WO2022105810A1 - Resorcinol compounds, preparation method therefor and use thereof in nervous system diseases - Google Patents
Resorcinol compounds, preparation method therefor and use thereof in nervous system diseases Download PDFInfo
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- 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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- 238000007619 statistical method Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000009182 swimming Effects 0.000 description 1
- 210000003568 synaptosome Anatomy 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- 235000007586 terpenes Nutrition 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229960004394 topiramate Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- UAEJRRZPRZCUBE-UHFFFAOYSA-N trimethoxyalumane Chemical compound [Al+3].[O-]C.[O-]C.[O-]C UAEJRRZPRZCUBE-UHFFFAOYSA-N 0.000 description 1
- XMQSELBBYSAURN-UHFFFAOYSA-M triphenyl(propyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CCC)C1=CC=CC=C1 XMQSELBBYSAURN-UHFFFAOYSA-M 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229960004688 venlafaxine Drugs 0.000 description 1
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 1
- 229960002263 vortioxetine Drugs 0.000 description 1
- YQNWZWMKLDQSAC-UHFFFAOYSA-N vortioxetine Chemical compound CC1=CC(C)=CC=C1SC1=CC=CC=C1N1CCNCC1 YQNWZWMKLDQSAC-UHFFFAOYSA-N 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 229960000607 ziprasidone Drugs 0.000 description 1
- MVWVFYHBGMAFLY-UHFFFAOYSA-N ziprasidone Chemical compound C1=CC=C2C(N3CCN(CC3)CCC3=CC=4CC(=O)NC=4C=C3Cl)=NSC2=C1 MVWVFYHBGMAFLY-UHFFFAOYSA-N 0.000 description 1
- 229960002911 zonisamide Drugs 0.000 description 1
- UBQNRHZMVUUOMG-UHFFFAOYSA-N zonisamide Chemical compound C1=CC=C2C(CS(=O)(=O)N)=NOC2=C1 UBQNRHZMVUUOMG-UHFFFAOYSA-N 0.000 description 1
Classifications
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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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- 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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- 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
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- 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
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- 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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- 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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- 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
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- 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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- 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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- 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
The present invention relates to resorcinol compounds, a preparation method therefor and a use thereof in nervous system diseases. Specifically, the present invention provides a resorcinol compound represented by formula (I), an enantiomer, diastereomer and racemate thereof and a mixture of the three, a pharmaceutically acceptable inorganic or organic salt, a crystalline hydrate and a solvate. The present invention further provides a preparation method for the compounds and a use of the compounds in the preparation of medicines for preventing and/or treating central nervous system diseases.
Description
本发明涉及药物化学和化学合成领域。具体而言,本发明涉及一类结构新颖的间苯二酚类化合物,及其制备方法以及在中枢神经系统疾病中的应用。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.
1940年,研究者从植物大麻中分离得到了大麻二酚(Cannabidiol,CBD),随后于1963年鉴定了其化学结构,结构上含间苯二酚和萜烯模块。在500余个植物大麻来源的天然化合物中,CBD因其广泛的药理学作用与功效而受到越来越多的关注。In 1940, researchers isolated cannabidiol (CBD) from the plant cannabis, and then identified its chemical structure in 1963, which contains resorcinol and terpene modules. Among the more than 500 natural compounds derived from the plant cannabis, CBD has received increasing attention due to its wide range of pharmacological effects and efficacy.
2005年GW公司研发的
(THC/CBD含量比值为1的口腔黏膜喷雾剂)获批上市,用于多发性硬化症的治疗以及缓解癌症相关的疼痛。2018年6月,FDA批准了GW公司的CBD口服液上市,商品名为
用于治疗两岁及以上患者的Dravet综合征和Lennox-Gastaut综合征引起的癫痫。除了在神经精神系统疾病领域的应用以外,CBD还在心血管、肿瘤等疾病领域展现出潜在的临床应用价值。
Developed by GW in 2005 (Oral mucosal spray with a THC/CBD content ratio of 1) approved for the treatment of multiple sclerosis and relief of cancer-related pain. In June 2018, the FDA approved the listing of GW's CBD oral liquid under the trade name of For the treatment of epilepsy due to Dravet syndrome and Lennox-Gastaut syndrome in patients two years of age and older. In addition to its application in the field of neuropsychiatric diseases, CBD has also shown potential clinical application value in the fields of cardiovascular, tumor and other diseases.
临床和临床前研究发现,CBD对多种神经精神疾病均有改善作用。然而,CBD存在口服生物利用度低,熔点低,理化性质差,靶点作用选择性差等问题,且作为单一疗法口服时较低的人体血药浓度限制了其进一步的临床应用。Clinical and preclinical studies have found that CBD has improved effects on a variety of neuropsychiatric diseases. However, 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.
因此,本领域迫切需要开发一类口服生物利用度提高、药效更强的新型大麻二酚类似物以用于各种中枢神经系统疾病的治疗。Therefore, there is an urgent need in the art to develop a new class of cannabidiol analogs with improved oral bioavailability and stronger efficacy for the treatment of various central nervous system diseases.
发明内容SUMMARY OF THE INVENTION
本发明的目的在于开发一类口服生物利用度提高、药效更强的大麻二酚类似物以用于各种中枢神经系统疾病的治疗。具体地,本发明提供了一系列口服生物利用度提高、理化性质好,药效更强的大麻二酚类似物及其制备方法,以及其在制备治疗神经系统疾病的药物中的应用。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. Specifically, 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.
在本发明的第一方面,提供了一种化合物或其对映异构体、非对映异构体、外消旋体、以及其药学上可接受的无机或有机盐、结晶水合物及溶剂合物,所述化合物为式I所示:In the first aspect of the present invention, there is provided a compound or its enantiomer, diastereomer, racemate, and pharmaceutically acceptable inorganic or organic salts, crystalline hydrates and solvents thereof compound, the compound is shown in formula I:
式中,In the formula,
R
1选自羟基C
1-C
6烷基、C
1-C
6烷硫基、C
3-C
10环烷基取代的甲酰基、氨基、被C
1-C
6烷基取代的氨基、被C
1-C
6烷酰基取代的氨基、氰基、氨基C
1-C
6烷基、氰基C
1-C
6烷基、C
1-C
6烷酰基、磺酰氨基(-SO
2NH
2)、氨基甲酰基(-CONH
2)、被C
1-C
6烷基取代的氨基甲酰基、被羟基C
1-C
6烷基取代的氨基甲酰基(HO-C
1-C
6烷基-NH-CO-)、被C
3-C
10环烷基取代的氨基甲酰基、羧基C
1-C
6烷基、C
1-C
6烷磺酰基、被C
1-C
6烷基取代的氨基C
1-C
6烷基、被C
1-C
6烷酰基取代的氨基C
1-C
6烷基、氨基甲酰基C
1-C
6烷基或被C
1-C
6烷基取代的氨基甲酰基C
1-C
6烷基;
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, amino substituted by C 1 -C 6 alkyl C 1 -C 6 alkyl, amino C 1 -C 6 alkyl substituted with C 1 -C 6 alkanoyl, carbamoyl C 1 -C 6 alkyl or aminomethyl substituted with C 1 -C 6 alkyl Acyl C 1 -C 6 alkyl;
R
2选自C
1-C
12烷基、被一个或多个卤素取代的C
1-C
12烷基、C
3-C
10环烷基、取代的C
3-C
10环烷基、或取代或未取代的-(C
1-C
3亚烷基)-(C
3-C
10环烷基);其中,所述的取代指具有1-3个选自下组的取代基:C
1-C
6烷基、C
1-C
6烯基、C
1-C
6卤代烷基;优选地,R
2为取代的C
3-C
10环烷基;更优选地,R
2为取代的C
3-C
10环烷基,所述取代的取代基为C
1-C
6烷基;最优选地,R
2为取代的环丙基,所述取代的取代基为C
1-C
6烷基;
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选自H、羟基、-OC(O)-C
1-C
6烷基、-OC(O)(CH
2)nN(C
1-C
6烷基)
2;其中n为1-6的任意整数;
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;
且式I不包括选自下组的化合物:and Formula I does not include compounds selected from the group consisting of:
在另一优选例中,R
1选自羟基C
1-C
4烷基、C
1-C
4烷硫基、C
3-C
7环烷基取代的甲酰基、氨基、被C
1-C
4烷基取代的氨基、被C
1-C
4烷酰基取代的氨基、氰基、氨基C
1-C
4烷基、氰基C
1-C
4烷基、C
1-C
4烷酰基、磺酰氨基(-SO
2NH
2)、氨基甲酰 基(-CONH
2)、被C
1-C
4烷基取代的氨基甲酰基、被羟基C
1-C
4烷基取代的氨基甲酰基(HO-C
1-C
4烷基-NH-CO-)、被C
3-C
7环烷基取代的氨基甲酰基、羧基C
1-C
4烷基、C
1-C
4烷磺酰基、被C
1-C
4烷基取代的氨基C
1-C
4烷基、被C
1-C
4烷酰基取代的氨基C
1-C
4烷基、氨基甲酰基C
1-C
4烷基或被C
1-C
4烷基取代的氨基甲酰基C
1-C
4烷基;
In another preferred example, 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 alkanesulfonyl, by C 1 - C 4 alkyl substituted amino C 1 -C 4 alkyl, C 1 -C 4 alkanoyl substituted amino C 1 -C 4 alkyl, carbamoyl C 1 -C 4 alkyl or C 1 -C 4 alkyl substituted 4 alkyl-substituted carbamoyl C 1 -C 4 alkyl;
R
2选自C
1-C
10烷基、被一个或多个卤素取代的C
1-C
10烷基、C
3-C
7环烷基;
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选自H、羟基、-OC(O)-C
1-C
4烷基、-OC(O)(CH
2)nN(C
1-C
4烷基)
2;其中n为1-3的任意整数。
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.
在另一优选例中,R
1选自-CH
2OH、-CH
2CH
2OH、-SCH
3、-SCH
2CH
3、
氨基、N-甲基氨基、N-乙基氨基、N,N-二甲基氨基、N,N-二乙基氨基、氰基、-NHCOCH
3、-CH
2NH
2、-CH
2CH
2NH
2、-CH
2CN、-CH
2CH
2CN、甲酰基、乙酰基、丙酰基、磺酰氨基(-SO
2NH
2)、氨基甲酰基、N-甲基氨基甲酰基、N,N-二甲基氨基甲酰基、N-乙基氨基甲酰基、N,N-二乙基氨基甲酰基、-CONHCH
2CH
2OH、
-CH
2CO
2H、-CH
2CH
2CO
2H、-SO
2CH
3、-CH
2NHMe、-CH
2NMe
2、-CH
2NHCOCH
3、-CH
2CONH
2、-CH
2CONHMe或-CH
2CONMe
2;
In another preferred embodiment, 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 , -SO2CH3 , -CH2NHMe , -CH2NMe2 , -CH2NHCOCH3 , -CH2CONH2 , -CH2CONHMe or -CH 2 CONMe 2 ;
R
2选自正丁基、正戊基或环丙基;
R is selected from n - butyl, n-pentyl or cyclopropyl;
R
3选自H、羟基或-OC(O)-CH
3。
R3 is selected from H, hydroxy or -OC(O) -CH3 .
在另一优选例中,所述式(I)化合物,选自通式(I-A)所示的化合物:In another preferred embodiment, the compound of formula (I) is selected from the compounds represented by general formula (I-A):
式中,R
1、R
2、R
3如上定义。
In the formula, R 1 , R 2 and R 3 are as defined above.
在另一优选例中,所述式(I)化合物选自通式(I-A-1)所示的化合物:In another preferred embodiment, the compound of formula (I) is selected from the compounds represented by general formula (I-A-1):
在另一优选例中,所述式(I)化合物选自通式(I-A-1-1)所示的化合物:In another preferred example, the compound of formula (I) is selected from compounds represented by general formula (I-A-1-1):
在另一优选例中,所述式(I)化合物选自下列化合物:In another preferred embodiment, the compound of formula (I) is selected from the following compounds:
在本发明的第二方面提供了一种制备式I-1化合物的方法,包括步骤:提供醛 基取代的式(II)化合物,在还原剂存在下发生还原反应得到所述化合物;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;
所述步骤如反应式1所示:The steps are shown in reaction formula 1:
式I-1中,R
2、R
0如上定义。
In formula I-1, R 2 and R 0 are as defined above.
在本发明的第三方面,提供了一种制备式I-2化合物的方法,包括步骤:提供式(III)化合物,和NH(R
4)
2经氨解反应得到所述化合物,所述步骤如反应式2所示:
In a third aspect of the present invention, there is provided 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:
式I-2中,In formula I-2,
R
2、R
0如上定义;
R 2 and R 0 are as defined above;
R
4各自独立地为H、C
1-C
6烷基、羟基C
1-C
6烷基、C
3-C
10环烷基。
R 4 is each independently H, C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl.
在本发明的第四方面,提供了一种制备式I-3化合物的方法,包括步骤:以式(II)为原料,经两步反应得到式(I-3)化合物,所述步骤如反应式3所示:In the fourth aspect of the present invention, there is provided a method for preparing a compound of formula I-3, comprising the steps of: taking formula (II) as a raw material, and obtaining a compound of formula (I-3) through a two-step reaction, the steps are as follows: Equation 3 shows:
式I-3中,In formula I-3,
R
2、R
0如上定义。
R 2 and R 0 are as defined above.
在另一优选例中,所述方法具体包括以下步骤:In another preferred embodiment, the method specifically includes the following steps:
1)式(II)化合物在碱存在下和硝基甲烷在催化剂存在下发生Henry反应,生成式(IV)化合物;1) Henry reaction of the compound of formula (II) and nitromethane in the presence of a catalyst in the presence of a base generates a compound of formula (IV);
2)式(IV)化合物在还原剂存在下发生还原反应得到式(I-3)化合物;2) The compound of formula (IV) undergoes a reduction reaction in the presence of a reducing agent to obtain the compound of formula (I-3);
在另一优选例中,提供按照本发明第二、三、四方面的方法制备的产物,进行官能团转化得到式I化合物。In another preferred embodiment, 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.
在另一优选例中,所述官能团转化反应选自下组:缩合酰化反应、还原反应、酰化反应、酯化反应、或其组合。In another preferred embodiment, 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.
在另一优选例中,所述缩合酰化反应在缩合剂存在下进行。In another preferred embodiment, the condensation acylation reaction is carried out in the presence of a condensing agent.
在另一优选例中,所述缩合剂包括但不限于:N,N'-二环己基碳二亚胺(DCC)、1-乙基-3-(3-二甲氨基丙基)碳二亚胺(EDCI)、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯(TBTU)。In another preferred example, 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).
在另一优选例中,所述还原反应在还原剂存在下进行。In another preferred embodiment, the reduction reaction is carried out in the presence of a reducing agent.
在另一优选例中,所述还原剂包括但不限于:氢气、甲酸铵、硼氢化钠、硼氢化钾、二异丁基氢化铝(DIBAL)、硼烷。In another preferred example, the reducing agent includes, but is not limited to, hydrogen, ammonium formate, sodium borohydride, potassium borohydride, diisobutylaluminum hydride (DIBAL), and borane.
在另一优选例中,所述酰化反应在酰化试剂存在下进行。In another preferred embodiment, the acylation reaction is carried out in the presence of an acylation reagent.
在另一优选例中,所述酰化试剂包括但不限于:乙酰氯、乙酸酐、丙酰氯、丙酸酐、甲磺酰氯。In another preferred example, the acylating reagents include but are not limited to: acetyl chloride, acetic anhydride, propionyl chloride, propionic anhydride, and methanesulfonyl chloride.
在另一优选例中,所述酯化反应体系包括但不限于:氯化亚砜/甲醇、氯化亚砜/乙醇。In another preferred example, the esterification reaction system includes but is not limited to: thionyl chloride/methanol, thionyl chloride/ethanol.
在本发明的第五方面,提供了一种如第一方面所述的化合物或其对映异构体、非对映异构体、外消旋体、以及其药学上可接受的无机或有机盐、结晶水合物及溶剂合物的用途,所述化合物用于制备一药物组合物或制剂,所述药物组合物或制剂用于治疗、缓解和/或预防中枢神经系统疾病。In the fifth aspect of the present invention, there is provided 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.
在另一优选例中,所述药物组合物或制剂还包含其他治疗中枢神经系统疾病的药物。In another preferred embodiment, the pharmaceutical composition or preparation further comprises other drugs for the treatment of central nervous system diseases.
在另一优选例中,所述中枢神经系统疾病选自下组:癫痫、精神分裂症、难控制的、难处理的或慢性精神分裂症、情感紊乱、精神紊乱、情绪紊乱、I型双极情感障碍、II型双极情感障碍、抑郁症、内因性抑郁症、重性抑郁症、难控制的抑郁症、情绪恶劣性障碍、循环情感性障碍、恐慌发作、惊恐性障碍、社交恐惧症、强迫性观念与行为病症、冲动性病症、创伤后精神紧张性障碍、焦虑症、急性应激障碍、癔病、神经性厌食症、适应性障碍、认知障碍、自闭症、疼痛、狂躁症、帕金森症、亨廷顿舞蹈症、阿尔茨海默症、各种痴呆症、记忆障碍、多动症、药物成瘾、睡眠障碍、注意力缺乏/亢进类疾病、抽动症或其组合。In another preferred embodiment, 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.
在另一优选例中,所述制剂为口服制剂或非口服制剂。In another preferred embodiment, the preparation is an oral preparation or a non-oral preparation.
在另一优选例中,所述制剂选自下组:片剂、丸剂、胶囊剂、颗粒剂、混悬液、溶液、霜剂、软膏、粉剂、栓剂、气雾剂、注射剂或其组合。In another preferred embodiment, the preparation is selected from the group consisting of tablets, pills, capsules, granules, suspensions, solutions, creams, ointments, powders, suppositories, aerosols, injections or combinations thereof.
在本发明的第六方面,提供了一种药物组合物,所述药物组合物含有:In the sixth aspect of the present invention, a pharmaceutical composition is provided, the pharmaceutical composition contains:
(1)作为活性成分的式I化合物;(1) a compound of formula I as an active ingredient;
(2)任选地选自下组的其他治疗中枢神经系统疾病的药物:抗精神病药物、 抗癫痫药物或抗抑郁药物;(2) other drugs for the treatment of central nervous system diseases optionally selected from the group consisting of antipsychotic drugs, antiepileptic drugs or antidepressant drugs;
(3)药学上可接受的载体或赋形剂。(3) A pharmaceutically acceptable carrier or excipient.
在另一优选例中,所述抗精神病药物包括但不限于阿立哌唑、利培酮、氟哌啶醇、喹硫平、帕潘立酮、齐拉西酮、阿塞那平、依匹哌唑、奥氮平、氯氮平、氨磺必利和卡利拉嗪。In another preferred embodiment, the antipsychotic drugs include but are not limited to aripiprazole, risperidone, haloperidol, quetiapine, paliperidone, ziprasidone, asenapine, Pipiprazole, olanzapine, clozapine, amisulpride, and cariprazine.
在另一优选例中,所述抗癫痫药物包括但不限于卡马西平、拉莫三嗪、奥卡西平、加巴喷丁、托吡酯、唑尼沙胺、拉科酰胺和丙戊酸。In another preferred example, the antiepileptic drugs include but are not limited to carbamazepine, lamotrigine, oxcarbazepine, gabapentin, topiramate, zonisamide, lacosamide and valproic acid.
在另一优选例中,所述抗抑郁药物包括但不限于氟西汀、氟伏沙明、舍曲林、艾司西酞普兰、阿米替林、文拉法辛、度洛西汀、伏硫西汀和西酞普兰。In another preferred example, the antidepressant drugs include but are not limited to fluoxetine, fluvoxamine, sertraline, escitalopram, amitriptyline, venlafaxine, duloxetine, vortioxetine and citalopram.
在本发明的第七方面,提供了一种治疗中枢神经系统疾病的方法,包括步骤给有需要的患者施用医学有效量的本发明第一方面所述的化合物或第六方面所述的药物组合物。In the seventh aspect of the present invention, there is provided 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.
在另一优选例中,所述患者为中枢神经系统疾病患者。In another preferred embodiment, the patient is a patient with a central nervous system disease.
在另一优选例中,所述中枢神经系统疾病如上定义。In another preferred embodiment, the central nervous system disease is as defined above.
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (eg, the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, it is not repeated here.
本发明人经过广泛而深入的研究首次发现了一类具有口服生物利用度提高、药效更强的特点的大麻二酚类似物能够有效治疗神经系统疾病,在此基础上完成了本发明。After extensive and in-depth research, the inventors have discovered for the first time that a class of cannabidiol analogs with the characteristics of improved oral bioavailability and stronger efficacy can effectively treat nervous system diseases, and the present invention is completed on this basis.
具体地本发明制备了式I所示的大麻二酚类似物,它们相比于大麻二酚具有口服生物利用度提高、理化性质好,药效更强的优点,在治疗神经系统疾病中的效果也优于CBD,因此可以更好地用于制备预防、减缓和/或治疗神经系统疾病的药物。并且本发明提供了制备这些大麻二酚类似物的方法。Specifically, 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.
术语the term
如本文所用,“本发明的化合物”、“本发明的活性成分”可互换使用,均指的是相比CBD具有更好的口服生物利用度、理化性质,靶点作用选择性的式I所示的大麻二酚类似物。As used herein, "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.
术语“卤素”通常是指氟、氯、溴及碘;优选为氟、氯或溴;更优选为氟或氯;The term "halogen" generally refers to fluorine, chlorine, bromine and iodine; preferably fluorine, chlorine or bromine; more preferably fluorine or chlorine;
“C
1-C
12烷基”指含有1-12个碳原子的直链或支链的饱和烃基,例如,甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1-乙基丙基、 异戊基、新戊基、异己基、3-甲基戊基或正己基等,优选为甲基、乙基、正丙基、异丙基、丁基、异丁基、叔丁基或戊基;
"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烷硫基”指含有1-6个碳原子的直链或支链烷硫基,例如,甲硫基、乙硫基、正丙硫基、异丙硫基、正丁硫基、异丁硫基、叔丁硫基、仲丁硫基、正戊硫基、异戊硫基、新戊硫基或正己硫基等,优选为甲硫基、乙硫基、正丙硫基、异丙硫基、正丁硫基、异丁硫基或叔丁硫基;
"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烷酰基”指含有1-6个碳原子的直连或支链烷酰基,如甲酰基、乙酰基、丙酰基、丁酰基、异丁酰基、戊酰基、叔丁酰基或己酰基等;
"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.;
“被C
1-C
6烷基取代的氨基甲酰基”是指氨基甲酰基上的氢原子被1个或2个相同或不同的C
1-C
6烷基取代,例如-CONHMe、-CONHEt、-CON(Me)Et、-CONEt
2或-CONMe
2等;
"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.;
“羟基C
1-C
6烷基”指含有1-6个碳原子的直链或支链烷基的一个碳原子与羟基连接,如-CH
2OH、-CH
2CH
2OH、-CH(OH)CH
3、-CH
2CH
2CH
2OH、-CH
2CH
2CH
2CH
2OH或-CH
2CH(CH
3)CH
2OH等;
"Hydroxy 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.;
“氨基C
1-C
6烷基”指与含有1-6个碳原子的直链或支链烷基的一个碳原子与氨基连接,如-CH
2NH
2、-CH
2CH
2NH
2、-CH(NH
2)CH
3、-CH
2CH
2CH
2NH
2或-CH
2CH
2CH
2CH
2NH
2等;
"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 .;
“被C
1-C
6烷基取代的氨基C
1-C
6烷基”是指氨基上的氢原子被1个或2个相同或不同的C
1-C
6烷基取代,例如-CH
2NHMe或-CH
2CH
2NEt
2等;
"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.;
“氨基甲酰基C
1-C
6烷基”是指含有1-6个碳原子的直链或支链烷基的一个碳原子与氨基甲酰基的羰基碳连接,例如-CH
2CONH
2、-CH
2CH
2CONH
2、-CH(CONH
2)CH
3或-CH
2CH
2CH
2CONH
2等;
"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.;
“被C
1-C
6烷基取代的氨基甲酰基C
1-C
6烷基”是指氨基甲酰基C
1-C
6烷基上的氨基氢原子被1个或2个相同或不同的C
1-C
6烷基取代,例如-CH
2CONHMe、-CH
2CH
2CONHEt、-CH
2CH
2CONMe
2或-CH
2CONEt
2等;
"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.;
“氰基C
1-C
6烷基”是指含有1-6个碳原子的直链或支链烷基的一个碳原子与氰基连接,如氰基甲基、2-氰基乙基、1-氰基乙基、3-氰基丙基、4-氰基丁基或5-氰基戊基等;
"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.;
“羧基C
1-C
6烷基”指与含有1-6个碳原子的直链或支链烷基的一个碳原子与羧基连接,如羧基甲基、2-羧基乙基、1-羧基乙基、3-羧基丙基、4-羧基丁基或5-羧基戊基等;
"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烷磺酰基”是指含有1-6个碳原子的直链或支链烷磺酰基,如甲磺酰基、乙磺酰基或丙磺酰基等;
"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.;
“被C
1-C
6烷基取代的氨基”是指氨基上的氢原子被1个或2个相同或不同的C
1-C
6烷基或C
1-C
6烷酰基取代,例如-NHMe或-NEt
2等;
"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环烷基”是指含有3-10个碳原子的饱和环烃基,如环丙基、环丁基、环 戊基、环己基等;
"C 3 -C 10 cycloalkyl" refers to a saturated cyclic hydrocarbon group containing 3-10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.;
大麻二酚(CBD)Cannabidiol (CBD)
大麻二酚(CBD)是一种来自大麻植物的非精神类成分,对于神经系统具有多种药理作用。其结构式如下:Cannabidiol (CBD) 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具有广谱的药理作用,现有证据表明,CBD除了对大麻素受体(CB1/CB2)有一定的作用外,还可作用于神经精神疾病相关的G蛋白偶联受体和离子通道,如五羟色胺(serotonin,5-HT)受体、甘氨酸受体、腺苷受体及瞬时受体电位离子通道(transient receptor potential,TRP)等,并且能抑制突触小体对去甲肾上腺素、多巴胺、5-HT和GABA等神经递质的摄取及细胞对内源性大麻素的摄取过程,同时还可影响线粒体的钙离子存储,阻断低电压激活的T型钙离子通道。CBD has a broad spectrum of pharmacological effects. Existing evidence shows that in addition to having certain effects on cannabinoid receptors (CB1/CB2), CBD can also act on G protein-coupled receptors and ion channels related to neuropsychiatric diseases. Such as serotonin (serotonin, 5-HT) receptors, glycine receptors, adenosine receptors and transient receptor potential ion channels (transient receptor potential, TRP), etc., and can inhibit synaptosomes on norepinephrine, dopamine 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.
药物组合物及施用方法Pharmaceutical compositions and methods of administration
本发明中所述“药学上可接受的无机或有机盐”为通式(I)表示的化合物与如盐酸、氢溴酸、氢碘酸、氢氟酸、硫酸、硝酸或磷酸等无机酸形成的盐,与如甲酸、乙酸、丙酸、草酸、丙二酸、马来酸、酒石酸、苹果酸、富马酸、甲磺酸、柠檬酸等有机酸形成的盐,或者与氢氧化钠、氢氧化钾、氢氧化钙或氨水等碱形成的钠、钾、钙或氨盐。“药学上可接受的盐”也包括它们的溶剂合物,溶剂合物的例子有,水合物、醇合物等。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.
本发明还提供根据本发明的通式(I)所示的化合物、其对映异构体、非对映异构体、外消旋体、以及其药学上可接受的盐、结晶水合物及溶剂合物在制备预防和/或治疗中枢神经系统疾病的药物中的应用。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. Application of solvate in the preparation of medicaments for preventing and/or treating central nervous system diseases.
本发明还提供一种用于治疗和/或预防中枢神经系统疾病的方法,这种方法包括向人或动物施用上述本发明的通式(I)表示的化合物、其对映异构体、非对映异构体、外消旋体、以及其药学上可接受的盐、结晶水合物及溶剂合物中的一种或几种的混合物。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.
本发明还提供一种药物组合物,其包含治疗有效量的上述通式(I)所示的化合物、其对映异构体、非对映异构体、外消旋体、以及其药学上可接受的盐、结晶水合物及溶剂合物中的一种或几种混合物,和任选的可药用载体。所述药物组合物可用于治疗或者预防中枢神经系统疾病。The present invention also provides 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.
本发明还提供一种制备所述药物组合物的方法,包括将上述通式(I)所示的化合物、其对映异构体、非对映异构体、外消旋体、以及其药学上可接受的盐、结晶水合物及溶剂合物中的一种或几种的混合物与可药用载体混合。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.
药物组合物包括那些适合于口服、鼻、局部(包括透皮、颊和舌下)、阴道或肠胃外(包括皮下、肌肉内、静脉内和真皮内)给药或通过植入物给药的药物组合物。在本发明的药物组合物中,根据治疗目的可以选择多种药物制剂形式,一般包括:片剂、丸剂、胶囊剂、颗粒剂、混悬液、溶液、霜剂、软膏、粉剂、栓剂、气雾剂和注射剂等。Pharmaceutical 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. In the pharmaceutical composition of the present invention, 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.
对于肠胃外施用,合适的组合物包括含水和非含水的无菌注射剂。组合物可以被提供在单位剂量或多剂量容器中,例如密封的小瓶和安剖,并且可储存在冷冻干燥(冻干)条件下,仅需要在使用前添加无菌液体载体,例如水。对于经皮施用,可以预期比如凝胶、贴剂或喷雾剂。适合用于肺部施用比如通过鼻吸入的组合物或制剂包括可以借助于定量加压气溶胶、喷雾器或吹药器产生的细粉尘或薄雾。组合物的施用的精确剂量和方案将必须取决于待被实现的治疗性或营养性效果并且可以因特定配方、施用途径和组合物被施用于的个体受试者的年龄和状况而不同。For parenteral administration, suitable 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. For 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.
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药学上可接受的盐及药学上可以接受的赋形剂或载体。其中“安全有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有1-2000mg本发明化合物/剂,更佳地,含有10-1000mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。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. Usually, 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. Preferably, the "one dose" is a capsule or tablet.
“药学上可以接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和,而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
"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.
所述的药物组合物为注射剂、囊剂、片剂、丸剂、散剂或颗粒剂。The pharmaceutical composition is an injection, a capsule, a tablet, a pill, a powder or a granule.
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。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 .
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, 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 monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, hard Calcium fatty acid, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。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.
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, 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.
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。Besides these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。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.
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。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.
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入 剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。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.
本发明化合物可以单独给药,或者与其他药学上可接受的其他化合物联合给药。The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
本发明治疗方法可以单独施用,或者与其它治疗手段或者治疗药物联用。The therapeutic methods of the present invention may be administered alone or in combination with other therapeutic means or therapeutic agents.
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为1~2000mg,优选50~1000mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。When using the pharmaceutical composition, 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. Of course, 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.
制备方法Preparation
本发明还提供了通式(I)化合物及其中间体的制备方法,所述化合物可通过如下方法中的任一种制备,本发明所用起始原料为商业购买或按照相似化合物的已知合成方法制备: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:
方法一:以含醛基取代的式(II)为原料,在还原剂存在下发生还原反应得到化合物(I-1),如反应式1所示:Method 1: Using the formula (II) substituted with an aldehyde group as a raw material, a reduction reaction occurs in the presence of a reducing agent to obtain compound (I-1), as shown in reaction formula 1:
其中,R
2、R
0的定义同上所述;
Wherein, the definitions of R 2 and R 0 are the same as above;
方法二:以式(III)为原料,和NH(R
4)
2经氨解反应得到式(I-2)化合物,如反应式所示:
Method 2: Using formula (III) as a raw material, and NH(R 4 ) 2 through an aminolysis reaction to obtain a compound of formula (I-2), as shown in the reaction formula:
其中,R
2、R
0的定义同上所述;R
4各自独立地为H、C
1-C
6烷基、羟基C
1-C
6烷基、C
3-C
10环烷基。
Wherein, 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.
方法三:以式(II)为原料,经两步反应得到式(I-3)化合物,如反应式所示:Method 3: Using formula (II) as a raw material, the compound of formula (I-3) is obtained through a two-step reaction, as shown in the reaction formula:
所述方法三包括以下步骤:The third method includes the following steps:
1)式(II)化合物在碱存在下和硝基甲烷在催化剂存在下发生Henry反应生成式(IV)化合物;1) the compound of formula (II) generates the compound of formula (IV) by Henry reaction in the presence of a base and nitromethane in the presence of a catalyst;
2)式(IV)化合物在还原剂存在下发生还原反应得到式(I-3)化合物;2) The compound of formula (IV) undergoes a reduction reaction in the presence of a reducing agent to obtain the compound of formula (I-3);
其中,R
2、R
0的定义同上所述;
Wherein, the definitions of R 2 and R 0 are the same as above;
方法四:Method four:
由方法一至三所得到的式I化合物进行官能团转化得到。The compounds of formula I obtained by methods 1 to 3 are obtained by functional group transformation.
所述官能团转化反应如通过缩合酰化反应、还原反应、酰化反应、酯化反应、等。The functional group conversion reaction is, for example, by condensation acylation reaction, reduction reaction, acylation reaction, esterification reaction, and the like.
所述缩合酰化反应在缩合剂存在下进行,所述缩合剂包括但不限于:N,N'-二环己基碳二亚胺(DCC)、1-乙基-3-(3-二甲氨基丙基)碳二亚胺(EDCI)、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯(TBTU)等。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.
所述还原反应在还原剂存在下进行,所述还原剂包括但不限于:氢气、甲酸铵、硼氢化钠、硼氢化钾、二异丁基氢化铝(DIBAL)、硼烷等。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.
所述酰化反应在酰化试剂存在下进行,所述酰化试剂包括但不限于:乙酰氯、乙酸酐、丙酰氯、丙酸酐、甲磺酰氯等。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.
所述酯化反应体系包括但不限于:氯化亚砜/甲醇、氯化亚砜/乙醇等。The esterification reaction system includes but is not limited to: thionyl chloride/methanol, thionyl chloride/ethanol and the like.
本发明的主要优点在于:The main advantages of the present invention are:
1)本发明化合物相比大麻二酚(CBD)具有更好的理化性质、口服生物利用度。1) Compared with cannabidiol (CBD), the compound of the present invention has better physicochemical properties and oral bioavailability.
2)本发明化合物对大麻素CB1、CB2受体具有较好的作用,可用于治疗各种与大麻素CB1、CB2受体功能紊乱相关的疾病。2) 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.
3)本发明化合物的中枢神经系统活性优于大麻二酚(CBD),具有起效剂量低、毒副作用小等特点,可用于治疗各种中枢神经系统疾病,如癫痫、帕金森氏症、精神分裂症、双相情感障碍、抑郁、焦虑、躁狂、多动症、药物成瘾或神经痛,具有良好的临床应用前景。3) 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.
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数是重量百分比和重量份数。The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. In the following examples, the experimental methods without specific conditions are usually in accordance with conventional conditions or in accordance with the conditions suggested by the manufacturer. Percentages and parts are weight percentages and parts unless otherwise specified.
实施例1制备下式化合物1Example 1 Preparation of compound 1 of the following formula
参照文献(WO 2019033168;WO 2019033164)制备得到大麻二酚酸甲酯1-1,取大麻二酚酸甲酯1-1(1.5g)溶于10mL甲胺/乙醇溶液,封管中100度反应过夜,TLC监测反应结束。浓缩反应液后,柱层析(石油醚/乙酸乙酯=100/1→20/1)分离产品,产品用石油醚打浆,过滤得到标题化合物1,固体212mg。
1H NMR(400MHz,CDCl
3)δ11.21(br,1H),6.30(br,1H),6.21(s,1H),5.88(br,1H),5.54(s,1H),4.53(s,1H),4.39(s,1H),4.07(br,1H),2.98(d,3H),2.64(t,2H),2.41–2.39(m,1H),2.37–2.17(m,1H),2.11–2.05(m,1H),1.82–1.76(m,2H),1.78(s,3H),1.70(s,3H),1.67–1.56(m,2H),1.37–1.30(m,4H),0.90(t,3H).ESI-MS m/z 370.2(M-H)
-.
Referring to the literature (WO 2019033168; WO 2019033164), methyl CBD 1-1 was prepared, and methyl CBD 1-1 (1.5 g) was dissolved in 10 mL of methylamine/ethanol solution, and the reaction was carried out at 100 degrees in a sealed tube. Overnight, TLC monitored the end of the reaction. After concentrating the reaction solution, the product was separated by column chromatography (petroleum ether/ethyl acetate=100/1→20/1). The product was slurried with petroleum ether and filtered to obtain the title compound 1, 212 mg of solid. 1 H NMR (400MHz, CDCl 3 )δ11.21(br,1H), 6.30(br,1H), 6.21(s,1H), 5.88(br,1H), 5.54(s,1H), 4.53(s, 1H), 4.39(s, 1H), 4.07(br, 1H), 2.98(d, 3H), 2.64(t, 2H), 2.41–2.39(m, 1H), 2.37–2.17(m, 1H), 2.11 –2.05(m,1H),1.82–1.76(m,2H),1.78(s,3H),1.70(s,3H),1.67–1.56(m,2H),1.37–1.30(m,4H),0.90 (t,3H).ESI-MS m/z 370.2(MH) - .
实施例2制备下式化合物2Example 2 Preparation of compound 2 of the following formula
滴加草酰氯(4.1g,2eq)到二氯甲烷(40mL)和DMF(2.35g,1.2eq)中,控温-10-0℃,保温2分钟,将CBD(8.45g)溶于40mL二氯甲烷,-10℃下将CBD滴加到上述体系中,反应0.5小时,TLC(石油醚/乙酸乙酯=20/1)监测反应完全。用饱和碳酸氢钠溶液淬灭反应,分出二氯甲烷层,无水硫酸钠干燥,浓缩干过柱, PE→PE/acetone=100/1,分离得9.42g产品2-a,收率99%。核磁确认同文献报道一致(WO 2020031179)。Add oxalyl chloride (4.1g, 2eq) dropwise to dichloromethane (40mL) and DMF (2.35g, 1.2eq), control the temperature to -10-0°C, keep the temperature for 2 minutes, dissolve CBD (8.45g) in 40mL of dichloromethane Methyl chloride, CBD was added dropwise to the above system at -10°C, and the reaction was carried out for 0.5 hours. TLC (petroleum ether/ethyl acetate=20/1) monitored the completion of the reaction. The reaction was quenched with saturated sodium bicarbonate solution, the dichloromethane layer was separated, dried over anhydrous sodium sulfate, concentrated to dryness and passed through a column, PE→PE/acetone=100/1, and 9.42 g of product 2-a was isolated in a yield of 99 %. The NMR confirmation is consistent with the literature report (WO 2020031179).
将化合物2-a溶于甲醇中,加入1eq的NaBH
4,室温反应过夜,浓缩干直接过柱,得标题化合物,收率约80%。
1H NMR(400MHz,DMSO)δ8.71–8.54(m,2H),6.06(s,1H),5.57(br,1H),5.10(s,1H),4.55–4.53(m,2H),4.51(m,1H),4.42(m,1H),3.89,3.89–3.86(m,1H),3.04(t,1H),2.37(t,1H),2.11–2.08(m,1H),1.94–1.90(m,1H),1.61(s,3H),1.59(s,3H),1.71–1.57(m,3H),1.45–1.38(m,2H),1.33–1.27(m,4H),0.87(t,3H).ESI-MS m/z 343.2(M-H)
–.
Compound 2-a was dissolved in methanol, 1 eq of NaBH 4 was added, the reaction was carried out at room temperature overnight, concentrated to dryness and directly passed through a column to obtain the title compound in a yield of about 80%. 1 H NMR (400MHz, DMSO)δ8.71-8.54(m,2H), 6.06(s,1H), 5.57(br,1H), 5.10(s,1H), 4.55-4.53(m,2H), 4.51 (m, 1H), 4.42 (m, 1H), 3.89, 3.89–3.86 (m, 1H), 3.04 (t, 1H), 2.37 (t, 1H), 2.11–2.08 (m, 1H), 1.94–1.90 (m, 1H), 1.61 (s, 3H), 1.59 (s, 3H), 1.71–1.57 (m, 3H), 1.45–1.38 (m, 2H), 1.33–1.27 (m, 4H), 0.87 (t ,3H).ESI-MS m/z 343.2(MH) – .
实施例3制备下式化合物3Example 3 Preparation of compound 3 of the following formula
将化合物2-a(3g)溶于二氯甲烷/甲醇(50/50mL)混合体系中,加入甲胺乙醇溶液(10eq),氮气下搅拌过夜,TLC监测原料消失。反应液浓缩干,加入甲醇50mL,冰浴下滴加NaBH
4(1eq)的甲醇溶液,搅拌15分钟,反应完全。加水和乙酸乙酯(20mL/50mL),HCl调pH=8,分出乙酸乙酯层,浓缩干过柱,PE/EA=2/1→EA,得标题化合物3共1.8g,收率40%。
1H NMR(400MHz,CDCl
3)δ6.16(s,1H),5.94(m,1H),5.59(s,1H),4.53(m,1H),4.42(m,1H),4.11–4.04(m,1H),3.88(s,2H),2.51–2.41(m,2H),2.41(s,3H),2.20–2.10(m,1H),2.10–2.05(m,1H),1.81–1.77(m,2H),1.77(s,3H),1.70(s,3H),1.50–1.43(m,2H),1.32–1.25(m,4H),0.88(t,3H).ESI-MS m/z 358.03(M+H)
+.
Compound 2-a (3 g) was dissolved in a mixed system of dichloromethane/methanol (50/50 mL), methylamine ethanol solution (10 eq) was added, stirred overnight under nitrogen, and the disappearance of raw materials was monitored by TLC. The reaction solution was concentrated to dryness, 50 mL of methanol was added, a methanol solution of NaBH 4 (1 eq) was added dropwise under an ice bath, and the mixture was stirred for 15 minutes, and the reaction was complete. Add water and ethyl acetate (20mL/50mL), adjust pH=8 with HCl, separate the ethyl acetate layer, concentrate to dryness and pass through the column, PE/EA=2/1→EA, to obtain the title compound 3, a total of 1.8g, the yield is 40 %. 1 H NMR (400MHz, CDCl 3 ) δ 6.16(s, 1H), 5.94(m, 1H), 5.59(s, 1H), 4.53(m, 1H), 4.42(m, 1H), 4.11–4.04( m,1H), 3.88(s,2H), 2.51–2.41(m,2H), 2.41(s,3H), 2.20–2.10(m,1H), 2.10–2.05(m,1H), 1.81–1.77( m,2H),1.77(s,3H),1.70(s,3H),1.50–1.43(m,2H),1.32–1.25(m,4H),0.88(t,3H).ESI-MS m/z 358.03(M+H) + .
实施例4制备下式化合物4Example 4 Preparation of compound 4 of the following formula
取大麻二酚酸甲酯1-1(5g,13.4mmol)溶于氨乙醇中,封管回流36h,将反应液浓缩至干,柱层析得202mg标题化合物4,白色固体。
1H NMR(500MHz,CDCl
3)δ11.95(s,1H),6.41(s,1H),6.23(s,1H),5.90(br,2H),5.55(s,1H),4.53(m,1H),4.39(m,1H),4.08(m,1H),2.77–2.70(m,2H),2.40–2.37(m,1H),2.24–2.20(m,1H),2.12–2.06(m,1H),1.83–1.77(m,2H),1.78(s,3H),1.71(s,3H),1.65–1.63(m,2H),1.35–1.31(m,4H),0.88(t,3H).ESI-MS m/z 358.13(M+H)
+.
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. 1 H NMR (500MHz, CDCl 3 )δ11.95(s,1H), 6.41(s,1H), 6.23(s,1H), 5.90(br,2H), 5.55(s,1H), 4.53(m, 1H), 4.39 (m, 1H), 4.08 (m, 1H), 2.77–2.70 (m, 2H), 2.40–2.37 (m, 1H), 2.24–2.20 (m, 1H), 2.12–2.06 (m, 1H), 1.83–1.77(m, 2H), 1.78(s, 3H), 1.71(s, 3H), 1.65–1.63(m, 2H), 1.35–1.31(m, 4H), 0.88(t, 3H) .ESI-MS m/z 358.13(M+H) + .
实施例5制备下式化合物5Example 5 Preparation of compound 5 of the following formula
将化合物2-a(200mg,0.584mmol)溶于硝基甲烷中,加入乙酸铵(100mg,2.2eq),加热回流12h,TLC显示原料完全反应,浓缩干溶剂,柱层析得中间体5-a(200mg)。
1H NMR(400MHz,Chloroform-d)δ8.24(d,J=13.3Hz,1H),8.08(d,J=13.2Hz,1H),7.12(s,1H),6.26(s,1H),5.56(s,1H),5.42–5.23(m,1H),4.62(s,1H),4.47(s,1H),3.91(d,J=9.9Hz,1H),2.67(m,2H),2.37(m,1H),2.32–2.21(m,2H),1.83–1.77(m,2H),1.85(s,3H),1.66(s,3H),1.66-1.53(m,2H),1.37–1.32(m,4H),0.90(t,3H).ESI-MS m/z 384.08(M–H)
–.
Compound 2-a (200 mg, 0.584 mmol) was dissolved in nitromethane, ammonium acetate (100 mg, 2.2 eq) was added, heated to reflux for 12 h, TLC showed that the raw materials were completely reacted, the dry solvent was concentrated, and the intermediate 5- was obtained by column chromatography a (200 mg). 1 H NMR (400MHz, Chloroform-d) δ 8.24 (d, J=13.3Hz, 1H), 8.08 (d, J=13.2Hz, 1H), 7.12 (s, 1H), 6.26 (s, 1H), 5.56(s, 1H), 5.42–5.23(m, 1H), 4.62(s, 1H), 4.47(s, 1H), 3.91(d, J=9.9Hz, 1H), 2.67(m, 2H), 2.37 (m, 1H), 2.32–2.21 (m, 2H), 1.83–1.77 (m, 2H), 1.85 (s, 3H), 1.66 (s, 3H), 1.66–1.53 (m, 2H), 1.37–1.32 (m,4H),0.90(t,3H).ESI-MS m/z 384.08(M–H) – .
取化合物5-a(200mg,0.51mmol)溶于THF中,加入四氢锂铝(194mg,10eq),加热回流4h,TLC显示完全反应,将反应液倒入水中,稀盐酸调节pH=8-9,正丁醇萃取,有机相干燥浓缩,柱层析得标题化合物70mg。ESI-MS m/z 358.16(M+H)
+,356.18(M–H)
–.
1H NMR(400MHz,DMSO-d
6)δ8.66(s,1H),7.65(s,3H),6.10(s,1H),5.18(s,1H),4.64–4.30(m,2H),3.87(d,J=10.1Hz,1H),2.94(m,1H),2.71(m,4H),2.38(dd,J=9.0,6.4Hz,2H),2.13(m,1H),2.00–1.91(m,1H),1.71–1.67(m,2H),1.63(s,3H),1.57(s,3H),1.47–1.39(m,2H),1.33–1.24(m,4H),0.87(t,3H).
Dissolve compound 5-a (200 mg, 0.51 mmol) in THF, add lithium aluminum tetrahydrogen (194 mg, 10 eq), heat under reflux for 4 h, TLC shows complete reaction, pour the reaction solution into water, dilute hydrochloric acid to adjust pH=8- 9. Extraction with n-butanol, the organic phase was dried and concentrated, and 70 mg of the title compound was obtained by column chromatography. ESI-MS m/z 358.16(M+H) + , 356.18(M–H) – . 1 H NMR (400MHz, DMSO-d 6 )δ8.66(s,1H),7.65(s,3H),6.10 (s, 1H), 5.18(s, 1H), 4.64–4.30(m, 2H), 3.87(d, J=10.1Hz, 1H), 2.94(m, 1H), 2.71(m, 4H), 2.38( dd, J=9.0, 6.4Hz, 2H), 2.13 (m, 1H), 2.00–1.91 (m, 1H), 1.71–1.67 (m, 2H), 1.63 (s, 3H), 1.57 (s, 3H) ,1.47–1.39(m,2H),1.33–1.24(m,4H),0.87(t,3H).
实施例6制备下式化合物6Example 6 Preparation of compound 6 of the following formula
取大麻二酚酸甲酯1-1(100mg,0.27mmol)溶于2ml的环丙胺溶液中,110℃封管反应过夜。浓缩干溶剂,柱层析得标题化合物12.7mg。ESI-MS m/z 398.33(M+H)
+,396.19(M–H)
–.
1H NMR(400MHz,Chloroform-d)δ11.27(s,1H),6.31(br,1H),6.19(s,1H),6.02(s,1H),5.53(s,1H),4.53(t,J=2.0Hz,1H),4.39(s,1H),4.06(s,1H),2.93–2.86(m 1H),2.72–2.52(m,2H),2.47–2.38(m,1H),2.22–2.17(m,1H),2.12–2.05(m,1H),1.80–1.76(m,2H),1.78(s,3H),1.70(s,3H),1.62–1.50(m,2H),1.30(m,4H),0.91–0.86(m,5H),0.61–0.57(m,2H).
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) – . 1 H NMR(400MHz, Chloroform-d)δ11.27(s,1H),6.31(br,1H),6.19( s, 1H), 6.02(s, 1H), 5.53(s, 1H), 4.53(t, J=2.0Hz, 1H), 4.39(s, 1H), 4.06(s, 1H), 2.93–2.86(m 1H), 2.72–2.52 (m, 2H), 2.47–2.38 (m, 1H), 2.22–2.17 (m, 1H), 2.12–2.05 (m, 1H), 1.80–1.76 (m, 2H), 1.78 ( s, 3H), 1.70 (s, 3H), 1.62–1.50 (m, 2H), 1.30 (m, 4H), 0.91–0.86 (m, 5H), 0.61–0.57 (m, 2H).
实施例7制备下式化合物7Example 7 Preparation of compound 7 of the following formula
取大麻二酚酸甲酯1-1(100mg,0.27mmol)溶于2ml的戊胺中,加热回流过夜。TLC显示原料基本完全反应,浓缩干溶剂,柱层析得标题化合物40mg。ESI-MS m/z 429.28(M+2H)
+,426.27(M–H)
–.
1H NMR(400MHz,Chloroform-d)δ11.18(br,1H)6.40–6.23(m,1H),6.21(s,1H),5.87(s,1H),5.54(s,1H),4.53(br,1H),4.40(br,1H),4.17–4.00(m,1H),3.43(p,J=6.6Hz,2H),2.76–2.57(m,2H),2.43–2.37(m,1H),2.24–2.20(m,1H),2.14–2.02(m,1H),1.82–1.79(m,2H),1.78(s,3H),1.70(s,3H),1.64–1.57(m,4H),1.42–1.30(m,8H),0.94–0.88(m,6H).
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) – . 1 H NMR (400MHz, Chloroform-d)δ11.18(br,1H)6.40–6.23(m,1H),6.21 (s,1H), 5.87(s,1H), 5.54(s,1H), 4.53(br,1H), 4.40(br,1H), 4.17–4.00(m,1H), 3.43(p,J=6.6 Hz, 2H), 2.76–2.57 (m, 2H), 2.43–2.37 (m, 1H), 2.24–2.20 (m, 1H), 2.14–2.02 (m, 1H), 1.82–1.79 (m, 2H), 1.78(s,3H), 1.70(s,3H), 1.64–1.57(m,4H), 1.42–1.30(m,8H), 0.94–0.88(m,6H).
实施例8制备下式化合物10Example 8 Preparation of compound 10 of the following formula
5mL(1.7M)叔丁基氯化镁于0-10℃下滴入5mL(2M)的二甲胺四氢呋喃溶液 中,缓慢滴入大麻二酚酸甲酯1-1的四氢呋喃溶液,封管加热至110℃回流24h,TLC显示原料少量剩余,柱层析得标题化合物900mg。
1H NMR(400MHz,DMSO)δ8.99(br,1H),8.02(br,1H),7.28(br,1H),6.15(s,1H),5.19(s,1H),4.41(m,2H),3.84(d,1H),3.00–2.65(m,7H),2.25–2.13(m,1H),1.97–1.93(m,1H),1.67–1.58(m,2H),1.63(s,3H),1.58(s,3H),1.41–1.40(m,2H),1.30–1.16(m,4H),0.84(t,3H).ESI-MS m/z 384.12(M–H)
–.
5mL (1.7M) of tert-butylmagnesium chloride was added dropwise to 5mL (2M) of dimethylamine tetrahydrofuran solution at 0-10°C, slowly dropped into the tetrahydrofuran solution of methyl cannabidiolate 1-1, sealed and heated to 110 The mixture was refluxed at ℃ for 24 h, TLC showed that a small amount of raw material remained, and 900 mg of the title compound was obtained by column chromatography. 1 H NMR (400MHz, DMSO) δ8.99(br,1H), 8.02(br,1H), 7.28(br,1H), 6.15(s,1H), 5.19(s,1H), 4.41(m,2H) ), 3.84 (d, 1H), 3.00–2.65 (m, 7H), 2.25–2.13 (m, 1H), 1.97–1.93 (m, 1H), 1.67–1.58 (m, 2H), 1.63 (s, 3H) ),1.58(s,3H),1.41–1.40(m,2H),1.30–1.16(m,4H),0.84(t,3H).ESI-MS m/z 384.12(M–H) – .
实施例9制备下式化合物24Example 9 Preparation of compound 24 of the following formula
步骤一:step one:
取3,5-二甲氧基苯乙腈24-a(5.0g,28.2mmol,1.0eq.)溶于四氢呋喃中(250mL),氮气置换三次,向溶液中加入二(三甲基硅基)氨基钾(85mL,170mmol,6.0eq.),将1,2-二溴乙烷(15.9g,84.7mmol,3.0eq.)缓慢滴入反应体系。在0℃下搅拌3h,TLC监测反应完毕。反应液滴入饱和氯化铵溶液中淬灭,用乙酸乙酯萃取,有机相用无水硫酸钠干燥,浓缩,柱层析分离得化合物24-b约4g,收率80%。
1H NMR(500MHz,CDCl
3)δ6.44(d,J=2.4Hz,2H),6.38(t,J=2.4Hz,1H),3.80(s,6H),1.71–1.68(dd,J=7.4Hz,J=5.2Hz,2H),1.41–1.38(dd,J=7.4Hz,J=5.2Hz,2H)。
Dissolve 3,5-dimethoxyphenylacetonitrile 24-a (5.0 g, 28.2 mmol, 1.0 eq.) in tetrahydrofuran (250 mL), replace with nitrogen three times, and add bis(trimethylsilyl)amino to the solution Potassium (85mL, 170mmol, 6.0eq.), 1,2-dibromoethane (15.9g, 84.7mmol, 3.0eq.) was slowly added dropwise to the reaction system. It was stirred at 0 °C for 3 h, and the completion of the reaction was monitored by TLC. The reaction was dropped into saturated ammonium chloride solution to quench, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain about 4 g of compound 24-b in a yield of 80%. 1 H NMR (500MHz, CDCl 3 ) δ 6.44 (d, J=2.4Hz, 2H), 6.38 (t, J=2.4Hz, 1H), 3.80 (s, 6H), 1.71-1.68 (dd, J= 7.4Hz, J=5.2Hz, 2H), 1.41–1.38 (dd, J=7.4Hz, J=5.2Hz, 2H).
步骤二:Step 2:
取化合物24-b(355.0mg,1.75mmol,1.0eq.)溶于DCM中(16mL),降温至-67℃,氮气置换三次,向溶液中缓慢加入DIBAL-H(4.4mL,4.4mmol),于-67至-62℃温度下反应2h,TLC监测反应完毕。反应液滴入饱和氯化铵溶液淬灭,二氯甲烷萃取,有机相用无水硫酸钠干燥,浓缩得24-c,透明油状物272mg,收率77%。
1H NMR(300MHz,CDCl
3)δ9.32(s,1H),6.46(d,J=2.4Hz,2H),6.40(t,J=2.4Hz,1H),3.78(s,6H),1.53(m,2H),1.37(m,2H).
Compound 24-b (355.0 mg, 1.75 mmol, 1.0 eq.) was dissolved in DCM (16 mL), cooled to -67 °C, replaced with nitrogen three times, and DIBAL-H (4.4 mL, 4.4 mmol) was slowly added to the solution, The reaction was carried out at a temperature of -67 to -62° C. for 2 h, and the completion of the reaction was monitored by TLC. The reaction was quenched by dropping into saturated ammonium chloride solution, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain 24-c, 272 mg of transparent oil, yield 77%. 1 H NMR (300 MHz, CDCl 3 ) δ 9.32 (s, 1H), 6.46 (d, J=2.4 Hz, 2H), 6.40 (t, J=2.4 Hz, 1H), 3.78 (s, 6H), 1.53 (m,2H),1.37(m,2H).
步骤三:Step 3:
三苯基丙基溴化磷(8.6g,24.3mmol,5.0eq.)置于三口瓶中,氮气置换三次,加入THF(15mL),冰浴下加入二(三甲基硅基)氨基钾(24mL,23.8mmol,4.9eq.),搅拌30min,将24-c(1g,4.85mmol,1.0eq.)溶于25mL THF中,缓慢加入反应体系。在0℃下搅拌反应1h,TLC监测反应完毕。反应液滴入饱和氯化铵溶液淬灭,用乙酸乙酯萃取,有机相干燥浓缩,柱层析分离得化合物24-d,淡黄色固体993mg。
1H NMR(400MHz,CDCl
3)δ6.40(d,2H),6.26(t,1H),5.65–5.62(m,1H),5.53–5.48(m,1H),3.77(s,6H),2.12–2.08(m,2H),1.10–1.08(m,2H),0.98–0.96(m,2H),0.91(t,3H).
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. The reaction was dropped into saturated ammonium chloride solution to quench, extracted with ethyl acetate, the organic phase was dried and concentrated, and separated by column chromatography to obtain compound 24-d, 993 mg of pale yellow solid. 1 H NMR (400MHz, CDCl 3 )δ6.40(d,2H), 6.26(t,1H), 5.65-5.62(m,1H), 5.53-5.48(m,1H), 3.77(s,6H), 2.12–2.08 (m, 2H), 1.10–1.08 (m, 2H), 0.98–0.96 (m, 2H), 0.91 (t, 3H).
步骤四:Step 4:
化合物24-d(375mg,1.6mmol,1.0eq.)溶于乙二醇二甲醚(38.1mL)中,再加入对甲苯磺酰肼(3.6g,19.2mmol,12.0eq.),混合液回流,缓慢加入37mL乙酸钠水溶液(3.1g,41.6mmol,26.0eq)。在93℃下搅拌反应4h,TLC监测反应完毕。反应液滴入水淬灭,乙酸乙酯萃取,有机相干燥浓缩,柱层析分离得24-e,353mg油状物,收率94%。
1H NMR(500MHz,CDCl
3)δ6.47(s,1H),6.46(s,1H),6.29(t,1H),3.79(s,6H),1.57–1.50(m,2H),1.26–1.23(m,4H),0.84–0.81(m,3H),0.78–0.76(m,2H),0.63–0.61(m,2H).
Compound 24-d (375mg, 1.6mmol, 1.0eq.) was dissolved in ethylene glycol dimethyl ether (38.1mL), p-toluenesulfonyl hydrazide (3.6g, 19.2mmol, 12.0eq.) was added, and the mixture was refluxed , and slowly added 37 mL of aqueous sodium acetate (3.1 g, 41.6 mmol, 26.0 eq). The reaction was stirred at 93 °C for 4 h, and the completion of the reaction was monitored by TLC. The reaction was dropped into water to quench, extracted with ethyl acetate, the organic phase was dried and concentrated, and separated by column chromatography to obtain 24-e, 353 mg of an oily product with a yield of 94%. 1 H NMR (500MHz, CDCl 3 )δ6.47(s,1H), 6.46(s,1H), 6.29(t,1H), 3.79(s,6H), 1.57–1.50(m,2H), 1.26– 1.23 (m, 4H), 0.84–0.81 (m, 3H), 0.78–0.76 (m, 2H), 0.63–0.61 (m, 2H).
步骤五:Step 5:
化合物24-e(13.2g,56.4mmol,1.0eq.)和NBS(10.54g,59.2mmol,1.05eq.)溶于乙腈中(250mL),N
2置换三次,反应体系在60℃下反应4h,TLC监测反应完毕。反应液滴入饱和碳酸氢钠溶液和乙酸乙酯萃取,有机相干燥浓缩,柱层析分离得化合物24-f,约8g,收率为61%。
1H NMR(500MHz,CDCl
3)δ6.47(d,1H),6.38(d,1H),3.87(s,3H),3.80(s,3H),1.24–1.20(m,5H),0.83–0.78(m,8H).
Compound 24-e (13.2g, 56.4mmol, 1.0eq.) and NBS (10.54g, 59.2mmol, 1.05eq.) were dissolved in acetonitrile (250mL), N 2 was replaced three times, and the reaction system was reacted at 60°C for 4h, The completion of the reaction was monitored by TLC. The reaction was dropped into saturated sodium bicarbonate solution and extracted with ethyl acetate, the organic phase was dried and concentrated, and the compound 24-f was separated by column chromatography, about 8 g, and the yield was 61%. 1 H NMR (500MHz, CDCl 3 )δ6.47(d,1H), 6.38(d,1H), 3.87(s,3H), 3.80(s,3H), 1.24–1.20(m,5H), 0.83– 0.78(m,8H).
步骤六:Step 6:
化合物24-f(500mg,1.596mmol,1.0eq.)溶于四氢呋喃中(16mL),降温至-60℃,N
2置换三次,向溶液中缓慢加入n-BuLi(1.6mL,2.5M,2.5eq),反应2h,加入氯甲酸甲酯(378mg,4mmol,2.5eq.)继续反应2h,TLC监测反应完毕。反应液滴入饱和氯化铵溶液中淬灭,乙酸乙酯萃取;有机相用无水硫酸钠干燥,浓缩得284mg 24-g。
1H NMR(500MHz,CDCl
3)δ6.43(d,J=2.3Hz,1H),6.33(d,J=2.2Hz,1H),3.88(s,3H),3.81(s,3H),3.78(s,3H),1.53–1.50(m,2H),1.25–1.22(m,4H),0.83(t,3H),0.77–0.75(m,2H),0.60–0.58(m,2H).
Compound 24-f (500 mg, 1.596 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (16 mL), cooled to -60 °C, replaced by N 2 three times, and n-BuLi (1.6 mL, 2.5 M, 2.5 eq.) was slowly added to the solution. ), reacted for 2h, added methyl chloroformate (378mg, 4mmol, 2.5eq.) to continue the reaction for 2h, and TLC monitored the completion of the reaction. The reaction was dropped into saturated ammonium chloride solution to quench, and extracted with ethyl acetate; the organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain 284 mg of 24-g. 1 H NMR (500 MHz, CDCl 3 ) δ 6.43 (d, J=2.3 Hz, 1H), 6.33 (d, J=2.2 Hz, 1H), 3.88 (s, 3H), 3.81 (s, 3H), 3.78 (s, 3H), 1.53–1.50 (m, 2H), 1.25–1.22 (m, 4H), 0.83 (t, 3H), 0.77–0.75 (m, 2H), 0.60–0.58 (m, 2H).
步骤七:Step seven:
化合物24-g(670mg,2.29mmol,1.0eq.)和氢氧化钾(1.27g,22.9mmol,10.0eq.)溶于10ml DMSO中,N
2保护,于100℃下搅拌反应过夜,TLC监测反应完毕。反应液滴入饱和氯化钠溶液淬灭,用1M盐酸调成pH酸性,用甲基叔丁基醚萃取, 有机相干燥浓缩,柱层析得24-h,约488mg。
1H NMR(500MHz,DMSO)δ12.53(s,1H),6.47(d,1H),6.36(d,1H),3.76(s,3H),3.74(s,3H),1.51–1.48(m,2H),1.19–1.16(m,4H),0.79(t,3H),0.74–0.71(t,J=5.0Hz,2H),0.57–0.55(m,2H).ESI-MS m/z 277.32(M–H)
–.
Compound 24-g (670mg, 2.29mmol, 1.0eq.) and potassium hydroxide (1.27g, 22.9mmol, 10.0eq.) were dissolved in 10ml DMSO, protected by N2 , and the reaction was stirred at 100 °C overnight, and the reaction was monitored by TLC complete. The reaction was quenched by dropwise addition of saturated sodium chloride solution, adjusted to pH acidity with 1M hydrochloric acid, extracted with methyl tert-butyl ether, the organic phase was dried and concentrated, and the obtained was obtained by column chromatography for 24-h, about 488 mg. 1 H NMR (500MHz, DMSO) δ 12.53(s, 1H), 6.47(d, 1H), 6.36(d, 1H), 3.76(s, 3H), 3.74(s, 3H), 1.51–1.48(m ,2H),1.19–1.16(m,4H),0.79(t,3H),0.74–0.71(t,J=5.0Hz,2H),0.57–0.55(m,2H).ESI-MS m/z 277.32 (M–H) – .
步骤八:Step 8:
将化合物24-h(1.15g,4.14mmol,1.0eq)溶于DCM中,冰浴下加入SOCl
2(984mg,8.27mmol,2.0eq)和2滴DMF,常温搅拌1小时,TLC监测反应完毕,浓缩去除SOCl
2。另取反应容器加入甲胺盐酸盐(800mg,3eq)、4-二甲氨基吡啶(558mg,8.27mmol,2.0eq)和Et
3N(1.67g,16.5mmol,4.0eq)搅拌20分钟,冰浴条件下加入酰氯的DCM溶液,继续冰浴反应30分钟,室温条件下反应过夜。二氯甲烷萃取,有机相干燥浓缩,柱层析得化合物24-i约780mg。
1H NMR(500MHz,DMSO)δ7.7(d,1H),6.44(d,1H),6.34(d,1H),3.75(s,3H),3.71(s,3H),2.69(d,3H),1.48–1.45(m,2H),1.16–1.15(m,4H),0.79(t,3H),0.74–0.72(m,2H),0.50–0.48(m,2H).
Compound 24-h (1.15 g, 4.14 mmol, 1.0 eq) was dissolved in DCM, SOCl 2 (984 mg, 8.27 mmol, 2.0 eq) and 2 drops of DMF were added under ice bath, stirred at room temperature for 1 hour, TLC monitored the completion of the reaction, Concentrate to remove SOCl 2 . Take another reaction vessel and add methylamine hydrochloride (800mg, 3eq), 4-dimethylaminopyridine (558mg, 8.27mmol, 2.0eq) and Et3N (1.67g, 16.5mmol, 4.0eq), stir for 20 minutes, ice The DCM solution of acid chloride was added under the bath condition, and the ice bath reaction was continued for 30 minutes, and the reaction was carried out at room temperature overnight. Dichloromethane was extracted, the organic phase was dried and concentrated, and about 780 mg of compound 24-i was obtained by column chromatography. 1 H NMR(500MHz, DMSO)δ7.7(d,1H), 6.44(d,1H), 6.34(d,1H), 3.75(s,3H), 3.71(s,3H), 2.69(d,3H) ), 1.48–1.45 (m, 2H), 1.16–1.15 (m, 4H), 0.79 (t, 3H), 0.74–0.72 (m, 2H), 0.50–0.48 (m, 2H).
步骤九:Step nine:
将24-i(780mg,2.68mmol,1.0eq)置于反应瓶,N
2置换3次,加入30mL DCM,降温至-65℃,缓慢加入BBr
3(2.01g,8.04mmol,3.0eq),反应2小时,自然升温反应过夜,TLC监测反应,加入饱和食盐水萃取,干燥浓缩,柱层析得化合物24-j约440mg。
1H NMR(400MHz,DMSO)δ9.38(s,1H),9.20(s,1H),7.62(d,1H),6.14(d,1H),6.09(d,1H),2.68(d,3H),1.46–1.43(m,2H),1.24–1.15(m,4H),0.80(t,3H),0.68–0.67(m,2H),0.47–0.45(m,2H).ESI-MS m/z 262.35(M–H)
–.
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. 1 H NMR (400MHz, DMSO)δ9.38(s,1H), 9.20(s,1H), 7.62(d,1H), 6.14(d,1H), 6.09(d,1H), 2.68(d,3H) ),1.46–1.43(m,2H),1.24–1.15(m,4H),0.80(t,3H),0.68–0.67(m,2H),0.47–0.45(m,2H).ESI-MS m/ z 262.35(M–H) – .
步骤十:Step ten:
将化合物24-j(100mg,0.38mmol,1.0eq)置于反应瓶,N
2置换3次,加入30mL DCM,降温至0-5℃,缓慢加入Tf
2O(10mg,0.04mmol,0.1eq),搅拌30分钟,缓慢加入(+)-柠檬烯(70mg,0.46mmol,1.35eq)的DCM溶液,TLC监测反应,加入饱和食盐水萃取,干燥浓缩,柱层析得标题化合物24约50mg。
1H NMR(400MHz,DMSO)δ11.10(br,1H),9.30(s,1H),7.70(d,1H),6.22(s,1H),5.08(s,1H),4.48(s,1H),4.42(s,1H),3.88(d,1H),3.00(t,1H),2.82(d,3H),2.12–2.09(m,1H),1.94–1.90(m,1H),1.75–1.61(m,2H),1.61(s,3H),1.58(s,3H),1.44–1.40(m,2H),1.17–1.07(m,4H),0.89–0.82(m,2H),0.77(t,3H),0.73–0.62(m,2H).ESI-MS m/z 396.41(M–H)
–.
Compound 24-j (100 mg, 0.38 mmol, 1.0 eq) was placed in a reaction flask, replaced by N 2 three times, 30 mL of DCM was added, the temperature was lowered to 0-5 °C, and Tf 2 O (10 mg, 0.04 mmol, 0.1 eq) was slowly added , Stir for 30 minutes, slowly add (+)-limonene (70 mg, 0.46 mmol, 1.35 eq) in DCM, monitor the reaction by TLC, add saturated brine for extraction, dry and concentrate, and column chromatography to obtain about 50 mg of the title compound 24. 1 H NMR (400MHz, DMSO)δ11.10(br,1H), 9.30(s,1H), 7.70(d,1H), 6.22(s,1H), 5.08(s,1H), 4.48(s,1H) ), 4.42(s, 1H), 3.88(d, 1H), 3.00(t, 1H), 2.82(d, 3H), 2.12–2.09(m, 1H), 1.94–1.90(m, 1H), 1.75– 1.61(m,2H),1.61(s,3H),1.58(s,3H),1.44–1.40(m,2H),1.17–1.07(m,4H),0.89–0.82(m,2H),0.77( t,3H),0.73–0.62(m,2H).ESI-MS m/z 396.41(M–H) – .
实施例10制备下式化合物27Example 10 Preparation of compound 27 of the following formula
步骤一:step one:
27-a(100mg,0.56mmol,1.0eq.)和NBS(105mg,0.59mmol,1.05eq.)溶于乙腈中(6mL),N
2置换三次,反应体系在60℃下反应,TLC监测反应完毕,淬灭,乙酸乙酯萃取,柱层析,得目标化合物27-b约95mg。
1H NMR(400MHz,CDCl
3)δ6.70(d,1H),6.47(d,1H),3.88(s,3H),3.84(s,5H).GC-MS m/z 255.0.
27-a (100 mg, 0.56 mmol, 1.0 eq.) and NBS (105 mg, 0.59 mmol, 1.05 eq.) were dissolved in acetonitrile (6 mL), replaced by N 2 three times, the reaction system was reacted at 60 °C, and the completion of the reaction was monitored by TLC , quenched, extracted with ethyl acetate, and subjected to column chromatography to obtain about 95 mg of the target compound 27-b. 1 H NMR (400MHz, CDCl 3 ) δ 6.70(d,1H), 6.47(d,1H), 3.88(s,3H), 3.84(s,5H).GC-MS m/z 255.0.
步骤二:Step 2:
氢化钠(375mg,15.62mmol,4.0eq.)置于三口瓶中,N
2置换三次,加入N,N-二甲基甲酰胺(6mL),冰盐浴降温至0℃;将27-b(1.0g,3.9mmol,1.0eq.)、碘甲烷(0.73mL,11.71mmol,3.0eq.)溶于N,N-二甲基甲酰胺(10mL),缓慢滴入反应体系,保持体系温度在-5℃~5℃之间。反应1h,TLC监测反应完毕。淬灭,乙酸乙酯萃取,柱层析,得目标化合物27-c约930mg。
1H NMR(500MHz,CDCl
3)δ6.71(d,1H),5.51(d,8H),3.93(s,3H),3.86(s,3H),1.92(s,6H).GC-MS m/z 283.1.
Sodium hydride (375mg, 15.62mmol, 4.0eq.) was placed in a three-necked flask, replaced by N 3 times, N,N-dimethylformamide (6mL) was added, and the ice-salt bath was cooled to 0°C; 27-b ( 1.0g, 3.9mmol, 1.0eq.), iodomethane (0.73mL, 11.71mmol, 3.0eq.) were dissolved in N,N-dimethylformamide (10mL), slowly dropped into the reaction system, keeping the system temperature at - Between 5°C and 5°C. The reaction was completed for 1 h, and the completion of the reaction was monitored by TLC. After quenching, extraction with ethyl acetate, and column chromatography, about 930 mg of the target compound 27-c was obtained. 1 H NMR (500MHz, CDCl 3 )δ6.71(d,1H), 5.51(d,8H), 3.93(s,3H), 3.86(s,3H), 1.92(s,6H).GC-MS m /z 283.1.
步骤三:Step 3:
将化合物27-c(200mg,0.7mmol,1.0eq.)置于三口瓶中,N
2置换三次,加入二氯甲烷(10mL),体系降温至-68℃,缓慢加入1M二异丁基氢化铝(1.77mL,1.77mmol,2.51eq.)。于-68℃条件下反应1.5h,TLC监测反应完毕,淬灭,过滤不溶物,二氯甲烷萃取,柱层析分离得目标化合物27-d 170mg。
1H NMR(400MHz,CDCl
3)δ9.78(s,1H),6.60(d,1H),6.49(d,1H),3.88(s,3H),3.84(s,3H),1.50(s,6H).GC-MS m/z 286.1.
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. 1 H NMR (400MHz, CDCl 3 )δ9.78(s,1H), 6.60(d,1H), 6.49(d,1H), 3.88(s,3H), 3.84(s,3H), 1.50(s, 6H).GC-MS m/z 286.1.
步骤四:Step 4:
三苯基丙基溴化磷(403mg,1.045mmol,3.0eq.)于三口瓶中,N
2置换三次,加入THF 5mL,冰浴下加入二(三甲基硅基)氨基钾(1mL,1.01mmol,2.9eq.)冰浴搅拌30min,将27-d(100mg,0.348mmol,1.0eq.)溶于5mL THF中,缓慢加入反应体系。在0℃下搅拌反应1h,TLC监测反应完毕,淬灭,乙酸乙酯萃取,柱层 析得目标化合物27-e约400mg。
1H NMR(400MHz,CDCl
3)δ6.74(d,1H),6.40(d,1H),5.74–5.68(m,1H),5.12(dt,1H),3.85(d,6H),1.59–1.53(m,2H),1.52(s,6H),0.66(t,3H).GC-MS m/z 314.1.
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. for 1 h, monitored by TLC for completion of the reaction, quenched, extracted with ethyl acetate, and subjected to column chromatography to obtain about 400 mg of the target compound 27-e. 1 H NMR (400MHz, CDCl 3 ) δ 6.74(d,1H), 6.40(d,1H), 5.74-5.68(m,1H), 5.12(dt,1H), 3.85(d,6H), 1.59- 1.53(m,2H),1.52(s,6H),0.66(t,3H).GC-MS m/z 314.1.
步骤五:Step 5:
27-e(500mg,1.596mmol,1.0eq.)溶于20mL乙二醇二甲醚中,再加入对甲苯磺酰肼(3.57g,19.15mmol,12.0eq.),混合液于95℃加热回流,缓慢加入乙酸钠水溶液(3.4g,41.5mmol,26.0eq)。TLC监测反应完毕,淬灭,二氯甲烷萃取,柱层析得目标化合物27-f 420mg。
1H NMR(400MHz,CDCl
3)δ6.60(d,1H),6.39(d,1H),3.87(s,3H),3.81(s,3H),2.07–1.97(m,2H),1.46(s,6H),1.25(m,2H),0.96(m,2H),0.82(t,3H).
27-e (500mg, 1.596mmol, 1.0eq.) was dissolved in 20mL of ethylene glycol dimethyl ether, p-toluenesulfonyl hydrazide (3.57g, 19.15mmol, 12.0eq.) was added, and the mixture was heated to reflux at 95°C , and slowly added aqueous sodium acetate (3.4 g, 41.5 mmol, 26.0 eq). The completion of the reaction was monitored by TLC, quenched, extracted with dichloromethane, and 420 mg of the target compound 27-f was obtained by column chromatography. 1 H NMR (400MHz, CDCl 3 )δ6.60(d,1H), 6.39(d,1H), 3.87(s,3H), 3.81(s,3H), 2.07-1.97(m,2H), 1.46( s,6H),1.25(m,2H),0.96(m,2H),0.82(t,3H).
步骤六:Step 6:
27-f(200mg,0.634mmol,1.0eq.)置于反应瓶,氮气置换后加入5mL THF,降温至-65℃,缓慢加入n-BuLi(0.38mL,0.95mmol,1.5eq.),在-60至-65℃条件下反应一小时,将反应体系置换为CO
2。TLC监测反应,淬灭,乙酸乙酯萃取,柱层析,得27-g 120mg。
1H NMR(500MHz,DMSO)δ12.61(s,1H),6.51(d,1H),6.44(d,1H),3.77(d,6H),1.67–1.58(m,2H),1.29(s,6H),1.23–1.15(m,2H),1.06–0.97(m,2H),0.80(t,3H).
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. 1 H NMR (500MHz, DMSO) δ 12.61(s, 1H), 6.51(d, 1H), 6.44(d, 1H), 3.77(d, 6H), 1.67–1.58(m, 2H), 1.29(s) ,6H),1.23–1.15(m,2H),1.06–0.97(m,2H),0.80(t,3H).
步骤七:Step seven:
27-g(100mg,0.36mmol,1.0eq.)于3mL二氯甲烷中,冰浴(0-2℃)下加入二氯亚砜(0.1mL,1.43mmol,4.0eq.)和1滴DMF,之后反应于冰浴搅拌1小时。TLC监测原料反应完全,浓缩去除溶剂和二氯亚砜。另取反应瓶加入甲胺盐酸盐(97mg,1.44mmol,4.0eq.)于5mL二氯甲烷中,加入三乙胺(0.4mL,1.43mmol,4.0eq.),冰浴下将原反应液缓慢加入反应体系,室温反应1h(22℃)。TLC监测反应完毕,氯化铵淬灭后加入少量稀盐酸调至酸性,二氯甲烷萃取,干燥浓缩,柱层析,得目标化合物27-h。
1H NMR(500MHz,DMSO)δ7.86(m,1H),6.49(d,1H),6.44(d,1H),3.77(s,3H),3.72(s,3H),2.65(d,3H),1.65–1.56(m,2H),1.26(s,6H),1.22–1.11(m,2H),1.03(m,2H),0.82(t,3H).
27-g (100mg, 0.36mmol, 1.0eq.) in 3mL of dichloromethane, add thionyl chloride (0.1mL, 1.43mmol, 4.0eq.) and 1 drop of DMF under an ice bath (0-2°C), The reaction was then stirred in an ice bath for 1 hour. The reaction of the starting materials was monitored by TLC, and the solvent and thionyl chloride were removed by concentration. Take another reaction flask and add methylamine hydrochloride (97mg, 1.44mmol, 4.0eq.) in 5mL of dichloromethane, add triethylamine (0.4mL, 1.43mmol, 4.0eq.), and mix the original reaction solution under ice bath. The 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. 1 H NMR(500MHz, DMSO)δ7.86(m,1H), 6.49(d,1H), 6.44(d,1H), 3.77(s,3H), 3.72(s,3H), 2.65(d,3H) ), 1.65–1.56(m, 2H), 1.26(s, 6H), 1.22–1.11(m, 2H), 1.03(m, 2H), 0.82(t, 3H).
步骤八:Step 8:
27-h(50mg,0.17mmol,1.0eq),氮气置换后加入2.5mL二氯甲烷,降温至-62℃后缓慢加入三溴化硼(0.04mL,0.43mmol,2.5eq.),控制反应于-60℃搅拌3小时。TLC监测反应完全,淬灭,萃取,干燥浓缩,柱层析,得目标化合物,27-i。
1H NMR(500MHz,DMSO)δ9.12(s,1H),9.07(s,1H),7.71(d,1H),6.18(dd,2H),2.63(d,3H),1.64–1.50(m,2H),1.23(s,6H),1.20–1.11(m,2H),1.08–0.96(m,2H),0.82(t,3H).
27-h (50mg, 0.17mmol, 1.0eq), after nitrogen replacement, 2.5mL of dichloromethane was added, cooled to -62°C, and then boron tribromide (0.04mL, 0.43mmol, 2.5eq.) was slowly added, and the reaction was controlled at Stir at -60°C for 3 hours. The completion of the reaction was monitored by TLC, quenched, extracted, dried and concentrated, and subjected to column chromatography to obtain the target compound, 27-i. 1 H NMR (500MHz, DMSO) δ 9.12(s, 1H), 9.07(s, 1H), 7.71(d, 1H), 6.18(dd, 2H), 2.63(d, 3H), 1.64–1.50(m ,2H),1.23(s,6H),1.20–1.11(m,2H),1.08–0.96(m,2H),0.82(t,3H).
步骤九:Step nine:
将27-i(300mg,1.1mmol,1.0eq)溶于30mL DCM中,氮气置换3次,降温至-10—0℃,缓慢加入Tf
2O(20mg,0.11mmol,0.1eq),搅拌30分钟,缓慢加入(+)-柠檬烯(200mg,1.32mmol,1.2eq)的DCM溶液,TLC监测反应,淬灭,二氯甲烷萃取,柱层析得化合物27约100mg。
1H NMR(400MHz,DMSO)δ8.84(s,1H),7.68(d,1H),6.29(s,1H),5.16(s,1H),4.49(d,2H),3.86(d,1H),2.90(s,1H),2.63(d,3H),2.14(s,1H),1.94(d,1H),1.58(m,8H),1.20(m,6H),1.17(d,3H),1.00(d,3H),0.90–0.72(t,3H).ESI-MS m/z 398.5(M–H)
–.
27-i (300 mg, 1.1 mmol, 1.0 eq) was dissolved in 30 mL of DCM, replaced with nitrogen three times, cooled to -10-0 °C, Tf 2 O (20 mg, 0.11 mmol, 0.1 eq) was slowly added, and stirred for 30 minutes , slowly adding (+)-limonene (200mg, 1.32mmol, 1.2eq) in DCM, TLC monitoring the reaction, quenching, dichloromethane extraction, column chromatography to obtain about 100mg of compound 27. 1 H NMR(400MHz,DMSO)δ8.84(s,1H),7.68(d,1H),6.29(s,1H),5.16(s,1H),4.49(d,2H),3.86(d,1H) ), 2.90(s, 1H), 2.63(d, 3H), 2.14(s, 1H), 1.94(d, 1H), 1.58(m, 8H), 1.20(m, 6H), 1.17(d, 3H) ,1.00(d,3H),0.90–0.72(t,3H).ESI-MS m/z 398.5(M–H) – .
实施例11制备下式化合物9Example 11 Preparation of compound 9 of the following formula
步骤一:step one:
于反应瓶中加入9-a(500mg,2.30mmol,1.0eq)和Pd(dppf)Cl
2(169mg,0.23mmol,0.1eq),氮气置换,加入环丙基溴化镁(10mL,10mmol,5.0eq),75℃回流,搅拌过夜。TLC监测反应,淬灭,乙酸乙酯萃取,浓缩,柱层析得9-b约350mg。
1H NMR(500MHz,CDCl
3)δ6.30(d,1H),6.28(d,2H),3.81(s,6H),1.97–1.81(m,1H),0.97(m,2H),0.79–0.63(m,2H).GC-MS m/z 178.1.
9-a (500mg, 2.30mmol, 1.0eq) and Pd(dppf)Cl 2 (169mg, 0.23mmol, 0.1eq) were added to the reaction flask, nitrogen was replaced, and cyclopropylmagnesium bromide (10mL, 10mmol, 5.0 eq), reflux at 75°C, and stir overnight. The reaction was monitored by TLC, quenched, extracted with ethyl acetate, concentrated, and subjected to column chromatography to obtain about 350 mg of 9-b. 1 H NMR (500MHz, CDCl 3 )δ6.30(d,1H), 6.28(d,2H), 3.81(s,6H), 1.97-1.81(m,1H), 0.97(m,2H), 0.79- 0.63(m,2H).GC-MS m/z 178.1.
步骤二:Step 2:
将9-b(100mg,0.56mmol,1.0eq)溶解于5mL乙腈中,加入NBS(105mg,0.59mmol,1.05eq),反应于室温搅拌4小时,TLC监测反应,淬灭,乙酸乙酯萃取,浓缩,柱层析得9-c约60mg。
1H NMR(500MHz,CDCl
3)δ6.37(d,1H),6.16(d,1H),3.90(s,3H),3.81(s,3H),2.27–2.20(m,1H),1.06–1.00(m,2H),0.71–0.66(m,2H).GC-MS m/z 258.0.
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. 1 H NMR (500MHz, CDCl 3 )δ6.37(d,1H), 6.16(d,1H), 3.90(s,3H), 3.81(s,3H), 2.27–2.20(m,1H), 1.06– 1.00(m,2H),0.71–0.66(m,2H).GC-MS m/z 258.0.
步骤三:Step 3:
9-c(200mg,0.78mmol,1.0eq)置于反应瓶,氮气置换后加入5mL四氢呋喃。 降温至-62℃,缓慢加入正丁基锂(0.47mL,1.17mmol,1.5eq),控制反应温度于-62℃到-64℃之间搅拌1小时,之后将反应瓶中气体置换为CO
2,并在-60℃~-50℃继续搅拌1小时,TLC监测反应,淬灭,乙酸乙酯萃取,浓缩,柱层析得9-d约130mg。
1H NMR(400MHz,DMSO)δ12.62(s,1H),6.41(d,1H),6.00(d,1H),3.74(s,6H),2.01–1.78(m,1H),1.04–0.82(m,2H),0.81–0.53(m,2H).ESI-MS m/z 221.2(M-H)
-.
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. 1 H NMR (400MHz, DMSO)δ12.62(s,1H), 6.41(d,1H), 6.00(d,1H), 3.74(s,6H), 2.01–1.78(m,1H), 1.04–0.82 (m,2H),0.81–0.53(m,2H).ESI-MS m/z 221.2(MH) - .
步骤四:Step 4:
9-d(50mg,0.22mmol,1.0eq)溶于4mL二氯甲烷中,冰浴下加入二氯亚砜(0.06mL,0.9mmol,4.0eq)和1滴DMF,于冰浴下搅拌1小时。TLC监测原料反应完全,浓缩去除溶剂和二氯亚砜。另取单口瓶中加入甲胺盐酸盐(61mg,0.9mmol,4.0eq)于4mL二氯甲烷中,加入三乙胺(0.12mL,0.9mmol,4.0eq)和DMAP(55mg,0.44mmol,2.0eq),冰浴下缓慢加入前述酰氯的二氯甲烷(2.5mL)溶液,于室温反应1小时。TLC监测反应,淬灭,二氯甲烷萃取,浓缩,柱层析得9-e约30mg。
1H NMR(500MHz,DMSO)δ7.98(d,1H),6.39(d,1H),5.96(d,1H),3.74(s,3H),3.72(s,3H),2.71(d,3H),1.89–1.73(m,1H),0.89–0.84(m,2H),0.68–0.64(m,2H).ESI-MS m/z 235.9(M+H)
+.
9-d (50 mg, 0.22 mmol, 1.0 eq) was dissolved in 4 mL of dichloromethane, thionyl chloride (0.06 mL, 0.9 mmol, 4.0 eq) and 1 drop of DMF were added under an ice bath, and the mixture was stirred under an ice bath for 1 hour . The reaction of the starting materials was monitored by TLC, and the solvent and thionyl chloride were removed by concentration. In another single-necked bottle, add methylamine hydrochloride (61mg, 0.9mmol, 4.0eq) in 4mL of dichloromethane, add triethylamine (0.12mL, 0.9mmol, 4.0eq) and DMAP (55mg, 0.44mmol, 2.0 eq), slowly add the dichloromethane (2.5 mL) solution of the aforementioned acid chloride under an ice bath, and react at room temperature for 1 hour. The reaction was monitored by TLC, quenched, extracted with dichloromethane, concentrated, and subjected to column chromatography to obtain about 30 mg of 9-e. 1 H NMR(500MHz, DMSO)δ7.98(d,1H), 6.39(d,1H), 5.96(d,1H), 3.74(s,3H), 3.72(s,3H), 2.71(d,3H) ),1.89–1.73(m,1H),0.89–0.84(m,2H),0.68–0.64(m,2H).ESI-MS m/z 235.9(M+H) + .
步骤五:Step 5:
9-e(100mg,0.43mmol,1.0eq),氮气置换后加入10mL二氯甲烷,降温至-15℃后缓慢加入三溴化硼(0.13mL,1.3mmol,3.0eq.),控制反应温度不超过-10℃搅拌30min,自然升温反应3小时,TLC监测反应完全,淬灭,正丁醇萃取,干燥浓缩,柱层析,得化合物9-f约55mg。
1H NMR(400MHz,DMSO)δ9.65(s,1H),9.26(s,1H),7.81(d,1H),6.10(d,1H),5.72(d,1H),2.71(d,3H),1.92–1.80(m,1H),0.92–0.76(m,2H),0.60–0.41(m,2H).ESI-MS m/z 206.3(M-H)
-.
9-e (100mg, 0.43mmol, 1.0eq), 10mL of dichloromethane was added after nitrogen replacement, cooled to -15°C, and then boron tribromide (0.13mL, 1.3mmol, 3.0eq.) was slowly added to control the reaction temperature. The mixture was stirred for 30 min over -10°C, and the reaction was naturally heated for 3 hours. The reaction was completed by TLC monitoring, quenched, extracted with n-butanol, dried and concentrated, and subjected to column chromatography to obtain about 55 mg of compound 9-f. 1 H NMR(400MHz, DMSO)δ9.65(s,1H), 9.26(s,1H), 7.81(d,1H), 6.10(d,1H), 5.72(d,1H), 2.71(d,3H) ),1.92–1.80(m,1H),0.92–0.76(m,2H),0.60–0.41(m,2H).ESI-MS m/z 206.3(MH) - .
步骤六:Step 6:
9-f(250mg,1.2mmol,1.0eq)溶于30mL DCM中,氮气置换3次,降温至-10—0℃,缓慢加入Tf
2O(34mg,0.12mmol,0.1eq),搅拌30分钟,缓慢加入(+)-柠檬烯(218mg,1.44mmol,1.2eq)的DCM溶液,TLC监测反应,淬灭,二氯甲烷萃取,柱层析得化合物9约70mg。
1H NMR(400MHz,DMSO)δ11.42(s,1H),9.35(s,1H),7.88(s,1H),6.02(s,1H),5.05(s,1H),4.45(d,2H),3.87(d,1H),3.03(t,1H),2.09(s,3H),1.97(m,2H),1.68(s,2H),1.68(s,1H),1.65–1.51(m,6H),0.89(m,2H),0.52(d,2H).ESI-MS m/z 340.6(M-H)
-.
9-f (250 mg, 1.2 mmol, 1.0 eq) was dissolved in 30 mL of DCM, replaced with nitrogen three times, cooled to -10-0 °C, slowly added Tf 2 O (34 mg, 0.12 mmol, 0.1 eq), stirred for 30 minutes, A solution of (+)-limonene (218 mg, 1.44 mmol, 1.2 eq) in DCM was slowly added, the reaction was monitored by TLC, quenched, extracted with dichloromethane, and about 70 mg of compound 9 was obtained by column chromatography. 1 H NMR(400MHz,DMSO)δ11.42(s,1H),9.35(s,1H),7.88(s,1H),6.02(s,1H),5.05(s,1H),4.45(d,2H) ), 3.87(d, 1H), 3.03(t, 1H), 2.09(s, 3H), 1.97(m, 2H), 1.68(s, 2H), 1.68(s, 1H), 1.65–1.51(m, 6H),0.89(m,2H),0.52(d,2H).ESI-MS m/z 340.6(MH) - .
实施例12制备下式化合物8Example 12 Preparation of compound 8 of the following formula
步骤一:step one:
9-d(50mg,0.22mmol,1.0eq)溶于4mL二氯甲烷中,冰浴下加入二氯亚砜(0.06mL,0.9mmol,4.0eq)和1滴DMF,于冰浴下搅拌1小时。TLC监测原料反应完全,浓缩去除溶剂和二氯亚砜。另取单口瓶中加入氯化铵(48mg,0.9mmol,4.0eq)于4mL二氯甲烷中,加入三乙胺(0.12mL,0.9mmol,4.0eq)和DMAP(55mg,0.44mmol,2.0eq),冰浴下缓慢加入前述酰氯的二氯甲烷(2.5mL)溶液,于室温反应1小时。TLC监测反应,淬灭,二氯甲烷萃取,浓缩,柱层析得8-a约27mg。
1H NMR(500MHz,DMSO)δ7.53(s,1H),7.28(s,1H),6.38(d,1H),5.95(d,1H),3.74(t,6H),1.97–1.90(m,1H),0.95–0.80(m,2H),0.75–0.64(m,2H).ESI-MS m/z 222.1(M+H)
+.
9-d (50 mg, 0.22 mmol, 1.0 eq) was dissolved in 4 mL of dichloromethane, thionyl chloride (0.06 mL, 0.9 mmol, 4.0 eq) and 1 drop of DMF were added under an ice bath, and the mixture was stirred under an ice bath for 1 hour . The reaction of the starting materials was monitored by TLC, and the solvent and thionyl chloride were removed by concentration. In another single-necked bottle, add ammonium chloride (48mg, 0.9mmol, 4.0eq) to 4mL of dichloromethane, add triethylamine (0.12mL, 0.9mmol, 4.0eq) and DMAP (55mg, 0.44mmol, 2.0eq) , The dichloromethane (2.5 mL) solution of the aforementioned acid chloride was slowly added under an ice bath, and the reaction was carried out at room temperature for 1 hour. The reaction was monitored by TLC, quenched, extracted with dichloromethane, concentrated, and subjected to column chromatography to obtain about 27 mg of 8-a. 1 H NMR (500MHz, DMSO) δ7.53(s,1H), 7.28(s,1H), 6.38(d,1H), 5.95(d,1H), 3.74(t,6H), 1.97–1.90(m ,1H),0.95–0.80(m,2H),0.75–0.64(m,2H).ESI-MS m/z 222.1(M+H) + .
步骤二:Step 2:
8-a(50mg,0.24mmol,1.0eq)置于反应瓶中,氮气置换后加入2.5mL二氯甲烷,降温至-25~-15℃后缓慢加入三溴化硼(0.07mL,0.72mmol,3.0eq.),维持该温度搅拌2小时。TLC监测反应完全,淬灭,正丁醇萃取,干燥浓缩,柱层析,得化合物8-b约27mg。
1H NMR(400MHz,DMSO)δ10.62(s,1H),9.40(s,1H),7.39(s,2H),6.09(d,1H),5.83(d,1H),2.05(m,1H),0.94–0.81(m,2H),0.67–0.50(m,2H).
8-a (50mg, 0.24mmol, 1.0eq) was placed in a reaction flask, replaced with nitrogen, and then added with 2.5mL of dichloromethane, cooled to -25 to -15°C, and then slowly added boron tribromide (0.07mL, 0.72mmol, 3.0 eq.), stirring at this temperature for 2 hours. The reaction was completed by TLC monitoring, quenched, extracted with n-butanol, dried and concentrated, and subjected to column chromatography to obtain about 27 mg of compound 8-b. 1 H NMR (400MHz, DMSO) δ 10.62(s, 1H), 9.40(s, 1H), 7.39(s, 2H), 6.09(d, 1H), 5.83(d, 1H), 2.05(m, 1H) ),0.94–0.81(m,2H),0.67–0.50(m,2H).
步骤三:Step 3:
将8-b(300mg,1.6mmol,1.0eq)溶于30mL DCM中,氮气置换3次,降温至0~5℃,缓慢加入Tf
2O(45mg,0.16mmol,0.1eq),搅拌30分钟,缓慢加入(+)-柠檬烯(292mg,1.92mmol,1.2eq)的DCM溶液,TLC监测反应,饱和碳酸氢钠淬灭,二氯甲烷萃取,柱层析得化合物8约190mg。
1H NMR(400MHz,DMSO)δ12.89(s,1H),9.46(s,1H),7.95(s,1H),7.49(s,1H),6.08(s,1H),5.05(s,1H),4.45(d,2H),3.87(d,1H), 3.04(t,1H),2.15(m,2H),1.98(m,2H),1.73–1.64(m,1H),1.63–1.52(m,6H),1.00–0.91(m,2H),0.59(d,2H).ESI-MS m/z 326.4(M-H)
-.
8-b (300 mg, 1.6 mmol, 1.0 eq) was dissolved in 30 mL of DCM, replaced with nitrogen three times, cooled to 0-5 °C, Tf 2 O (45 mg, 0.16 mmol, 0.1 eq) was slowly added, stirred for 30 minutes, A solution of (+)-limonene (292 mg, 1.92 mmol, 1.2 eq) in DCM was slowly added, the reaction was monitored by TLC, quenched with saturated sodium bicarbonate, extracted with dichloromethane, and subjected to column chromatography to obtain about 190 mg of compound 8. 1 H NMR (400MHz, DMSO)δ12.89(s,1H), 9.46(s,1H), 7.95(s,1H), 7.49(s,1H), 6.08(s,1H), 5.05(s,1H) ), 4.45(d, 2H), 3.87(d, 1H), 3.04(t, 1H), 2.15(m, 2H), 1.98(m, 2H), 1.73–1.64(m, 1H), 1.63–1.52( m,6H),1.00–0.91(m,2H),0.59(d,2H).ESI-MS m/z 326.4(MH) - .
实施例13制备下式化合物34Example 13 Preparation of compound 34 of the following formula
步骤一:step one:
化合物34-b(11.59g,48.6mmol,1.5eq.)置于三口瓶中,N
2置换三次,加入香叶醇34-a(5.0g,32.4mmol,1.0eq.)、二氯甲烷(150mL),降温至-20℃,加入8M三氟化硼乙醚(1.6mL,12.96mmol,0.4eq.)。-20℃下反应2h。反应液加入水中淬灭,二氯甲烷萃取,有机相用无水硫酸钠干燥,过滤、浓缩,柱层析分离,得产物34-c约4.9g。
1H NMR(400MHz,Chloroform-d)δ12.01(s,1H),6.23(s,1H),5.88(s,1H),5.31–5.23(m,1H),5.09–5.01(m,1H),3.91(s,3H),3.43(d,J=7.1Hz,2H),2.84–2.76(m,2H),2.13–2.02(m,4H),1.83–1.78(m,3H),1.69–1.65(m,3H),1.61–1.56(m,3H),1.51(dtt,J=10.4,5.2,2.6Hz,2H),1.33(dt,J=7.4,3.2Hz,4H),0.96–0.86(m,3H).
Compound 34-b (11.59g, 48.6mmol, 1.5eq.) was placed in a three-necked flask, N 2 was replaced three times, and geraniol 34-a (5.0g, 32.4mmol, 1.0eq.), dichloromethane (150mL) were added ), cooled to -20° C., and added 8M boron trifluoride ether (1.6 mL, 12.96 mmol, 0.4 eq.). The reaction was carried out at -20°C for 2h. The reaction solution was quenched by adding water, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to obtain about 4.9 g of product 34-c. 1 H NMR (400MHz, Chloroform-d) δ12.01(s,1H), 6.23(s,1H), 5.88(s,1H), 5.31–5.23(m,1H), 5.09–5.01(m,1H) ,3.91(s,3H),3.43(d,J=7.1Hz,2H),2.84-2.76(m,2H),2.13-2.02(m,4H),1.83-1.78(m,3H),1.69-1.65 (m, 3H), 1.61–1.56 (m, 3H), 1.51 (dtt, J=10.4, 5.2, 2.6Hz, 2H), 1.33 (dt, J=7.4, 3.2Hz, 4H), 0.96–0.86 (m , 3H).
步骤二:Step 2:
化合物34-c(2.0g,5.34mmol,1.0eq.)溶于12.5%(w/w%)的甲胺/甲基四氢呋喃溶液(5.3g,21.4mmol,4.0eq.)中,降温至0℃,加入1.7M叔丁基氯化镁/四氢呋喃溶液(14.1mL,24.03mmol,4.5eq.),封管,110℃下回流过夜。冰水浴条件下,将反应液缓慢滴入饱和氯化铵溶液中淬灭,二氯甲烷萃取,有机相用饱和食盐水洗涤、无水硫酸钠干燥;过滤、浓缩,柱层析分离,得标题化合物34,白色絮状固体1.0g。
1H NMR(500MHz,DMSO)δ9.52(s,1H),9.37(d,J=6.4Hz,1H),7.94(d,J=4.7Hz,1H),6.22(d,J=12.1Hz,1H),5.15(t,J=7.1Hz,1H),5.06(t,J=7.1Hz,1H),3.18(d,J=7.1Hz,2H),2.73(d,J=4.5Hz,3H),2.55(d,J=7.8Hz,2H),2.01(dt,J=15.5,8.3Hz,2H),1.90(dd,J=9.2,6.2Hz,2H),1.71(s,3H),1.62(s,3H),1.55(s,3H),1.44(p,J=7.2Hz,2H),1.26(dt,J=9.9,6.5Hz,4H),0.86(t,J=7.0Hz, 3H).
Compound 34-c (2.0g, 5.34mmol, 1.0eq.) was dissolved in 12.5% (w/w%) methylamine/methyltetrahydrofuran solution (5.3g, 21.4mmol, 4.0eq.), cooled to 0°C , add 1.7M tert-butylmagnesium chloride/tetrahydrofuran solution (14.1mL, 24.03mmol, 4.5eq.), seal the tube, and reflux at 110°C overnight. Under ice-water bath conditions, the reaction solution was slowly dropped into saturated ammonium chloride solution to quench, extracted with dichloromethane, the organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate; filtered, concentrated, and separated by column chromatography to obtain the title Compound 34, white flocculent solid 1.0 g. 1 H NMR(500MHz, DMSO)δ9.52(s,1H),9.37(d,J=6.4Hz,1H),7.94(d,J=4.7Hz,1H),6.22(d,J=12.1Hz, 1H), 5.15(t, J=7.1Hz, 1H), 5.06(t, J=7.1Hz, 1H), 3.18(d, J=7.1Hz, 2H), 2.73(d, J=4.5Hz, 3H) ,2.55(d,J=7.8Hz,2H),2.01(dt,J=15.5,8.3Hz,2H),1.90(dd,J=9.2,6.2Hz,2H),1.71(s,3H),1.62( s, 3H), 1.55 (s, 3H), 1.44 (p, J=7.2Hz, 2H), 1.26 (dt, J=9.9, 6.5Hz, 4H), 0.86 (t, J=7.0Hz, 3H).
实施例14制备下式化合物37Example 14 Preparation of compound 37 of the following formula
化合物27-i(2.58g,9.72mmol,1.5eq.)置于三口瓶中,N
2置换三次,加入香叶醇34-a(1.0g,6.48mmol,1.0eq.)、二氯甲烷(40mL),降温至-20℃,加入8M三氟化硼乙醚(324μL,2.59mmol,0.4eq.)。-20℃下反应4h。反应液加入水中,二氯甲烷萃取,有机相用无水硫酸钠干燥,过滤、浓缩,柱层析分离得标题化合物37,约1.3g。
1H NMR(500MHz,DMSO)δ9.02(s,1H),7.81(s,1H),7.80(d,J=4.8Hz,1H),6.37(s,1H),5.17(t,J=7.1Hz,1H),5.07(t,J=7.0Hz,1H),3.21(d,J=7.0Hz,2H),2.65(d,J=4.6Hz,3H),2.02(q,J=7.5Hz,2H),1.91(dd,J=9.4,6.2Hz,2H),1.71(s,3H),1.63(s,3H),1.56(s,3H),1.27–1.24(m,2H),1.23(s,6H),1.20–1.15(m,2H),1.03(dq,J=9.0,4.7,4.1Hz,2H),0.82(t,J=7.3Hz,3H).ESI-MS m/z 400.6(M-H)
-.
Compound 27-i (2.58g, 9.72mmol, 1.5eq.) was placed in a three-necked flask, N 2 was replaced three times, and geraniol 34-a (1.0g, 6.48mmol, 1.0eq.), dichloromethane (40mL) were added ), cooled to -20° C., and added 8M boron trifluoride ether (324 μL, 2.59 mmol, 0.4 eq.). The reaction was carried out at -20°C for 4h. The reaction solution was added to water, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to obtain the title compound 37, about 1.3 g. 1 H NMR(500MHz, DMSO)δ9.02(s,1H),7.81(s,1H),7.80(d,J=4.8Hz,1H),6.37(s,1H),5.17(t,J=7.1 Hz, 1H), 5.07(t, J=7.0Hz, 1H), 3.21(d, J=7.0Hz, 2H), 2.65(d, J=4.6Hz, 3H), 2.02(q, J=7.5Hz, 2H), 1.91(dd, J=9.4, 6.2Hz, 2H), 1.71(s, 3H), 1.63(s, 3H), 1.56(s, 3H), 1.27–1.24(m, 2H), 1.23(s ,6H),1.20–1.15(m,2H),1.03(dq,J=9.0,4.7,4.1Hz,2H),0.82(t,J=7.3Hz,3H).ESI-MS m/z 400.6(MH ) - .
实施例15制备下式化合物57Example 15 Preparation of compound 57 of the following formula
将化合物24-j(200mg,0.76mmol,1.0eq.)和60%NaH(30mg,0.76mmol,1.0eq.)置于反应瓶,氮气置换,加3mL二氯甲烷溶解,50℃加热回流反应4h,降温至35℃,加入香叶基溴57-a(217mg,1.0mmol,1.3eq.),反应过夜。加水淬灭,二氯甲烷萃取,柱层析,得标题化合物57约30mg。
1H NMR(500MHz,DMSO)δ10.50(s,1H),9.42(s,1H),7.74(d,1H),6.29(s,1H),5.15(t,1H),5.05(t,1H),3.18(d,2H),2.81(d,3H),2.03–1.97(m,2H),1.94–1.86(m,2H),1.71(s,3H),1.61(s,3H),1.54(s,3H),1.45(d,2H),1.16(d,4H),0.80(m,5H),0.68(s,2H).ESI-MS m/z 398.5(M-H)
-.
Compound 24-j (200 mg, 0.76 mmol, 1.0 eq.) and 60% NaH (30 mg, 0.76 mmol, 1.0 eq.) were placed in a reaction flask, replaced with nitrogen, dissolved in 3 mL of dichloromethane, and heated under reflux at 50 °C for 4 h. , cooled to 35 ℃, added geranyl bromide 57-a (217 mg, 1.0 mmol, 1.3 eq.), and reacted overnight. Quenched with water, extracted with dichloromethane, and subjected to column chromatography to obtain about 30 mg of the title compound 57. 1 H NMR(500MHz,DMSO)δ10.50(s,1H),9.42(s,1H),7.74(d,1H),6.29(s,1H),5.15(t,1H),5.05(t,1H) ),3.18(d,2H),2.81(d,3H),2.03–1.97(m,2H),1.94–1.86(m,2H),1.71(s,3H),1.61(s,3H),1.54( s,3H),1.45(d,2H),1.16(d,4H),0.80(m,5H),0.68(s,2H).ESI-MS m/z 398.5(MH) - .
实施例16制备下式化合物43Example 16 Preparation of compound 43 of the following formula
将9-f(35mg,0.17mmol,1.0eq.)置于反应瓶,氮气置换,加四氢呋喃溶解,降温至-62℃,加入2.5M正丁基锂(136μL,0.34mmol,2.0eq.)和TMEDA(30mg,0.255mmol,1.5eq.)反应60min,加入香叶基溴57-a(55mg,0.255mmol,1.5eq.),该温度下反应20min,自然升至室温,升温至60~70℃,TLC监测反应。加水淬灭,乙酸乙酯萃取,柱层析得标题化合物43。
1H NMR(500MHz,DMSO)δ11.28(s,1H),9.56(s,1H),7.91(d,1H),6.10(s,1H),5.14(t,1H),5.05(t,1H),3.17(d,2H),2.82(d,3H),2.12–2.06(m,1H),2.00(m,2H),1.92–1.87(m,2H),1.70(s,3H),1.61(s,3H),1.54(s,3H),0.94–0.90(m,2H),0.54–0.50(m,2H).ESI-MS m/z 342.5(M-H)
-.
9-f (35mg, 0.17mmol, 1.0eq.) was placed in a reaction flask, replaced with nitrogen, dissolved in tetrahydrofuran, cooled to -62°C, added with 2.5M n-butyllithium (136μL, 0.34mmol, 2.0eq.) and TMEDA (30mg, 0.255mmol, 1.5eq.) was reacted for 60min, geranyl bromide 57-a (55mg, 0.255mmol, 1.5eq.) was added, the reaction was conducted at this temperature for 20min, the temperature was naturally raised to room temperature, and the temperature was raised to 60~70℃ , the reaction was monitored by TLC. Quenched with water, extracted with ethyl acetate, and column chromatography gave the title compound 43. 1 H NMR(500MHz,DMSO)δ11.28(s,1H),9.56(s,1H),7.91(d,1H),6.10(s,1H),5.14(t,1H),5.05(t,1H) ), 3.17(d, 2H), 2.82(d, 3H), 2.12–2.06(m, 1H), 2.00(m, 2H), 1.92–1.87(m, 2H), 1.70(s, 3H), 1.61( s,3H),1.54(s,3H),0.94–0.90(m,2H),0.54–0.50(m,2H).ESI-MS m/z 342.5(MH) - .
实施例17制备下式化合物26Example 17 Preparation of compound 26 of the following formula
步骤一:step one:
将化合物24-h(1.2g,4.32mmol,1.0eq)溶于DCM中,冰浴下加入SOCl
2(2.06g,17.3mmol,4.0eq)和2滴DMF,常温搅拌1小时,TLC监测反应完毕,浓缩去除SOCl
2。另取反应容器加入二甲胺盐酸盐(1.41g,17.3mmol,4.0eq),4-二甲氨基吡啶(1.05g,8.63mmol,2.0eq)和Et
3N(1.75g,17.3mmol,4.0eq)搅拌20分钟,冰浴条件下加入酰氯的DCM溶液,继续冰浴反应30分钟,室温条件下反应过夜。二氯甲烷萃取,有机相干燥浓缩,柱层析得化合物26-a约1.17g。
1H NMR(400MHz,CDCl
3)δ6.46(d,1H),6.32(d,1H),3.81(s,3H),3.77(s,3H),3.11(s,3H),2.75(s,3H),1.24(m,6H),0.82(t,4H),0.61(m,2H),0.58–0.52(m,1H).
Compound 24-h (1.2 g, 4.32 mmol, 1.0 eq) was dissolved in DCM, SOCl 2 (2.06 g, 17.3 mmol, 4.0 eq) and 2 drops of DMF were added under ice bath, stirred at room temperature for 1 hour, TLC monitored the completion of the reaction , concentrated to remove SOCl 2 . Take another reaction vessel and add dimethylamine hydrochloride (1.41g, 17.3mmol, 4.0eq), 4-dimethylaminopyridine (1.05g, 8.63mmol, 2.0eq) and Et3N (1.75g, 17.3mmol, 4.0eq) eq) Stir for 20 minutes, add the DCM solution of acid chloride under ice-bath conditions, continue the ice-bath reaction for 30 minutes, and react overnight under room temperature conditions. Dichloromethane was extracted, the organic phase was dried and concentrated, and about 1.17 g of compound 26-a was obtained by column chromatography. 1 H NMR (400MHz, CDCl 3 )δ6.46(d,1H), 6.32(d,1H), 3.81(s,3H), 3.77(s,3H), 3.11(s,3H), 2.75(s, 3H), 1.24(m, 6H), 0.82(t, 4H), 0.61(m, 2H), 0.58–0.52(m, 1H).
步骤二:Step 2:
将26-a(1.17g,3.84mmol,1.0eq)置于反应瓶,N
2置换3次,加入DCM,降温至-10℃,缓慢加入BBr
3(2.88g,11.51mmol,3.0eq),反应20min,自然升温反应2h,TLC监测反应,将反应液缓慢滴加入冰水中淬灭,DCM萃取,干燥浓缩,柱层析得化合物26-b。
1H NMR(400MHz,DMSO)δ9.33(s,1H),9.23(s,1H),6.16(d,1H),6.13(d,1H),2.92(s,3H),2.70(s,3H),1.72(d,1H),1.23–1.07(m,5H),0.80(t,3H),0.62(d,1H),0.45(m,3H).
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. 1 H NMR(400MHz, DMSO)δ9.33(s,1H), 9.23(s,1H), 6.16(d,1H), 6.13(d,1H), 2.92(s,3H), 2.70(s,3H) ), 1.72(d, 1H), 1.23–1.07(m, 5H), 0.80(t, 3H), 0.62(d, 1H), 0.45(m, 3H).
步骤三:Step 3:
将化合物26-b(150mg,0.54mmol,1.0eq)置于反应瓶,N
2置换3次,加入30mL DCM,降温至0~-5℃,缓慢加入Tf
2O(15mg,0.054mmol,0.1eq),搅拌30分钟,缓慢加入含(+)-柠檬烯(97mg,0.73mmol,1.35eq)的DCM溶液,TLC监测反应,加入饱和食盐水淬灭,萃取,干燥浓缩,柱层析得标题化合物26。ESI-MS m/z 410.6(M-H)
-,412.4(M+H)
+.
Compound 26-b (150 mg, 0.54 mmol, 1.0 eq) was placed in a reaction flask, replaced by N 2 three times, 30 mL of DCM was added, the temperature was lowered to 0 ~ -5 °C, and Tf 2 O (15 mg, 0.054 mmol, 0.1 eq) was slowly added ), stirred for 30 minutes, slowly added a DCM solution containing (+)-limonene (97 mg, 0.73 mmol, 1.35 eq), monitored the reaction by TLC, added saturated brine to quench, extracted, dried and concentrated, and column chromatography gave the title compound 26 . ESI-MS m/z 410.6(MH) - ,412.4(M+H) + .
在下表中显示的是实施例18~53中的化合物,除了使用与最终产物相对应的起始原料和中间体以外,使用与以上实施例中相同的方法,就可以制备出这些化合物。Shown in the table below are the compounds of Examples 18-53, which were prepared using the same procedures as in the above examples, except that starting materials and intermediates corresponding to the final product were used.
体内药效实验In vivo efficacy test
1)热板实验(Hot Plate Test):1) Hot Plate Test:
受试药用5%DMSO混匀后加入
HS 15混匀,再加入90%生理盐水,配制成合适浓度的溶液,现配现用。雌性ICR小鼠,18-22g。
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. Female ICR mice, 18-22g.
试验前一天将小鼠进行热板筛选,筛选时间45s,热板温度55℃,筛选出热痛潜伏期相近的小鼠,剔除对疼痛过于敏感和过于迟钝的小鼠。One day before the test, the 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.
正式实验,给药前,进行热痛潜伏期测试,测试时间90s,热板温度55℃,记录热痛潜伏期,对动物随机分组,分为空白对照组和各受试药组,每组动物8只,各组小鼠分别腹腔注射给予溶媒处方或者各受试药。给药后60分钟,进行热板测试,测试时间90s,温度55℃,记录标准动物舔后足或者跳起时间,作为热痛潜伏期,统计各组小鼠的给药前的热痛潜伏期以及给药后的热痛潜伏期,以及MPE百分比。MPE百分比计算采用以下公式:[(T1-T0)/T0]*100,药物注射前和注 射后的潜伏期分别为T0和T1,结果用mean±SD表示。对各组给药前后小鼠热痛潜伏期、MPE百分比分别进行对比,结果采用单因素方差分析进行统计。In the formal experiment, before administration, the heat pain latency test was performed, the test time was 90s, the temperature of the hot plate was 55°C, and the heat pain latency was recorded, and the animals were randomly divided into blank control group and each test drug group, with 8 animals in each group , each group of mice were given the vehicle prescription or each test drug by intraperitoneal injection. 60 minutes after administration, a hot plate test was performed, the test time was 90s, the temperature was 55°C, and the time of licking the hind feet or jumping of the standard animals was recorded as the heat pain latency period. The thermal pain latency after the drug, and the percentage of MPE. 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.
药物组(实施例1、实施例4和实施例12的化合物)都表现出了显著的镇痛作用,而CBD在100mpk剂量下未表现出显著的镇痛作用。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.
2)强迫游泳实验(Forced Swim Test):2) Forced Swim Test:
受试药用5%DMSO混匀后加入
HS 15混匀,再加入90%生理盐水,配制成合适浓度的溶液,现配现用。雄性ICR小鼠,32g左右。对动物随机分组,分为空白对照组和各受试药组,每组动物8只,各组小鼠分别腹腔注射给予溶媒处方或者各受试药。强迫游泳设备中水位为45cm,水温25℃,实验开始前将小鼠置于实验房间适应环境1h。实验开始时将小鼠置于设备中,时长6min,整个过程用摄像头记录,分析数据时只统计最后4min小鼠的不动时间。
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.
药物组(实施例1和实施例4的化合物)在3mg/kg低剂量下都表现出了显著的抗抑郁样作用,而CBD在30mpk剂量下才表现出显著的抗抑郁样作用。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.
3)应激诱发的高热反应实验3) Stress-induced hyperthermia experiment
受试药用10%DMSO混匀后加入
HS 15混匀,再加入80%生理盐水,配制成合适浓度的溶液,现配现用。雄性ICR小鼠,35g左右。对动物随 机分组,分为空白对照组和各受试药组,每组动物8只,各组小鼠分别皮下注射给予溶媒处方或者各受试药。应激诱发的高热反应(stress-induced hyperthermia,SIH)是一种核心体温在应对压力时的短暂升高,是所有哺乳动物均存在的现象。压力可以是身体或情绪上的,或者两者兼有,导致体温迅速升高(10到15分钟后升最高)。根据应激的强度和持续时间,温度在60-120分钟内恢复至基础水平。当小鼠预先服用抗焦虑药物(如苯二氮卓类药物或5-HT
1A受体激动剂)后,SIH反应降低,使其成为筛选抗焦虑药物的相对简单的程序。本方案描述了一种以直肠温度测量作为应激源来量化单饲养小鼠(n=1/笼)的SIH的操作过程。直肠温度每10分钟测量两次。由于第一次测温时所经历的压力,第二次测温(T2)比第一次测温(T1)高出0.8-1.5摄氏度。这种温度差异(dT=T2-T1)被定义为应激诱发高热反应(SIH),被认为反映了焦虑相关的过程。统计分析T1值、T2值及ΔT值(参考文献:Current Protocols in Pharmacology 5.16.1-5.16.12,June 2009)。
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), a transient increase in core body temperature in response to stress, is a phenomenon present in all mammals. 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. 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. This protocol describes a procedure to quantify SIH in single-housed mice (n=1/cage) using rectal temperature measurement as a stressor. Rectal temperature was measured twice every 10 minutes. Due to the pressure experienced during the first temperature measurement, the second temperature measurement (T2) was 0.8-1.5 degrees Celsius higher than the first temperature measurement (T1). This temperature difference (dT=T2-T1), defined as stress-induced hyperthermia (SIH), is thought to reflect anxiety-related processes. Statistical analysis of T1 value, T2 value and ΔT value (Reference: Current Protocols in Pharmacology 5.16.1-5.16.12, June 2009).
药物组在3-30mg/kg剂量下都表现出了显著的抗抑郁样作用,而CBD在100mpk剂量下才表现出显著的抗焦虑样作用。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.
4)埋珠实验4) Buried bead experiment
受试药用5%DMSO混匀后加入
HS 15混匀,再加入90%生理盐水,配制成合适浓度的溶液,现配现用。雄性ICR小鼠,32g左右。对动物随机分组,分为空白对照组和各受试药组,每组动物8-10只,各组小鼠分别腹腔注射给予溶媒处方或者各受试药。
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. 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.
准备大鼠笼(6cm x 48cm x 20cm),新鲜的垫料,不同颜色的玻璃珠(直径15mm,5.2g左右,每次使用后清洗晾干);动物应饲养在12小时明暗循环的房间内,所有小鼠自主获得食物和水。将大鼠笼中加入5cm厚的新鲜垫料,把垫料铺平。将20个玻璃珠放入笼中(4排*5列放置),给药后15min将小鼠放在尽可能远离玻璃珠的角落,将笼盖盖好,30min后小心将小鼠放回;统计测试笼中玻璃珠被埋藏数量。Prepare 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.
本发明化合物在3-30mg/kg剂量范围内相比空白对照组显著降低埋珠数目,表现出显著的抗抑郁样作用,而CBD在该实验中30-60mg/kg剂量下才表现出显著的抗抑郁样作用。Compared with the blank control group, 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.
5)高架十字迷宫实验5) Elevated plus maze experiment
受试药用5%DMSO混匀后加入
混匀,再加入90%生理盐水,配制成合适浓度的溶液,现配现用。雄性ICR小鼠,32g左右。对动物随机分组,分为空白对照组和各受试药组,每组动物8-10只,各组小鼠分别腹腔注射给予溶 媒处方或者各受试药。
The 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.
高架十字迷宫(Elevated plus-maze,EPM)实验装置:医用有机板制作,两个相对的开放臂(open arm,长×宽分别为30cm×5cm),两个相对的封闭臂(enclosed arm,长×宽×高分别为30cm×5cm×15cm)及一个连接四只臂的中央平台(centre platform,5cm×5cm)构成十字形状,距离地面40cm。小鼠高架十字迷宫视频采集系统采购自上海移数信息科技有限公司。腹腔给药30min后,用移数高架十字迷宫视频采集系统记录5min内动物活动轨迹,再用移数视频分析系统记录统计小鼠5min内进入开臂的次数及在开臂的累计停留时间。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. After 30 minutes of intraperitoneal administration, 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.
本发明化合物在3-30mg/kg剂量范围内相比空白对照组显著增加开臂停留时间,表现出显著的抗焦虑样作用,而CBD在该实验中30mg/kg剂量以上才表现出显著作用。Compared with the blank control group, 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.
6)药代动力学实验6) Pharmacokinetic experiment
将实施例1制备的化合物、实施例9制备的化合物进行了小鼠体内药代动力学实验(ICR小鼠,灌胃给药,剂量25mg/kg,n=3),采血点:0.25h、0.5h、1h、2h、4h、6h、8h、24h。结果见下表。The compound prepared in Example 1 and the compound prepared in Example 9 were subjected to pharmacokinetic experiments in mice (ICR mice, intragastric administration, dose 25 mg/kg, n=3), blood collection points: 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 24h. The results are shown in the table below.
实验结果表明,当通式(I)中R
2为取代的C
3-C
10环烷基时(例如实施例9制备的化合物),化合物具有更高的血药浓度。
The experimental results show that when 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.
体外实验In vitro experiments
1)溶解度测定1) Solubility determination
采用高效液相色谱外标法定量分析进行溶解度的测试。Solubility was tested by high performance liquid chromatography with external standard method.
色谱条件:Chromatographic conditions:
流动相A:10mM KH
2PO
4 PH2.0
Mobile phase A: 10mM KH 2 PO 4 PH2.0
流动相B:乙腈Mobile Phase B: Acetonitrile
色谱柱:ZORBAX Bonus-RP Rapid Resolution 150×4.6mm,3.5μm LC-SH-510Chromatographic column: ZORBAX Bonus-RP Rapid Resolution 150×4.6mm, 3.5μm LC-SH-510
波长:220nmWavelength: 220nm
柱温:30℃Column temperature: 30℃
流速:1ml/minFlow rate: 1ml/min
进样量:10μlInjection volume: 10μl
稀释剂:乙腈Thinner: Acetonitrile
溶液配制:供试品溶液:取1mg供试品置1ml离心管中,加10mM的KH
2PO
4 PH6.8溶液(1ml),置震动仪里在25℃条件下震荡30min,取出置离心机中离心1.5min后取上清液进样。对照品溶液:取对照品约1mg置1ml离心管中,用1ml乙腈溶解,摇匀,取所得溶液1ml置5ml量瓶中,用乙腈稀释至刻度,摇匀。溶解度结果见下表:
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:
相比CBD,实施例化合物的溶解度得到显著的改善,有利于药物吸收。Compared with CBD, the solubility of the example compounds is significantly improved, which is beneficial to drug absorption.
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单 独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。All documents mentioned herein are incorporated by reference in this application as if each document were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.
Claims (10)
- 一种化合物或其对映异构体、非对映异构体、外消旋体、以及其药学上可接受的无机或有机盐、结晶水合物及溶剂合物,其特征在于,所述化合物为式I所示:A compound or its enantiomers, diastereomers, racemates, and pharmaceutically acceptable inorganic or organic salts, crystalline hydrates and solvates thereof, characterized in that the compound It is shown in formula I:式中,In the formula,R 1选自羟基C 1-C 6烷基、C 1-C 6烷硫基、C 3-C 10环烷基取代的甲酰基、氨基、被C 1-C 6烷基取代的氨基、被C 1-C 6烷酰基取代的氨基、氰基、氨基C 1-C 6烷基、氰基C 1-C 6烷基、C 1-C 6烷酰基、磺酰氨基(-SO 2NH 2)、氨基甲酰基(-CONH 2)、被C 1-C 6烷基取代的氨基甲酰基、被羟基C 1-C 6烷基取代的氨基甲酰基(HO-C 1-C 6烷基-NH-CO-)、被C 3-C 10环烷基取代的氨基甲酰基、羧基C 1-C 6烷基、C 1-C 6烷磺酰基、被C 1-C 6烷基取代的氨基C 1-C 6烷基、被C 1-C 6烷酰基取代的氨基C 1-C 6烷基、氨基甲酰基C 1-C 6烷基或被C 1-C 6烷基取代的氨基甲酰基C 1-C 6烷基; 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, amino substituted by C 1 -C 6 alkyl C 1 -C 6 alkyl, amino C 1 -C 6 alkyl substituted with C 1 -C 6 alkanoyl, carbamoyl C 1 -C 6 alkyl or aminomethyl substituted with C 1 -C 6 alkyl Acyl C 1 -C 6 alkyl;R 2选自C 1-C 12烷基、被一个或多个卤素取代的C 1-C 12烷基、C 3-C 10环烷基、取代的C 3-C 10环烷基、或取代或未取代的-(C 1-C 3亚烷基)-(C 3-C 10环烷基);其中,所述的取代指具有1-3个选自下组的取代基:C 1-C 6烷基、C 1-C 6烯基、C 1-C 6卤代烷基;优选地,R 2为取代的C 3-C 10环烷基; 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;R 3选自H、羟基、-OC(O)-C 1-C 6烷基、-OC(O)(CH 2)nN(C 1-C 6烷基) 2;其中n为1-6的任意整数; 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;且式I不包括选自下组的化合物:and Formula I does not include compounds selected from the group consisting of:
- 一种制备式I-1化合物的方法,其特征在于,包括步骤:提供醛基取代的式(II)化合物,在还原剂存在下发生还原反应得到所述化合物;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;所述步骤如反应式1所示:The steps are shown in reaction formula 1:反应式1;Reaction formula 1;式I-1中,R 2、R 0如权利要求1所定义。 In formula I-1, R 2 and R 0 are as defined in claim 1 .
- 一种制备式I-2化合物的方法,其特征在于,包括步骤:提供式(III)化合物,和NH(R 4) 2经氨解反应得到所述化合物,所述步骤如反应式2所示: A method for preparing a compound of formula I-2, comprising the steps of: providing a compound of formula (III), and NH(R 4 ) 2 is subjected to an aminolysis reaction to obtain the compound, and the step is shown in reaction formula 2 :反应式2;Reaction formula 2;式I-2中,In formula I-2,R 2、R 0如权利要求1所定义; R 2 and R 0 are as defined in claim 1;R 4各自独立地为H、C 1-C 6烷基、羟基C 1-C 6烷基、C 3-C 10环烷基。 R 4 is each independently H, C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl.
- 一种制备式I-3化合物的方法,其特征在于,包括步骤:以式(II)为原料,经两步反应得到式(I-3)化合物,所述步骤如反应式3所示:A method for preparing a compound of formula I-3, characterized in that it comprises the steps of: taking formula (II) as a raw material, and obtaining a compound of formula (I-3) through a two-step reaction, and the step is shown in reaction formula 3:反应式3;Reaction formula 3;式I-3中,In formula I-3,R 2、R 0如权利要求1所定义。 R 2 , R 0 are as defined in claim 1 .
- 一种如权利要求1所述的化合物或其对映异构体、非对映异构体、外消旋体、以及其药学上可接受的无机或有机盐、结晶水合物及溶剂合物的用途,其特征在于,所述化合物用于制备一药物组合物或制剂,所述药物组合物或制剂用于治疗、缓解和/或预防中枢神经系统疾病。A compound as claimed in claim 1 or its enantiomers, diastereomers, racemates, and pharmaceutically acceptable inorganic or organic salts, crystalline hydrates and solvates thereof Use, characterized in that the compound is used for preparing a pharmaceutical composition or preparation, and the pharmaceutical composition or preparation is used for treating, alleviating and/or preventing central nervous system diseases.
- 如权利要求7所述的用途,其特征在于,所述中枢神经系统疾病选自下组:癫痫、精神分裂症、难控制的、难处理的或慢性精神分裂症、情感紊乱、精神紊 乱、情绪紊乱、I型双极情感障碍、II型双极情感障碍、抑郁症、内因性抑郁症、重性抑郁症、难控制的抑郁症、情绪恶劣性障碍、循环情感性障碍、恐慌发作、惊恐性障碍、社交恐惧症、强迫性观念与行为病症、冲动性病症、创伤后精神紧张性障碍、焦虑症、急性应激障碍、癔病、神经性厌食症、适应性障碍、认知障碍、自闭症、疼痛、狂躁症、帕金森症、亨廷顿舞蹈症、阿尔茨海默症、各种痴呆症、记忆障碍、多动症、药物成瘾、睡眠障碍、注意力缺乏/亢进类疾病、抽动症或其组合。The use of claim 7, wherein the central nervous system disease is selected from the group consisting of epilepsy, schizophrenia, refractory, refractory or chronic schizophrenia, affective disorder, mental disorder, mood Disorders, Bipolar I Disorder, Bipolar II Disorder, Depression, Intrinsic Depression, Major Depressive Disorder, Uncontrolled Depression, Dysthymic Disorder, Cyclic Affective Disorder, Panic Attack, Panic Disorder Disorders, social phobia, obsessive-compulsive disorders, impulsivity disorders, post-traumatic stress disorder, anxiety disorders, acute stress disorder, hysteria, anorexia nervosa, adaptive disorders, cognitive disorders, 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 combinations thereof .
- 如权利要求7所述的用途,其特征在于,所述制剂为口服制剂或非口服制剂。The use according to claim 7, wherein the preparation is an oral preparation or a non-oral preparation.
- 一种药物组合物,其特征在于,所述药物组合物含有:A pharmaceutical composition, characterized in that the pharmaceutical composition contains:(1)作为活性成分的式I化合物;(1) a compound of formula I as an active ingredient;(2)任选地选自下组的其他治疗中枢神经系统疾病的药物:抗精神病药物、抗癫痫药物或抗抑郁药物;(2) other medicines for the treatment of central nervous system diseases optionally selected from the group consisting of antipsychotics, antiepileptics or antidepressants;(3)药学上可接受的载体或赋形剂。(3) A pharmaceutically acceptable carrier or excipient.
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Citations (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102115429A (en) * | 2010-01-06 | 2011-07-06 | 中国科学院上海药物研究所 | (E)-1-(3,5-dimethoxyphenyl)-2-(3,5-dihydroxy-4-methoxyphenyl)ethylene, and preparation method and application thereof |
WO2012011112A1 (en) * | 2010-07-22 | 2012-01-26 | Yissum Research Development Company Of The Hebrew University Of Jerusalem, Ltd. | Non psychoactive cannabinoids and uses thereof |
WO2014062965A1 (en) * | 2012-10-17 | 2014-04-24 | Northeastern University | 2-cycloalkyl resorcinol cannabinergic ligands |
CN105085433A (en) * | 2014-05-19 | 2015-11-25 | 中国科学院上海药物研究所 | Substituted-amide phenolic compound, preparation method, pharmaceutical composition and application thereof |
CN108024973A (en) * | 2015-07-16 | 2018-05-11 | 耶路撒冷希伯来大学伊森姆研究发展有限公司 | CBD compounds, its composition and the purposes of fluorination |
WO2019079677A1 (en) * | 2017-10-20 | 2019-04-25 | Corbus Pharmaceuticals, Inc. | Methods and compositions relating to ultrapure 5-(1,1-dimethylheptyl)-resorcinol |
CN109970516A (en) * | 2019-03-20 | 2019-07-05 | 栾云鹏 | A kind of synthetic method of the cannabinoids substance of preparation of industrialization high-purity high-yield |
US20200093755A1 (en) * | 2017-05-31 | 2020-03-26 | Phytecs, Inc. | Pharmaceutical compositions comprising cannabidiol and beta-caryophyllene and methods for their use |
WO2020185661A1 (en) * | 2019-03-08 | 2020-09-17 | The Regents Of The University Of California | Use of 8,9-dihydrocannabidiol compounds |
WO2021102567A1 (en) * | 2019-11-26 | 2021-06-03 | Canopy Growth Corporation | Cannabigerol derivatives and use thereof as cannabinoid receptor modulators |
WO2021102568A1 (en) * | 2019-11-26 | 2021-06-03 | Canopy Growth Corporation | Cannabinoid derivatives |
WO2021150885A1 (en) * | 2020-01-24 | 2021-07-29 | Perkinelmer Health Sciences, Inc. | Cannabinoid derivatives |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2547354T3 (en) * | 2013-09-03 | 2015-10-05 | Symrise Ag | Mixtures of cannabinoid compounds, their preparation and use |
US20190060300A1 (en) * | 2016-03-04 | 2019-02-28 | Sharon Anavi-Goffer | Self-Emulsifying Compositions of CB2 Receptor Modulators |
WO2019234728A1 (en) * | 2018-06-04 | 2019-12-12 | Al&Am Pharmachem Ltd. | Cannabinolic acid derivatives and uses thereof |
US11485700B2 (en) * | 2018-06-28 | 2022-11-01 | Symrise Ag | Synthesis of (+)-cannabinoids and their therapeutic effects |
WO2020031179A1 (en) * | 2018-08-06 | 2020-02-13 | Beetlebung Pharma Ltd. | Methods for synthesis of cannabinoid compounds |
EP3999490A4 (en) * | 2019-07-12 | 2023-03-08 | Canopy Growth Corporation | Cannabinoid derivatives |
WO2021062559A1 (en) * | 2019-10-02 | 2021-04-08 | Canopy Growth Corporation | Cannabinoid derivatives |
-
2021
- 2021-11-17 CN CN202111364553.1A patent/CN114507153A/en active Pending
- 2021-11-17 WO PCT/CN2021/131303 patent/WO2022105810A1/en active Application Filing
Patent Citations (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102115429A (en) * | 2010-01-06 | 2011-07-06 | 中国科学院上海药物研究所 | (E)-1-(3,5-dimethoxyphenyl)-2-(3,5-dihydroxy-4-methoxyphenyl)ethylene, and preparation method and application thereof |
WO2012011112A1 (en) * | 2010-07-22 | 2012-01-26 | Yissum Research Development Company Of The Hebrew University Of Jerusalem, Ltd. | Non psychoactive cannabinoids and uses thereof |
WO2014062965A1 (en) * | 2012-10-17 | 2014-04-24 | Northeastern University | 2-cycloalkyl resorcinol cannabinergic ligands |
US20150274623A1 (en) * | 2012-10-17 | 2015-10-01 | Northeastern Uiversity | 2-cycloalkyl resorcinol cannabinergic ligands |
CN105085433A (en) * | 2014-05-19 | 2015-11-25 | 中国科学院上海药物研究所 | Substituted-amide phenolic compound, preparation method, pharmaceutical composition and application thereof |
CN108024973A (en) * | 2015-07-16 | 2018-05-11 | 耶路撒冷希伯来大学伊森姆研究发展有限公司 | CBD compounds, its composition and the purposes of fluorination |
US20200093755A1 (en) * | 2017-05-31 | 2020-03-26 | Phytecs, Inc. | Pharmaceutical compositions comprising cannabidiol and beta-caryophyllene and methods for their use |
WO2019079677A1 (en) * | 2017-10-20 | 2019-04-25 | Corbus Pharmaceuticals, Inc. | Methods and compositions relating to ultrapure 5-(1,1-dimethylheptyl)-resorcinol |
WO2020185661A1 (en) * | 2019-03-08 | 2020-09-17 | The Regents Of The University Of California | Use of 8,9-dihydrocannabidiol compounds |
CN109970516A (en) * | 2019-03-20 | 2019-07-05 | 栾云鹏 | A kind of synthetic method of the cannabinoids substance of preparation of industrialization high-purity high-yield |
WO2021102567A1 (en) * | 2019-11-26 | 2021-06-03 | Canopy Growth Corporation | Cannabigerol derivatives and use thereof as cannabinoid receptor modulators |
WO2021102568A1 (en) * | 2019-11-26 | 2021-06-03 | Canopy Growth Corporation | Cannabinoid derivatives |
WO2021150885A1 (en) * | 2020-01-24 | 2021-07-29 | Perkinelmer Health Sciences, Inc. | Cannabinoid derivatives |
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