WO2022213931A1 - 大麻二酚前药及其药物组合物和应用 - Google Patents

大麻二酚前药及其药物组合物和应用 Download PDF

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WO2022213931A1
WO2022213931A1 PCT/CN2022/085086 CN2022085086W WO2022213931A1 WO 2022213931 A1 WO2022213931 A1 WO 2022213931A1 CN 2022085086 W CN2022085086 W CN 2022085086W WO 2022213931 A1 WO2022213931 A1 WO 2022213931A1
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compound
independently selected
pharmaceutically acceptable
enantiomer
alkyl
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French (fr)
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白信法
蒋王林
王文艳
孙晓琳
杨会杰
张睿
田京伟
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山东绿叶制药有限公司
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Priority to CN202280002921.4A priority Critical patent/CN115315418B/zh
Priority to CN202310149197.4A priority patent/CN116253642A/zh
Publication of WO2022213931A1 publication Critical patent/WO2022213931A1/zh

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    • C07F9/091—Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a class of prodrugs of cannabidiol suitable for mammals; and pharmaceutical compositions comprising cannabidiol prodrugs and their use in the treatment and prevention of diseases and disorders.
  • Dravet syndrome and Lennox-Gastaut syndrome belong to the type of generalized combined focal epilepsy and the type of refractory epilepsy.
  • the incidence of Dravet syndrome in children aged 3-13 years is 11/10
  • the incidence of Lennox-Gastaut syndrome in children aged 3-13 years is 4/10
  • the incidence of seizures with tuberous sclerosis syndrome is 8 /10.
  • Refractory epilepsy refers to seizures that cannot be controlled by medication, i.e. not easily controlled or relieved, also known as controlled or drug-resistant seizures.
  • Door-to-door studies estimate the prevalence of intractable epilepsy to be 2.7-7.1/1000 in high-income areas and 2.2-22.2/1000 in low- and middle-income areas.
  • drug-resistant epilepsy based on large population surveys is difficult to obtain.
  • the incidence of drug-resistant epilepsy in children and adults was 15% and 30%, respectively.
  • Cannabidiol is a white to pale yellow resin or crystal with a melting point of 66°C to 67°C. It is almost insoluble in water and soluble in organic solvents such as ethanol, methanol, ether, benzene, and chloroform.
  • Cannabidiol oral liquid approved by the FDA in 2018, is clinically used to treat (1) Dravet syndrome-related seizures; (2) Lennox-Gastaut syndrome-related seizures in patients one year old and older; Approved in 2020 for the treatment of seizures associated with tuberous sclerosis syndrome (https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/210365s005s006s007lbl.pdf).
  • each 100ml bottle contains absolute ethanol (7.9% w/v), sesame oil, strawberry flavor and sucralose. Since it contains 7.9% absolute ethanol, it is a big problem for infants and young children. At the same time, cannabidiol has poor water solubility, the bioavailability of oral administration is only 6%, and the absorption level of the gastrointestinal tract is unstable.
  • the present invention provides a compound represented by formula (I), a pharmaceutically acceptable salt or enantiomer thereof,
  • R 1 and R 2 are the same or different, and are independently selected from -OH, -OC(O)-R 4 , or -OC(O)-X-(CH 2 )nN(Y 1 Y 2 );
  • X is NH or O
  • Y 1 is independently selected from C 2-10 alkyl
  • Y 2 is independently selected from hydrogen, C 2-10 alkyl
  • Y 1 and Y 2 form a ring system with the connected N atom, and the ring system is not substituted heterocyclyl or heteroaryl;
  • R 3 is an alkyl group of C 1-10 ;
  • R 4 is an alkyl group of C 1-10 ;
  • n 2-10;
  • R 1 or R 2 is -OC(O)-X-(CH 2 )nN(Y 1 Y 2 ).
  • R 1 and R 2 are the same or different, and are independently selected from -OH, -OC(O)-R 4 , or -OC(O)-X-(CH 2 )nN(Y 1 Y 2 );
  • X is NH or O
  • Y 1 is independently selected from C 2-6 alkyl
  • Y 2 is independently selected from hydrogen, C 2-6 alkyl
  • Y 1 and Y 2 form a ring system with the connected N atom, and the ring system is not substituted heterocyclyl or heteroaryl;
  • R 3 is C 1-6 alkyl
  • R 4 is C 1-6 alkyl
  • n 2, 3, 4, 5, 6, 7, 8, 9 or 10;
  • R 1 or R 2 is -OC(O)-X-(CH 2 )nN(Y 1 Y 2 ).
  • R 1 and R 2 are the same or different, and are independently selected from -OH, -OC(O)-R 4 , or -OC(O)-X-(CH 2 )nN(Y 1 Y 2 );
  • X is NH or O
  • Y 1 is independently selected from C 2-6 linear or branched alkyl
  • Y 2 is independently selected from hydrogen, C 2-6 linear or branched alkyl
  • Y 1 and Y 2 form a ring system with the attached N atom, and the ring system is an unsubstituted 3-8 membered heterocyclic group or a 3-8 membered heteroaryl group.
  • R 3 is C 1-6 straight-chain or branched alkyl
  • R 4 is C 1-6 straight-chain or branched alkyl
  • n 2, 3, 4, 5, 6, 7, 8, 9 or 10;
  • R 1 or R 2 is -OC(O)-X-(CH 2 )nN(Y 1 Y 2 ).
  • R 1 and R 2 are the same or different, each independently selected from -OH, OC(O)-R 4 , or --OC(O)-X-(CH 2 )nN(Y 1 Y 2 );
  • X is NH or O
  • Y 1 is independently selected from ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl , isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl;
  • Y 2 is independently selected from hydrogen, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl , hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl;
  • R 3 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl , isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl;
  • R 4 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl , isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl;
  • n 2, 3, 4, 5, 6, 7, 8, 9 or 10;
  • R 1 or R 2 is -OC(O)-X-(CH 2 )nN(Y 1 Y 2 ).
  • R 1 and R 2 are the same or different, and are independently selected from -OH, -OC(O)-R 4 , or -OC(O)-X-(CH 2 )nN(Y 1 Y 2 );
  • X is NH or O
  • Y 1 , Y 2 form a ring system with the attached N atom, and the ring system is selected from
  • R 3 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl , isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl;
  • R 4 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl , isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl;
  • n 2, 3, 4, 5, 6, 7, 8, 9 or 10;
  • R 1 or R 2 is -OC(O)-X-(CH 2 )nN(Y 1 Y 2 ).
  • R 1 is independently selected from
  • R 2 is independently selected from -OH,
  • R 3 is pentyl
  • R 1 is -OC(O)-X-(CH 2 )nN(Y 1 Y 2 );
  • R 2 is selected from -OH, -OC(O)-R 4 , or -OC(O)-X-(CH 2 )nN(Y 1 Y 2 );
  • X is NH or O; preferably O;
  • R 3 is C 1-6 alkyl
  • R 4 is C 1-6 alkyl
  • n 2, 3, 4 or 5.
  • R 1 is -OC(O)-X-(CH 2 )nN(Y 1 Y 2 );
  • R 2 is selected from -OH, -OC(O)-R 4 , or -OC(O)-X-(CH 2 )nN(Y 1 Y 2 );
  • the present invention provides a compound represented by formula (II), a pharmaceutically acceptable salt or enantiomer thereof,
  • R 1 and R 2 are the same or different, each independently selected from -OH, OC(O)-R 4 , or --OC(O)-X-(CH 2 )nN(Y 1 Y 2 );
  • X is NH or O
  • Y 1 is independently selected from C 2-10 alkyl
  • Y 2 is independently selected from hydrogen, C 2-10 alkyl
  • Y 1 and Y 2 form a ring system with the connected N atom, and the ring system is not substituted heterocyclyl or heteroaryl;
  • R 3 is an alkyl group of C 1-10 ;
  • R 4 is an alkyl group of C 1-10 ;
  • n 2-10;
  • R 1 or R 2 is -OC(O)-X-(CH 2 )nN(Y 1 Y 2 ).
  • R 1 and R 2 are the same or different, and are independently selected from -OH, -OC(O)-R 4 , or -OC(O)-X-(CH 2 )nN(Y 1 Y 2 );
  • X is NH or O
  • Y 1 is independently selected from C 2-6 alkyl
  • Y 2 is independently selected from hydrogen, C 2-6 alkyl
  • Y 1 , Y 2 and the connected N atom form a ring system, and the ring system is an unsubstituted heterocyclic group or a heteroaryl group;
  • R 3 is C 1-6 alkyl
  • R 4 is C 1-6 alkyl
  • n 2, 3, 4, 5, 6, 7, 8, 9 or 10;
  • R 1 or R 2 is -OC(O)-X-(CH 2 )nN(Y 1 Y 2 ).
  • R 1 and R 2 are the same or different, and are independently selected from -OH, -OC(O)-R 4 , or -OC(O)-X-(CH 2 )nN(Y 1 Y 2 );
  • X is NH or O
  • Y 1 is independently selected from C 2-6 linear or branched alkyl
  • Y 2 is independently selected from hydrogen, C 2-6 linear or branched alkyl
  • Y 1 and Y 2 form a ring system with the attached N atom, and the ring system is an unsubstituted 3-8 membered heterocyclic group or a 3-8 membered heteroaryl group.
  • R 3 is C 1-6 straight-chain or branched alkyl
  • R 4 is C 1-6 straight-chain or branched alkyl
  • n 2, 3, 4, 5, 6, 7, 8, 9 or 10;
  • R 1 or R 2 is -OC(O)-X-(CH 2 )nN(Y 1 Y 2 ).
  • R 1 and R 2 are the same or different, and are independently selected from -OH, -OC(O)-R 4 , or -OC(O)-X-(CH 2 )nN(Y 1 Y 2 );
  • X is NH or O
  • Y 1 is independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl yl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl;
  • Y 2 is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethyl propylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl;
  • R 3 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl , isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl;
  • R 4 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl , isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl;
  • n 2, 3, 4, 5, 6, 7, 8, 9 or 10;
  • R 1 or R 2 is -OC(O)-X-(CH 2 )nN(Y 1 Y 2 ).
  • R 1 and R 2 are the same or different, and are independently selected from -OH, -OC(O)-R 4 , or -OC(O)-X-(CH 2 )nN(Y 1 Y 2 );
  • X is NH or O
  • Y 1 , Y 2 form a ring system with the attached N atom, and the ring system is selected from
  • R 3 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl , isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl;
  • R 4 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl , isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl;
  • n 2, 3, 4, 5, 6, 7, 8, 9 or 10;
  • R 1 or R 2 is -OC(O)-X-(CH 2 )nN(Y 1 Y 2 ).
  • R 1 is independently selected from
  • R 2 is independently selected from -OH,
  • R 3 is pentyl
  • R 1 is -OC(O)-X-(CH 2 )nN(Y 1 Y 2 );
  • R 2 is selected from -OH, -OC(O)-R 4 , or -OC(O)-X-(CH 2 )nN(Y 1 Y 2 );
  • X is NH or O; preferably O;
  • R 3 is C 1-6 alkyl
  • R 4 is C 1-6 alkyl
  • n 2, 3, 4 or 5.
  • R 1 is -OC(O)-X-(CH 2 )nN(Y 1 Y 2 );
  • R 2 is selected from -OH, -OC(O)-R 4 , or -OC(O)-X-(CH 2 )nN(Y 1 Y 2 );
  • the present invention provides the following compounds, pharmaceutically acceptable salts or enantiomers thereof:
  • the present invention provides a salt of any one of the above-mentioned compounds or an enantiomer thereof, said salt is selected from the group consisting of p-toluenesulfonate, fumarate, maleate, oxalate , phosphate, hydrochloride, sulfate, malate, tartaric acid, citric acid or trifluoroacetate.
  • the present invention provides a maleate, p-toluenesulfonate, fumarate, or hydrochloride salt of Compound 25.
  • the present invention provides the maleate salt form I of Compound 25, which has characteristic diffraction peaks at the following 2 ⁇ angles in an X-ray powder diffraction pattern using Cu-K ⁇ radiation: 9.016 ⁇ 0.2°, 13.765 ⁇ 0.2°, 17.411 ⁇ 0.2°, 18.411 ⁇ 0.2°, 21.575 ⁇ 0.2°, 27.798 ⁇ 0.2°.
  • the compound 25 maleate salt form I in the X-ray powder diffraction pattern using Cu-K ⁇ radiation, has characteristic diffraction peaks at the following 2 ⁇ angles: 9.016 ⁇ 0.2°, 13.765 ⁇ 0.2°, 17.411 ⁇ 0.2°, 18.411 ⁇ 0.2°, 21.575 ⁇ 0.2°, 23.289 ⁇ 0.2°, 27.798 ⁇ 0.2°.
  • the compound 25 maleate salt form I in the X-ray powder diffraction pattern using Cu-K ⁇ radiation, has characteristic diffraction peaks at the following 2 ⁇ angles: 8.676 ⁇ 0.2°, 9.016 ⁇ 0.2°, 9.580 ⁇ 0.2°, 13.765 ⁇ 0.2°, 16.154 ⁇ 0.2°, 17.411 ⁇ 0.2°, 18.411 ⁇ 0.2°, 21.575 ⁇ 0.2°, 23.289 ⁇ 0.2°, 27.798 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the compound 25 maleate salt form I using Cu-K ⁇ radiation is shown in Figures 1-1.
  • the present invention provides compound 25 maleate salt form II, which has characteristic diffraction peaks at the following 2 ⁇ angles in an X-ray powder diffraction pattern using Cu-K ⁇ radiation: 7.868 ⁇ 0.2°, 10.713 ⁇ 0.2 °, 12.122 ⁇ 0.2°, 18.535 ⁇ 0.2°.
  • the compound 25 maleate salt form II in the X-ray powder diffraction pattern using Cu-K ⁇ radiation, has characteristic diffraction peaks at the following 2 ⁇ angles: 7.868 ⁇ 0.2°, 8.892 ⁇ 0.2°, 9.111 ⁇ 0.2°, 9.760 ⁇ 0.2°, 10.713 ⁇ 0.2°, 12.122 ⁇ 0.2°, 18.061 ⁇ 0.2°, 18.535 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the compound 25 maleate salt form II using Cu-K ⁇ radiation is shown in Figure 2-1.
  • the present invention provides compound 25 maleate salt form III, which has characteristic diffraction peaks at the following 2 ⁇ angles in an X-ray powder diffraction pattern using Cu-K ⁇ radiation: 8.730 ⁇ 0.2°, 10.010 ⁇ 0.2 °, 12.578 ⁇ 0.2°, 15.928 ⁇ 0.2°, 17.679 ⁇ 0.2°.
  • the compound 25 maleate salt form III in the X-ray powder diffraction pattern using Cu-K ⁇ radiation, has characteristic diffraction peaks at the following 2 ⁇ angles: 6.241 ⁇ 0.2°, 8.730 ⁇ 0.2°, 10.010 ⁇ 0.2°, 12.578 ⁇ 0.2°, 15.928 ⁇ 0.2°, 17.679 ⁇ 0.2°, 19.581 ⁇ 0.2°, 23.836 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the compound 25 maleate salt form III using Cu-K ⁇ radiation is shown in Figure 3-1.
  • the present invention provides compound 25 maleate salt form IV, which has characteristic diffraction peaks at the following 2 ⁇ angles in an X-ray powder diffraction pattern using Cu-K ⁇ radiation: 8.004 ⁇ 0.2°, 10.575 ⁇ 0.2 °, 12.151 ⁇ 0.2°, 16.137 ⁇ 0.2°, 22.366 ⁇ 0.2°, 24.308 ⁇ 0.2°.
  • the compound 25 maleate salt form IV has characteristic diffraction peaks at the following 2 ⁇ angles in an X-ray powder diffraction pattern using Cu-K ⁇ radiation: 8.004 ⁇ 0.2°, 9.600 ⁇ 0.2°, 10.575 ⁇ 0.2°, 12.151 ⁇ 0.2°, 16.137 ⁇ 0.2°, 17.008 ⁇ 0.2°, 22.366 ⁇ 0.2°, 23.296 ⁇ 0.2°, 24.308 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the compound 25 maleate salt form IV using Cu-K ⁇ radiation is shown in Figure 4-1.
  • the present invention provides compound 25 fumarate crystalline form, which has characteristic diffraction peaks at the following 2 ⁇ angles in an X-ray powder diffraction pattern using Cu-K ⁇ radiation: 7.692 ⁇ 0.2°, 8.305 ⁇ 0.2° , 10.407 ⁇ 0.2°, 18.680 ⁇ 0.2°, 22.187 ⁇ 0.2°.
  • the compound 25 fumarate salt crystal form has characteristic diffraction peaks at the following 2 ⁇ angles in the X-ray powder diffraction pattern using Cu-K ⁇ radiation: 7.692 ⁇ 0.2°, 8.305 ⁇ 0.2°, 10.407 ⁇ 0.2°, 15.332 ⁇ 0.2°, 17.377 ⁇ 0.2°, 18.680 ⁇ 0.2°, 20.344 ⁇ 0.2°, 22.187 ⁇ 0.2°, 23.210 ⁇ 0.2°, 23.688 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the compound 25 fumarate salt crystal form using Cu-K ⁇ radiation is shown in Figure 5-1.
  • the present invention provides compound 25 p-toluenesulfonate salt crystal form, which has characteristic diffraction peaks at the following 2 ⁇ angles in an X-ray powder diffraction pattern using Cu-K ⁇ radiation: 5.768 ⁇ 0.2°, 8.367 ⁇ 0.2 °, 11.406 ⁇ 0.2°, 17.183 ⁇ 0.2°, 23.035 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the compound 25 p-toluenesulfonate salt crystal form using Cu-K ⁇ radiation is shown in Figure 6-1.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of any of the above-mentioned compounds or a stereoisomer or a pharmaceutically acceptable salt thereof, or a crystal of any of the above-mentioned compounds form and a pharmaceutically acceptable carrier.
  • the carrier includes conventional adjuvant ingredients in the art, such as fillers, binders, diluents, disintegrants, lubricants, colorants, flavoring agents, antioxidants, and wetting agents.
  • the pharmaceutical composition can be prepared into various pharmaceutically acceptable dosage forms, such as tablets, capsules, oral liquids, suspensions, granules, powders, microparticles, pills, microtablets, fast-dissolving films, Nasal sprays, transdermal patches, injections or various sustained and controlled release preparations, etc.
  • the pharmaceutical compositions can be administered orally, transmucosally, rectally or parenterally (including intravascular, intravenous, intraperitoneal, subcutaneous, intramuscular and intrasternal).
  • the administered dose can be appropriately adjusted according to the patient's age, sex and disease type.
  • the pharmaceutical compositions may be in the form of, for example, tablets, capsules, liquid capsules, suspensions or liquids.
  • the pharmaceutical compositions are preferably prepared in dosage unit form containing specified quantities of active ingredients.
  • the pharmaceutical composition may be provided as a tablet or capsule containing the active ingredient in an amount ranging from about 0.1 to 1000 mg, preferably about 0.25 to 250 mg, and more preferably about 0.5 to 100 mg.
  • Suitable daily dosages for humans or other mammals can vary widely depending on the condition of the patient and other factors, but can be determined using routine methods.
  • the present invention provides the use of any one of the compounds described above, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, for the treatment of a disease or condition.
  • diseases or symptoms include: epilepsy (including seizures, seizures with tuberous sclerosis syndrome, Dravet syndrome, Lennox-Gastaut syndrome, mycoplasma seizures, mycoplasma juvenile epilepsy, intractable epilepsy); seizures (including adolescents) Spasticity, West syndrome, intractable pediatric spasms, pediatric spasms, hemifacial spasms); encephalopathy (including somnolence, attention/concentration problems, and cognitive problems); pain (including radiculopathy and neuropathy, lower back pain and fibromyalgia); neuropathic pain; numbness and/or tingling; anxiety and other mood disorders; hypertension and autonomic dysfunction; Parkinson's disease and tremor (including essential tremor); insomnia; Belle's palsy and facial nerve Dysfunction; Glaucoma; Multiple S
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue , without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts refers to salts of the compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting the neutral forms of such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
  • Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base or acid addition salts.
  • Certain compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the present invention.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to within the scope of the present invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • Optically active (R)- and (S)-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art
  • the diastereoisomers were resolved and the pure enantiomers recovered.
  • separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate).
  • pharmaceutically acceptable carrier refers to any formulation or carrier medium representative of any formulation or carrier medium capable of delivering an effective amount of the active substance of the present invention, without interfering with the biological activity of the active substance, and without toxic side effects to the host or patient.
  • an "effective amount” or “therapeutically effective amount” with respect to a drug or pharmacologically active agent refers to a nontoxic but sufficient amount of the drug or agent to achieve the desired effect.
  • an "effective amount” of one active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition.
  • the determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance, and the appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
  • active ingredient refers to a chemical entity that is effective in treating the target disorder, disease, or condition.
  • alkyl is used to denote a straight or branched chain saturated hydrocarbon group, which may be monosubstituted (eg -CH2F ) or polysubstituted (eg -CF3 ), may be monovalent (eg methyl), divalent (eg methylene), or polyvalent (eg methine).
  • the alkyl group is preferably a C 1-10 alkyl group, for example: C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 .
  • alkyl groups include methyl (Me), ethyl (Et), propyl (eg, n-propyl and isopropyl), butyl (eg, n-butyl, isobutyl, s-butyl) , t-butyl), pentyl (eg, n-pentyl, isopentyl, neopentyl, 1-ethylpropyl), hexyl (eg, n-hexyl, isohexyl, 1,1-dimethyl butyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl), heptyl, octyl, nonyl, decyl, etc.
  • Me methyl
  • Et ethyl
  • propyl eg, n-propyl and isopropyl
  • butyl eg, n-butyl, iso
  • heterocycle or “heterocyclyl” means a stable heteroatom or heteroatom-containing monocyclic, bicyclic, or tricyclic ring, which may be saturated, partially unsaturated, or unsaturated ( aromatic), which contain carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a benzene ring to form a bicyclic ring.
  • Nitrogen and sulfur heteroatoms can optionally be oxidized (ie, NO and S(O)p, where p is 1 or 2).
  • Nitrogen atoms can be substituted or unsubstituted (ie, N or NR, where R is H or other substituents already defined herein).
  • the heterocycle can be attached to any heteroatom or pendant carbon atom to form a stable structure.
  • the heterocycles described herein may undergo substitution at the carbon or nitrogen positions if the resulting compound is stable.
  • the nitrogen atoms in the heterocycle are optionally quaternized.
  • a preferred solution is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred solution is that the total number of S and O atoms in the heterocycle does not exceed 1.
  • aromatic heterocyclic group or “heteroaryl” means an aromatic ring of a stable 5, 6, 7 membered monocyclic or bicyclic or 7, 8, 9 or 10 membered bicyclic heterocyclic group, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S.
  • Nitrogen atoms can be substituted or unsubstituted (ie, N or NR, where R is H or other substituents already defined herein).
  • Nitrogen and sulfur heteroatoms can optionally be oxidized (ie, NO and S(O)p, where p is 1 or 2). Notably, the total number of S and O atoms on the aromatic heterocycle does not exceed 1.
  • Bridged rings are also included in the definition of heterocycle.
  • a bridged ring is formed when one or more atoms (ie, C, O, N, or S) link two non-adjacent carbon or nitrogen atoms.
  • Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a triple ring. In bridged rings, substituents on the ring may also appear on the bridge.
  • heterocyclic compounds include, but are not limited to: azetidinyl, acridinyl, acridine, benzimidazolyl, benzofuranyl, benzomercaptofuranyl, benzomercaptophenyl, benzoxanyl azolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carboline, chromanyl, chromene, cinnolinyl decahydroquinolyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[ 2,3-b]tetrahydrofuranyl, furanyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazo
  • aryl refers to a polyunsaturated aromatic hydrocarbon substituent, which may be mono- or polysubstituted, monovalent, divalent or polyvalent, which may be monocyclic or polycyclic (such as 1 to 3 rings; at least one of which is aromatic), fused together or covalently linked.
  • heteroaryl refers to an aryl group (or ring) containing one to four heteroatoms. In an illustrative example, the heteroatoms are selected from B, N, O, and S, wherein nitrogen and sulfur atoms are optionally oxidized, and nitrogen atoms are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • Non-limiting examples of aryl or heteroaryl groups include phenyl, naphthyl, 4-biphenyl, furyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, thiadiazolyl, pyrrolyl , pyrazolyl, pyrazolinyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyranyl, triazinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl , indolyl, benzothienyl, benzodioxolyl, benzoxazolyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, coumarinyl , Cinolinyl, Quinoxalinyl.
  • Non-limiting examples of aryl or heteroaryl groups are preferably: phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3- Pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-iso oxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3- Thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl
  • Figure 1-1, 1-2, 1-3, 1-4 XRPD spectrum, DSC spectrum, TGA spectrum, 1 H NMR spectrum of compound 25 maleate salt form I, respectively
  • Figure 3-1, 3-2, 3-3 XRPD spectrum, DSC/TGA spectrum, 1 H NMR spectrum of compound 25 maleate salt form III, respectively
  • Figure 4-1, 4-2, 4-3 XRPD spectrum, DSC/TGA spectrum, 1 H NMR spectrum of compound 25 maleate salt form IV, respectively
  • Figure 5-1, 5-2, 5-3, 5-4 XRPD spectrum, DSC spectrum, TGA spectrum, 1 H NMR spectrum of compound 25 fumarate, respectively
  • Figure 6-1, 6-2, 6-3, 6-4 XRPD spectrum, DSC spectrum, TGA spectrum, 1 H NMR spectrum of compound 25 p-toluenesulfonate, respectively
  • Figure 7-1 The drug-time curve of the original drug of compound 24 and 25 hydrochloride in beagle dogs
  • Figure 7-2 Drug-time curve of compound 24 and 25 hydrochloride metabolite CBD in beagle dogs
  • Figure 7-3 Time-to-dose curve of compound 25 maleate and CBD in high-fat diet and fasting model beagle dogs
  • Figure 9-2 XRPD spectra of compound 25 maleate salt form I before and after hygroscopicity test
  • Figure 10-1 XRPD spectra of compound 25 maleate crystal form I and crystal form II in room temperature competitive beating experiment
  • Figure 10-2 XRPD spectra of compound 25 maleate crystal form I and crystal form II high temperature competitive beating experiment
  • Figure 11 XRPD spectra of compound 25 maleate salt form I before and after tableting experiment
  • the CBD was dissolved in the solvent and an alkaline catalyst was added, and the reaction was stirred at room temperature. Add phenyl p-nitrochloroformate and react at room temperature. Add water to quench, then extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the organic phase under reduced pressure, and separate by column chromatography to obtain fragment 1.
  • Fragment 1 was dissolved in solvent, reagents were added, and the reaction was performed at room temperature/heat. It was quenched by adding water, then extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure and separated by high performance liquid chromatography.
  • the product of formula (II) is obtained (ie, the product in which one of R 1 or R 2 is OH).
  • the product of formula (II) (that is, the product in which one of R 1 or R 2 is OH) is dissolved in a solvent with an alkaline reagent, different reagents are added dropwise, and the reaction is performed at room temperature after ice bathing. It was quenched by adding water, then extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure and separated by high performance liquid chromatography.
  • the products of formula (II) with different structures of R 1 and R 2 are obtained.
  • the CBD is dissolved in the solvent and an alkaline reagent is added, and the reaction is stirred at room temperature.
  • CBD (2.0 g, 6.4 mmol, 1 eq) was dissolved in 60 mL of dichloromethane and triethylamine (1.3 g, 12.8 mmol, 2.0 eq) was added, and the reaction was stirred at room temperature for 0.5 h. Phenyl p-nitrochloroformate (1.54g, 7.68mmol, 1.2eq) was added, and the reaction was carried out at room temperature for 2h.
  • Fragment 1 (479 mg, 0.9 mmol, 1.0 eq) was dissolved in 10 mL of dichloromethane, ethylenediamine (108 mg, 1.8 mmol, 2.0 eq) was added, and the reaction was carried out at room temperature for 3 h. Add water to quench, then extract with ethyl acetate (50mL*3), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the organic phase under reduced pressure, pass high performance liquid chromatography (Waters autopurification HPLC-system C18 50*250mm Wavelength 254nm water(0.1%TFA)-MeCN(0.1%TFA)) separation.
  • Fragment 1 (479 mg, 0.9 mmol, 1.0 eq) was dissolved in 10 mL of dichloromethane, diethylaminoethanol (320 mg, 2.7 mmol, 3.0 eq) was added, and the reaction was carried out at room temperature for 3 h. Add water to quench, then extract with ethyl acetate (50mL*3), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the organic phase under reduced pressure, pass high performance liquid chromatography (Waters autopurification HPLC-system C18 50*250mm Wavelength 254nm water(0.1%TFA)-MeCN(0.1%TFA)) separation.
  • the fragment 1 (2.0 g, 4.0 mmol, 1 eq) was dissolved in 60 mL of dichloromethane, 2-morpholinoethanol (2.6 g, 20.0 mmol, 5.0 eq) was added, and the reaction was heated under reflux overnight. Add water to quench, then extract with ethyl acetate (50mL*3), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the organic phase under reduced pressure, pass high performance liquid chromatography (Waters autopurification HPLC-system C18 50*250mm Wavelength 254nm water(0.1%TFA)-MeCN(0.1%TFA)) separation. Compound 18 was obtained as trifluoroacetate (211 mg, oil), yield: 9%.
  • Fragment 1 (450 mg, 0.94 mmol, 1 eq) was dissolved in 10 mL of dichloromethane, N,N-diethylethylenediamine (210 mg, 1.9 mmol, 2.0 eq) was added, and the reaction was carried out at room temperature for 2 h. Add water to quench, then extract with ethyl acetate (50mL*3), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the organic phase under reduced pressure, pass high performance liquid chromatography (Waters autopurification HPLC-system C18 50*250mm Wavelength 254nm water(0.1%TFA)-MeCN(0.1%TFA)) separation.
  • Fragment 1 (450 mg, 0.94 mmol, 1 eq) was dissolved in 10 mL of dichloromethane, 2-morpholinoethylamine (227 mg, 1.9 mmol, 2.0 eq) was added, and the reaction was carried out at room temperature for 2 h. Add water to quench, then extract with ethyl acetate (50mL*3), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the organic phase under reduced pressure, pass high performance liquid chromatography (Waters autopurification HPLC-system C18 50*250mm Wavelength 254nm water(0.1%TFA)-MeCN(0.1%TFA)) separation.
  • CBD (2.0 g, 6.4 mmol, 1 eq) was dissolved in 60 mL of dichloromethane and triethylamine (1.3 g, 12.8 mmol, 2.0 eq) was added, and the reaction was stirred at room temperature for 0.5 h. Add phenyl p-nitrochloroformate (5.1 g, 25.5 mmol, 4 eq), and react at 0 °C for 2 h.
  • Fragment 2 (1.0g, 1.6mmol, 1.0eq), 2-morpholinoethanol (2.0g, 16.0mmol, 10eq) and triethylamine (9.39g, 9.30mmol, 6eq) were dissolved in 30mL of dichloromethane, heated to reflux React overnight. Add water to quench, then extract with ethyl acetate (50mL*3), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the organic phase under reduced pressure, pass high performance liquid chromatography (Waters autopurification HPLC-system C18 50*250mm Wavelength 254nm water(0.1%TFA)-MeCN(0.1%TFA)) separation.
  • CBD (0.80g, 2.50mmol, 1eq) was dissolved in 8mL of tetrahydrofuran, sodium hydride (0.091g, 3.80mmol, 1.5eq) was added, and the reaction was stirred at 0°C for 0.5h. Add iodomethane (0.43g, 3.0mmol, 1.2eq), and react at 0°C for 2h.
  • step (2) The maleic acid solution of step (2) was added dropwise to the solution of compound 25 of step (1) (the dropwise addition was completed within 5 min), stirred for 24 h, and no solid was precipitated.
  • the X-ray diffraction pattern was acquired by the D2Phaser of Bruker Instruments, and the instrument parameters are shown in Table 1-1.
  • the XRPD spectrum is shown in Figure 1-1, and the spectrum analysis data is shown in Table 1-2.
  • the DSC curve was acquired by the DSC3 type of Mettler instruments. The sample was weighed into a sample pan, accurately weighed, the weight was recorded, and the temperature was raised from 30°C to 350°C at a heating rate of 10°C/min. The nitrogen flow rate was 50 mL/min. The crucible was kept in a sealed state during the experiment.
  • the TGA curve was acquired by NETZSCH TG209F3.
  • a sample was weighed into a sample pan (Al 2 O 3 ), accurately weighed, and the weight was recorded.
  • the temperature was raised from 40°C to 350°C at a ramp rate of 20°C/min.
  • the nitrogen flow rate was 70 mL/min.
  • test results are shown in Figures 1-3, and the results show that the compound 25 maleate salt crystal form I loses 0.2% in weight in the endothermic peak temperature range.
  • test results are shown in Figures 1-4, the results show that compound 25 maleate salt crystal form I has no solvent residue, is an anhydrous crystal form, and the molar ratio of maleic acid to free base is 2.0:1.0.
  • compound 25 maleate salt crystal form I was weighed, 1.8 mL of isopropyl acetate was added at 50° C., and 0.8 mL of acetone was added, and filtered. The filtrate was transferred to -10°C for 1 day after continuous stirring, and then filtered, and the obtained solid was vacuum-dried at 50°C for 4 hours to obtain compound 25 maleate salt crystal form II.
  • the TGA curve was acquired by TGA550 of TA Instruments. A sample was weighed into a sample pan (Al 2 O 3 ), and the temperature was raised to 300° C. at a heating rate of 10° C./min.
  • the DSC curve was acquired by the DSC250 model of TA Instruments. Weigh the sample into the sample pan, accurately weigh it, and record the weight. The temperature was raised from 25°C to 300°C at a ramp rate of 10°C/min.
  • the XPRD spectrum is shown in Figure 2-1, and the spectrum analysis data is shown in Table 2.
  • DSC results show that compound 25 maleate salt form II has an endothermic peak at 76.47 °C; TGA results show that compound 25 maleate salt form II has no weight loss in the melting point range; 1 H NMR results show that compound 25 Maleate crystal form II is an anhydrous crystal form, and the molar ratio of maleic acid to free base is 2.0:1.0.
  • the DSC/TGA spectrum is shown in Figure 2-2, and the 1 H NMR spectrum is shown in Figure 2-3.
  • compound 25 maleate salt form I About 1 g of compound 25 maleate salt form I was weighed, the raw material was dissolved with 4 mL of acetonitrile and 40 mL of water, frozen on dry ice and then freeze-dried to obtain compound 25 maleate salt amorphous. Weigh 30.64 mg of compound 25 maleate amorphous into a sample bottle, add 0.2 mL of isopropanol, and stir at about 15° C. for 3 days to obtain compound 25 maleate crystal form III.
  • DSC results show that compound 25 maleate salt form III has an endothermic peak at 115.31 °C, which is the melting point of this crystal form; TGA results show that compound 25 maleate salt form III has no weight loss within the melting point range, 1 H NMR The results show that compound 25 maleate salt form III is anhydrous, and the mole ratio of maleic acid to free base is 2.0:1.0.
  • the DSC/TGA spectrum is shown in Figure 3-2, and the 1H NMR spectrum is shown in Figure 3-3.
  • compound 25 maleate salt form I About 1 g of compound 25 maleate salt form I was weighed, the raw material was dissolved with 4 mL of acetonitrile and 40 mL of water, frozen on dry ice and then freeze-dried to obtain compound 25 maleate salt amorphous. Weigh about 30 mg of compound 25 maleate amorphous into a sample bottle, add 0.1 mL of acetonitrile-methyl tert-butyl ether (1:8), and stir at about 15°C for 3 days to obtain compound 25 maleate crystals Type IV.
  • Figure 5-1 shows the X-ray powder diffraction pattern of compound 25 fumarate salt crystal form using Cu-K ⁇ radiation.
  • DSC results showed that the compound 25 fumarate crystal form had an endothermic peak at 91.76 °C; TGA results showed that the compound 25 fumarate crystal form had no weight loss before 120 °C; 1 H NMR results showed that the compound 25 fumarate salt
  • the crystal form has no solvent residue, is an anhydrous crystal form, and the molar ratio of fumaric acid to free base is 2.0:1.0.
  • the DSC/TGA/ 1 H NMR spectra are shown in Figure 5-2, Figure 5-3, and Figure 5-4, respectively.
  • Example 21 Preparation and characterization of compound 25 p-toluenesulfonate crystal form
  • DSC results show that compound 25 p-toluenesulfonate crystal form has an endothermic peak at 148.41 °C; TGA results show that compound 25 p-toluenesulfonate crystal form has a weight loss of 0.6% before 200 °C; 1 H NMR results show that , Compound 25 p-toluenesulfonic acid salt crystal form has no solvent residue, and the molar ratio of p-toluenesulfonic acid to free base is 2.0:1.0.
  • the DSC/TGA/ 1 H NMR spectra are shown in Figure 6-2, Figure 6-3, and Figure 6-4, respectively.
  • Cannabidiol (5g, 16mmol) was dissolved in 100mL of dry dichloromethane, and triphosgene (4.76g, 16mmol) and N,N-diisopropylethylamine (4.12g, 32mmol) were added successively at 0°C, and the reaction was carried out.
  • Test Example 1 Pharmacokinetic test of prodrug compound in Beagle dogs
  • Beagle dogs weighing about 10 kg were randomly divided into groups, three in each group, fasting 12 hours before administration, drinking water freely, and compound 24 hydrochloride aqueous solution, compound 25 hydrochloride aqueous solution, and compound 27 hydrochloride at a dose of 32 ⁇ mol/kg.
  • Saline solution and CBD sesame oil solution (1mL vehicle containing 79mg ethanol, 736mg sesame oil) were administered by gavage, respectively before and after administration at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 24 Blood was collected every hour, placed in a heparinized EP tube, and centrifuged to separate the plasma. After the plasma was pretreated, the concentrations of the active metabolite CBD and each prodrug in the plasma were detected by LC-MS/MS.
  • Table 7-1, Figure 7-1 and Figure 7-2 show the pharmacokinetic parameters and drug-time curves of the prodrug prototype compound and/or CBD after oral administration of Compound 24 hydrochloride, Compound 25 hydrochloride and CBD to beagle dogs picture.
  • the results showed that most of compound 24 hydrochloride and compound 25 hydrochloride were metabolized into CBD after entering the body of beagle dogs through the gastrointestinal tract.
  • the relative bioavailability of the metabolite CBD of compound 24 and compound 25 was 364.7% and 307.5%, respectively.
  • Table 7-2 shows the main pharmacokinetic parameters of the prodrug parent compound and/or CBD after oral administration of Compound 27 hydrochloride or CBD to beagle dogs.
  • the results showed that the prodrug compound 27 hydrochloride was mostly metabolized to CBD after entering the body of beagle dogs through the gastrointestinal tract. Taking the CBD administration group as a reference, the relative bioavailability of compound 27 metabolite CBD was 113.2%.
  • Group 3 was given CBD sesame oil solution (1mL solvent containing 79mg ethanol, 736mg sesame oil) by gavage, and the administration volume was 0.2ml/kg, and after administration, 6ml sesame oil and 30ml water were used for infusion.
  • group 4 the CBD sesame oil solution (1mL vehicle containing 79mg ethanol, 736mg sesame oil) was injected into the immediate-release capsule for intragastric administration (about 1ml sesame oil), and 38ml water was used for administration after administration.
  • Blood was collected before administration and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours after administration, respectively. The blood was placed in a heparinized EP tube, and the plasma was centrifuged to separate the plasma. The concentrations of compound 25 and CBD in plasma were determined by LC-MS/MS. The test results are shown in Figure 7-3 and Table 7-3.
  • the test results showed that compound 25 maleate was mostly metabolized to CBD in Beagle dogs.
  • the exposure of compound 25 maleate (group 1) to the active metabolite CBD was 2.2 times higher than that of the CBD group (group 4).
  • the CBD exposure and Cmax generated by compound 25 maleate administered with high oil (group 2) were comparable to those in the normal group (group 1); ) and Cmax were both 4.8 times that of the normal group (group 4). That is, the effect of high-fat diet on compound 25 maleate exposure and Cmax was much smaller than that of CBD.
  • Test Example 2 Pharmacokinetic test of prodrug compounds in fasting model rats
  • SD rats with a body weight of about 200 grams were randomly divided into groups, four in each group, with a dose of 47.7 ⁇ mol/kg, fasting for 12 hours before administration, and free drinking water.
  • Solutol HS 15 aqueous solution (containing 5% anhydrous ethanol) was collected before administration and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours after administration, and the blood was placed in heparin Plasma was separated by centrifugation in EP tubes, and the concentrations of active metabolite CBD and each prodrug in plasma were detected by LC-MS/MS after plasma pretreatment.
  • Table 8-1 and Fig. 8 are the pharmacokinetic parameters and drug-time curve diagrams of the metabolite CBD after the rats were given compound 24 hydrochloride and compound 25 hydrochloride by gavage. The results showed that compound 24 hydrochloride and compound 25 hydrochloride were metabolized to the active metabolite CBD immediately after entering the rat through the gastrointestinal tract. The concentration of the original compound was very low, which was lower than the lower limit of quantification of detection. Oral administration is basically converted into the active metabolite CBD. However, after oral administration of compound 26 trifluoroacetate, neither prodrug nor CBD was detected.
  • Tables 8-2 and 8-3 are the pharmacokinetic parameters and drug-time curves of the prodrug prototype drug and metabolite CBD after oral administration of compound 13/compound 19/compound 21 trifluoroacetate to rats. The results showed that the exposure of carbamate compounds in vivo metabolite CBD was lower than or equivalent to that of CBD administered by direct gavage.
  • Table 8-4 shows the pharmacokinetic parameters of the metabolite CBD after oral administration of compound 17/compound 18 trifluoroacetate to rats, and no compound 17 and compound 18 prototype compounds were detected. The results showed that carbonates containing morpholine rings had higher exposure to the metabolite CBD in vivo.
  • the XRPD method is the same as that in Example 16, and the HPLC method is shown in Table 9-1.
  • Drying process stable for about 1.5h at 40°C/0%RH until dm/dt is less than 0.002%.
  • Test process After the temperature is lowered to 25°C, the measurement is started after the dm/dt is less than 0.002%.
  • Test Example 5 Competitive beating test of compound 25 maleate crystal form
  • the amorphous saturated solution of compound 25 maleate in the solvent of Table 10 was prepared respectively, and then compound 25 maleate crystal form I and crystal form II were added to each saturated medicinal solution at a mass ratio of 1:1, at room temperature. (about 17° C.) or 50° C. for 3 days, the obtained solids are all compound 25 maleate salt crystal form I, and the result shows that the crystal form I is more stable than the crystal form II.

Abstract

一种大麻二酚的前药及其制备方法和药物组合物。还涉及含有所述前药化合物或药物组合物在制备治疗哺乳动物或人的相关疾病的药物中的应用，所述疾病包括癫痫、痉挛、脑病、疼痛、焦虑和其它情绪障碍、帕金森氏病和震颤、多发性硬化、癌症、炎症等。

Description

大麻二酚前药及其药物组合物和应用 技术领域
本发明涉及一类适合于哺乳动物的大麻二酚的前药；和包含大麻二酚前药的药物组合物及其治疗和预防疾病和病症的用途。
背景技术
Datamonitor Healthcare估计，2018年，美国、日本和五大欧盟市场有660万确诊的活动性癫痫，2038年病例将增至710万例。国内流行病学资料显示，我国癫痫“终生患病率”约7‰，约有900万癫痫患者，其中约600万是活动性癫痫患者，每年新增癫痫患者约40万。
根据临床症状及脑电图，2017ILAE确定癫痫类型为四个大类，包括局灶性、全面性、全面性合并局灶性(Combined generalized and focal epilepsy)以及不明分类的癫痫。Dravet综合征及Lennox-Gastaut综合征属于全面性合并局灶性癫痫类型，属于难治性癫痫类型。Dravet综合征在3-13岁儿童的发病率为11/10，Lennox-Gastaut综合征在3-13岁儿童的发病率为4/10，癫痫发作伴结节性硬化综合征的发病率为8/10。
难治性癫痫是指癫痫发作不能通过药物控制，即不易控制或缓解，也被称为受控制或抗药性癫痫发作。Door-to-door研究估计难治性癫痫的流行率在高收入地区为2.7-7.1/1000，在中低收入地区为2.2-22.2/1000。目前，药物抵抗性癫痫基于大样本人群调查的发病率难以获得。总的来说，儿童和成人药物抵抗性癫痫发病率分别为15％和30％。
大麻二酚(cannabidiol，简称CBD)，性状表现为白色至淡黄色树脂或结晶，熔点为66℃～67℃，几乎不溶于水，溶于乙醇、甲醇、乙醚、苯、氯仿等有机溶剂。
Figure PCTCN2022085086-appb-000001
为大麻二酚口服液，于2018年被FDA批准上市，临床用于治疗一岁及以上的患者的(1)Dravet综合征相关的癫痫发作；(2)Lennox-Gastaut综合征相关的癫痫发作；2020年批准用于治疗结节性硬化综合征相关的癫痫发作(https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/210365s005s006s007lbl.pdf)。
Figure PCTCN2022085086-appb-000002
制剂的规格：1ml：100mg；一岁及以上Lennox-Gastaut综合征和Dravet综合征相关的癫痫发作患者的最大推荐维持剂量为10mg/kg，BID；一岁及以上结节性硬化综合征相关的癫痫发作患者的最大推荐维持剂量为12.5mg/kg，BID。每瓶100ml，含有无水乙醇(7.9％w/v)，芝麻油，草莓香精和三氯蔗糖。由于含7.9％无水乙醇，因此，对于婴幼儿患者是个很大的问题。同时，大麻二酚水溶性差，口服给药的生物利用度仅为6％，且胃肠道吸收水平不稳定，高脂饮食导致AUC 0-∞及C max等PK参数波动大(相对于禁食状态C max增加5倍，AUC增加4倍)，出现肝毒性(https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf)。基于上述缺陷，提供一种提高生物利用度，除去制剂中的无水乙醇和芝麻油，进入体内快速转化为大麻二酚的前药口服制剂是临床需要解决的问题。
发明内容
在一个方面中，本发明提供了式(I)所示化合物、其药学上可接受的盐或对映异构体，
Figure PCTCN2022085086-appb-000003
其中，
R 1、R 2相同或不同，各自独立地选自-OH、-OC(O)-R 4、或-OC(O)-X-(CH 2)n-N(Y 1Y 2)；
X为NH或O；
Y 1独立地选自C 2-10的烷基；Y 2独立地选自氢、C 2-10的烷基；或者Y 1、Y 2与相连N原子形成环系，所述环系为未被取代的杂环基或杂芳基；
R 3为C 1-10的烷基；R 4为C 1-10的烷基；n＝2-10；
条件是：R 1或R 2中至少一个为-OC(O)-X-(CH 2)n-N(Y 1Y 2)。
在式(I)化合物的一个实施方案中，
R 1、R 2相同或不同，各自独立地选自-OH、-OC(O)-R 4、或-OC(O)-X-(CH 2)n-N(Y 1Y 2)；
X为NH或O；
Y 1独立地选自C 2-6的烷基；Y 2独立地选自氢、C 2-6的烷基；或者Y 1、Y 2与相连N原子形成环系，所述环系为未被取代的杂环基或杂芳基；
R 3为C 1-6的烷基；R 4为C 1-6的烷基；
n＝2、3、4、5、6、7、8、9或10；
条件是：R 1或R 2中至少一个为-OC(O)-X-(CH 2)n-N(Y 1Y 2)。
在式(I)化合物的一个实施方案中，
R 1、R 2相同或不同，各自独立地选自-OH、-OC(O)-R 4、或-OC(O)-X-(CH 2)n-N(Y 1Y 2)；
X为NH或O；
Y 1独立地选自C 2-6直链或支链的烷基；
Y 2独立地选自氢、C 2-6直链或支链的烷基；
或者Y 1、Y 2与相连N原子形成环系，所述环系为未被取代的3-8元杂环基或3-8元杂芳基。
R 3为C 1-6直链或支链的烷基；
R 4为C 1-6直链或支链的烷基；
n＝2、3、4、5、6、7、8、9或10；
条件是：R 1或R 2中至少一个为-OC(O)-X-(CH 2)n-N(Y 1Y 2)。
在式(I)化合物的一个实施方案中，
R 1、R 2相同或不同，各自独立地选自-OH、OC(O)-R 4、或--OC(O)-X-(CH 2)n-N(Y 1Y 2)；
X为NH或O；
Y 1独立地选自乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、1-乙基丙基、己基、异己基、1，1-二甲基丁基、2，2-二甲基丁基、3，3-二甲基丁基和2-乙基丁基；
Y 2独立地选自氢、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、1-乙基丙基、己基、异己基、1，1-二甲基丁基、2，2-二甲基丁基、3，3-二甲基丁基和2-乙基丁基；
R 3为甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、1-乙基丙基、己基、异己基、1，1-二甲基丁基、2，2-二甲基丁基、3，3-二甲基丁基和2-乙基丁基；
R 4为甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新 戊基、1-乙基丙基、己基、异己基、1，1-二甲基丁基、2，2-二甲基丁基、3，3-二甲基丁基和2-乙基丁基；
n＝2、3、4、5、6、7、8、9或10；
条件是：R 1或R 2中至少一个为-OC(O)-X-(CH 2)n-N(Y 1Y 2)。
在式(I)化合物的一个实施方案中，
R 1、R 2相同或不同，各自独立地选自-OH、-OC(O)-R 4、或-OC(O)-X-(CH 2)n-N(Y 1Y 2)；
X为NH或O；
Y 1、Y 2与相连N原子形成环系，所述环系选自
Figure PCTCN2022085086-appb-000004
Figure PCTCN2022085086-appb-000005
R 3为甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、1-乙基丙基、己基、异己基、1，1-二甲基丁基、2，2-二甲基丁基、3，3-二甲基丁基和2-乙基丁基；
R 4为甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、1-乙基丙基、己基、异己基、1，1-二甲基丁基、2，2-二甲基丁基、3，3-二甲基丁基和2-乙基丁基；
n＝2、3、4、5、6、7、8、9或10；
条件是：R 1或R 2中至少一个为-OC(O)-X-(CH 2)n-N(Y 1Y 2)。
在式(I)化合物的一个实施方案中，
R 1独立地选自
Figure PCTCN2022085086-appb-000006
R 2独立地选自-OH、
Figure PCTCN2022085086-appb-000007
Figure PCTCN2022085086-appb-000008
R 3为戊基。
在式(I)化合物的一个实施方案中，
R 1为-OC(O)-X-(CH 2)n-N(Y 1Y 2)；
R 2选自-OH、-OC(O)-R 4、或-OC(O)-X-(CH 2)n-N(Y 1Y 2)；
X为NH或O；优选为O；
Y 1、Y 2与相连N原子形成环系，所述环系为
Figure PCTCN2022085086-appb-000009
R 3为C 1-6的烷基；R 4为C 1-6的烷基；
n＝2、3、4或5。
在式(I)化合物的一个实施方案中，
R 1为-OC(O)-X-(CH 2)n-N(Y 1Y 2)；
R 2选自-OH、-OC(O)-R 4、或-OC(O)-X-(CH 2)n-N(Y 1Y 2)；
Y 1、Y 2与相连N原子形成环系，所述环系为
Figure PCTCN2022085086-appb-000010
X为O；R 3为戊基；R 4为甲基、乙基或丙基；n＝2、3、4或5，优选n＝2。
在一个方面中，本发明提供了式(II)所示化合物、其药学上可接受的盐或对映异构体，
Figure PCTCN2022085086-appb-000011
其中，
R 1、R 2相同或不同，各自独立地选自-OH、OC(O)-R 4、或--OC(O)-X-(CH 2)n-N(Y 1Y 2)；
X为NH或O；
Y 1独立地选自C 2-10的烷基；Y 2独立地选自氢、C 2-10的烷基；或者Y 1、Y 2与相连N原子形成环系，所述环系为未被取代的杂环基或杂芳基；
R 3为C 1-10的烷基；R 4为C 1-10的烷基；n＝2-10；
条件是：R 1或R 2中至少一个为-OC(O)-X-(CH 2)n-N(Y 1Y 2)。
在式(II)化合物的一个实施方案中，
R 1、R 2相同或不同，各自独立地选自-OH、-OC(O)-R 4、或-OC(O)-X-(CH 2)n-N(Y 1Y 2)；
X为NH或O；
Y 1独立地选自C 2-6的烷基；
Y 2独立地选自氢、C 2-6的烷基；
或者Y 1、Y 2与相连N原子形成环系，所述环系为未被取代的杂环基或杂芳基；
R 3为C 1-6的烷基；R 4为C 1-6的烷基；
n＝2、3、4、5、6、7、8、9或10；
条件是：R 1或R 2中至少一个为-OC(O)-X-(CH 2)n-N(Y 1Y 2)。
在式(II)化合物的一个实施方案中，
R 1、R 2相同或不同，各自独立地选自-OH、-OC(O)-R 4、或-OC(O)-X-(CH 2)n-N(Y 1Y 2)；
X为NH或O；
Y 1独立地选自C 2-6直链或支链的烷基；
Y 2独立地选自氢、C 2-6直链或支链的烷基；
或者Y 1、Y 2与相连N原子形成环系，所述环系为未被取代的3-8元杂环基或3-8元杂芳基。
R 3为C 1-6直链或支链的烷基；
R 4为C 1-6直链或支链的烷基；
n＝2、3、4、5、6、7、8、9或10；
条件是：R 1或R 2中至少一个为-OC(O)-X-(CH 2)n-N(Y 1Y 2)。
在式(II)化合物的一个实施方案中，
R 1、R 2相同或不同，各自独立地选自-OH、-OC(O)-R 4、或-OC(O)-X-(CH 2)n-N(Y 1Y 2)；
X为NH或O；
Y 1独立地选自甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、1-乙基丙基、己基、异己基、1，1-二甲基丁基、2，2-二甲基丁基、3，3-二甲基丁基和2-乙基丁基；
Y 2独立地选自氢、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、1-乙基丙基、己基、异己基、1，1-二甲基丁基、2，2-二甲基丁基、3，3-二甲基丁基和2-乙基丁基；
R 3为甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、1-乙基丙基、己基、异己基、1，1-二甲基丁基、2，2-二甲基丁基、3，3-二甲基丁基和2-乙基丁基；
R 4为甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、1-乙基丙基、己基、异己基、1，1-二甲基丁基、2，2-二甲基丁基、3，3-二甲基丁基和2-乙基丁基；
n＝2、3、4、5、6、7、8、9或10；
条件是：R 1或R 2中至少一个为-OC(O)-X-(CH 2)n-N(Y 1Y 2)。
在式(II)化合物的一个实施方案中，
R 1、R 2相同或不同，各自独立地选自-OH、-OC(O)-R 4、或-OC(O)-X-(CH 2)n-N(Y 1Y 2)；
X为NH或O；
Y 1、Y 2与相连N原子形成环系，所述环系选自
Figure PCTCN2022085086-appb-000012
Figure PCTCN2022085086-appb-000013
R 3为甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、1-乙基丙基、己基、异己基、1，1-二甲基丁基、2，2-二甲基丁基、3，3-二甲基丁基和2-乙基丁基；
R 4为甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、1-乙基丙基、己基、异己基、1，1-二甲基丁基、2，2-二甲基丁基、3，3-二甲基丁基和2-乙基丁基；
n＝2、3、4、5、6、7、8、9或10；
条件是：R 1或R 2中至少一个为-OC(O)-X-(CH 2)n-N(Y 1Y 2)。
在式(II)化合物的一个实施方案中，
R 1独立地选自
Figure PCTCN2022085086-appb-000014
R 2独立地选自-OH、
Figure PCTCN2022085086-appb-000015
Figure PCTCN2022085086-appb-000016
R 3为戊基。
在式(II)化合物的一个实施方案中，
R 1为-OC(O)-X-(CH 2)n-N(Y 1Y 2)；
R 2选自-OH、-OC(O)-R 4、或-OC(O)-X-(CH 2)n-N(Y 1Y 2)；
X为NH或O；优选为O；
Y 1、Y 2与相连N原子形成环系，所述环系为
Figure PCTCN2022085086-appb-000017
R 3为C 1-6的烷基；R 4为C 1-6的烷基；
n＝2、3、4或5。
在式(II)化合物的一个实施方案中，
R 1为-OC(O)-X-(CH 2)n-N(Y 1Y 2)；
R 2选自-OH、-OC(O)-R 4、或-OC(O)-X-(CH 2)n-N(Y 1Y 2)；
Y 1、Y 2与相连N原子形成环系，所述环系为
Figure PCTCN2022085086-appb-000018
X为O；R 3为戊基；R 4为甲基、乙基或丙基；n＝2、3、4或5；优选n＝2。
在一个方面中，本发明提供了下述化合物、其药学上可接受盐或对映异构体：
Figure PCTCN2022085086-appb-000019
Figure PCTCN2022085086-appb-000020
Figure PCTCN2022085086-appb-000021
在一个方面中，本发明提供了上述任一所述化合物或其对映异构体的盐，所说的盐选自对甲苯磺酸盐、富马酸盐、马来酸盐、草酸盐、磷酸盐、盐酸盐、硫酸盐、苹果酸盐、酒石酸、柠檬酸或三氟乙酸盐。
在一个方面中，本发明提供了化合物25的马来酸盐、对甲苯磺酸盐、富马酸盐或盐酸盐。
在一个方面中，本发明提供了化合物25的马来酸盐晶型I，使用Cu-Kα辐射的X射线粉末衍射图中，在下列2θ角处有特征衍射峰：9.016±0.2°，13.765±0.2°，17.411±0.2°，18.411±0.2°，21.575±0.2°，27.798±0.2°。
Figure PCTCN2022085086-appb-000022
在一个方面中，所述化合物25马来酸盐晶型I，使用Cu-Kα辐射的X射线粉末衍射图中，在下列2θ角处有特征衍射峰：9.016±0.2°，13.765±0.2°，17.411±0.2°，18.411±0.2°，21.575±0.2°，23.289±0.2°，27.798±0.2°。
在一个方面中，所述化合物25马来酸盐晶型I，使用Cu-Kα辐射的X射线粉末衍射图中，在下列2θ角处有特征衍射峰：8.676±0.2°，9.016±0.2°，9.580±0.2°，13.765±0.2°，16.154±0.2°，17.411±0.2°，18.411±0.2°，21.575±0.2°，23.289±0.2°，27.798±0.2°。
在一个方面中，所述化合物25马来酸盐晶型I，使用Cu-Kα辐射的X射线粉末衍射图如图1-1所示。
在一个方面中，本发明提供了化合物25马来酸盐晶型II，使用Cu-Kα辐射的X射线粉末衍射图中，在下列2θ角处有特征衍射峰：7.868±0.2°，10.713±0.2°，12.122±0.2°，18.535±0.2°。
在一个方面中，所述化合物25马来酸盐晶型II，使用Cu-Kα辐射的X射线粉末衍射图中，在下列2θ角处有特征衍射峰：7.868±0.2°，8.892±0.2°，9.111±0.2°，9.760±0.2°，10.713±0.2°，12.122±0.2°，18.061±0.2°，18.535±0.2°。
在一个方面中，所述化合物25马来酸盐晶型II，使用Cu-Kα辐射的X射线粉末衍射图如图2-1所示。
在一个方面中，本发明提供了化合物25马来酸盐晶型III，使用Cu-Kα辐射的X射线粉末衍射图中，在下列2θ角处有特征衍射峰：8.730±0.2°，10.010±0.2°，12.578±0.2°，15.928±0.2°，17.679±0.2°。
在一个方面中，所述化合物25马来酸盐晶型III，使用Cu-Kα辐射的X射线粉末衍射图 中，在下列2θ角处有特征衍射峰：6.241±0.2°，8.730±0.2°，10.010±0.2°，12.578±0.2°，15.928±0.2°，17.679±0.2°，19.581±0.2°，23.836±0.2°。
在一个方面中，所述化合物25马来酸盐晶型III，使用Cu-Kα辐射的X射线粉末衍射图如图3-1所示。
在一个方面中，本发明提供了化合物25马来酸盐晶型IV，使用Cu-Kα辐射的X射线粉末衍射图中，在下列2θ角处有特征衍射峰：8.004±0.2°，10.575±0.2°，12.151±0.2°，16.137±0.2°，22.366±0.2°，24.308±0.2°。
在一个方面中，所述化合物25马来酸盐晶型IV，使用Cu-Kα辐射的X射线粉末衍射图中，在下列2θ角处有特征衍射峰：8.004±0.2°，9.600±0.2°，10.575±0.2°，12.151±0.2°，16.137±0.2°，17.008±0.2°，22.366±0.2°，23.296±0.2°，24.308±0.2°。
在一个方面中，所述化合物25马来酸盐晶型IV，使用Cu-Kα辐射的X射线粉末衍射图如图4-1所示。
在一个方面中，本发明提供了化合物25富马酸盐晶型，使用Cu-Kα辐射的X射线粉末衍射图中，在下列2θ角处有特征衍射峰：7.692±0.2°，8.305±0.2°，10.407±0.2°，18.680±0.2°，22.187±0.2°。
在一个方面中，所述化合物25富马酸盐晶型，使用Cu-Kα辐射的X射线粉末衍射图中，在下列2θ角处有特征衍射峰：7.692±0.2°，8.305±0.2°，10.407±0.2°，15.332±0.2°，17.377±0.2°，18.680±0.2°，20.344±0.2°，22.187±0.2°，23.210±0.2°，23.688±0.2°。
在一个方面中，所述化合物25富马酸盐晶型，使用Cu-Kα辐射的X射线粉末衍射图如图5-1所示。
在一个方面中，本发明提供了化合物25对甲苯磺酸盐晶型，使用Cu-Kα辐射的X射线粉末衍射图中，在下列2θ角处有特征衍射峰：5.768±0.2°，8.367±0.2°，11.406±0.2°，17.183±0.2°，23.035±0.2°。
在一个方面中，所述化合物25对甲苯磺酸盐晶型，使用Cu-Kα辐射的X射线粉末衍射图如图6-1所示。
在一个方面中，本发明提供了一种药物组合物，包括治疗有效量的上述任一所述化合物或其立体异构体或其药学上可接受的盐，或上述任一所述化合物的结晶形式以及药学上可接受的载体。所述载体，包括本领域中常规的辅料成分，例如、填充剂、粘合剂、稀释剂、崩解剂、润滑剂、着色剂、调味剂、抗氧化剂和润湿剂等。
所述药物组合物可以制备成药学上可接受的各种剂型，如片剂、胶囊剂、口服液剂、混悬液、颗粒剂、粉剂、微粒剂、丸剂、微型片剂、速溶膜剂、鼻喷雾剂、透皮贴剂、注射剂或各种缓控释制剂等。所述药物组合物可以经口服、经粘膜、经直肠或肠胃外(包括血管内、静脉内、腹膜内、皮下、肌肉内和胸骨内)给药。给药剂量可根据患者的年龄、性别和疾病类型进行适当调整。
对于口服给药，所述药物组合物可呈例如片剂、胶囊、液体胶囊、悬浮液或液体形式。所述药物组合物优选以含有特定量活性成分的剂量单位形式制得。例如，所述药物组合物可以包含约0.1至1000mg，优选约0.25至250mg，且更优选约0.5至100mg范围内的量的活性成分的片剂或胶囊提供。用于人类或其它哺乳动物的适合日剂量可根据患者的病况及其它因素而广泛变化，但可使用常规方法确定。
在一个方面中，本发明提供了上述任一所述化合物、其药学上可接受的盐或其立体异构 体用于治疗疾病或症状的用途。所述疾病或症状包括：癫痫(包括癫痫发作，癫痫发作伴结节性硬化综合征，Dravet综合征，Lennox-Gastaut综合征，支原体癫痫发作，青少年支原体癫痫，顽固性癫痫)；痉挛(包括青少年痉挛，West综合征，顽固性小儿痉挛，小儿痉挛，半脸痉挛)；脑病(包括嗜睡，注意力/注意力集中问题和认知问题)；疼痛(包括神经根病和神经病，下背痛和纤维肌痛)；神经性疼痛；麻木和/或刺痛；焦虑和其它情绪障碍；高血压和自主功能障碍；帕金森氏病和震颤(包括原发性震颤)；失眠；贝氏麻痹和面神经功能障碍；青光眼；多发性硬化；癌症，包括脑瘤；创伤后应激障碍(PTSD)；三叉神经痛；自闭症/阿斯珀格氏病；注意力缺陷障碍和多动症；社会隔离；枕神经痛；TMJ功能障碍相关症状；认知问题(包括记忆障碍)；头痛，(包括偏头痛，紧张)；周围神经病；末梢神经病变；呼吸暂停，包括中枢性睡眠呼吸暂停，阻塞性睡眠呼吸暂停综合症和混合呼吸暂停；戒烟；关节炎，包括类风湿性关节炎；凹陷；呕吐；抗肥胖；恶心；酒精使用障碍；张力障碍；炎性肠综合征；与疱疹后神经痛相关的神经性疼痛；糖尿病性神经病变；带状疱疹；烧伤；光化性角化病；口腔溃疡；光化性角化病；口腔溃疡和溃疡上颅切开术后疼痛；银屑病；瘙痒接触性皮炎；湿疹；大疱性疱疹样皮炎；剥脱性皮炎；真菌病；天疱疮；严重的多形性红斑；脂溢性皮炎；强直性脊柱炎；银屑病关节炎；Reiter's综合症；痛风；软骨钙化病；关节疼痛；痛经；肌肉骨骼疼痛；肌炎；滑囊炎；上髁炎骨关节炎；滑膜炎；胰腺炎；对本领域技术人员而言显而易见的其他疾病状态和状况。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
本发明的某些化合物可以具有不对称碳原子(光学中心)或双键。外消旋体、非对映异构体、几何异构体和单个的异构体都包括在本发明的范围之内。
除非另有说明，用楔形键和虚线键
Figure PCTCN2022085086-appb-000023
表示一个立体中心的绝对构型，用
Figure PCTCN2022085086-appb-000024
表示一个立体中心的相对构型。当本文所述化合物含有烯属双键或其它几何不对称中心，除非另有规定，它们包括E、Z几何异构体。同样地，所有的互变异构形式均包括在本发明的范围之内。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物， 所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂或载体介质代表性的载体。
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
术语“活性成分”、“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。
除非另有规定，术语“烷基”用于表示直链或支链的饱和烃基,可以是单取代(如-CH 2F)或多取代的(如-CF 3)，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。烷基优选C 1-10的烷基，例如：C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10的。烷基的例子包括甲基(Me)，乙基(Et)，丙基(如，n-丙基和异丙基)，丁基(如，n-丁基，异丁基，s-丁基，t-丁基)，戊基(如，n-戊基，异戊基，新戊基，1-乙基丙基)，己基(如，n-己基，异己基、1，1-二甲基丁基、2，2-二甲基丁基、3，3-二甲基丁基和2-乙基丁基)，庚基，辛基，壬基，癸基等。
除非另有规定，术语“杂环”或“杂环基”意指稳定的含杂原子或杂原子团的单环、双环或三环，它们可以是饱和的、部分不饱和的或不饱和的(芳族的)，它们包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子，其中上述任意杂环可以稠合到一个苯环上形成双环。氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。该杂环可以附着到任何杂原子或碳原子的侧基上从而形成稳定的结构。如果产生的化合物是稳定的，本文所述的杂环可以发生碳位或氮位上的取代。杂环中的氮原子任选地被季铵化。一个优选方案是，当杂环中S及O原子的总数超过1时，这些杂原子彼此不相邻。另一个优选方案是，杂环中S及O原子的总数不超过1。如本文所用，术语“芳族杂环基团”或“杂芳基”意指稳定的5、6、7元单环或双环或7、8、9或10元双环杂环基的芳香环，它包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。值得注意的是，芳香杂环上S和O原子的总数不超过1。桥环也包含在杂环的定义中。当一个或多个原子(即C、O、N或S)连接两个不相邻的碳原子或氮原子时形成桥环。优选的桥环包括但不限于：一个碳原子、两个碳原子、一个氮原子、两个氮原子和一个碳-氮基。 值得注意的是，一个桥总是将单环转换成三环。桥环中，环上的取代基也可以出现在桥上。
杂环化合物的实例包括但不限于：氮杂环丁基、吖啶基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并巯基呋喃基、苯并巯基苯基、苯并噁唑基、苯并噁唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异噁唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、苯并二氢吡喃基、色烯、噌啉基十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、吲哚烯基、二氢吲哚基、中氮茚基、吲哚基、3H-吲哚基、异苯并呋喃基、异吲哚基、异二氢吲哚基、异喹啉基、异噻唑基、异噁唑基、亚甲二氧基苯基、吗啉基、萘啶基，八氢异喹啉基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噁唑烷基、噁唑基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪、吩噻嗪、苯并黄嘌呤基、酚噁嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶并噁唑、吡啶并咪唑、吡啶并噻唑、吡啶基、吡咯烷基、吡咯啉基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、四唑基，6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、异噻唑基噻吩基、噻吩并噁唑基、噻吩并噻唑基、噻吩并咪唑基、噻吩基、三嗪基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基和呫吨基。还包括稠环和螺环化合物。
除非另有规定，术语“芳基”表示多不饱和的芳族烃取代基，可以是单取代或多取代的，可以是一价、二价或者多价，它可以是单环或多环(比如1至3个环；其中至少一个环是芳族的)，它们稠合在一起或共价连接。术语“杂芳基”是指含有一至四个杂原子的芳基(或环)。在一个示范性实例中，杂原子选自B、N、O和S，其中氮和硫原子任选地被氧化，氮原子任选地被季铵化。杂芳基可通过杂原子连接到分子的其余部分。芳基或杂芳基的非限制性实施例包括苯基、萘基、4-联苯基、呋喃基、噁唑基、异噁唑基、噻吩基、噻唑基、噻二唑基、吡咯基、吡唑基、吡唑啉基、咪唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、吡喃基、三嗪基，喹啉基、四氢异喹啉基、异喹啉基、吲哚基、苯并噻吩基、苯并二氧杂环戊烯基、苯并噁唑基、苯并咪唑基、苯并吡喃基、吲嗪基、苯并呋喃基、香豆素基、噌啉基、喹喔啉基。芳基或杂芳基的非限制性实施例优选：苯基、1-萘基、2-萘基、4-联苯基、1-吡咯基、2-吡咯基、3-吡咯基、3-吡唑基、2-咪唑基、4-咪唑基、吡嗪基、2-噁唑基、4-噁唑基、2-苯基-4-噁唑基、5-噁唑基、3-异噁唑基、4-异噁唑基、5-异噁唑基、2-噻唑基、4-噻唑基、5-噻唑基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-苯并噻唑基、嘌呤基、2-苯并咪唑基、5-吲哚基、1-异喹啉基、5-异喹啉基、2-喹喔啉基、5-喹喔啉基、3-喹啉基和6-喹啉基。上述任意一个芳基和杂芳基环系的取代基选自下文所述的可接受的取代基。
化合物经手工或者
Figure PCTCN2022085086-appb-000025
软件命名，市售化合物采用供应商目录名称。
附图说明
图1-1、1-2、1-3、1-4：分别为化合物25马来酸盐晶型I的XRPD谱图、DSC谱图、TGA图、 1H NMR谱图
图2-1、2-2、2-3：分别为化合物25马来酸盐晶型II的XRPD谱图、DSC/TGA谱图、 1H NMR谱图
图3-1、3-2、3-3：分别为化合物25马来酸盐晶型III的XRPD谱图、DSC/TGA谱图、 1H NMR谱图
图4-1、4-2、4-3：分别为化合物25马来酸盐晶型IV的XRPD谱图、DSC/TGA谱图、 1H NMR谱图
图5-1、5-2、5-3、5-4：分别为化合物25富马酸盐的XRPD谱图、DSC谱图、TGA图、 1H NMR谱图
图6-1、6-2、6-3、6-4：分别为化合物25对甲苯磺酸盐的XRPD谱图、DSC谱图、TGA图、 1H NMR谱图
图7-1：化合物24和25盐酸盐在比格犬体内原形药物的药时曲线图
图7-2：化合物24和25盐酸盐在比格犬体内代谢产物CBD的药时曲线图
图7-3：化合物25马来酸盐和CBD在高油饮食和禁食模型比格犬体内CBD的药时曲线图
图8：前体药物在大鼠体内代谢产物CBD的药时曲线图
图9-1：化合物25马来酸盐晶型I吸湿性曲线图
图9-2：化合物25马来酸盐晶型I吸湿性实验前后XRPD谱图
图10-1：化合物25马来酸盐晶型I和晶型II室温竞争打浆实验XRPD谱图
图10-2：化合物25马来酸盐晶型I和晶型II高温竞争打浆实验XRPD谱图
图11：化合物25马来酸盐晶型I压片实验前后XRPD谱图
具体实施方式
合成方法I
Figure PCTCN2022085086-appb-000026
将CBD溶于溶剂中并加入碱性催化剂，室温搅拌反应。加入对硝基氯甲酸苯酯，室温反应。加水淬灭，然后用乙酸乙酯萃取，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩有机相，用柱层析分离，得片段1。
将片段1溶于溶剂，加入反应试剂，室温/加热反应。加水淬灭，然后用乙酸乙酯萃取，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩有机相，通过高效液相色谱分离。得式(II)产物(即R 1或R 2其中一个为OH的产物)。
任选地、将式(II)产物(即R 1或R 2其中一个为OH的产物)与碱性试剂溶于溶剂，滴加不同的反应试剂，冰浴后室温反应。加水淬灭，然后用乙酸乙酯萃取，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩有机相，通过高效液相色谱分离。得R 1和R 2结构不同的式(II)产物。
合成方法II
Figure PCTCN2022085086-appb-000027
将CBD溶于溶剂并加入碱性试剂，室温搅拌反应。加入对硝基氯甲酸苯酯，0℃反应。加水淬灭，然后用乙酸乙酯萃取，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩有机相，用柱层析分离，得片段2。
将片段2、反应试剂与碱性试剂溶于溶剂，加热回流反应过夜。加水淬灭，然后用乙酸乙酯萃取，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩有机相，通过高效液相色谱分离。得式(II)产物(即R 1或R 2均不为OH的产物)。
下面结合具体实施例和试验例，进一步阐述本发明，但不以任何形式限制本发明的范围。
实施例1：片段1的合成
Figure PCTCN2022085086-appb-000028
合成路线：
Figure PCTCN2022085086-appb-000029
将CBD(2.0g,6.4mmol,1eq)溶于60mL二氯甲烷并加入三乙胺(1.3g,12.8mmol,2.0eq)，室温搅拌反应0.5h。加入对硝基氯甲酸苯酯(1.54g,7.68mmol,1.2eq)，室温反应2h。加水淬灭，然后用乙酸乙酯萃取(50mL*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩有机相，用柱层析分离(石油醚：乙酸乙酯＝5:1)，得片段1(1.1g，油状物)，产率：33％。MS m/z(ESI)：480.4[M+1]。
实施例2：化合物13三氟乙酸盐的合成
Figure PCTCN2022085086-appb-000030
合成路线：
Figure PCTCN2022085086-appb-000031
将片段1(479mg,0.9mmol,1.0eq)溶于10mL二氯甲烷，加入乙二胺(108mg,1.8mmol,2.0eq)，室温反应3h。加水淬灭，然后用乙酸乙酯萃取(50mL*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩有机相，通过高效液相色谱(Waters autopurification HPLC-system C18 50*250mm Wavelength 254nm water(0.1％TFA)-MeCN(0.1％TFA))分离。得化合物13三氟乙酸盐(185mg，白色固体)，产率：40％。MS m/z(ESI)：401.3[M+1] +。 1H NMR(400MHz,DMSO-d 6):δ9.26(br,1H),8.13(br,2H),7.60(br,1H),6.45(s,1H),6.26(s,1H),5.01(s,1H),4.44(d,J＝5.2Hz,2H),3.60-3.75(m,1H),3.14-3.32(m,3H),2.86-2.89(m,2H),2.40(t,J＝8.0Hz,2H),2.20-2.40(m,1H),1.70-1.80(m,1H),1.45-1.60(m,9H),1.20-1.45(m,5H),0.86(t,J＝7.2Hz,3H).
实施例3：化合物17三氟乙酸盐的合成
Figure PCTCN2022085086-appb-000032
合成路线：
Figure PCTCN2022085086-appb-000033
将片段1(479mg,0.9mmol,1.0eq)溶于10mL二氯甲烷，加入二乙氨基乙醇(320mg,2.7mmol,3.0eq)，室温反应3h。加水淬灭，然后用乙酸乙酯萃取(50mL*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩有机相，通过高效液相色谱(Waters autopurification HPLC-system C18 50*250mm Wavelength 254nm water(0.1％TFA)-MeCN(0.1％TFA))分离。得化合物17三氟乙酸盐(56.6mg，白色固体)，产率：11％。MS m/z(ESI)：458.3[M+1] +。 1H NMR(400MHz,DMSO-d 6):δ10.0-10.50(br,1H),9.50(s,1H),6.50(s,1H),6.38(s,1H),5.04(s,1H),4.30-4.50(m,3H),3.60-3.80(m,1H),3.06-3.30(m,5H),2.56-2.60(m,1H),2.35-2.48(m,2H),2.05-2.20(m,1H),1.81-2.00(m,1H),1.48-1.75(m,9H),1.30-1.70(m,10H),0.75-0.80(m,3H).
实施例4：化合物18三氟乙酸盐的合成
Figure PCTCN2022085086-appb-000034
合成路线：
Figure PCTCN2022085086-appb-000035
将片段1(2.0g,4.0mmol,1eq)溶于60mL二氯甲烷，加入2-吗啉乙醇(2.6g,20.0mmol,5.0eq)，加热回流反应过夜。加水淬灭，然后用乙酸乙酯萃取(50mL*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩有机相，通过高效液相色谱(Waters autopurification HPLC-system C18 50*250mm Wavelength 254nm water(0.1％TFA)-MeCN(0.1％TFA))分离。得化合物18三氟乙酸盐(211mg，油状物)，产率：9％。MS m/z(ESI)：472.3[M+1] +。 1H NMR(400MHz,DMSO-d 6):δ9.42(s,1H),6.50(s,1H),6.35(s,1H),5.07(s,1H),4.45(s,2H),4.26-4.34(m,1H),4.14-4.20(m,1H),3.70-3.90(m,1H),3.60(t,J＝6.0Hz,4H),2.60-2.75(m,3H),2.41-2.50(m,6H),2.05-2.25(m,1H),1.90-2.00(m,1H),1.49-1.75(m,10H),1.30-1.45(m,5H),0.89(t,J＝8.8Hz,3H).
实施例5：化合物19三氟乙酸盐的合成
Figure PCTCN2022085086-appb-000036
合成路线：
Figure PCTCN2022085086-appb-000037
将片段1(450mg,0.94mmol,1eq)溶于10mL二氯甲烷，加入N,N-二乙基乙二胺(210mg,1.9mmol,2.0eq)，室温反应2h。加水淬灭，然后用乙酸乙酯萃取(50mL*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩有机相，通过高效液相色谱(Waters autopurification HPLC-system C18 50*250mm Wavelength 254nm water(0.1％TFA)-MeCN(0.1％TFA))分离。得化合物19三氟乙酸盐(236mg，白色固体)，产率：44％。MS m/z(ESI)：457.3[M+1] +。 1H NMR(400MHz,DMSO-d 6):δ9.34(br,1H),9.23(s,1H),7.60(br,1H),6.43(s,1H),6.22(s,1H),5.03(s,1H),4.44(d,J＝5.2Hz,2H),3.60-3.75(m,1H),3.14-3.32(m,6H),2.60-2.80(m, 1H),2.40(t,J＝8.0Hz,2H),2.20-2.40(m,1H),1.70-1.80(m,1H),1.45-1.60(m,10H),1.20-1.45(m,10H),0.86(t,J＝7.2Hz,3H).
实施例6：化合物21三氟乙酸盐的合成
Figure PCTCN2022085086-appb-000038
合成路线：
Figure PCTCN2022085086-appb-000039
将片段1(450mg,0.94mmol,1eq)溶于10mL二氯甲烷，加入2-吗啉乙胺(227mg,1.9mmol,2.0eq)，室温反应2h。加水淬灭，然后用乙酸乙酯萃取(50mL*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩有机相，通过高效液相色谱(Waters autopurification HPLC-system C18 50*250mm Wavelength 254nm water(0.1％TFA)-MeCN(0.1％TFA))分离。得化合物21三氟乙酸盐(242mg，白色固体)，产率：44％。MS m/z(ESI)：471.3[M+1] +。 1H NMR(400MHz,DMSO-d 6):δ9.95(br,1H),9.22(s,1H),7.58(br,1H),6.43(s,1H),6.25(s,1H),5.02(s,1H),4.43(d,J＝5.2Hz,2H),3.00-4.02(m,14H),2.70-2.83(br,1H),2.40(t,J＝8.0Hz,2H),2.10-2.28(m,1H),1.78-1.90(m,1H),1.45-1.60(m,10H),1.45-1.75(m,10H),1.25-1.40(m,5H),0.86(t,J＝7.2Hz,3H).
实施例7：化合物24三氟乙酸盐的合成
Figure PCTCN2022085086-appb-000040
合成路线：
Figure PCTCN2022085086-appb-000041
将化合物18(320mg,0.67mmol,1eq)游离态与三乙胺(130mg,1.3mmol,2eq)溶于5mL二氯甲烷，滴加乙酰氯(130mg,1.3mmol,2.0eq)，冰浴，室温反应3h。加水淬灭，然后用乙酸乙酯萃取(50mL*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩有机相，通 过高效液相色谱(Waters autopurification HPLC-system C18 50*250mm Wavelength 254nm water(0.1％TFA)-MeCN(0.1％TFA))分离。得化合物24三氟乙酸盐(260mg，蜡状体)，产率：62％。MS m/z(ESI)：514.3[M+1] +。 1H NMR(400MHz,DMSO-d 6):δ6.88(s,1H),6.80(s,1H),5.22(s,1H),4.72-4.80(m,1H),4.60(s,1H),4.50(m,1H),4.03(t,J＝6.0Hz,4H),3.58-3.62(m,1H),3.35-3.41(m,2H),3.05-3.35(m,3H),2.58-2.80(m,3H),1.95-2.35(m,12H),1.75-1.95(m,3H),1.72(s,3H),1.38-1.42(m,6H),0.95(t,J＝7.6Hz,3H).
实施例8：片段2的合成
Figure PCTCN2022085086-appb-000042
合成路线：
Figure PCTCN2022085086-appb-000043
将CBD(2.0g,6.4mmol,1eq)溶于60mL二氯甲烷并加入三乙胺(1.3g,12.8mmol,2.0eq)，室温搅拌反应0.5h。加入对硝基氯甲酸苯酯(5.1g,25.5mmol,4eq)，0℃反应2h。加水淬灭，然后用乙酸乙酯萃取(50mL*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩有机相，用柱层析分离(石油醚：乙酸乙酯＝10:1)，得片段2(3.2g，油状物)，产率：78％。MS m/z(ESI)：645.2[M+1]。
实施例9：化合物25三氟乙酸盐的合成
Figure PCTCN2022085086-appb-000044
合成路线：
Figure PCTCN2022085086-appb-000045
将片段2(1.0g,1.6mmol,1.0eq)、2-吗啉乙醇(2.0g,16.0mmol,10eq)与三乙胺(9.39g,9.30mmol,6eq)溶于30mL二氯甲烷，加热回流反应过夜。加水淬灭，然后用乙酸乙酯萃取(50mL*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩有机相，通过高效液相色谱(Waters autopurification HPLC-system C18 50*250mm Wavelength 254nm water(0.1％TFA)-MeCN(0.1％TFA))分离。得化合物25三氟乙酸盐(850mg，蜡状体)，产率：62％。MS m/z(ESI)：629.2[M+1] +。 1H NMR(400MHz,DMSO-d 6):δ7.00(s,2H),5.02(s,1H),4.53-4.60(m,2H),4.40-4.53(m,3H),4.34(s,1H),3.60-4.02(br,9H),3.10-3.52(br,8H),2.55(t,J＝8.0Hz,3H),2.05-2.30(m,1H),1.90-2.00(m,1H),1.50-1.65(m,10H),1.20-1.30(m,5H),0.86(t,J＝6.8Hz,3H).
实施例10：片段3的合成
Figure PCTCN2022085086-appb-000046
合成路线：
Figure PCTCN2022085086-appb-000047
将CBD(0.80g,2.50mmol,1eq)溶于8mL四氢呋喃，加入氢化钠(0.091g,3.80mmol,1.5eq)，0℃搅拌反应0.5h。加入碘甲烷(0.43g,3.0mmol,1.2eq)，0℃反应2h。加水淬灭，然后用乙酸乙酯萃取(50mL*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩有机相，用柱层析分离(石油醚：乙酸乙酯＝10:1)，得片段3(0.13g，油状物)，产率：15％。
实施例11：化合物26三氟乙酸盐的合成
Figure PCTCN2022085086-appb-000048
合成路线：
Figure PCTCN2022085086-appb-000049
将3-(4-吗啉基)丙酸(74.5mg,0.46mmol,1.2eq),EDCI(113g,0.59mmol,1.5eq)与DMAP(60mg,0.46mmol,1.2eq)溶于10mL二氯甲烷中，室温反应0.5h。加入片段3(130mg,0.39mmol,1.0eq)室温搅拌反应3h。加水淬灭，然后用乙酸乙酯萃取(50mL*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩有机相，通过高效液相色谱(Waters autopurification HPLC-system C18 50*250mm Wavelength 254nm water(0.1％TFA)-MeCN(0.1％TFA))分离。得化合物26三氟乙酸盐(75mg，蜡状体)，产率：33％。MS m/z(ESI)：470.3[M+1] +。 1H NMR(400MHz,DMSO_d 6):δ10.12(br,1H),6.68(s,1H),6.45(s,1H),5.0(s,1H),4.35-4.42(m,2H),3.05-3.99(m,11H),1.94-2.19(m,2H),1.50-1.69(m,9H),1.24-1.32(m,5H),0.85(t,J＝9Hz,3H).
实施例12：化合物24的合成
Figure PCTCN2022085086-appb-000050
合成路线：
Figure PCTCN2022085086-appb-000051
将化合物24三氟乙酸盐(628mg,1mmol,1.0eq)溶于10mL水中，滴加饱和碳酸氢钠溶液，调pH＝9，室温搅拌1h。用乙酸乙酯萃取(50mL*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩有机相。得化合物24(488mg，油状物)，产率：95％。MS m/z(ESI)：514.3[M+1] +。 1H NMR(600MHz,CDCl 3-d):δ6.80(s,1H),6.73(s,1H),5.20(s,1H),4.54(s,1H),4.45(s,1H),4.35–4.43(m,1H),4.20–4.33(m,1H),3.68–3.80(m,4H),3.52–3.65(m,1H),2.63–2.77(m,3H),2.46–2.62(m,6H),2.13–2.33(m,4H),1.96–2.05(m,1H),1.76–1.83(m,1H), 1.69–1.76(m,1H),1.67(s,3H),1.57–1.63(m,5H),1.28–1.35(m,4H),0.82–0.96(t,J＝7.6Hz,3H).
实施例13：化合物24盐酸盐的合成
Figure PCTCN2022085086-appb-000052
合成路线：
Figure PCTCN2022085086-appb-000053
将化合物24(514mg,1mmol,1.0eq)溶于10mL乙酸乙酯中，滴加盐酸二氧六环溶液(4N)，调pH＝3，室温搅拌2h。将反应液减压浓缩。得化合物24盐酸盐(550mg，白色固体)，产率：100％。MS m/z(ESI)：514.3[M+1] +。
实施例14：化合物25的合成
Figure PCTCN2022085086-appb-000054
合成路线：
Figure PCTCN2022085086-appb-000055
将化合物25三氟乙酸盐(857mg,1mmol,1.0eq)溶于10mL水中，滴加饱和碳酸氢钠溶液，调pH＝9，室温搅拌1h。用乙酸乙酯萃取(50mL*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩有机相。得化合物25(604mg，白色固体)，产率：96％。MS m/z(ESI)：629.4[M+1] +。 1H NMR(600MHz,CDCl 3-d):δ6.82(s,2H),5.20(s,1H),4.53(s,1H),4.44(s,1H),4.36–4.43(m,2H),4.19–4.32(m,2H),3.69–3.79(m,8H),3.60–3.66(m,1H),2.65–2.76(m, 5H),2.46–2.63(m,10H),2.13–2.27(m,1H),1.95–2.02(m,1H),1.74–1.83(m,1H),1.67–1.73(m,1H),1.64–1.67(m,3H),1.57–1.63(m,5H),1.27–1.36(m,4H),0.84–0.93(t,J＝7.0Hz,3H).
实施例15：化合物25盐酸盐的合成
Figure PCTCN2022085086-appb-000056
合成路线：
Figure PCTCN2022085086-appb-000057
将化合物25(629mg,1mmol,1.0eq)溶于10mL乙酸乙酯中，滴加盐酸二氧六环溶液(4N)，调pH＝3，析出固体，室温搅拌2h。过滤，用乙酸乙酯(5mL*3)洗涤滤饼，收集滤饼并干燥。得化合物25盐酸盐(491mg，白色固体)，产率：70％。MS m/z(ESI)：629.4[M+1] +。
实施例16：化合物25马来酸盐晶型I的制备和表征
Figure PCTCN2022085086-appb-000058
1.1化合物25马来酸盐晶型I的制备
(1)称取505.03mg化合物25，加入5.0mL丙酮(10vol)，在20℃下搅拌5min，完全溶清。
(2)称取190.45mg马来酸(2.0eq)加入5.0mL丙酮(10vol)，搅拌30min，完全溶清。
(3)将步骤(2)的马来酸溶液滴加入步骤(1)的化合物25溶液中(5min内滴加完毕)，搅拌24h，无固体析出。
(4)加入5.0mL甲基叔丁基醚(10min内滴加完毕)，搅拌24h内析出，继续搅拌24h，过滤，真空干燥(40℃)4天后，得到339.56mg化合物25马来酸盐晶型I。
1.2化合物25马来酸盐晶型I的表征
1.2.1粉末X-射线衍射(XRPD)
X射线衍射图由布鲁克仪器的D2Phaser型采集获得，仪器参数见表1-1。XRPD图谱见图1-1，图谱解析数据见表1-2。
表1-1 XRPD仪器参数
Figure PCTCN2022085086-appb-000059
表1-2 化合物25马来酸盐晶型I的XRPD图谱解析数据
Figure PCTCN2022085086-appb-000060
1.2.2差示扫描量热分析(DSC)
方法：DSC曲线由梅特勒仪器的DSC3型采集获得。称取样品至样品盘中，精密称定，记录重量，以10℃/min的升温速率从30℃升温至350℃。氮气流速率为50mL/min。实验过程中坩埚处于密封状态。
试验结果见图1-2，结果表明化合物25马来酸盐晶型I在115.03℃处有吸热峰。
1.2.3热重分析(TGA)
TGA曲线由耐驰TG209F3采集获得。称取样品至样品盘(Al 2O 3)中，精密称定，记录重量。以20℃/min的升温速率从40℃升温至350℃。氮气流速率为70mL/min。
试验结果见图1-3，结果表明化合物25马来酸盐晶型I在吸热峰温度范围内失重0.2％。
1.2.4  1H NMR
核磁结果由瓦里安(Varian)400MHz型采集获得，使用氘代溶剂为DMSO。
试验结果见图1-4，结果显示化合物25马来酸盐晶型I无溶剂残留，为无水晶型，马来酸与游离碱摩尔比为2.0:1.0。
实施例17：化合物25马来酸盐晶型II的制备和表征
1.1制备方法
称取约90mg化合物25马来酸盐晶型I，50℃加入1.8mL乙酸异丙酯，再加入丙酮0.8mL，过滤。将滤液转至-10℃持续搅拌1天后过滤，所得固体于50℃真空干燥4小时，即得化合物25马来酸盐晶型II。
1.2表征方法：
1.2.1 XPRD和 1HNMR：与实施例16的表征方法相同。
1.2.2 TGA
TGA曲线由TA仪器的TGA550采集获得。称取样品至样品盘(Al 2O 3)中，以10℃/min的升温速率升温至300℃。
1.2.3 DSC
DSC曲线由TA仪器的DSC250型采集获得。称取样品至样品盘中，精密称定，记录重量。以10℃/min的升温速率从25℃升温至300℃。
1.3试验结果
1.3.1 XPRD
XPRD图谱见图2-1，图谱解析数据见表2。
表2 化合物25马来酸盐晶型II的XRPD图谱解析数据
序号 2θ±0.2(°) 相对强度(％) 序号 2θ±0.2(°) 相对强度(％)
1 7.868 100.0 7 14.239 34.7
2 8.892 44.4 8 15.898 35.9
3 9.111 47.2 9 16.632 31.9
4 9.760 42.9 10 18.061 55.7
5 10.713 33.6 11 18.535 92.8
6 12.122 98.6      
1.3.2 DSC/TGA/ 1H NMR
DSC结果表明，化合物25马来酸盐晶型II在76.47℃处有一处吸热峰；TGA结果表明，化合物25马来酸盐晶型II在熔点范围内无失重； 1H NMR结果表明，化合物25马来酸盐晶 型II为无水晶型，马来酸与游离碱摩尔比为2.0:1.0。DSC/TGA谱图见图2-2， 1H NMR谱图见图2-3。
实施例18：化合物25马来酸盐晶型III的制备和表征
1.1制备方法
称取约1g化合物25马来酸盐晶型I，用4mL乙腈以及40mL水将原料溶解，干冰冷冻后冻干，得到化合物25马来酸盐无定形。称取30.64mg化合物25马来酸盐无定形于样品瓶中，加入0.2mL异丙醇，约15℃搅拌3天，即得化合物25马来酸盐晶型III。
1.2表征方法：XPRD、TGA/DSC和 1HNMR的表征方法与实施例17的方法相同。
1.3试验结果
1.3.1 XPRD
XRPD图谱见图3-1，图谱解析数据见表3。
化合物25马来酸盐晶型III，使用Cu-Kα辐射的X射线粉末衍射图如图3-1所示。
表3 化合物25马来酸盐晶型III的XRPD图谱解析数据
序号 2θ±0.2(°) 相对强度(％) 序号 2θ±0.2(°) 相对强度(％)
1 6.241 16.6％ 11 19.581 42.1％
2 7.384 4.1％ 12 20.385 12.5％
3 8.730 23.5％ 13 21.894 9.6％
4 10.010 17.7％ 14 22.400 13.8％
5 12.578 44.8％ 15 23.836 28.0％
6 15.303 11.1％ 16 26.001 7.4％
7 15.928 49.5％ 17 26.435 16.2％
8 17.219 11.1％ 18 26.564 19.8％
9 17.679 100.0％ 19 27.674 9.1％
10 19.254 19.5％ 20 28.164 10.5％
1.3.2 DSC/TGA/ 1H NMR
DSC结果表明化合物25马来酸盐晶型III在115.31℃处有一处吸热峰，为该晶型熔点；TGA结果表明化合物25马来酸盐晶型III在熔点范围内无失重， 1H NMR结果表明化合物25马来酸盐晶型III为无水晶型，马来酸与游离碱摩尔比为2.0:1.0。DSC/TGA谱图见图3-2，1H NMR谱图见图3-3。
实施例19：化合物25马来酸盐晶型IV的制备和表征
1.1制备方法
称取约1g化合物25马来酸盐晶型I，用4mL乙腈以及40mL水将原料溶解，干冰冷冻后冻干，得到化合物25马来酸盐无定形。称取约30mg化合物25马来酸盐无定形于样品瓶中，加入0.1mL乙腈-甲基叔丁基醚(1:8)，约15℃搅拌3天，即得化合物25马来酸盐晶型IV。
1.2表征方法：XPRD、TGA/DSC和 1HNMR的表征方法与实施例17的方法相同。
1.3试验结果
1.3.1 XPRD
XRPD图谱见图4-1，图谱解析数据见表4。
表4 化合物25马来酸盐晶型IV的XRPD图谱解析数据
序号 2θ±0.2(°) 相对强度(％) 序号 2θ±0.2(°) 相对强度(％)
1 8.004 100 9 16.137 70.6
2 9.600 27.1 10 17.008 30.7
3 10.575 37.6 11 18.177 20.4
4 11.105 12.1 12 19.061 19.2
5 12.151 34.6 13 21.307 26.9
6 13.523 18.8 14 22.366 45.2
7 14.327 13.3 15 23.296 31.9
8 15.182 24.3 16 24.308 55.2
1.3.2 DSC/TGA/ 1H NMR
1H NMR谱图可见0.8％(0.18mol)的乙腈和1.6％甲基叔丁基醚残留；DSC结果表明化合物25马来酸盐晶型IV在125℃前可见两处吸热峰；TGA结果表明化合物25马来酸盐晶型IV在125℃前有3.2％的失重，加热至100℃后，转变为无定形。DSC/TGA图谱见4-2， 1H NMR图谱见4-3。
实施例20：化合物25富马酸盐晶型的制备和表征
1.1制备方法
(1)称取504.59mg化合物25，加入5.0mL乙腈(10vol)，在20℃下搅拌5min，完全溶清。
(2)称取187.45mg富马酸(2.0eq)加入5.0mL丙酮(10vol)，搅拌30min，完全溶清。
(3)将富马酸溶液滴加入原料溶液中(5min内滴加完毕)，搅拌24h，有固体析出。
(4)继续搅拌24h，过滤，真空干燥(40℃4天、50℃2天)后，得到560.28mg化合物25富马酸盐晶型。
1.2表征方法：XPRD、TGA/DSC和 1HNMR的表征方法与实施例16的表征方法相同。
1.3试验结果
1.3.1 XPRD
XRPD图谱见图5-1，图谱解析数据见表5。
化合物25富马酸盐晶型，使用Cu-Kα辐射的X射线粉末衍射图如图5-1所示。
表5 化合物25富马酸盐晶型的XRPD图谱解析数据
序号 2θ±0.2(°) 相对强度(％) 序号 2θ±0.2(°) 相对强度(％)
1 6.397 18.7 19 19.373 43.4
2 7.692 99.1 20 19.804 33.8
3 8.305 77.8 21 20.344 70.4
4 8.602 48.6 22 20.582 35.1
5 9.044 27.4 23 21.185 49.5
6 9.841 9.5 24 21.620 36.2
7 10.407 57.9 25 22.187 93.6
8 11.764 27.2 26 22.574 22.1
9 12.312 47.1 27 23.210 58.2
10 12.829 39.8 28 23.688 54.8
11 13.479 32.3 29 24.157 36.1
12 13.784 35.5 30 24.916 47.3
13 14.467 50.0 31 26.319 14.2
14 15.332 32.9 32 30.760 16.0
15 16.681 17.8 33 31.457 19.1
16 17.377 73.5 34 31.933 12.3
17 18.340 52.4 35 35.543 9.0
18 18.680 100.0      
1.3.2 DSC/TGA/ 1H NMR
DSC结果表明，化合物25富马酸盐晶型在91.76℃处有吸热峰；TGA结果表明化合物25富马酸盐晶型在120℃前无失重； 1H NMR结果表明化合物25富马酸盐晶型无溶剂残留，为无水晶型，富马酸与游离碱摩尔比为2.0:1.0。DSC/TGA/ 1H NMR谱图分别见图5-2，图5-3，图5-4。
实施例21：化合物25对甲苯磺酸盐晶型的制备和表征
1.1制备方法
(1)称取500.80mg化合物25，加入5.0mL丙酮(10vol)，在20℃下搅拌5min，完全溶清。
(2)称取307.70mg对甲苯磺酸(2.0eq)加入5.0mL丙酮(10vol)，搅拌30min，完全溶清。
(3)将对甲苯磺酸溶液滴加入原料溶液中(5min内滴加完毕)，搅拌24h，无固体析出。
(4)加入5.0mL甲基叔丁基醚(10min内滴加完毕)，搅拌24h内析出，继续搅拌24h，过滤，真空干燥(40℃)4天后，得到533.47mg化合物25对甲苯磺酸盐晶型。
1.2表征方法：XPRD、TGA/DSC和 1HNMR的表征方法与实施例16的表征方法相同。
1.3试验结果
1.3.1 XPRD
XRPD图谱见图6-1，图谱解析数据见表6。
表6 化合物25对甲苯磺酸盐晶型的XRPD图谱解析数据
序号 2θ±0.2(°) 相对强度(％) 序号 2θ±0.2(°) 相对强度(％)
1 5.768 100.0 11 19.620 5.6
2 8.367 24.3 12 20.082 3.8
3 11.406 21.7 13 20.904 2.6
4 12.430 2.0 14 21.639 1.8
5 13.413 2.3 15 21.819 1.8
6 13.705 4.7 16 22.183 2.7
7 16.139 1.8 17 23.035 10.4
8 16.866 6.2 18 25.069 2.8
9 17.183 9.7 19 26.606 3.1
10 18.708 2.1 20 31.640 1.3
1.3.2 DSC/TGA/ 1H NMR
DSC结果表明，化合物25对甲苯磺酸盐晶型在148.41℃处有吸热峰；TGA结果表明，化合物25对甲苯磺酸盐晶型在200℃前有0.6％的失重； 1H NMR结果显示，化合物25对甲苯磺酸盐晶型无溶剂残留，对甲苯磺酸与游离碱摩尔比为2.0:1.0。DSC/TGA/ 1H NMR谱图分别见图6-2，图6-3，图6-4。
实施例22：化合物27盐酸盐的合成
Figure PCTCN2022085086-appb-000061
合成路线：
Figure PCTCN2022085086-appb-000062
将2-溴乙醇(10g，80mmol)溶解在装有乙醇(140mL)的500mL烧瓶中，在氩气下室温搅拌缓慢滴加二乙胺(29g,400mmol),反应在60℃下加热搅拌6h，反应液冷却后加入DCM(300mL)，混合物通过5％的NaHCO 3溶液(3×100mL)，水(50mL)洗涤，分离有机相，无水硫酸钠干燥，过滤，浓缩后得到二乙胺基乙醇，无色油状物600mg，收率9.5％。MS(m/z):118[M+H] +。
将大麻二酚(5g，16mmol)溶解在100mL干燥二氯甲烷里，0℃下依次加入三光气(4.76g，16mmol)和N，N-二异丙基乙胺(4.12g，32mmol)，反应在0℃下搅拌2h，继续加入2-二乙胺基乙醇(3.74g，32mmol)和N,N-二异丙基乙胺(4.12g，32mmol)，反应在0℃下搅拌4h反应完全后用二氯甲烷/水萃取，有机相浓缩后经过四次正相柱纯化(生物素，Agela 120g，二氯甲烷/乙酸乙酯：10％～80％)得到无色油状物2.4g，将无色油状物溶解在40ml二氯甲烷中，滴加2mL盐酸/二氧(4M)六环溶液，室温搅拌两小时后，浓缩至少量溶剂，加入100mL乙酸乙酯，剧烈搅拌出现白色固体，抽滤真空干燥后得到化合物27盐酸盐(2.1g，白色固体)，收率22％。MS(m/z)：602[M+2H] +。 1H NMR(400MHz，Chloroform-d):δ12.88(s，2H)，6.85(s，2H)，5.15(s，1H)，4.78(dd，J＝11.8，6.6Hz，4H)，4.52(s，1H)，4.40(s，1H)，3.55(d，J＝10.4Hz，1H)，3.37(q，J＝4.8Hz，4H)，3.20(q，J＝6.6Hz，8H)，2.66～2.54(m，3H)，2.13(d，J＝13.3Hz，1H)，2.03(s，1H)，1.77(s，1H)，1.66(s，3H)，1.63(s，6H)，1.44(t，J＝7.2Hz，12H)，1.35-1.29(m，4H)，0.89(t，J＝6.6Hz，3H)。
试验例1：前药化合物比格犬体内的药代动力学试验
1.前药化合物在禁食模型比格犬体内的药代动力学试验
体重10公斤左右的比格犬随机分组，每组三只，给药前12h禁食，自由饮水，按32μmol/kg剂量将化合物24盐酸盐水溶液、化合物25盐酸盐水溶液、化合物27盐酸盐水溶液和CBD芝麻油溶液(1mL溶媒含79mg乙醇，736mg芝麻油)进行灌胃给药，分别于给药前及给药后0.25、0.5、1、2、3、4、6、8、12、24小时采血，血液置于肝素化的EP管中，离心分离血浆，血浆经前处理后用LC-MS/MS分别检测血浆中活性代谢物CBD以及各前体药 物的浓度。
表7-1、图7-1和图7-2为比格犬口服给予化合物24盐酸盐、化合物25盐酸盐及CBD后前药原形化合物和/或CBD的药代参数和药时曲线图。结果显示，化合物24盐酸盐和化合物25盐酸盐经胃肠道进入比格犬体内后，大多被代谢为CBD。以CBD给药组为参比，化合物24和化合物25代谢产物CBD的相对生物利用度分别为364.7％和307.5％。
表7-1 化合物24/化合物25及CBD犬体内主要药代参数
Figure PCTCN2022085086-appb-000063
*与CBD相比的相对生物利用度
表7-2为比格犬口服给予化合物27盐酸盐或CBD后前药原形化合物和/或CBD的主要药代参数。结果显示，前体药物化合物27盐酸盐经胃肠道进入比格犬体内后，大多被代谢为CBD。以CBD给药组为参比，化合物27代谢产物CBD的相对生物利用度为113.2％。
对比表7-1和7-2可知，以CBD给药组为参比，化合物24、化合物25体内代谢产物CBD的暴露量(AUC)可提高至3倍多，而化合物27与CBD的暴露量(AUC)相当。
表7-2 化合物27及CBD犬体内主要药代参数
Figure PCTCN2022085086-appb-000064
*与CBD相比的相对生物利用度
2.前药化合物在高油饮食模型比格犬体内的药代动力学试验
通过给药后冲服芝麻油模拟高脂饮食，考察高脂饮食对比格犬体内CBD生物利用度的影响。16条体重为10kg左右的Beagle犬随机分为4组，每组4只，给药剂量为32μmol/kg，给药前12h禁食，自由饮水。组1、组2灌胃给予化合物25马来酸盐水溶液，给药体积为3ml/kg，给药后组1用8ml水冲服，组2用8ml芝麻油冲服。组3灌胃给予CBD芝麻油溶液(1mL溶媒含79mg乙醇，736mg芝麻油)，给药体积为0.2ml/kg，给药后用6ml芝麻油及30ml水冲服。组4将CBD芝麻油溶液(1mL溶媒含79mg乙醇，736mg芝麻油)灌进速释胶囊中灌胃给药(约1ml芝麻油)，给药后用38ml水冲服。分别于给药前及给药后0.25、0.5、1、2、3、4、6、8、12、24小时采血，血液置于肝素化的EP管中，离心分离血浆，血浆经前处理后用LC-MS/MS法测定血浆中化合物25及CBD的浓度。试验结果见图7-3和表7-3。
试验结果表明：化合物25马来酸盐在Beagle犬体内大多被代谢为CBD。在禁食组中， 化合物25马来酸盐(组1)生成的活性代谢产物CBD的暴露量是CBD组(组4)的2.2倍。对比禁食组和高脂饮食组，化合物25马来酸盐给予高油后(组2)生成的CBD暴露量和C max与正常组(组1)相当；而CBD给予高油后(组3)的暴露量和C max均是正常组(组4)的4.8倍。即高脂饮食对化合物25马来酸盐暴露量和C max的影响远小于CBD。
表7-3 化合物25马来酸盐及CBD犬体内主要药代参数
Figure PCTCN2022085086-appb-000065
*与CBD相比的相对生物利用度
试验例2：前药化合物在禁食模型大鼠体内的药代动力学试验
体重为200克左右的SD大鼠随机分组，每组四只，给药剂量47.7μmol/kg，给药前12h禁食，自由饮水，每组分别灌胃给药，试验化合物分别配制为20％Solutol HS 15水溶液(含5％无水乙醇)，分别于给药前及给药后0.25、0.5、1、2、3、4、6、8、12、24小时的时间采血，血液置于肝素化的EP管中，离心分离血浆，血浆经前处理后用LC-MS/MS分别检测血浆中活性代谢物CBD以及各前体药物的浓度。
表8-1和图8为大鼠灌胃给予化合物24盐酸盐和化合物25盐酸盐后代谢产物CBD的药代参数和药时曲线图。结果显示：化合物24盐酸盐和化合物25盐酸盐经胃肠道进入大鼠体内后立即代谢为活性代谢物CBD，原形化合物的浓度很低，低于检测的定量下限水平，前体药物经口服基本全部转化为活性代谢物CBD。而化合物26三氟乙酸盐灌胃给药后，既未检测到前药，也未检测到CBD。
表8-1 化合物24盐酸盐和化合物25盐酸盐代谢产物CBD的药代参数
Figure PCTCN2022085086-appb-000066
表8-2和8-3为大鼠灌胃给予化合物13/化合物19/化合物21三氟乙酸盐后前药原形药物及代谢产物CBD的药代参数和药时曲线图。结果表明，氨基甲酸酯类化合物体内代谢产物CBD的暴露量低于或相当于直接灌胃给药CBD。
表8-2 化合物13三氟乙酸盐及CBD大鼠体内药代参数
Figure PCTCN2022085086-appb-000067
*与CBD相比的相对生物利用度
表8-3 化合物19/化合物21三氟乙酸盐及CBD大鼠体内药代参数
Figure PCTCN2022085086-appb-000068
*与CBD相比的相对生物利用度
表8-4为大鼠灌胃给予化合物17/化合物18三氟乙酸盐后代谢产物CBD的药代参数，未检测到化合物17和化合物18原形化合物。结果表明，含有吗啉环的碳酸酯类化合物体内代谢产物CBD具有更高的暴露量。
表8-4 化合物17/化合物18三氟乙酸盐及CBD大鼠体内药代参数
Figure PCTCN2022085086-appb-000069
试验例3：化合物25不同盐稳定性研究
1.试验方法
称取10～15mg化合物25的马来酸盐晶型I(实施例16)、富马酸盐晶型(实施例20)、对甲苯磺酸盐晶型(实施例21)分别敞口放置在稳定性箱中，分别在第5天和第10天取固体进行XRPD和HPLC分析检测。
XRPD方法与实施例16相同，HPLC方法见表9-1。
表9-1 HPLC分析方法
Figure PCTCN2022085086-appb-000070
2.试验结果
结果显示化合物25的马来酸盐晶型I在试验条件下具有良好的物理和化学稳定性，而富马酸盐和对甲苯磺酸盐在高温高湿条件下晶型会发生变化，纯度有所降低。具体见表9-2和表9-3。
表9-2 不同盐型第5天稳定性试验结果
Figure PCTCN2022085086-appb-000071
表9-3 不同盐型第10天稳定性试验结果
Figure PCTCN2022085086-appb-000072
试验例4：化合物25马来酸盐晶型I吸湿性研究
1.试验方法
干燥过程：40℃/0％RH条件下稳定约1.5h，直至dm/dt小于0.002％。
测试过程：降温至25℃后，dm/dt小于0.002％后开始测量。
时间模式25℃测样，0％-90％-0％RH，10％梯度，每个梯度停留1h。
2.试验结果
试验结果见图9-1和图9-2，结果显示化合物25马来酸盐晶型I在90％RH湿度下水分增加0.1251％，无或几乎无引湿性。化合物25马来酸盐晶型I在引湿实验(DVS)前后晶型未发生变化。
试验例5：化合物25马来酸盐晶型竞争打浆试验
1.试验方法
分别配制表10溶剂中化合物25马来酸盐无定形的饱和溶液，再将化合物25马来酸盐晶型I和晶型II以1:1的质量比加入到各饱和药液中，在室温(约17℃)或50℃搅拌3天，所得固体均为化合物25马来酸盐晶型I，结果表明晶型I比晶型II更为稳定。
具体试验条件及结果见表10。XRPD结果见图10-1和图10-2。
表10 竞争打浆实验条件及结果
编号 溶剂 晶型I(mg) 晶型II(mg) 温度 结果
1 正庚烷，0.5mL 8.63 8.62 室温 晶型I
2 甲苯，0.6mL 6.02 6.05 室温 晶型I
3 乙酸乙酯，0.6mL 6.14 6.16 室温 晶型I
4 异丙醇，0.6mL 6.54 6.57 室温 晶型I
5 正庚烷，0.5mL 8.63 8.62 50℃ 晶型I
6 甲苯，0.6mL 6.02 6.05 50℃ 晶型I
7 乙酸乙酯，0.6mL 6.14 6.16 50℃ 晶型I
8 异丙醇，0.6mL 6.54 6.57 50℃ 晶型I
试验例6：化合物25马来酸盐晶型I压片试验
称取约15mg化合物25马来酸盐晶型I，30MPa下压片后，轻轻研磨成粉末，进行XRPD测试，试验结果见图11。结果表明，化合物25马来酸盐晶型I经压片后，晶型未发生改变，结晶度未见明显下降。

Claims (15)

  1. 式(I)所示化合物、其药学上可接受的盐或对映异构体，
    Figure PCTCN2022085086-appb-100001
    其中，
    R 1、R 2相同或不同，各自独立地选自-OH、-OC(O)-R 4、或-OC(O)-X-(CH 2)n-N(Y 1Y 2)；X为NH或O；
    Y 1独立地选自C 2-10的烷基；Y 2独立地选自氢、C 2-10的烷基；或者Y 1、Y 2与相连N原子形成环系，所述环系为未被取代的杂环基或杂芳基；
    R 3为C 1-10的烷基；R 4为C 1-10的烷基；n＝2-10；
    条件是：R 1或R 2中至少一个为-OC(O)-X-(CH 2)n-N(Y 1Y 2)。
  2. 式(II)所示化合物、其药学上可接受的盐或对映异构体，
    Figure PCTCN2022085086-appb-100002
    其中，
    R 1、R 2相同或不同，各自独立地选自-OH、-OC(O)-R 4、或-OC(O)-X-(CH 2)n-N(Y 1Y 2)；X为NH或O；
    Y 1独立地选自C 2-10的烷基；Y 2独立地选自氢、C 2-10的烷基；或者Y 1、Y 2与相连N原子形成环系，所述环系为未被取代的杂环基或杂芳基；
    R 3为C 1-10的烷基；R 4为C 1-10的烷基；n＝2-10；
    条件是：R 1或R 2中至少一个为-OC(O)-X-(CH 2)n-N(Y 1Y 2)。
  3. 根据权利要求1或2所述的化合物、其药学上可接受的盐或对映异构体，其中，
    R 1、R 2相同或不同，各自独立地选自-OH、-OC(O)-R 4、或-OC(O)-X-(CH 2)n-N(Y 1Y 2)；
    X为NH或O；
    Y 1独立地选自C 2-6的烷基；Y 2独立地选自氢、C 2-6的烷基；或者Y 1、Y 2与相连N原子形成环系，所述环系为未被取代的杂环基或杂芳基；
    R 3为C 1-6的烷基；R 4为C 1-6的烷基；
    n＝2、3、4、5、6、7、8、9或10；
    条件是：R 1或R 2中至少一个为-OC(O)-X-(CH 2)n-N(Y 1Y 2)。
  4. 根据权利要求1或2所述的化合物、其药学上可接受的盐或对映异构体，其中，
    Y 1独立地选自乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、1-乙基丙基、己基、异己基、1，1-二甲基丁基、2，2-二甲基丁基、3，3-二甲基丁基和2-乙基丁基；
    Y 2独立地选自氢、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、1-乙基丙基、己基、异己基、1，1-二甲基丁基、2，2-二甲基丁基、3，3-二甲基丁基和2-乙基丁基；
    或者，Y 1、Y 2与相连N原子形成环系，所述环系为
    Figure PCTCN2022085086-appb-100003
    Figure PCTCN2022085086-appb-100004
  5. 根据权利要求1或2所述化合物、其药学上可接受的盐或对映异构体，其中：
    R 1独立地选自
    Figure PCTCN2022085086-appb-100005
    R 2独立地选自-OH、
    Figure PCTCN2022085086-appb-100006
    Figure PCTCN2022085086-appb-100007
    R 3为戊基。
  6. 根据权利要求1或2所述化合物、其药学上可接受的盐或对映异构体，其中，
    R 1为-OC(O)-X-(CH 2)n-N(Y 1Y 2)；
    R 2选自-OH、-OC(O)-R 4、或-OC(O)-X-(CH 2)n-N(Y 1Y 2)；
    X为NH或O；优选为O；
    Y 1、Y 2与相连N原子形成环系，所述环系为
    Figure PCTCN2022085086-appb-100008
    R 3为C 1-6的烷基；R 4为C 1-6的烷基；
    n＝2、3、4或5。
  7. 根据权利要求6所述化合物、其药学上可接受的盐或对映异构体，其中，
    R 3为戊基；R 4为甲基、乙基或丙基；X为O。
  8. 一种化合物、其药学上可接受盐或对映异构体，其选自：
    Figure PCTCN2022085086-appb-100009
  9. 根据权利要求8所述化合物、其药学上可接受盐或对映异构体，其选自：
    Figure PCTCN2022085086-appb-100010
  10. 根据权利要求1-9任一所述化合物、其药学上可接受盐或对映异构体，所说的盐选自对甲苯磺酸盐、富马酸盐、马来酸盐、草酸盐、磷酸盐、盐酸盐、硫酸盐、苹果酸盐、酒石酸盐、柠檬酸盐或三氟乙酸盐。
  11. 下式化合物马来酸盐的晶型I，使用Cu-Kα辐射的X射线粉末衍射图中，在下列2θ角处有特征衍射峰：9.016±0.2°，13.765±0.2°，17.411±0.2°，18.411±0.2°，21.575±0.2°，27.798±0.2°
    Figure PCTCN2022085086-appb-100011
  12. 根据权利要求11所述的晶型I，使用Cu-Kα辐射的X射线粉末衍射图中，在下列2θ角处有特征衍射峰：9.016±0.2°，13.765±0.2°，17.411±0.2°，18.411±0.2°，21.575±0.2°，23.289±0.2°，27.798±0.2°。
  13. 根据权利要求11所述的晶型I，使用Cu-Kα辐射的的X射线粉末衍射图如图1-1所示。
  14. 一种药物组合物，包括权利要求1-10任一所述化合物、其药学上可接受的盐或对映异构体、或者权利要求11-13任一所述晶型和药学上可接受的载体。
  15. 权利要求1-10任一所述化合物、其药学上可接受的盐或对映异构体、权利要求11-13任一所述晶型、或者权利要求14所述药物组合物在制备用于预防和治疗哺乳动物的医学病症的药物中的用途，其中所述医学病症选自以下组成的组：癫痫，癫痫发作伴结节性硬化综合征，Dravet综合征，Lennox-Gastaut综合征，痉挛)，脑病，神经性疼痛，麻木和/或刺痛，焦虑和其它情绪障碍，高血压和自主功能障碍，帕金森氏病和震颤，失眠，贝氏麻痹和面神经功能障碍，青光眼，多发性硬化，癌症，包括脑瘤，创伤后应激障碍(PTSD)，三叉神经痛，自闭症/阿斯珀格氏病，注意力缺陷障碍和多动症，社会隔离，枕神经痛，TMJ功能障碍相关症状，认知问题，头痛，偏头痛，紧张，周围神经病，末梢神经病变，呼吸暂停，包括中枢性睡眠呼吸暂停，阻塞性睡眠呼吸暂停综合症和混合呼吸暂停，戒烟，关节炎，包括类风湿性关节炎，凹陷，呕吐，肥胖，恶心，酒精使用障碍，张力障碍，炎性肠综合征，与疱疹后神经痛相关的神经性疼痛，糖尿病性神经病变，带状疱疹，烧伤，光化性角化病，口腔溃疡，光化性角化病，口腔溃疡和溃疡上颅切开术后疼痛，银屑病，瘙痒接触性皮炎，湿疹，大疱性疱疹样皮炎，剥脱性皮炎，真菌病，天疱疮，严重的多形性红斑，脂溢性皮炎，强直性脊柱炎，银屑病关节炎，Reiter's综合症，痛风，软骨钙化病，关节疼痛，痛经，肌肉骨骼疼痛，肌炎，滑囊炎，上髁炎骨关节炎，滑膜炎，胰腺炎。
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