A melatonin receptor agonist and methods of making and using the same

Abstract

The present application belongs to the technical field of medicine, and particularly relates to a melatonin receptor agonist and a preparation method and application thereof. The present application synthesizes a compound shown in formula I, which has significant agonistic activity on a melatonin receptor, can be used as a melatonin receptor agonist, and is used for preventing and / or treating various neurodegenerative diseases mediated by the melatonin receptor, and has a wide application prospect.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and particularly relates to a melatonin receptor agonist and a preparation method and use thereof. BACKGROUND

[0002] Melatonin, also known as melatonin, is a kind of indole amine neurohormone widely existing in the body, which is mainly secreted by the pineal gland in the human body. It regulates a variety of important physiological functions such as circadian rhythm, sleep, endocrine, immunity and anti-aging.

[0003] Melatonin is an endogenous agonist of two G protein-coupled receptors (MT1 and MT2), which shows high affinity at nanomolar concentrations, and another lower affinity MT3 binding site is identified as quinone reductase 2. MT1 and MT2 receptors produce biological effects through a series of cascade signal transduction effects such as regulating intracellular calcium levels, nitric oxide (NO) release and cyclic guanosine phosphate (cGMP) levels, and coupling MEK / ERK signal transduction pathways. In the central nervous system, the distinction of MT1 and MT2 receptor functions is only partially elucidated, and activation of MT1 receptors can inhibit suprachiasmatic nucleus (SCN) neuron firing and promote cardiovascular contraction; while activation of MT2 receptors can regulate circadian rhythm and dilate coronary artery vessels; the exact biological relationship between MT3 binding site and melatonin is still unclear, but it has been confirmed to be involved in acute inflammatory response in rats and regulation of intraocular pressure in rabbits.

[0004] Although MT1 and MT2 in the human body are highly homologous, there are significant differences in their distribution and signal pathways in the human body. The physiological functions of MT1 and MT2 also show significant differences: MT1 mainly plays a regulatory role in the rapid eye movement period of sleep, while MT2 is mainly responsible for increasing non-rapid eye movement sleep. However, the melatonin drugs on the current drug market lack selectivity between MT1 and MT2, and cannot achieve precise treatment of related diseases. Human peripheral blood granulocytes have mRNA expression of MT1 receptor subtypes, but not mRNA expression of MT2 receptor subtypes. Therefore, MT subtype selective drugs are helpful for precise treatment of diseases, improve treatment specificity, reduce drug adverse reactions, and improve drug safety.

[0005] Neurodegenerative disease is a disease state of loss of neurons in the brain and spinal cord. The brain and spinal cord are composed of neurons, and neurodegenerative disease is caused by loss of neurons or their myelin sheaths, which worsens over time to cause dysfunction. Such diseases mainly include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and neuron degeneration caused by cerebral ischemia and hypoxia.

[0006] Many studies have shown that the level of melatonin in the cerebrospinal fluid (CSF) of Alzheimer's disease patients decreases compared with the same year. After the patient with Parkinson's syndrome is given L-dopa, the peak time of melatonin level at night is advanced, and the melatonin level in serum during the day is increased, which suggests that the neuroprotective effect of melatonin may be closely related to the progression of the disease. The occurrence of Huntington's disease (HD) is most closely related to mitochondria, and melatonin can prevent lipid peroxidation in rat brain tissue and prevent the death of hippocampal neurons.

[0007] The pathogenesis of neurodegenerative disease is complex, involving inflammation, oxidative stress, neuronal damage and other pathological processes. At present, there is no effective treatment for neurodegenerative disease, and the lesion is irreversible, and only symptomatic relief or disease management can delay the progression of the disease, and the early symptoms of some neurodegenerative diseases are not obvious, which easily leads to delayed treatment opportunity. Therefore, it is of great significance to find a melatonin receptor agonist for the treatment of neurodegenerative disease. SUMMARY

[0008] In view of the problems of the prior art, the present application provides a melatonin receptor agonist and a preparation method and use thereof.

[0009] The compound shown in formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterium compound thereof, or a solvate thereof, or a crystal form thereof:

[0010]

[0011] R1 is selected from hydrogen, halogen;

[0012] Ring A is selected from 3-10 membered heterocycloalkyl, 3-10 membered heteroaryl;

[0013] L1is selected from substituted or unsubstituted C1-C5alkylene, wherein the substituents are selected from halogen, hydroxyl, C1-C5alkyl, cyano, amino, C3-C6cycloalkyl, and C1-C5haloalkyl; 10 alkyl, cyano, amino, C3-C6cycloalkyl, and C1-C5haloalkyl; 10 cycloalkyl;

[0014] L2is selected from an amide bond;

[0015] L3is selected from C1-C5alkyl, C3-C6cycloalkyl, methylcyclopropanyl, methylcyclobutanyl, methylcyclopentanyl, and methylcyclohexanyl; 10 cycloalkyl;

[0016] R2is selected from hydrogen, substituted or unsubstituted C1-C5alkyl, substituted or unsubstituted C3-C6cycloalkyl, wherein the substituents are selected from halogen, hydroxyl, C1-C5alkyl, cyano, amino, C3-C6cycloalkyl, and C1-C5haloalkyl; 10 cycloalkyl; 10 cycloalkyl.

[0017] Preferably, the compound of Formula I has the structure of Formula II:

[0018]

[0019] wherein R1is selected from hydrogen, halogen;

[0020] L3is selected from C1-C5alkyl, C3-C6cycloalkyl. 10 cycloalkyl.

[0021] Preferably, R1is selected from hydrogen, fluorine; and L3is selected from C2alkyl, C3cycloalkyl. Preferably, L3is selected from C2alkyl.

[0022] Preferably, the compound of Formula I has the structure of Formula III:

[0023]

[0024] wherein R1is selected from hydrogen, halogen;

[0025] L3is selected from C1-C5alkyl.

[0026] Preferably, R1is selected from hydrogen, fluorine; and L3is selected from C3alkyl.

[0027] Preferably, R1is selected from fluorine.

[0028] Preferably, the compound of Formula I has one of the following structures:

[0029] The present application also provides a preparation method of the above-mentioned compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated compound thereof, or a solvate thereof, or a crystal form thereof, comprising the following steps:

[0030]

[0031] Step 1, reacting compound a with acrylonitrile to obtain compound b;

[0032] Step 2, hydrolyzing and cyclizing compound b to obtain compound c;

[0033] Step 3, reacting diethyl cyanomethylphosphonate with a strong base to prepare an intermediate;

[0034] Step 4, condensing compound c with the intermediate to obtain compound d;

[0035] Step 5, performing one of the following operations: a. reducing compound d to obtain compound e; and then reacting compound e with a carboxylic acid to obtain a compound shown in formula II;

[0036] or, b. hydrolyzing and reducing compound d to obtain compound f; and then reacting compound f with an amine compound to obtain a compound shown in formula III.

[0037] Preferably, in Step 1, the reaction is performed in the presence of a basic catalyst selected from at least one of sodium methoxide, n-butyllithium and potassium tert-butoxide;

[0038] and / or, in Step 2, the hydrolysis is performed in the presence of an acid selected from at least one of hydrochloric acid, sulfuric acid and phosphoric acid; and the cyclization is performed in the presence of a catalyst selected from polyphosphoric acid;

[0039] and / or, in Step 3, the solvent of the reaction is selected from ethanol, and the strong base is selected from potassium tert-butoxide;

[0040] and / or, in Step 4, the reaction temperature is 20-25°C, and the reaction time is 1-5h;

[0041] and / or, in Step 5a, the solvent of the reduction reaction is selected from methanol; the reduction reaction is performed in the presence of a catalyst selected from palladium-carbon catalyst and a reducing agent selected from hydrogen; and / or, the carboxylic acid is selected from at least one of propionic acid and cyclopropylacetic acid; the solvent of the reaction is selected from pyridine; and the reaction is performed in the presence of a dehydrating agent selected from N,N'-dicyclohexyl carbodiimide;

[0042] In step 5b, the hydrolysis is carried out in the presence of an acid selected from at least one of hydrochloric acid, sulfuric acid, phosphoric acid; the reduction reaction is carried out in the presence of a catalyst selected from palladium on carbon catalyst, and a reducing agent selected from hydrogen; the amine compound is selected from propylamine; the reaction is carried out in the presence of a condensing agent selected from N,N'-dicyclohexylcarbodiimide.

[0043] The present application also provides use of the above-mentioned compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated compound thereof, or a solvate thereof, or a crystal form thereof in the preparation of a melatonin receptor agonist.

[0044] Preferably, the melatonin receptor agonist is a drug for treating neurodegenerative diseases.

[0045] The present application provides a pharmaceutical composition which is the above-mentioned compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated compound thereof, or a solvate thereof, or a crystal form thereof as an active ingredient, added with a pharmaceutically acceptable adjuvant.

[0046] The compounds and derivatives provided in the present application can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstract Service, Columbus, OH) nomenclature system.

[0047] Definitions of terms used in connection with the present application: unless otherwise indicated, the initial definition of a group or term provided herein is intended to apply throughout the description of the specification to that group or term; to the extent a term is not specifically defined, it should be given the meaning that would be given by one of ordinary skill in the art in light of the disclosure and context.

[0048] The minimum and maximum number of carbon atoms in a hydrocarbon group is indicated by a prefix, e.g., the prefix C a -C b Alkyl means any alkyl having "a" to "b" carbon atoms. Thus, for example, "C1-C6alkyl" means an alkyl group containing from 1 to 6 carbon atoms.

[0049] "Alkyl" means a saturated hydrocarbon chain having the indicated number of members. For example, C1-C6alkyl means an alkyl group having from 1 to 6 members, e.g., from 1 to 4 members. Alkyl groups can be straight or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl groups can be optionally substituted with one or more substituents as defined herein. Alkyl includes methyl, ethyl, propyl (n-propyl and i-propyl), butyl (n-butyl, i-butyl, and t-butyl), pentyl (n-pentyl, i-pentyl, and neopentyl), and hexyl. Alkyl groups can also be part of other groups, e.g., C1-C6alkoxy.

[0050] "Cycloalkyl" refers to saturated or partially saturated ring(s) of from 3 to 14 carbon atoms having no ring heteroatoms and having a single ring or multiple rings (including fused, bridged, and spiro ring systems). For multiple ring systems having both aromatic and non-aromatic rings free of ring heteroatoms, the term "cycloalkyl" applies when the point of attachment is to a non-aromatic carbon atom (e.g., 5,6,7,8,- tetrahydronaphthalen-5-yl). The term "cycloalkyl" includes cycloalkenyl groups, such as cyclohexenyl. Examples of cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl.

[0051] "Halogen" is fluorine, chlorine, bromine, or iodine.

[0052] The "amide bond" structure is "-CONH-," a covalent bond formed by the combination of an acyl (-CO-) and an amino (-NH-).

[0053] The term "pharmaceutically acceptable" means that which is generally compatible with the other ingredients in a pharmaceutical dosage form and physiologically acceptable to the recipient with respect to chemical and physical compatibility, stability, and lack of toxicity.

[0054] The terms "salt" and "pharmaceutically acceptable salt" refer to the acid and / or base salts of the foregoing compounds or stereoisomers thereof, and include anionic, cationic, and zwitterionic salts, as well as quaternary ammonium salts. These salts can be formed by conventional means, such as by reacting a compound or stereoisomer thereof with an inorganic or organic acid or base. These salts can be precipitated from solution and collected by filtration, recovered upon evaporation of a solvent, or prepared by freeze-drying following reaction in an aqueous medium. The salts of the present application can be hydrochlorides, sulfates, citrates, besylates, hydrobromides, hydrofluorides, phosphates, acetates, propionates, succinates, oxalates, malates, succinates, fumarates, maleates, tartrates, or trifluoroacetates of the compounds.

[0055] In certain embodiments, one or more compounds of the present application can be used in combination with one another. The compounds of the present application can also be used in combination with any other active agents useful in modulating cellular function or treating a disease. If a combination of compounds is used, the compounds can be administered simultaneously, separately or sequentially to the subject.

[0056] The present application provides a new compound shown in formula I, which exhibits good melatonin receptor agonistic activity, provides a new drug selection for preventing or / and treating various neurodegenerative diseases mediated by melatonin receptor, and has wide application prospect.

[0057] Obviously, according to the above content of the present application, according to the ordinary technical knowledge and common means in the art, other various forms of modification, replacement or change can be made without departing from the above basic technical idea of the present application.

[0058] The above content of the present application will be further explained in detail through the following embodiment. However, it should not be understood that the above subject matter of the present application is limited to the following examples. Any technology realized based on the above content of the present application belongs to the scope of the present application. DETAILED DESCRIPTION

[0059] In the following examples and experimental examples, the reagents and raw materials not specifically explained are commercially available.

[0060] Example 1 Preparation of benzodioxane compound

[0061] The structure of the benzodioxane compound is shown as follows:

[0062]

[0063] The specific synthesis route is as follows:

[0064]

[0065] The preparation method is as follows:

[0066] (1) 4-Fluorophenol 1.12 g was weighed, acrylonitrile 10 ml was added, and after stirring uniformly, sodium methoxide 0.81 g was added in batches in ice bath, and slowly warmed to room temperature under inert gas protection, then heated to reflux for 5 h, acrylonitrile was removed by concentration under reduced pressure, then water 30 ml was added, extracted with ethyl acetate (3×20 ml), the organic layers were combined, washed with water (1×30 ml), saturated brine (1×30 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography (PE:EA=20:1-10:1 gradient elution) was performed to obtain 3-(4-fluorophenoxy) propionitrile 1.33 g in white solid, with a yield of 80.6%. 1 H-NMR (400 MHz, CDCl3 / TMS) δ: 2.82 (t, J=8.4 Hz, 2H, CH2), 4.31 (t, J=8.8 Hz, 2H, CH2), 7.18 (m, 2H, ArH), 7.51 (m, 2H, ArH).

[0067] (2) Take 1.65 g of 3-(4-fluorophenoxy) propionitrile, add 10 ml of 6M hydrochloric acid, reflux for 5 h, and then dry under reduced pressure to obtain a light yellow solid. Add 5 g of polyphosphoric acid (PPA) to the solid, stir at room temperature for 10 h, then add 30 ml of ice water, extract with ethyl acetate (3 x 20 ml), combine the organic layers, wash with water (2 x 30 ml), wash with saturated brine (1 x 30 ml), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and then column chromatograph (PE:EA = 20:1-10:1 gradient elution) to obtain 1.30 g of yellow solid 6-fluorochromen-4-one with a yield of 78.3%. 1 H-NMR (400 MHz, CDCl3 / TMS) δ: 2.91 (t, J = 8.8 Hz, 2H, CH2), 4.16 (t, J = 8.8 Hz, 2H, CH2), 7.05 (m, 1H, ArH), 7.34 (m, 1H, ArH), 7.56 (m, 1H, ArH).

[0068] (3) Take 2.12 g of cyanomethyl phosphonic acid diethyl ester, add 30 ml of ethanol, and cool in an ice-salt bath. Slowly add 1.68 g of potassium tert-butoxide at 0°C while controlling the temperature, and then keep the temperature at 0°C for half an hour after the potassium tert-butoxide is added. Finally, add 1.66 g of 6-fluorochromen-4-one, and then warm to room temperature to react. After 3 hours of reaction, add 50 ml of ice water to the reaction solution, extract with ethyl acetate (3 x 30 ml), combine the organic layers, wash with water (2 x 30 ml), wash with saturated brine (1 x 30 ml), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and then column chromatograph (PE:EA = 20:1-10:1 gradient elution) to obtain 1.77 g of yellow solid 2-(6-fluorochromen-4-ylidene) acetonitrile with a yield of 93.6%. 1 H-NMR (400 MHz, CDCl3 / TMS) δ: 2.41 (t, J = 8.8 Hz, 2H, CH2), 4.01 (t, J = 8.4 Hz, 2H, CH2), 5.44 (s, 1H, CH), 6.89 (m, 1H, ArH), 6.96 (m, 1H, ArH), 7.11 (m, 1H, ArH).

[0069] (4) Place 1.89 g of 2-(6-fluorochromen-4-ylidene) acetonitrile in a reaction bottle, add 20 ml of anhydrous methanol, and then add 50 mg of 10% Pd-C. After the air is exhausted, stir at room temperature under a hydrogen atmosphere for 5 h. After the reaction is complete, perform suction filtration, concentrate the filtrate under reduced pressure, and then column chromatograph (PE:EA = 10:1-5:1, 0.1% TEA gradient elution) to obtain 1.88 g of white solid 6-fluorochromen-4-yl ethylamine with a yield of 96.4%.

[0070] 1H-NMR (400 MHz, CDC13 / TMS) δ: 0.98 (t, J = 8.8 Hz, 3H, CH3), 1.81-1.85 (m, 3H, CH2, CH2), 2.10 (m, 1H, CH2), 2.60 (m, 3H, CH, CH2), 3.18 (m, 2H, CH2), 3.98 (m, 2H, CH2), 6.89 (m, 1H, ArH), 6.96 (m, 1H, ArH), 7.11 (m, 1H, ArH), 7.73 (s, 1H, NH).

[0071] (5) 6-Fluorochroman-4-yl ethylamine 1.95 g and 0.82 g of propionic acid were added to 20 ml of anhydrous pyridine, and 3.0 g of N,N'-dicyclohexyl carbodiimide (DCC) was added. After stirring at room temperature for 5 h, the pyridine was removed by concentration under reduced pressure, and extraction was performed with ethyl acetate (3 x 20 ml). The organic layers were combined, washed with water (1 x 30 ml), saturated brine (1 x 30 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatographed (PE:EA = 20:1-10:1 gradient elution) to obtain a chroman compound as a white solid 2.45 g in a yield of 97.6%. 1 H-NMR (400 MHz, CDC13 / TMS) δ: 0.98 (t, J = 8.8 Hz, 3H, CH3), 1.81-1.85 (m, 3H, CH2, CH2), 2.10 (m, 1H, CH2), 2.60 (m, 3H, CH, CH2), 3.18 (m, 2H, CH2), 3.98 (m, 2H, CH2), 6.89 (m, 1H, ArH), 6.96 (m, 1H, ArH), 7.11 (m, 1H, ArH), 7.73 (s, 1H, NH).

[0072] Example 2 Preparation of a chroman compound

[0073] The structure of the chroman compound is as follows:

[0074]

[0075] The preparation method thereof is as follows:

[0076] (1) Phenol 1.12 g and acrylonitrile 10 ml were stirred, and sodium methoxide 0.81 g was added in batches under ice bath. After slowly warming to room temperature under inert gas protection, heating was performed under reflux for 5 h. After removing acrylonitrile by concentration under reduced pressure, 30 ml of water was added, extraction was performed with ethyl acetate (3 x 20 ml), the organic layers were combined, washed with water (1 x 30 ml), saturated brine (1 x 30 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatographed (PE:EA = 20:1-10:1 gradient elution) to obtain a white solid phenoxy propionitrile 1.33 g in a yield of 80.6%. 1H-NMR (400 MHz, CDC13 / TMS) δ: 2.82 (t, J = 8.4 Hz, 2H, CH2), 4.31 (t, J = 8.4 Hz, 2H, CH2), 6.93 (m, 3H, ArH), 7.28 (m, 2H, ArH).

[0077] (2) Take 1.65 g of phenoxypropionitrile, add 6M hydrochloric acid 10 ml, reflux for 5h, dryness under reduced pressure, add PPA 5g to the solid, stir at room temperature for 10h, add ice water 30 ml, extract with ethyl acetate (3x20ml), combine the organic layer, wash with water (2x30ml), wash with saturated brine (1x30ml), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and column chromatography (PE:EA=20:1-10:1 gradient elution) to obtain yellow solid benzodihydropyran-4-ketone 1.30g, yield 78.3%. 1 H-NMR (400 MHz, CDC13 / TMS) δ: 2.91 (t, J = 8.8 Hz, 2H, CH2), 4.16 (t, J = 8.8 Hz, 2H, CH2), 6.94 (t, J = 8.0 Hz, 1H, ArH), 6.92 (d, J = 8.0 Hz, 1H, ArH), 7.40 (d, J = 8.0 Hz, 1H, ArH), 7.512 (t, J = 8.0 Hz, 1H, ArH).

[0078] (3) Take cyanomethylphosphonic acid diethyl ester 2.12g, add ethanol 30ml, cool to ice salt bath, slowly add potassium tert-butoxide 1.68g at 0°C, keep the temperature at 0°C for half an hour after the addition of potassium tert-butoxide, finally add 1.66g of benzodihydropyran-4-ketone, warm to room temperature, react for 3h, add ice water 50ml to the reaction solution, extract with ethyl acetate (3x30ml), combine the organic layer, wash with water (2x30ml), wash with saturated brine (1x30ml), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and column chromatography (PE:EA=20:1-10:1 gradient elution) to obtain yellow solid 1.77g, yield 93.6%. 1 H-NMR (400 MHz, CDC13 / TMS) δ: 2.38 (t, J = 8.8 Hz, 2H, CH2), 4.01 (t, J = 8.4 Hz, 2H, CH2), 5.44 (s, 1H, CH), 7.02-7.05 (m, 2H, ArH), 7.23 (d, J = 8.0 Hz, 1H, ArH), 7.32 (t, J = 8.0 Hz, 1H, ArH).

[0079] (4) The yellow solid 1.89 g obtained in step (3) was placed in a reaction flask, anhydrous methanol (20 mL) was added, followed by 10% Pd-C (50 mg), air was exhausted, and hydrogen atmosphere was stirred at room temperature for 5 h. After the reaction was completed, it was filtered under reduced pressure, and the filtrate was concentrated under reduced pressure and column chromatography (PE:EA=10:1-5:1, 0.1% TEA gradient elution) to obtain benzodihydropyran-4-yl ethylamine 1.88 g as a white solid, with a yield of 96.4%. 1 H-NMR (400 MHz, CDCl3 / TMS) δ: 1.80-1.85 (m, 3H, CH2, CH2), 2.10-2.20 (m, 1H, CH2), 2.55-2.63 (m, 3H, CH, CH2), 3.95 (m, 2H, CH2), 7.02-7.05 (m, 2H, ArH), 7.23 (d, J=8.0 Hz, 1H, ArH), 7.32 (t, J=8.0 Hz, 1H, ArH), 8.5 (brs, 2H, NH2).

[0080] (5) Benzodihydropyran-4-yl ethylamine 1.95 g and 0.82 g propionic acid were added to 20 ml of anhydrous pyridine, followed by 3.0 g of DCC. After stirring at room temperature for 5 h, the pyridine was removed as much as possible under reduced pressure, extracted with ethyl acetate (3 x 20 mL), the organic layers were combined, washed with water (1 x 30 mL), saturated brine (1 x 30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography (PE:EA=20:1-10:1 gradient elution) to obtain a benzodihydropyran compound as a white solid 2.45 g, with a yield of 97.6%. 1 H-NMR (400 MHz, CDCl3 / TMS) δ: 0.98 (t, J=8.8 Hz, 3H, CH3), 1.80-1.85 (m, 3H, CH2, CH2), 2.10-2.20 (m, 1H, CH2), 2.31 (q, J=8.8 Hz, 2H, CH2), 2.58 (m, 1H, CH), 3.18 (t, J=8.8 Hz, 2H, CH2), 3.98 (m, 2H, CH2), 6.82-6.91 (m, 2H, ArH), 7.33 (d, J=8.0 Hz, 1H, ArH), 7.51 (t, J=8.0 Hz, 1H, ArH), 7.73 (s, 1H, NH).

[0081] Example 3 Preparation of a benzodihydropyran compound

[0082] The structure of the benzodihydropyran compound is as follows:

[0083]

[0084] The preparation method is as follows:

[0085] (1) Take 4-fluorophenol 1.12 g, add acrylonitrile 10 ml, stir evenly, then add sodium methoxide 0.81 g in ice bath, slowly warm to room temperature under inert gas protection, then heat to reflux for 5 h, then add water 30 ml, extract with ethyl acetate (3 x 20 ml), combine the organic layers, wash with water (1 x 30 ml), wash with saturated brine (1 x 30 ml), dry over anhydrous sodium sulfate, concentrate under reduced pressure, then column chromatography (PE:EA=20:1-10:1 gradient elution) to obtain 3-(4-fluorophenoxy)propionitrile 1.33 g as a white solid, with a yield of 80.6%. 1 H-NMR (400 MHz, CDCl3 / TMS) δ: 2.82 (t, J = 8.4 Hz, 2H, CH2), 4.31 (t, J = 8.8 Hz, 2H, CH2), 7.18 (m, 2H, ArH), 7.51 (m, 2H, ArH).

[0086] (2) Take 1.65 g of 3-(4-fluorophenoxy)propionitrile, add 10 ml of 6M hydrochloric acid, reflux for 5 h, then dry by concentrating under reduced pressure to obtain a light yellow solid, add PPA 5 g to the solid, stir at room temperature for 10 h, then add ice water 30 ml, extract with ethyl acetate (3 x 20 ml), combine the organic layers, wash with water (2 x 30 ml), wash with saturated brine (1 x 30 ml), dry over anhydrous sodium sulfate, concentrate under reduced pressure, then column chromatography (PE:EA=20:1-10:1 gradient elution) to obtain 6-fluorochromen-4-one 1.30 g as a yellow solid, with a yield of 78.3%. 1 H-NMR (400 MHz, CDCl3 / TMS) δ: 2.91 (t, J = 8.8 Hz, 2H, CH2), 4.16 (t, J = 8.8 Hz, 2H, CH2), 7.05 (m, 1H, ArH), 7.34 (m, 1H, ArH), 7.56 (m, 1H, ArH).

[0087] (3) Take cyanomethyl phosphonic acid diethyl ester 2.12 g, add ethanol 30 ml, cool the reaction to ice salt bath, slowly add potassium tert-butoxide 1.68 g at 0°C while controlling the temperature, keep the temperature at 0°C for half an hour after the addition of potassium tert-butoxide, then add 1.66 g of 6-fluorochromen-4-one, warm to room temperature and react, react for 3 hours, then add ice water 50 ml to the reaction liquid, extract with ethyl acetate (3 x 30 ml), combine the organic layers, wash with water (2 x 30 ml), wash with saturated brine (1 x 30 ml), dry over anhydrous sodium sulfate, concentrate under reduced pressure, then column chromatography (PE:EA=20:1-10:1 gradient elution) to obtain 2-(6-fluorochromen-4-ylidene)acetonitrile 1.77 g as a yellow solid, with a yield of 93.6%. 1H-NMR (400 MHz, CDC13 / TMS) δ: 2.41 (t, J = 8.8 Hz, 2H, CH2), 4.01 (t, J = 8.4 Hz, 2H, CH2), 5.44 (s, 1H, CH), 6.89 (m, 1H, ArH), 6.96 (m, 1H, ArH), 7.11 (m, 1H, ArH).

[0088] (4) 2-(6-Fluorochroman-4-ylidene)acetonitrile 1.89 g was placed in a reaction flask, anhydrous methanol (20 mL) was added, followed by 10% Pd-C (50 mg), air was exhausted, and hydrogen atmosphere was stirred at room temperature for 5 h. After the reaction was completed, it was filtered, the filtrate was concentrated under reduced pressure, and column chromatography (PE:EA = 10:1-5:1, 0.1% TEA gradient elution) was performed to obtain 6-fluorochroman-4-yl ethylamine 1.88 g as a white solid, with a yield of 96.4%.

[0089] 1 H-NMR (400 MHz, CDC13 / TMS) δ: 2.41 (t, J = 8.8 Hz, 2H, CH2), 4.01 (t, J = 8.4 Hz, 2H, CH2), 5.44 (s, 1H, CH), 6.89 (m, 1H, ArH), 6.96 (m, 1H, ArH), 7.11 (m, 1H, ArH).

[0090] (5) 6-Fluorochroman-4-yl ethylamine 1.95 g and 0.82 g cyclopropylcarboxylic acid were added to 20 ml of anhydrous pyridine, followed by DCC 3.0 g. After stirring at room temperature for 5 h, the pyridine was removed as much as possible by reduced pressure concentration, extracted with ethyl acetate (3 x 20 mL), the organic layers were combined, washed with water (1 x 30 mL), saturated brine (1 x 30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography (PE:EA = 20:1-10:1 gradient elution) was performed to obtain a chroman compound as a white solid 2.45 g, with a yield of 97.6%. 1 H-NMR (400 MHz, CDC13 / TMS) δ: 2.41 (t, J = 8.8 Hz, 2H, CH2), 4.01 (t, J = 8.4 Hz, 2H, CH2), 5.44 (s, 1H, CH), 6.89 (m, 1H, ArH), 6.96 (m, 1H, ArH), 7.11 (m, 1H, ArH).

[0091] Example 4 Preparation of chroman compounds

[0092] The structure of chroman compounds is shown below:

[0093]

[0094] The specific synthesis route is:

[0095]

[0096] The preparation method is:

[0097] (1) 4-Fluorophenol 1.12 g was weighed, acrylonitrile 10 ml was added, and after stirring uniformly, sodium methoxide 0.81 g was added in batches in an ice bath. Slowly warmed to room temperature under inert gas protection, then heated to reflux for 5 h. After removing acrylonitrile under reduced pressure, 30 ml of water was added, and ethyl acetate was extracted (3 x 20 ml). The organic layers were combined, washed with water (1 x 30 ml), saturated brine (1 x 30 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography (PE:EA = 20:1-10:1 gradient elution) to obtain 3-(4-fluorophenoxy) propionitrile 1.33 g as a white solid, with a yield of 80.6%. 1 H-NMR (400 MHz, CDCl3 / TMS) δ: 2.82 (t, J = 8.4 Hz, 2H, CH2), 4.31 (t, J = 8.8 Hz, 2H, CH2), 7.18 (m, 2H, ArH), 7.51 (m, 2H, ArH).

[0098] (2) 1.65 g of 3-(4-fluorophenoxy) propionitrile was weighed, 10 ml of 6M hydrochloric acid was added, and refluxed for 5 h. After drying under reduced pressure, a yellowish solid was obtained. PPA 5 g was added to the solid, stirred at room temperature for 10 h, then 30 ml of ice water was added, and ethyl acetate was extracted (3 x 20 ml). The organic layers were combined, washed with water (2 x 30 ml), saturated brine (1 x 30 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography (PE:EA = 20:1-10:1 gradient elution) to obtain 6-fluorochroman-4-one 1.30 g as a yellow solid, with a yield of 78.3%. 1 H-NMR (400 MHz, CDCl3 / TMS) δ: 2.91 (t, J = 8.8 Hz, 2H, CH2), 4.16 (t, J = 8.8 Hz, 2H, CH2), 7.05 (m, 1H, ArH), 7.34 (m, 1H, ArH), 7.56 (m, 1H, ArH).

[0099] (3) Weigh cyanomethylphosphonic acid diethyl ester 2.12 g, add ethanol 30 mL, move the reaction to an ice-salt bath to cool, slowly add potassium tert-butoxide 1.68 g at 0 °C under temperature control, keep the temperature at 0 °C for half an hour after the addition of potassium tert-butoxide, finally add 1.66 g of 6-fluorochroman-4-one, warm to room temperature and react, react for 3 hours after the reaction is complete. Add ice water 50 ml to the reaction solution, extract with ethyl acetate (3 x 30 mL), combine the organic layers, wash with water (2 x 30 mL), wash with saturated brine (1 x 30 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and then column chromatography (PE:EA = 20:1-10:1 gradient elution) to obtain yellow solid 2-(6-fluorochroman-4-ylidene)acetonitrile 1.77 g, yield 93.6%. 1 H-NMR (400 MHz, CDCl3 / TMS) δ: 2.41 (t, J = 8.8 Hz, 2H, CH2), 4.01 (t, J = 8.4 Hz, 2H, CH2), 5.44 (s, 1H, CH), 6.89 (m, 1H, ArH), 6.96 (m, 1H, ArH), 7.11 (m, 1H, ArH).

[0100] (4) Weigh 2-(6-fluorochroman-4-ylidene)acetonitrile 2.03 g, add 6M hydrochloric acid 20 ml, reflux for 5 h, dry by concentrating under reduced pressure, add isopropyl alcohol 20 ml, add 10% Pd-C (100 mg), remove air, stir under hydrogen atmosphere at room temperature for 5 h, after the reaction is complete, filter, concentrate the filtrate under reduced pressure, and then column chromatography (PE:EA = 10:1-5:1, 0.1% glacial acetic acid gradient elution) to obtain white solid 2-(6-fluorochroman-4-yl)-acetic acid 1.79 g, two-step yield 79.9%. 1 H-NMR (400 MHz, CDCl3 / TMS) δ: 1.85-2.10 (m, 2H, CH2), 2.36-2.57 (m, 2H, CH2), 2.99 (m, 1H, CH), 3.97 (m, 2H, CH2), 6.93 (m, 1H, ArH), 7.02 (m, 1H, ArH), 7.11 (m, 1H, ArH), 11.4 (brs, 1H, COOH).

[0101] (5) Take 2-(6-fluorobenzodihydropyran-4-yl)-acetic acid 2.10 g and propylamine 0.65 g, add pyridine 20 ml, then add N,N'-dicyclohexyl carbodiimide (DCC) 3.0 g, stir at room temperature for 5 h, then remove pyridine under reduced pressure, extract with ethyl acetate (3 x 20 ml), combine the organic layers, wash with water (1 x 30 ml), wash with saturated brine (1 x 30 ml), dry over anhydrous sodium sulfate, concentrate under reduced pressure, then column chromatograph (PE:EA = 20:1-10:1 gradient elution) to obtain the benzodihydropyran compound as a white solid 2.31 g in a yield of 92.0%. 1 H-NMR (400 MHz, CDCl3 / TMS) δ: 0.88 (t, J = 8.8 Hz, 3H, CH3), 1.55 (m, 2H, CH2), 1.80-2.10 (m, 2H, CH2), 2.35-2.51 (m, 2H, CH2), 2.99 (m, 1H, CH), 3.42 (t, J = 8.8 Hz, 2H, CH2), 3.98 (m, 2H, CH2), 6.94 (m, 1H, ArH), 7.02 (m, 1H, ArH), 7.11 (m, 1H, ArH), 7.81 (s, 1H, NH).

[0102] Example 5 Preparation of benzodihydropyran compound

[0103] The structure of the benzodihydropyran compound is as follows:

[0104]

[0105] The preparation method is as follows:

[0106] (1) Take phenol 1.12 g, add acrylonitrile 10 ml, stir uniformly, then add sodium methoxide 0.81 g in batches under ice bath, slowly warm to room temperature under inert gas protection, then heat to reflux for 5 h, remove acrylonitrile under reduced pressure, then add water 30 ml, extract with ethyl acetate (3 x 20 ml), combine the organic layers, wash with water (1 x 30 ml), wash with saturated brine (1 x 30 ml), dry over anhydrous sodium sulfate, concentrate under reduced pressure, then column chromatograph (PE:EA = 20:1-10:1 gradient elution) to obtain the phenoxy propyl cyanide as a white solid 1.33 g in a yield of 80.6%. 1 H-NMR (400 MHz, CDCl3 / TMS) δ: 2.82 (t, J = 8.4 Hz, 2H, CH2), 4.31 (t, J = 8.4 Hz, 2H, CH2), 6.93 (m, 3H, ArH), 7.28 (m, 2H, ArH).

[0107] (2) Take 1.65 g of phenoxypropionitrile, add 10 ml of 6M hydrochloric acid, reflux for 5 h, then dry under reduced pressure to obtain a light yellow solid. Add 5 g of PPA to the solid, stir at room temperature for 10 h, then add 30 ml of ice water, extract with ethyl acetate (3 x 20 ml), combine the organic layers, wash with water (2 x 30 ml), wash with saturated brine (1 x 30 ml), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and then column chromatograph (PE:EA = 20:1-10:1 gradient elution) to obtain a yellow solid of benzodihydropyran-4-one 1.30 g, with a yield of 78.3%. 1 H-NMR (400 MHz, CDCl3 / TMS) δ: 2.91 (t, J = 8.8 Hz, 2H, CH2), 4.16 (t, J = 8.8 Hz, 2H, CH2), 6.94 (t, J = 8.0 Hz, 1H, ArH), 6.92 (d, J = 8.0 Hz, 1H, ArH), 7.40 (d, J = 8.0 Hz, 1H, ArH), 7.512 (t, J = 8.0 Hz, 1H, ArH).

[0108] (3) Take 2.12 g of cyanomethyl phosphonic acid diethyl ester, add 30 ml of ethanol, and cool the reaction in an ice-salt bath. At 0°C, slowly add 1.68 g of potassium tert-butoxide at a controlled temperature, and keep the temperature at 0°C for half an hour after the addition of potassium tert-butoxide. Finally, add 1.66 g of benzodihydropyran-4-one, and react at room temperature. After 3 hours of reaction, add 50 ml of ice water to the reaction liquid, extract with ethyl acetate (3 x 30 ml), combine the organic layers, wash with water (2 x 30 ml), wash with saturated brine (1 x 30 ml), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and then column chromatograph (PE:EA = 20:1-10:1 gradient elution) to obtain a yellow solid 1.77 g, with a yield of 93.6%. 1 H-NMR (400 MHz, CDCl3 / TMS) δ: 2.38 (t, J = 8.8 Hz, 2H, CH2), 4.01 (t, J = 8.4 Hz, 2H, CH2), 5.44 (s, 1H, CH), 7.02-7.05 (m, 2H, ArH), 7.23 (d, J = 8.0 Hz, 1H, ArH), 7.32 (t, J = 8.0 Hz, 1H, ArH).

[0109] (4) Take 2-(chroman-4-ylidene)acetonitrile 1.71 g, add 6M hydrochloric acid 20 ml, reflux for 5 h, then dry under reduced pressure, add isopropyl alcohol 20 ml, add 10% Pd-C (100 mg), exhaust air, stir under hydrogen atmosphere at room temperature for 5 h, after the reaction is completed, filter, and the filtrate is concentrated under reduced pressure, then column chromatography (PE:EA=10:1-5:1, 0.1% glacial acetic acid gradient elution) to obtain white solid 2-(chroman-4-yl)-acetic acid 1.55 g, two-step yield 80.7%. 1 H-NMR (400MHz, CDCl3 / TMS) δ: 1.84-2.12 (m, 2H, CH2), 2.38-2.65 (m, 2H, CH2), 3.01 (m, 1H, CH), 3.98 (m, 2H, CH2), 6.85-6.90 (m, 2H, ArH), 7.31 (d, J=8.0 Hz, 1H, ArH), 7.52 (t, J=8.0 Hz, 1H, ArH), 12.7 (brs, 1H, COOH).

[0110] (5) Take 2-(chroman-4-yl)-acetic acid 1.92 g and propylamine 0.65 g, add pyridine 20 ml, then add N,N'-dicyclohexyl carbodiimide (DCC) 3.0 g, stir at room temperature for 5 h, then remove pyridine under reduced pressure as much as possible, extract with ethyl acetate (3x20 ml), combine the organic layers, wash with water (1x30 ml), wash with saturated brine (1x30 ml), dry over anhydrous sodium sulfate, concentrate under reduced pressure, then column chromatography (PE:EA=20:1-10:1 gradient elution) to obtain chroman compound as white solid 2.18 g, yield 93.6%. 1 H-NMR (400MHz, CDCl3 / TMS) δ: 0.87 (t, J=8.8 Hz, 3H, CH3), 1.54 (m, 2H, CH2), 1.82-2.13 (m, 2H, CH2), 2.31-2.49 (m, 2H, CH2), 2.98 (m, 1H, CH), 3.42 (t, J=8.8 Hz, 2H, CH2), 3.98 (m, 2H, CH2), 6.85-6.90 (m, 2H, ArH), 7.33 (d, J=8.0 Hz, 1H, ArH), 7.52 (t, J=8.0 Hz, 1H, ArH), 7.81 (s, 1H, NH).

[0111] The technical solutions of the present application are further described below through experiments.

[0112] Experimental Example 1 Biological activity screening of chroman compounds

[0113] I. Experimental method

[0114] MT1 and MT2 cell lines correspond to human renal epithelial cells MT1-HEK293 and MT2-HEK293, respectively.

[0115] The cells were cultured at a rate of 4 × 10 4 The cells were plated in a 96-well plate coated with Matrigel matrix at a density of 100 μL and cultured in a 37°C constant temperature incubator with a CO2 concentration of 5% for 24 hours. The supernatant was aspirated, and the original culture medium was discarded. 100 μL / well of freshly prepared commercially available HDB wash-free calcium flux kit dye solution was added and incubated at 37°C in the dark for 60 minutes. The test compound and positive drug were dissolved in 10 μL dimethyl sulfoxide (DMSO) and 990 μL HBSS buffer, respectively (all sample concentrations were 1.00 mmol / L), and 100 μL / well was extracted from each well of a 96-well transparent bottom plate coated with Matrigel. Prepare the sample to be tested: prepare a 1.00 mmol / L sample to be tested, and place the test sample in another transparent bottom plate. The above two 96-well plates were placed in the Flex Station 3 desktop multi-function microplate reader at the same time. Absorbance values ​​were read at room temperature using a Flexstation 3 benchtop multimode microplate reader at wavelengths (excitation: 485 nm; emission: 525 nm; emission cutoff: 515 nm). Antagonistic activity, expressed as X ± SD (n = 3), was obtained by comparing the highest antagonistic activity obtained with the highest concentration of melatonin and set to 100%. Experimental data were read using a Flexstation 3 benchtop multi-function microplate reader, and EC 50 The values ​​were calculated using Graph Pad Prism 5 software; activation ratio = (Δδa / Δδc) × 100% (a: test sample; c: positive control), the positive control was melatonin (1.00 mmol / L).

[0116] 2. Experimental Results

[0117] As shown in Table 1, the chromanoids prepared in Examples 1 and 2 exhibited significant agonist activity on the melatonin receptor MT2, at 151±3.88% and 197±6.41%, respectively. The chromanoids prepared in Example 4 exhibited significant agonist activity on both the melatonin receptors MT1 (117±5.21%) and MT2 (134±4.78%). These results demonstrate that the chromanoids prepared in the present invention exhibit significant agonist activity on melatonin receptors and are useful for preventing and / or treating various neurodegenerative diseases mediated by melatonergic receptors.

[0118] Table 1

[0119]

Claims

1. A compound of formula III, or a pharmaceutically acceptable salt thereof: ###0001### Formula III R1 is selected from the group consisting of hydrogen, fluorine; L3 is selected from the group consisting of C3 alkyl.

2. The compound of claim 1, wherein R1 is hydrogen. wherein 3. The compound of claim 1, wherein L3 is propyl.

4. The use of a compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, for the manufacture of a melatonin receptor agonist.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: Compounds of Formula III are one of the following structures: , .

3. A process for the preparation of a compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that, 5. The use of a compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of neurodegenerative diseases.

6. A medicament for the treatment of neurodegenerative diseases, which comprises a compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, as an active ingredient.

7. The medicament of claim 6, wherein the melatonin receptor agonist is for the treatment of neurodegenerative diseases.

8. The medicament of claim 6, wherein the compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, is used as an active ingredient in combination with a pharmaceutically acceptable adjuvant. ​ ​ ​ 5. Use according to claim 4, characterized in that: ​ 6. A pharmaceutical composition, characterized by: ​

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