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WO2022105810A1 - Composés de résorcinol, leur procédé de préparation et leur utilisation dans des maladies du système nerveux - Google Patents

Composés de résorcinol, leur procédé de préparation et leur utilisation dans des maladies du système nerveux Download PDF

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Publication number
WO2022105810A1
WO2022105810A1 PCT/CN2021/131303 CN2021131303W WO2022105810A1 WO 2022105810 A1 WO2022105810 A1 WO 2022105810A1 CN 2021131303 W CN2021131303 W CN 2021131303W WO 2022105810 A1 WO2022105810 A1 WO 2022105810A1
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compound
alkyl
formula
reaction
substituted
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Chinese (zh)
Inventor
沈敬山
何洋
吴春晖
公绪栋
朱富强
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Lian V Nantong Co Ltd
Shanghai Institute of Materia Medica of CAS
Topharman Shanghai Co Ltd
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Lian V Nantong Co Ltd
Shanghai Institute of Materia Medica of CAS
Topharman Shanghai Co Ltd
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    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/60—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
    • C07C215/50—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
    • C07C215/52—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/62—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/23—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing six-membered aromatic rings and other rings, with unsaturation outside the aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the present invention relates to the fields of medicinal chemistry and chemical synthesis. Specifically, the present invention relates to a class of resorcinol compounds with novel structures, a preparation method thereof, and applications in central nervous system diseases.
  • CBD cannabidiol
  • CBD has improved effects on a variety of neuropsychiatric diseases.
  • CBD has problems such as low oral bioavailability, low melting point, poor physicochemical properties, and poor selectivity of target action, and the low human blood concentration when taken orally as a monotherapy limits its further clinical application.
  • the purpose of the present invention is to develop a class of cannabidiol analogs with improved oral bioavailability and stronger efficacy for the treatment of various central nervous system diseases.
  • the present invention provides a series of cannabidiol analogs with improved oral bioavailability, good physicochemical properties, and stronger medicinal effects, a preparation method thereof, and their application in the preparation of medicines for treating nervous system diseases.
  • R 0 is selected from Preferably, R 0 is
  • R 1 is selected from hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylthio, formyl substituted by C 3 -C 10 cycloalkyl, amino, amino substituted by C 1 -C 6 alkyl, C 1 -C 6 alkanoyl substituted amino, cyano, amino C 1 -C 6 alkyl, cyano C 1 -C 6 alkyl, C 1 -C 6 alkanoyl, sulfonamido (-SO 2 NH 2 ), carbamoyl (-CONH 2 ), carbamoyl substituted by C 1 -C 6 alkyl, carbamoyl substituted by hydroxy C 1 -C 6 alkyl (HO-C 1 -C 6 alkyl- NH-CO-), carbamoyl substituted by C 3 -C 10 cycloalkyl, carboxyl C 1 -C 6 alkyl, C 1 -C 6 alkanesulfonyl,
  • R 2 is selected from C 1 -C 12 alkyl, C 1 -C 12 alkyl substituted with one or more halogens, C 3 -C 10 cycloalkyl, substituted C 3 -C 10 cycloalkyl, or substituted Or unsubstituted -(C 1 -C 3 alkylene)-(C 3 -C 10 cycloalkyl); wherein, the substitution refers to having 1-3 substituents selected from the group consisting of: C 1 - C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 haloalkyl; preferably, R 2 is substituted C 3 -C 10 cycloalkyl; more preferably, R 2 is substituted C 3 - C 10 cycloalkyl, the substituted substituent is C 1 -C 6 alkyl; most preferably, R 2 is substituted cyclopropyl, and the substituted substituent is C 1 -C 6 alkyl;
  • R 3 is selected from H, hydroxyl, -OC(O)-C 1 -C 6 alkyl, -OC(O)(CH 2 )nN(C 1 -C 6 alkyl) 2 ; wherein n is 1-6 any integer;
  • R 1 is selected from hydroxy C 1 -C 4 alkyl, C 1 -C 4 alkylthio, C 3 -C 7 cycloalkyl substituted formyl, amino, C 1 -C 4 Alkyl substituted amino, C 1 -C 4 alkanoyl substituted amino, cyano, amino C 1 -C 4 alkyl, cyano C 1 -C 4 alkyl, C 1 -C 4 alkanoyl, sulfonyl Amino (-SO 2 NH 2 ), carbamoyl (-CONH 2 ), carbamoyl substituted with C 1 -C 4 alkyl, carbamoyl substituted with hydroxy C 1 -C 4 alkyl (HO-C 1 -C 4 alkyl-NH-CO-), carbamoyl substituted by C 3 -C 7 cycloalkyl, carboxyl C 1 -C 4 alkyl, C 1 -C 4 alkanesulfon
  • R 2 is selected from C 1 -C 10 alkyl, C 1 -C 10 alkyl substituted by one or more halogens, C 3 -C 7 cycloalkyl;
  • R 3 is selected from H, hydroxyl, -OC(O)-C 1 -C 4 alkyl, -OC(O)(CH 2 )nN(C 1 -C 4 alkyl) 2 ; wherein n is 1-3 any integer.
  • R 1 is selected from -CH 2 OH, -CH 2 CH 2 OH, -SCH 3 , -SCH 2 CH 3 , Amino, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, cyano, -NHCOCH 3 , -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CN, -CH 2 CH 2 CN, formyl, acetyl, propionyl, sulfonamido (-SO 2 NH 2 ), carbamoyl, N-methylcarbamoyl, N,N -Dimethylcarbamoyl, N-ethylcarbamoyl, N,N-diethylcarbamoyl, -CONHCH 2 CH 2 OH, -CH2CO2H , -CH2CH2CO2H , -SO
  • R is selected from n - butyl, n-pentyl or cyclopropyl
  • R3 is selected from H, hydroxy or -OC(O) -CH3 .
  • the compound of formula (I) is selected from the compounds represented by general formula (I-A):
  • R 1 , R 2 and R 3 are as defined above.
  • the compound of formula (I) is selected from the compounds represented by general formula (I-A-1):
  • the compound of formula (I) is selected from compounds represented by general formula (I-A-1-1):
  • the compound of formula (I) is selected from the following compounds:
  • a second aspect of the present invention provides a method for preparing a compound of formula I-1, comprising the steps of: providing a compound of formula (II) substituted with an aldehyde group, and performing a reduction reaction in the presence of a reducing agent to obtain the compound;
  • reaction formula 1 The steps are shown in reaction formula 1:
  • R 2 and R 0 are as defined above.
  • a method for preparing a compound of formula I-2 comprising the steps of: providing a compound of formula (III), and performing an aminolysis reaction with NH(R 4 ) 2 to obtain the compound, and the step As shown in Reaction 2:
  • R 2 and R 0 are as defined above;
  • R 4 is each independently H, C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl.
  • Equation 3 shows:
  • R 2 and R 0 are as defined above.
  • the method specifically includes the following steps:
  • the products prepared according to the methods of the second, third and fourth aspects of the present invention are provided, and the compound of formula I is obtained by functional group transformation.
  • the functional group conversion reaction is selected from the group consisting of condensation acylation reaction, reduction reaction, acylation reaction, esterification reaction, or a combination thereof.
  • condensation acylation reaction is carried out in the presence of a condensing agent.
  • the condensing agent includes but is not limited to: N,N'-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Imine (EDCI), O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate (TBTU).
  • DCC N,N'-dicyclohexylcarbodiimide
  • EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Imine
  • TBTU O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate
  • the reduction reaction is carried out in the presence of a reducing agent.
  • the reducing agent includes, but is not limited to, hydrogen, ammonium formate, sodium borohydride, potassium borohydride, diisobutylaluminum hydride (DIBAL), and borane.
  • the acylation reaction is carried out in the presence of an acylation reagent.
  • the acylating reagents include but are not limited to: acetyl chloride, acetic anhydride, propionyl chloride, propionic anhydride, and methanesulfonyl chloride.
  • the esterification reaction system includes but is not limited to: thionyl chloride/methanol, thionyl chloride/ethanol.
  • a compound as described in the first aspect or its enantiomer, diastereomer, racemate, and pharmaceutically acceptable inorganic or organic compounds thereof Use of salts, crystalline hydrates and solvates for preparing a pharmaceutical composition or formulation for treating, alleviating and/or preventing central nervous system diseases.
  • the pharmaceutical composition or preparation further comprises other drugs for the treatment of central nervous system diseases.
  • the central nervous system disease is selected from the group consisting of epilepsy, schizophrenia, refractory, intractable or chronic schizophrenia, affective disorder, mental disorder, mood disorder, type I bipolar disorder Affective disorder, bipolar disorder type II, depression, intrinsic depression, major depressive disorder, difficult-to-control depression, dysthymic disorder, cyclic affective disorder, panic attacks, panic disorder, social phobia, Obsessive-compulsive conception and behavior disorder, impulsivity disorder, post-traumatic stress disorder, anxiety disorder, acute stress disorder, hysteria, anorexia nervosa, adaptive disorder, cognitive disorder, autism, pain, mania, Parkinson's disease, Huntington's disease, Alzheimer's disease, various dementias, memory disorders, ADHD, drug addiction, sleep disorders, attention deficit/hyperactivity disorders, tics, or a combination thereof.
  • epilepsy schizophrenia, refractory, intractable or chronic schizophrenia, affective disorder, mental disorder, mood disorder, type I bipolar disorder Affective disorder, bipolar disorder type II,
  • the preparation is an oral preparation or a non-oral preparation.
  • the preparation is selected from the group consisting of tablets, pills, capsules, granules, suspensions, solutions, creams, ointments, powders, suppositories, aerosols, injections or combinations thereof.
  • a pharmaceutical composition in the sixth aspect of the present invention, contains:
  • the antipsychotic drugs include but are not limited to aripiprazole, risperidone, haloperidol, quetiapine, paliperidone, ziprasidone, asenapine, Pipiprazole, olanzapine, clozapine, amisulpride, and cariprazine.
  • the antiepileptic drugs include but are not limited to carbamazepine, lamotrigine, oxcarbazepine, gabapentin, topiramate, zonisamide, lacosamide and valproic acid.
  • the antidepressant drugs include but are not limited to fluoxetine, fluvoxamine, sertraline, escitalopram, amitriptyline, venlafaxine, duloxetine, vortioxetine and citalopram.
  • a method for treating diseases of the central nervous system comprising the step of administering a medically effective amount of the compound described in the first aspect of the present invention or the pharmaceutical combination described in the sixth aspect to a patient in need thereof thing.
  • the patient is a patient with a central nervous system disease.
  • the central nervous system disease is as defined above.
  • the present invention prepares the cannabidiol analogs shown in formula I. Compared with cannabidiol, they have the advantages of improved oral bioavailability, good physicochemical properties, and stronger drug efficacy, and are effective in treating nervous system diseases. It is also superior to CBD, so it can be better used to prepare medicines for preventing, slowing and/or treating nervous system diseases. And the present invention provides methods of making these cannabidiol analogs.
  • the compound of the present invention and “the active ingredient of the present invention” can be used interchangeably, and both refer to formula I with better oral bioavailability, physicochemical properties, and selectivity of target action than CBD. Cannabidiol analogs shown.
  • halogen generally refers to fluorine, chlorine, bromine and iodine; preferably fluorine, chlorine or bromine; more preferably fluorine or chlorine;
  • C 1 -C 12 alkyl refers to a straight or branched chain saturated hydrocarbon group containing 1-12 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , tert-butyl, sec-butyl, n-pentyl, 1-ethylpropyl, isopentyl, neopentyl, isohexyl, 3-methylpentyl or n-hexyl, etc., preferably methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, tert-butyl or pentyl;
  • C 1 -C 6 alkylthio refers to a straight or branched chain alkylthio group containing 1 to 6 carbon atoms, for example, methylthio, ethylthio, n-propylthio, isopropylthio, n-butyl Thio, isobutylthio, tert-butylthio, sec-butylthio, n-pentylthio, isopentylthio, neopentylthio or n-hexylthio, etc., preferably methylthio, ethylthio, n-propyl Thio, isopropylthio, n-butylthio, isobutylthio or tert-butylthio;
  • C 1 -C 6 alkanoyl refers to a straight or branched chain alkanoyl group containing 1 to 6 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, tert-butyryl or hexanoyl, etc.;
  • Carbamoyl substituted by C 1 -C 6 alkyl means that the hydrogen atom on the carbamoyl group is substituted with 1 or 2 identical or different C 1 -C 6 alkyl groups, such as -CONHMe, -CONHEt, -CON(Me)Et, -CONEt 2 or -CONMe 2 , etc.;
  • Hydro C 1 -C 6 alkyl refers to a straight or branched chain alkyl group containing 1 to 6 carbon atoms in which one carbon atom is attached to a hydroxyl group, such as -CH 2 OH, -CH 2 CH 2 OH, -CH ( OH)CH 3 , -CH 2 CH 2 CH 2 OH, -CH 2 CH 2 CH 2 CH 2 OH or -CH 2 CH(CH 3 )CH 2 OH, etc.;
  • Amino C 1 -C 6 alkyl refers to one carbon atom of a straight or branched chain alkyl group containing 1-6 carbon atoms attached to an amino group, such as -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH ( NH2 ) CH3 , -CH2CH2CH2NH2 or -CH2CH2CH2CH2NH2 etc .;
  • Amino C 1 -C 6 alkyl substituted with C 1 -C 6 alkyl means that the hydrogen atom on the amino group is substituted with 1 or 2 identical or different C 1 -C 6 alkyl groups, eg -CH 2 NHMe or -CH 2 CH 2 NEt 2 etc.;
  • Carbamoyl C 1 -C 6 alkyl refers to one carbon atom of a straight or branched chain alkyl group containing 1-6 carbon atoms attached to the carbonyl carbon of the carbamoyl group, for example -CH 2 CONH 2 , - CH 2 CH 2 CONH 2 , -CH(CONH 2 )CH 3 or -CH 2 CH 2 CH 2 CONH 2 , etc.;
  • Carbamoyl C 1 -C 6 alkyl substituted by C 1 -C 6 alkyl means that the amino hydrogen atom on the carbamoyl C 1 -C 6 alkyl group is replaced by 1 or 2 identical or different C 1 -C 6 alkyl substitution, such as -CH 2 CONHMe, -CH 2 CH 2 CONHEt, -CH 2 CH 2 CONMe 2 or -CH 2 CONEt 2 , etc.;
  • Cyano C 1 -C 6 alkyl refers to a straight or branched chain alkyl group containing 1 to 6 carbon atoms where one carbon atom is attached to a cyano group, such as cyanomethyl, 2-cyanoethyl, 1-cyanoethyl, 3-cyanopropyl, 4-cyanobutyl or 5-cyanopentyl, etc.;
  • Carboxy C 1 -C 6 alkyl refers to a carbon atom attached to a carboxyl group with a straight or branched chain alkyl group containing 1 to 6 carbon atoms, such as carboxymethyl, 2-carboxyethyl, 1-carboxyethyl group, 3-carboxypropyl, 4-carboxybutyl or 5-carboxypentyl, etc.;
  • C 1 -C 6 alkanesulfonyl refers to a straight or branched chain alkanesulfonyl group containing 1-6 carbon atoms, such as methanesulfonyl, ethanesulfonyl or propanesulfonyl, etc.;
  • Amino substituted with C 1 -C 6 alkyl means that the hydrogen atom on the amino group is substituted with 1 or 2 identical or different C 1 -C 6 alkyl or C 1 -C 6 alkanoyl groups, eg -NHMe or -NEt 2 etc;
  • C 3 -C 10 cycloalkyl refers to a saturated cyclic hydrocarbon group containing 3-10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.;
  • CBD Cannabidiol
  • Cannabidiol is a non-psychoactive component from the cannabis plant that has various pharmacological effects on the nervous system. Its structural formula is as follows:
  • CBD has a broad spectrum of pharmacological effects.
  • CBD1/CB2 cannabinoid receptors
  • CBD can also act on G protein-coupled receptors and ion channels related to neuropsychiatric diseases.
  • serotonin serotonin
  • 5-HT serotonin
  • glycine receptors glycine receptors
  • adenosine receptors transient receptor potential ion channels
  • TRP transient receptor potential
  • the uptake of neurotransmitters such as , 5-HT and GABA and the uptake of endocannabinoids by cells can also affect mitochondrial calcium ion storage and block low-voltage-activated T-type calcium ion channels.
  • compositions and methods of administration are provided.
  • the "pharmaceutically acceptable inorganic or organic salts” in the present invention are compounds represented by the general formula (I) formed with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, nitric acid or phosphoric acid. salts, salts with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, maleic acid, tartaric acid, malic acid, fumaric acid, methanesulfonic acid, citric acid, etc., or with sodium hydroxide, Sodium, potassium, calcium or ammonia salts formed from bases such as potassium hydroxide, calcium hydroxide or ammonia.
  • “Pharmaceutically acceptable salts” also include their solvates, exemplified by hydrates, alcoholates, and the like.
  • the present invention also provides the compound represented by the general formula (I), its enantiomers, diastereomers, racemates, and pharmaceutically acceptable salts, crystalline hydrates and pharmaceutically acceptable salts thereof according to the present invention.
  • the present invention also provides a method for treating and/or preventing diseases of the central nervous system, comprising administering the compound represented by the general formula (I) of the present invention, its enantiomer, non- One or more mixtures of enantiomers, racemates, and pharmaceutically acceptable salts, crystalline hydrates and solvates thereof.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the compound represented by the above general formula (I), its enantiomers, diastereomers, racemates, and pharmaceutically One or more mixtures of acceptable salts, crystalline hydrates and solvates, and optional pharmaceutically acceptable carriers.
  • the pharmaceutical composition can be used for treating or preventing diseases of the central nervous system.
  • the present invention also provides a method for preparing the pharmaceutical composition, comprising compounding the compound represented by the above general formula (I), its enantiomer, diastereomer, racemate, and its pharmaceutical A mixture of one or more of the above acceptable salts, crystalline hydrates and solvates is mixed with a pharmaceutically acceptable carrier.
  • compositions include those suitable for oral, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration or administration by implants pharmaceutical composition.
  • various pharmaceutical preparation forms can be selected according to the purpose of treatment, generally including: tablets, pills, capsules, granules, suspensions, solutions, creams, ointments, powders, suppositories, gas Aerosols and injections, etc.
  • compositions include aqueous and non-aqueous sterile injectables.
  • the compositions can be presented in unit-dose or multi-dose containers, such as sealed vials and ampoules, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, such as water, before use.
  • a sterile liquid carrier such as water
  • transdermal administration eg gels, patches or sprays are contemplated.
  • Compositions or formulations suitable for pulmonary administration such as by nasal inhalation, include fine dusts or mists that can be generated by means of metered-dose pressurized aerosols, nebulizers or insufflators.
  • the precise dosage and schedule of administration of the composition will necessarily depend on the therapeutic or nutritional effect to be achieved and may vary with the particular formulation, route of administration, and age and condition of the individual subject to which the composition is administered.
  • the pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or carrier within a safe and effective amount.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention/dose, more preferably, 10-1000 mg of the compound of the present invention/dose.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid filler or gelling substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity. "Compatibility” as used herein means that the components of the composition can be admixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • Examples of pharmaceutically acceptable carrier moieties include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween) ), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate
  • the pharmaceutical composition is an injection, a capsule, a tablet, a pill, a powder or a granule.
  • the mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, and the like.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylform
  • compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • the therapeutic methods of the present invention may be administered alone or in combination with other therapeutic means or therapeutic agents.
  • a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) in need of treatment, and the dose is the effective dose considered pharmaceutically, for a 60kg body weight, the daily dose is
  • the administration dose is usually 1 to 2000 mg, preferably 50 to 1000 mg.
  • the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.
  • the present invention also provides a method for the preparation of the compound of general formula (I) and its intermediates, the compound can be prepared by any one of the following methods, and the starting materials used in the present invention are commercially purchased or according to known synthesis of similar compounds Method preparation:
  • R 2 and R 0 are the same as above;
  • R 2 and R 0 are as defined above;
  • R 4 is each independently H, C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, and C 3 -C 10 cycloalkyl.
  • the third method includes the following steps:
  • R 2 and R 0 are the same as above;
  • the compounds of formula I obtained by methods 1 to 3 are obtained by functional group transformation.
  • the functional group conversion reaction is, for example, by condensation acylation reaction, reduction reaction, acylation reaction, esterification reaction, and the like.
  • the condensation acylation reaction is carried out in the presence of a condensing agent, and the condensing agent includes but is not limited to: N,N'-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylene) Aminopropyl) carbodiimide (EDCI), O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate (TBTU), etc.
  • DCC N,N'-dicyclohexylcarbodiimide
  • EDCI 1-ethyl-3-(3-dimethylene) Aminopropyl) carbodiimide
  • TBTU O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate
  • the reduction reaction is performed in the presence of a reducing agent, and the reducing agent includes, but is not limited to, hydrogen, ammonium formate, sodium borohydride, potassium borohydride, diisobutylaluminum hydride (DIBAL), borane and the like.
  • a reducing agent includes, but is not limited to, hydrogen, ammonium formate, sodium borohydride, potassium borohydride, diisobutylaluminum hydride (DIBAL), borane and the like.
  • the acylation reaction is performed in the presence of an acylating reagent, including but not limited to: acetyl chloride, acetic anhydride, propionyl chloride, propionic anhydride, methanesulfonyl chloride, and the like.
  • an acylating reagent including but not limited to: acetyl chloride, acetic anhydride, propionyl chloride, propionic anhydride, methanesulfonyl chloride, and the like.
  • the esterification reaction system includes but is not limited to: thionyl chloride/methanol, thionyl chloride/ethanol and the like.
  • the compound of the present invention has better physicochemical properties and oral bioavailability.
  • the compounds of the present invention have good effects on cannabinoid CB1 and CB2 receptors, and can be used to treat various diseases related to the dysfunction of cannabinoid CB1 and CB2 receptors.
  • the central nervous system activity of the compound of the present invention is better than that of cannabidiol (CBD), and it has the characteristics of low onset dose, small toxic and side effects, etc., and can be used for the treatment of various central nervous system diseases, such as epilepsy, Parkinson's disease, psychosis It has good clinical application prospects in schizophrenia, bipolar disorder, depression, anxiety, mania, ADHD, drug addiction or neuralgia.
  • CBD cannabidiol
  • Methyl cannabidiolate 1-1 (5 g, 13.4 mmol) was dissolved in ammonia ethanol, the tube was sealed and refluxed for 36 h, the reaction solution was concentrated to dryness, and 202 mg of the title compound 4 was obtained by column chromatography as a white solid.
  • Methyl cannabidiolate 1-1 (100 mg, 0.27 mmol) was dissolved in 2 ml of cyclopropylamine solution, and the tube was sealed at 110° C. to react overnight. The dry solvent was concentrated, and 12.7 mg of the title compound was obtained by column chromatography. ESI-MS m/z 398.33(M+H) + , 396.19(M–H) – .
  • Methyl cannabidiolate 1-1 (100 mg, 0.27 mmol) was dissolved in 2 ml of amylamine, and heated to reflux overnight. TLC showed that the starting material was almost completely reacted, the solvent was concentrated to dryness, and 40 mg of the title compound was obtained by column chromatography. ESI-MS m/z 429.28(M+2H) + , 426.27(M–H) – .
  • Triphenylpropylphosphorus bromide (8.6g, 24.3mmol, 5.0eq.) was placed in a three-necked flask, replaced with nitrogen three times, THF (15mL) was added, and bis(trimethylsilyl) potassium amide ( 24mL, 23.8mmol, 4.9eq.), stirred for 30min, 24-c (1g, 4.85mmol, 1.0eq.) was dissolved in 25mL of THF, and slowly added to the reaction system. The reaction was stirred at 0 °C for 1 h, and the completion of the reaction was monitored by TLC.
  • 24-i (780mg, 2.68mmol, 1.0eq) was placed in a reaction flask, N 2 was replaced 3 times, 30mL DCM was added, the temperature was lowered to -65°C, BBr 3 (2.01g, 8.04mmol, 3.0eq) was slowly added, and the reaction was carried out. For 2 hours, the reaction was naturally heated overnight, the reaction was monitored by TLC, extracted with saturated brine, dried and concentrated, and about 440 mg of compound 24-j was obtained by column chromatography.
  • Step ten
  • the compound 27-c (200 mg, 0.7 mmol, 1.0 eq.) was placed in a three-necked flask, N 2 was replaced three times, dichloromethane (10 mL) was added, the system was cooled to -68 °C, and 1M diisobutylaluminum hydride was slowly added (1.77 mL, 1.77 mmol, 2.51 eq.). The reaction was carried out at -68°C for 1.5 h, the completion of the reaction was monitored by TLC, quenched, the insolubles were filtered, extracted with dichloromethane, and 170 mg of the target compound 27-d was obtained by column chromatography.
  • Triphenylpropylphosphonium bromide (403mg, 1.045mmol, 3.0eq.) was placed in a three-necked flask, replaced by N 3 times, THF 5mL was added, and bis(trimethylsilyl)potassium amide (1mL, 1.01mL) was added under an ice bath mmol, 2.9eq.) was stirred in an ice bath for 30min, 27-d (100mg, 0.348mmol, 1.0eq.) was dissolved in 5mL of THF and slowly added to the reaction system. The reaction was stirred at 0° C.
  • 27-f (200mg, 0.634mmol, 1.0eq.) was placed in a reaction flask, nitrogen was replaced, 5mL of THF was added, the temperature was lowered to -65°C, n-BuLi (0.38mL, 0.95mmol, 1.5eq.) was slowly added, at - The reaction was carried out at 60 to -65°C for one hour, and the reaction system was replaced with CO 2 . The reaction was monitored by TLC, quenched, extracted with ethyl acetate, and subjected to column chromatography to give 27-g 120 mg.
  • reaction system was slowly added, and the reaction was carried out at room temperature for 1 h (22 °C). TLC monitoring the completion of the reaction, quenched with ammonium chloride, added a small amount of dilute hydrochloric acid to make it acidic, extracted with dichloromethane, dried and concentrated, and subjected to column chromatography to obtain the target compound 27-h.
  • 9-b (100mg, 0.56mmol, 1.0eq) was dissolved in 5mL of acetonitrile, NBS (105mg, 0.59mmol, 1.05eq) was added, the reaction was stirred at room temperature for 4 hours, the reaction was monitored by TLC, quenched, extracted with ethyl acetate, Concentration and column chromatography gave about 60 mg of 9-c.
  • 9-c (200 mg, 0.78 mmol, 1.0 eq) was placed in a reaction flask, and 5 mL of tetrahydrofuran was added after nitrogen replacement. Cool down to -62°C, slowly add n-butyllithium (0.47mL, 1.17mmol, 1.5eq), control the reaction temperature to stir between -62°C and -64°C for 1 hour, then replace the gas in the reaction flask with CO 2 , and continued to stir at -60°C to -50°C for 1 hour, the reaction was monitored by TLC, quenched, extracted with ethyl acetate, concentrated, and about 130 mg of 9-d was obtained by column chromatography.
  • 26-a (1.17g, 3.84mmol, 1.0eq) was placed in a reaction flask, N 2 was replaced 3 times, DCM was added, the temperature was lowered to -10°C, BBr 3 (2.88g, 11.51mmol, 3.0eq) was slowly added, and the reaction was carried out. 20min, the reaction was naturally heated for 2h, the reaction was monitored by TLC, the reaction solution was slowly added dropwise to ice water to quench, extracted with DCM, dried and concentrated, and the compound 26-b was obtained by column chromatography.
  • test drug was mixed with 5% DMSO and added Mix HS 15, then add 90% normal saline to prepare a solution of appropriate concentration, which is ready for use.
  • mice were screened on the hot plate, the screening time was 45 s, and the temperature of the hot plate was 55 °C. The mice with similar heat pain latency were selected, and the mice that were too sensitive and too dull to pain were excluded.
  • the MPE percentage was calculated using the following formula: [(T1-T0)/T0]*100, the latency before and after drug injection were T0 and T1, respectively, and the results were expressed as mean ⁇ SD.
  • the thermal pain latency and the percentage of MPE were compared in each group before and after administration, and the results were calculated by one-way analysis of variance.
  • the drug groups (the compounds of Example 1, Example 4 and Example 12) all showed significant analgesic effect, while CBD did not show significant analgesic effect at the dose of 100 mpk.
  • the test drug was mixed with 5% DMSO and added Mix HS 15, then add 90% normal saline to prepare a solution of appropriate concentration, which is ready for use.
  • Male ICR mice about 32g. The animals were randomly divided into blank control group and each test drug group, with 8 animals in each group, and the mice in each group were given the vehicle prescription or each test drug by intraperitoneal injection.
  • the water level in the forced swimming equipment was 45 cm, the water temperature was 25 °C, and the mice were placed in the experimental room to adapt to the environment for 1 h before the start of the experiment. At the beginning of the experiment, the mice were placed in the equipment for 6 minutes. The whole process was recorded with a camera. When analyzing the data, only the immobility time of the mice in the last 4 minutes was counted.
  • the drug groups (the compounds of Example 1 and Example 4) all showed significant antidepressant-like effects at a low dose of 3 mg/kg, while CBD only showed significant antidepressant-like effects at a dose of 30 mpk.
  • the test drug was mixed with 10% DMSO and added Mix HS 15, then add 80% normal saline to prepare a solution of appropriate concentration, which is ready to use.
  • Male ICR mice about 35g. The animals were randomly divided into blank control group and each test drug group, with 8 animals in each group. The mice in each group were given the vehicle prescription or each test drug by subcutaneous injection.
  • Stress-induced hyperthermia SIH
  • Stress can be physical or emotional, or both, causing a rapid rise in body temperature (maximum after 10 to 15 minutes). Depending on the intensity and duration of stress, temperature returns to basal levels within 60-120 minutes.
  • mice When mice were pre-administered with anxiolytics, such as benzodiazepines or 5-HT 1A receptor agonists, SIH responses were reduced, making it a relatively simple procedure for screening for anxiolytics.
  • Statistical analysis of T1 value, T2 value and ⁇ T value (Reference: Current Protocols in Pharmacology 5.16.1-5.16.12, June 2009).
  • the drug groups showed significant antidepressant-like effects at doses of 3-30mg/kg, while CBD only showed significant anti-anxiety-like effects at doses of 100mpk.
  • test drug was mixed with 5% DMSO and added Mix HS 15, then add 90% normal saline to prepare a solution of appropriate concentration, which is ready for use.
  • Male ICR mice about 32g. Animals were randomly divided into blank control group and each test drug group, with 8-10 animals in each group, and the mice in each group were given the vehicle prescription or each test drug by intraperitoneal injection.
  • rat cage (6cm x 48cm x 20cm), fresh litter, glass beads of different colors (diameter 15mm, about 5.2g, wash and dry after each use); animals should be kept in a room with a 12-hour light-dark cycle , all mice obtained food and water autonomously. 5 cm thick fresh litter was added to the rat cage, and the litter was flattened. Put 20 glass beads into the cage (4 rows * 5 columns), put the mice in the corner as far away from the glass beads as possible 15 minutes after administration, cover the cage, and carefully put the mice back after 30 minutes; The number of glass beads buried in the test cage was counted.
  • the compound of the present invention significantly reduces the number of embedded beads in the dose range of 3-30 mg/kg, showing a significant antidepressant-like effect, while CBD only shows a significant effect at the dose of 30-60 mg/kg in this experiment. Antidepressant-like effects.
  • test drug was mixed with 5% DMSO and added Mix well, then add 90% physiological saline to prepare a solution of appropriate concentration, which is prepared and used now.
  • Male ICR mice about 32g. The animals were randomly divided into blank control group and each test drug group, with 8-10 animals in each group, and the mice in each group were given the vehicle prescription or each test drug by intraperitoneal injection.
  • Elevated plus-maze (EPM) experimental device made of medical organic board, two opposite open arms (open arms, length ⁇ width are 30cm ⁇ 5cm respectively), two opposite closed arms (closed arms, length ⁇ width ⁇ height are 30cm ⁇ 5cm ⁇ 15cm respectively) and a central platform (centre platform, 5cm ⁇ 5cm) connecting the four arms forms a cross shape, 40cm from the ground.
  • the mouse elevated plus maze video acquisition system was purchased from Shanghai Shift Information Technology Co., Ltd.
  • the animal movement trajectory within 5 minutes was recorded by the video acquisition system of the Elevated Plus Maze, and the number of times the mice entered the open arm and the cumulative residence time in the open arm within 5 minutes were recorded and counted by the video analysis system.
  • the compound of the present invention significantly increases the open-arm residence time in the dose range of 3-30 mg/kg, and shows a significant anxiolytic-like effect, while CBD shows a significant effect only when the dose is above 30 mg/kg in this experiment.
  • R 2 in the general formula (I) is a substituted C 3 -C 10 cycloalkyl (such as the compound prepared in Example 9), the compound has a higher blood concentration.
  • Solubility was tested by high performance liquid chromatography with external standard method.
  • Solution preparation Test solution: Take 1mg of the test product and put it in a 1ml centrifuge tube, add 10mM KH 2 PO 4 PH6.8 solution (1ml), put it in a shaker and shake it at 25°C for 30min, take it out and set it in a centrifuge After centrifugation for 1.5 min, the supernatant was injected.
  • Reference substance solution take about 1 mg of the reference substance and put it in a 1 ml centrifuge tube, dissolve it in 1 ml of acetonitrile, shake well, take 1 ml of the obtained solution and put it in a 5 ml measuring bottle, dilute it with acetonitrile to the mark, and shake well. The solubility results are shown in the table below:
  • the solubility of the example compounds is significantly improved, which is beneficial to drug absorption.

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Abstract

La présente invention concerne des composés de résorcinol, leur procédé de préparation et leur utilisation dans des maladies du système nerveux. Plus particulièrement, la présente invention concerne un composé de résorcinol représenté par la formule (I), un énantiomère, un diastéréoisomère et un racémate de celui-ci et un mélange des trois, un sel inorganique ou organique pharmaceutiquement acceptable, un hydrate cristallin et un solvate. La présente invention concerne en outre un procédé de préparation des composés et une utilisation des composés dans la préparation de médicaments destinés à la prévention et/ou au traitement de maladies du système nerveux central.
PCT/CN2021/131303 2020-11-17 2021-11-17 Composés de résorcinol, leur procédé de préparation et leur utilisation dans des maladies du système nerveux Ceased WO2022105810A1 (fr)

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