(400MHz,Methanol-d4)δ7.66(d,J＝2.9Hz,1H),7.45(dd,J＝9.5,2.9Hz,1H),7.20(d,J＝8.5Hz,1H),6.93–6.80(m,2H),6.71(d,J＝2.4Hz,1H),4.54(d,J＝15.4Hz,1H),4.39–4.23(m,2H),3.77(s,4H),3.39(td,J＝11.6,5.2Hz,1H),3.29–3.16(m,3H),3.09(dt,J＝17.4,4.4Hz,1H),1.95–1.83(m,2H),1.19(d,J＝6.5Hz,6H),1.08(t,J＝7.4Hz,3H).MS(ESI)m/z 340([M+H] +).
实施例14:5-((2-(环丁基甲基)-1,2,3,4-四氢异喹啉-7-基)(异丙基)氨基)-1-甲基吡啶-2(1H)-酮
Figure PCTCN2021103543-appb-000032
1H NMR(400MHz,Methanol-d4)δ7.64(d,J＝2.8Hz,1H),7.42(dd,J＝9.5,2.8Hz,1H),7.17(d,J＝8.4Hz,1H),6.81(dd,J＝8.9,4.9Hz,2H),6.67(d,J＝2.4Hz,1H),4.43(d,J＝15.3Hz,1H),4.35–4.28(m,1H),4.25(d,J＝15.4Hz,1H),3.74(s,3H),3.32(d,J＝1.7Hz,3H),3.27–3.13(m,1H),3.08(s,1H),2.91(s,1H),2.26(dd,J＝7.5,2.8Hz,2H),2.07(d,J＝11.8Hz,1H),2.03–1.88(m,4H),1.19(d,J＝6.5Hz,6H).MS(ESI)m/z 366([M+H] +).
实施例15:5-(异丙基(2-(3,3,3-三氟丙基)-1,2,3,4-四氢异喹啉-7-基)氨基)-1-甲基吡啶-2(1H)-酮
Figure PCTCN2021103543-appb-000033
1H NMR(400MHz,Methanol-d4)δ7.67(d,J＝2.9Hz,1H),7.48(dd,J＝9.5,2.8Hz,1H),7.22(d,J＝8.4Hz,1H),6.93–6.83(m,2H),6.75(d,J＝2.4Hz,1H),4.58(s,1H),4.46–4.19(m,2H),3.80(s,4H),3.69–3.54(m,2H),3.47(t,J＝1.7Hz,1H),3.29–3.02(m,2H),2.99–2.86(m,2H),1.17(d,J＝6.5Hz,6H).MS(ESI)m/z 394([M+H] +).
实施例16:5-((2-(2-羟乙基)-1,2,3,4-四氢异喹啉-7-基)(异丙基)氨基)-1-甲基吡啶-2(1H)-酮
Figure PCTCN2021103543-appb-000034
1H NMR(400MHz,Methanol-d4)δ7.60(d,J＝2.8Hz,1H),7.42(dd,J＝9.5,2.9Hz,1H),7.15(d,J＝8.4Hz,1H),6.91–6.77(m,2H),6.71(d,J＝2.4Hz,1H),4.50(d,J＝15.5Hz,1H),4.30(d,J＝15.5Hz,1H),4.20(p,J＝6.5Hz,1H),3.89(t,J＝5.1Hz,2H),3.74(s,3H),3.44–3.28(m,3H),3.25–3.10(m,2H),3.02(dt,J＝17.6,4.7Hz,1H),1.08(d,J＝6.5Hz,6H).MS(ESI)m/z 342([M+H] +).
实施例17:5-((2-(2-甲氧基乙基)-1,2,3,4-四氢异喹啉-7-基)(异丙基)氨基)-1-甲基吡啶-2(1H)-酮
Figure PCTCN2021103543-appb-000035
1H NMR(400MHz,Methanol-d4)δ7.69(d,J＝2.9Hz,1H),7.52(dd,J＝9.5,2.9Hz,1H),7.25(d,J＝8.4Hz,1H),6.98(d,J＝9.5Hz,1H),6.92(dd,J＝8.3,2.4Hz,1H),6.83(d,J＝2.3Hz,1H),4.56(d,J＝15.5Hz,1H),4.38(d,J＝15.5Hz,1H),4.34–4.22(m,1H),3.89–3.79(m,6H),3.50(q,J＝4.4Hz,2H),3.43(s,4H),3.28–3.19(m,1H),3.17–3.06(m,1H),1.17(d,J＝6.5Hz,6H).MS(ESI)m/z 356([M+H] +).
实施例19:5-((2-(2-环丙基甲氧基乙基)-1,2,3,4-四氢异喹啉-7-基)(异丙基)氨基)-1-甲基吡啶-2(1H)-酮
Figure PCTCN2021103543-appb-000036
1H NMR(400MHz,Methanol-d4)δ7.68(d,J＝2.8Hz,1H),7.49(dd,J＝9.5,2.9Hz,1H),7.23(d,J＝8.4Hz,1H),6.97–6.84(m,2H),6.77(d,J＝2.3Hz,1H),4.57(d,J＝15.5Hz,1H),4.40(d,J＝15.5Hz,1H),4.29(p,J＝6.5Hz,1H),3.91(t,J＝5.1Hz,2H),3.89–3.83(m,1H),3.81(s,3H),3.52(m,3H),3.41(dd,J＝7.0,2.2Hz,2H),3.24(m,1H),3.11(m,1H),1.18(d,J＝6.5Hz,6H),1.14–1.06(m,1H),0.59–0.50(m,2H),0.29–0.21(m,2H)..MS(ESI)m/z 396([M+H] +).
实施例21:5-((2-(环丙基甲基)-1,2,3,4-四氢异喹啉-7-基)(异丙基)氨基)-1-乙基吡啶-2(1H)-酮
Figure PCTCN2021103543-appb-000037
1H NMR(400MHz,Methanol-d 4)δ7.63(s,1H),7.35(d,J＝9.3Hz,1H),7.13(d,J＝8.5Hz,1H),6.81–6.63(m,2H),6.59(s,1H),4.60(d,J＝14.4Hz,1H),4.46–4.29(m,2H),4.22–4.09(m,2H),3.89(d,J＝11.7Hz,1H),3.23(q,J＝9.0,7.9Hz,3H),3.08(d,J＝17.1Hz,1H),1.72–1.58(m,1H),1.35(d,J＝7.7Hz,9H),0.96(d,J＝6.4Hz,1H),0.86(d,J＝7.2Hz,2H),0.55(d,J＝4.3Hz,2H)..MS(ESI)m/z366([M+H] +).
实施例22:5-((2-(环丙基甲基)-1,2,3,4-四氢异喹啉-7-基)(异丙基)氨基)-1-丙基吡啶-2(1H)-酮
Figure PCTCN2021103543-appb-000038
1H NMR(400MHz,Chloroform-d)δ7.26–7.14(m,2H),7.05(dd,J＝21.5,8.7Hz,2H),6.65(d,J＝8.2Hz,1H),6.56–6.48(m,1H),4.51(d,J＝13.9Hz,1H),4.13(m,2H),3.99(m,2H),3.70(m,1H),3.38(m,2H),3.07(d,J＝43.9Hz,2H),2.89(d,J＝16.2Hz,1H),1.76(q,J＝7.3Hz,2H),1.33–1.25(m,1H),1.08(d,J＝6.1Hz,6H),0.89(t,J＝7.1Hz,3H),0.71(d,J＝7.9Hz,2H),0.44(s,2H).MS(ESI)m/z 380([M+H] +).
实施例23:5-((2-(环丙基甲基)-1,2,3,4-四氢异喹啉-7-基)(异丙基)氨基)-1-异丙基吡啶-2(1H)-酮
Figure PCTCN2021103543-appb-000039
1H NMR(400MHz,Methanol-d4)δ7.54(d,J＝2.8Hz,1H),7.47(dd,J＝9.5,2.8Hz,1H),7.21(d,J＝8.4Hz,1H),6.94(d,J＝9.4Hz,1H),6.90–6.75(m,2H),5.21(p,J＝6.8Hz,1H),4.60(d,J＝15.4Hz,1H),4.52–4.20(m,2H),3.96–3.71(m,1H),3.39(td,J＝11.7,5.0Hz,1H),3.33–3.25(m,1H),3.22–3.11(m,2H),3.11–3.01(m,1H),1.46(d,J＝6.8Hz,6H),1.23(ddd,J＝7.9,6.2,3.7Hz,1H),1.13(d,J＝6.5Hz,6H),0.76(ddd,J＝7.8,5.6,3.7Hz,2H),0.47(dd,J＝5.6,4.0Hz,2H).MS(ESI)m/z 380([M+H] +).
实施例25:1-(环丙基甲基)-5-((2-(环丙基甲基)-1,2,3,4-四氢异喹啉-7-基)(异丙基)氨基)吡啶-2(1H)-酮
Figure PCTCN2021103543-appb-000040
1H NMR(400MHz,Chloroform-d)δ7.55(d,J＝8.9Hz,1H),7.39(d,J＝9.3Hz,1H),7.31(s,1H),7.16(d,J＝8.2Hz,1H),6.83(d,J＝8.1Hz,1H),6.64(s,1H),4.62(d,J＝13.3Hz,1H),4.25–4.14(m,2H),4.03(s,2H),3.79(s,1H),3.63–3.52(m,1H),3.24(d,J＝52.8Hz,2H),3.10–2.92(m,2H),1.18(m,6H),0.85(m,4H),0.67(m,2H),0.58–0.40(m,4H).MS(ESI)m/z 392([M+H] +).
实施例26:5-((2-(环丙基甲基)-1,2,3,4-四氢异喹啉-7-基)(异丙基)氨基)-1-异丁基吡啶-2(1H)-酮
Figure PCTCN2021103543-appb-000041
1H NMR(400MHz,Methanol-d4)δ7.59(d,J＝2.8Hz,1H),7.44(dd,J＝9.5,2.9Hz,1H),7.19(d,J＝8.5Hz,1H),6.90–6.79(m,2H),6.71(d,J＝2.4Hz,1H),4.60(d,J＝15.4Hz,1H),4.32(dd,J＝13.5,6.8Hz,2H),3.99(d,J＝7.5Hz,2H),3.94–3.80(m,1H),3.41(td,J＝11.7,5.3Hz,1H),3.21(qd,J＝7.5,6.6,2.9Hz,2H),3.14–3.03(m,1H),2.23(dt,J＝13.8,7.0Hz,1H),1.30-1.20(m,1H),1.18(d,J＝6.5Hz,6H),0.98(d,J＝6.8Hz,6H),0.90(ddt,J＝10.2,5.1,2.7Hz,2H),0.85–0.78(m,2H),0.56–0.45(m,2H)..MS(ESI)m/z 394([M+H] +).
实施例27:5-((2-(环丙基甲基)-1,2,3,4-四氢异喹啉-7-基)(甲基)氨基)-1-异丁基吡啶-2(1H)-酮
Figure PCTCN2021103543-appb-000042
1H NMR(400MHz,Methanol-d4)δ7.82–7.68(m,2H),7.24(d,J＝8.3Hz,1H),7.06–6.95(m,2H),4.63(d,J＝15.4Hz,1H),4.36(d,J＝15.5Hz,1H),4.08(d,J＝7.5Hz,2H),3.94–3.82(m,1H),3.42(td,J＝11.6,5.1Hz,1H),3.29(s,3H),3.28–3.16(m,3H),3.16–3.07(m,1H),2.26(m,1H)， 1.30–1.21(m,1H),1.00(d,J＝6.7Hz,6H),0.93–0.86(m,1H),0.80-0.83(m,2H),0.51(dt,J＝5.8,4.5Hz,2H)..MS(ESI)m/z 366([M+H] +).
实施例29:5-((2-(3,3,3-三氟丙基)-1,2,3,4-四氢异喹啉-7-基)(异丙基)氨基)-1-乙基吡啶-2(1H)-酮
Figure PCTCN2021103543-appb-000043
1H NMR(400MHz,Methanol-d4)δ7.69(d,J＝2.9Hz,1H),7.47(dd,J＝9.5,2.9Hz,1H),7.24(d,J＝8.5Hz,1H),6.99–6.85(m,2H),6.79(d,J＝2.3Hz,1H),4.74–4.18(m,5H),3.86(s,1H),3.67–3.36(m,3H),3.29(s,1H),3.21–2.84(m,3H),1.42(t,J＝7.2Hz,3H),1.17(d,J＝6.5Hz,6H).
实施例30:5-(异丁基(2-环丙基甲基)-1,2,3,4-四氢异喹啉-7-基)氨基)-1-甲基吡啶-2(1H)-酮
Figure PCTCN2021103543-appb-000044
1H NMR(400MHz,Methanol-d4)δ7.61(d,J＝2.8Hz,1H),7.46(dd,J＝9.5,2.9Hz,1H),7.17(d,J＝8.4Hz,1H),6.90–6.77(m,2H),6.73(d,J＝2.6Hz,1H),4.57(dt,J＝15.6,2.0Hz,1H),4.29(d,J＝15.4Hz,1H),3.97(q,J＝6.8Hz,1H),3.91–3.77(m,1H),3.75(s,3H),3.36(dt,J＝11.8,5.7Hz,1H),3.25–3.09(m,3H),3.09–2.99(m,1H),1.70–1.54(m,1H),1.37–1.18(m,2H),1.13(d,J＝6.6Hz,3H),0.96(t,J＝7.4Hz,3H),0.82–0.69(m,2H),0.46(q,J＝4.9Hz,2H).MS(ESI)m/z366([M+H] +).
实施例31 5-((2-丁基-1,2,3,4-四氢异喹啉-7-基)(异丙基)氨基)-1-甲基吡啶-2(1H)-酮
Figure PCTCN2021103543-appb-000045
1H NMR(400MHz,Methanol-d4)δ7.63(d,J＝2.8Hz,1H),7.41(dd,J＝9.5,2.8Hz,1H),7.16(d,J＝8.5Hz,1H),6.98–6.71(m,2H),6.65(d,J＝2.4Hz,1H),4.52(d,J＝15.4Hz,1H),4.40–4.20(m,2H),3.80(d,J＝12.0Hz,1H),3.72(s,3H),3.37(q,J＝6.4Hz,1H),3.31–3.14(m,3H),3.12–3.01(m,1H),1.84(p,J＝7.9Hz,2H),1.48(h,J＝7.4Hz,2H),1.19(d,J＝6.5Hz,6H),1.04(t,J＝7.4Hz,3H).MS(ESI)m/z 354([M+H] +).
实施例32:5-((2-(环戊基甲基)-1,2,3,4-四氢异喹啉-7-基)(异丙基)氨基)-1-甲基吡啶-2(1H)-酮
Figure PCTCN2021103543-appb-000046
1H NMR(400MHz,Methanol-d4)δ7.65(d,J＝2.9Hz,1H),7.45(dd,J＝9.5,2.9Hz,1H),7.20(d,J＝8.4Hz,1H),6.85(dd,J＝8.9,2.5Hz,2H),6.73(d,J＝2.3Hz,1H),4.55(d,J＝15.4Hz,1H),4.42–4.16(m,2H),3.77(s,4H),3.40(ddd,J＝12.3,10.5,5.3Hz,1H),3.30–3.18(m,3H),3.08(dt,J＝17.5,4.5Hz,1H),2.52–2.31(m,1H),1.98(s,1H),1.79–1.61(m,4H),1.34(ddd,J＝13.1,9.7,6.2Hz,3H),1.17(d,J＝6.4Hz,6H)..MS(ESI)m/z 380([M+H] +).
实施例33:5-((2-(环己基甲基)-1,2,3,4-四氢异喹啉-7-基)(异丙基)氨基)-1-甲基吡啶-2(1H)-酮
Figure PCTCN2021103543-appb-000047
1H NMR(400MHz,Methanol-d4)δ7.58(d,J＝2.8Hz,1H),7.39(dd,J＝9.5,2.9Hz,1H),7.13(d,J＝8.4Hz,1H),6.84–6.75(m,2H),6.68(d,J＝2.4Hz,1H),4.55(d,J＝15.4Hz,1H),4.42–4.16(m,2H),3.83-3.79(m,1H),3.77(s,3H),3.41-3.36(m,1H),3.30–3.18(m,3H),3.08(dt,J＝17.5,4.5Hz,1H),2.52–2.31(m,1H),1.98-1.87(m,1H),1.79–1.61(m,4H),1.37-1.30(m,3H),1.17(d,J＝6.4Hz,6H).MS(ESI)m/z 394([M+H] +).
实施例34:5-((2-(环丙基甲基)-1,2,3,4-四氢异喹啉-7-基)(异丙基)氨基)吡啶-2(1H)-酮
Figure PCTCN2021103543-appb-000048
1H NMR(400MHz,Methanol-d4)δ7.61(dd,J＝9.6,3.0Hz,1H),7.42(d,J＝3.0Hz,1H),7.27(d,J＝8.3Hz,1H),7.00–6.89(m,2H),6.84(d,J＝2.3Hz,1H),4.64(d,J＝15.4Hz,1H),4.43–4.24(m,2H),3.95–3.82(m,1H),3.43(td,J＝11.6,5.1Hz,1H),3.30–3.17(m,3H),3.18–3.07(m,1H),1.25(d,J＝20.3Hz,1H),1.18(d,J＝6.5Hz,6H),0.82(ddd,J＝7.9,5.6,4.0Hz,2H),0.56–0.47(m,2H).MS(ESI)m/z 338([M+H] +).
药理测试例
除非另外指明，否则本发明测试例中所使用的细胞系和相关试剂均可以源自商售。
测试例1:体外sigma-1受体结合实验
测试了本发明某些有代表性的化合物对sigma-1(σ-1)结合位点的体外亲和力，具体试验方案如下：
受试化合物配制：试供品全部使用终浓度为1％DMSO溶解，如溶解不好或混悬不均匀，适当加入HCl(10％，10μL)，起始浓度为1.0×10 -5M(即10μM)，然后依次为1μM、333nM、100nM、33nM、10nM、3.3nM、1nM、0.33nM、0.1nM、0.01nM，备用。
sigma-1受体结合活性测试：
受体膜制备：使用含320mM蔗糖pH＝7.4的10mM Tris-HCl缓冲液将豚鼠全脑匀浆，调整重量，1000g离心10min，取上层液加入含蔗糖pH＝7.4的10mM Tris-HCl缓冲液匀浆，然后1000g、4℃离心10min，取上清液，50000g、4℃再离心25min，取沉淀加入不含蔗糖pH＝7.4的10mM Tris-HC缓冲液匀浆，50000g、4℃离心25min、取沉淀重复上一操作，最后将沉淀于-80℃储存备用。
结合试验：将制备好的受体膜用不含蔗糖pH＝7.4的10mM Tris-HCl缓冲液制成220mg/ml膜的混悬液，备用。各反应管分别加入膜制备物100μL。总结合管总结合管(TB)加入100μL不含蔗糖pH＝7.4的10mM Tris-HC缓冲液，非特异性结合管(NB)加入氟哌啶醇100μL(终浓度1.0×10 -5M)，各受试化合物管(CB)加入100μL受试化合物。所有反应管分别加入放射性配体4nM[ 3H]-Pentazocine 10μL。将各反应管25℃温孵135min，反应完毕后，结合的配基通过减压快 速过滤，Whatman GF/C试纸提前用0.5％PEI浸泡1h以上，用冰冷的试验缓冲液充分洗涤，将滤片取出放到4mL闪烁杯中，加入1mL的甲苯闪烁液并混匀，最后，将闪烁瓶放入HIDEX液闪计数仪计数。
实验结果如下表2所示：
表2：部分化合物对sigma-1受体的Ki值
化合物编号 Sigma-1(Ki值,nM)
1 13
2 59.7
3 36.64
4 2.04
5 33.34
6 14.98
7 11.41
8 9.23
9 1804.44
10 1005.17
11 104.3
12 39.38
13 7.86
14 0.83
15 84.62
16 >1000
17 70.14
19 19.66
21 45.57
22 3.11
23 6.05
25 1.97
26 2.4
27 4.3
29 9.52
30 41.44
31 3.71
32 14.49
33 12.77
34 14.2
测试例2：sigma-1激动剂功能测试
根据文献报道([J].Synapse,2005,55(3):192-195.)，苯妥英可以改变sigma-1受体的构型，在苯妥英的存在下，激动剂的Ki值和正常Ki值相比变小，抑制剂的Ki值和正常Ki值相比变大。
参考文献([J].Synapse,2005,55(3):192-195.)中的具体操作，以化合物4为例，检测本发明化合物的Ki值，苯妥英组Ki值检测方法为在受试物管中额外加入苯妥英，检测加入苯妥英后的Ki值。正常Ki值/苯妥英组Ki值>1，即可判定为激动剂。
图1及表3实验结果标明，化合物4比值(正常Ki/苯妥英组Ki)>1，为激动剂。
表3.正常组与苯妥英组Ki值及比值
  Ki值(nM)
Sigma-1(正常Ki) 49.62
Sigma-1(苯妥英组Ki) 47.88
比值 1.04
本发明提供的其他化合物进行受体激动功能测试，得出比值＞1的类似的结果。
测试例3：受体选择性筛选实验
本发明还对实施例化合物进行了靶点选择性筛选实验。以化合物4为例，根据受体靶点的不同类型，分别采用酶学检测方法、FLIPR试验、核受体结合试验、膜受体结合试验和离子通道检测方法进行了相应的试验。
(1)酶学检测方法
靶点LCK：准备50mL的1X缓冲液：50mM HEPES(pH 7.5)，1mM EDTA，0.01％Brij TM-35和10mM MgCl 2，4℃保存备用。使用Echo转移100nL/孔的化合物到测试板中，添加5μL40nM的酶与0％磷酸化Tyr2(4μM)的混合物到化合物孔以及DMSO溶媒孔中，无酶对照组中添加100％抑制剂。添加5μL 100％磷酸化Tyr2(4μM)作为完全磷酸化对照组。1000rpm离心30s。每孔添加5μL 180μM的ATP混合物，1000rpm离心30s，23℃孵育60min。每孔添加5μL的Development混合物(使用缓冲液128倍稀释)，23℃孵育60min，然后在Envision上读取445/520两个波长的数据，计算比例。
靶点MAO-A：使用Echo转移100nL/孔的化合物到测试板中，添加5μL 2X的16μM的MAO底物混合物到测试板中，1000rpm离心30s，添加5μL 2X的0.25μM的MAO底物混合物到测试板中，1000rpm离心30s，使用封膜封住测试板，23℃孵育90min。添加10μL检测液到测试孔中，1000rpm离心30s，使用封膜封住测试板，23℃孵育60min，Envision上读板。
靶点PDE3A、PDE4D2：使用Echo转移化合物到测试板中，4倍梯度稀释，10个浓度梯度。1X反应液配置：40mM Tris-HCL(PH 7.5)，10mM MgCl 2，0.1mg/mL BSA。添加5μL的稀释好的酶至384孔板中(400pM PDE3A以及400pM PDE4D2)，1000rpm离心1min，室温孵育20min。每孔添加5uL的稀释好的1000nM的cAMP，室温孵育60min。每孔添加5μL的AMP-Glo TM试剂1，1000rpm离心1min，23℃孵育60min。每孔添加10μL AMP检测溶液，1000rpm离心1min，23℃孵育60min。在Envision上读板。
靶点ACHE：稀释1M Tris-HCl到50mM，pH＝8.0，用于准备200mM碘代硫代乙酰胆碱溶液，配置50mM NaH 2PO 4-Na 2HPO 4溶液用于准备10mM的DTNB溶液。配置含有0.1％BSA的50mM Tris-HCl缓冲液。将酶储存液用Tris缓冲液稀释至4.4nM，在96孔板中添加50uL稀释后的酶溶液。添加2μL的对照品或者待测化合物，对照品最大终浓度为100μM，作为下限对照，2％的DMSO作为上限对照。将酶与化合物在摇床上室温孵育5min。将100mM碘代 硫代乙酰胆碱与10mM DTNB混合，然后吸取48μL加入到孔板中。底物的终浓度为400μM，DTNB为0.5mM。1000rpm离心，37℃孵育1h。在SpectraMax上读板。
靶点COX-1、COX-2：对照品使用10％的DMSO进行3倍或4倍稀释，DMSO终浓度为0.5％。稀释待测化合物至4mM。使用Echo转移500nL的待测化合物至测试板中，终浓度为10μM，添加100μL的40nM 2X COX-1以及250X Heme混合物；添加100uL的80nM 2X COX-2以及250X Heme混合物。室温孵育10min，然后每孔添加50μL的100μM 4X ADHP以及50μL的10μM的4X ARA，1000rpm离心30s。在ElexStation上读板，激发光为530nM，吸收光为590nM。
(2)FLIPR试验测试
测试靶点为ETA，具体方法：使用Eta/HEK293细胞系(由上海药明康德新药开发有限公司提供)，37℃水浴快速解冻细胞并将细胞悬液转移到50mL锥形管中，加入培养液至45ml的刻度处，室温离心后轻轻吸出上清，注意不要吸出细胞，用45mL培养基中重新悬浮细胞，用无菌移液管上下吹打使细胞悬浮；用ViCell计数细胞浓度。每孔加入20μL细胞悬液到384孔板(每孔20K细胞)，将细胞板放在37℃5％CO 2培养箱中孵育过夜。FLIPR检测，首先制备250mM丙磺霉素(使用FLIPR缓冲液制备)，77mg丙黄霉素加1mLFLIPR缓冲液溶解；2X(8μM)Fluo-4 DirectTM上样缓冲液(10ml)，解冻一管Fluo-4 DirectTM(F10471)，加入10mL的FLIPR缓冲液，每10mL的Fluo-Direct添加0.2mL的丙黄霉素至终浓度为2.5mM，涡旋至少5分钟；化合物制备：激动剂DRC板：使用Echo仪器用100％DMSO按照1：3的比例依次稀释激动剂10个点，然后将900nL的化合物转移到激动剂DRC平板上。化合物板：使用Echo仪器用100％DMSO按照1：3的比例依次稀释对照化合物8个点，然后将900nL的化合物转移到目标板。将待测化合物稀释至2mM，然后用ECHO转移900nL，终浓度从10μΜ开始。化合物板和DRC板各孔加入30μL的FLIPR缓冲液，1000rpm离心1min。从培养箱中取出细胞板，使用移液管将20μl的2X Fluo-4 DirectTM免洗上样缓冲液轻轻滴到384孔细胞培养板上，使终体积40μl每孔；37℃ 5％CO 2孵育50分钟，室温孵育10min。从培养箱中取出细胞板，放入FLIPR中读板并进行数据处理。
(3)核受体结合试验
AR与GR属于核受体，具体测试方法：用缓冲液将细胞溶质与放射性配体稀释到特定浓度，将1μL的化合转移到测试板中。其中对照品进行4倍梯度稀释，总共8个浓度点，待测化合物的终浓度为10μM，两个复孔。将1uL的非特异性结合化合物根据测试图谱(规定好非特异性结合、总结和、对照品、待测化合物的位置图谱)加入到测试孔中，将1μL的DMSO加入到总结合管中。根据测试图谱，加入100μL的细胞溶质储存液。加入100μL放射性配体后盖好，使用振荡器振荡测试板，反应一段时间，不同靶点的反应时间以及温度不一样。结合完成后，加入100μL方式下配体吸收缓冲液然后振荡15min 4℃。转移100μL的上清液到闪烁管内，添加2mL Ultima Gold混合物，然后使用TriCap进行闪烁计数，然后分析结果。
(4)膜受体结合试验
其余靶点如5HT2B、5HT3、5HTT、DAT、op-kappa、op-mu、D1、5HT1A、H1、5HT2A、M1、M2、M3、D2、GABAA等采用膜受体结合试验检测，具体方法为：用缓冲液将受体膜与放射性配体稀释到特定浓度，将1μL的化合转移到测试板中。其中对照品进行4倍梯度稀释， 总共8个浓度点，待测化合物的终浓度为10μM，两个复孔。将1μL的非特异性结合化合物根据测试图谱(规定好非特异性结合、总结和、对照品、待测化合物的位置图谱)加入到测试孔中，将1μL的DMSO加入到总结合管中。根据测试图谱，加入一定体积的受体膜储存液。加入一定体积的放射性配体后盖好，使用振荡器振荡测试板，反应一段时间，不同靶点的反应时间以及温度不一样。将混合物加入到
Figure PCTCN2021103543-appb-000049
96GF/C过滤板中，并每孔加入50μL of 0.3％PEI，放置室温反应至少0.5h。结合完成后转移到GF/C板中并使用Perkin Elmer Filtermate收集器过滤反应复合物，然后每孔使用冰冷的洗涤缓冲液清洗4次，然后50℃干燥1h。干燥完成后，使用专用的Perkin Elmer底部封膜封住过滤板底部，加入50μL的Perkin Elmer Microscint 20混合物，使用Perkin Elmer顶部封膜封住顶部。使用Perkin Elmer MicroBeta2 Reader读取 3H信号，分析结果。
具体试验结果如下表4所示：
表4部分受体靶点选择性筛选结果
Figure PCTCN2021103543-appb-000050
Figure PCTCN2021103543-appb-000051
(5)离子通道检测方法
hNav1.5手动膜片钳：使用HEK-293 hNav1.5稳转细胞系(由上海药明康德新药开发有限公司提供)记录；细胞内液：(mM)：CsF 140，NaCl 10，EGTA 1，CsOH 5，HEPES 10，pH＝7.3，～285mOsm；细胞外液：(mM)：CsF 140，NaCl 10，EGTA 1，CsOH 5，HEPES 10，pH＝7.3，～285mOsm。待测化合物与对照品使用100％DMSO稀释并储存，使用细胞外液稀释至终浓度，肉眼检查是否有沉淀，且DMSO的终浓度≤0.3％。然后使用手动膜片钳记录电流信号(钳制电压-120mM，设置8s梯度提高至-60mV使钠离子通道失活，然后设置20ms梯度降至-120mV，然后设置20ms梯度升至-10mV来打开钠离子通道，然后再降至-120mV的强制电压，一个循环检测15s，持续记录)，分析数据。结果如下表5所示：
表5 Tetracaine与实施例化合物4抑制效果对比
化合物 测试浓度(μM) ％抑制率
Tetracaine 10 96.43
实施例4化合物 10 5.34
hKCNQ1手动膜片钳：使用CHO-hKCNQ/mink钾通道稳转细胞系(由上海药明康德新药开发有限公司提供)记录；细胞外液：(mM)：NaCl 145，KCl 4，CaCl 2 2，MgCl 2 1，Glucose 10，HEPES 10，pH＝7.4，～295mOsm；细胞内液：(mM)：KOH 31.25，KCl 120，EGTA 10，MgCl 2 1.75，CaCl 2 5.374，HEPES 10，Na-ATP 4，pH＝7.2，～285mOsm；待测化合物与对照品使用100％DMSO稀释并储存，使用细胞外液稀释至终浓度，肉眼检查是否有沉淀，且DMSO的终浓度≤0.3％。然后使用手动膜片钳记录电流信号(牵制电压为-80mV，设置2000ms使电压梯度升至40mV，然后设置1000ms电压梯度降至-50mV，最终电压梯度降至牵制电压，每150000ms重复一个循环)，分析数据。结果如下表6所示：
表6 Chromanol 293B与实施例4化合物抑制效果对比
化合物 测试浓度(μM) ％抑制率
Chromanol 293B 10 59.05
实施例4化合物 10 35.68
综合表4-6的结果并结合测试例1的结果，表明本发明的化合物是对Sigma-1受体具有良好的选择性。
测试例4：小鼠体内药效试验
小鼠强迫游泳实验(FST)
小鼠强迫游泳实验：采用雄性ICR小鼠，体重18-22g，分为溶媒对照组，阳性对照组(度洛西汀，15mg/kg)，受试组(化合物1～34，30，60，90mg/kg)。受试组，溶媒组和阳性对照组均在正式游泳前30分钟腹腔注射受试物或溶媒，然后进行小鼠强迫游泳试验。将小鼠放入透明的玻璃圆筒(水深15cm，水温23-25℃)中6分钟，并视频记录小鼠的活动状态，实验结束后采用Forced Swim ScanTM 2.0软件分析小鼠在6分钟强迫游泳期间后4分钟的累积不动时间结果。
以化合物4为例，通过图2的FST试验结果表明，在小鼠强迫游泳模型中，度洛西汀组(阳性对照)展示出极显著药效(p<0.0001)，化合物4在30mg/kg没有药效，在60mg/kg有显著药效(p<0.05)，在90mg/kg有极显著药效(p<0.0001)。
测试例5：体外肝微粒体代谢稳定性试验
取160μL 1.25μM冰冷的底物工作溶液加入20μL冰冷的5g/L大鼠、比格犬和人肝微粒体蛋白(反应浓度为0.5g/L)，37℃恒温水浴锅内预孵5min，再加入20μL同样预孵5min的10mM NADPH(反应浓度为1.0mM)启动反应，摇匀，37℃水浴锅内孵育0h，5min，15min和60min，300μL反应终止液终止反应，涡旋3min，4℃下12,000rpm离心10min，取300μL上清液加入100μL纯水，涡旋混匀，利用建立好的LC-MS方法检测各孵育时间点孵育体系中目标化合物的浓度，通过与0小时样品浓度比较，测定目标化合物经与大鼠、比格犬和人肝微粒体孵育后的代谢率。
化合物的大鼠、犬、人体外肝微粒体代谢稳定性结果表明其代谢稳定高。
实验结果见下表7：
表7.实施例化合物的肝微粒体代谢稳定性结果
Figure PCTCN2021103543-appb-000052
测试例6：转棒试验
实验前1天进行转棒初筛，小鼠转棒仪的转速设定为定速状态25rpm/min。将5只小鼠放到直径为3cm的转棒上，启动转棒仪，小鼠若在实验过程中掉落，则再次把它放到棒上。每次训练5分钟，连续训练3次，两次训练之间间隔20min以上作为疲劳恢复时间。第3次把小鼠放到棒上后，记录小鼠停留在棒上的时间，剔除停留时间小于5分钟、抱轴不动、跳跃及身体协调能力差小鼠，筛选后合格小鼠重新分组。实验在22-24℃空调室温条件下进行。将初筛合格的ICR小鼠随机分组，分别为正常对照组、药物高剂量组、药物中剂量组以及药物低剂量组，每组10只。各药物组灌胃给予相应剂量的受试药，正常对照组灌胃给予相同体积的溶媒(每5只间隔5min)。各组小鼠给药后测定给药后0.5h、1h、2h的4min内掉落潜伏期。
以化合物4为例，试验结果如图3所示，可以看出，低剂量组(32mg/kg)和高剂量组(128mg/kg)给药后均未出现运动障碍，中剂量组(64mg/kg)只有1只动物在0.5h出现运动障碍，之后恢复(溶媒组与低剂量组(32mg/kg)曲线与高剂量组(128mg/kg)曲线重合，中剂量组(64mg/kg)除了0.5h对应的点外，其余点也与高剂量组重合)。其结果表明，目标化合物对运动协调能力影响较小。
工业应用性
本发明提供一种对sigma-1受体具有高亲和力和选择性的5-((1,2,3,4-四氢异喹啉-7-基)氨基)吡啶-2(1H)-酮衍生物，可用于抑郁症、焦虑症等精神疾病的治疗。因而，可将其制成相应的药物，适于工业应用。

Claims (15)

  1. 一种如通式(I)所示的化合物或其药学可接受的盐：
    Figure PCTCN2021103543-appb-100001
    其中：
    R 1独立地选自氢、直链或支链烷基、环烷基、被至少一个卤素取代的烷基中的任意一种；
    R 2、R 3各自独立地选自氢、直链或支链烷基、环烷基中的任意一种；
    R 4独立地选自氢、直链或支链烷基、被至少一个卤素取代的烷基、环烷基中的任意一种；
    R 5、R 6、R 7和R 8各自独立地为氢；
    n1、n2、n3和n4各自独立地为0-3之间的任意一个整数；
    X为O或CH 2中的任意一种。
  2. 一种如通式(I’)所示的化合物或其药学可接受的盐：
    Figure PCTCN2021103543-appb-100002
    其中：
    R 1独立地选自氢、羟基、直链或支链烷基、环烷基、被至少一个卤素取代的烷基中的任意一种；
    R 10为氢或
    Figure PCTCN2021103543-appb-100003
    R 2、R 3各自独立地选自氢、直链或支链烷基、环烷基中的任意一种；
    R 4独立地选自氢、直链或支链烷基、被至少一个卤素取代的烷基、环烷基中的任意一种；
    R 5、R 6、各自独立地选自氢、卤素、氨基、羟基、直链或支链烷基和环烷基，其中所述的烷基、环烷基未被取代或被至少一个独立选自R X的取代基取代；
    R 7和R 8各自独立地选自氢、卤素、氨基、羟基、直链或支链烷基和环烷基，其中所述的烷基、环烷基未被取代或被至少一个独立选自R X的取代基取代；
    或R 7和R 8连同与它们相连的原子一起形成三元环或四元环；R X独立选自卤素、氰基、羟基、氨基、C 1-6烷基和C 3-6环烷基；
    n1、n2、n3和n4各自独立地为0-3之间的任意一个整数；
    X为O、CH 2中的任意一种或不存在。
  3. 如权利要求1或2所述的化合物或其药学可接受的盐，其特征在于，所述卤素选自氟、氯、溴或碘中的任意一种。
  4. 如权利要求1-3中任一项所述的化合物或其药学可接受的盐，其特征在于，所述的直链或支链烷基选自C1-C5的直链或支链烷基；所述环烷基选自C3-C6的环烷基；所述被至少一个卤素取代的烷基选自被至少一个卤素取代的C1-C5的烷基。
  5. 如权利要求4所述的化合物或其药学可接受的盐，其特征在于，所述C1-C5的直链或支链烷基选自甲基、乙基、丙基、丁基、戊基中的至少一种；所述C3-C6的环烷基选自环丙基、环丁基、环戊基或环己基中的一种；所述被至少一个卤素取代的C1-C5的烷基选自三氟甲基、二氟甲基中的一种。
  6. 如权利要求2所示的通式(I’)所示的化合物或其药学可接受的盐，其特征在于，所述化合物具有如下式(i)所示的结构：
    Figure PCTCN2021103543-appb-100004
    其中R 9、R 10’、R 11分别独立的选自氢、C1-C5的直链或支链烷基、环烷基和C 1-6烷基-C 3-6环烷基，其中所述烷基、环烷基任选地被至少一个独立选自R X的取代基取代；其中所述的R X独立选自卤素、氰基、羟基、氨基、C 1-6烷基和C 3-6环烷基，优选卤素和C 3-6环烷基。
  7. 如权利要求6所述的化合物或其药学可接受的盐，其特征在于，
    其中R 9、R 10’、R 11各自独立的选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、羟乙基、甲氧基乙基、环丙基甲基，环丁基甲基、环戊基甲基、环己基甲基、环丙基甲氧基乙基、3-三氟丙基、2-二氟乙基、三氟甲基和2-三氟乙基；
    优选地，R 9为环丙基甲基、R 10’为异丙基、R 11为甲基。
  8. 如权利要求2所示的通式(I’)所示的化合物或其药学可接受的盐，其特征在于，所述化合物具有如下式(ii)所示的结构：
    Figure PCTCN2021103543-appb-100005
    其中R 9’、R 10’、R 11独立的选自氢、C1-C5的直链或支链烷基、C3-C6的环烷基和C 1-6烷基-C 3-6环烷基，其中所述烷基、环烷基任选地被至少一个独立选自R X的取代基取代；其中所述的R X独立选自卤素、氰基、羟基、氨基、C 1-6烷基和C 3-6环烷基，优选卤素和C 3-6环烷基。
  9. 如权利要求8所述的化合物或其药学可接受的盐，其特征在于，所述式(ii)所示的结构，其中R 9’选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、环丙基、环丙基甲基、三氟甲基、3-三氟丙基、2-二氟乙基、三氟甲基和2-三氟乙基；更优选地，R 9’独立选自氢、甲基、三氟甲基、环丙基和环丙基甲基；进一步优选地，R 9’独立选自氢、甲基和环丙基甲基；
    R 10’独立选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、环丙基亚甲基、3-三氟丙基和三氟甲基；更优选地，R 10’独立选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、环丙基甲基和环丁基甲基；
    R 11独立选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、环丙基、3-三氟丙基、2-二氟乙基、三氟甲基、和环丙基甲基；更优选地，R 11独立选自氢、甲基、乙基、正丙基、异丙基、异丁基、环丙基、2-二氟乙基和环丙基甲基；进一步优选地，R 11独立选自氢、甲基、乙基、正丙基、异丙基、异丁基和环丙基甲基；
    n5为1～3的整数，例如为1、2或3。
  10. 如权利要求1-9任一项所述的化合物或其药学可接受的盐，其特征在于，选自如下任意一个化合物：
    Figure PCTCN2021103543-appb-100006
    Figure PCTCN2021103543-appb-100007
    Figure PCTCN2021103543-appb-100008
    Figure PCTCN2021103543-appb-100009
  11. 一种药物组合物，其特征在于包含权利要求1-10任一项所述的化合物，任选地进一步包含药学上可接受的赋形剂、载体、佐剂、溶媒或它们的组合。
  12. 如权利要求1-10中任一项所述的化合物或权利要求11所述的药物组合物在制备治疗神经精神类疾病药物中的应用。
  13. 如权利要求12所述的用途，其特征在于，所述神经精神类疾病选自抑郁、焦虑中的任意一种。
  14. 通式(I’)所示的化合物或其药学可接受的盐的制备方法，包括以下步骤：
    Figure PCTCN2021103543-appb-100010
    (1)：中间体(III)与化合物Reagent-2经Buchwald–Hartwig偶联反应制备得到通式(I’)；
    或者
    (2)：中间体(III)与化合物Reagent-3经Buchwald–Hartwig偶联反应制备得到中间体(IV)，中间体(IV)与化合物Reagent-4经取代反应制备得到通式(I’)；
    其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8和R 10以及n1、n2、n3、n4和X的定义如权利要求2。
  15. 中间体(III)的制备方法，包括以下步骤：
    Figure PCTCN2021103543-appb-100011
    将中间体(II)与化合物Reagent-1溶解在在有机溶剂中，以弱碱为催化剂，经取代反应制备得到中间体(III)，
    其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7和R 8以及n1、n2、n3、n4和X的定义如权利要求1或2。
PCT/CN2021/103543 2020-06-30 2021-06-30 5-((1,2,3,4-四氢异喹啉-7-基)氨基)吡啶-2(1h)-酮衍生物及其应用 WO2022002131A1 (zh)

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