Medicine for reducing intraocular pressure and preparation method thereof

Abstract

The invention relates to a series of cannabinoid derivatives which can be used for reducing intraocular pressure so as to treat various diseases including glaucoma, tumors and the like.

Description

Technical Field

[0001] The present invention relates to a cannabinoid derivative, a preparation method thereof and uses thereof, and relates to the field of medicine. Background Art

[0002] Cannabis plants have been used medicinally since ancient times, and more than 100 different structural analogs of its main component, cannabinoids, have been identified so far. The currently marketed cannabinoids are mainly dronabinol nabilone nabiximol and CBD The prior art has demonstrated that cannabinoids can be used for chronic pain, multiple sclerosis, cancer-related nausea and vomiting, weight loss, anorexia, spasticity and other conditions, and have multiple pharmacological effects. However, since cannabinoids are controlled drugs, their clinical applications are greatly restricted. In recent years, researchers have focused on cannabis derivatives.

[0003] The present invention relates to a series of cannabinoid derivatives, which can be used to reduce intraocular pressure to treat various diseases including glaucoma, tumors, etc. Summary of the Invention

[0004] The present invention provides a compound, a pharmaceutically acceptable salt thereof, an isomer thereof and a prodrug thereof, and the compound has a structural formula of Formula I Wherein, when X is O, is a single bond and Y is -C(O)-; when X is CR 3 , is a double bond and Y is -CH-;

[0005] Wherein, R 1 is optionally selected from hydrogen, OR 1a , COOR 1b , wherein R 1a is optionally selected from hydrogen, C 1-20 alkanoyl, C 1-20 alkyl, preferably R 1a is optionally selected from hydrogen, C 1-5 alkanoyl, C 1-5 alkyl, preferably R 1a is optionally selected from hydrogen, -C(O)C5H 11 , -C5H 11 . The R 1b is optionally selected from hydrogen, C 1-20 alkyl, preferably R 1b is optionally selected from hydrogen, C 1-5 alkyl, preferably R 1b is optionally selected from hydrogen, methyl. In certain embodiments, the R 1is hydrogen, -OH, -O-alkyl, -COOMe, -COOH, -OC(O)alkyl, preferably selected from -OH, -O(C 1-5 alkyl), -COOMe, -COOH, -OC(O)(C 1-5 alkyl). In certain embodiments, the R 1 is -OH, -OC5H 11 , -COOMe, -COOH, -OC(O)C5H 11 ;

[0006] R 2 is R 2a substituted C 1-20 alkyl, C 1-20 alkenyl, wherein R 2a is H, C 1-10 alkyl or phenyl, preferably R 2a is H, methyl, phenyl; preferably R 2a substituted C 1-20 alkyl, C 1-20 alkenyl is or or or or or or

[0007] Preferably R 2 is or or or

[0008] R 3 is OR 3a or O(CO)R 3a , the R 3a is H or C 1-5 alkyl, preferably R 3a is H or -C5H 11 .

[0009] R 4 is hydrogen, -C(O)OCH2CH3, -CH2C(O)OCH3, C 1-20 alkyl, COOR 4a , or C1-20 alkoxy, preferably R 4 is hydrogen, -C(O)OCH2CH3, -CH2C(O)OCH3, C 1-10 alkyl, COOR 4a , Preferably the R4 be -C(O)OCH2CH3, -CH2C(O)OCH3, -C5H 11 , -C4H9, COOR 4a , Preferably, the R 4 be -CH2C(O)OCH3, -C5H 11 , COOR 4a , The R 4a be H or alkyl, preferably R 4a be H or C 1-5 alkyl, preferably R 4a be H or methyl;

[0010] R 5 Optionally selected from -H, alkenyl, alkyl, preferably R5 is -H, C 1-20 alkenyl, C 1-20 alkyl, preferably R 5 be H, or Preferably H or

[0011] Furthermore, the present invention provides a compound, its pharmaceutically acceptable salt, its isomer and its prodrug, and the compound has the structural formula of formula II Wherein, the R 1 Optionally selected from hydrogen and COOR 1b , preferably the R 1b Selected from hydrogen, methyl;

[0012] R 2 be C 1-20 alkenyl; preferably R 2 be

[0013] R 4 be H or -COOR 4a or C 1-20 alkoxy, preferably R 4 be H or -COOR 4a , preferably the R 4a be H or C 1-20 alkyl, preferably R 4a be methyl;

[0014] R5 is alkyl, preferably C 1-20 alkyl, preferably C 1-12 alkyl, preferably C 1-5 alkyl, preferably -C5H 11 .

[0015] Furthermore, the compound has the structure of formula III, Among them, the R 1 is arbitrary and can be selected from hydrogen and COOR 1b , preferably the R 1b is selected from hydrogen and methyl; R 4 is H or -COOR 4a or C 1-20 alkoxy, preferably R 4 is H or -COOR 4a , preferably the R 4a is -H or C 1-20 alkyl, preferably R 4a is methyl;

[0016] Furthermore, the structural formula of the compound is

[0017] Furthermore, the structural formula of the compound is

[0018] Furthermore, the structural formula of the compound is

[0019] Furthermore, the present invention provides a compound, its pharmaceutically acceptable salt, its isomer and its prodrug, and the compound has the structural formula of Formula IV The R1 is OR 1a , the R 1a is arbitrarily selected from hydrogen, C 1-20 alkanoyl, C 1-20 alkyl, preferably R 1a is arbitrarily selected from hydrogen, C 1-5 alkanoyl, -C 1-5 alkyl, preferably R 1a is arbitrarily selected from hydrogen, OC(O)C5H 11 , OC5H 11 .

[0020] R 2 is the C 2a alkyl or C 1-20 alkenyl substituted by R 1-20 , where R 2a is H, C 1-5 alkyl or phenyl, preferably H, methyl, phenyl; preferably R 2a substituted C 1-20 alkyl, C 1-20 alkenyl is or or

[0021] R 3 is OR 3a or O(CO)R3a ; said R 3a is H or a C 1-5 alkyl group, preferably R 3a is H or -C5H 11 ;

[0022] R 4 optionally selected from C 1-20 alkyl, -CH 2 C(O)OCH3, preferably said R 4 is -CH2C(O)OCH3, -C5H 11 ,

[0023] R 5 optionally selected from H.

[0024] Furthermore, the chemical formula of the compound is

[0025]

[0026] Furthermore, the compound is a cannabinoid derivative.

[0027] Furthermore, the present invention provides a pharmaceutical composition, which comprises the above-mentioned compound or its salt. Furthermore, the pharmaceutical composition comprises a pharmaceutically acceptable excipient. Furthermore, the pharmaceutical composition is selected from tablets, capsules, granules, powders for inhalation, sprays, oral solutions and suspensions.

[0028] Furthermore, the present invention provides the use of the above-mentioned compound or its pharmaceutical composition for the preparation of a medicament for treating eye diseases, which include but are not limited to reducing intraocular pressure, glaucoma, cataract, macular degeneration, uveitis, etc. In certain embodiments, the compound or its pharmaceutical composition can be used for the preparation of an intraocular pressure-reducing medicament. In certain embodiments, the compound or its pharmaceutical composition can be used for the preparation of an intraocular pressure-reducing medicament for treating glaucoma.

[0029] The present invention further provides a preparation method for the above-mentioned compound.

[0030] Chemical definition

[0031] The compounds described herein may include one or more asymmetric centers and, therefore, may exist in various isomeric forms, for example, enantiomeric and / or diastereomeric forms. For example, the compounds described herein may be individual enantiomers, diastereomers, or geometric isomers, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be separated from the mixture by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or the preferred isomers can be prepared by asymmetric synthesis.

[0032] The following terms are intended to have the meanings provided below and are useful in understanding the specification and intended scope of the present invention. When describing the present invention, it may include compounds, pharmaceutical compositions containing the compounds, and test methods for the compounds and compositions. The definitions of the terms involved in the present invention can be referred to the following description, and any of the following defined parts can be substituted by many substituents, and the corresponding definitions are within the scope listed below, including such substituted parts. Unless otherwise specified, the term "substituted" is defined as follows.

[0033] "Alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon group having 1 to 20 carbon atoms ("C1-20 alkyl"). In some embodiments, the alkyl has 1 to 12 carbon atoms ("C1-12 alkyl"). In some embodiments, the alkyl has 1 to 10 carbon atoms ("C1-10 alkyl"). In some embodiments, the alkyl has 1 to 5 carbon atoms ("C1-5 alkyl"). In some embodiments, the alkyl has 1 to 5 carbon atoms ("C1-5 alkyl"). Examples of C1-6 alkyl include: methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5). Other examples of alkyl include n-heptyl (C7), n-octyl (C8), and so on. Unless otherwise specified, each of the alkyls is independently optionally substituted, that is, unsubstituted ("unsubstituted alkyl") or substituted by one or more substituents ("substituted alkyl"); for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In some embodiments, the alkyl is unsubstituted C1-10 alkyl (e.g., -CH3). In some embodiments, the alkyl is substituted C1-10 alkyl.

[0034] "Alkenyl" refers to a straight-chain or branched hydrocarbon group having 2 to 20 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) ("C2-20 alkenyl"). In some embodiments, the alkenyl has 2 to 20 carbon atoms ("C2-20 alkenyl"). One or more carbon-carbon double bonds can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). Examples of alkenyl include: hexenyl (C6), heptenyl (C7), octenyl (C8), octatrieneyl (C8), and the like. Unless otherwise specified, each alkenyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents ("substituted alkenyl"); e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In some embodiments, the alkenyl is an unsubstituted C2-20 alkenyl. In some embodiments, the alkenyl is a substituted C2-20 alkenyl.

[0035] "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system having 6-14 ring carbon atoms and zero heteroatoms in the aromatic ring system (e.g., having 6, 10, or 14 π electrons arranged in a ring and shared) ("C6-14 aryl"). In some embodiments, the aryl has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl has ten ring carbon atoms ("C10 aryl"; e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). In some embodiments, the aryl has fourteen ring carbon atoms ("C14 aryl"; e.g., anthryl). "Aryl" also includes such ring systems in which the above aryl ring is fused to one or more carbocyclic or heterocyclic groups, where the moiety or point of attachment is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. Typical aryls include, but are not limited to, groups derived from: aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, coronene, fluoranthene, fluorene, hexacene, indane, indene, naphthalene, octacene, octaphene, ovalene, penta-2,4-diene, pentacene, pentaphene, pentaphenylene, perylene, phenalene, phenanthrene, picene, heptacene, pyrene, picene, rubicene, benzo[c]phenanthrene, and terphenyl. Specifically, aryl includes phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each aryl is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In some embodiments, the aryl is an unsubstituted C6-14 aryl. In some embodiments, the aryl is a substituted C6-14 aryl. In some embodiments, the aryl is substituted with one or more groups selected from halogen, C1-C8 alkyl, C1-C8 haloalkyl, cyano, hydroxy, C1-C8 alkoxy, and amino.

[0036] "Alkoxy" refers to the group -OR, where R is a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. Specific alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentyloxy, n-hexyloxy, and 1,2-dimethylbutoxy. Specific alkoxy groups are lower alkoxy groups, that is, having 1 to 6 carbon atoms. Further specific alkoxy groups have 1-4 carbon atoms. Exemplary "substituted alkoxy groups" include, but are not limited to: -O-(CH2)t(C6-C10 aryl), -O-(CH2)t(5-10 membered heteroaryl), -O-(CH2)t(C3-C10 cycloalkyl), and -O-(CH2)t(4-10 membered heterocyclic group), where t is an integer from 0 to 4, and any aryl, heteroaryl, cycloalkyl, or heterocyclic group present may itself be substituted by an unsubstituted C1-C4 alkyl group, a halogen, an unsubstituted C1-C4 alkoxy group, an unsubstituted C1-C4 haloalkyl group, an unsubstituted C1-C4 hydroxyalkyl group, or an unsubstituted C1-C4 haloalkoxy group or hydroxy group.

[0037] "Alkanoyl" refers to the group formed by removing the hydroxyl group from a saturated fatty acid containing a single carboxyl group. For example, C1-6 alkanoyl, C1-4 alkanoyl, C1-2 alkanoyl; specific examples include, but are not limited to, formyl, acetyl, n-propionyl, isopropionyl, etc.; the alkanoyl group can be unsubstituted or substituted, and exemplary "substituted alkanoyl groups" include, but are not limited to, being substituted by the following substituents: an unsubstituted C1-C4 alkyl group, a halogen, an unsubstituted C1-C4 alkoxy group, an unsubstituted C1-C4 haloalkyl group, an unsubstituted C1-C4 hydroxyalkyl group, an unsubstituted C1-C4 haloalkoxy group, a hydroxy group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted heterocyclic group; and the above aryl, heteroaryl, cycloalkyl, or heterocyclic group can be substituted by an unsubstituted C1-C4 alkyl group, a halogen, an unsubstituted C1-C4 alkoxy group, an unsubstituted C1-C4 haloalkyl group, an unsubstituted C1-C4 hydroxyalkyl group, or an unsubstituted C1-C4 haloalkoxy group or hydroxy group.

[0038] "Carboxyl" refers to the group -C(O)OH.

[0039] "Hydroxy" refers to the group -OH.

[0040] Other definitions

[0041] The term "pharmaceutically acceptable salts" refers to salts that, within the scope of sound medical judgment, are suitable for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in detail by Berge et al. in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by the reaction of an amino group with an inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with an organic acid such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or salts formed using methods well known in the art, such as ion exchange methods. Other pharmaceutically acceptable salts include: adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, gluconates, glycerophosphates, glucuronates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxyethanesulfonates, lactates, lactobionates, laurates, laurylsulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectinate, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, etc. Pharmaceutically acceptable salts derived from suitable bases include alkali metal, alkaline earth metal, ammonium and tetraalkylammonium salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium salts, etc. Further pharmaceutically acceptable salts, where appropriate, include non-toxic ammonium salts, quaternary ammonium salts and amine cations formed using counterions such as halide ions, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkylsulfonate and arylsulfonate.

[0042] Specific implementation examples

[0043] The technical solution of the present invention will be further elaborated in detail below in conjunction with the accompanying drawings of the specification and specific implementation examples, but the implementation of the present invention is not limited thereto. Equivalent substitutions, combinations, improvements or modifications made by those skilled in the art to the technical solution of the present invention based on the description of the present invention should all be covered by the protection scope of the present invention.

[0044] Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the technical field. Unless otherwise specified, the reagents and raw materials used in the following examples are all commercially available products.

[0045] Synthesis of Compound 5 in Example 1

[0046]

[0047] Weigh 40 g of Compound 1, 68 g of DMAP, and 480 mL of dichloromethane, add them to a reaction flask, and cool the temperature to -5 °C; slowly drip a 150 mL dichloromethane solution of 41 g of hexanoyl chloride, control the dripping temperature not to exceed 0 °C, and naturally raise the temperature to room temperature and stir for reaction for 1.5 hours. Stop the stirring reaction, filter the reaction solution, collect the filtrate, wash it with 40 mL of dichloromethane, combine the filtrates, wash the extract with 100 mL of 1M hydrochloric acid, then wash it with water until neutral, dry it with anhydrous sodium sulfate, and concentrate to obtain 63.8 g of an oily substance, and the crude product yield is 95%.

[0048] Weigh 0.5 g of the crude product, add 4 mL of methanol solution, stir and reflux at 70 °C for 3 hours under nitrogen protection, stop the reaction, cool to room temperature, spin-dry the solvent of the reaction solution to obtain a crude oily product, and perform silica gel column chromatography (PE:EA = 100:1 to 10:1) to obtain 285 mg of oily Compound 2, with a yield of 80%.

[0049] Weigh 2.4 g of Compound 2, 2.1 g of N-methylimidazole, 1.96 g of triethylamine, and 30 mL of dichloromethane and add them to a reaction flask, cool the temperature to -1.5 °C, slowly drip a 10 mL dichloromethane solution of 3.7 g of p-toluenesulfonyl chloride, control the temperature not to exceed 0 °C, finish dripping in 15 minutes, stir and react for 2.5 hours after adding, stop the reaction, spin-dry the solvent, then extract three times with 30 mL of ethyl acetate, wash the organic phase with 10 mL of saturated brine, dry it with anhydrous sodium sulfate, and concentrate to obtain 4.8 g of a crude oily product. Perform silica gel column chromatography (PE:EA = 100:1 to 20:1) to obtain 3.1 g of oily Compound 3, with a yield of 63%.

[0050] Weigh 1.059 g of Compound 4, 1.152 g of Compound 3, 1.527 g of anhydrous potassium phosphate, and 60 mL of acetonitrile and add them to a reaction flask, heat to 80 °C and react for 30 hours, then stop the reaction. Spin-dry the solvent, then extract three times with 30 mL of ethyl acetate, wash the organic phase with 10 mL of saturated brine, dry it with anhydrous sodium sulfate, and concentrate to obtain a crude oily product. Perform silica gel column chromatography (PE:EA = 60:1 to 15:1) to obtain 580 mg of oily Compound 5, with a yield of 44.6%.

[0051] Compound 5 was characterized as follows: 1H NMR (400 MHz, CDCl3) δ 6.03 (s, 1H), 5.12 - 5.09 (m, 2H), 3.88 (s, 3H), 2.65 - 2.61 (m, 2H), 2.50 - 2.48 (m, 2H), 2.42 - 2.40 (m, 2H), 2.08 - 1.98 (m, 4H), 1.70 (s, 3H), 1.63 - 1.61 (m, 6H), 1.55 - 1.49 (m, 2H), 1.36 - 1.31 (m, 4H), 0.93 - 0.90 (m, 3H).

[0052] Synthesis of Compound 6 in Example 2

[0053]

[0054] Add 400 mg of 5 and 136 mg of lithium chloride to a three-necked flask, then add 3 mL of DMSO and 48 mg of water. Replace the gas with nitrogen three times, heat the reaction to 140 °C and stir for 3.5 hours, then stop the reaction. Let the reaction solution cool naturally to room temperature, add 10 mL of water, stir for 5 minutes, extract three times with 20 mL of ethyl acetate, combine the organic phases and evaporate to dryness. Add a solution of 1.6 g of sodium carbonate dissolved in 40 ml of water, stir for 5 minutes, then extract twice with 10 ml of n-hexane, combine the organic phases and evaporate to dryness. Adjust the pH to 6.5 with 10% citric acid, then extract three times with 15 ml of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and evaporate to dryness to obtain 279 mg of Compound 6, with a yield of 73%.

[0055] Compound 6 was characterized as follows: 1H HNMR (400 MHz, CDCl3) δ 5.16 - 5.05 (m, 2H), 2.86 - 2.76 (m, 3H), 2.64 - 2.61 (m, 2H), 2.47 - 2.42 (m, 2H), 2.08 - 1.95 (m, 4H), 1.71 - 1.69 (m, 2H), 1.68 - 1.55 (m, 7H), 1.39 - 1.27 (m, 5H), 0.94 - 0.89 (m, 3H).

[0056] Synthesis of Compound 8 in Example 3

[0057]

[0058] Weigh 1.85 g of compound 7, add 74 mL of anhydrous acetonitrile to the reaction flask, displace with nitrogen three times, stir at room temperature for 15 minutes, add 44 mg of anhydrous potassium tert-butoxide to the reaction flask at once, heat up to 70 °C, and the reaction is complete in about two hours. Stop the reaction, rotary evaporate the solvent, adjust the pH value to neutral with saturated sodium bicarbonate solution, extract with 30 mL of ethyl acetate three times, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and obtain a crude oil after concentration under reduced pressure. Silica gel column chromatography (PE:EA = 100:2 - 100:6) gives 1.5 g of compound 8 with a yield of 73%.

[0059] Compound 8 was characterized as follows: 1HNMR (400 MHz, CDCl3) δ 5.11 - 5.08 (m, 2H), 3.92 (s, 3H), 3.89 (s, 3H), 2.63 - 2.52 (m, 4H), 2.42 - 2.37 (m, 2H), 2.08 - 1.99 (m, 4H), 1.70 (s, 3H), 1.62 (s, 6H), 1.55 - 1.46 (m, 2H), 1.34 - 1.28 (m, 4H), 0.92 - 0.89 (m, 3H).

[0060] Synthesis of Compound 11 in Example 4

[0061]

[0062] Add compound 9 (134 mg, 1 mmol), compound 10 (246 mg, 1 mmol), acidic aluminum oxide (1 g, 1 g / mmol) to a three-necked flask, then add 5 ml of dichloroethane, displace with nitrogen three times, heat and stir at 92 °C for 5 hours, let the reaction solution cool to room temperature naturally, rotary evaporate the reaction solution, and silica gel column chromatography (PE - PE:EA = 100:3) gives 95 mg of white solid compound 11 with a yield of 23%.

[0063] 1H NMR (400 MHz, CDCl3) δ 7.37 - 7.29 (m, 6H), 7.25 - 7.21 (m, 1H), 7.02 - 6.96 (m, 3H), 6.55 - 6.50 (m, 1H), 6.40 - 6.35 (m, 1H), 6.12 (s, 2H), 5.00 (s, 2H), 4.34 - 4.27 (m, 4H), 3.59 - 3.57 (m, 2H).

[0064] Synthesis of Compound 13 in Example 5

[0065]

[0066] Add CBG (1.6 g, 5 mmol), compound 12 (2.0 g, 13.0 mmol), and potassium carbonate (1.4 g, 10 mmol) into a three-necked flask. Then add 15 ml of DMF, and heat the mixture to 50 °C and stir for 22 hours. Stop the reaction, extract it three times with 30 ml of ethyl acetate, dry it over anhydrous sodium sulfate, and rotary evaporate to obtain an oily substance. Silica gel column chromatography (PE~PE:EA = 100:1) gives 580 mg of oily liquid compound 13, with a yield of 25%.

[0067] 1H NMR (400 MHz, CDCl3) δ 6.32 (s, 2H), 5.23 (m, 1H), 5.07 (m, 1H), 3.93 (m, 4H), 3.33 (d, J = 7.2 Hz, 2H), 2.52 (t, J = 8.0 Hz, 2H), 2.07 - 2.02 (m, 2H), 1.95 - 1.92 (m, 2H), 1.82 - 1.74 (m, 7H), 1.64 (s, 3H), 1.61 - 1.57 (m, 5H), 1.43 - 1.29 (m, 12H), 0.94 - 0.87 (m, 9H).

[0068] Synthesis of Compound 15 in Example 6

[0069]

[0070] Add CBG (1.6 g, 5 mmol), compound 14 (1.99 g, 7.5 mmol), and triethylamine (3 g, 15 mmol) into a three-necked flask. Then add 20 ml of dichloromethane, and stir at room temperature for 4 hours. Stop the reaction, rotary evaporate the reaction solution to obtain a black oily substance. Silica gel column chromatography (PE~PE:EA = 100:3) gives 2 g of colorless oily compound 15, with a yield of 97%.

[0071] 1H NMR (400 MHz, CDCl3) δ 6.78 (s, 2H), 5.10 - 5.03 (m, 2H), 3.15 (d, J = 6.4 Hz, 2H), 2.60 - 2.53 (m, 6H), 2.07 - 1.94 (m, 4H), 1.80 - 1.58 (m, 17H), 1.45 - 1.31 (m, 13H), 0.96 - 0.89 (m, 9H).

[0072] Synthesis of Compound 16 in Example 7

[0073]

[0074] Add compound 15 (511 mg, 1 mmol), lithium hydroxide (12 mg, 0.5 mmol) into a three-necked flask, then add 10 ml of ethanol and 10 ml of water. Stir at room temperature for 15 hours, stop the reaction, adjust the pH to 3 with 1 M hydrochloric acid, extract three times with 20 ml of ethyl acetate, dry over anhydrous sodium sulfate, rotary evaporate to obtain an oily substance, and obtain 283 mg of oily liquid compound 16 by silica gel column chromatography (PE~PE:EA = 100:1), with a yield of 68%.

[0075] 1H NMR (400 MHz, CDCl3) δ 6.78 (s, 2H), 5.10 - 5.03 (m, 2H), 3.15 (d, J = 6.4 Hz, 2H), 2.60 - 2.53 (m, 6H), 2.07 - 1.94 (m, 4H), 1.80 - 1.58 (m, 17H), 1.45 - 1.31 (m, 13H), 0.96 - 0.89 (m, 9H).

[0076] Synthesis of Compound 18 in Example 8

[0077]

[0078] Add m-benzenetriol (3.78 g, 0.03 mol), benzyl chloride (3.78 g, 0.03 mol), potassium carbonate (4.2 g, 0.03 mol) into a three-necked flask, then add 20 ml of DMF. Stir at room temperature for 16 hours, stop the reaction, add 30 ml of water, then extract three times with 30 ml of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, rotary evaporate, and obtain 1.1 g of compound 17 by silica gel column chromatography (PE~PE:EA = 100:1), with a yield of 15%.

[0079] Add geraniol (432 mg, 2 mmol), compound 17 (306 mg, 2 mmol), acidic aluminum oxide (1 g, 2 g / mmol) into a three-necked flask, then add 15 ml of dichloroethane, displace with nitrogen three times, heat and stir at 88 °C for 3 hours, let the reaction solution cool naturally to room temperature, rotary evaporate the reaction solution, obtain 320 mg of oily liquid by silica gel column chromatography (PE~PE:EA = 100:5), and then recrystallize with 5 ml of PE to obtain 120 mg of compound 18, with a yield of 17%.

[0080] 1H NMR (400 MHz, CDCl3) δ 7.44 - 7.32 (m, 5H), 6.12 (s, 2H), 5.30 - 5.26 (m, 1H), 5.19 (s, 2H), 5.12 - 5.00 (m, 3H), 4.20 - 4.12 (m, 1H), 3.38 (d, J = 8.0 Hz, 2H), 2.14 - 2.06 (m, 6H), 1.83 (s, 3H), 1.74 - 1.62 (m, 10H), 1.30 - 1.27 (m, 1H), 0.94 - 0.88 (m, 1H).

[0081] Synthesis of Compound 20 in Example 9

[0082]

[0083] Add geraniol (310 mg, 2 mmol), compound 19 (365 mg, 2 mmol), and acidic aluminum oxide (20 g, 1 g / mmol) to a three-necked flask. Then add 5 ml of dichloroethane, displace the air with nitrogen three times, heat and stir at 90 °C for 6 hours. Let the reaction solution cool to room temperature naturally, rotary evaporate the reaction solution, and perform silica gel column chromatography (PE:EA = 100:1 - 10:7) to obtain 120 mg of compound 20 with a yield of 19%.

[0084] 1H NMR (400 MHz, CDCl3) δ 6.37 (s, 2H), 5.64 (s, 2H), 5.30 - 5.25 (m, 1H), 5.09 - 5.05 (m, 1H), 3.72 (s, 3H), 3.50 (s, 2H), 3.42 - 3.41 (m, 2H), 2.14 - 2.06 (m, 4H), 1.82 (s, 3H), 1.65 (s, 3H), 1.61 (s, 3H), 1.32 - 1.27 (m, 1H).

[0085] Synthesis of Compound 22 in Example 10

[0086]

[0087] Add compound 21 (500 mg, 5 mmol), oleanol (900 mg, 5 mmol), and acidic aluminum oxide (5 g, 1 g / mmol) to a three-necked flask. Then add 10 ml of dichloroethane, displace the air with nitrogen three times, heat and stir at 80 °C for 7 hours. Let the reaction solution cool to room temperature naturally, rotary evaporate the reaction solution, and perform silica gel column chromatography (PE:EA = 100:1) to obtain 620 mg of compound 22 with a yield of 48%.

[0088] 1H NMR (400 MHz, CDCl3) δ 6.28 (s, 2H), 6.20 - 6.02 (m, 2H), 5.74 - 5.60 (m, 2H), 5.02 (s, 2H), 3.46 (d, J = 4 Hz, 2H), 2.48 (t, J = 8 Hz, 2H), 1.82 - 1.74 (m, 4H), 1.63 - 1.57 (m, 2H), 1.39 - 1.29 (m, 4H), 0.95 - 0.90 (m, 3H).

[0089] Synthesis of Compounds 25 and 26 in Example 11

[0090]

[0091] Add compound 23 (10 g, 0.065 mol) to a three-necked flask, then add ethanol (100 ml, 1.95 mol) to dissolve it. Slowly add thionyl chloride (10 g, 0.085 mol), then stir at room temperature for 3 hours, and then heat to reflux for 2 hours. Stop the reaction, cool to room temperature, rotary evaporate the remaining ethanol in the reaction solution, add 100 ml of water, then adjust the pH value to neutral with saturated sodium carbonate solution, and then extract three times with 100 ml of dichloromethane. Combine the organic phases, dry over anhydrous sodium sulfate, and rotary evaporate to obtain 10.2 g of oily substance compound 24, with a yield of 85.7%.

[0092] Add geraniol (3.08 g, 20 mmol), compound 24 (3.66 g, 20 mmol), acidic aluminum oxide (20 g, 1 g / mmol) to a three-necked flask, then add 60 ml of toluene, displace with nitrogen three times, heat and stir at 100 °C for 7 hours. Let the reaction solution cool to room temperature naturally, rotary evaporate the reaction solution, and perform silica gel column chromatography (PE:EA = 100:1 - 10:1) to obtain 1.0 g of compound 25 with a yield of 12.9% and 230 mg of compound 26 with a yield of 2.5%.

[0093] 1H NMR (400 MHz, CDCl3) δ 6.33 - 6.30 (m, 2H), 5.60 (s, 1H), 5.50 (s, 1H), 5.14 - 5.07 (m, 3H), 3.71 (s, 3H), 3.60 (s, 2H), 3.32 - 3.30 (m, 2H), 2.26 - 1.80 (m, 9H), 1.74 - 1.60 (m, 14H),

[0094] Compound 26 1H NMR (400 MHz, CDCl3) δ 6.94 (s, 1H), 5.64 (s, 1H), 5.42 (s, 1H), 5.27 - 5.23 (m, 2H), 5.09 - 5.05 (m, 2H), 4.37 - 4.31 (m, 2H), 3.67 (d, J = 8.0 Hz, 2H), 3.47 (d, J = 8.0 Hz, 2H), 2.19 - 2.07 (m, 8H), 1.83 - 1.82 (m, 6H), 1.74 - 1.61 (m, 9H), 1.38 - 1.21 (m, 11H).

[0095] Synthesis of Compound 27 in Example 12

[0096]

[0097] Geraniol (17 g, 0.11 mol), olivetol (20 g, 0.11 mol), and acidic aluminum oxide (112 g, 1 g / mmol) were added to a three-necked flask, and then 250 ml of dichloroethane was added. The mixture was purged with nitrogen three times and heated with stirring at 86 °C for 4.5 hours. The reaction solution was allowed to cool to room temperature naturally, filtered by suction, and then the filter cake was washed with 350 ml of DCE. The organic phases were combined and evaporated to dryness to obtain 29.16 g of a pale yellow viscous liquid. 100 ml was added to dissolve it, and then it was left overnight at -40 °C. The mixture was filtered by suction under frozen conditions to obtain 19 g of a white solid as the filter cake, and the filtrate was evaporated to dryness to obtain 6.95 g of a yellow oily liquid. 1 g of the yellow oily filtrate was taken for preparation and separation to obtain 230 mg of Compound 27, with a yield of 23%.

[0098] 1H NMR (400 MHz, CDCl3) δ 6.29 - 6.24 (m, 2H), 5.19 - 5.06 (m, 2H), 3.32 (d, J = 8.0 Hz, 2H), 2.57 - 2.52 (m, 2H), 2.13 - 2.05 (m, 4H), 1.82 (s, 3H), 1.77 - 1.70 (m, 4H), 1.62 - 1.51 (m, 5H), 1.39 - 1.32 (m, 4H), 0.94 - 0.91 (m, 3H).

[0099] Synthesis of Compound 29 in Example 13

[0100]

[0101] Add geraniol (12.6 g, 0.1 mol), compound 28 (15.4 g, 0.1 mol), and acidic aluminum oxide (100 g, 1 g / mmol) to a three-necked flask. Then add 400 ml of dichloroethane, displace with nitrogen three times, heat under reflux and stir for 3 hours. Let the reaction solution cool naturally to room temperature, filter by suction, then rinse the filter cake with 200 ml of DCE. Combine the organic phases and rotary evaporate to dryness. Perform silica gel column chromatography (PE:EA = 100:1 - 50:1) to obtain 120 mg of compound 29, with a yield of 2.4%.

[0102] 1HNMR (400 MHz, CDCl3) δ 5.98 (s, 1H), 5.56 (s, 1H), 5.27 - 5.26 (m, 2H), 5.09 - 5.00 (m, 4H), 3.37 (d, J = 4.0 Hz, 4H), 2.16 - 2.03 (m, 8H), 1.83 (s, 6H), 1.70 (S, 6H), 1.62 (s, 6H).

[0103] Synthesis of Compound 34 in Example 14

[0104]

[0105] Add compound 30 (5 g, 36 mmol), p-toluenesulfonyl chloride (8.2 g, 43 mmol), and triethylamine (9.09 g, 90 mmol) to a three-necked flask. Then add 50 ml of dichloromethane and stir at room temperature for 20 hours. Confirm the completion of the reaction by TLC spotting. Add 50 ml of water for washing. Dry the organic phase with anhydrous sodium sulfate and rotary evaporate to obtain a grayish-white solid. Wash it with petroleum ether to obtain 6.1 g of white solid compound 31, with a yield of 58%.

[0106] Add compound 31 (5.8 g, 20 mmol), phloroglucinol (5.04 g, 40 mmol), and potassium carbonate (5.6 g, 40 mmol) to a three-necked flask. Then add 40 ml of DMF, heat to 80 °C, and react for 4 hours. Stop the reaction, add 60 ml of water, extract twice with 40 ml of ethyl acetate. Combine the organic phases, dry with anhydrous sodium sulfate, and rotary evaporate to obtain 2.3 g of compound 32, with a yield of 47%.

[0107] Add compound 32 (246 mg, 1 mmol), compound 33 (222 mg, 1 mmol), and acidic aluminum oxide (1 g, 1 g / mmol) to a three-necked flask. Then add 5 ml of dichloroethane, displace with nitrogen three times, heat and stir at 92 °C for 5 hours. Let the reaction solution cool naturally to room temperature, rotary evaporate the reaction solution to dryness. Perform silica gel column chromatography (PE~PE:EA = 100:3) to obtain 260 mg of compound 34, with a yield of 58%.

[0108] 1H NMR (400 MHz, CDCl3) δ 7.34 - 7.30 (m, 3H), 7.01 - 6.96 (m, 3H), 6.08 (s, 2H), 5.29 - 5.28 (m, 1H), 5.16 (s, 2H), 5.12 - 5.09 (m, 2H), 4.32 - 4.25 (m, 4H), 3.38 (d, J = 8.0 Hz, 2H), 2.15 - 1.98 (m, 8H), 1.84 (s, 3H), 1.70 (s, 3H), 1.62 (s, 6H).

[0109] Synthesis of Compound 36 in Example 15

[0110]

[0111] Add geraniol (306 mg, 2 mmol), compound 35 (492 mg, 2 mmol), and acidic aluminum oxide (2 g, 1 g / mmol) to a three-necked flask. Then add 15 ml of dichloroethane, displace the air with nitrogen three times, heat and stir at 88 °C for 5 hours. Let the reaction solution cool to room temperature naturally, rotary evaporate the reaction solution to dryness, and perform silica gel column chromatography (PE:EA = 100:1 - 100:5) to obtain 150 mg of compound 36 with a yield of 20%.

[0112] 1H NMR (400 MHz, CDCl3) δ 7.34 - 7.29 (m, 2H), 7.01 - 6.96 (m, 3H), 6.09 (s, 2H), 5.30 - 5.26 (m, 1H), 5.17 (s, 2H), 5.09 - 5.07 (m, 1H), 4.32 - 4.25 (m, 4H), 3.38 (d, J = 8.0 Hz, 2H), 2.15 - 2.08 (m, 4H), 1.83 (s, 3H), 1.71 (s, 3H), 1.62 (s, 3H).

[0113] Synthesis of Compound 37 in Example 16

[0114]

[0115] Add CBG (200 mg, 0.64 mmol) to a three-necked flask, then add 20 mg of Pd / C, add 5 ml of ethanol, stir at room temperature, then introduce hydrogen gas, react and stir for 19 hours, stop the reaction, filter, wash the filter cake with 20 ml of ethanol, rotary evaporate the filtrate, and recrystallize with PE to obtain 95 mg of compound 37 with a yield of 46%.

[0116] 1H NMR (400 MHz, CDCl3) δ 6.24 (s, 2H), 4.62 (s, 2H), 2.62 - 2.56 (m, 2H), 2.49 - 2.45 (m, 2H), 1.62 - 1.51 (m, 6H), 1.39 - 1.29 (m, 8H), 1.19 - 1.15 (m, 2H), 0.98 (d, J = 6.4 Hz, 3H), 0.93 - 0.88 (m, 9H).

[0117] Synthesis of Compound 39 in Example 17

[0118]

[0119] Add compound 38 (330 mg, 2 mmol), geraniol (310 mg, 2 mmol), and acidic aluminum oxide (2 g, 2 g / mmol) to a three-necked flask, then add 15 ml of dichloroethane. Replace the air with nitrogen three times, heat and stir at 88 °C for 4 hours. Let the reaction solution cool to room temperature naturally, rotary evaporate the reaction solution to dryness, and perform silica gel column chromatography (PE~PE:EA = 100:1) to obtain 320 mg of compound 39 with a yield of 43%.

[0120] 1H NMR (400 MHz, CDCl3) δ 7.02 (d, J = 7.6 Hz, 1H), 6.72 - 6.67 (m, 2H), 5.37 - 5.33 (m, 1H), 5.12 - 5.08 (m, 2H), 3.36 (d, J = 7.6 Hz, 2H), 2.55 (t, J = 8.0 Hz, 2H), 2.16 - 2.07 (m, 4H), 1.79 (s, 3H), 1.71 (s, 3H), 1.66 - 1.58 (m, 6H), 1.39 - 1.26 (m, 4H), 0.91 (t, J = 6.4 Hz, 3H).

[0121] Synthesis of Compound 41 in Example 18

[0122]

[0123] Add CBG (0.79 g, 2.5 mmol), compound 40 (0.5 g, 3.0 mmol), and potassium carbonate (0.7 g, 5.0 mmol) to a three-necked flask, then add 10 ml of DMF. Replace the air with nitrogen three times, stir at 30 °C for 17 hours, and stop the reaction. Extract with 30 ml of ethyl acetate three times, dry over anhydrous sodium sulfate, rotary evaporate to obtain an oily substance, and perform silica gel column chromatography (PE~PE:EA = 100:1) to obtain 115 mg of compound 41 with a yield of 12%.

[0124] 1H NMR (400 MHz, CDCl3) δ 6.32 (d, J = 8 Hz, 2H), 5.30 - 5.27 (m, 1H), 5.22 (s, 1H), 5.10 - 5.06 (m, 1H), 3.96 (t, J = 5.6 Hz, 2H), 3.42 (d, J = 8.0 Hz, 2H), 2.52 (t, J = 8.0 Hz, 2H), 2.15 - 2.03 (m, 5H), 1.84 - 1.56 (m, 16H), 1.51 - 1.29 (m, 11H), 0.97 - 0.90 (m, 7H).

[0125] Synthesis of Compound 42 in Example 19

[0126]

[0127] Add geraniol (431 mg, 2.8 mmol), olivetol (360 mg, 2.0 mmol), and acidic aluminum oxide (1 g, 1 g / mmol) to a three-necked flask, then add 10 ml of dichloroethane. Replace the air with nitrogen three times, heat and stir at 92 °C for 5 hours. Let the reaction solution cool to room temperature naturally, filter, wash the filter cake with 20 ml of dichloroethane, evaporate the filtrate to dryness, and perform silica gel column chromatography (PE~PE:EA = 100:3) to obtain 197 mg of Compound 42 with a yield of 16%.

[0128] 1H NMR (400 MHz, CDCl3) δ 6.19 (s, 1H), 5.33 (s, 1H), 5.21 - 5.18 (m, 1H), 5.09 - 5.05 (m, 1H), 5.00 - 4.93 (m, 3H), 3.33 (d, J = 8.0 Hz, 2H), 3.23 (d, J = 8.0 Hz, 2H), 2.46 - 2.42 (m, 2H), 2.06 - 1.96 (m, 8H), 1.73 (s, 6H), 1.60 (s, 6H), 1.52 (s, 6H), 1.49 - 1.41 (m, 2H), 1.30 - 1.21 (m, 4H), 0.85 - 0.80 (m, 3H).

[0129] Synthesis of Compound 45 in Example 20

[0130]

[0131] Weigh compound 43 (0.72 g, 4 mmol) into a 100 mL dried reaction flask, add 20 mL of 1,2-dichloroethane to dissolve it. Add compound 44 (0.88 g, 4 mmol) and aluminum oxide (4 g, 1 g / mmol) to the reaction flask all at once. Replace the air with nitrogen three times and react at 100 °C for 6.5 h. Monitor the reaction by TLC until it is completed (developing solvent: EA:PE = 1:3). Take the upper clear liquid, concentrate it, and purify it by flash column chromatography (developing solvent: EA:PE = 1:3) to obtain 0.16 g of compound 45, with a yield of 10%.

[0132] 1H NMR (400 MHz, CDCl3) δ 6.37 (s, 2H), 5.38 (s, 2H), 5.30 - 5.26 (m, 1H), 5.13 - 5.08 (m, 2H), 3.72 (s, 3H), 3.50 (s, 2H), 3.42 (d, J = 7.2 Hz, 2H), 2.15 - 1.99 (m, 8H), 1.83 (s, 3H), 1.70 (s, 3H), 1.62 - 1.61 (m, 6H).

[0133] Synthesis of Compound 46 in Example 21

[0134]

[0135] Weigh m-diphenol (1 g, 9.1 mmol) into a 100 mL dried reaction flask, add 30 mL of 1,2-dichloroethane to dissolve it. Add geraniol (1.4 g, 9.1 mmol) and aluminum oxide (9.1 g, 1 g / mmol) to the reaction flask all at once. Replace the air with nitrogen three times and react at 95 °C for 8.5 h. Monitor the reaction by TLC until it is completed (developing solvent: EA:PE = 1:3). Filter by suction, concentrate the filtrate, and perform column chromatography (eluent: EA:PE = 1:5) to obtain 0.26 g of compound 46, with a yield of 12%.

[0136] 1H NMR (400 MHz, CDCl3) δ 6.99 (t, J = 8.4 Hz, 1H), 6.43 (d, J = 8.4 Hz, 2H), 5.46 (s, 2H), 5.33 - 5.29 (m, 1H), 5.10 - 5.07 (m, 1H), 3.46 (d, J = 6.8 Hz, 2H), 2.11 - 2.07 (m, 4H), 1.84 (s, 3H), 1.70 (s, 3H), 1.62 (s, 3H)

[0137] Pharmacodynamic Experiment in Example 22

[0138] Experimental animals: 30 male C57BL / 6JGpt mice. Their body weights were 23 - 25 g when purchased and 21 - 25 g when entering the experiment. Their ages were approximately 42 days old when purchased and approximately 48 days old when entering the experiment.

[0139] Grouping: The experiment was divided into 6 groups, namely Group 1: Blank group, Group 2: Solvent group (instilled 30 μl of solvent into the eyes), Group 3: Cannabidiol (instilled 30 μl into the eyes), Group 4: Compound 13 (instilled 30 μl into the eyes), Group 5: Compound 11 (instilled 30 μl into the eyes), and Group 6: Compound 15 (instilled 30 μl into the eyes). 5 animals were included in each group, and all were subjected to model establishment.

[0140] Model establishment: Anesthetize C57BL / 6 mice and inject the preparation into the conjunctival sac of both eyes. Regularly detect the intraocular pressure of the animals after model establishment. When the intraocular pressure reaches about 18 - 22 mmHg, start grouping. If it does not increase, inject the preparation again. Immediately after grouping, perform instillation administration, and detect the intraocular pressure 1 h after administration.

[0141] Experimental results: 1 h after administration, the intraocular pressure measurements are shown in Table 1:

[0142] Table 1

[0143]

[0144]

[0145] The above results suggest that under the conditions of this experiment, there is no difference in intraocular pressure before and after administration in the Blank group and the model group; compared with the model group, the intraocular pressure in Group 4, Group 5, and Group 6 decreased significantly (P < 0.05), showing an obvious effect of reducing intraocular pressure on glaucoma.

[0146] Pharmacodynamic experiment of Example 23

[0147] Experimental animals: 35 male C57BL / 6JGpt mice, the same as in Example 22.

[0148] Grouping: The experiment was divided into 7 groups, namely Group 1: Blank group, Group 2: Solvent group (instilled 30 μl of solvent into the eyes), Group 3: Compound 16 (instilled 30 μl into the eyes), Group 4: Compound 18 (instilled 30 μl into the eyes), Group 5: Compound 20 (instilled 30 μl into the eyes), Group 6: Compound 6 (instilled 30 μl into the eyes), and Group 7: Compound 22 (instilled 30 μl into the eyes). 5 animals were included in each group, and all were subjected to model establishment, and the model establishment method was the same as in Example 1.

[0149] Experimental results: 1 h after administration, the intraocular pressure measurements are shown in Table 2:

[0150] Table 2

[0151] Group Average intraocular pressure before drug administration Average intraocular pressure 1 hour after drug administration (mmHg) Group 1 11.2±0.3 12.2±0.2 Group 2 18.4±0.3 18.7±0.5 Group 3 18.0±0.7 14.5±0.4 Group 4 17.9±0.4 14.6±0.4 Group 5 18.0±0.4 14.2±0.3 Group 6 17.9±0.4 14.4±0.4 Group 7 17.9±0.4 14.3±0.2

[0152] The above results suggest that under the conditions of this experiment, there was no difference in intraocular pressure before and after administration between the Blank group and the model group; compared with the model group, the intraocular pressures of groups 3, 4, 5, 6, and 7 were significantly decreased (P < 0.05), indicating an obvious effect of reducing intraocular pressure on glaucoma.

[0153] Pharmacodynamic Experiment of Example 24

[0154] Experimental animals: 20 male C57BL / 6JGpt mice, the same as in Example 22.

[0155] Grouping: The experiment was divided into 4 groups, namely Group 1: Blank group, Group 2: Solvent group (instilled 30 μl of solvent into the eyes), Group 3: Compound 8 (instilled 30 μl into the eyes), and Group 4: Compound 5 (instilled 30 μl into the eyes). Each group had 5 animals, and all were subjected to modeling, and the modeling method was the same as in Example 1.

[0156] Experimental results: After 1 h of administration, the intraocular pressure was measured as shown in Table 3:

[0157] Table 3

[0158]

[0159] The above results suggest that under the conditions of this experiment, there was no difference in intraocular pressure before and after administration between the Blank group and the model group; compared with the model group, the intraocular pressures of groups 3 and 4 were significantly decreased (P < 0.05), indicating an obvious effect of reducing intraocular pressure on glaucoma.

Claims

1. A compound, its pharmaceutically acceptable salts, isomers and prodrugs, characterized in that The compound has the structural formula of Formula I wherein when X is O, is a single bond and Y is -C(O)-; when X is CR 3 then is a double bond and Y is -CH-; wherein R 1 Optionally selected from hydrogen, OR 1a , COOR 1b , where R 1a Optionally selected from hydrogen, C 1-20 alkanoyl, C 1-20 alkyl, preferably R 1a Optionally selected from hydrogen, C 1-5 alkanoyl, C 1-5 alkyl, preferably R 1a Optionally selected from hydrogen, -C(O)C5H 11 , -C5H 11 , said R 1b Optionally selected from hydrogen, C 1-20 alkyl, preferably R 1b Optionally selected from hydrogen, C 1-5 alkyl, preferably R 1b Optionally selected from hydrogen, methyl; R 2 is R 2a substituted C 1-20 alkyl, C 1-20 alkenyl, wherein R 2a is H, C 1-10 alkyl or phenyl, preferably R 2a is H, methyl, phenyl; preferably R 2a substituted C 1-20 alkyl, C 1-20 alkenyl is or or Or Or Or Or Preferably R 2 is or or or R 3 is OR 3a or O(CO)R 3a , said R 3a is H or C 1-5 alkyl, preferably R 3a is H or -C5H 11 ; R 4 is hydrogen, -C(O)OCH2CH3, -CH2C(O)OCH3, C 1-20 alkyl, COOR 4a , or C1-20 alkoxy, preferably R 4 is hydrogen, -C(O)OCH2CH3, -CH2C(O)OCH3, C 1-10 alkyl, COOR 4a , Preferably, the R 4 is -C(O)OCH2CH3, -CH2C(O)OCH3, -C5H 11 , butyl, COOR 4a , Preferably, the R 4 is -CH2C(O)OCH3, -C5H 11 , COOR 4a , The R 4a is H or alkyl, preferably R 4a is H or C 1-5 alkyl, preferably R 4a is H or methyl; R 5 Optionally selected from -H, alkenyl, alkyl, preferably R5 is -H, C 1-20 alkenyl, C 1-20 alkyl, preferably R 5 is H, or preferably H or 2. The compound according to claim 1, wherein The compound has the structural formula of Formula II (Formula II), wherein the R 1 optionally may be selected from hydrogen and COOR 1b , preferably R 1b is selected from hydrogen and methyl; R 2 is C 1-20 alkenyl; preferably R 2 is R 4 is H or -COOR 4a or C 1-20 alkoxy group, preferably R 4 is H or -COOR 4a , preferably said R 4a is H or C 1-20 alkyl group, preferably R 4a is methyl; R5 is an alkyl group, preferably C 1-20 alkyl group, preferably C 1-12 alkyl group, preferably C 1-5 alkyl group, preferably -C5H 11 .

3. The compound according to claim 2, wherein The said compound has the structure of Formula III, wherein the said R 1 optionally can be selected from hydrogen and COOR 1b , preferably R 1b is selected from hydrogen and methyl; R 4 is H or -COOR 4a or C 1-20 alkoxy, preferably R 4 is H or -COOR 4a , preferably the said R 4a is -H or C 1-20 alkyl, preferably R 4a is methyl.

4. The compound according to claim 3, wherein The structural formula of the said compound is or or 5. The compound according to claim 1, characterized in that The said compound has the structural formula of Formula IV (Formula IV), wherein R1 is OR 1a , and R 1a is arbitrarily selected from hydrogen, C 1-20 alkanoyl, C 1-20 alkyl, preferably R 1a is arbitrarily selected from hydrogen, C 1-5 alkanoyl, C 1-5 alkyl, preferably R 1a is arbitrarily selected from hydrogen, -C(O)C5H 11 , -C5H 11 ; R 2 is R 2a substituted C 1-20 alkyl, C 1-20 alkenyl, wherein R 2a is H, C 1-5 alkyl or phenyl, preferably H, methyl, phenyl; preferably R 2a substituted C 1-20 alkyl, C 1-20 alkenyl is or or R 3 is OR 3a or O(CO)R 3a ; said R 3a is H or C 1-5 alkyl, preferably R 3a is H or -C5H 11 ; R4 is optionally selected from C1-20 alkyl, -CH2C(O)OCH3, Preferably, the R 4 is -CH2C(O)OCH3, -C5H 11 , R5 is optionally selected from H.

6. The compound according to claim 5, wherein The structural formula of the said compound is 7. The compound according to any one of claims 1-6, characterized in that The compound is a cannabinoid derivative.

8. A pharmaceutical composition comprising the compound according to any one of claims 1-6, characterized in that The pharmaceutical composition comprises a pharmaceutically acceptable excipient.

9. Use of a compound according to any one of claims 1-8 or a pharmaceutical composition thereof for the preparation of a medicament for treating an eye disease, said eye disease including intraocular pressure reduction, glaucoma, cataract, macular lesion, uveitis, preferably glaucoma.

10. A method for preparing a compound according to any one of claims 1-8.

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