Honokiol derivative, preparation method therefor, and use thereof

Abstract

The present invention relates to a honokiol derivative represented by the following formula I or formula II, a preparation method therefor, and use thereof. The compound according to the present invention can serve as a prodrug of honokiol, greatly improving the bioavailability of honokiol, overcoming the problem that honokiol monomer cannot be developed into a drug due to its low bioavailability in vivo, and making the clinical development of honokiol possible.

Description

A magnolol derivative, its preparation method and uses Technical Field

[0001] This invention belongs to the field of medical pharmaceuticals, and specifically relates to a magnolol derivative, its preparation method, and its uses. Background Technology

[0002] Magnolol is a brownish-white fine powder with a fragrant odor and a pungent, slightly bitter taste. The monomer is a colorless, flaky crystal and is one of the main components of the traditional Chinese medicine Magnolia officinalis. Structurally, it belongs to the biphenyl-type neolignan class. Modern pharmacological studies have found that magnolol possesses various pharmacological effects, such as antiviral, antibacterial, antitumor, anti-inflammatory, cholesterol-lowering, anti-anxiety, antidepressant, analgesic, lung injury treatment, antioxidant, lipid regulation, cardiovascular protection, antidiabetic, anti-allergic, anti-Parkinson's disease, Alzheimer's disease treatment, ALS treatment, and hair growth promotion. However, natural magnolol has poor water solubility and low bioavailability, making it unsuitable for pharmaceutical formulation and severely limiting its clinical application. Therefore, various magnolol derivatives have been developed to improve its bioavailability. For example, CN108883082A describes obtaining a derivative by replacing the hydroxyl group of magnolol with a long-chain alkylene group and simultaneously attaching a triphenylphosphine group to the end. In CN115215771A, a derivative was obtained by linking magnolol with a hydrazine-containing structure.

[0003] However, the derivatives obtained by the existing technologies have not completely overcome the problems of poor water solubility and low bioavailability of magnolol, while its pharmacological toxicity has been significantly increased. To improve the physicochemical properties of magnolol, various technical means have been employed to attempt to enhance its bioavailability, such as converting it to an injectable form, preparing various salt forms, and using novel formulation methods (e.g., nano-formulations, gels, patches, liposomes, etc.). Liposomes and magnolol are currently in Phase II clinical trials for the treatment of gliomas; furthermore, no suitable form of magnolol has been commercialized for public use. Summary of the Invention

[0004] To address the problems existing in the prior art, this invention develops a magnolol derivative with low pharmaceutical toxicity and significantly increased bioavailability. It can serve as a good magnolol prodrug and has good therapeutic effects on a variety of diseases.

[0005] According to one aspect of the invention, an object of the invention is to provide a magnolol derivative, or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer, or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, represented by Formula I or Formula II:

[0006] R1 is selected from hydrogen, hydroxyl, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted saturated or unsaturated four- to eighteen-membered heterocyclic groups containing 1-3 heteroatoms selected from N, O, and S, substituted or unsubstituted five- to twelve-membered heteroaryl groups containing 1-3 heteroatoms selected from N, O, and S, and substituted or unsubstituted six- to fourteen-membered aryl groups. The term "substituted" refers to each of the above groups containing 1 to 3 R1 groups. 1a The R 1a Selected from halogen, hydroxyl, amino, carbonyl, cyano, C1-C6 alkyl, carboxyl, saturated or unsaturated four- to ten-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O and S, five- to twelve-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O and S, and six- to fourteen-membered aryl groups, provided that R1 in Formula I is not hydrogen.

[0007] R2 is selected from hydrogen, hydroxyl, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted saturated or unsaturated four- to eighteen-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, substituted or unsubstituted five- to fourteen-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S, and substituted or unsubstituted six- to fourteen-membered aryl groups, wherein "substituted" means that each of the above groups contains 1 to 3 R2 atoms. 2a The R 2a The group is selected from halogen, hydroxyl, amino, carbonyl, cyano, C1-C6 alkyl, carboxyl, saturated or unsaturated four- to ten-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O and S, five- to twelve-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O and S, and six- to fourteen-membered aryl groups, provided that R2 in Formula II is not hydrogen.

[0008] Preferably, R1 is selected from hydroxyl, amino, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted saturated or unsaturated four- to twelve-membered heterocyclic groups containing 1-3 heteroatoms selected from N, O, and S, substituted or unsubstituted five- to twelve-membered heteroaryl groups containing 1-3 heteroatoms selected from N, O, and S, and substituted or unsubstituted six- to fourteen-membered aryl groups, wherein "substituted" means that each of the above groups contains 1 or 2 R1 groups. 1a The R 1a The group is selected from halogen, hydroxyl, amino, carbonyl, cyano, C1-C4 alkyl, carboxyl, saturated or unsaturated four- to ten-membered heterocyclic groups containing one or two heteroatoms selected from N or O, five- to ten-membered heteroaryl groups containing one or two heteroatoms selected from N or O, and six- to fourteen-membered aryl groups, provided that R1 in Formula I is not hydrogen.

[0009] More preferably, R1 is selected from hydroxyl, amino, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted saturated or unsaturated five- to twelve-membered heterocyclic group containing one or two heteroatoms selected from N or O, substituted or unsubstituted five- to twelve-membered heteroaryl group containing one or two heteroatoms selected from N or O, and substituted or unsubstituted six- to fourteen-membered aryl, wherein "substituted" means that each of the above groups contains one or two R1 atoms. 1a The R 1a The group is selected from halogen, hydroxyl, amino, carbonyl, cyano, C1-C3 alkyl, carboxyl, saturated or unsaturated four- to ten-membered heterocyclic groups containing one or two heteroatoms selected from N or O, five- to ten-membered heteroaryl groups containing one or two heteroatoms selected from N or O, and six- to fourteen-membered aryl groups, provided that R1 in Formula I is not hydrogen.

[0010] More preferably, R1 is selected from hydrogen, hydroxyl, amino, substituted or unsubstituted methyl, ethyl, n-propyl, isopropyl, substituted or unsubstituted saturated or unsaturated five- to twelve-membered heterocyclic groups containing one or two heteroatoms selected from N or O, substituted or unsubstituted five- to twelve-membered heteroaryl groups containing one or two heteroatoms selected from N or O, and substituted or unsubstituted six- to fourteen-membered aryl groups; wherein "substituted" means that each of the above groups contains one or two R1 atoms. 1a The R 1a The group is selected from halogen, carbonyl, cyano, methyl, ethyl, n-propyl, isopropyl, carboxyl, saturated or unsaturated four- to six-membered heterocyclic groups containing one or two heteroatoms selected from N or O, five- to six-membered heteroaryl groups containing one or two heteroatoms selected from N or O, and phenyl, provided that R1 in Formula I is not hydrogen.

[0011] More preferably, R1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl,

[0012] Preferably, R2 is selected from hydrogen, hydroxyl, amino, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted saturated or unsaturated four- to twelve-membered heterocyclic groups containing 1-3 heteroatoms selected from N, O, and S, substituted or unsubstituted five- to twelve-membered heteroaryl groups containing 1-3 heteroatoms selected from N, O, and S, and substituted or unsubstituted six- to fourteen-membered aryl groups, wherein "substituted" means that each of the above groups contains 1 or 2 R. 2a The R 2a The group is selected from halogen, hydroxyl, amino, carbonyl, cyano, C1-C4 alkyl, carboxyl, saturated or unsaturated four- to six-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O and S, five- to ten-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O and S, and six- to fourteen-membered aryl groups, provided that R2 in Formula II is not hydrogen.

[0013] More preferably, R2 is selected from hydrogen, hydroxyl, amino, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 carbonyl alkyl, substituted or unsubstituted saturated or unsaturated four- to twelve-membered heterocyclic groups containing one or two heteroatoms selected from N or O, substituted or unsubstituted five- to twelve-membered heteroaryl groups containing one or two heteroatoms selected from N, O, and S, and substituted or unsubstituted six- to fourteen-membered aryl groups, wherein "substituted" means that each of the above groups contains one or two R atoms. 2a The R 2a The group is selected from halogen, hydroxyl, amino, carbonyl, cyano, C1-C3 alkyl, carboxyl, saturated or unsaturated four- to six-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O and S, five- to ten-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O and S, and six- to fourteen-membered aryl groups, provided that R2 in Formula II is not hydrogen.

[0014] More preferably, R2 is selected from hydrogen, hydroxyl, amino, substituted or unsubstituted methyl, ethyl, n-propyl, isopropyl, substituted or unsubstituted C1-C3 carbonyl alkyl, substituted or unsubstituted saturated or unsaturated four- to twelve-membered heterocyclic groups containing one or two heteroatoms selected from N or O, substituted or unsubstituted five- to twelve-membered heteroaryl groups containing one or two heteroatoms selected from N or O, and substituted or unsubstituted six- to fourteen-membered aryl groups; wherein "substituted" means that each of the above groups contains one or two R... 2a The R 2a The group is selected from halogen, hydroxyl, amino, carbonyl, cyano, methyl, ethyl, n-propyl, isopropyl, carboxyl, saturated or unsaturated four- to six-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O and S, five- to six-membered heteroaryl groups containing 1 or 2 heteroatoms selected from N or O, and phenyl, provided that R2 in Formula II is not hydrogen.

[0015] More preferably, R2 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl,

[0016] Preferably, according to the present invention, magnolol derivatives, or isotopically labeled compounds thereof, or optical isomers, geometric isomers, tautomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or prodrugs thereof, or metabolites thereof, represented by Formula I or Formula II, may be represented by Formula Ia, Formula Ib, Formula Ic or Formula Id:

[0017] The definitions of R1 and R2 are the same as those in Equation I or Equation II;

[0018] Ring A and ring B are each independently selected from saturated or unsaturated four- to twelve-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O and S, five- to twelve-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O and S, and six- to twelve-membered aryl groups.

[0019] R 11 and R 21 Each of the following groups is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, saturated or unsaturated four- to eight-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O and S, five- to twelve-membered heteroaryl, and six- to fourteen-membered aryl groups containing 1 to 3 heteroatoms selected from N, O and S.

[0020] R 111 and R 211 Each group is independently selected from hydroxyl, carboxyl, cyano, amino, and halogen groups.

[0021] n1 and n2 are each independently selected from integers from 1 to 6.

[0022] Preferably, R 11 and R 21 Each of the following is independently selected from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, saturated or unsaturated four- to six-membered heterocyclic groups containing one or two heteroatoms selected from N and O, five- to eight-membered heteroaryl, and six- to ten-membered aryl groups containing one or two heteroatoms selected from N and O.

[0023] More preferably, R 11 and R 21 Each of the following is independently selected from methyl, ethyl, n-propyl, isopropyl, furanyl, pyrrolyl, thiazolyl, pyranyl, pyridyl, imidazole, tetrahydrofuranyl, hexahydropyridyl, tetrahydropyrrolyl, pyrazinyl, phenyl, and naphthyl.

[0024] Preferably, n1 and n2 are each independently selected from integers from 1 to 4, for example, integers of 1, 2, 3 or 4.

[0025] Preferably, the compounds according to the present invention represented by formula I, II, Ia, Ib, Ic or Id, and magnolol derivatives, or isotopically labeled compounds thereof, or optical isomers, geometric isomers, tautomers or mixtures of isomers thereof, or pharmaceutically acceptable salts thereof, are selected from the following compounds:

[0026] According to a second aspect of the invention, another object of the invention is to provide a method for preparing magnolol derivatives, or isotopically labeled compounds thereof, or optical isomers, geometric isomers, tautomers, or mixtures of isomers thereof, or pharmaceutically acceptable salts thereof, represented by formulas I, II, Ia, Ib, Ic, or Id, which can be carried out with reference to conventional synthetic methods in the art, for example, by methods selected from:

[0027] Method 1

[0028] 1) At room temperature, dissolve magnolol in an organic solvent, add 2-4 molar amounts of base, and then add acyl chloride or acid anhydride. Stir and react for 1 hour to overnight at room temperature to 70°C. This produces mixed esters. Controlling the amount of acyl chloride or acid anhydride added, for example, 1 to 3 molar amounts, can yield products with different structures, such as… These products can be easily separated using techniques such as chromatographic columns;

[0029] 2) The obtained product is reacted with different halogenated or acyl chloride compounds under alkaline conditions at room temperature to 70°C for 1 hour to overnight to obtain magnolol derivatives represented by formula I, II, Ia, Ib, Ic or Id.

[0030] Method 2

[0031] 1) At room temperature, dissolve magnolol in an organic solvent, add 2-4 times the amount of alkali, add 1 mole of acetic anhydride, and stir the reaction at room temperature to 70°C for 1 hour to overnight. This yields a monoacetyl-protected intermediate.

[0032] The monoacetyl-protected intermediate is dissolved in an organic solvent, and 2 to 4 times the amount of base is added. It is then reacted with different acyl chlorides at room temperature to 70°C for 1 hour to overnight. By controlling the amount of acyl chloride or acid anhydride added, for example, 1 to 3 moles of acyl chloride or acid anhydride, products with different structures can be obtained.

[0033] 2) The product obtained in step 1) is added to an organic solvent and stirred overnight at room temperature in the presence of an alkali to remove the acetyl group. Then it is reacted with different halogenated compounds or acyl chloride compounds under alkaline conditions at room temperature to 70°C for 1 hour to overnight to obtain the final product.

[0034] Preferably, the organic solvent used in Method 1 and Method 2 is selected from one or more of acetone, ethyl acetate, tetrahydrofuran, dimethylformamide, and dimethyl sulfoxide.

[0035] Preferably, the base in Method 1 and Method 2 is an organic base or an inorganic base, wherein the organic base is selected from triethylamine, diisopropylamine, diisopropylethylamine, pyridine, piperidine, morpholine, dimethylisopropylamine, N-methylmorpholine, 1-methylpyrrole, 1-methylpiperidine, tetramethylethylenediamine, N,N-dimethylaniline, imidazole, 2-methylpyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-undec-7- The inorganic base is selected from one or more of the following: alkene, 1,5-diazabicyclo[4.3.0]-undec-7-ene, sodium methoxide, sodium ethoxide, sodium tert-butoxide, sodium acetate, potassium tert-butoxide, n-butyllithium, n-octyllithium, n-hexyllithium, phenyllithium, diisopropylaminolithium, and hexamethyldisilaminolithium; the inorganic base is selected from one or more of the following: sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydroxide, barium hydroxide, lithium hydroxide, nickel hydroxide, and cesium hydroxide.

[0036] Preferably, the acyl chloride in method one is selected from... R 111 (CH2) n1 COCl and R 211 (CH2) n2 One or more of COCl.

[0037] Preferably, the acid anhydride in method one is selected from... R 111 (CH2) n1 (CO)O(CO)(CH2) n1 R 111 and R 211 (CH2) n2 (CO)O(CO)(CH2) n2 R 211 One or more of them.

[0038] Preferably, the organic solvent in step 2) of method two is selected from one or more of methanol and ethanol.

[0039] Preferably, the alkali in step 2) of method two is selected from one or more of potassium carbonate and sodium carbonate.

[0040] Preferably, the substituents R1, R2, and R in Method 1 and Method 2 are... 11 R 111 R 211 The definitions of n1 and n2 are the same as those in the general formulas above.

[0041] According to a third aspect of the invention, another object of the invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of a magnolol derivative, or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture thereof, or a pharmaceutically acceptable salt thereof, as described in the invention, and a pharmaceutically acceptable carrier.

[0042] According to a fourth aspect of the invention, another object of the invention is to provide the use of magnolol derivatives, or isotopically labeled compounds thereof, or optical isomers, geometric isomers, tautomers or mixtures thereof, or pharmaceutically acceptable salts thereof, as magnolol prodrugs according to the invention, represented by formula I, II, Ia, Ib, Ic or Id.

[0043] According to a fifth aspect of the invention, another object of the invention is to provide magnolol derivatives, or isotopically labeled compounds thereof, or optical isomers, geometric isomers, tautomers or mixtures thereof, or pharmaceutically acceptable salts thereof, as described in the invention, in the preparation of anticancer drugs (e.g., for glioma, liver cancer, lung cancer, pancreatic cancer, colon cancer, breast cancer, skin cancer, melanoma), antioxidants, and antivirals. Uses in medications for (influenza, herpes, reovirus, COVID-19), antibacterial (e.g., Gram-positive bacteria, Staphylococcus aureus, Escherichia coli, Actinobacillus, methicillin-resistant Staphylococcus aureus, Prevotella intermedius, Micrococcus luteus, Porphyromonas gingivalis, Bacillus subtilis), anti-anxiety, antidepressant, anti-inflammatory, ALS, analgesic, anti-lung injury, antimalarial, central nervous system disorders (e.g., Parkinson's disease, Alzheimer's disease, stroke), autoimmune diseases, gastrointestinal protection, and cardioprotective purposes.

[0044] According to a fifth aspect of the invention, another object of the invention is to provide a method for treating cancer (e.g., glioma, liver cancer, lung cancer, pancreatic cancer, colon cancer, breast cancer, skin cancer, melanoma), the method comprising administering to a subject in need an effective amount of a magnolol derivative, or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the invention, represented by formula I, II, Ia, Ib, Ic, or Id, to a subject in need. Beneficial effects

[0045] The compound described in this invention can be used as a prodrug of magnolol, which greatly improves the bioavailability of magnolol and overcomes the problem that magnolol monomers have low bioavailability in vivo and cannot be drugged, thus making the clinical development of magnolol possible. Attached Figure Description

[0046] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0047] Figure 1 shows the test results of the therapeutic effect of the compound in Example 2 on mice with glioma model prepared by subcutaneous injection of microglia. Detailed Implementation

[0048] The present invention will now be described in detail. Before proceeding with the description, it should be understood that the terminology used in this specification and the appended claims should not be construed as limited to its general or dictionary meaning, but rather should be interpreted according to the meaning and concept corresponding to the technical aspects of the invention, based on the principle that the inventors are allowed to appropriately define the terms for the best interpretation. Therefore, the description presented herein is merely a preferred example for illustrative purposes and is not intended to limit the scope of the invention. It should be understood that other equivalents or modifications can be obtained from it without departing from the spirit and scope of the invention.

[0049] In this document, the terms “comprising,” “including,” “having,” “containing,” or any other similar terms are open-ended conjunctions intended to cover non-exclusive inclusions. For example, a composition or article containing a plurality of elements is not limited to those listed herein, but may also include other elements not explicitly listed but typically inherent to the composition or article. Furthermore, unless explicitly stated to the contrary, the term “or” is inclusive, not exclusive. For example, the condition “A or B” is satisfied in any of the following cases: A is true (or exists) and B is false (or does not exist); A is false (or does not exist) and B is true (or exists); A and B are both true (or exist). Moreover, in this document, the terms “comprising,” “including,” “having,” and “containing” should be interpreted as specifically disclosed and simultaneously cover closed or semi-closed conjunctions such as “composed of” and “substantially composed of.”

[0050] In this document, all features or conditions defined in the form of numerical ranges or percentage ranges are for the sake of brevity and convenience only. Accordingly, descriptions of numerical ranges or percentage ranges should be considered as covering and specifically disclosing all possible secondary ranges and individual values ​​within those ranges, particularly integer values. For example, a range description of "1 to 8" should be considered as specifically disclosing all secondary ranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, etc., particularly secondary ranges defined by all integer values, and should be considered as specifically disclosing individual values ​​within those ranges such as 1, 2, 3, 4, 5, 6, 7, 8, etc. Unless otherwise specified, the foregoing interpretation applies to all content throughout this invention, regardless of its scope.

[0051] If a quantity or other numerical value or parameter is expressed as a range, a preferred range, or a series of upper and lower limits, it should be understood that this document has specifically disclosed all ranges consisting of any upper or preferred value of that range and the lower or preferred value of that range, regardless of whether such ranges are separately disclosed. Furthermore, when a range of numerical values ​​is mentioned herein, unless otherwise stated, the range shall include its endpoints and all integers and fractions within the range.

[0052] In this document, numerical values ​​are to be understood as having a precision with significant digits, provided that the purpose of the invention can be achieved. For example, the number 40.0 should be understood to cover the range from 39.50 to 40.49.

[0053] When listing a range of values, the aim is to include every value within that range and its subranges. For example, "C 1–6 "Aims to cover C1, C2, C3, C4, C5, C6, C 1–6 C 1–5 C 1–4 C 1–3 C 1–2 C 2–6 C 2–5 C 2–4 C 2–3 C 3–6 C 3–5 C 3–4 C 4–6 C 4–5 and C 5–6 .

[0054] In this document, when Markush groups or alternative terms are used to describe features or examples of the invention, those skilled in the art should understand that subgroups of all elements within a Markush group or option list, or any individual element, can also be used to describe the invention. For example, if X is described as "selected from the group consisting of X1, X2, and X3," it also indicates that the claim that X is X1 and the claim that X is X1 and / or X2 have been fully described. Furthermore, when Markush groups or alternative terms are used to describe features or examples of the invention, those skilled in the art should understand that any combination of subgroups of all elements within a Markush group or option list, or any combination of individual elements, can also be used to describe the invention. Accordingly, for example, if X is described as "selected from the group consisting of X1, X2, and X3," and Y is described as "selected from the group consisting of Y1, Y2, and Y3," it indicates that the claim that X is X1 or X2 or X3 and Y is Y1 or Y2 or Y3 has been fully described.

[0055] The compounds disclosed herein can exist in isotopically labeled or isotopically rich forms, wherein the forms comprise one or more atoms whose atomic mass or mass number differs from the most common atomic mass or mass number found in nature. The isotopes can be radioactive or non-radioactive. Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, and iodine include, but are not limited to, those... 2 H, 3 H, 13 C 14 C 15 N、 18 O、 32 P, 35 S, 18 F, 36 Cl and 125 I. Compounds containing other isotopes of these and / or other atoms are within the scope of this invention.

[0056] definition

[0057] The term "alkyl," used alone or as part of another group, refers to a straight-chain or branched aliphatic saturated hydrocarbon. In some embodiments, the alkyl group may be C1-C2. 1-6 Alkyl group. In another embodiment, the alkyl group may have a C-chain. 3-6 Alkyl group. In another embodiment, the alkyl group is a straight-chain C14 group. 1-4 Alkyl groups. For example, C14 used in this article. 1-4 Alkyl groups are selected from methyl, ethyl, propyl (n-propyl), isopropyl, butyl (n-butyl), sec-butyl, tert-butyl, and isobutyl groups. Substituted C 1-4 Alkyl refers to the C1646-C ... 1-4 Alkyl groups, which may optionally be substituted with one or more permitted substituents as described herein.

[0058] The term "alkenyl," used alone or as part of another group, refers to an alkyl group as defined above containing one, two, or three carbon-carbon double bonds. In one embodiment, the alkenyl group is C0. 2-6 Alkenyl group. In another embodiment, the alkenyl group is C. 2-4 Alkenyl. Non-limiting exemplary alkenyl groups include vinyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

[0059] The term "alkynyl," used alone or as part of another group, refers to an alkyl group as defined above containing one, two, or three carbon-carbon triple bonds. In one embodiment, the alkynyl group has one carbon-carbon triple bond. In one embodiment, the alkynyl group is C0. 2-6 Alkyne group. In another embodiment, the alkynyl group is C. 2-4 Alkyne group. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentylyl, and hexynyl.

[0060] "Heterocyclic group" or "heterocycle," used alone or as part of another group, refers to a group having a 4- to 18-membered non-aromatic ring system with a cyclic carbon atom and 1-3 ring heteroatoms (each heteroatom independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon) ("quaternary to 18-membered heterocyclic group"). Where valence permits, in a heterocyclic group containing one or more nitrogen atoms, the linking point can be either a carbon or a nitrogen atom. Heterocyclic groups can be monocyclic ("monocyclic heterocyclic group") or fused, bridged, or spirocyclic systems, such as bicyclic systems ("bicyclic heterocyclic group"), and can be saturated or partially unsaturated. A bicyclic heterocyclic system may contain one or more heteroatoms in one or both rings. "Heterocyclic group" also includes a ring system in which a heterocycle as defined above is fused with one or more carbocyclic groups, wherein the connection point is on the carbocyclic group or the heterocycle, or a ring system in which a heterocycle as defined above is fused with one or more aryl or heteroaryl groups, wherein the connection point is on the heterocycle, and in this case, the number of ring members continues to represent the number of ring members in the heterocyclic system.

[0061] "Aryl", used alone or as part of another group, refers to a group that has a certain aromatic ring structure in the aromatic ring system ("C"). 6-14 A group comprising a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the ring array) of 6-14 carbon atoms and 0 heteroatoms. In some embodiments, the aryl group has 6 ring carbon atoms (“C6 aryl”; e.g., phenyl). In some embodiments, the aryl group has 10 ring carbon atoms (“C…”). 10Aryl; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 cyclic carbon atoms (“C”). 14 "Aryl"; for example, anthracene. "Aryl" also includes ring systems in which the aryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the radical or linkage is on the aryl ring, and in this case, the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system.

[0062] "Heteroaryl," used alone or as part of another group, refers to a group ("5-12-membered heteroaryl") having a cyclic carbon atom provided in the aromatic ring system and 1-4 cyclic heteroatoms (each heteroatom independently selected from nitrogen, oxygen, and sulfur) of a 5-12-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in the ring array). Where valence permits, in heteroaryls containing one or more nitrogen atoms, the linking point can be a carbon or nitrogen atom. A heteroaryl bicyclic system may contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the linking point is on the heteroaryl ring, and in this case, the number of ring members continues to indicate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused with one or more aryl groups, wherein the connection point is on the aryl or heteroaryl ring, and in this case, the number of ring members represents the number of ring members in the fused (aryl / heteroaryl) ring system. A bicyclic heteroaryl group (e.g., indolyl, quinolinyl, carbazolyl, etc.) in which one ring does not contain a heteroatom can have the connection point on either ring, i.e., a ring with a heteroatom (e.g., 2-indolyl) or a ring without a heteroatom (e.g., 5-indolyl).

[0063] "Halogen" refers to fluorine (fluorine, -F), chlorine (chlorine, -Cl), bromine (bromine, -Br) or iodine (iodine, -I).

[0064] The term "pharmaceutically acceptable salt" refers to salts that, within reasonable medical judgment, are suitable for contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art.

[0065] The term "tautomer" or "tautomerism" refers to two or more interconvertible compounds resulting from the migration of at least one form of hydrogen atom and at least one change in valence (e.g., from single to double, triple to single, or vice versa). The exact proportions of tautomers depend on several factors, including temperature, solvent, and pH. Tautomerization (i.e., the reaction that provides tautomer pairs) can be catalyzed by acids or bases. Exemplary tautomerizations include ketone-to-enol, amide-to-imide, lactam-to-lactamimide, enamine-to-imide, and enamine-to-(different enamines) tautomerizations.

[0066] The term "subject" refers to an animal, preferably a mammal, and most preferably a human, that has been used for treatment, observation, or experimentation.

[0067] The term "treatment" refers to the elimination, reduction, or improvement of a disease or condition and / or its associated symptoms. While not excluded, treatment of a disease or condition does not necessarily require the complete elimination of the disease, condition, or its associated symptoms. As used herein, the term "treatment," etc., can include "preventive treatment," which refers to reducing the likelihood of disease or condition recurrence or previously controlled recurrence in subjects who do not have disease or condition recurrence or are at risk of disease or condition recurrence or have a tendency for disease or condition recurrence or recurrence. The term "treatment" and its synonyms refer to the administration of a therapeutically effective amount of the compound described herein to a subject who requires such treatment.

[0068] The following embodiments are merely examples illustrating implementations of the present invention and do not constitute any limitation on the present invention. Those skilled in the art will understand that modifications made without departing from the spirit and concept of the present invention fall within the protection scope of the present invention. Unless otherwise specified, the reagents and instruments used in the following embodiments are commercially available products.

[0069] Furthermore, unless otherwise stated, the reagents and solvents disclosed below were purchased from Beijing Innocare Technology Co., Ltd., and 1 ¹H NMR was performed using a Bruker 400M / AvIII NMR spectrometer. LCMS was performed using an Agilent 1260-6125 LC-MS system. HPLC was performed using an Agilent Technologies 1260 series system; purity was calculated as area % by HPLC, and Pre-SFC was performed using a Waters SFC-80Q series system.

[0070] Intermediate 1: Acetic acid-2-[4-hydroxy-3-(prop-2-enyl)phenyl]-4-(prop-2-enyl)phenyl ester

[0071] Intermediate 2-acetic acid-4-[2-hydroxy-5-(prop-2-enyl)phenyl]-2-(prop-2-enyl)phenyl ester

[0072] Prepared as follows:

[0073] Magnolol (3.0 g, 11.2 mmol, 1.0 equivalent) was dissolved in dry acetone (50 mL), and potassium carbonate (1.6 g, 11.3 mmol, 1.0 equivalent) was added. The mixture was stirred at 0°C for 30 minutes under nitrogen protection. Acetic anhydride (1.3 g, 12.4 mmol, 1.1 equivalent) was added to the solution, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 60:1 to 2:1) to give a clear oily intermediate 1 (970 mg, yield 27.9%). The remaining mixture was purified by preparative liquid chromatography (50%–55% acetonitrile aqueous solution) to give a colorless oily intermediate 2 (170 mg, yield 4.9%).

[0074] Intermediate 1: 1 H NMR (400MHz, CDCl3): δppm 7.36-7.33(m,2H),7.16-7.13(m,1H),7.09-7.04(m,2H),6.91(d,J=8.1Hz,1 H),6.04-5.85(m,2H),5.16-5.04(m,4H),3.35(d,J=6.3Hz,1H),2.34(s,3H).

[0075] LCMS:309.1,([M+H] + ).

[0076] Intermediate 2: 1 H NMR (400MHz, DMSO-d6): δppm 9,57(brs,1H),7.19-7.12(m,2H),7.07-7.04(m,3H),6.87-6.84(m,1H) ,6.05-5.90(m,2H),5.16-5.00(m,4H),3.39-3.30(m,4H),2.07(s,3H).

[0077] LCMS:309.1([M+H] + ).

[0078] Example

[0079] Example 1: Preparation of 4-(hexahydropyridin-1-yl)hexahydropyridin-1-carboxylic acid-2-[4-hydroxy-3-(prop-2-enyl)phenyl]-4-(prop-2-enyl)phenyl ester

[0080] Example 2 Preparation of 4-(hexahydropyridin-1-yl)hexahydropyridin-1-carboxylic acid-4-[2-hydroxy-5-(prop-2-enyl)phenyl]-2-(prop-2-enyl)phenyl ester

[0081] Under nitrogen protection, magnolol (2.0 g, 7.51 mmol, 1.0 equivalent) was added to acetone (20 mL), stirred and dissolved, and potassium carbonate (3.1 g, 22.53 mmol, 3.0 equivalent) was added. The reaction mixture was stirred at 65 °C for 30 minutes, and 1-chloroformyl-4-piperidinylpiperidine hydrochloride (2.0 g, 7.51 mmol, 1.0 equivalent) was added, and the reaction was carried out overnight at 65 °C. After the reaction was completed, water (25 mL) was added, stirred for 5 minutes, and extracted with ethyl acetate (20 mL x 3). The organic layers were combined, washed with saturated brine (15 mL x 3), dried over anhydrous sodium sulfate, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 50:1 to 1:1) to give a mixture of 1 and 2. This mixture was separated by supercritical fluid chromatography (CO2 / 0.1DEA in MeOH = 75:25) to give compound 4-(hexahydropyridin-1-yl)hexahydropyridin-1-carboxylic acid-2-[4-hydroxy-3-(prop-2-enyl)phenyl]-4-(prop-2-enyl)phenyl ester (compound 1, 400 mg, yield 11.6%) and compound 4-(hexahydropyridin-1-yl)hexahydropyridin-1-carboxylic acid-4-[2-hydroxy-5-(prop-2-enyl)phenyl]-2-(prop-2-enyl)phenyl ester (compound 2, 900 mg, yield 26.1%).

[0082] NMR data of compound 1

[0083] 1 H NMR (400MHz, DMSO-d6): δppm 9.58(s,1H),7.14-7.04(m,5H),6.89(d,J=8.8Hz,1H),6.03-5.91(m,2H),5.14-5.02(m,4H),4.11-4.03(m,2H),3.39(d,J=6.8 Hz,2H),3.30-3.26(m,5H),2.87-2.85(m,4H),2.07-2.04(m,2H),1.87-1.69(m,5H),1.41-1.38(m,3H).LCMS:461.3([M-HCl+H] + ).

[0084] NMR data of compound 2

[0085] 1H NMR (400MHz, DMSO-d6): δppm 9.39(s,1H),7.45-7.35(m,2H),7.09(d,J=8.8Hz,1H),7.03(d,J=2.0Hz,1H) ,6.96(dd,J=8.0,2.0Hz,1H),6.86(d,J=8.4Hz,1H),6.02-5.83(m,2H),5.12 -4.97(m,4H),4.43-4.10(m,2H),3.50-3.37(m,3H),3.35-3.20(m,3H),3.17 -2.80(m,4H),2.23-2.10(m,2H),1.90-1.32(m,9H).LCMS:461.3([M-HCl+H] + ).

[0086] Example 3 Preparation of 4-(hexahydropyridin-1-yl)hexahydropyridin-1-carboxylic acid-4-[2-({[4-(hexahydropyridin-1-yl)hexahydropyridin-1-yl]carbonyl}oxy)-5-(prop-2-enyl)phenyl]-2-(prop-2-enyl)phenyl ester dihydrochloride

[0087] Step 1: Preparation of 4-(hexahydropyridin-1-yl)hexahydropyridin-1-carboxylic acid-4-[2-({[4-(hexahydropyridin-1-yl)hexahydropyridin-1-yl]carbonyl}oxy)-5-(prop-2-enyl)phenyl]-2-(prop-2-enyl)phenyl ester

[0088] Honokiol (1.0 g, 3.7 mmol, 1.0 equivalent), dimethylaminopyridine (2.7 g, 22.5 mmol, 6.0 equivalent), and 1-chloroformyl-4-piperidinylpiperidine hydrochloride (4.0 g, 15.0 mmol, 4.0 equivalent) were dissolved in pyridine (10 mL), and the mixture was stirred overnight at 60 °C. After the reaction was complete, water (10 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (from petroleum ether / ethyl acetate = 5:1 to dichloromethane / methanol = 10:1) to give a brown oily compound, 4-(hexahydropyridin-1-yl)hexahydropyridin-1-carboxylic acid-4-[2-({[4-(hexahydropyridin-1-yl)hexahydropyridin-1-yl]carbonyl}oxy)-5-(prop-2-enyl)phenyl]-2-(prop-2-enyl)phenyl ester (1.6 g, yield 65.0%).

[0089] The second step is to make salt.

[0090] The 4-(hexahydropyridin-1-yl)hexahydropyridin-1-carboxylic acid-4-[2-({[4-(hexahydropyridin-1-yl)hexahydropyridin-1-yl]carbonyl}oxy)-5-(prop-2-enyl)phenyl]-2-(prop-2-enyl)phenyl ester (1.2 g, 1.8 mmol, 1.0 equivalent) prepared in the first step was dissolved in ethyl acetate hydrochloride solution (4 M, 4.6 mL, 18.4 mmol, 10.0 equivalent). The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated, and the residue was washed with methyl tert-butyl ether (3 mL). The residue was then freeze-dried to give a white solid, 4-(hexahydropyridin-1-yl)hexahydropyridin-1-carboxylic acid-4-[2-({[4-(hexahydropyridin-1-yl)hexahydropyridin-1-yl]carbonyl}oxy)-5-(prop-2-enyl)phenyl]-2-(prop-2-enyl)phenyl ester dihydrochloride (1.0 g, yield 75.0%).

[0091] 1 H NMR (400MHz, DMSO-d6): δppm 11.00-10.70(m,2H),7.40-7.02(m,6H),6.10-5.82(m,2H),5.20-4.93(m,4H),4.42-3.90(m,4H),3.60-3.20(m,10H),3 .18-2.63(m,8H),2.31-2.15(m,2H),2.14-2.02(m,2H),2.01-1.60(m,12H),1.58-1.28(m,4H).LCMS:655.4([M-2HCl+H] + ).

[0092] Example 4 Preparation of 4-methylpiperazine-1-carboxylic acid-2-[4-hydroxy-3-(prop-2-enyl)phenyl]-4-(prop-2-enyl)phenyl ester

[0093] Step 1: Acetic acid-4-(2-{[(4-methylpiperazin-1-yl)carbonyl]oxy}-5-(prop-2-enyl)phenyl)-2-(prop-2-enyl)phenyl ester

[0094] Intermediate 2 (310.0 mg, 1.0 mmol, 1 equivalent) was added to pyridine (5 mL), and 4-methylpiperazine-1-formyl chloride hydrochloride (398.0 mg, 2.0 mmol, 2 equivalent) was added with stirring. The mixture was stirred overnight at room temperature. After the reaction was monitored by electrophoresis, water (3 mL) was added and stirred for 3 minutes. The mixture was extracted with ethyl acetate (10 mL x 3), and the organic layers were combined, washed with saturated brine (3 mL x 3), dried over anhydrous sodium sulfate, evaporated to dryness, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to give the target product (231.3 mg, yield 53.3%) as a yellow oil.

[0095] 1 H NMR (400MHz, DMSO-d6): δppm 7.20-7.11(m,2H),7.07-7.04(m,3H),6.85-6.82(m,1H),6.05-5.91(m,2H),5.16-5.02(m, 4H),3.41-3.20(m,8H),2.17(t,J=8.4Hz,4H),2.07(s,3H),1.78(s,3H).LCMS:435.2([M+H] + )

[0096] Step 2: 4-Methylpiperazine-1-carboxylic acid-2-[4-hydroxy-3-(prop-2-enyl)phenyl]-4-(prop-2-enyl)phenyl ester

[0097] 4-(2-{[(4-methylpiperazin-1-yl)carbonyl]oxy}-5-(prop-2-enyl)phenyl)-2-(prop-2-enyl)phenyl ester (100 mg, 0.23 mmol) was dissolved in methanol (1 mL), potassium carbonate (31.7 mg, 0.23 mmol) was added, and the reaction mixture was stirred at room temperature for 3 hours. Water (5 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 2), washed with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was purified by preparative liquid chromatography (DCM:MeOH = 20:1) to give 4-methylpiperazin-1-carboxylic acid-2-[4-hydroxy-3-(prop-2-enyl)phenyl]-4-(prop-2-enyl)phenyl ester (64.2 mg, yield 71.2%).

[0098] 1 H NMR (400MHz, DMSO-d6): δppm 9.59 (s, 1H), 7.19 -7.11(m,2H),7.07-7.04(m,3H),6.85-6.82(m,1H),6.04-5.92(m,2H),5.18-5.02 (m,4H),3.41-3.21(m,8H),2.18(t,J=8.4Hz,4H),2.07(s,3H).LCMS:393.2([M+H] + )

[0099] Example 5 Preparation of 4-methylpiperazine-1-carboxylic acid-4-[2-hydroxy-5-(prop-2-enyl)phenyl]-2-(prop-2-enyl)phenyl ester

[0100] Step 1: 4-Methylpiperazine-1-carboxylic acid-4-[2-acetoxy-5-(prop-2-enyl)phenyl]-2-(prop-2-enyl)phenyl ester

[0101] Intermediate 1 (310.0 mg, 1.0 mmol, 1 equivalent) was added to pyridine (5 mL), and 4-methylpiperazine-1-formyl chloride hydrochloride (398.0 mg, 2.0 mmol, 2 equivalents) was added with stirring. The mixture was stirred overnight at room temperature. After the reaction was monitored by electrophoresis, water (3 mL) was added and stirred for 3 minutes. The mixture was extracted with ethyl acetate (10 mL x 3), and the organic layers were combined, washed with saturated brine (3 mL x 3), dried over anhydrous sodium sulfate, evaporated to dryness, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to give the target product (247.8 mg, yield 57.1%) as a pale yellow oil.

[0102] 1 H NMR (400MHz, DMSO-d6): δppm 7.21-7.11(m,2H),7.07-7.04(m,3H),6.85-6.83(m,1H),6.05-5.91(m,2H),5.16-5.02(m, 4H),3.41-3.20(m,8H),2.17(t,J=8.4Hz,4H),2.07(s,3H),1.78(s,3H).LCMS:435.2([M+H] + )

[0103] Step 2: Preparation of 4-methylpiperazine-1-carboxylic acid-4-[2-hydroxy-5-(prop-2-enyl)phenyl]-2-(prop-2-enyl)phenyl ester

[0104] 4-Methylpiperazine-1-carboxylic acid-4-[2-acetoxy-5-(prop-2-enyl)phenyl]-2-(prop-2-enyl)phenyl ester (100 mg, 0.23 mmol) was dissolved in methanol (1 mL), potassium carbonate (31.7 mg, 0.23 mmol) was added, and the reaction mixture was stirred at room temperature for 3 hours. Water (5 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 2), washed with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was purified by preparative liquid chromatography (DCM:MeOH = 20:1) to give 4-methylpiperazine-1-carboxylic acid-4-[2-hydroxy-5-(prop-2-enyl)phenyl]-2-(prop-2-enyl)phenyl ester (74.2 mg, yield 82.3%).

[0105] 1H NMR (400MHz, DMSO-d6): δppm 9.72 (s, 1H), 7.19 -7.11(m,2H),7.07-7.04(m,3H),6.85-6.83(m,1H),6.04-5.92(m,2H),5.18-5.02 (m,4H),3.41-3.21(m,8H),2.18(t,J=8.4Hz,4H),2.07(s,3H).LCMS:393.2([M+H] + )

[0106] Example 6 Preparation of 4-methylpiperazine-1-carboxylic acid-4-(2-{[(4-methylpiperazine-1-yl)carbonyl]oxy}-5-(prop-2-enyl)phenyl)-2-(prop-2-enyl)phenyl ester

[0107] Honokiol (1.0 g, 3.7 mmol, 1.0 equivalent), dimethylaminopyridine (2.7 g, 22.5 mmol, 6.0 equivalent), and 4-methylpiperazine-1-carboxyl chloride hydrochloride (3.0 g, 15.0 mmol, 4.0 equivalent) were dissolved in pyridine (10 mL), and the mixture was stirred overnight at 60 °C. After the reaction was complete, water (10 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (from petroleum ether / ethyl acetate = 5:1 to dichloromethane / methanol = 10:1) to give a brown oily compound, 4-methylpiperazin-1-carboxylic acid-4-(2-{[(4-methylpiperazin-1-yl)carbonyl]oxy}-5-(prop-2-enyl)phenyl)-2-(prop-2-enyl)phenyl ester (1.3 g, yield 69.3%).

[0108] 1 H NMR (400MHz, DMSO-d6): δppm 7.20 -7.12(m,2H),7.06-7.01(m,3H),6.86-6.80(m,1H),6.03-5.90(m,2H),5.16-5.02 (m,4H),3.41-3.21(m,12H),2.24(t,J=8.2Hz,8H),2.01(s,6H).LCMS:519.3([M+H] + )

[0109] Example 7 Preparation of 2-keto-tetrahydropyrrole-1-carboxylic acid-2-[4-hydroxy-3-(prop-2-enyl)phenyl]-4-(prop-2-enyl)phenyl ester

[0110] Example 8 Preparation of 2-keto-tetrahydropyrrole-1-carboxylic acid-4-[2-hydroxy-5-(prop-2-enyl)phenyl]-2-(prop-2-enyl)phenyl ester

[0111] Preparation of step 1-formyl chloride-2-one-tetrahydropyrrole

[0112] 2-Pyrrolidone (2.0 g, 23.5 mmol) and triethylamine (7.1 g, 70.5 mmol) were added to dichloromethane (20 mL) at -10 °C. Separately, triphosgene (7.0 g, 23.5 mmol) dissolved in dichloromethane (20 mL) was added dropwise to the above solution. The reaction was carried out at -10 °C for 1 hour, then heated to room temperature and stirred for another 2 hours. The solvent was evaporated, and tetrahydrofuran (10 mL) was added to the residue. The mixture was filtered, and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to give a white solid 1-formylchloro-2-one-tetrahydropyrrole (2.2 g, 63.4%).

[0113] 1 H NMR (400MHz, CDCl3): δppm 3.99 (t, J = 7.2Hz, 2H), 2.66 (t, J = 8.1Hz, 2H), 2.20-2.06 (m, 2H).

[0114] Step 2: Preparation of 2-keto-tetrahydropyrrole-1-carboxylic acid-4-[2-hydroxy-5-(prop-2-enyl)phenyl]-2-(prop-2-enyl)phenyl ester

[0115] A solution of 1-formylchloro-2-one-tetrahydropyrrole (200.0 mg, 1.4 mmol) was prepared by dissolving it in dichloromethane (20 mL). Honokiol (374.2 mg, 1.4 mmol) was dissolved in pyridine (10 mL) and slowly added dropwise to the above solution. After the addition was complete, the mixture was stirred overnight at room temperature. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 50:1 to 1:1) to give a mixture of compounds 7 and 8. This mixture was separated by supercritical fluid chromatography (CO2 / 0.1DEA in MeOH = 75:25) to give compound 2-keto-tetrahydropyrrole-1-carboxylic acid-2-[4-hydroxy-3-(prop-2-enyl)phenyl]-4-(prop-2-enyl)phenyl ester (compound 7, 58.8 mg, yield 15.6%) and compound 2-keto-tetrahydropyrrole-1-carboxylic acid-4-[2-hydroxy-5-(prop-2-enyl)phenyl]-2-(prop-2-enyl)phenyl ester (compound 8, 38.1 mg, yield 10.1%).

[0116] 1 H NMR (400MHz, DMSO-d6): δppm 9.59 (brs, 1H), 7.19 -7.11(m,2H),7.07-7.04(m,3H),6.85-6.82(m,1H),6.04-5.92(m,2H),5.18-5.02(m,4H),3. 92(t,J=8.2Hz,2H),3.41-3.21(m,4H),2.61(t,J=8.2Hz,2H),2.09(m,2H).LCMS:378.1([M+H] + )

[0117] 1 H NMR (400MHz, DMSO-d6): δppm 9.21 (brs, 1H), 7.20 -7.11(m,2H),7.08-7.04(m,3H),6.85-6.81(m,1H),6.04-5.92(m,2H),5.18-5.02(m,4H),3. 93(t,J=8.2Hz,2H),3.40-3.21(m,4H),2.63(t,J=8.2Hz,2H),2.06(m,2H).LCMS:378.1([M+H] + )

[0118] Example 9 Preparation of 2-keto-tetrahydropyrrole-1-carboxylic acid-4-(2-{[(2-ketotetrahydro-1H-pyrrole-1-yl)carbonyl]oxy}-5-(prop-2-enyl)phenyl)-2-(prop-2-enyl)phenyl ester

[0119] 1-Formylchloro-2-one-tetrahydropyrrole (441.0 mg, 3.0 mmol) was dissolved in dichloromethane (10 mL) to prepare a solution. Honokiol (266.0 mg, 1.0 mmol) was dissolved in pyridine (5 mL) and slowly added dropwise to the above solution. After the addition was complete, the mixture was stirred overnight at room temperature. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 30:1 to 1:1) to give 2-one-tetrahydropyrrole-1-carboxylic acid-4-(2-{[(2-one-tetrahydro-1H-pyrrole-1-yl)carbonyl]oxy}-5-(prop-2-enyl)phenyl)-2-(prop-2-enyl)phenyl ester (compound 9) (255.2 mg, 52.3%).

[0120] 1H NMR (400MHz, DMSO-d6): δppm 7.20 -7.10(m,2H),7.08-7.04(m,3H),6.85-6.81(m,1H),6.05-5.92(m,2H),5.17-5.02(m,4H),3. 94(t,J=8.2Hz,4H),3.40-3.21(m,4H),2.63(t,J=8.2Hz,4H),2.06(m,4H).LCMS:489.2([M+H] + )

[0121] Example 10 Preparation of 4-({2-[4-hydroxy-3-(prop-2-enyl)phenyl]-4-(prop-2-enyl)phenyl}oxy)-4-oxonylbutyric acid

[0122] Step 1: Preparation of acetic acid-4-{2-[(4-ethoxy-1,4-dioxane-butyl)oxy]-5-(prop-2-enyl)phenyl}-2-(prop-2-enyl)phenyl ester

[0123] Intermediate 2 (310.0 mg, 1.0 mmol, 1 equivalent) was added to pyridine (5 mL), and succinic acid monoethyl ester chloride (329.0 mg, 2.0 mmol, 2 equivalents) was added with stirring. The mixture was stirred overnight at room temperature. After the reaction was monitored by TLC, water (3 mL) was added and stirred for 5 minutes. The mixture was extracted with ethyl acetate (10 mL x 3), and the organic layers were combined, washed with saturated brine (3 mL x 3), dried over anhydrous sodium sulfate, evaporated to dryness, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8:1) to give a yellow oily target product (204.0 mg, yield 46.8%).

[0124] 1 H NMR (400MHz, DMSO-d6): δppm 7.21-7.11(m,2H),7.07-7.04(m,3H),6.85-6.83(m,1H),6.05-5.91(m,2H),5.16-5.02(m,4H),4.01(q,J=8.4Hz,2H),3.36(d ,J=8.2Hz,4H),2.93(t,J=8.4Hz,2H),2.73(t,J=8.4Hz,2H),2.35(q,J=8.4Hz,3H), 1.07(t,J=8.2Hz,3H).LCMS:437.5([M+H] + )

[0125] Step 2: Preparation of 4-({2-[4-hydroxy-3-(prop-2-enyl)phenyl]-4-(prop-2-enyl)phenyl}oxy)-4-oxonylbutyric acid (compound 10)

[0126] 4-{2-[(4-ethoxy-1,4-dioxanedibutyl)oxy]-5-(prop-2-enyl)phenyl}-2-(prop-2-enyl)phenyl ester (100 mg, 0.23 mmol) was dissolved in methanol (1 mL), potassium carbonate (31.7 mg, 0.23 mmol) was added, and the reaction mixture was stirred overnight at room temperature. Water (5 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 2), washed with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was purified by preparative liquid chromatography (DCM:MeOH = 10:1) to give 4-({2-[4-hydroxy-3-(prop-2-enyl)phenyl]-4-(prop-2-enyl)phenyl}oxy)-4-oxanediol butyric acid (compound 10) (74.2 mg, yield 82.3%).

[0127] 1 H NMR (400MHz, DMSO-d6): δppm 12.12(s,1H), 9.72(s,1H), 7.20 -7.11(m,2H),7.07-7.01(m,3H),6.86-6.83(m,1H),6.04-5.92(m,2H),5. 18-5.02(m,4H),3.41-3.21(m,4H),2.80-2.71(m,4H).LCMS:367.4([M+H] + )

[0128] Example 11 Preparation of 4-({4-[2-hydroxy-5-(prop-2-enyl)phenyl]-2-(prop-2-enyl)phenyl}oxy)-4-oxonylbutyric acid

[0129] Step 1: Preparation of 4-ethoxy-4-oxoylidenebutyric acid-4-[2-acetoxy-5-(prop-2-enyl)phenyl]-2-(prop-2-enyl)phenyl ester

[0130] Intermediate 1 (310.0 mg, 1.0 mmol, 1 equivalent) was added to pyridine (5 mL), and succinic acid monoethyl ester chloride (329.0 mg, 2.0 mmol, 2 equivalents) was added with stirring. The mixture was stirred overnight at room temperature. After the reaction was monitored by TLC, water (3 mL) was added and stirred for 5 minutes. The mixture was extracted with ethyl acetate (10 mL x 3), and the organic layers were combined, washed with saturated brine (3 mL x 3), dried over anhydrous sodium sulfate, evaporated to dryness, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8:1) to give a yellow oily target product (188.4 mg, yield 43.2%).

[0131] 1H NMR (400MHz, DMSO-d6): δppm 7.21-7.11(m,2H),7.07-7.04(m,3H),6.85-6.83(m,1H),6.05-5.91(m,2H),5.16-5.02(m,4H),4.01(q,J=8.4Hz,2H),3. 36(d,J=8.2Hz,4H),2.93(t,J=8.4Hz,2H),2.73(t,J=8.4Hz,2H),2.35(s,3H), 1.07(t,J=8.2Hz,3H).LCMS:437.5([M+H] + )

[0132] Step 2: Preparation of 4-({4-[2-hydroxy-5-(prop-2-enyl)phenyl]-2-(prop-2-enyl)phenyl}oxy)-4-oxonylbutyric acid (compound 11)

[0133] 4-ethoxy-4-oxoylidenebutyric acid-4-[2-acetoxy-5-(prop-2-enyl)phenyl]-2-(prop-2-enyl)phenyl ester (100 mg, 0.23 mmol) was dissolved in methanol (1 mL), potassium carbonate (31.7 mg, 0.23 mmol) was added, and the reaction mixture was stirred overnight at room temperature. Water (5 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 2), washed with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was purified by preparative liquid chromatography (DCM:MeOH = 10:1) to give 4-({2-[4-hydroxy-3-(prop-2-enyl)phenyl]-4-(prop-2-enyl)phenyl}oxy)-4-oxoylidenebutyric acid (compound 11, 66.0 mg, yield 78.4%).

[0134] 1 H NMR (400MHz, DMSO-d6): δppm 11.89 (s, 1H), 9.70 (s, 1H), 7.20 -7.11 (m, 2H), 7.06 -7.01(m,3H),6.86-6.82(m,1H),6.04-5.93(m,2H),5.18-5.02(m,4H),3.40-3.21(m,4H),2.80-2.71(m,4H).LCMS:367.2([M+H] + )

[0135] Example 12 Preparation of 4-[(4-{2-[3-carboxypropionyl)oxy]-5-(prop-2-enyl)phenyl}-2-(prop-2-enyl)phenyl)oxy]-4-oxonylbutyric acid

[0136] Step 1: Preparation of 4-ethoxy-4-oxoylidenebutyric acid-4-{2-[(4-ethoxy-1,4-oxoylidenebutyryl)oxy]-5-(prop-2-enyl)phenyl}-2-(prop-2-enyl)phenyl ester

[0137] Honokiol (266.0 mg, 1.0 mmol, 1 equivalent) was added to pyridine (5 mL), and succinic acid monoethyl ester chloride (494.0 mg, 3.0 mmol, 3 equivalents) was added with stirring. The mixture was stirred overnight at room temperature. After the reaction was monitored by TLC, water (3 mL) was added and stirred for 5 minutes. The mixture was extracted with ethyl acetate (10 mL x 3), and the organic layers were combined, washed with saturated brine (3 mL x 3), dried over anhydrous sodium sulfate, evaporated to dryness, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6:1) to give a yellow oily target product (446.8 mg, yield 85.6%).

[0138] 1 H NMR (400MHz, DMSO-d6): δppm 7.21-7.11(m,2H),7.07-7.04(m,3H),6.85-6.83(m,1H),6.05-5.91(m,2H),5.16-5.02(m,4H),4.01(q,J=8.4Hz,4H),3.36(d ,J=8.2Hz,4H),2.93(t,J=8.4Hz,4H),2.73(t,J=8.4Hz,4H),2.35(q,J=8.4Hz,3H), 1.07(t,J=8.2Hz,6H).LCMS:523.2([M+H] + )

[0139] Step 2: Preparation of 4-[(4-{2-[3-carboxypropionyl)oxy]-5-(prop-2-enyl)phenyl}-2-(prop-2-enyl)phenyl)oxy]-4-oxonylbutyric acid (compound 12)

[0140] 4-ethoxy-4-oxoylidenebutyric acid-4-{2-[(4-ethoxy-1,4-oxoylidenebutyryl)oxy]-5-(prop-2-enyl)phenyl}-2-(prop-2-enyl)phenyl ester (120 mg, 0.23 mmol) was dissolved in methanol (1 mL), potassium carbonate (31.7 mg, 0.23 mmol) was added, and the reaction mixture was stirred overnight at room temperature. Water (5 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 2), washed with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was purified by preparative liquid chromatography (DCM:MeOH = 10:1) to give 4-[(4-{2-[3-carboxypropionyl)oxy]-5-(prop-2-enyl)phenyl}-2-(prop-2-enyl)phenyl)oxy]-4-oxoylidenebutyric acid (compound 12, 66.0 mg, yield 78.4%).

[0141] 1 H NMR (400MHz, DMSO-d6): δppm 12.09 (s, 2H), 9.72 (s, 1H), 7.20 -7.11 (m, 2H), 7.05 -7.01(m,3H),6.87-6.82(m,1H),6.04-5.93(m,2H),5.15-5.02(m,4H),3.40-3.21(m,4H),2.80-2.71(m,8H).LCMS:467.2([M+H] + )

[0142] Example 13 Preparation of 4-(hexahydropyridin-1-yl)hexahydropyridin-1-carboxylic acid-4-(2-{[(4-methylpiperazin-1-yl)carbonyl]oxy}-5-(prop-2-enyl)phenyl)-2-(prop-2-enyl)phenyl ester (compound 13)

[0143] 4-Methylpiperazine-1-carboxylic acid-2-[4-hydroxy-3-(prop-2-enyl)phenyl]-4-(prop-2-enyl)phenyl ester (102.0 mg, 0.26 mmol, 1.0 equivalent), dimethylaminopyridine (190.3 mg, 1.56 mmol, 6.0 equivalent), and 1-chloroformyl-4-piperidinylpiperidine hydrochloride (138.8 mg, 0.52 mmol, 2.0 equivalent) were dissolved in pyridine (5 mL) and reacted overnight at 60 °C with stirring. After the reaction was complete, water (5 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (from petroleum ether / ethyl acetate = 5:1 to dichloromethane / methanol = 10:1) to give a brown oily target product (compound 13, 93.2 mg, yield 61.2%).

[0144] 1 H NMR (400MHz, DMSO-d6): δppm 7.14-7.04(m,5H),6.89(d,J=8.8Hz,1H),6.03-5.91(m,2H),5.14-5.02(m,4H),4.11-4.03(m,2H),3.42-3.20 (m,15H),2.87-2.85(m,4H),2.07-2.04(m,5H),1.87-1.69(m,5H),1.41-1.38(m,3H).LCMS:587.4([M-HCl+H] + ).

[0145] Example 14 Preparation of 4-(hexahydropyridin-1-yl)hexahydropyridin-1-carboxylic acid-4-(2-{[(2-onetetrahydro-1H-pyrrolo-1-yl)carbonyl]oxy}-5-(prop-2-enyl)phenyl)-2-(prop-2-enyl)phenyl ester

[0146] 2-Keto-tetrahydropyrrole-1-carboxylic acid-2-[4-hydroxy-3-(prop-2-enyl)phenyl]-4-(prop-2-enyl)phenyl ester (100.0 mg, 0.26 mmol, 1.0 equivalent), dimethylaminopyridine (190.3 mg, 1.56 mmol, 6.0 equivalent), and 1-chloroformyl-4-piperidinylpiperidine hydrochloride (138.8 mg, 0.52 mmol, 2.0 equivalent) were dissolved in pyridine (5 mL), and the mixture was stirred overnight at 60 °C. After the reaction was complete, water (5 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (from petroleum ether / ethyl acetate = 5:1 to dichloromethane / methanol = 10:1) to give a brown oily target product (compound 14, 82.8 mg, yield 55.8%).

[0147] 1 H NMR (400MHz, DMSO-d6): δppm 7.45-7.32(m,2H),7.11(d,J=8.4Hz,1H),7.05(d,J=2.0Hz,1H),6.97(dd ,J=8.0,2.0Hz,1H),6.86(d,J=8.4Hz,1H),6.02-5.83(m,2H),5.12-4.97 (m,4H),4.43-3.90(m,4H),3.50-3.37(m,3H),3.35-3.20(m,7H),3.17-2 .60(m,6H),2.23-2.10(m,4H),1.90-1.32(m,9H).LCMS:572.3([M-HCl+H]+ ).

[0148] Example 15 Preparation of 2-ketotetrahydropyrrole-1-carboxylic acid-4(2-{[(4-methylpiperazin-1-yl)carbonyl]oxy}-5-(prop-2-enyl)phenyl)-2-(prop-2-enyl)phenyl ester

[0149] 2-Keto-tetrahydropyrrole-1-carboxylic acid-4-[2-hydroxy-5-(prop-2-enyl)phenyl]-2-(prop-2-enyl)phenyl ester (100.0 mg, 0.26 mmol, 1.0 equivalent), dimethylaminopyridine (190.3 mg, 1.56 mmol, 6.0 equivalent), and 4-methylpiperazine-1-carboxyl chloride hydrochloride (103.5 mg, 0.52 mmol, 2.0 equivalent) were dissolved in pyridine (5 mL), and the mixture was stirred overnight at 60 °C. After the reaction was complete, water (5 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (from petroleum ether / ethyl acetate = 5:1 to dichloromethane / methanol = 10:1) to give the oily target product (compound 15, 93.9 mg, yield 71.8%).

[0150] 1 H NMR (400MHz, DMSO-d6): δppm 7.19 -7.11(m,2H),7.07-7.04(m,3H),6.85-6.82(m,1H),6.04-5.92(m,2H),5.18-5.02(m,4H),3.9 3(t,J=8.2Hz,2H),3.41-3.21(m,8H),2.63-2.45(m,6H),2.18-2.07(m,5H).LCMS:504.2([M+H] + )

[0151] Example 16 4-Methylpiperazine-1-carboxylic acid-2-[4-methoxy-3-(prop-2-enyl)phenyl]-4-(prop-2-enyl)phenyl ester

[0152] 4-Methylpiperazine-1-carboxylic acid-2-[4-hydroxy-3-(prop-2-enyl)phenyl]-4-(prop-2-enyl)phenyl ester (compound 4) (102.0 mg, 0.26 mmol, 1.0 equivalent) was dissolved in acetonitrile (10 mL), and potassium carbonate (72.0 mg, 0.52 mmol, 2.0 equivalent) and iodomethane (48.28 mg, 0.34 mmol, 1.3 equivalent) were added. The mixture was stirred at room temperature for 6 hours. After the reaction was complete, the solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate (10 mL x 3). The organic layers were combined, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (from petroleum ether / ethyl acetate = 5:1 to dichloromethane / methanol = 10:1) to give the target product (compound 16, 90.4 mg, yield 85.6%) as an oil.

[0153] 1 H NMR (400MHz, DMSO-d6): δppm 7.20 -7.13(m,2H),7.08-7.04(m,3H),6.85-6.80(m,1H),6.03-5.91(m,2H),5.18-5.02(m,4H ),3.67(s,3H),3.41-3.21(m,8H),2.18(t,J=8.4Hz,4H),2.07(s,3H).LCMS:407.2([M+H] + )

[0154] Example 17 4-Methylpiperazine-1-carboxylic acid-4-[2-methoxy-5-(prop-2-enyl)phenyl]-2-(prop-2-enyl)phenyl ester

[0155] 4-Methylpiperazine-1-carboxylic acid-4-[2-hydroxy-5-(prop-2-enyl)phenyl]-2-(prop-2-enyl)phenyl ester (compound 5) (102.0 mg, 0.26 mmol, 1.0 equivalent) was dissolved in acetonitrile (10 mL), and potassium carbonate (72.0 mg, 0.52 mmol, 2.0 equivalent) and methyl iodoform (48.28 mg, 0.34 mmol, 1.3 equivalent) were added. The mixture was stirred at room temperature for 6 hours. After the reaction was complete, the solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate (10 mL x 3). The organic layers were combined, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (from petroleum ether / ethyl acetate = 5:1 to dichloromethane / methanol = 10:1) to give the target product (compound 17, 93.6 mg, yield 88.7%) as an oil.

[0156] 1H NMR (400MHz, DMSO-d6): δppm 7.19 -7.11(m,2H),7.07-7.04(m,3H),6.85-6.83(m,1H),6.04-5.92(m,2H),5.18-5.02(m,4H ),3.70(s,3H),3.41-3.21(m,8H),2.17(t,J=8.2Hz,4H),2.08(s,3H).LCMS:407.2([M+H] + )

[0157] Test Example 1

[0158] Pharmacokinetic experiments:

[0159] Fifteen male SD rats, weighing 200–220 g, were divided into five groups of three. Rats were fasted for 16 hours prior to single intravenous (iv) and intragastric (ig) administration, but were allowed normal water intake. Rats were administered 5 mg / kg of magnolol solution, 9.34 mg / kg of compound 1 and compound 5 solutions, and 13.8 mg / kg of compound 13 solution via gavage (the molar mass of magnolol, compound 1, 5, and 13 solutions in the ig group was 0.019 mmol / kg). Approximately 300 μL of blood was collected from the ocular venous sinus before and after isoflurane anesthesia. Blood collection time points were arranged as follows: before administration and at 5, 15, 30 min, 1, 2, 4, 6, 8, 10, and 24 h after the start of administration. Blood samples were collected and mixed in 1.5 mL heparin-anticoagulated EP tubes. Immediately after collection, the samples were centrifuged at 12000 rpm for 2 min. The supernatant plasma was transferred to 1.5 mL EP tubes and aliquoted into two 50 μL tubes. The remaining plasma was stored at -70 °C until analysis. Pharmacokinetic data are shown in Table 1 below.

[0160] Table 1 *PK: Pharmacokinetic parameters; Cmax: Maximum plasma concentration; Tmax: Time to maximum plasma concentration; t1 / 2: Elimination half-life; MRT: Mean residence time; F: Oral bioavailability; Fr / h: Ratio of in vivo exposure of magnolol produced by metabolism to that of an equimolar dose of magnolol administered orally.

[0161] As shown in Table 1, the pharmacokinetic properties of magnolol in vivo were greatly improved through group modification.

[0162] Test Example 2: Therapeutic effect of the compound on mice with glioma model induced by subcutaneous injection of microglia

[0163] Test methods

[0164] Establishment of mouse xenograft model: Cells (purchased from Shangen Biotechnology) were digested with 0.25% trypsin and pipetted into a single-cell suspension. After centrifugation, the suspension was resuspended in serum-free medium and the concentration was adjusted to 1×10⁻⁶. 6 indivual / 0.2 mL of cell suspension was drawn using a 1 mL sterile syringe and injected subcutaneously into the right shoulder axilla of each mouse. Ten days later, a noticeable mass was palpable under the skin, protruding from the skin surface, irregular in shape, and with clear borders, indicating that the mouse subcutaneous xenograft model was successfully established.

[0165] Animal grouping and treatment: Mice with established xenografts were randomly divided into four groups: a model group (n=5), a honokiol group (n=5), a compound 3 group (n=5), and a compound 4 group (n=5). The mice were administered the drugs via gavage once daily for 12 consecutive days. The mice were then sacrificed by cervical dislocation, and the xenografts were completely removed, weighed, and statistically analyzed.

[0166] The experimental results are shown in Figure 1 and Table 2 below:

[0167] Table 2: Effects of magnolol, compound 3, and compound 4 on the size of gliomas in model mice. Note: *p<0.05 compared to the model group.

[0168] The data in Figure 1 and Table 2 show that magnolol, compound 3, and compound 4 exhibit a trend of reducing glioma tumor growth, indicating a therapeutic effect on glioma model mice prepared by subcutaneous injection of microglia. Table 2 data shows that compounds 3 and 4 have significantly better efficacy than magnolol.

[0169] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A magnolol derivative, or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer, or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, represented by Formula I or Formula II: R1 is selected from hydrogen, hydroxyl, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted saturated or unsaturated four- to eighteen-membered heterocyclic groups containing 1-3 heteroatoms selected from N, O, and S, substituted or unsubstituted five- to twelve-membered heteroaryl groups containing 1-3 heteroatoms selected from N, O, and S, and substituted or unsubstituted six- to fourteen-membered aryl groups. The term "substituted" refers to each of the above groups containing 1 to 3 R1 groups. 1a The R 1a Selected from halogen, hydroxyl, amino, carbonyl, cyano, C1-C6 alkyl, carboxyl, saturated or unsaturated four- to ten-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O and S, five- to twelve-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O and S, and six- to fourteen-membered aryl groups, provided that R1 in Formula I is not hydrogen. R2 is selected from hydrogen, hydroxyl, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted saturated or unsaturated four- to eighteen-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, substituted or unsubstituted five- to fourteen-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S, and substituted or unsubstituted six- to fourteen-membered aryl groups, wherein "substituted" means that each of the above groups contains 1 to 3 R2 atoms. 2a The R 2a The group is selected from halogen, hydroxyl, amino, carbonyl, cyano, C1-C6 alkyl, carboxyl, saturated or unsaturated four- to ten-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O and S, five- to twelve-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O and S, and six- to fourteen-membered aryl groups, provided that R2 in Formula II is not hydrogen.

2. The honokiol derivative represented by the following Formula I or Formula II, or an isotopically labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer, or an isomer mixture thereof, or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, Preferably, R1is selected from the group consisting of hydroxyl, amino, substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted C2-C4alkenyl, substituted or unsubstituted C2-C4alkynyl, substituted or unsubstituted saturated or unsaturated four to twelve membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, substituted or unsubstituted five to twelve membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, substituted or unsubstituted six to fourteen membered aryl, wherein the "substituted" means that each of the above groups contains 1 or 2 R 1a , which is selected from the group consisting of halogen, hydroxyl, amino, carbonyl, cyano, C1-C4alkyl, carboxyl, saturated or unsaturated four to ten membered heterocyclyl containing 1 or 2 heteroatoms selected from N or O, five to ten membered heteroaryl containing 1 or 2 heteroatoms selected from N or O, six to fourteen membered aryl, with the proviso that R1in formula I is not hydrogen; 1a , which is selected from the group consisting of halogen, hydroxyl, amino, carbonyl, cyano, C1-C4alkyl, carboxyl, saturated or unsaturated four to ten membered heterocyclyl containing 1 or 2 heteroatoms selected from N or O, five to ten membered heteroaryl containing 1 or 2 heteroatoms selected from N or O, six to fourteen membered aryl, with the proviso that R1in formula I is not hydrogen; More preferably, R1 is selected from hydroxyl, amino, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted saturated or unsaturated five- to twelve-membered heterocyclic group containing one or two heteroatoms selected from N or O, substituted or unsubstituted five- to twelve-membered heteroaryl group containing one or two heteroatoms selected from N or O, and substituted or unsubstituted six- to fourteen-membered aryl, wherein "substituted" means that each of the above groups contains one or two R1 atoms. 1a The R 1a Selected from halogen, hydroxyl, amino, carbonyl, cyano, C1-C3 alkyl, carboxyl, saturated or unsaturated four- to ten-membered heterocyclic groups containing one or two heteroatoms selected from N or O, five- to ten-membered heteroaryl groups containing one or two heteroatoms selected from N or O, and six- to fourteen-membered aryl groups, provided that R1 in Formula I is not hydrogen. More preferably, R1is selected from the group consisting of hydrogen, hydroxyl, amino, substituted or unsubstituted methyl, ethyl, n-propyl, i-propyl, substituted or unsubstituted saturated or unsaturated five to twelve-membered heterocyclyl containing one or two heteroatoms selected from N or O, substituted or unsubstituted five to twelve-membered heteroaryl containing one or two heteroatoms selected from N or O, substituted or unsubstituted six to fourteen-membered aryl; wherein the "substitution" means that each of the above groups contains one or two R 1a 1a selected from halogen, carbonyl, cyano, methyl, ethyl, n-propyl, i-propyl, carboxyl, saturated or unsaturated four to six-membered heterocyclyl containing one or two heteroatoms selected from N or O, five to six-membered heteroaryl containing one or two heteroatoms selected from N or O, phenyl, with the proviso that R1in formula I is not hydrogen;​ More preferably, R1is selected from hydrogen, methyl, ethyl, n-propyl, i-propyl, 3. The honokiol derivative represented by the following Formula I or Formula II, or an isotopically labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer, or an isomer mixture thereof, or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, Preferably, R2is selected from the group consisting of hydrogen, hydroxyl, amino, substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted C2-C4alkenyl, substituted or unsubstituted C2-C4alkynyl, substituted or unsubstituted saturated or unsaturated four to twelve membered heterocyclyl containing 1-3 heteroatoms selected from the group consisting of N, O and S, substituted or unsubstituted five to twelve membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, O and S, substituted or unsubstituted six to fourteen membered aryl, wherein the "substituted" means that each of the above groups contains 1 or 2 R 2a , which is selected from the group consisting of halogen, hydroxyl, amino, carbonyl, cyano, C1-C4alkyl, carboxyl, saturated or unsaturated four to six membered heterocyclyl containing 1-3 heteroatoms selected from the group consisting of N, O and S, five to ten membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, O and S, six to fourteen membered aryl, with the proviso that R2in formula II is not hydrogen; 2a , which is selected from the group consisting of halogen, hydroxyl, amino, carbonyl, cyano, C1-C4alkyl, carboxyl, saturated or unsaturated four to six membered heterocyclyl containing 1-3 heteroatoms selected from the group consisting of N, O and S, five to ten membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, O and S, six to fourteen membered aryl, with the proviso that R2in formula II is not hydrogen; More preferably, R2is selected from the group consisting of hydrogen, hydroxyl, amino, substituted or unsubstituted C1-C3alkyl, substituted or unsubstituted C1-C3carbonylalkyl, substituted or unsubstituted saturated or unsaturated four to twelve-membered heterocyclyl containing one or two heteroatoms selected from N or O, substituted or unsubstituted five to twelve-membered heteroaryl containing one or two heteroatoms selected from N, O and S, substituted or unsubstituted six to fourteen-membered aryl, wherein the "substitution" means that each of the above groups contains one or two R 2a , which is selected from the group consisting of halogen, hydroxyl, amino, carbonyl, cyano, C1-C3alkyl, carboxyl, saturated or unsaturated four to six-membered heterocyclyl containing one to three heteroatoms selected from N, O and S, five to ten-membered heteroaryl containing one to three heteroatoms selected from N, O and S, six to fourteen-membered aryl, with the proviso that R2is not hydrogen in formula II; 2a , which is selected from the group consisting of halogen, hydroxyl, amino, carbonyl, cyano, C1-C3alkyl, carboxyl, saturated or unsaturated four to six-membered heterocyclyl containing one to three heteroatoms selected from N, O and S, five to ten-membered heteroaryl containing one to three heteroatoms selected from N, O and S, six to fourteen-membered aryl, with the proviso that R2is not hydrogen in formula II; More preferably, R2is selected from the group consisting of hydrogen, hydroxyl, amino, substituted or unsubstituted methyl, ethyl, n-propyl, i-propyl, substituted or unsubstituted C1-C3carbonylalkyl, substituted or unsubstituted saturated or unsaturated four to twelve membered heterocyclyl containing one or two heteroatoms selected from N or O, substituted or unsubstituted five to twelve membered heteroaryl containing one or two heteroatoms selected from N or O, substituted or unsubstituted six to fourteen membered aryl; wherein the "substituted" means that each of the above groups contains one or two R 2a , which is selected from the group consisting of halogen, hydroxyl, amino, carbonyl, cyano, methyl, ethyl, n-propyl, i-propyl, carboxyl, saturated or unsaturated four to six membered heterocyclyl containing one to three heteroatoms selected from N, O and S, five to six membered heteroaryl containing one or two heteroatoms selected from N or O, phenyl, with the proviso that R2in formula II is not hydrogen; and 2a , which is selected from the group consisting of halogen, hydroxyl, amino, carbonyl, cyano, methyl, ethyl, n-propyl, i-propyl, carboxyl, saturated or unsaturated four to six membered heterocyclyl containing one to three heteroatoms selected from N, O and S, five to six membered heteroaryl containing one or two heteroatoms selected from N or O, phenyl, with the proviso that R2in formula II is not hydrogen; and More preferably, R2is selected from hydrogen, methyl, ethyl, n-propyl, i-propyl, 4. The magnolol derivative, or its isotopically labeled compound, or its optical isomer, geometric isomer, tautomer, or mixture of isomers, or its pharmaceutically acceptable salt, as described in claim 1, characterized in that, The honokiol derivative represented by Formula I or Formula II, or an isotopically labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer, or an isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof is represented by Formula I-a, Formula I-b, Formula I-c, or Formula I-d as follows: wherein the definitions of R1and R2are the same as those in Formula I or Formula II; ring A and ring B are each independently selected from a saturated or unsaturated four to twelve-membered heterocyclylene group containing 1-3 heteroatoms selected from N, O and S, a five to twelve-membered heteroarylene group containing 1-3 heteroatoms selected from N, O and S, and a six to twelve-membered arylene group; R 11 and R 21 each independently of one another is selected from the group consisting of Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, saturated or unsaturated four- to eight-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of N, O and S, five- to twelve-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, O and S, six- to fourteen-membered aryl; R 111 and R 211 each independently of one another is selected from the group consisting of hydroxyl, carboxyl, cyano, amino, halogen; n1and n2are each independently selected from an integer from 1 to 6.

5. The honokiol derivative represented by the following Formula I or Formula II, or an isotopically labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer, or an isomer mixture thereof, or a pharmaceutically acceptable salt thereof according to claim 4, characterized in that, Preferably, R 11 and R 21 Each of the following is independently selected from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, saturated or unsaturated four- to six-membered heterocyclic groups containing one or two heteroatoms selected from N and O, five- to eight-membered heteroaryl, and six- to ten-membered aryl groups containing one or two heteroatoms selected from N and O; More preferably, R 11 and R 21 are each independently selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, furanyl, pyrrolyl, thiazolyl, pyranyl, pyridyl, imidazolyl, tetrahydrofuranyl, hexahydropyridyl, tetrahydropyrrolyl, pyrazinyl, phenyl, naphthyl; Preferably, n1and n2are each independently selected from an integer from 1 to 4, for example, an integer of 1, 2, 3 or 4.

6. The (±)-phellopterin derivative represented by the following Formula I or Formula II according to any one of claims 1 to 5, or an isotopically labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer, or a mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, characterized in that, which is selected from the group consisting of:

7. A pharmaceutical composition comprising a therapeutically effective amount of the honokiol derivative represented by Formula I, Formula II, Formula I-a, Formula I-b, Formula I-c or Formula I-d, or an isotopically labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer, or an isomer mixture thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, and a pharmaceutically acceptable carrier.

8. Use of the honokiol derivative represented by Formula I, Formula II, Formula I-a, Formula I-b, Formula I-c or Formula I-d, or an isotopically labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer, or an isomer mixture thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, as a honokiol prodrug.

9. Use of a honokiol derivative represented by Formula I, Formula II, Formula I-a, Formula I-b, Formula I-c, or Formula I-d, or an isotopically-labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer, or an isomer mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 6, in the manufacture of a medicament for the treatment of cancer (e.g., brain glioma, liver cancer, lung cancer, pancreatic cancer, colon cancer, breast cancer, skin cancer, melanoma), antioxidant, antiviral (influenza, herpes, reovirus, coronavirus), antibacterial (e.g., gram-positive bacteria, Staphylococcus aureus, Escherichia coli, Actinobacillus, methicillin-resistant Staphylococcus aureus, Prevotella intermedia, Micrococcus luteus, Porphyromonas gingivalis, Bacillus subtilis), anti-anxiety, anti-depression, anti-inflammatory, amyotrophic lateral sclerosis, analgesic, anti-lung injury, anti-malaria, central nervous system (e.g., Parkinson’s disease, Alzheimer’s disease, stroke), autoimmune, gastrointestinal protection, cardioprotective, and the like.

10. A method of treating cancer (e.g., brain glioma, liver cancer, lung cancer, pancreatic cancer, colon cancer, breast cancer, skin cancer, melanoma), the method comprising administering to a subject in need thereof an effective amount of a honokiol derivative represented by Formula I, Formula II, Formula I-a, Formula I-b, Formula I-c, or Formula I-d, or an isotopically-labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer, or an isomer mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 6, or a pharmaceutical composition according to claim 7.

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