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WO2024208207A1 - Composé naphtalène disubstitué et composition pharmaceutique et utilisation de celui-ci - Google Patents

Composé naphtalène disubstitué et composition pharmaceutique et utilisation de celui-ci Download PDF

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Publication number
WO2024208207A1
WO2024208207A1 PCT/CN2024/085564 CN2024085564W WO2024208207A1 WO 2024208207 A1 WO2024208207 A1 WO 2024208207A1 CN 2024085564 W CN2024085564 W CN 2024085564W WO 2024208207 A1 WO2024208207 A1 WO 2024208207A1
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butyl
edema
halo
substituted
hydrogen
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Chinese (zh)
Inventor
韩化敏
季奇
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Biocells Beijing Biotech Co Ltd
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Biocells Beijing Biotech Co Ltd
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Priority to CN202480015921.7A priority Critical patent/CN120787218A/zh
Publication of WO2024208207A1 publication Critical patent/WO2024208207A1/fr
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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
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • 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
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • A61K31/09—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon having two or more such linkages
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • 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
    • A61P25/06—Antimigraine agents
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C15/00—Cyclic hydrocarbons containing only six-membered aromatic rings as cyclic parts
    • C07C15/20—Polycyclic condensed hydrocarbons
    • C07C15/24—Polycyclic condensed hydrocarbons containing two rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

Definitions

  • the present invention relates to, but is not limited to, medicinal chemistry technology, and in particular to a disubstituted naphthalene compound and its pharmaceutical composition and use.
  • the compound or its pharmaceutical composition has a cell protection effect against brain edema or nervous system diseases.
  • Cerebral edema refers to the pathological process in which the water content in the brain parenchyma increases, leading to an increase in brain volume. It is the most common symptom associated with many diseases and a problem frequently faced by neurosurgeons. It can be caused by various factors such as various craniocerebral injuries, cerebrovascular diseases (cerebral hemorrhage or cerebral infarction), intracranial tumors, intracranial inflammation (encephalitis, meningitis, ventriculitis, brain abscess), lead poisoning or other systemic poisoning, and radiation damage to the brain. It is an important cause of acute death in many patients with brain diseases.
  • cerebral edema The pathogenesis of cerebral edema is very complex, and there are many related factors, including blood-brain barrier, microcirculatory disorders, cerebral ischemia and hypoxia, increased free radicals in the brain, changes in thromboxane A2 and prostacyclin, changes in neurotransmitters and neuropeptides, and calcium overload in nerve cells, which can all affect the occurrence and development of cerebral edema.
  • cerebral edema can be divided into two main types: vasogenic edema and cytotoxic edema.
  • Brain edema usually reaches its peak within 3-5 days after acute brain injury and gradually subsides in about 7-10 days. Since the four walls of the closed cranial cavity are bony structures and lack elasticity, the increase in brain volume after edema causes increased intracranial pressure, further aggravating neurological damage and even endangering life. Therefore, the severity and progression of brain edema directly affect the prognosis of the disease. Controlling and improving brain edema is crucial to reducing mortality and alleviating patients' neurological deficits. Since brain edema and brain cell necrosis are the main causes of brain dysfunction, and brain cell necrosis is irreversible, preventing and treating brain edema is the focus of clinical treatment.
  • aquaporins are cell membrane proteins that act as molecular water channels that mediate water flow in and out of cells. Although there is a certain degree of passive diffusion of water or osmotic penetration through the cell membrane, water quickly and selectively enters and exits cells and involves aquaporins. These water channels selectively guide water molecules in and out of cells, while blocking ions and other solutes from passing through, thus protecting the membrane potential of cells. Aquaporins are actually found in all life forms, from bacteria to plants, and then to animals. In the human body, they are found in cells throughout the body. Effective nerve cell hypotonic protective effects can be achieved by inhibiting aquaporins.
  • the present application provides a disubstituted naphthalene compound, which has a cell protective effect against brain edema or nervous system diseases.
  • the present application provides a disubstituted naphthalene compound, wherein the disubstituted naphthalene compound is represented by the general formula (I), or a stereoisomer, a mixture of stereoisomers, a solvate, or a pharmaceutically acceptable salt thereof:
  • R 1 is halogen or methyl
  • L 1 is O, S, or -CH 2 -N(R 2 )-, where R 2 is hydrogen or unsubstituted C1-C4 alkyl;
  • L 2 is -(C(R 3 )(R 4 )) n -, where n is 0, 1, 2, 3 or 4, and R 3 and R 4 are each independently hydrogen, unsubstituted C1-C4 alkyl or halogenated C1-C4 alkyl;
  • L 3 is -N(R 5 )(R 6 ) or
  • R5 and R6 are each independently hydrogen, unsubstituted C1-C6 alkyl or halogenated C1-C6 alkyl, or R5 and R6 together with the nitrogen atom to which they are attached form a C2-C8 azacycloalkyl, or one of R5 and R6 together with one of R3 and R4 and the atoms and carbon atoms to which they are respectively attached form a C2-C8 azacycloalkyl;
  • the substituents R 7 , R 8 , R 9 , R 10 and R 11 are each independently selected from hydrogen, halogen, unsubstituted C1-C4 alkyl, halogenated C1-C4 alkyl, -N(R 12 )(R 13 ) substituted C1-C4 alkyl and -N(R 14 )(R 15 ).
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned disubstituted naphthalene compound or its stereoisomers, mixtures of stereoisomers, solvates, or pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier.
  • the present application provides a method for protecting cells from nervous system diseases or a method for preventing or treating diseases, the method comprising administering to an individual in need thereof a therapeutically effective amount of the above-mentioned disubstituted naphthalene compound or its stereoisomers, mixtures of stereoisomers, solvates, or pharmaceutically acceptable salts, or pharmaceutical compositions thereof.
  • the present application provides the use of the above-mentioned disubstituted naphthalene compound or its stereoisomers, mixtures of stereoisomers, solvates, or pharmaceutically acceptable salts, or pharmaceutical compositions thereof in the preparation of drugs for treating or preventing the following diseases or in the preparation of drugs for protecting cells of nervous system diseases.
  • the present application provides the above-mentioned disubstituted naphthalene compound or its stereoisomer, mixture of stereoisomers, solvate, or pharmaceutically acceptable salt, or the above-mentioned pharmaceutical composition, for use in protecting cells of nervous system diseases or for treating or preventing the following diseases.
  • FIG1 shows the protective effect of the compound of Example 1 of the present application on astrocytes under hypotonic conditions
  • FIG2 shows the fitting curve of the protective effect of the compound of Example 1 of the present application on astrocytes under hypotonic conditions
  • FIG3 shows the protective effect of the compound of Example 2 of the present application on astrocytes under hypotonic conditions
  • FIG4 shows the protective effect of the compound of Example 3 of the present application on astrocytes under hypotonic conditions
  • FIG5 shows the fitting curve of the protective effect of the compound of Example 3 of the present application on astrocytes under hypotonic conditions
  • FIG6 shows the protective effect of the compound of Example 4 of the present application on astrocytes under hypotonic conditions
  • FIG7 shows the fitting curve of the protective effect of the compound of Example 4 of the present application on astrocytes under hypotonic conditions
  • FIG8 shows the protective effect of the compound of Example 5 of the present application on astrocytes under hypotonic conditions
  • FIG9 shows the protective effect of the compound of Example 6 of the present application on astrocytes under hypotonic conditions
  • FIG10 shows the protective effect of the compound of Example 7 of the present application on astrocytes under hypotonic conditions
  • FIG11 shows the protective effect of the compound of Example 8 of the present application on astrocytes under hypotonic conditions
  • FIG12 shows the survival curve of water intoxication in mice of the compound of Example 1 of the present application.
  • FIG13 shows the survival curve of water intoxication in mice of the compound of Example 3 of the present application.
  • FIG14 shows the survival curve of water intoxication in mice of the compound of Example 4 of the present application.
  • FIG15 shows the effect of the vehicle group in the 24h cerebral ischemia model in rats
  • FIG16 shows the protective effect of the compound of Example 1 of the present application after three administrations in a rat cerebral ischemia 24h model
  • FIG17 shows the protective effect of the compound of Example 1 of the present application on cerebral infarction and brain edema after three administrations;
  • FIG18 shows that 6 administrations of the compound of Example 1 of the present application reduced the mortality rate in a rat cerebral ischemia 48h model.
  • FIG19 shows that the compound of Example 1 of the present application reduces neurological function damage in a rat cerebral ischemia 48h model after 6 administrations;
  • FIG20 shows the protective effect of the compound of Example 1 of the present application on neurobehavior in a rat cerebral ischemia 48h model after 6 administrations;
  • FIG21 shows the protective effect of the compound of Example 1 of the present application on neurobehavioral sub-items in a rat cerebral ischemia 48h model after 6 administrations;
  • FIG22 shows the protective effect of the compound of Example 1 of the present application on cerebral infarction in a rat cerebral ischemia 48h model after 6 administrations;
  • FIG23 shows the infarction condition of the vehicle group in the rat cerebral ischemia model for 48 h
  • FIG. 24 shows the infarction condition of the compound group of Example 1 in the rat cerebral ischemia 48h model.
  • the present application provides a disubstituted naphthalene compound, wherein the disubstituted naphthalene compound is represented by the general formula (I), or a stereoisomer, a mixture of stereoisomers, a solvate, or a pharmaceutically acceptable salt thereof:
  • R 1 is halogen or methyl
  • L 1 is O, S, or -CH 2 -N(R 2 )-, where R 2 is hydrogen or unsubstituted C1-C4 alkyl;
  • L 2 is -(C(R 3 )(R 4 )) n -, where n is 0, 1, 2, 3 or 4, and R 3 and R 4 are each independently hydrogen, unsubstituted C1-C4 alkyl or halogenated C1-C4 alkyl;
  • L 3 is -N(R 5 )(R 6 ) or
  • R5 and R6 are each independently hydrogen, unsubstituted C1-C6 alkyl or halogenated C1-C6 alkyl, or R5 and R6 together with the nitrogen atom to which they are attached form a C2-C8 azacycloalkyl, or one of R5 and R6 together with one of R3 and R4 and the atoms and carbon atoms to which they are respectively attached form a C2-C8 azacycloalkyl, wherein the C2-C8 azacycloalkyl optionally has one or more hydrogen atoms on the ring substituted by a group selected from halogen, unsubstituted C1-C4 alkyl and halogenated C1-C4 alkyl, and optionally one or more carbon atoms on the ring replaced by an atom selected from O, S and N;
  • the substituents R 7 , R 8 , R 9 , R 10 and R 11 are each independently selected from hydrogen, halogen, unsubstituted C1-C4 alkyl, halogenated C1-C4 alkyl, -N(R 12 )(R 13 ) substituted C1-C4 alkyl and -N(R 14 )(R 15 ); here, the substituents R 12 , R 13 , R 14 and R 15 are each independently selected from hydrogen and unsubstituted C1-C4 alkyl.
  • the present application provides a disubstituted naphthalene compound as shown in the general formula (I), wherein R 1 in the formula (I) is chlorine, fluorine, bromine, iodine or methyl.
  • the present application provides a disubstituted naphthalene compound as shown in the general formula (I), wherein R 1 in the formula (I) is chlorine; that is, the formula (I) is the formula (I-1):
  • L 1 , L 2 and L 3 are as defined in formula (I).
  • the present application provides a disubstituted naphthalene compound as shown in the general formula (I), wherein R 1 in the formula (I) is chlorine, L 1 is O and L 3 is -N(R 5 )(R 6 ); that is, the formula (I) is the formula (I-1-1):
  • the present application provides a disubstituted naphthalene compound as shown in formula (I-1-1):
  • L 2 is -(CH 2 ) n -, n is 1, 2, 3 or 4;
  • R 5 and R 6 are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
  • the present application provides a disubstituted naphthalene compound as shown in formula (I-1-1):
  • L 2 is -(CH 2 ) n -, n is 2 or 3; R 5 and R 6 are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
  • the present application provides a disubstituted naphthalene compound as shown in formula (I-1-1):
  • L 2 is -(CH 2 ) n -, n is 2 or 3; R 5 and R 6 are each independently ethyl.
  • the present application provides a disubstituted naphthalene compound as shown in formula (I-1-1):
  • L 2 is -(CH 2 ) n -, n is 1, 2, 3 or 4; R 5 and R 6 together with the nitrogen atom to which they are connected form a C2-C8 azacycloalkyl group, wherein the C2-C8 azacycloalkyl group optionally has one or more hydrogen atoms on its ring replaced by a group selected from fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, halomethyl, haloethyl, halo-n-propyl, haloisopropyl, halo-n-butyl, haloisobutyl and halo-tert-butyl, and optionally one carbon atom on its ring is replaced by an atom selected from O, S and N.
  • the present application provides a disubstituted naphthalene compound as shown in formula (I-1-1):
  • L 2 is -(CH 2 ) n -, n is 2 or 3; R 5 and R 6 together with the nitrogen atom to which they are connected form a pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl or morpholinyl group, wherein the pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl or morpholinyl group, optionally, has one or more hydrogen atoms on the ring thereof replaced by a group selected from fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, halomethyl, haloethyl, halo-n-propyl, halo-isopropyl, halo-n-butyl, halo-isobutyl and
  • the present application provides a disubstituted naphthalene compound as shown in formula (I-1-1):
  • L 2 is -(CH 2 ) n -, n is 2 or 3; R 5 and R 6 together with the nitrogen atom to which they are attached form a piperidinyl or morpholinyl group, wherein the piperidinyl or morpholinyl group, optionally, has one or more hydrogen atoms on its ring replaced by a group selected from fluorine, chlorine, bromine and iodine.
  • the present application provides a disubstituted naphthalene compound as shown in formula (I-1-1):
  • L 2 is -(CH 2 ) n -, n is 2 or 3; R 5 and R 6 together with the nitrogen atom to which they are attached form a piperidinyl group or a morpholinyl group, wherein the piperidinyl group is optionally a 4-fluoropiperidinyl group or a 4,4-difluoropiperidinyl group.
  • the present application provides a disubstituted naphthalene compound as shown in formula (I-1-1):
  • L 2 is -(C(R 3 )(R 4 )) n , and n is 1, 2, 3 or 4; one of R 5 and R 6 together with one of R 3 and R 4 and the nitrogen atom and carbon atom to which they are respectively attached form a C2-C8 azacycloalkyl group, and the other of R 5 and R 6 and the other of R 3 and R 4 are both hydrogen; here, the C2-C8 azacycloalkyl group optionally has one or more hydrogen atoms on its ring replaced by a group selected from fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, halomethyl, haloethyl, halo-n-propyl, halo-isopropyl, halo-n-butyl, halo-isobutyl and
  • the present application provides a disubstituted naphthalene compound as shown in formula (I-1-1):
  • L 2 is -(C(R 3 )(R 4 )) n , n is 2 or 3; one of R 5 and R 6 together with one of R 3 and R 4 and the nitrogen atom and carbon atom to which they are respectively attached form a pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl or morpholinyl group, and the other of R 5 and R 6 and the other of R 3 and R 4 are both hydrogen.
  • the present application provides a disubstituted naphthalene compound as shown in formula (1-1-1):
  • L 2 is -(C(R 3 )(R 4 )) n , n is 2 or 3; one of R 5 and R 6 together with one of R 3 and R 4 and the nitrogen atom and carbon atom to which they are respectively attached form a pyrrolidinyl or piperidinyl group, and the other of R 5 and R 6 and the other of R 3 and R 4 are both hydrogen.
  • the present application provides a disubstituted naphthalene compound as shown in the general formula (I), wherein R 1 in the formula (I) is chlorine, L 3 is That is, formula (I) is formula (I-1-2):
  • L 1 , L 2 , R 7 , R 8 , R 9 , R 10 and R 11 have the same meanings as in formula (I).
  • the present application provides a disubstituted naphthalene compound as shown in formula (I-1-2):
  • L 1 is O, S or -CH 2 -N(R 2 )-, where R 2 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;
  • L 2 is -(C(R 3 )(R 4 )) n -, where n is 0, 1, 2, 3 or 4, and R 3 and R 4 are each independently hydrogen;
  • the substituents R7 , R8 , R9 , R10 and R11 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, halogenated methyl, halogenated ethyl, halogenated n-propyl, halogenated isopropyl, halogenated n-butyl, halogenated isobutyl, halogenated tert-butyl, -N(R12)( R13 ) substituted methyl, -N( R12 )(R13) substituted ethyl, -N(R12)(R13) substituted n-propyl, -N( R12 )( R13 ) substituted isopropyl, -N( R12 )( R13 ) substituted n-but
  • the present application provides a disubstituted naphthalene compound as shown in formula (I-1-2):
  • L 1 is O or -CH 2 -N(R 2 )-, where R 2 is hydrogen or methyl;
  • L 2 is -(C(R 3 )(R 4 )) n -, where n is 0, 1, 2 or 3, and R 3 and R 4 are each independently hydrogen;
  • the substituents R7 , R8 , R9 , R10 and R11 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, halogenated methyl, halogenated ethyl, halogenated n-propyl, halogenated isopropyl, halogenated n-butyl, halogenated isobutyl, halogenated tert-butyl, -N(R12)( R13 ) substituted methyl, -N( R12 )(R13) substituted ethyl, -N(R12)(R13) substituted n-propyl, -N( R12 )( R13 ) substituted isopropyl, -N( R12 )( R13 ) substituted n-but
  • the present application provides a disubstituted naphthalene compound as shown in formula (I-1-2):
  • L 1 is O or -CH 2 -N(R 2 )-, where R 2 is hydrogen or methyl;
  • L 2 is -(C(R 3 )(R 4 )) n -, where n is 0, 1, 2 or 3, and R 3 and R 4 are each independently hydrogen;
  • the substituents R7 , R8 , R9 , R10 and R11 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, halomethyl, haloethyl, halo-n-propyl, halo-isopropyl, halo-n-butyl, halo-isobutyl, halo-tert-butyl, -N(R12)( R13 )-substituted methyl, -N( R12)(R13)-substituted ethyl, -N(R12 )(R13)-substituted n-propyl, -N(R12)( R13 )-substituted isopropyl, -N(R12)(R13)-substituted n-butyl, -N( R12 )( R13 )-substituted isopropyl, -N(R
  • the present application provides a disubstituted naphthalene compound as shown in formula (I-1-2):
  • L 1 is O or -CH 2 -N(R 2 )-, where R 2 is hydrogen or methyl;
  • L 2 is -(C(R 3 )(R 4 )) n -, where n is 0, 1, 2 or 3, and R 3 and R 4 are each independently hydrogen;
  • the substituents R7 , R8 , R9 , R10 and R11 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, methyl substituted by -N( R12 )( R13 ), ethyl substituted by -N( R12 )( R13 ) and -N( R14 )( R15 ); here, the substituents R12 and R13 are each independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl; the substituents R14 and R15 are both hydrogen.
  • the present application provides a disubstituted naphthalene compound as shown in formula (I-1-2):
  • L 1 is O or -CH 2 -N(R 2 )-, where R 2 is hydrogen or methyl;
  • L 2 is -(C(R 3 )(R 4 )) n -, where n is 0, 1, 2 or 3, and R 3 and R 4 are each independently hydrogen;
  • the substituents R 7 , R 8 , R 9 , R 10 and R 11 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, N,N- dimethylaminomethyl, N,N-diethylaminomethyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl and amino.
  • the present application provides a disubstituted naphthalene compound as shown in formula (I-1-2):
  • L 1 is O or -CH 2 -N(R 2 )-, where R 2 is hydrogen or methyl;
  • L 2 is -(C(R 3 )(R 4 )) n -, where n is 0, 1, 2 or 3, and R 3 and R 4 are each independently hydrogen;
  • Substituents R7 and R11 are both hydrogen, and R8 , R9 and R10 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, N,N-dimethylaminomethyl, N,N-diethylaminomethyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl and amino.
  • the present application provides a disubstituted naphthalene compound as shown in formula (I-1-2):
  • L 1 is O
  • L 2 is -(CH 2 ) n -, where n is 0, 1, 2 or 3;
  • Substituents R7 and R11 are both hydrogen, and R8 , R9 and R10 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, N,N-dimethylaminomethyl, N,N-diethylaminomethyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl and amino.
  • the present application provides a disubstituted naphthalene compound as shown in formula (I-1-2):
  • L 1 is -CH 2 -N(R 2 )-, where R 2 is hydrogen or methyl;
  • L 2 is -(CH 2 ) n -, where n is 1, 2 or 3;
  • Substituents R7 and R11 are both hydrogen, and R8 , R9 and R10 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, N,N-dimethylaminomethyl, N,N-diethylaminomethyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl and amino.
  • the disubstituted naphthalene compound of formula (I), formula (I-1), formula (I-1-1) or formula (I-1-2) provided herein is one of the following compounds:
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned disubstituted naphthalene compound or its stereoisomers, mixtures of stereoisomers, solvates, or pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier includes an inert diluent or filler, water or various organic solvents. It may also include flavoring agents, adhesives, excipients, etc.
  • the excipients include various solvents, dispersion media, coating agents, antibacterial and antifungal agents, isotonic agents, delayed absorption agents, diluents, etc.
  • the pharmaceutical composition can be prepared into a form suitable for oral administration, such as tablets, capsules, powders, sustained-release preparations, suspensions; sterile injections (solutions, suspensions or emulsions) for non-gastrointestinal administration, such as liquid solutions (injections, infusions or lyophilized preparations for injection); preparations for external administration such as ointments, creams, powders, liposomes, suppositories (e.g., rectal administration).
  • a form suitable for oral administration such as tablets, capsules, powders, sustained-release preparations, suspensions; sterile injections (solutions, suspensions or emulsions) for non-gastrointestinal administration, such as liquid solutions (injections, infusions or lyophilized preparations for injection); preparations for external administration such as ointments, creams, powders, liposomes, suppositories (e.g., rectal administration).
  • the present application provides a method for protecting cells from nervous system diseases or a method for preventing or treating diseases, the method comprising administering a pharmacologically effective amount of the above-mentioned disubstituted naphthalene compound or Its stereoisomers, mixtures of stereoisomers, solvates, or pharmaceutically acceptable salts, or a pharmaceutical composition comprising the above-mentioned disubstituted naphthalene compound or its stereoisomers, mixtures of stereoisomers, solvates, or pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier;
  • the disease is selected from one or more of the following diseases: cerebral edema, spinal cord edema, retinal edema, optic nerve edema, cardiogenic edema, and diseases associated with cerebral edema, spinal cord edema, retinal edema, optic nerve edema and/or cardiogenic edema.
  • the present application provides the use of the above-mentioned disubstituted naphthalene compound or its stereoisomer, mixture of stereoisomers, solvate, or pharmaceutically acceptable salt, or a pharmaceutical composition comprising the above-mentioned disubstituted naphthalene compound or its stereoisomer, mixture of stereoisomers, solvate, or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier in the preparation of a medicament for treating or preventing the following diseases or in the preparation of a medicament for protecting cells of nervous system diseases, wherein the diseases are selected from one or more of the following diseases: cerebral edema, spinal cord edema, retinal edema, optic nerve edema, cardiogenic edema, and diseases associated with cerebral edema, spinal cord edema, retinal edema, optic nerve edema and/or cardiogenic edema.
  • the present application provides the above-mentioned disubstituted naphthalene compound or its stereoisomer, mixture of stereoisomers, solvate, or pharmaceutically acceptable salt, or the above-mentioned pharmaceutical composition, for use in protecting cells of nervous system diseases or for treating or preventing the following diseases, wherein the disease is selected from one or more of the following diseases: cerebral edema, spinal cord edema, retinal edema, optic nerve edema, cardiogenic edema, and diseases associated with cerebral edema, spinal cord edema, retinal edema, optic nerve edema and/or cardiogenic edema.
  • the diseases associated with cerebral edema include cerebral ischemia, cerebral infarction, hydrocephalus, epilepsy, migraine, cerebral small vessel disease and neurodegenerative diseases;
  • Conditions associated with spinal cord edema include water imbalance, hyponatremia, excess fluid retention, and sepsis;
  • the diseases associated with retinal edema include retinal ischemia;
  • the diseases associated with optic nerve edema include neuromyelitis optica, other eye diseases associated with abnormal intraocular pressure and/or tissue hydration;
  • the diseases associated with cardiogenic edema include myocardial ischemia, myocardial ischemia-reperfusion injury, myocardial infarction, myocardial hypoxia and congestive heart failure;
  • the neurodegenerative diseases include Parkinson's disease and Alzheimer's disease.
  • halogen or halo refers to a fluorine, chlorine, bromine or iodine atom, or a substituent thereof.
  • the C1-C4 alkyl group refers to a -C n H 2n+1 alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;
  • the C1-C6 alkyl group refers to a -C n H 2n+1 alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl or n-hexyl.
  • the halogenated C1-C4 alkyl or halogenated C1-C6 alkyl refers to a C1-C4 alkyl or C1-C6 alkyl in which one or more hydrogens are replaced by one or more selected from chlorine, fluorine, bromine or iodine, and may be monosubstituted, such as chloromethyl; or disubstituted, such as dichloromethyl, 1,2-dichloro-ethyl; or trisubstituted, such as trifluoromethyl, etc.
  • the disubstituted naphthalene compounds of the present application include all stereoisomers, geometric isomers, tautomers and isotopes of the described structure. Unless otherwise specified, compounds whose structures or names are determined with a specific tautomer herein also include other tautomers. Unless otherwise specified, the disubstituted naphthalene compounds of the present application can exist as enantiomers, diastereomers or its racemates or mixtures.
  • the stereoisomers of the disubstituted naphthalene compounds of the present application include cis and trans isomers, optical isomers (such as enantiomers), diastereomers, geometric isomers, rotational isomers, sterically hindered isomers, conformational isomers and tautomers of the disubstituted naphthalene compounds of the present application, and also include mixtures of multiple isomerizations, and mixtures (racemates and diastereomer pairs).
  • the atoms in the disubstituted naphthalene compounds of the present application can be present in natural isotopic abundance, or one or more of the atoms are specific isotopes that exist in artificial enrichment, and the isotopes have the same atomic number, but their original mass is different from the original mass that exists predominantly in nature.
  • the present application includes all suitable isotopic variants of the disubstituted naphthalene compounds described herein, such as deuterated compounds, and deuterium enrichment can provide certain therapeutic advantages, such as increasing the half-life in vivo or reducing the dosage requirements, or can provide a compound that can be used as a standard for biological sample characterization.
  • isotopically enriched reagents or intermediates according to known conventional techniques, or with reference to the preparation methods in the embodiments of this article, to prepare isotopically enriched compounds.
  • isotopes that may be incorporated into the disubstituted naphthalene compounds of the present application include 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 129 I, and 131 I.
  • the disubstituted naphthalene compound of the present application can exist as a solvate or an unsolvated compound.
  • the solvate described herein includes a hydrate, and the solvent or water in the solvate or hydrate and the disubstituted naphthalene compound of the present application can be a strong binding relationship (i.e. stoichiometric), or a weak binding relationship (e.g. adsorbed solvent or water).
  • the solvate refers to a complex formed by the disubstituted naphthalene compound of the present application and more than one pharmaceutically acceptable solvent molecule, and the pharmaceutically acceptable solvent can be methanol, ethanol, acetone, diformamide or water etc. When the solvent is water, the solvate is a hydrate.
  • the disubstituted naphthalene compound of the present invention may be present in the form of a pharmaceutically acceptable salt thereof, such as an acid addition salt or a base addition salt of the disubstituted naphthalene compound of the present invention.
  • the acid may be an inorganic acid or an organic acid, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, acidic sulfuric acid, sulfurous acid, acidic sulfurous acid, phosphoric acid, acidic phosphoric acid, carbonic acid, acidic carbonic acid, and the organic acid may be formic acid, acetic acid, propionic acid, pantothenic acid, lactic acid, oxalic acid, salicylic acid, citric acid, acidic citric acid, tartaric acid, acidic tartaric acid, succinic acid, maleic acid, fumaric acid, acetic acid, propionic acid, pantothenic acid, lactic acid, oxalic acid, salicylic acid, citric acid, acidic citric acid, tartaric acid, acidic tartaric acid, succinic acid, maleic acid, fumaric acid, citric acid, tartaric ...
  • the organic acid may be formic acid, acetic acid, propi
  • the base may be an inorganic base or an organic base, such as sodium, potassium, calcium, magnesium, manganese, iron, zinc or aluminum, and the organic base includes basic amino acids (such as arginine, lysine, histidine), ammonia, primary amines, secondary amines, tertiary amines, cyclic amines (such as piperidine, morpholine, piperazine).
  • basic amino acids such as arginine, lysine, histidine
  • ammonia such as arginine, lysine, histidine
  • ammonia such as arginine, lysine, histidine
  • primary amines secondary amines
  • tertiary amines such as piperidine, morpholine, piperazine
  • the C2-C8 azacycloalkyl group includes, but is not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, 1,4-diazepanyl, and 3-oxabicyclo[3.1.0]hexanyl.
  • the effective amount refers to the disubstituted naphthalene compound or pharmaceutical composition of the present application is sufficient to affect any one or more beneficial or desired amounts of the disease, including the biochemical, histological and/or behavioral symptoms of the disease, its complications and the intermediate pathological phenotypes presented during the disease development.
  • the therapeutically effective amount refers to the amount of the compound administered to alleviate one or more symptoms of the disease being treated to a certain extent.
  • AQP4 aquaporin 4
  • Calcein-AM Calcein AM
  • DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
  • DIAD diisopropyl azodicarboxylate
  • 1,4-dioxane 1,4-dioxane
  • DMSO dimethyl sulfoxide
  • EGTA ethylene glycol bis(2-aminoethyl ether) tetraacetic acid
  • Glucose glucose
  • HEPES N-(2-hydroxyethyl)piperazine-N′-2-ethanesulfonic acid
  • K-Aspartic Potassium aspartate
  • LCMS or LC-MS Liquid spectrometry and mass spectrometry
  • Na 2 -ATP disodium adenosine triphosphate
  • Oxone potassium persulfate
  • PBS phosphate buffered saline
  • Pd 2 (dba) 3 tris(dibenzylideneacetone)dipalladium
  • t-BuXphos 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl;
  • TTC red tetrazolium
  • Step 1 (R)-tert-butyl 3-(7-chloronaphthalene-1-yl)piperidine-1-carboxylate
  • the compound of the present invention was injected into the tail vein, followed by intraperitoneal injection of pure water, and the mortality rate of the mice was observed for 2 hours to determine the protective effect of the drug in the animal model.
  • the pMACO model of male SD rats was established.
  • the drug was administered three times after embolization.
  • the protective effect of the drug in this model was determined by detecting cerebral infarction and brain edema after TTC staining.
  • the pMCAO model of male SD rats was established.
  • the drug was administered six times after embolization.
  • the protective effect of the drug in this model was determined by detecting animal mortality, neurobehavior, and cerebral infarction after TTC staining.
  • Experimental groups DMSO control group, and different doses of the example compounds experimental groups.
  • the cells were pretreated with different doses of the example compounds or DMSO (solvent control) under isotonic conditions for 30 min, then the culture medium was aspirated (as dry as possible), hypotonic culture medium (diluted with water to 20-25% of the osmotic pressure of the normal culture medium) was added, and the corresponding dose of DMSO or compound was added to each well, and the cells were cultured in an incubator overnight;
  • Example 1 starts to take effect at 0.1 ⁇ M, reaches maximum protection at 10-30 ⁇ M, and EC 50 is 0.9097 ⁇ M.
  • Example 2 has a protective effect at 1 ⁇ M, but is basically ineffective at 10 ⁇ M.
  • Example 3 starts to take effect at 0.1 ⁇ M, reaches maximum protection at 3-10 ⁇ M, and EC 50 is 0.3947 ⁇ M.
  • Example 4 starts to take effect at 0.3 ⁇ M and reaches maximum protection at 10 ⁇ M, but is cytotoxic at 30 ⁇ M, with an EC 50 of 1.019 ⁇ M.
  • Example 5 had a protective effect at both 1 ⁇ M and 10 ⁇ M.
  • Example 6 had a protective effect of about 20% at 10 ⁇ M, and the effect was slightly weakened at 1 ⁇ M.
  • Example 7 has a protective effect of about 10% at 10 ⁇ M, and the efficacy decreases at 1 ⁇ M.
  • Example 8 had a protective effect of about 30% at 1 ⁇ M, but was cytotoxic at 10 ⁇ M.
  • mice Eight-week-old male ICR mice were randomly divided into a treatment group and a control group (the number of mice in each group is shown in Figures 12 to 14).
  • the blank control group was injected with normal saline via the tail vein, and then intraperitoneally injected with 22-22.5% body weight of pure water containing 10 ⁇ g/kg vasopressin; the treatment group was injected with different doses of compounds via the tail vein, and then intraperitoneally injected with 22-22.5% body weight of pure water containing 10 ⁇ g/kg vasopressin, and the survival time of the animals within 2 hours was observed and recorded.
  • the compound of Example 1 can effectively increase the survival rate of experimental animals and prolong the survival time of animals at a dose of 4 mg/kg. After administration of the compound of Example 1, the survival rate of animals increased from 16% to 31.1%.
  • Rat pMCAO-24h model TTC staining
  • mice Male SD rats weighing 280-320 g were randomly divided into a vehicle group (10 rats) and a drug administration group (9 rats) and subjected to a pMCAO-24h surgical model.
  • the external carotid artery was used for line entry and the observation endpoint was 24h.
  • Three tail vein injections were performed at 1h, 2h and 3h after embolization.
  • the vehicle control group was injected with saline solvent by tail vein, and the drug administration group was injected with 5mg/kg saline injection of Example 1 compound.
  • TTC staining was performed 24h after surgery to calculate the volume of cerebral infarction and brain edema.
  • the results showed that in terms of the indicators of cerebral infarction and brain edema volume calculated by TTC staining, the brain edema volume of the group treated with Example 1 was lower when the infarction was more severe than that of the solvent control group, indicating that the compound of the present invention has a protective effect in the rat cerebral ischemia model.
  • Male SD rats weighing 280-320g were randomly divided into a vehicle group (28 rats) and a drug administration group (24 rats) and subjected to a pMCAO-48h surgical model.
  • the external carotid artery was used for line entry and the observation endpoint was 48h.
  • Six tail vein injections were performed at 1h, 2h and 3h after embolization and 1h, 2h and 3h after 24h.
  • the vehicle control group was injected with saline solvent in the tail vein, and the drug administration group was injected with 5mg/kg saline injection of Example 1 compound.
  • Neurobehavioral scoring was performed 48h after surgery, and TTC staining was used to calculate the percentage of cerebral infarction.
  • Example 1 can reduce the mortality rate of rats after pMCAO-48h.
  • the results show that the 6-point neurological score is based on the Longa score, and the dead animals are scored 6 points.
  • the specific criteria are: 0 points for no nerve damage, 1 point for walking in a curve, 2 points for turning in circles to one side, 3 points for turning in circles to one side, 4 points for moving/walking only after being stimulated, 5 points for being unable to walk spontaneously and being unconscious, and 6 points for death from stroke.
  • the 6-point score has a significant downward trend. It is suggested that Example 1 can alleviate the neurological damage of rat pMCAO-48h.
  • Example 1 As shown in FIG20 , the results showed that the compound of Example 1 was effectively administered for six times at 5 mg/kg to improve the neurobehavioral function of rats for 48 hours, with a Garcia 18-point score of 7.1, which was significantly improved compared to the vehicle control group score of 5.5.
  • the Garcia sub-item scoring results indicate that the compound of Example 1 can significantly improve the symmetry of the rat's limbs and the tactile response of both sides of the body, and also has a pharmacological effect on the 5-minute spontaneous activity and forelimb extension.
  • TTC staining results showed that the infarct volume was reduced to a certain extent after six administrations of 5 mg/kg of the compound of Example 1.
  • the infarct percentage of the vehicle control group was 50.8% ( Figure 23), and the infarct percentage of the compound of Example 1 group was 44.4% ( Figure 24).
  • HEK-293 cell lines stably expressing hERG potassium channel were used.
  • hERG potassium channel cells were purchased from Creacell (Cat. No.: A-0320). The cell culture method is as follows:
  • HEK-293 cell lines stably expressing hERG potassium channel were cultured in DMEM medium containing 10% fetal bovine serum and 0.8 mg/mL G418 at a temperature of 37°C and a carbon dioxide concentration of 5%.
  • Cell passaging Remove the old culture medium and wash once with PBS, then add 1 mL of TrypLE TM Express solution (Gibco 12604-021) and incubate at 37°C for about 1 minute. When the cells detach from the bottom of the dish, add about 5 mL of complete culture medium preheated at 37°C. Gently blow the cell suspension with a pipette to separate the aggregated cells. Transfer the cell suspension to a sterile centrifuge tube and centrifuge at 1000 rpm for 5 minutes to collect the cells. For expansion or maintenance culture, inoculate the cells in a 10 cm cell culture medium. Each cell culture dish was inoculated with 6105 cells (final volume: 5 mL).
  • the cell density must not exceed 80%.
  • the extracellular solution can be stored for 1 week. After the intracellular solution is prepared, it is divided into 10 mL per tube and stored in a -20°C refrigerator. Freshly thawed intracellular solution is used for daily testing. All intracellular solution should be used up within one week. If it exceeds one week, the old intracellular solution should be discarded and re-prepared.
  • This topic uses the fully automatic patch clamp QPatch 48X (Sophion) device for electrophysiological testing.
  • the prepared cells are placed on the centrifuge of the Qpatch workbench, and the cells are washed by multiple centrifugation/suspension methods, and the cell culture medium is replaced with extracellular fluid.
  • the robotic arm scans the barcodes of the MTP-96 plate and QPlate chip and grabs them to the measurement station.
  • the intracellular fluid and extracellular fluid are respectively drawn from the liquid pool and added to the intracellular fluid pool and cell and compound pool of the QPlate chip.
  • all measurement sites on the QPlate must undergo initial quality control.
  • the quality control process includes drawing cell suspension from the cell container of the centrifuge, and positioning the cells on the chip wells through the pressure controller to establish a high-resistance seal to form a whole-cell recording mode. Once a stable control current baseline is obtained, the test substances can be drawn from the test substance MTP-96 plate in order of concentration and applied to the cells.
  • the voltage stimulation scheme for recording hERG current by whole-cell patch clamp is as follows: After the whole-cell seal is formed, the cell membrane voltage is clamped at -80mV. The clamping voltage is depolarized from -80mV to -50mV for 0.5s (as leakage current detection), then stepped to 30mV for 2.5s, and then quickly restored to -50mV for 4s to stimulate the tail current of the hERG channel. Data is collected repeatedly every 10s to observe the effect of drugs on the hERG tail current. The experimental data is collected by the QPatch screening workstation and stored in the database server.
  • Each drug concentration was administered twice for at least 5 minutes.
  • the current detected in the external solution without compound was used as the control group for each cell, and two cells were tested independently. All electrophysiological experiments were performed at room temperature.
  • the second of the two dosings was used for data analysis.
  • the average of the last three data points before the next dosing concentration was taken for each drug concentration to represent the current value after the action of that concentration.
  • the current value representing each drug concentration was normalized with the reference current value as the blank control, and then the inhibition rate corresponding to each drug concentration was calculated.
  • the hERG inhibition rates of multiple examples at 1 ⁇ M and 10 ⁇ M were tested using the above method and compared with AER-270 (structure shown in the following table), an active ingredient of a clinical drug for cerebral edema. The results are shown in the following table.

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Abstract

La présente invention concerne un composé naphtalène disubstitué et une composition pharmaceutique et son utilisation. Le composé naphtalène disubstitué est représenté par la formule générale (I), la définition de substituants étant détaillée dans la description. L'invention concerne également une composition pharmaceutique du composé et une utilisation du composé dans la protection cellulaire contre l'oedème cérébral ou les maladies du système nerveux.
PCT/CN2024/085564 2023-04-03 2024-04-02 Composé naphtalène disubstitué et composition pharmaceutique et utilisation de celui-ci Pending WO2024208207A1 (fr)

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