TETRAHYDROCANNABINOL DERIVATIVES, PREPARATION METHOD THEREOF AND USE THEREOF

Abstract

Tetrahydrocannabinol derivatives and medical use thereof, in particular to the compounds represented by general formula (I), or stereoisomers, solvates, metabolites, pharmaceutically acceptable salts or cocrystals thereof, wherein the definitions of substituents in general formula (I) are the same as those in the description

##STR00001##

Claims

1. A compound represented by general formula (I), or stereoisomers, solvates, metabolites, pharmaceutically acceptable salts or cocrystals thereof: ##STR00040## wherein: R.sub.1 is C.sub.1-6 alkyl; R.sub.2 is ##STR00041## R.sub.3 is selected from the group consisting of methyl, C.sub.3-8 carbocyclic group, —CH.sub.2OH, carboxyl, —C(═O)OC.sub.1-6 alkyl and —C(═O)NR.sup.b1R.sup.b2; R.sub.4 and R.sub.5 are each independently selected from the group consisting of H, halogen and carboxyl; R.sub.a is selected from the group consisting of H and C.sub.1-6 alkyl; R.sub.b and R.sub.c are each independently selected from the group consisting of H, C.sub.1-6 alkyl, amino acid side chain, —C.sub.1-6 alkylene-C.sub.3-12 carbocyclic ring and —C.sub.1-6 alkylene-C.sub.3-12 heterocyclic ring; the C.sub.3-12 heterocyclic ring contains 1 to 4 heteroatoms selected from the group consisting of N, O and S; the C.sub.1-6 alkylene, the C.sub.1-6 alkyl, the C.sub.3-12 carbocyclic ring and the C.sub.3-12 heterocyclic ring are optionally further substituted by 0 to 3 substituents selected from the group consisting of hydroxyl, carboxyl, halogen, cyano, ═O, C.sub.1-6 alkyl, C.sub.1-6 heteroalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, —NR.sup.b1R.sup.b2, —C(═O)OC.sub.1-6 alkyl, —C(═O)N.sup.b1R.sup.b2, C.sub.3-12 cycloalkyl, C.sub.3-12 heterocycloalkyl, C.sub.6-12 aryl or C.sub.5-12 heteroaryl; and the C.sub.1-6 alkyl, the C.sub.1-6 heteroalkyl, the C.sub.2-6 alkenyl or the C.sub.2-6 alkynyl are optionally further substituted by one or more groups selected from the group consisting of hydroxyl, carboxyl, cyano, halogen, —O—R.sup.b1, —NR.sup.b1R.sup.b2, C.sub.3-12 cycloalkyl, C.sub.3-12 heterocycloalkyl, C.sub.6-12 aryl and C.sub.5-12 heteroaryl; when the amino acid side chain contains hydroxyl, mercapto or carboxyl, the hydroxyl, the mercapto or the carboxyl is optionally esterified; R.sup.b1 and R.sup.b2 are each independently selected from the group consisting of H, C.sub.1-6 alkyl, —C(═O)R.sup.b3 and —C(═O)NR.sup.b4R.sup.b5, wherein the C.sub.1-6 alkyl is optionally further substituted by one or more substituents selected from the group consisting of hydroxyl, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.6-12 aryl, C.sub.5-12 heteroaryl, C.sub.3-12 cycloalkyl and C.sub.3-12 heterocycloalkyl; R.sup.b3 is selected from the group consisting of C.sub.1-6 alkyl, C.sub.1-6 alkoxy and C.sub.6-12 aryl; R.sup.b4 and R.sup.b5 are each independently selected from the group consisting of H and C.sub.1-6 alkyl; or R.sup.b4 and R.sup.bs together with N atom form a 3 to 12 membered heterocycle containing 1 to 4 heteroatoms selected from the group consisting of N, O and S; or, R.sub.b and R.sub.c together with the atom to which they are attached form a 3 to 6 membered carbocyclic ring or a 3 to 6 membered heterocyclic ring, the 3 to 6 membered carbocyclic ring or the 3 to 6 membered heterocyclic ring is optionally further substituted by 0 to 3 substituents selected from the group consisting of F, Cl, Br, I, hydroxyl, carboxyl and amino, wherein the 3 to 6 membered heterocyclic ring contains 1 to 4 heteroatoms selected from the group consisting of N, O and S; R.sub.d is selected from the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 carbocyclic ring, 3 to 10 membered heterocyclic ring, —C.sub.1-6 alkylene-C.sub.3-10 carbocyclic ring, —C.sub.1-6 alkylene-3 to 10 membered heterocyclic ring, —C.sub.1-6 alkylene-O—C.sub.1-6 alkylene-C.sub.3-10 carbocyclic ring, —C.sub.1-6 alkylene-O—C.sub.1-6 alkylene-3 to 10 heterocyclic ring and —C.sub.1-6 alkylene-O—C.sub.1-4 alkyl; the C.sub.1-6 alkylene, the C.sub.2-6 alkenyl, the C.sub.2-6 alkynyl, the C.sub.1-6 alkyl, the C.sub.3-10 carbocyclic ring and the 3 to 10 membered heterocyclic ring are optionally further substituted with 0 to 4 substituents selected from the group consisting of H, F, Cl, Br, I, hydroxyl, carboxyl, amino, 1-cyclopropylethyl, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, —OC(═O)OR.sub.d1 and —OC(═O)R.sub.d2, wherein the 3 to 10 membered heterocyclic ring contains 1 to 6 heteroatoms selected from the group consisting of N, O and S; R.sub.d1 and R.sub.d2 are each independently selected from the group consisting of C.sub.1-4 alkyl, C.sub.3-10 carbocyclic ring and 3 to 10 membered heterocyclic ring, the C.sub.1-4 alkyl, the C.sub.3-10 carbocyclic ring or the 3 to 10 membered heterocyclic ring is optionally further substituted with 0 to 4 substituents selected from the group consisting of H, F, Cl, Br, I, hydroxyl, carboxyl, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.3-10 carbocyclic ring and 3 to 10 membered heterocylic ring, wherein the 3 to 10 membered heterocylic ring contains 1 to 6 heteroatoms selected from the group consisting of N, O and S; R.sub.6 is selected from the group consisting of C.sub.1-12 alkyl, C.sub.1-12 heteroalkyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.1-12 alkylene, C.sub.3-12 carbocyclic group, C.sub.3-12 heterocyclic group, —C.sub.1-6 alkylene-C.sub.3-12 carbocyclic group, —C.sub.1-6 alkylene-C.sub.3-12 heterocyclic group, —NR.sup.b1R.sup.b2, —C.sub.1-6 alkylene-C(═O)OC.sub.1-6 alkyl and —C.sub.1-6 alkylene-C(═O)N.sup.b1R.sup.b2, wherein the C.sub.1-12 alkyl, the C.sub.1-12 heteroalkyl, the C.sub.2-12 alkenyl, the C.sub.2-12 alkynyl, C.sub.1-12 alkylene, the C.sub.3-12 carbocyclic group and the C.sub.3-12 heterocyclic group are optionally substituted with one or more substituents selected from the group consisting of hydroxyl, carboxyl, halogen, cyano, ═O, C.sub.1-6 alkyl, —NR.sup.b1R.sup.b2, C.sub.3-12 carbocyclic group, C.sub.3-12 heterocyclic group, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, —C(═O)OC.sub.1-6 alkyl, —C(═O)C.sub.1-6 alkyl, —C(═O)NR.sup.b1R.sup.b2, —S(═O)C.sub.1-6 alkyl and —S(═O).sub.2C.sub.1-6 alkyl, wherein as substituents, the C.sub.1-6 alkyl, the C.sub.3-12 carbocyclic group and the C.sub.3-12 heterocyclic group are optionally further substituted with one or more substituents selected from the group consisting of ═O, hydroxyl, carboxyl, halogen, cyano, —C(═O)OC.sub.1-6 alkyl and —C(═O)C.sub.1-6 alkyl; is a single bond or a double bond; or, the general formula (I) is optionally substituted with one or more D atoms.

2. The compound, or stereoisomers, solvates, metabolites, pharmaceutically acceptable salts or cocrystals thereof according to claim 1, wherein the compound is represented by general formula (II): ##STR00042## wherein, R.sub.1 is C.sub.1-6 alkyl; R.sub.2 is ##STR00043## R.sub.a is H; R.sub.b and R.sub.c are each independently selected from the group consisting of H and amino acid side chain; when the amino acid side chain contains hydroxyl, mercapto or carboxyl, the hydroxyl, the mercapto or the carboxyl is optionally esterified; R.sub.d is selected from the group consisting of C.sub.1-6 alkyl, —C.sub.3-10 carbocyclic ring and 3 to 10 membered heterocyclic ring, and the C.sub.1-6 alkyl, the —C.sub.3-10 carbocyclic ring or the 3 to 10 membered heterocyclic ring is optionally further substituted with 0 to 4 substituents selected from the group consisting of H, F, Cl, Br, I, hydroxyl, carboxyl, amino, 1-cyclopropylethyl, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, —OC(═O)OR.sub.d1 and —OC(═O)R.sub.d2, wherein the 3 to 10 membered heterocyclic ring contains 1 to 6 heteroatoms selected from the group consisting of N, O and S; R.sub.d1 and R.sub.d2 are each independently C.sub.1-4 alkyl; R.sub.6 is selected from the group consisting of C.sub.1-12 alkyl, C.sub.3-12 carbocyclic group, and C.sub.3-12 heterocyclic group, wherein the C.sub.1-12 alkyl, the C.sub.3-12 carbocyclic group and the C.sub.3-12 heterocyclic group are optionally substituted by one or more substituents selected from the group consisting of hydroxyl, carboxyl, halogen, cyano, ═O, C.sub.1-6 alkyl, —NR.sup.b1R.sup.b2, C.sub.3-12 carbocyclic group, C.sub.3-12 heterocyclic group, C.sub.2-6 alkenyl group, C.sub.2-6 alkynyl group, —C(═O)OC.sub.1-6 alkyl, —C(═O)C.sub.1-6 alkyl, —C(═O)NR.sup.b1R.sup.b2, —S(═O)C.sub.1-6 alkyl and —S(═O).sub.2C.sub.1-6 alkyl, wherein as substituents, the C.sub.1-6 alkyl, the C.sub.3-12 carbocylic group, the C.sub.3-12 heterocyclic group are optionally substituted by one or more substituents selected from the group consisting of ═O, hydroxyl, carboxyl, halogen, cyano, —C(═O)OC.sub.1-6 alkyl and —C(═O)C.sub.1-6 alkyl; R.sup.b1 and R.sup.b2 are each independently selected from the group consisting of H, C.sub.1-6 alkyl, —C(═O)R.sup.b3 and —C(═O)NR.sup.b4R.sup.b5, wherein the C.sub.1-6 alkyl is optionally further substituted by one or more substituents selected from the group consisting of hydroxyl, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.6-12 aryl, C.sub.5-12 heteroaryl, C.sub.3-12 cycloalkyl and C.sub.3-12 heterocycloalkyl; R.sup.b3 is selected from the group consisting of C.sub.1-6 alkyl, C.sub.1-6 alkoxy and C.sub.6-12 aryl; R.sup.b4 and R.sup.b5 are each independently selected from the group consisting of H and C.sub.1-6 alkyl; or R.sup.b4 and R.sup.b5 together with N atom form a 3 to 12 membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of N, O and S; or, the general formula (II) is optionally substituted with one or more D atoms.

3. The compound, or stereoisomers, solvates, metabolites, pharmaceutically acceptable salts or cocrystals thereof according to claim 2, wherein the compound is represented by general formula (III): ##STR00044## wherein, R.sub.1 is C.sub.1-6 alkyl; R.sub.2 is ##STR00045## R.sub.d is selected from the group consisting of C.sub.1-6 alkyl, C.sub.3-10 carbocyclic ring and 3 to 10 membered heterocyclic ring, wherein the C.sub.1-6 alkyl, the C.sub.3-10 carbocyclic ring or the 3 to 10 membered heterocyclic ring is optionally further substituted with 0 to 4 substituents selected from the group consisting of H, F, Cl, Br, I, hydroxyl, carboxyl, amino, 1-cyclopropylethyl, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, —OC(═O)OR.sub.d1 and —OC(═O)R.sub.d2, wherein the 3 to 10 membered heterocyclic ring contains 1 to 6 heteroatoms selected from the group consisting of N, O and S; R.sub.d1 and R.sub.d2 are each independently C.sub.1-4 alkyl; or, the general formula (III) is optionally substituted with one or more D atoms.

4. The compound, or stereoisomers, solvates, metabolites, pharmaceutically acceptable salts or cocrystals thereof according to claim 3, wherein the compound has one of the following structures: ##STR00046## ##STR00047## ##STR00048## ##STR00049## ##STR00050##

5. A pharmaceutical composition comprising: (1) the compound, or stereoisomers, solvates, metabolites, pharmaceutically acceptable salts or cocrystals thereof according to claim 4, (2) optional one or more other active ingredients; and (3) a pharmaceutically acceptable carrier and/or excipient.

6. The pharmaceutical composition according to claim 5, wherein, the other active ingredient is one or more selected from the group consisting of ginkgolides, antineoplastic agents, anticoagulants, antiepileptic agents, antidepressants, anxiolytics, hypnotics, analgesics and anesthetics, or stereoisomers, metabolites, hydrates, solvates, pharmaceutically acceptable salts or cocrystals of the other active ingredients; preferably, the ginkgolides are one selected from the group consisting of ginkgolides A, ginkgolides B, ginkgolides C, ginkgolides D, ginkgolides J, ginkgolides M, ginkgolides K, ginkgolides L, ginkgolides N, ginkgolide P, ginkgolide Q and bilobalide or combinations of two or more thereof in any ratio.

7. A method for treating post-traumatic stress disorder, facial paralysis, stroke, migraine, coronary heart disease stable angina pectoris, cerebral infarction, thromboembolism, myocardial infarction, cardiac ischemia, coronary artery disease, hypertension, cerebral ischemia, improvement of sexual function, spasm, acute and chronic pain, fibromyalgia, postoperative pain, cluster headache, tension headache, back pain, limb pain, lumbago, neck pain, neuropathic pain, cancer pain, trigeminal neuralgia, arthritic pain, inflammatory pain, Dravet syndrome, Lennox-Gastaut syndrome, Prader-Willi syndrome, Sturge-Weber syndrome, fragile X syndrome, anxiety, bipolar affective disorder, autism, general anxiety disorder, social anxiety disorder, epilepsy, Parkinson's disease, Alzheimer's disease, Huntington's disease, opioid abuse, alcoholism, nicotine addiction, anorexia, cachexia, chemotherapy-related nausea and vomiting, postoperative nausea and vomiting, amyotrophic lateral sclerosis (ALS), Friedreich ataxia, schizophrenia, obsessive-compulsive disorder, multiple sclerosis, depression, sleep disorder, spasm caused by multiple sclerosis, dysmyotonia, sleep apnea, paralytic dementia, hypomnesis or glioblastoma, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of the compound of claim 1, or stereoisomers, solvates, metabolites, pharmaceutically acceptable salts or cocrystals thereof.

Description

SPECIFIC EMBODIMENTS

[0074] The following examples will illustrate the technical solution of the present application in detail, and the scope of the present application comprises, but is not limited to the examples.

[0075] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shift (δ) was given in units of 10.sup.−6 (ppm). The NMR test was conducted by using nuclear magnetic instrument (Bruker Avance III 400 and Bruker Avance 300), and the solvent for the test was deuterated dimethyl sulfoxide (DMSO-d.sub.6), deuterated chloroform (CDCl.sub.3), deuterated methanol (CD.sub.3OD), and the internal standard was tetramethylsilane (TMS).

[0076] MS test was conducted on Agilent 6120B(ESI) and Agilent 6120B(APCI);

[0077] HPLC test was conducted on Agilent 1260DAD high pressure liquid chromatograph (zorbax sb-C18 100×4.6 mm, 3.5 μm).

[0078] HSGF254 silica gel plate from Yantai Huanghai or Qingdao GF254 silica gel plate was used for thin layer chromatography (TLC), and the size of the silica gel plate for thin layer chromatography (TLC) was 0.15 mm to 0.20 mm, and the size of the silica gel plate for thin layer chromatography separation and purification products was 0.4 mm to 0.5 mm;

[0079] Silica gel of 200-300 mesh by Yantai Huanghai was generally used as carrier of the column chromatography.

[0080] The known starting materials in the present application can be synthesized by using the methods known in the field, or can be purchased from Titan Technology company, Annaiji Chemical company, Shanghai DEMO Medical Tech Co., Ltd, Chengdu Kelong Chemical company, Shaoyuan Chemical Technology company, Bailingwei Technology company, etc.

[0081] Nitrogen atmosphere means that the reaction flask was connected with a nitrogen balloon with a volume of about 1 L.

[0082] Hydrogen atmosphere means that the reaction flask was connected with a hydrogen balloon with a volume of about 1 L.

[0083] Hydrogenation reaction was usually vacuumized, filled with hydrogen, and repeated for 3 times.

[0084] Unless otherwise stated in Examples, the reaction was carried out in nitrogen atmosphere.

[0085] Unless otherwise stated in Examples, the solution was an aqueous solution.

[0086] Unless otherwise stated in Examples, the reaction temperature was room temperature, and the most suitable reaction temperature for room temperature was 20° C.-30° C.

[0087] DCM: dichloromethane;

[0088] EA: ethyl acetate;

[0089] HCl: hydrochloric acid;

[0090] THF: tetrahydrofuran;

[0091] DMF: N,N-dimethyl formamide;

[0092] PE: petroleum ether;

[0093] TLC: Thin layer chromatography;

[0094] SFC: supercritical fluid chromatography;

[0095] NCS: N-chlorosuccinimide;

[0096] Pd(dppf)Cl.sub.2: [1,1′-bis (diphenylphosphine) ferrocene] palladium dichloride.

EXAMPLES

[0097] The technical solution of the present application will be illustrated by the following Examples in detail, and the scope of the present application comprises, but is not limited to the examples.

Example 1

Isopropyl((ethoxycarbonyl)(((6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-yl)oxy)phosphoryl)-L-alaninate, compound 1

[0098] ##STR00015##

[0099] In a dry round-bottom flask, (6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol 1a (0.78 g, 1.6 mmol, 1.0 eq.) was dissolved in dichloromethane (5 mL), followed by adding triethylamine (0.45 mL, 2.0 eq.). The round-bottom flask was placed in a reaction bath at −60° C., followed by adding ethyl(dichlorophosphoryl)formate (0.31 g, 1.6 mmol, 1.0 eq.) in dichloromethane (1 mL) and stirred at −60° C. for 1.5 hours. Then triethylamine (0.25 mL, 1.1 eq.) was added dropwise, followed by adding isopropyl L-alaninate hydrochloride (0.3 g, 1.6 mmol, 1.0 eq.) in dichloromethane (1 mL) and then the resultant mixture was warmed up naturally to room temperature and stirred overnight. Saturated solution of ammonium chloride was added at 0° C., and then the thus obtained mixture was extracted with dichloromethane. The resultant organic phase was dried over sodium sulfate and dried by rotary evaporator. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v)=10:1) to obtain isopropyl((ethoxycarbonyl)(((6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-yl)oxy)phosphoryl)-L-alaninate, compound 1 (128 mg, with a yield of 15%, yellow oil).

[0100] .sup.1H NMR (300 MHz, Chloroform-d) δ 6.79 (t, 1H), 6.52-6.42 (m, 1H), 6.18-6.07 (m, 1H), 5.07-4.99 (m, 1H), 4.36-4.15 (m, 1H), 4.21-4.08 (m, 2H), 3.83-3.69 (m, 1H), 3.30 (d, 1H), 2.54-2.36 (m, 2H), 2.24-2.06 (m, 3H), 2.00-1.82 (m, 1H), 1.76-1.60 (m, 6H), 1.53 (t, 1H), 1.48-1.35 (m, 6H), 1.29-1.23 (m, 8H), 1.17-1.11 (m, 3H), 1.06 (s, 3H), 0.90-0.83 (m, 4H).

[0101] .sup.31P NMR (121 MHz, Chloroform-d) δ-2.85.

[0102] LC-MS m/s (ESI)=564.30[M+1].

Example 2

Isopropyl((isopropoxycarbonyl)(((6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-yl)oxy)phosphoryl)-L-alaninate, compound 2

[0103] ##STR00016##

[0104] The target compound 2 (130 mg, with a yield of 16%, yellow oil) was prepared by the same method as that of compound 1.

[0105] .sup.1H NMR (300 MHz, Chloroform-d) δ 6.79 (d, 1H), 6.50-6.42 (m, 1H), 6.14-6.11 (m, 1H), 5.13-4.89 (m, 2H), 4.37-4.16 (m, 1H), 3.79-3.71 (m, 1H), 3.30 (d, 1H), 2.50-2-40 (t, 2H), 2.16 (d, 2H), 1.98-1.83 (m, 1H), 1.67 (d, 4H), 1.54 (t, 1H), 1.43 (d, 3H), 1.40 (s, 3H), 1.34-1.13 (m, 15H), 1.09-1.02 (m, 6H), 0.92-0.79 (m, 3H).

[0106] .sup.31P NMR (121 MHz, Chloroform-d) δ-2.77.

[0107] LC-MS m/s (ESI)=578.32[M+1].

Example 3

[0108] Isopropyl 2-(((ethoxycarbonyl)(((6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-yl)oxy)phosphoryl)amino)-2-methylpropanoate, compound 3

##STR00017##

[0109] The target compound 3 (125 mg, with a yield of 14%, yellow oil) was prepared by the same method as that of compound 1.

[0110] .sup.1H NMR (300 MHz, Chloroform-d) δ 6.77 (t, 1H), 6.46 (m, 1H), 6.17-6.15 (m, 1H), 5.08-4.99 (m, 1H), 4.35-4.09 (m, 3H), 3.33 (d, 1H), 2.51-2.39 (m, 2H), 2.19-2.08 (m, 2H), 1.96-1.82 (m, 1H), 1.70-1.65 (m, 4H), 1.63 (s, 3H), 1.57 (s, 4H), 1.52-1.40 (m, 1H), 1.39 (s, 3H), 1.37-1.32 (m, 1H), 1.31-1.27 (m, 3H), 1.27-1.22 (m, 6H), 1.21 (d, 1H), 1.19 (d, 2H), 1.17 (t, 1H), 1.07 (s, 3H), 0.93-0.80 (m, 3H).

[0111] .sup.31P NMR (121 MHz, Chloroform-d) δ-2.78.

[0112] LC-MS m/s (ESI)=578.32[M+1].

Example 4

Isopropyl 2-(((isopropoxycarbonyl)(((6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-yl)oxy)phosphoryl)amino)-2-methylpropanoate, compound 4

[0113] ##STR00018##

[0114] The target compound 4 (126 mg, with a yield of 15%, yellow oil) was prepared by the same method as that of compound 1.

[0115] .sup.1H NMR (300 MHz, Chloroform-d) δ 6.75 (t, 1H), 6.42 (d, 1H), 6.15-6.13 (m, 1H), 5.11-4.90 (m, 2H), 4.19 (d, 1H), 3.30 (d, 1H), 2.48-2.36 (m, 2H), 2.15-2.05 (m, 2H), 1.98-1.78 (m, 1H), 1.67-1.61 (m, 4H), 1.59 (s, 3H), 1.54 (s, 3H), 1.53-1.46 (m, 2H), 1.45-1.37 (m, 1H), 1.36 (s, 3H), 1.29 (d, 2H), 1.25 (d, 2H), 1.23-1.19 (m, 9H), 1.10-1.08 (m, 3H), 1.04 (s, 3H), 0.89-0.77 (m, 3H).

[0116] .sup.31P NMR (121 MHz, Chloroform-d) δ-2.60.

[0117] LC-MS m/s (ESI)=592.33[M+1].

Example 5

Ethyl ((isopropoxycarbonyl)(((6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-yl)oxy)phosphoryl)-L-alaninate, compound 5

[0118] ##STR00019##

[0119] The target compound 5 (130 mg, with a yield of 8%, yellow oil) was prepared by the same method as that of compound 1.

[0120] .sup.1H NMR (300 MHz, Chloroform-d) δ 6.80 (t, 1H), 6.47 (t, 1H), 6.14-6.12 (m, 1H), 5.04-4.95 (m, 1H), 4.40-4.10 (m, 3H), 3.81-3.67 (m, 1H), 3.29 (d, 1H), 2.48-2.42 (m, 2H), 2.16 (d, 2H), 1.71-1.67 (m, 4H), 1.61 (s, 2H), 1.58-1.51 (m, 2H), 1.46 (d, 3H), 1.40 (s, 3H), 1.31-1.24 (m, 7H), 1.21-1.18 (m, 3H), 1.07 (s, 3H), 1.06-1.03 (m, 3H), 0.92-0.81 (m, 3H).

[0121] .sup.31P NMR (121 MHz, Chloroform-d) δ-2.87.

[0122] LC-MS m/s (ESI)=564.30[M+1].

[0123] According to the synthesis method disclosed in US20100152283, WO2020165902, WO2020252277, Bioorg. Med. Chem. 2010, 18, 7809-7815 and a book with ISBN: 978-0-470-84289-8, the following fragments 8a-20a and 22a were synthesized.

##STR00020## ##STR00021## ##STR00022##

[0124] The following compounds were prepared using the same method as that of compound 1.

TABLE-US-00001 No. Structural formula [M + 1]+ Compound 6 [00023] 536.6 Compound 7 [00024] 564.7 Compound 8 [00025] 592.7 Compound 9 [00026] 567.7 Compound 10 [00027] 580.7 Compound 11 [00028] 582.7 Compound 12 [00029] 575.7 Compound 13 [00030] 578.8 Compound 14 [00031] 566.7 Compound 15 [00032] 566.7 Compound 16 [00033] 566.7 Compound 17 [00034] 566.3 Compound 18 [00035] 560.6 Compound 19 [00036] 604.6 Compound 20 [00037] 564.7 Compound 21 [00038] 536.6 Compound 22 [00039] 564.7

Pharmacokinetics in Rats

[0125] Healthy adult SD rats (n=3 per group) were fasted overnight (free access to water), and then were administrated the drugs by intragastric administration (i.g.) (10 mg/kg). 0.1 mL of blood was collected from jugular plexus of the rats at 30 minutes, 1 hour and 8 hour after administration. All blood samples were anticoagulated with K.sub.2EDTA, then centrifuged at 3500 rpm at 5° C. for 10 minutes to separate plasma, and stored at −20° C. for test. Parent drug concentration in plasma was determined by LC/MS/MS method. Using the above method, the blood drug concentration (ng/mL) of the parent drugs of the compounds at each time point in the rats were measured, the results are as follows:

TABLE-US-00002 Administration Parent No. dose drug 30 min 1 h 8 h Compound 1 10 mg/kg THC 274.4 536.1 38.7 Compound 8 10 mg/kg  8a 184.6 483.4 25.9 Compound 9 10 mg/kg  9a 367.8 457.8 51.4 Compound 11 10 mg/kg 11a 128.0 591.7 58.6 Compound 13 10 mg/kg 13a 308.9 498.4 69.4 Compound 18 10 mg/kg 18a 458.9 1044.1 63.2

[0126] Experiment results showed that the parent drugs can respectively be detected in plasma after intragastric administration of compounds of the present application, which indicates that the compounds of the present application can be absorbed orally, and the compounds can be quickly converted into the parent drugs in vivo, and they show better oral bioavailability than the parent drugs.

[0127] Although the specific embodiments are described in detail in the description of the present application, those skilled in the art should understand that the above embodiments are exemplary and cannot be understood as limitations to the present application. If those skilled in the art make improvements and modifications to the present application without departing from the principle of the present application, the technical solution obtained by these improvements and modifications shall also fall within the protection scope of the claims of the present application.