WO2021139739A1 - 大麻二酚衍生物及其制备方法和在医药上的应用 - Google Patents

大麻二酚衍生物及其制备方法和在医药上的应用 Download PDF

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WO2021139739A1
WO2021139739A1 PCT/CN2021/070728 CN2021070728W WO2021139739A1 WO 2021139739 A1 WO2021139739 A1 WO 2021139739A1 CN 2021070728 W CN2021070728 W CN 2021070728W WO 2021139739 A1 WO2021139739 A1 WO 2021139739A1
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alkyl
group
carbocyclic
heterocyclic ring
membered heterocyclic
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PCT/CN2021/070728
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English (en)
French (fr)
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许学珍
张靖
魏用刚
楚洪柱
赵富强
苏桂转
王美微
孙毅
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成都百裕制药股份有限公司
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Priority to US17/772,126 priority Critical patent/US20230002425A1/en
Priority to EP21738886.7A priority patent/EP4088723A4/en
Publication of WO2021139739A1 publication Critical patent/WO2021139739A1/zh

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    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/004—Acyclic, carbocyclic or heterocyclic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen, sulfur, selenium or tellurium

Definitions

  • the present invention relates to cannabidiol derivatives, or their stereoisomers, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, their pharmaceutical compositions and their applications in the preparation of medicines.
  • Cannabis sativa (Cannabis sativa L.) is an annual herb of the genus Moraceae, which originated in Central and East Asia, and is widely distributed in the United States, India, Brazil and other places. Cannabis has a long history of medicinal use, but its addictive and psychogenic effects have greatly restricted its clinical application. Cannabis contains hundreds of different chemical substances, and there are about 70 ingredients called cannabinoids, mainly including cannabidiol (Cannabidiol, CBD), cannabidiol (cannabinol, CBN), Tetrahydrocannabinol (THC) And its homologues, among which cannabidiol (CBD) has the highest content.
  • CBD cannabidiol
  • CBD cannabidiol
  • CBN cannabidiol
  • THC Tetrahydrocannabinol
  • CBD cannabidiol
  • CBD can not only antagonize the psychoactive caused by THC, but also has a wide range of therapeutic characteristics. It can significantly improve neurological diseases including anxiety, schizophrenia, addiction, neurodegenerative diseases, neonatal hypoxic-ischemic encephalopathy, and epilepsy. Function, in addition to anti-tumor, anti-inflammatory, liver and liver protection, pain, anti-anxiety, anti-insomnia, anti-convulsive, anti-vomiting, anti-spasm, anti-oxidation, neuroprotection treatment, also shows good application prospects.
  • the oral bioavailability of CBD is low (human oral bioavailability is about 6%), and new technologies need to be developed to improve the absorption, distribution, transport and metabolism of the drug in the body, increase the bioavailability, and increase the target site of the drug Technical effects such as selectivity of action, reduction of toxic and side effects of drugs, and extension of action time.
  • the purpose of this application is to provide new cannabidiol derivatives, or their stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or prodrugs, their pharmaceutical compositions and their use in the preparation of medicines.
  • the compound of the present application can be converted into its prototype drug after being ingested, and compared with the prototype drug, it has higher bioavailability (for example, oral bioavailability) and more Long half-life, and can improve and improve the treatment effect, reduce toxic side effects.
  • bioavailability for example, oral bioavailability
  • One or more embodiments of the present application provide a compound represented by general formula (I), or its stereoisomers, solvates, metabolites, pharmaceutically acceptable salts or co-crystals:
  • X is selected from hydrogen, hydroxyl, C 1-6 alkyl or halogen
  • Y is selected from hydrogen, carboxyl, C 1-6 alkyl or halogen
  • r is selected from 0, 1, 2 or 3;
  • n is selected from 0, 1 or 2;
  • R 1 is selected from a C 1-6 alkyl group, and the C 1-6 alkyl group may be optionally further substituted with 0 to 3 halogens;
  • Ra is selected from H or C 1-6 alkyl
  • R b3 is selected from C 1-6 alkyl, C 1-6 alkoxy or C 6-12 aryl;
  • R b4 and R b5 are each independently selected from H or C 1-6 alkyl; or R b4, R b5 and N atom form a 3 to 12 membered heterocyclic ring, and the 3 to 12 membered heterocyclic ring includes 1 to 4 One heteroatom selected from N, O or S;
  • Rb and Rc together with the atoms to which they are connected form a 3- to 6-membered carbocyclic ring or a 3- to 6-membered heterocyclic ring, and the 3- to 6-membered carbocyclic ring or 3- to 6-membered heterocyclic ring is optionally further selected from 0 to 3 Substituted by substituents of F, Cl, Br, I, hydroxyl, carboxyl or amino, the 3- to 6-membered heterocyclic ring contains 1 to 4 heteroatoms selected from N, O or S;
  • Rd is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocyclic ring, 3 to 10-membered heterocyclic ring, -C 1-6 alkylene-C 3 --10 carbocyclic, -C 1-6 alkylene -3 to 10-membered heterocyclyl, -C 1-6 alkylene -OC 1-6 -C3-10 carbocycle alkylene, -C 1-6 alkylene Alkyl-OC 1-6 alkylene-3 to 10-membered heterocycle or -C 1-6 alkylene-OC 1-4 alkyl, the C 1-6 alkylene, C 2-6 alkenyl , C 2-6 alkynyl, C 1-6 alkyl, C 3-10 carbocyclic or 3 to 10-membered heterocyclic ring optionally further selected from 0 to 4 selected from H, F, Cl, Br, I, hydroxyl, Substituted by substituents of carboxyl, amino, 1-cyclo
  • R d1 and R d2 each independently selected from C 1-4 alkyl, C 3-10 carbon ring or 3-10 membered heterocyclic, said C 1-4 alkyl group, C 3-10 carbon ring or 3-10
  • the membered heterocyclic ring is optionally further substituted by 0 to 4 selected from H, F, Cl, Br, I, hydroxyl, carboxyl, C 1-4 alkyl, C 1-4 alkoxy, C 3-10 carbocyclic or 3
  • the 3- to 10-membered heterocyclic ring containing 1 to 6 heteroatoms selected from N, O or S;
  • R 3 is selected from C 1-6 alkyl, C 3-8 carbocyclic group or C 2-6 alkenyl, said C 1-6 alkyl, C 2-6 alkenyl, C 3-8 carbon
  • the cyclic group is optionally further substituted with 0 to 3 substituents selected from halogen, C 3-8 carbocyclic group, hydroxyl group or C 1-6 alkyl group;
  • R is selected from an amino acid side chain; when the amino acid side chain contains a hydroxyl group, a sulfhydryl group or a carboxyl group, the hydroxyl group, a sulfhydryl group or a carboxyl group is optionally esterified;
  • the general formula (I) may be optionally substituted with one or more D atoms.
  • One or more embodiments of the present application provide a compound represented by general formula (II), or its stereoisomers, solvates, metabolites, pharmaceutically acceptable salts or co-crystals:
  • R 0 is methyl or -CH 2 OH
  • R 1 is C 1-6 alkyl
  • R b and R c are each independently selected from H or an amino acid side chain; when the amino acid side chain contains a hydroxyl group, a mercapto group or a carboxyl group, the hydroxyl group, a mercapto group or a carboxyl group is optionally esterified;
  • R d is selected from C 1-6 alkyl group, -C 3-10 carbocyclic ring or -3 to 10 membered heterocyclic ring, said C 1-6 alkyl group, C 3-10 carbocyclic ring or 3 to 10 membered heterocyclic ring
  • the 3- to 10-membered heterocyclic ring contains 1 to 6 heteroatoms selected from N, O or S;
  • Rd1 and Rd2 are each independently a C1-4 alkyl group
  • the general formula (II) is optionally substituted with one or more D atoms.
  • One or more embodiments of the present application provide a compound represented by the general formula (III), or its stereoisomers, solvates, metabolites, pharmaceutically acceptable salts or co-crystals:
  • R 1 is C 1-6 alkyl
  • Rd1 and Rd2 are each independently a C 1-4 alkyl group
  • the H atom of the general formula (IV) is optionally substituted by one or more D atoms.
  • One or more embodiments of the present application provide the following compound, or its stereoisomer, solvate, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is one of the following structures:
  • composition comprising:
  • the other active ingredients are selected from ginkgolides, antitumor agents, anticoagulants, antiepileptic agents, antidepressants, anxiolytics, hypnotic agents, analgesics
  • agents or anesthetics, or stereoisomers One or more of the agents or anesthetics, or stereoisomers, hydrates, metabolites, solvates, pharmaceutically acceptable salts or co-crystals of the other active ingredients.
  • One or more embodiments of the present application provide that the compound of the present application or its stereoisomers, solvates, metabolites, pharmaceutically acceptable salts or co-crystals or pharmaceutical compositions are prepared for the treatment of post-traumatic stress disorder.
  • One or more embodiments of the present application provide the above-mentioned compound of the present application or its stereoisomer, solvate, metabolite, pharmaceutically acceptable salt or co-crystal for use as a medicine.
  • One or more embodiments of the present application provide the above-mentioned compound of the present application or its stereoisomers, solvates, metabolites, pharmaceutically acceptable salts or co-crystals for use in a method of treating the following diseases: post-traumatic Stress disorder, facial paralysis, stroke, migraine, stable angina pectoris of coronary heart disease, cerebral infarction, thromboembolism, myocardial infarction, cardiac ischemia, coronary artery disease, hypertension, cerebral ischemia, improvement of sexual function, spasticity, acute and chronic Pain, fibromyalgia, postoperative pain, cluster headache, tension headache, back pain, limb pain, low back pain, neck pain, neuropathic pain, cancer pain, trigeminal neuralgia, arthritis pain, inflammatory pain, Dravet Syndrome, Lennox-Gastaut Syndrome, Prader-Willi Syndrome, Sturge-Weber Syndrome, Fragile X Syndrome, Anxiety, Bipolar Disorder, Autism, Generalized Anxiety Disorder, Social
  • One or more embodiments of the present application provide a method for treating the following diseases, which includes administering the above-mentioned compound of the present application or its stereoisomer, solvate, metabolite, or pharmaceutically acceptable salt to a subject in need thereof Or eutectic: post-traumatic stress disorder, facial paralysis, stroke, migraine, stable angina pectoris of coronary heart disease, cerebral infarction, thromboembolism, myocardial infarction, cardiac ischemia, coronary artery disease, hypertension, cerebral ischemia, improving sexual function , Cramps, acute and chronic pain, fibromyalgia, postoperative pain, cluster headache, tension headache, back pain, limb pain, low back pain, neck pain, neuropathic pain, cancer pain, trigeminal neuralgia, arthritis pain , Inflammatory pain, Dravet syndrome, Lennox-Gastaut syndrome, Prader-Willi syndrome, Sturge-Weber syndrome, Fragile X syndrome, anxiety, bipolar disorder, autism
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, and I involved in the groups and compounds of the present invention include their isotopes, and the carbon involved in the groups and compounds of the present invention , Hydrogen, oxygen, sulfur or nitrogen are optionally further replaced by one or more of their corresponding isotopes, wherein carbon isotopes include 12 C, 13 C and 14 C, and hydrogen isotopes include protium (H), deuterium (D, Also called heavy hydrogen), tritium (T, also called super heavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, and nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.
  • carbon isotopes include 12 C, 13 C and 14 C
  • hydrogen isotopes include
  • Hydrodynamical refers to a group containing only carbon and hydrogen atoms.
  • Alkyl refers to a linear or branched saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably 1 to 8 (for example, 1, 2, 3, 4, 5, 6, 7, 8) carbon atoms
  • the alkyl group of is more preferably an alkyl group of 1 to 6 carbon atoms, and still more preferably an alkyl group of 1 to 4 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl And its various branched isomers; when the alkyl group is substituted, it may be optionally further substituted with one or more substituents.
  • Heteroalkyl refers to a group in which at least one C atom of an alkyl group is substituted with an O, S, N, or P atom.
  • Non-limiting examples include thiomethyl, thioethyl, thion-propyl, thioisopropyl, thion-butyl, thiosec-butyl, and thiot-butyl.
  • the definition of the alkyl group is the same as the definition of "alkyl" mentioned above.
  • Alkoxy refers to a group formed by replacing at least one carbon atom in an alkyl group with an oxygen atom.
  • Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropyl Oxy and cyclobutoxy.
  • the definition of the alkyl group is the same as the definition of "alkyl" mentioned above.
  • Alkenyl refers to a straight line consisting of 1 to 10 (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon-carbon double bonds consisting of 2 to 20 carbon atoms. Chain or branched unsaturated aliphatic hydrocarbon group, preferably 2 to 12 (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms alkenyl group, more preferably 2 to The alkenyl group of 8 carbon atoms is more preferably the alkenyl group of 2 to 6 carbon atoms.
  • Non-limiting examples include vinyl, propen-2-yl, buten-2-yl, buten-2-yl, penten-2-yl, penten-4-yl, hexen-2-yl, Hexen-3-yl, hepten-2-yl, hepten-3-yl, hepten-4-yl, octen-3-yl, nonen-3-yl, decen-4-yl and undecenyl En-3-yl.
  • the alkenyl group may be further substituted with one or more substituents.
  • Alkynyl refers to those containing 1 to 10 (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon-carbon triple bonds, consisting of 2 to 20 carbon atoms Straight or branched chain unsaturated aliphatic hydrocarbon group, preferably 2 to 12 (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atom alkynyl group, more preferably 2 An alkynyl group having to 8 carbon atoms, and an alkynyl group having 2 to 6 carbon atoms is more preferable.
  • Non-limiting examples include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3,3-dimethyl Butyn-2-yl, pentyn-1-yl, pentyn-2-yl, hexyn-1-yl, 1-heptyn-1-yl, heptyn-3-yl, heptyn-4- Base, octyn-3-yl, nonyn-3-yl, decyn-4-yl, undecyn-3-yl, dodecyn-4-yl.
  • the alkynyl group may be optionally further substituted with 1 to more substituents.
  • Aryl refers to a substituted or unsubstituted aromatic ring, which can be a 5- to 8-membered (e.g., 5, 6, 7, 8-membered) monocyclic ring, 5 to 12-membered (e.g., 5, 6, 7 , 8, 9, 10, 11, 12 membered) bicyclic or 10 to 15 membered (for example, 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, which can be bridged or spiro ring, non-limiting implementation Examples include phenyl and naphthyl. The aryl group may be further substituted with one or more substituents.
  • Heteroaryl refers to a substituted or unsubstituted aromatic ring, which can be 3 to 8 membered (e.g. 3, 4, 5, 6, 7, 8 membered) monocyclic, 5 to 12 membered (e.g. 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic or 10 to 15 membered (e.g. 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1 to 6 (e.g. 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O or S, preferably 5 to 8 membered heteroaryl groups, and 1 to 4 (e.g. 1, 2 , 3, 4) N and S can be oxidized into various oxidation states.
  • 3 to 8 membered e.g. 3, 4, 5, 6, 7, 8 membered
  • monocyclic e.g. 5, 6, 7, 8, 9, 10, 11, 12 membered
  • 10 to 15 membered e.g. 10, 11, 12, 13, 14, 15 membered
  • tricyclic ring system contains 1 to
  • the heterocyclic group can be attached to a hetero atom or a carbon atom, and the heteroaryl group can be a bridged ring or a spiro ring.
  • Non-limiting examples include cyclopyridyl, furyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, Pyrazinyl, pyridazinyl, imidazolyl, piperidinyl benzimidazolyl, benzopyridyl, pyrrolopyridyl.
  • the heteroaryl group is optionally further substituted with one or more substituents.
  • Carbocyclic group or “carbocyclic ring” refers to a saturated or unsaturated aromatic ring or a non-aromatic ring.
  • aromatic ring When it is an aromatic ring, its definition is the same as the definition of "aryl”above; when it is a non-aromatic ring, it can be 3 to 10 members (for example, 3, 4, 5, 6, 7, 8, 9, 10 Yuan), 4 to 12 yuan (e.g. 4, 5, 6, 7, 8, 9, 10, 11, 12 yuan) bicyclic ring or 10 to 15 yuan (e.g.
  • tricyclic ring system which can be bridged or spiro ring
  • non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2 -Alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, cyclohexadienyl, cyclohexyl Heptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl,
  • the "carbocyclic group” or "carbocyclic ring” is optionally further substituted with one or more substituents.
  • Heterocyclic group or “heterocyclic ring” refers to a saturated or unsaturated aromatic heterocyclic ring or non-aromatic heterocyclic ring. When it is an aromatic heterocyclic ring, its definition is the same as the definition of "heteroaryl”above; when When it is a non-aromatic heterocyclic ring, it can be a 3- to 10-membered (e.g. 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic ring, 4 to 12-membered (e.g. 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic or 10 to 15 membered (e.g.
  • heterocyclic group 10, 11, 12, 13, 14, 15 membered tricyclic ring system, and contains 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from N, O or S, preferably 3 to 8 membered heterocyclic groups.
  • 1 to 4 e.g. 1, 2, 3, 4
  • N and S optionally substituted in the "heterocyclic group” or “heterocyclic ring” can be oxidized to various oxidation states;
  • heterocyclic group” or “Heterocycle” can be attached to a heteroatom or carbon atom;
  • heterocyclic group” or “heterocycle” can be a bridged ring or a spiro ring.
  • heterocyclic group or “heterocyclic ring” include oxirane, glycidyl, aziridinyl, oxetanyl, azetidinyl, thietanyl , 1,3-dioxolane, 1,4-dioxolane, 1,3-dioxanyl, azepanyl, oxepanyl, thiepanyl, oxygen Azepine, diazepine, thiazepine, pyridinyl, piperidinyl, homopiperidinyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyridine Azinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazinyl, 1,3-
  • Cycloalkyl refers to a saturated cyclic hydrocarbon group whose ring can be 3 to 10 membered (e.g. 3, 4, 5, 6, 7, 8, 9, 10 membered) monocyclic, 4 to 12 membered (e.g. 4 , 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic or 10- to 20-membered (for example, 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) polycyclic ring system, ring
  • the carbon atom is preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms.
  • Non-limiting examples of "cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexyl Alkenyl, cycloheptenyl, 1,5-cyclooctadienyl, 1,4-cyclohexadienyl and cycloheptatrienyl, etc. When the cycloalkyl group is substituted, it may be further substituted with one or more substituents.
  • Heterocycloalkyl refers to a substituted or unsubstituted saturated non-aromatic ring group, which can be 3 to 8 membered (for example, 3, 4, 5, 6, 7, 8 membered) monocyclic, 4 to 12 membered (E.g. 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic or 10 to 15-membered (e.g. 10, 11, 12, 13, 14, 15-membered) tricyclic ring system, including 1, 2 or 3 heteroatoms selected from N, O or S, preferably 3 to 8 membered heterocyclic group.
  • the selectively substituted N and S in the "heterocycloalkyl" ring can be oxidized to various oxidation states; the "heterocycloalkyl” can be connected to a heteroatom or a carbon atom; the “heterocycloalkyl” can be a bridge Ring or spiro ring.
  • heterocycloalkyl include oxirane ethyl, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolane, 1,4-dioxolane, Oxolane, 1,3-dioxanyl, azepanyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, tetrahydrofuranyl , Tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxa Tricyclic[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptyl.
  • amino acid side chain refers to groups other than amino and carboxyl groups in an amino acid molecule.
  • “Pharmaceutically acceptable salt” or “pharmaceutically acceptable salt thereof” means that the compound of the present invention maintains the biological effectiveness and characteristics of the free acid or free base, and the free acid is combined with a non-toxic inorganic base or A salt obtained by reaction with an organic base, and the free base is a salt obtained by reacting with a non-toxic inorganic acid or organic acid.
  • “Pharmaceutical composition” refers to a mixture of one or more compounds of the present invention, their pharmaceutically acceptable salts or prodrugs, and other chemical components, where "other chemical components” refer to pharmaceutically acceptable compounds. Accepted carriers, excipients and/or one or more other therapeutic agents.
  • Carrier refers to a material that does not cause significant irritation to the organism and does not eliminate the biological activity and characteristics of the administered compound.
  • Excipient refers to an inert substance added to a pharmaceutical composition to facilitate the administration of a compound.
  • Non-limiting examples include calcium carbonate, calcium phosphate, sugar, starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, adhesives Agent and disintegrant.
  • a “prodrug” refers to a compound of the present invention that can be converted into a biologically active compound by metabolism in the body.
  • the prodrug of the present invention is prepared by modifying the amino or carboxyl group in the compound of the present invention, and this modification can be removed by conventional operations or in vivo to obtain the parent compound.
  • the prodrug of the present invention is administered to a mammalian individual, the prodrug is split to form free amino or carboxyl groups.
  • Co-crystal refers to the crystal formed by the combination of active pharmaceutical ingredient (API) and co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds.
  • API active pharmaceutical ingredient
  • CCF co-crystal former
  • the pure state of API and CCF are both at room temperature. Solid, and there is a fixed stoichiometric ratio between the components.
  • a eutectic is a multi-component crystal, which includes both a binary eutectic formed between two neutral solids and a multi-element eutectic formed between a neutral solid and a salt or solvate.
  • Stepoisomers refer to isomers produced by the different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.
  • Optional or “optionally” or “selective” or “selectively” means that the event or condition described later can but does not necessarily occur, and the description includes the situation in which the event or condition occurs and its failures. What happened.
  • heterocyclic group optionally substituted by an alkyl group means that the alkyl group may but does not necessarily exist.
  • the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • NMR is measured with (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic instrument, the solvent is deuterated dimethylsulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD ), the internal standard is tetramethylsilane (TMS);
  • HPLC determination uses Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100 ⁇ 4.6mm, 3.5 ⁇ M);
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm-0.20mm, and the size used for thin layer chromatography separation and purification products is 0.4mm. -0.5mm;
  • the known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from Titan Technology, Anaiji Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Bailingwei Technology, etc. the company;
  • Nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon with a volume of about 1L;
  • the hydrogen atmosphere refers to the reaction flask connected to a hydrogen balloon with a volume of about 1L;
  • the hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times;
  • the reaction temperature is room temperature, and the most suitable reaction temperature for room temperature is 20°C-30°C;
  • THF Tetrahydrofuran
  • PE petroleum ether
  • NCS N-chlorosuccinimide
  • Pd(dppf)Cl 2 [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride;
  • red aluminum (67mL, 234.1mmol, 3.5N) was added dropwise to the tetrahydrofuran (200mL) solution of compound 9b (17.0g, 78.0mmol), and the solution was slowly raised to room temperature and stirred for 2h after dripping; TLC detected until the reaction was over; the temperature was lowered to 0°C, saturated ammonium chloride solution (13mL) was added dropwise to quench, suction filtered, the aqueous phase was extracted with ethyl acetate (200mL ⁇ 2), and the organic phases were combined with saturated brine (100mL) Wash, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product.
  • deuterated methyl magnesium iodide 34mL, 33.7mmol, 1.0N was added dropwise to anhydrous lithium chloride (1.4g, 33.7mmol) in tetrahydrofuran (20mL) solution under the protection of nitrogen.
  • the blood drug concentration (ng/mL) of the prototype drug of the compound in the rat body at each time point was measured as follows:
  • the experimental results show that after oral administration of the compound of the present invention, the concentration of the prototype drug can be detected in the plasma, indicating that the compound has oral absorption characteristics and can be quickly transformed into a prototype drug in the body, and has a better oral effect than the prototype drug. bioavailability.

Abstract

大麻二酚衍生物及其在医药上的应用，具体而言涉及如通式(I)所示的嘧啶衍生物，或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐或共晶，其中，通式(I)中各取代基的定义与说明书的定义相同。

Description

大麻二酚衍生物及其制备方法和在医药上的应用 技术领域
本发明涉及大麻二酚衍生物，或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其药物组合物以及在制备药物中的应用。
背景技术
大麻(Cannabis sativa L.)为桑科大麻属一年生草本植物，起源于中亚和东亚，广泛分布于美国、印度、巴西等地。大麻的药用历史悠久，但成瘾性和精神致幻作用，使其临床应用受到极大限制。大麻包含数百种不同的化学物质，大约有70多种成分被称为大麻素，主要包括大麻二酚(cannabidiol，CBD)、大麻酚(cannabinol，CBN)、四氢大麻酚(Tetrahydrocannabinol，THC)及其同系物等，其中大麻二酚(CBD)含量最高。CBD不但能拮抗THC所引发的精神活性，而且具有广泛的治疗特征，对神经疾病包括焦虑、精神分裂、成瘾、神经退行性疾病、新生儿低氧缺血性脑病、癫痫均具有明显的改善作用，另外在抗肿瘤、抗炎、肝肝保护、疼痛、抗焦虑、抗失眠、抗惊厥、抗呕吐、抗痉挛、抗氧化、神经保护的治疗上，也表现出很好的应用前景。但是CBD口服生物利用度低(人口服生物利用度大约6％)，需要开发新的技术，以达到改善药物在体内的吸收、分布、转运与代谢过程、提高生物利用度、提高药物对靶部位作用的选择性、降低药物的毒副作用、延长作用时间等的技术效果。
发明内容
本申请的目的是提供新的大麻二酚衍生物，或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或者前药，其药物组合物以及其在制备药物中的应用。
在本申请的一个或多个实施方式中，本申请的化合物被摄入后能够转换为其原型药，且与原型药相比，具有更高的生物利用度(例如口服生物利用度)和更长的半衰期，并且可以提高并改善治疗效果、降低毒副作用。
本申请的一个或多个实施方式提供了通式(I)所示的化合物，或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐或共晶：
Figure PCTCN2021070728-appb-000001
其中：
X选自氢、羟基、C 1-6烷基或者卤素；
Y选自氢、羧基、C 1-6烷基或者卤素；
r选自0、1、2或者3；
n选自0、1或者2；
R 0选自甲基、C 3-8碳环基、-CH 2OH、-C(＝O)OC 1-6烷基、-C(＝O)NR b1R b2或者羧基；
R 1选自C 1-6烷基，所述的C 1-6烷基可以任选进一步被0至3个卤素所取代；
R 2为
Figure PCTCN2021070728-appb-000002
Ra选自H或者C 1-6烷基；
R b、R c各自独立地选自H、C 1-6烷基、氨基酸侧链、-C 1-6亚烷基-C 3-12碳环或者-C 1-6亚烷基-C 3-12杂环；所述的C 3-12杂环包含1至4个选自N、O或者S的杂原子；所述的C 1-6亚烷基、C 1-6烷基、C 3-12碳环、C 3-12杂环任选地进一步被0至3个选自羟基、羧基、卤素、氰基、＝O、C 1-6烷基、C 1-6杂烷基、C 2-6烯基、C 2-6炔基、-NR b1R b2、-C(＝O)OC 1-6烷基、-C(＝O)NR b1R b2、C 3-12环烷基、C 3-12杂环烷基、C 6-12芳基或者C 5-12杂芳基的取代基所取代；且作为取代基的所述的C 1-6烷基、C 1-6杂烷基、C 2-6烯基或者C 2-6炔基任选进一步被1个或者多个选自羟基、羧基、氰基、卤素、-O-R b1、-NR b1R b2、C 3-12环烷基、C 3-12杂环烷基、C 6-12芳基或者C 5-12杂芳基的取代基所取代；当所述的氨基酸侧链包含羟基、巯基或羧基时，所述羟基、巯基或羧基任选地被酯化；
R b1、R b2各自独立地选自H、C 1-6烷基、-C(＝O)R b3或者-C(＝O)NR b4R b5，其中所述的C 1-6烷基任选进一步被1个或者多个选自羟基、卤素、C 1-6烷基、C 1-6烷氧基、C 6-12芳基、C 5-12杂芳基、C 3-12环烷基或者C 3-12杂环烷基的取代基所取代；
R b3选自C 1-6烷基、C 1-6烷氧基或者C 6-12芳基；
R b4、R b5各自独立地选自H或者C 1-6烷基；或者R b4与R b5及N原子形成一个3至12元杂环，所述的3至12元杂环包含1至4个选自N、O或者S的杂原子；
或者，Rb和Rc与其所连接的原子一起形成3至6元碳环或者3至6元杂环，所述3至6元碳环或者3至6元杂环任选进一步被0至3个选自F、Cl、Br、I、羟基、羧基或氨基的取代基所取代，所述的3至6元杂环包含1至4个选自N、O或者S的杂原子；
Rd选自自C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10碳环、3至10元杂环、-C 1-6亚烷基-C 3- 10碳环、-C 1-6亚烷基-3至10元杂环、-C 1-6亚烷基-O-C 1-6亚烷基-C3-10碳环、-C 1-6亚烷基-O-C 1-6亚烷基-3至10元杂环或-C 1-6亚烷基-O-C 1-4烷基，所述C 1-6亚烷基、C 2-6烯基、C 2-6炔基、C 1-6烷基、C 3-10碳环或3至10元杂环任选进一步被0至4个选自H、F、Cl、Br、I、羟基、羧基、氨基、1-环丙基乙基、C 1-4烷基、C 1-4烷氧基、-OC(＝O)OR d1或-OC(＝O)R d2的取代基所取代，所述3至10元杂环包含1至6个选自N、O或者S的杂原子；
R d1和R d2各自独立地选自C 1-4烷基、C 3-10碳环或3至10元杂环，所述C 1-4烷基、C 3-10碳环或3至10元杂环任选进一步被0至4个选自H、F、Cl、Br、I、羟基、羧基、C 1-4烷基、C 1-4烷氧基、C 3-10碳环或3至10元杂环的取代基所取代，所述3至10元杂环包含1至6个选自N、O或者S的杂原子；
R 3选自选自C 1-6烷基、C 3-8碳环基或者C 2-6烯基，所述的C 1-6烷基、C 2-6烯基、C 3-8碳环基任选进一步被0至3个选自卤素、C 3-8碳环基、羟基或者C 1-6烷基的取代基所取代；
R 4选自H、C 1-6烷氧基、-C(＝O)OR d1、-C(＝O)R d1、-C(＝O)C(NH 2)-R或者
Figure PCTCN2021070728-appb-000003
且-C(＝O)CH(NH 2)-R中的氨基任选地与氨基酸形成多肽链；
R选自氨基酸侧链；当所述的氨基酸侧链包含羟基、巯基或羧基时，该羟基、巯基或羧基任选地被酯化；
R 5选自C 1-12烷基、C 1-12杂烷基、C 2-12烯基、C 2-12炔基、C 3-12碳环基、C 3-12杂环基、-C 1-6亚烷基-C 3-12碳环基、-C 1-6亚烷基-C 3-12杂环基、-NR b1R b2、-C 1-6亚烷基-C(＝O)OC 1-6烷基或者-C 1-6亚烷基-C(＝O)NR b1R b2，且所述的C 1-12烷基、C 1-12杂烷基、C 2-12烯基、C 2-12炔基、C 1-6亚烷基、C 3-12碳环基、C 3-12杂环基任选被1个或者多个选 自羟基、羧基、卤素、氰基、＝O、C 1-6烷基、-NR b1R b2、C 3-12碳环基、C 3-12杂环基、C 2-6烯基、C 2-6炔基、-C(＝O)OC 1-6烷基、-C(＝O)C 1-6烷基、-C(＝O)NR b1R b2、-S(＝O)C 1-6烷基或者-S(＝O) 2C 1-6烷基的取代基所取代，且作为取代基的所述的C 1-6烷基、C 3-12碳环基、C 3-12杂环基任选进一步被1个或者多个选自＝O、羟基、羧基、卤素、氰基、-C(＝O)OC 1-6烷基或者-C(＝O)C 1-6烷基的取代基所取代；
Figure PCTCN2021070728-appb-000004
为单键或者双键。
或者，通式(I)可以任选被1个或者多个D原子取代。
本申请的一个或多个实施方式提供通式(II)所示的化合物，或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐或共晶：
Figure PCTCN2021070728-appb-000005
其中，
R 0为甲基或者-CH 2OH；
R 1为C 1-6烷基；
R 2为
Figure PCTCN2021070728-appb-000006
Ra为H；
R b、R c各自独立地选自H或者氨基酸侧链；当所述的氨基酸侧链包含羟基、巯基或羧基时，所述羟基、巯基或羧基任选地被酯化；
R d选自自C 1-6烷基、-C 3-10碳环或者-3至10元杂环，所述C 1-6烷基、C 3-10碳环或3至10元杂环任选进一步被0至4个选自H、F、Cl、Br、I、羟基、羧基、氨基、1-环丙基乙基、C 1-4烷基、C 1-4烷氧基、OC(＝O)OR d1或OC(＝O)R d2的取代基所取代，所述3至10元杂环包含1至6个选自N、O或者S的杂原子；
Rd1和Rd2各自独立地为C1-4烷基；
或者，通式(II)任选被1个或者多个D原子取代。
本申请的一个或多个实施方式提供通式(III)所示的化合物，或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐或共晶：
Figure PCTCN2021070728-appb-000007
其中，
R 1为C 1-6烷基；
R 2为
Figure PCTCN2021070728-appb-000008
Rd选自自C 1-6烷基、-C 3-10碳环或者-3至10元杂环，所述C 1-6烷基、C 3-10碳环或3至10元杂环任选进一步被0至4个选自H、F、Cl、Br、I、羟基、羧基、氨基、1-环丙基乙 基、C 1-4烷基、C 1-4烷氧基、OC(＝O)ORd1或OC(＝O)Rd2的取代基所取代，所述3至10元杂环包含1至6个选自N、O或者S的杂原子；
Rd1和Rd2各自独立地为C 1-4烷基；
或者，通式(IV)的H原子任选被1个或者多个D原子取代。
本申请的一个或多个实施方式提供以下的化合物，或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐或共晶，其中该化合物为以下结构之一：
Figure PCTCN2021070728-appb-000009
Figure PCTCN2021070728-appb-000010
Figure PCTCN2021070728-appb-000011
或者
Figure PCTCN2021070728-appb-000012
本申请的一个或多个实施方式提供药物组合物，所述药物组合物包含：
(1)本申请的化合物或其立体异构体、溶剂化物、代谢产物、药学上可接受的盐或者共晶；
(2)任选的一种或者多种其他活性成分；以及
(3)药学上可接受的载体和/或赋形剂。
在本申请的一个或多个实施方式中，所述的其他活性成分选自银杏内酯、抗肿瘤剂、抗凝血剂、抗癫痫剂、抗抑郁剂、抗焦虑剂、催眠剂、镇痛剂或者麻醉剂中的一种或多种，或者所述的其他活性成分的立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或共晶。
本申请的一个或多个实施方式提供本申请的化合物或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐或共晶或者药物组合物在制备用于治疗创伤后应激 障碍、面瘫、中风、偏头痛、冠心病稳定型心绞痛、脑梗塞、血栓栓塞、心肌梗塞、心脏缺血、冠状动脉疾病、高血压、脑缺血、改善性功能、痉挛、急性和慢性疼痛、纤维肌痛、术后疼痛、丛集性头痛、紧张性头痛、背疼、四肢痛、腰痛、颈部疼痛、神经性疼痛、癌痛、三叉神经痛、关节炎疼痛、炎性疼痛、Dravet综合征、Lennox-Gastaut综合征、Prader-Willi综合征、Sturge-Weber综合征、脆性X综合征、焦虑、双相情感障碍、自闭症、广泛性焦虑症、社交焦虑症、癫痫、帕金森氏病、阿尔茨海默氏病、亨廷顿氏病、阿片类药物滥用、酗酒、尼古丁成瘾、厌食症、恶病质、化疗相关恶心呕吐、术后恶心和呕吐、肌萎缩性侧索硬化症(ALS)、Friedreich共济失调、精神分裂症、强迫症、多发性硬化症、抑郁、睡眠障碍、多发性硬化引起的痉挛、肌张力障碍、睡眠呼吸暂停、麻痹性痴呆、记忆力减退或者胶质母细胞瘤的药物中的用途。
本申请的一个或多个实施方式提供了用作药物使用的本申请的上述化合物或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐或共晶。
本申请的一个或多个实施方式提供了在治疗以下疾病的方法中使用的本申请的上述化合物或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐或共晶：创伤后应激障碍、面瘫、中风、偏头痛、冠心病稳定型心绞痛、脑梗塞、血栓栓塞、心肌梗塞、心脏缺血、冠状动脉疾病、高血压、脑缺血、改善性功能、痉挛、急性和慢性疼痛、纤维肌痛、术后疼痛、丛集性头痛、紧张性头痛、背疼、四肢痛、腰痛、颈部疼痛、神经性疼痛、癌痛、三叉神经痛、关节炎疼痛、炎性疼痛、Dravet综合征、Lennox-Gastaut综合征、Prader-Willi综合征、Sturge-Weber综合征、脆性X综合征、焦虑、双相情感障碍、自闭症、广泛性焦虑症、社交焦虑症、癫痫、帕金森氏病、阿尔茨海默氏病、亨廷顿氏病、阿片类药物滥用、酗酒、尼古丁成瘾、厌食症、恶病质、化疗相关恶心呕吐、术后恶心和呕吐、肌萎缩性侧索硬化症(ALS)、Friedreich共济失调、精神分裂症、强迫症、多发性硬化症、抑郁、睡眠障碍、多发性硬化引起的痉挛、肌张力障碍、睡眠呼吸暂停、麻痹性痴呆、记忆力减退或者胶质母细胞瘤。
本申请的一个或多个实施方式提供了治疗以下疾病的方法，其包括向有此需要的对象给予本申请的上述化合物或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐或共晶：创伤后应激障碍、面瘫、中风、偏头痛、冠心病稳定型心绞痛、脑梗塞、血栓栓塞、心肌梗塞、心脏缺血、冠状动脉疾病、高血压、脑缺血、改善性功能、痉挛、急性和慢性疼痛、纤维肌痛、术后疼痛、丛集性头痛、紧张性头痛、背疼、四肢痛、腰痛、颈部疼痛、神经性疼痛、癌痛、三叉神经痛、关节炎疼痛、炎性疼痛、Dravet综合征、Lennox-Gastaut综合征、Prader-Willi综合征、Sturge-Weber综合征、脆性X综合征、焦虑、双相情感障碍、自闭症、广泛性焦虑症、社交焦虑症、癫痫、帕金森氏病、阿尔茨海默氏病、亨廷顿氏病、阿片类药物滥用、酗酒、尼古丁成瘾、厌食症、恶病质、化疗相关恶心呕吐、术后恶心和呕吐、肌萎缩性侧索硬化症(ALS)、Friedreich共济失调、精神分裂症、强迫症、多发性硬化症、抑郁、睡眠障碍、多发性硬化引起的痉挛、肌张力障碍、睡眠呼吸暂停、麻痹性痴呆、记忆力减退或者胶质母细胞瘤。
除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或F、Cl、Br、I均包括它们的同位素情况，及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选进一步被一个或多个它们对应的同位素所替代，其中碳的同位素包括 12C、 13C和 14C，氢的同位素包括氕(H)、氘(D，又叫重氢)、氚(T，又叫超重氢)，氧的同位素包括 16O、 17O和 18O，硫的同位素包括 32S、 33S、 34S和 36S，氮的同位素包括 14N和 15N，氟的同位素包括 17F和 19F，氯的同位素包括 35Cl和 37Cl，溴的同位素包括 79Br和 81Br。
“烃基”是指只含碳、氢两种原子的基团。
“烷基”是指1至20个碳原子的直链或支链饱和脂肪族烃基，优选为1至8个(例如1、2、3、4、5、6、7、8个)碳原子的烷基，更优选为1至6个碳原子的烷基，进一步优选为1至4个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、异戊基、新戊基、正己基及其各种支链异构体；当烷基被取代基时，可以任选进一步被1个或者多个取代基所取代。
“杂烷基”是指烷基至少一个C原子被O、S、N或者P原子取代的基团。非限制性实施例包括硫代甲基、硫代乙基、硫代正丙基、硫代异丙基、硫代正丁基、硫代仲丁基、硫代叔丁基。所述的烷基定义与上文所述的“烷基”定义相同。
“烷氧基”是指烷基中至少1个碳原子被氧原子取代所形成的基团。非限制性实施例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、环丙氧基和环丁氧基。所述的烷基定义与上文所述的“烷基”定义相同。
“烯基”是指包含1至10个(例如1、2、3、4、5、6、7、8、9、10个)碳-碳双键，由2至20个碳原子组成的直链或者支链不饱和脂肪族烃基，优选2至12个(例如2、3、4、5、6、7、8、9、10、11、12个)碳原子的烯基，更优选2至8个碳原子的烯基，进一步优选2至6个碳原子的烯基。非限制性实施例包括乙烯基、丙烯-2-基、丁烯-2-基、丁烯-2-基、戊烯-2-基、戊烯-4-基、己烯-2-基、己烯-3基、庚烯-2-基、庚烯-3-基、庚烯-4-基、辛烯-3-基、壬烯-3-基、癸烯-4-基和十一烯-3-基。所述的烯基可以任选进一步被1个或者多个取代基所取代。
“炔基”是指包含1至10个(例如1、2、3、4、5、6、7、8、9、或10个)碳-碳叁键，由2至20个碳原子组成的直链或者支链不饱和脂肪族烃基，优选2至12个(例如2、3、4、5、6、7、8、9、10、11或12个)碳原子的炔基，更优选2至8个碳原子的炔基，进一步优选2至6个碳原子的炔基。非限制性实施例包括乙炔基、丙炔-1-基、丙炔-2-基、丁炔-1-基、丁炔-2-基、丁炔-3-基、3,3-二甲基丁炔-2-基、戊炔-1-基、戊炔-2-基、己炔-1-基、1-庚炔-1-基、庚炔-3-基、庚炔-4-基、辛炔-3-基、壬炔-3-基、癸炔-4-基、十一炔-3-基、十二炔-4-基。所述的炔基可以任选进一步被1至多个取代基所取代。
“芳基”是指是指取代的或未取代的芳香环，其可以是5至8元(例如5、6、7、8元)的单环、5至12元(例如5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系，其可以是桥环或者螺环，非限制性实施例包括苯基、萘基。所述的芳基可以任选进一步被1个或者多个取代基所取代。
“杂芳基”是指取代的或未取代的芳香环，其可以是3至8元(例如3、4、5、6、7、8元)的单环、5至12元(例如5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系，且包含1至6个(例如1、2、3、4、5、6个)选自N、O或S的杂原子，优选5至8元杂芳基，杂芳基的环中选择性取代的1至4个(例如1、2、3、4个)N、S可被氧化成各种氧化态。杂环基可以连接在杂原子或者碳原子上，杂芳基可以是桥环或者螺环，非限制性实施例包括环吡啶基、呋喃基、噻吩基、吡喃基、吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基苯并咪唑基、苯并吡啶基、吡咯并吡啶基。杂芳基任选进一步被1个或多个取代基所取代。
“碳环基”或“碳环”是指饱和或者不饱和的芳香环或者非芳香环。当为芳香环时，其定义与上文“芳基”的定义相同；当为非芳香环时，其可以是3至10元(例如3、4、5、6、7、8、9、10元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系，可以是桥环或者螺环，非限制性实施例包括环丙基、环丁基、环戊基、1-环戊基-1-烯基、1-环戊基-2-烯基、 1-环戊基-3-烯基、环己基、1-环己基-2-烯基、1-环己基-3-烯基、环己烯基、环己二烯基、环庚基、环辛基、环壬基、环癸基、环十一烷基、环十二烷基、
Figure PCTCN2021070728-appb-000013
Figure PCTCN2021070728-appb-000014
所述的“碳环基”或“碳环”任选进一步被1个或者多个取代基所取代。
“杂环基”或“杂环”是指饱和或不饱和的芳香性杂环或者非芳香性杂环，当为芳香性杂环时，其定义与上文“杂芳基”定义相同；当为非芳香性杂环时，其可以是3至10元(例如3、4、5、6、7、8、9、10元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系，且包含1至4个(例如1、2、3、4个)选自N、O或S的杂原子，优选3至8元杂环基。“杂环基”或“杂环”的环中选择性取代的1至4个(例如1、2、3、4个)N、S可被氧化成各种氧化态；“杂环基”或“杂环”可以连接在杂原子或者碳原子上；“杂环基”或“杂环”可以为桥环或者螺环。“杂环基”或“杂环”的非限制性实施例包括环氧乙基、环氧丙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、硫杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、氧杂环庚基、硫杂环庚基、氧氮杂卓基、二氮杂卓基、硫氮杂卓基、吡啶基、哌啶基、高哌啶基、呋喃基、噻吩基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、哌嗪基、高哌嗪基、咪唑基、哌啶基、吗啉基、硫代吗啉基、噻噁烷基、1,3-二噻烷基、二氢呋喃基、二噻戊环基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、苯并咪唑基、苯并吡啶基、吡咯并吡啶基、苯并二氢呋喃基、2-吡咯啉基、3-吡咯啉基、二氢吲哚基、2H-吡喃基、4H-吡喃基、二氧杂环己基、1,3-二氧戊基、吡唑啉基、二噻烷基、二噻茂烷基、二氢噻吩基、吡唑烷基、咪唑啉基、咪唑烷基、1,2,3,4-四氢异喹啉基、3-氮杂双环[3.1.0]己基、3-氮杂双环[4.1.0]庚基、氮杂双环[2.2.2]己基、3H-吲哚基喹嗪基、N-吡啶基尿素、1,1-二氧硫代吗啉基、氮杂二环[3.2.1]辛烷基、
Figure PCTCN2021070728-appb-000015
氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基和氧杂螺[3.3]庚烷基。所述的“杂环基”或“杂环”任选进一步被1个或者多个取代基所取代。
“环烷基”是指饱和的环烃基，其环可以为3至10元(例如3、4、5、6、7、8、9、10元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至20元(例如4、5、6、7、8、9、10、11、12元)多环体系，环碳原子优选3至10个碳原子，进一步优选3至8个碳原子。“环烷基”非限制性实施例包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基、1,5-环辛二烯基、1,4-环己二烯基和环庚三烯基等。当环烷基被取代时，可以任选进一步被1个或者多个取代基所取代。
“杂环烷基”是指取代的或未取代的饱和非芳香环基，其可以是3至8元(例如3、4、5、6、7、8元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系，且包含1、2或3个选自N、O或S的杂原子，优选3至8元杂环基。“杂环烷基”的环中选择性取代的N、S可被氧化成各种氧化态；“杂环烷基”可以连接在杂原子或者碳原子上；“杂环烷基”可以为桥环或者螺环。“杂环烷基”非限制性实施例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、哌啶基、哌叮基、吗啉基、硫代吗啉基、1,3-二噻烷基、四氢呋喃基、四氢吡咯基、四氢 咪唑基、四氢噻唑基、四氢吡喃基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基和氧杂螺[3.3]庚烷基。
当上文所述的“烷基”、“烷氧基”、“烯基”、“炔基”、“芳基”、“杂芳基”、“碳环基”、“碳环”、“杂环基”、“杂环”、“环烷基”、“杂环烷基”或者“杂环基”被取代时，可以任选进一步被0、1、2、3、4、5、6、7、8、9或者10个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、C 1-6烷基氨基、＝O、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、-NR q4R q5、＝NR q6、-C(＝O)OC 1-6烷基、-OC(＝O)C 1-6烷基、-C(＝O)NR q4R q5、C 3-8环烷基、C 3-8杂环烷基、C 6-10芳基、C 5-10杂芳基、-C(＝O)OC 6-10芳基、-OC(＝O)C 6-10芳基、-OC(＝O)C 5-10杂芳基、-C(＝O)OC 5-10杂芳基、-OC(＝O)C 3-8杂环烷基、-C(＝O)OC 3-8杂环烷基、-OC(＝O)C 3-8环烷基、-C(＝O)OC 3-8环烷基、-NHC(＝O)C 3-8杂环烷基、-NHC(＝O)C 6-10芳基、-NHC(＝O)C 5-10杂芳基、-NHC(＝O)C 3-8环烷基、-NHC(＝O)C 3-8杂环烷基、-NHC(＝O)C 2-6烯基或者-NHC(＝O)C 2-6炔基的取代基所取代，且其中所述的取代基C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、C 3-8杂环烷基、C 6-10芳基、C 5-10杂芳基、-NHC(＝O)C 6-10芳基、-NHC(＝O)C 5-10杂芳基、-NHC(＝O)C 3-8杂环烷基或者-NHC(＝O)C 3-8环烷基任选进一步被1至3个选自OH、F、Cl、Br、I、C 1-6烷基、C 1-6烷氧基、-NR q4R q5或者＝O的取代基所取代；R q1选自C 1-6烷基、C 1-6烷氧基或者C 6-10芳基；R q2、R q3选自H或者C1-6烷基；其中，R q4、R q5选自H、C 1-6烷基、-NH(C＝NR q1)NR q2R q3、-S(＝O) 2NR q2R q3、-C(＝O)R q1或者-C(＝O)NR q2R q3，其中所述的C 1- 6烷基任选进一步被1个或者多个选自OH、F、Cl、Br、I、C 1-6烷基、C 1-6烷氧基、C 6- 10芳基、C 5-10杂芳基、C 3-8环烷基或者C 3-8杂环烷基的取代基所取代；或者R q4与R q5及N原子形成一个3至8元杂环，所述的杂环可以包含1个或者多个选自N、O或者S的杂原子。
“氨基酸侧链”是指氨基酸分子中除了氨基和羧基之外的基团。
“药学上可接受的盐”或者“其药学上可接受的盐”是指本发明化合物保持游离酸或者游离碱的生物有效性和特性，且所述的游离酸通过与无毒的无机碱或者有机碱反应获得的盐，所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。
“药物组合物”是指一种或多种本发明所述化合物、其药学上可接受的盐或前药和其它化学组分形成的混合物，其中，“其它化学组分”是指药学上可接受的载体、赋形剂和/或一种或多种其它治疗剂。
“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的材料。
“赋形剂”是指加入到药物组合物中以促进化合物给药的惰性物质。非限制性实施例包括碳酸钙、磷酸钙、糖、淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂和崩解剂。
“前药”是指可经体内代谢转化为具有生物活性的本发明化合物。本发明的前药通过修饰本发明化合物中的氨基或者羧基来制备，该修饰可以通过常规的操作或者在体内被除去，而得到母体化合物。当本发明的前药被施予哺乳动物个体时，前药被割裂形成游离的氨基或者羧基。
“共晶”是指活性药物成分(API)和共晶形成物(CCF)在氢键或其他非共价键的作用下结合而成的晶体，其中API和CCF的纯态在室温下均为固体，并且各组分间存在固定的化学计量比。共晶是一种多组分晶体，既包含两种中性固体之间形成的二元共晶，也包含中性固体与盐或溶剂化物形成的多元共晶。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体和构象异构体。
“任选”或“任选地”或“选择性的”或“选择性地”是指随后所述的事件或状况可以但未 必发生，该描述包括其中发生该事件或状况的情况及其中未发生的情况。例如，“选择性地被烷基取代的杂环基”是指该烷基可以但未必存在，该描述包括其中杂环基被烷基取代的情况，及其中杂环基未被烷基取代的情况。
本发明说明书对具体实施方案进行了详细描述，本领域技术人员应认识到，下述实施方案是示例性的，不能理解为对本发明的限制，对于本领域技术人员来说，在不脱离本发明原理的前提下，通过对本发明进行若干改进和修饰，这些改进和修饰获得技术方案也落在本发明的权利要求书的保护范围内。
具体实施方式
以下实施例详细说明本发明的技术方案，但本发明的保护范围包括但是不限于此。
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker Avance 300)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代氯仿(CDCl 3)，氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)；
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))；
HPLC的测定使用Agilent 1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm,3.5μM)；
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm-0.20mm，薄层层析分离纯化产品采用的规格是0.4mm-0.5mm；
柱层析一般使用烟台黄海硅胶200-300目硅胶为载体；
本发明的己知起始原料可以采用或按照本领域已知的方法来合成，或可购买于泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、百灵威科技等公司；
氮气氛是指反应瓶连接约1L容积的氮气气球；
氢气氛是指反应瓶连接约1L容积的氢气气球；
氢化反应通常抽真空，充入氢气，反复操作3次；
实施例中无特殊说明，反应在氮气氛下进行；
实施例中无特殊说明，溶液是指水溶液；
实施例中无特殊说明，反应的温度为室温，室温最适宜的反应温度，为20℃-30℃；
DCM：二氯甲烷；
EA：乙酸乙酯；
HCl：盐酸；
THF：四氢呋喃；
DMF：N,N-二甲基甲酰胺；
PE:石油醚；
TLC:薄层色谱；
SFC：超临界流体色谱法；
NCS：N-氯代丁二酰亚胺；
Pd(dppf)Cl 2：[1,1'-双(二苯基膦)二茂铁]二氯化钯；
实施例
以下实施例详细说明本发明的技术方案，但本发明的保护范围包括但是不限于 此。
实施例1
isopropyl((ethoxycarbonyl)(((1'R,2'R)-6-hydroxy-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2-yl)oxy)phosphoryl)-L-alaninate
异丙基((乙氧基羰基)(((1'R,2'R)-6-羟基-5'-甲基-4-戊基-2'-(丙-1-烯-2-基)-1',2',3',4'-四氢-[1,1'-联苯]-2-基)氧基)磷酰基)-L-丙氨酸盐(化合物1)
Figure PCTCN2021070728-appb-000016
在干燥的圆底烧瓶中将(二氯磷酰基)甲酸乙酯(0.31g,1.6mmol)溶解于二氯甲烷(1ml)，在-60℃下加入三乙胺(0.25mL,1.1eq)，然后滴加L-丙氨酸异丙酯盐酸盐(0.16g,0.95mmol,0.6eq)溶解于二氯甲烷的溶液，-60℃下搅拌1.5小时。(1'R,2'R)-5'-甲基-4-戊基-2'-(丙-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯基]-2,6-二醇1(0.78g,1.6mmol,1eq)和三乙胺(0.5mL,2.2eq)依次加到反应溶液中，然后缓慢升至室温，搅拌过夜。LC-MS监测至反应结束。在0℃下加入氯化铵饱和溶液，在用二氯甲烷萃取。有机相用硫酸钠干燥、旋干，残留物使用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝10:1～1:10)，得到标题化合物1异丙基((乙氧基羰基)((((1'R,2'R)-6-羟基-5'-甲基-4-戊基-2'-(丙-1-烯-2-基)-1’,2',3’,4'-四氢-[1,1'-联苯]-2-基)氧基)磷酰基)-L-丙氨酸盐的异构体1-1(113mg，33.5％产率，黄色油状物)和异构体1-2(64mg，19.3％产率，黄色油状物)。
异构体1-1。
1H NMR(300MHz,Chloroform-d)δ6.78(s,1H),6.49(s,1H),6.04(s,1H),5.54(s,1H),5.07-4.99(m,1H),4.66(s,1H),4.21(s,1H),4.31–4.08(m,3H),3.84–3.77(m,2H),2.49–2.44(m,3H),2.19–2.11(m,1H),2.04-1.55(m,10H),1.39–1.21(m,16H),0.87(t,3H)。
31P NMR(121MHz,Chloroform-d):-2.98。
LC-MS m/z(ESI)＝564.19[M+1]。
异构体1-2
1H NMR(300MHz,Chloroform-d)δ6.68(s,1H),6.47(s,1H),6.12(s,1H),5.55(s,1H),5.02-4.94(m,1H),4.52(s,1H),4.35(s,1H),4.28–4.04(m,3H),3.87–3.72(m,2H),2.45–2.40(m,3H),2.19–2.08(m,1H),1.79-1.46(m,10H),1.39–1.21(m,16H),0.84(t,3H)。
31P NMR(121MHz,Chloroform-d):-3.47。
LC-MS m/z(ESI)＝564.20[M+1]。
实施例2
ethyl((ethoxycarbonyl)(((1'R,2'R)-6-hydroxy-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2-yl)oxy)phosphoryl)-L-alaninate
乙基((乙氧基羰基)(((1'R,2'R)-6-羟基-5'-甲基-4-戊基-2'-(丙-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2-基)氧基)磷酰基)-L-丙氨酸盐(化合物2)
Figure PCTCN2021070728-appb-000017
化合物2的合成与分离方法与化合物1相同，得到标题化合物2的异构体2-1(68mg，8.1％产率，黄色油状物)和异构体2-2(77mg,6.7％产率，黄色油状物)。
异构体2-1
1H NMR(300MHz,Chloroform-d)δ6.78(s,1H),6.49(s,1H),6.04(s,1H),5.54(s,1H),4.65(s,1H),4.42(s,1H),4.22-4.15(m,4H),3.87–3.84(m,1H),3.79–3.72(m,1H),2.49–2.44(m,3H),2.23–2.04(m,2H),1.82–1.52(m,10H),1.41–1.24(m,13H),0.87(t,3H)。
31P NMR(121MHz,Chloroform-d):-2.98。
LC-MS m/z(ESI)＝550.22[M+1]。
异构体2-2
1H NMR(300MHz,Chloroform-d)δ6.69(s,1H),6.49(s,1H),6.09(s,1H),5.58(s,1H),4.55(s,1H),4.36(s,1H),4.31-4.10(m,4H),3.87–3.84(m,1H),3.77–3.70(m,1H),2.47–2.42(m,3H),2.20–2.04(m,2H),1.82–1.51(m,10H),1.32–1.22(m,13H),0.86(t,3H)。
31P NMR(121MHz,Chloroform-d):-3.49。
LC-MS m/z(ESI)＝550.20[M+1]。
实施例3
benzyl((ethoxycarbonyl)(((1'R,2'R)-6-hydroxy-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2-yl)oxy)phosphoryl)-L-alaninate
苄基((乙氧羰基)(((1'R,2'R)-6-羟基-5'-甲基-4-戊基-2'-(丙-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2-基)氧基)磷酰基)-L-丙氨酸盐(化合物3)
Figure PCTCN2021070728-appb-000018
化合物3的合成与分离方法与化合物1相同，得到标题化合物3的异构体3-1(66mg，5.7％产率，黄色油状物)和异构体3-2(76mg,6.3％产率，黄色油状物)。
异构体3-1
1H NMR(300MHz,Chloroform-d)δ7.39-7.29(m,5H),6.78(s,1H),6.49(s,1H),6.04(s,1H),5.53(s,1H),5.21–5.11(m,2H),4.63(s,1H),4.41(s,1H),4.33-4.10(m,3H),3.87–3.74(m,2H),2.46(t,3H),2.22–2.04(m,2H),1.83–1.20(m,20H),0.86(t,3H)。
31P NMR(121MHz,Chloroform-d):-3.05。
LC-MS m/z(ESI)＝612.45[M+1]。
异构体3-2
1H NMR(300MHz,Chloroform-d)δ7.39-7.29(m,5H),6.70(s,1H),6.49(s,1H),6.09(s,1H),5.55(s,1H),5.18–5.09(m,2H),4.54(s,1H),4.36(s,1H),4.27-4.20(m,3H),3.87–3.71(m,2H),2.45(t,3H),2.26–2.10(m,2H),1.83–1.18(m,20H),0.86(t,3H)。
31P NMR(121MHz,Chloroform-d):-3.61。
LC-MS m/z(ESI)＝612.53[M+1]。
实施例4
ethyl((((1'R,2'R)-6-hydroxy-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2-yl)oxy)(isopropoxycarbonyl)phosphoryl)-L-alaninate
乙基((((1'R,2'R)-6-羟基-5'-甲基-4-戊基-2'-(丙-1-烯-2-基)-1’,2’,3’,4′-四氢-[1，1′-联苯]-2-基)氧基)(异丙氧基羰基)磷酰基)-L-丙氨酸盐(化合物4)
Figure PCTCN2021070728-appb-000019
化合物4的合成与分离方法与化合物1相同，得到标题化合物4的异构体4-1(85mg，7.9％产率，黄色油状物)和异构体4-2(129mg,12％产率，黄色油状物)。
异构体4-1
1H NMR(300MHz,Chloroform-d)δ6.78(s,1H),6.48(s,1H),6.04(s,1H),5.54(s,1H),5.19-5.13(m,1H),4.65(s,1H),4.42(s,1H),4.22-4.14(m,4H),3.87–3.84(m,1H),3.78–3.71(m,1H),2.48–2.43(m,3H),2.22–2.10(m,2H),1.81–1.49(m,10H),1.40–1.1.23(m,15H),0.87(t,3H)。
31P NMR(121MHz,Chloroform-d):-2.86。
LC-MS m/z(ESI)＝564.28[M+1]。
异构体4-2
1H NMR(300MHz,Chloroform-d)δ6.70(s,1H),6.48(s,1H),6.07(s,1H),5.58(s,1H),5.17-5.12(m,1H),4.54(s,1H),4.37(s,1H),4.19-4.07(m,4H),3.89–3.86(m,1H),3.75–3.68(m,1H),2.47–2.42(m,3H),2.24–2.05(m,2H),1.79–1.42(m,10H),1.32–1.18(m,15H),0.86(t,3H)。
31P NMR(121MHz,Chloroform-d):-3.39。
LC-MS m/z(ESI)＝564.51[M+1]。
实施例5
isopropyl 2-(((ethoxycarbonyl)(((1'R,2'R)-6-hydroxy-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2-yl)oxy)phosphoryl)amino)-2-methylpropanoate
异丙基2-(((乙氧羰基)(((1'R,2'R)-6-羟基-5'-甲基-4-戊基-2'-(丙-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2-基)氧基)磷酰基)氨基)-2-甲基丙酸酯(化合物4)
Figure PCTCN2021070728-appb-000020
化合物5的合成与分离方法与化合物1类似，得到标题化合物5的异构体5-1(760mg，4.4％产率，白色固体)和异构体5-2(691mg,4％产率,白色固体)。
异构体5-1
1H NMR(300MHz,Chloroform-d)δ6.78(s,1H),6.45(s,1H),6.09(s,1H),5.48(s, 1H),4.57–3.81(m,6H),2.43–1.95(m,5H),1.72–1.50(m,16H),1.26–1.19(m,13H),0.81(t,3H)。
31P NMR(121MHz,Chloroform-d):-3.43。
LC-MS m/z(ESI)＝578.47[M+1]。
异构体5-2
1H NMR(300MHz,Chloroform-d)δ6.69(s,1H),6.43(s,1H),6.01(s,1H),5.47(s,1H),5.00–4.92(m,1H),4.46–3.82(m,6H),2.40–1.97(m,5H),1.70–1.44(m,16H),1.21–1.16(m,13H),0.79(t,3H)。
31P NMR(121MHz,Chloroform-d):-3.65。
LC-MS m/z(ESI)＝578.65[M+1]。
实施例6
isopropyl((((1'R,2'R)-6-hydroxy-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrah-ydro-[1,1'-biphenyl]-2-yl)oxy)(isopropoxycarbonyl)phosphoryl)-L-alaninate
异丙基((((1'R,2'R)-6-羟基-5'-甲基-4-戊基-2'-(丙-1-烯-2-基)-1’,2’,3’,4′-四氢-[1.1′-联苯]-2-基)氧基)(异丙氧基羰基)磷酰基)-L-丙氨酸盐(化合物6)
Figure PCTCN2021070728-appb-000021
化合物6的合成与分离方法与化合物1相同，得到标题化合物6的异构体6-1(30mg，1.8％产率，黄色油状物)和异构体6-2(120mg,7,3％产率，白色固体)。
异构体6-1
1H NMR(300MHz,Chloroform-d)δ6.78(s,1H),6.49(s,1H),6.04(s,1H),5.55(s,1H),5.18-5.01(m,2H),4.66(s,1H),4.42(s,1H),4.19–4.16(m,1H),3.88–3.77(m,2H),2.49–2.44(m,3H),2.21–2.05(m,2H),1.79-1.37(m,10H),1.28–1.19(m,19H),0.87(t,3H)。
31P NMR(121MHz,Chloroform-d):-2.89。
LC-MS m/z(ESI)＝578.05[M+1]。
异构体6-2
1H NMR(300MHz,Chloroform-d)δ6.70(s,1H),6.49(s,1H),6.08(s,1H),5.59(s,1H),5.17-4.99(m,2H),4.55(s,1H),4.37(s,1H),4.12–3.70(m,3H),2.47–2.42(m,3H),2.21–2.04(m,2H),1.81-1.51(m,10H),1.32–1.19(m,19H),0.87(t,3H)。
31P NMR(121MHz,Chloroform-d):-3.38。
LC-MS m/z(ESI)＝578.12[M+1]。
实施例7
isopropyl 2-(((((1'R,2'R)-6-hydroxy-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2-yl)oxy)(isopropoxycarbonyl)phosphoryl)amino)-2-methylpropanoate
异丙基2-(((((1'R,2'R)-6-羟基-5'-甲基-4-戊基-2'-(丙-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2-基)氧基)(异丙氧基羰基)磷酰基)氨基)-2-甲基丙酸酯(化合物7)
Figure PCTCN2021070728-appb-000022
化合物7的合成与分离方法与化合物1类似，得到标题化合物7的异构体7-1(21mg，1.2％产率，黄色油状物)和异构体7-2(163mg,9.3％产率，黄色油状物)。
异构体7-1
1H NMR(300MHz,Chloroform-d)δ6.81(s,1H),6.46(s,1H),6.04(s,1H),5.53(s,1H),5.18–5.09(m,1H),5.07-4.99(m,1H),4.62(s,1H),4.40(s,1H),4.19(d,1H),3.86(d,1H),2.47–2.42(m,3H),2.21-2.03(m,2H),1.81–1.21(m,32H),0.85(t,3H)。
31P NMR(121MHz,Chloroform-d):-3.36。
LC-MS m/z(ESI)＝592.45[M+1]。
异构体7-2
1H NMR(300MHz,Chloroform-d)δ6.75(s,1H),6.47(s,1H),6.04(s,1H),5.58(s,1H),5.29–5.12(m,1H),5.06-4.98(m,1H),4.55(s,1H),4.38(s,1H),4.12(d,1H),3.87(d,1H),2.48–2.43(m,3H),2.20-2.04(m,2H),1.83–1.20(m,32H),0.86(t,3H)。
31P NMR(121MHz,Chloroform-d):-3.39。
LC-MS m/z(ESI)＝592.10[M+1]。
实施例8
ethyl 2-(((ethoxycarbonyl)(((1'R,2'R)-6-hydroxy-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2-yl)oxy)phosphoryl)amino)-2-methylpropanoate
乙基2-(((((1'R,2'R)-6-羟基-5'-甲基-4-戊基-2'-(丙-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2-基)氧基)(异丙氧基羰基)磷酰基)氨基)-2-甲基丙酸酯(化合物8)
Figure PCTCN2021070728-appb-000023
化合物8的合成与分离方法与化合物1类似，得到标题化合物8的异构体8-1(180mg，5％产率，黄色油状物)和异构体8-2(175mg,5％产率，黄色油状物)。
异构体8-1
1H NMR(300MHZ,Chloroform-d)δ6.81(s,1H),6.47(s,1H),6.06(s,1H),5.53(s,1H),4.61(s,1H),4.39(s,1H),4.30-4.23(m,2H),4.20-4.12(m,2H),3.84(d,1H),2.45(t,2H),2.18(s,1H),2.10-2.03(m,1H),1.77(s,1H),1.68-1.61(m,2H),1.64(s,6H),1.59-1.48(m,2H),1.56(s,6H),1.30-1.24(m,6H),0.85(t,3H)。
31P NMR(121MHz,Chloroform-d):-3.45。
LC-MS m/z(ESI)＝564.40[M+1]。
异构体8-2
1H NMR(400MHZ,Chloroform-d)δ6.74(s,1H),6.47(s,1H),6.07(s,1H),5.56(s,1H),4.54(s,1H),4.36(s,1H),4.32-4.24(m,2H),4.21-4.02(m,2H),3.84(d,12.0Hz,1H),2.44(t,2H),2.19(s,1H),2.10-2.03(m,1H),1.78(s,1H),1.64-1.56(m,2H),1.60(s,3H),1.59(s,3H)1.55-1.47(m,2H),1.49(s,6H),1.32-1.20(m,6H),0.85(t,3H)。
31P NMR(121MHz,Chloroform-d):-3.56。
LC-MS m/z(ESI)＝564.40[M+1]。
实施例9
isopropyl((ethoxycarbonyl)((6-hydroxy-5'-(methyl-d3)-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2-yl)oxy)phosphoryl)-L-alaninate
异丙基((乙氧基羰基)((6-羟基-5'-(甲基-d3)-4-戊基-2'-(丙-1-烯-2-基)-1',2',3',4'-四氢-[1,1'-联苯]-2-基)氧基)磷酰基)-L-丙氨酸盐(化合物9)
Figure PCTCN2021070728-appb-000024
第一步：
3-ethoxy-6-(2-hydroxypropan-2-yl)cyclohex-2-en-1-one
3-乙氧基-6-(2-羟丙基-2-基)环己-2-烯-1-酮9b
在-70℃、氮气保护下，将3-乙氧基环己-2-烯-1-酮9a(10.0g，71.0mmol)滴加到二异丙基氨基锂(54mL，107.0mmol，2.0N)的四氢呋喃(100mL)溶液中，滴毕搅拌反应0.5h；滴加丙酮(9.2g，142.0mmol)，滴毕继续搅拌3h；TLC检测至反应结束；滴加饱和氯化铵溶液(180mL)淬灭反应，分液，水相用乙酸乙酯(150mL×2)萃取，合并有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到标题化合物9b(黄色油状物，18.0g，产率：99.0％)。
1H NMR(400MHz,DMSO).δ5.29(s,1H),4.93(s,1H),3.98–3.87(m,2H),2.46(dd,J＝11.2,5.0Hz,1H),2.37(dt,J＝17.4,4.5Hz,1H),2.21(dd,J＝12.1,4.7Hz,1H),2.12–2.03(m,1H),1.67(ddd,J＝24.2,12.3,5.1Hz,1H),1.27(t,J＝7.0Hz,3H),0.99(s,3H),0.73(s,3H)。
LC-MS m/z(ESI)＝199.21[M+1]。
第二步：
4-(2-hydroxypropan-2-yl)cyclohex-2-en-1-one
4-(2-羟基丙烷-2-基)环己-2-烯-1-酮9c
在0℃，氮气保护下，将红铝(67mL，234.1mmol，3.5N)滴加到化合物9b(17.0g，78.0mmol)的四氢呋喃(200mL)溶液中，滴毕缓慢升至室温搅拌反应2h；TLC检测 至反应结束；降至0℃，滴加饱和氯化铵溶液(13mL)淬灭，抽滤，水相用乙酸乙酯(200mL×2)萃取，合并有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品加入四氢呋喃(40mL)溶解，滴加盐酸水溶液(40mL，2N)，滴毕室温搅拌反应1.5h；TLC检测至反应结束，滴加饱和碳酸氢钠溶液淬灭反应，减压浓缩，水相用乙酸乙酯(100mL×4)萃取，合并有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩经硅胶柱层析(洗脱剂：乙酸乙酯/石油醚(v/v)＝1/3)纯化，得到标题化合物9c(无色油状物，5.8g，产率：48.0％)。
1H NMR(400MHz,DMSO)δ7.19(dt,J＝10.4,1.9Hz,1H),5.93(dd,J＝10.4,2.8Hz,1H),4.58(s,1H),2.44–2.38(m,1H),2.38–2.29(m,2H),2.08–1.96(m,1H),1.62(tdd,J＝12.9,9.4,5.0Hz,1H),0.99(s,3H),0.73(s,3H)。
LC-MS m/z(ESI)＝155.40[M+1]。
第三步：
4-(2-hydroxypropan-2-yl)-1-(methyl-d3)cyclohex-2-en-1-ol
4-(2-羟基丙烷-2-基)-1-(甲基-d3)环己-2-烯-1-醇9d
在0℃，氮气保护下，将氘代甲基碘化镁(34mL，33.7mmol，1.0N)滴加到无水氯化锂(1.4g，33.7mmol)的四氢呋喃(20mL)溶液中，滴毕搅拌反应0.5h；滴加化合物9c(1.8g，11.2mmol)的四氢呋喃溶液(5mL)，滴毕搅拌反应0.5h；TLC检测至反应结束；滴加饱和氯化铵溶液(20mL)淬灭，水相用乙酸乙酯(50mL×3)萃取，合并有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品，经硅胶柱层析(洗脱剂：乙酸乙酯/石油醚(v/v)＝2/1)纯化，得到标题化合物9d(白色固体，1.2g，产率：60.0％)。
1H NMR(400MHz,DMSO)δ5.61(d,J＝10.4Hz,1H),5.52(d,J＝10.6Hz,1H),4.38(s,1H),4.17(s,1H),2.00(ddd,J＝10.8,5.1,2.4Hz,1H),1.73–1.65(m,2H),1.57–1.48(m,1H),1.21(dd,J＝10.1,6.8Hz,1H),0.99(s,3H),0.73(s,3H)。
LC-MS m/z(ESI)＝174.62[M+1]。
第四步：
2'-(2-hydroxypropan-2-yl)-5'-(methyl-d3)-4-pentyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol
2'-(2-羟基丙-2-基)-5'-(甲基-d3)-4-戊基-1’,2’,3’,4'-四氢-[1,1'-联苯]-2，6-二酚9e
将4-(2-羟基丙烷-2-基)-1-(甲基-d3)环己-2-烯-1-醇9d(2.37g,13.7mmol)，3,5-二羟基戊苯(3.7g，20.6mmol)和4A分子筛(6g)溶于30mL二氯甲烷中，置换氮气，室温搅拌20分钟。最后加入左旋樟脑磺酸(317.8mg，1.37mmol)。室温搅拌1小时。向反应液中加入60mL饱和碳酸氢钠水溶液淬灭反应，乙酸乙酯萃取(30mL×4)。合并有机相，用无水硫酸钠干燥，过滤，浓缩得到粗品。经硅胶柱层析(洗脱剂：乙酸乙酯/石油醚(v/v)＝1/6)纯化，得到标题化合物9e(无色油状物，1.3g，产率：28.5％)。
1H NMR(400MHz,DMSO)δ9.04–8.43(m,2H),6.03(s,2H),4.89(s,1H),3.66(m,2H),2.32(m,3H),2.14–2.06(m,1H),2.02(m,1H),1.88–1.79(m,1H),1.47(m,2H),1.32–1.19(m,5H),0.97(s,3H),0.85(t,3H),0.80(s,3H)。
LC-MS m/z(ESI)＝336.20[M+1]。
第五步：
5'-(methyl-d3)-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol
5'-(甲基-d3)-4-戊基-2'-(丙-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二酚9f
在0℃下，向反应瓶中依次加入化合物9e(1.3g，3.9mmol)、伯吉斯试剂(1.1g， 4.7mmol)和四氢呋喃(10mL)，氮气保护下搅拌反应3h；TLC检测至反应结束；加入乙酸乙酯(50mL)，有机相用饱和食盐水(40mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品，经硅胶柱层析(洗脱剂：乙酸乙酯/石油醚(v/v)＝1/15)纯化，得到标题化合物9f(无色油状物，794mg，产率：64.0％)。
1H NMR(400MHz,DMSO)δ8.65(s,2H),6.01(s,2H),5.08(s,1H),4.49(d,1H),4.43–4.37(d,1H),3.85–3.78(m,1H),3.08–2.98(m,1H),2.32–2.26(m,2H),2.13–2.04(m,1H),1.95–1.87(m,1H),1.71–1.63(m,1H),1.58(s,3H),1.47(m,2H),1.35–1.22(m,5H),0.86(t,3H)。
LC-MS m/z(ESI)＝318.20[M+1]。
第六步
isopropyl((ethoxycarbonyl)((6-hydroxy-5'-(methyl-d3)-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2-yl)oxy)phosphoryl)-L-alaninate
异丙基((乙氧基羰基)((6-羟基-5'-(甲基-d3)-4-戊基-2'-(丙-1-烯-2-基)-1',2',3',4'-四氢-[1,1'-联苯]-2-基)氧基)磷酰基)-L-丙氨酸盐(化合物9)
采用化合物1的合成方法制备得到标题化合物9(69mg,23％产率，黄色油状物)。
LC-MS m/z(ESI)＝567.39[M+1]。
以下中间体按照表格中标注方法合成
Figure PCTCN2021070728-appb-000025
Figure PCTCN2021070728-appb-000026
Figure PCTCN2021070728-appb-000027
采用化合物1的合成方法，制备得到如下化合物：
Figure PCTCN2021070728-appb-000028
Figure PCTCN2021070728-appb-000029
Figure PCTCN2021070728-appb-000030
大鼠药代动力学
取健康成年SD大鼠3只，禁食过夜(自由饮水)后，给予灌胃(p.o.)给药(50mg/kg)。于给药后30min、1h、8h从颈静脉丛采血0.1mL。所有血样使用K 2EDTA抗凝，随后5℃，3500rpm离心10min分离血浆，于-20℃保存待测。建立LC/MS/MS法测定血浆中的原形药物浓度。
采用上述方法，测得化合物的原型药物在大鼠体内各时间点血药浓度(ng/mL)如下：
编号 给药剂量 原型药物 30min 1h 8h
化合物1 50mg/kg CBD 1408 1754 151.7
化合物3 50mg/kg CBD 1376 1604 145.9
化合物5 50mg/kg CBD 1388 1653 160.8
化合物9 50mg/kg 9f 1577 1993 260.5
化合物10 50mg/kg 中间体10 1409 1846 164.9
化合物11 50mg/kg 中间体11 1570 1982 248.3
化合物12 50mg/kg 中间体12 1593 2027 271.1
化合物13 50mg/kg 中间体13 1568 1981 260.9
化合物14 50mg/kg 中间体14 1674 2070 264.6
化合物18 50mg/kg 中间体18 1775 2280 299.1
化合物22 50mg/kg 中间体22 1401 1682 143.0
化合物24 50mg/kg 中间体24 1383 1691 170.2
化合物25 50mg/kg 中间体25 1566 1940 242.2
化合物26 50mg/kg 中间体26 1559 1969 268.3
化合物27 50mg/kg 中间体27 1402 1675 144.9
实验结果表明，本发明化合物经口服灌胃后，可在血浆中检测到原型药物浓度，表明本化合物具有口服吸收特性，且能在体内快速转化为原型药，并且具有比原型药更好的口服生物利用度。
本发明说明书对具体实施方案进行了详细描述，本领域技术人员应认识到，上述实施方案是示例性的，不能理解为对本发明的限制，对于本领域技术人员来说，在不脱离本发明原理的前提下，通过对本发明进行若干改进和修饰，这些改进和修饰获得技术方案也落在本发明的权利要求书的保护范围内。

Claims (7)

  1. 通式(I)所示的化合物，或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐或共晶：
    Figure PCTCN2021070728-appb-100001
    其中：
    X选自氢、羟基、C 1-6烷基或者卤素；
    Y选自氢、羧酸、C 1-6烷基或者卤素；
    r选自0、1、2或者3；
    n选自0、1或者2；
    R 0选自甲基、C 3-8碳环基、-CH 2OH、-C(＝O)OC 1-6烷基、-C(＝O)NR b1R b2或者羧基；
    R 1选自C 1-6烷基，所述的C 1-6烷基任选进一步被0至3个卤素所取6代；
    R 2为
    Figure PCTCN2021070728-appb-100002
    Ra选自H或者C 1-6烷基；
    R b、R c各自独立地选自H、C 1-6烷基、氨基酸侧链、-C 1-6亚烷基-C 3-12碳环或者-C 1-6亚烷基-C 3-12杂环；所述的C 3-12杂环包含1至4个选自N、O或者S的杂原子；所述的C 1-6亚烷基、C 1-6烷基、C 3-12碳环、C 3-12杂环任选地进一步被0至3个选自羟基、羧基、卤素、氰基、＝O、C 1-6烷基、C 1-6杂烷基、C 2-6烯基、C 2-6炔基、-NR b1R b2、-C(＝O)OC 1-6烷基、-C(＝O)NR b1R b2、C 3-12环烷基、C 3-12杂环烷基、C 6-12芳基或者C 5-12杂芳基的取代基所取代；且作为取代基的所述的C 1-6烷基、C 1-6杂烷基、C 2-6烯基或者C 2-6炔基任选进一步被1个或者多个选自羟基、羧基、氰基、卤素、-O-R b1、-NR b1R b2、C 3-12环烷基、C 3-12杂环烷基、C 6-12芳基或者C 5-12杂芳基的取代基所取代；当所述的氨基酸侧链包含羟基、巯基或羧基时，所述羟基、巯基或羧基任选地被酯化；
    R b1、R b2各自独立地选自H、C 1-6烷基、-C(＝O)R b3或者-C(＝O)NR b4R b5，其中所述的C 1-6烷基任选进一步被1个或者多个选自羟基、卤素、C 1-6烷基、C 1-6烷氧基、C 6-12芳基、C 5-12杂芳基、C 3-12环烷基或者C 3-12杂环烷基的取代基所取代；
    R b3选自C 1-6烷基、C 1-6烷氧基或者C 6-12芳基；
    R b4、R b5各自独立地选自H或者C 1-6烷基；或者R b4与R b5及N原子形成一个3至12元杂环，所述的3至12元杂环包含1至4个选自N、O或者S的杂原子；
    或者，R b和R c与其所连接的原子一起形成3至6元碳环或者3至6元杂环，所述3至6元碳环或者3至6元杂环任选进一步被0至3个选自F、Cl、Br、I、羟基、羧基或氨基的取代基所取代，所述的3至6元杂环包含1至4个选自N、O或者S的杂原子；
    R d选自C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10碳环、3至10元杂环、-C 1-6亚烷基-C 3-10碳环、-C 1-6亚烷基-3至10元杂环、-C 1-6亚烷基-O-C 1-6亚烷基-C 3-10碳环、-C 1-6亚烷基-O- C 1-6亚烷基-3至10元杂环或-C 1-6亚烷基-O-C 1-4烷基，所述C 1-6亚烷基、C 2-6烯基、C 2-6炔基、C 1-6烷基、C 3-10碳环或3至10元杂环任选进一步被0至4个选自H、F、Cl、Br、I、羟基、羧基、氨基、1-环丙基乙基、C 1-4烷基、C 1-4烷氧基、-OC(＝O)ORd1或-OC(＝O)Rd2的取代基所取代，所述3至10元杂环包含1至6个选自N、O或者S的杂原子；
    R d1和R d2各自独立地选自C 1-4烷基、C 3-10碳环或3至10元杂环，所述C 1-4烷基、C 3-10碳环或3至10元杂环任选进一步被0至4个选自H、F、Cl、Br、I、羟基、羧基、C 1-4烷基、C 1-4烷氧基、C 3-10碳环或3至10元杂环的取代基所取代，所述3至10元杂环包含1至6个选自N、O或者S的杂原子；
    R 3选自选自C 1-6烷基、C 3-8碳环基或者C 2-6烯基，所述的C 1-6烷基、C 2-6烯基、C 3-8碳环基任选进一步被0至3个选自卤素、C 3-8碳环基、羟基或者C 1-6烷基的取代基所取代；
    R 4选自H、羟基、C 1-6烷氧基、-C(＝O)ORd1、-C(＝O)Rd1、-C(＝O)CH(NH 2)-R或者
    Figure PCTCN2021070728-appb-100003
    且-C(＝O)CH(NH 2)-R中的氨基任选地与氨基酸形成多肽链；
    R选自氨基酸侧链；当所述的氨基酸侧链包含羟基、巯基或羧基时，所述羟基、巯基或羧基任选地被酯化；
    R 5选自C 1-12烷基、C 1-12杂烷基、C 2-12烯基、C 2-12炔基、C 3-12碳环基、C 3-12杂环基、-C 1-6亚烷基-C 3-12碳环基、-C 1-6亚烷基-C 3-12杂环基、-NR b1R b2、-C 1-6亚烷基-C(＝O)OC 1-6烷基或者-C 1-6亚烷基-C(＝O)NR b1R b2，且所述的C 1-12烷基、C 1-12杂烷基、C 2-12烯基、C 2-12炔基、C 1-6亚烷基、C 3-12碳环基、C 3-12杂环基任选被1个或者多个选自羟基、羧基、卤素、氰基、＝O、C 1-6烷基、-NR b1R b2、C 3-12碳环基、C 3-12杂环基、C 2-6烯基、C 2-6炔基、-C(＝O)OC 1-6烷基、-C(＝O)C 1-6烷基、-C(＝O)NR b1R b2、-S(＝O)C 1-6烷基或者-S(＝O) 2C 1-6烷基的取代基所取代，且作为取代基的所述的C 1-6烷基、C 3-12碳环基、C 3-12杂环基任选进一步被1个或者多个选自＝O、羟基、羧基、卤素、氰基、-C(＝O)OC 1-6烷基或者-C(＝O)C 1-6烷基的取代基所取代；
    Figure PCTCN2021070728-appb-100004
    为单键或者双键；
    或者，通式(I)任选被1个或者多个D原子取代。
  2. 根据权利要求1所述的化合物，或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐或共晶，其中所述化合物为通式(II)所示的化合物：
    Figure PCTCN2021070728-appb-100005
    其中，
    R 0选自甲基或者-CH 2OH；
    R 1为C 1-6烷基；
    R 2为
    Figure PCTCN2021070728-appb-100006
    R a为H；
    R b、R c各自独立地选自H或者氨基酸侧链；当所述的氨基酸侧链包含羟基、巯基或羧基时，所述羟基、巯基或羧基任选地被酯化；
    R d选自C 1-6烷基、C 3-10碳环或者3至10元杂环，所述C 1-6烷基、C 3-10碳环或3至10元杂环任选进一步被0至4个选自H、F、Cl、Br、I、羟基、羧基、氨基、1-环丙基乙基、C 1-4烷基、C 1-4烷氧基、-OC(＝O)ORd1或-OC(＝O)Rd2的取代基所取代，所述3至10元杂环包含1至6个选自N、O或者S的杂原子；
    Rd1和Rd2各自独立地为C 1-4烷基；
    或者，通式(II)任选被1个或者多个D原子取代。
  3. 根据权利要求2所述的化合物，或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐或共晶，其中所述化合物为通式(III)所示的化合物：
    Figure PCTCN2021070728-appb-100007
    其中，
    R 1为C 1-6烷基；
    R 2为
    Figure PCTCN2021070728-appb-100008
    Rd选自C 1-6烷基、C 3-10碳环或者3至10元杂环，所述C 1-6烷基、C 3-10碳环或3至10元杂环任选进一步被0至4个选自H、F、Cl、Br、I、羟基、羧基、氨基、1-环丙基乙基、C 1-4烷基、C 1-4烷氧基、-OC(＝O)ORd1或-OC(＝O)Rd2的取代基所取代，所述3至10元杂环包含1至6个选自N、O或者S的杂原子；
    Rd1和Rd2各自独立地为C 1-4烷基；
    或者，通式(III)任选被1个或者多个D原子取代。
  4. 根据权利要求1-3中任一项所述的化合物，或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐或共晶，其中该化合物为如下结构之一：
    Figure PCTCN2021070728-appb-100009
    Figure PCTCN2021070728-appb-100010
    Figure PCTCN2021070728-appb-100011
    Figure PCTCN2021070728-appb-100012
    或者
    Figure PCTCN2021070728-appb-100013
  5. 药物组合物，所述药物组合物包含：
    (1)权利要求1至4中任一项所述的化合物或其立体异构体、溶剂化物、代谢产物、药学上可接受的盐或共晶；
    (2)任选的一种或者多种其他活性成分；以及
    (3)药学上可接受的载体和/或赋形剂。
  6. 根据权利要求5的药物组合物，其特征在于，所述的其他活性成分选自银杏内酯、抗肿瘤剂、抗凝血剂、抗癫痫剂、抗抑郁剂、抗焦虑剂、催眠剂、镇痛剂或者麻醉剂中的一种或多种，或者所述的其他活性成分的立体异构体、溶剂化物、代谢产物、药学上可接受的盐或共晶；优选地，所述银杏内酯为银杏内酯A、银杏内酯B、银杏内酯C、银杏内酯D、银杏内酯J、银杏内酯M、银杏内酯K、银杏内酯L、银杏内酯N、银杏内酯P、银杏内酯Q、白果内酯中的一种或两种及以上以任意比例的组合。
  7. 权利要求1-4中任一项所述的化合物或其立体异构体、溶剂化物、代谢产物、药学上可接受的盐或共晶或者权利要求5或6所述的药物组合物在制备用于治疗创伤后应激障碍、面瘫、中风、偏头痛、冠心病稳定型心绞痛、脑梗塞、血栓栓塞、心肌梗塞、心脏缺血、冠状动脉疾病、高血压、脑缺血、改善性功能、痉挛、急性和慢性疼痛、纤维肌痛、术后疼痛、丛集性头痛、紧张性头痛、背疼、四肢痛、腰痛、颈部疼痛、神经性疼痛、癌痛、三叉神经痛、关节炎疼痛、炎性疼痛、Dravet综合征、Lennox-Gastaut综合征、Prader-Willi综合征、Sturge-Weber综合征、脆性X综合征、焦虑、双相情感障碍、自闭症、广泛性焦虑症、社交焦虑症、癫痫、帕金森氏病、阿尔茨海默氏病、亨廷顿氏病、阿片类药物滥用、酗酒、尼古丁成瘾、厌食症、恶病质、化疗相关恶心呕吐、术后恶心和呕吐、肌萎缩性侧索硬化症(ALS)、Friedreich共济失调、精神分裂症、强迫症、多发性硬化症、抑郁、睡眠障碍、多发性硬化引起的痉挛、肌张力障碍、睡眠呼吸暂停、麻痹性痴呆、记忆力减退或者胶质母细胞瘤的药物中的用途。
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