Carvone derivative as well as preparation method and application thereof

Abstract

The invention discloses a series of carvone derivatives as well as a synthesis method and application thereof, and particularly relates to a compound as shown in a formula I, a synthesis method thereof and application of the compound in treatment of cardiovascular diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical compounds and pharmaceutical technology, and in particular to carvone derivatives and preparation methods and uses thereof. Background Art

[0002] L-Carvone, also known as L-carvone, is a low cytotoxic monoterpene, which is widely used in the food industry and chemical industry, especially in toothpaste, hard candy, chewing gum and various beverages. Therefore, L-Carvone has important economic value. Its structural formula is shown below:

[0003]

[0004] At present, there are few reports on the drug development of L-carvone and its derivatives. Among them, Jin Can et al. reported in the document "Design, Synthesis, Crystal Structure and Fungicidal Activity of L-carvone Derivatives Containing Oxime Ester Groups", Organic Chemistry, Issue 5, 2021, 2008-2018, the antibacterial activity of L-carvone derivatives containing oxime esters against five plant pathogenic fungi, including rapeseed sclerotinia fungi, wheat fusarium fungi, rice blast fungi, watermelon wilt fungi and rice sheath blight fungi.

[0005] However, there are few reports on the pharmaceutical applications of L-carvone derivatives. Summary of the invention

[0006] The inventors of the present invention coupled L-carvone to obtain a series of derivatives. When studying such compounds, they unexpectedly found that the compounds of the present invention have the effect of promoting the activity of human cardiomyocytes, indicating that the compounds of the present invention have great potential in being developed into cardiovascular drugs, especially for cardiovascular diseases whose pathogenesis involves cardiomyocytes.

[0007] One of the purposes of the present invention is to disclose a compound represented by formula I or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof:

[0008]

[0009] in:

[0010] Ring A is selected from 6-9 membered cycloalkyl or 7-9 membered oxacyclic group;

[0011] R 1 Independently selected from =O, -OH, -NH2, =N-OH, C1-C6 alkyl, C2-C6 alkenyl, wherein the C1-C6 alkyl is optionally further substituted by one or more halogen atoms;

[0012] n is 1, 2, 3 or 4;

[0013] and,

[0014] The compounds of formula I do not include

[0015] A preferred embodiment of the present invention is a compound represented by formula I or its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, which is a compound represented by formula II or its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof:

[0016]

[0017] in,

[0018] R 2 Independently selected from =O, -OH, -NH2, =N-OH, C1-C6 alkyl, C2-C6 alkenyl, wherein the C1-C6 alkyl is optionally further substituted by one or more halogen atoms;

[0019] m is 1, 2 or 3.

[0020] A preferred embodiment of the present invention is a compound represented by formula I or its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, which is a compound represented by formula II-a or its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof:

[0021]

[0022] Among them, R 2 Selected from =O, -OH, -NH2, =N-OH or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally further substituted by one or more atoms selected from F, Cl, Br.

[0023] A preferred embodiment of the present invention is a compound represented by formula I or its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, which is a compound represented by formula III or its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof:

[0024]

[0025] in,

[0026] X is selected from -O-;

[0027] R 3 Independently selected from =O, -OH, -NH2, =N-OH, C1-C6 alkyl, C2-C6 alkenyl, wherein the C1-C6 alkyl is optionally further substituted by one or more halogen atoms;

[0028] p is 1, 2 or 3.

[0029] A preferred embodiment of the present invention is a compound represented by formula I or its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, which is a compound represented by formula III-a or its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof:

[0030]

[0031] Among them, R 4 The C1-C6 alkyl group is optionally further substituted by one or more atoms selected from Cl, Br or I.

[0032] The specific structures of the compounds represented by Formula I of the present invention include, but are not limited to:

[0033]

[0034]

[0035]

[0036] or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

[0037] The present invention provides a pharmaceutical composition, which contains an effective dose of a compound described in Formula I, Formula II, Formula II-a, Formula III or Formula III-a, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

[0038] The present invention provides a compound of formula I, formula II, formula II-a, formula III or formula III-a or its stereoisomers, tautomers or pharmaceutically acceptable salts, or a pharmaceutical composition thereof for use in preparing a drug for treating cardiovascular diseases, wherein the cardiovascular diseases are selected from myocardial hypertrophy, myocardial ischemia, coronary artery syndrome, angina pectoris, myocardial infarction, and heart failure.

[0039] The present invention also provides another pharmaceutical composition, which contains an effective dose of a compound of formula (1) or (2) and at least one pharmaceutically acceptable carrier or excipient.

[0040]

[0041] The present invention provides a use of a pharmaceutical composition comprising formula (1) or formula (2) in preparing a drug for treating cardiovascular diseases, wherein the cardiovascular disease is selected from myocardial hypertrophy, myocardial ischemia, coronary artery syndrome, angina pectoris, myocardial infarction, and heart failure.

[0042] Description of the Invention

[0043] Unless otherwise stated, some of the terms used in the specification and claims of the present invention are defined as follows:

[0044] In the present invention, the subscript of an atom or a group represents the number or the range of the number of the atom or group, such as "C 1-6 "C1-C6 alkyl" and "alkyl" have the same meaning, that is, they are all alkyl groups containing 1 to 6 carbon atoms. The subscript numbers represent the number of carbon atoms. The meanings of the other subscripts are the same and will not be repeated here.

[0045] "Alkyl" as a group or a part of a group refers to a group consisting of C1-C 20 A straight chain or branched aliphatic hydrocarbon group. Preferably C1-C 10 Alkyl, more preferably C1-C6 alkyl, particularly preferably C1-C3 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl may be substituted or unsubstituted.

[0046] "Alkenyl" refers to a linear or branched monovalent hydrocarbon group having a certain number of carbon atoms and at least one carbon-carbon double bond, wherein the carbon-carbon double bond can be located at any position within the alkenyl group, for example: C2-C6 alkenyl refers to an alkenyl group having 2-6 carbon atoms, including C2 alkenyl, C3 alkenyl, C4 alkenyl, C5 alkenyl, C6 alkenyl. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, and hexadienyl.

[0047] "Cycloalkyl" refers to a saturated monocyclic or polycyclic (e.g., cyclic, spirocyclic or bridged) hydrocarbon group formed by carbon atoms. In some embodiments, the cycloalkyl is a monocyclic group. In some embodiments, the 6-9 membered cycloalkyl can be cyclohexyl, cycloheptyl or cyclooctyl, preferably cyclohexyl.

[0048] "Heterocyclyl", "heterocycle" or "heterocyclic" are used interchangeably in the present invention and refer to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic non-aromatic heterocyclic group containing 3-12 ring atoms, wherein at least one ring atom is a heteroatom, such as oxygen, nitrogen, sulfur, etc. Preferably, it has a 6-9-membered monocyclic ring or a 6-9-membered bicyclic or tricyclic ring, more preferably a 7-9-membered bicyclic ring, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and / or sulfur, preferably a 7-9-membered oxygen heterocyclic group, more preferably a 7-9-membered oxygen bridged ring group. Examples of "heterocyclyl" include, but are not limited to and 8-oxa-3-aza-bicyclo[3.2.1]octyl. The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is the heterocyclyl. The heterocyclyl may be optionally substituted or unsubstituted.

[0049] "Optional" means that the event described can but does not have to occur. For example, "A is optionally substituted with 1 to more R" includes the situation that the A group can be substituted with 1 to more R or not substituted with R.

[0050] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds.

[0051] "Pharmaceutically acceptable salts" refer to certain salts of the above compounds that can maintain the original biological activity and are suitable for medical use. Pharmaceutically acceptable salts of the compounds represented by Formula I, Formula II, Formula II-a, Formula III or Formula III-a can be metal salts or amine salts formed with suitable acids.

[0052] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs with other chemical components, as well as other components such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote administration to an organism, facilitate the absorption of the active ingredient and thus exert biological activity. The pharmaceutical preparations of the pharmaceutical composition invention can be prepared by conventional methods in the art. For example: the active ingredient is mixed with a common adjuvant and / or diluent, and then the mixture is compressed in a conventional tablet press to prepare tablets. Examples of adjuvants or diluents include: microcrystalline cellulose, various starches, talc, magnesium stearate, gelatin, lactose, gums, etc. The purpose of using any other adjuvant or additive is usually dyeing, flavoring, preservation, etc., provided that they do not conflict with the active ingredient. The injection solution can be prepared by dissolving the active ingredient and possible additives in a portion of the injection solvent, preferably sterile water, adjusting the solution to the required volume, sterilizing and filling in a suitable ampoule or vial. Any suitable additive commonly used in the art, such as a tension regulator, a preservative, an antioxidant, etc., can be added. The pharmaceutical composition of the present invention or the pharmaceutical composition produced according to the present invention can be administered by any suitable route, for example, orally in tablet form, capsule, powder, syrup, etc., or parenterally in injection form. Such compositions can be prepared using methods well known in the art, and any pharmaceutically acceptable carrier, diluent, excipient or other additive commonly used in the art can be used. Conveniently, the compounds of the present invention are administered in unit dosage form, comprising about 0.01 to 100 mg of the compound.

[0053] "Therapeutically effective amount" refers to an amount of a compound that is sufficient to effectively treat or prevent a disease or condition described herein when administered to a patient. The "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as needed by those skilled in the art. Generally, when the compounds of the present invention are used for treatment, the human dosage range is 1-1000 mg / day. Depending on the dosage form and the severity of the disease, the dosage may exceed this range.

[0054] Synthesis method of the compound of the present invention

[0055] The compounds of formula I of the present invention can be prepared by the following two methods according to the different groups:

[0056] Method 1: When ring A in formula I is a 6-9 membered cycloalkyl group, the preparation method of the compound of the present invention is:

[0057]

[0058] L-carvone and the compound of formula Ia are coupled to generate the compound of formula Ib, and the compound of formula Ib is reacted with different reducing agents in an alkaline environment to generate the compounds of formula Ic, formula Id, and formula Ie, respectively. The reducing agents are MBH4 (M = Na, K or Li), NH2OH, and NaBH3CN.

[0059] in,

[0060] It is a 6-9 membered cycloalkanone;

[0061] R 5 Independently selected from C1-C6 alkyl, C2-C6 alkenyl, the C1-C6 alkyl is optionally further substituted by one or more halogen atoms;

[0062] q is 1, 2 or 3.

[0063] Method 2: When ring A is a 7-9 membered oxygen heterocyclic group, the preparation method of the compound of the present invention is:

[0064]

[0065] Formula Ic reacts with p-toluenesulfonic acid, or further reacts with N-halosuccinimide to produce Formula If.

[0066] in,

[0067] is a 6-8 membered cycloalkyl substituted with hydroxyl group;

[0068] R 5 The definitions of and q are as in Method 1, R 3 Independently selected from =O, -OH, -NH2, =N-OH, C1-C6 alkyl, C2-C6 alkenyl, wherein the C1-C6 alkyl is optionally further substituted by one or more halogen atoms;

[0069] N-halosuccinimide is N-chlorosuccinimide or N-bromosuccinimide;

[0070] p is 1, 2 or 3. DETAILED DESCRIPTION

[0071] The present invention will be further described below with reference to specific examples, but the present invention is not limited to these examples.

[0072] The L-carvone, hydroxylamine hydrochloride, lithium diisopropylamide, p-toluenesulfonic acid, potassium tert-butoxide, sodium borohydride, sodium bicarbonate, sodium cyanoborocyanide, ammonium acetate, N-chlorosuccinimide, N-bromosuccinimide, and triethylamine used in the examples of the present invention were all analytically pure and purchased from Inotech Technology Co., Ltd.;

[0073] Methanol, dichloromethane, petroleum ether, and ethyl acetate were all analytically pure and purchased from Guangdong Xilong Chemical Plant;

[0074] The instruments and devices used in the embodiments of the present invention are as follows:

[0075] SHB-IIIA circulating water multi-purpose vacuum pump, rotary evaporator (Zhengzhou Great Wall Science and Technology Industry and Trade Co., Ltd.); electronic intelligent temperature controller, 85-1A magnetic stirrer (Gongyi Yuhua Instrument Co., Ltd.); AVANCE AV 400Hz superconducting nuclear magnetic resonance instrument (Switzerland, Bruker); EL104 electronic balance (Mettler-Toledo Instrument Co., Ltd.); KQ5200E ultrasonic cleaner (Kunshan Ultrasonic Instrument Co., Ltd.); DHG-9140A electric constant temperature blast drying oven (Shanghai Yiheng Scientific Instrument Co., Ltd.); rotary evaporator N-1300V-W (Japan, Tokyo Rika Co., Ltd.); Agilent6545Q-TOF LC / MS liquid-mass spectrometry system (Agilent Technologies, USA).

[0076] Example 1 Synthesis of compounds of formula (1) to formula II-2

[0077]

[0078] A tetrahydrofuran solution of lithium diisopropylamide (2.0 M in THF, 16.7 mL, 1.0 equiv) was added to the reaction flask, and the mixture was precooled and stirred at -78°C for 10 minutes. L-carvone (5.0 g, 33.3 mmol) was added dropwise. After the addition of L-carvone was completed, the mixture was stirred and reacted at -78°C for 10 minutes. Then, another portion of L-carvone (5.0 g, 33.3 mmol) was added dropwise at -78°C and reacted for 10 minutes. Saturated ammonium chloride solution was then added dropwise to quench the reaction. The mixture was extracted with ethyl acetate (40 mL×2). The combined extracts were washed with brine (60 mL), dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluent and volume ratio: n-hexane: ethyl acetate = 100:1) to separate and obtain compound (1), compound (2), compound II-1 and compound II-2.

[0079]

[0080] Yield 25%, white solid;

[0081] 11H NMR (400 MHz, CDCl3): δ = 6.72 (m, 1H), 4.87 (s, 2H), 4.73 (t, J = 1.2 Hz, 1H), 4.71 (s, 1H), 2.92 (ddd, J = 11.8, 10.5, 5.0 Hz, 1H), 2.76 (dq, J = 12.8, 7.6 Hz, 1H), 2.46 (d, J = 12.0 Hz, 1H), 2.41 (dd, J = 8.8, 2.0 Hz, 1H), 2.36 (m, 1H), 2.34 - 2.22 (m, 3H), 2.17 - 2.09 (m, 2H), 1.78 (dt, J = 6.8, 1.6 Hz, 3H), 1.71 (s, 3H), 1.70 (s, 3H), 1.66 - 1.62 (m, 1H), 0.97 (d, J = 6.5 Hz, 3H) ppm.

[0082] 13 13C NMR (100 MHz, CDCl3): δ = 212.7, 200.0, 147.7, 146.0, 143.9, 136.0, 114.7, 110.0, 51.9, 47.2, 46.6, 46.5, 45.0, 43.5, 36.5, 31.8, 20.4, 19.1, 16.2, 13.1 ppm.

[0083] ESI - HRMS (m / z): C 20 H 28 O2 [M + H] + , 301.2160.

[0084]

[0085] The yield was 12%, oily;

[0086] 1 1H NMR (400 MHz, CDCl3): δ = 6.56 (t, J = 4.0 Hz, 1H), 4.81 (s, 1H), 4.78 (s, 1H), 4.72 (s, 1H), 4.64 (s, 1H), 2.69 (dd, J = 9.6, 5.2 Hz, 1H), 2.64 - 2.54 (m, 3H), 2.50, (dd, J = 9.2, 4.8 Hz, 1H), 2.48 - 2.43 (m, 1H), 2.42 - 2.34 (m, 2H), 2.19 - 2.10 (m, 1H), 1.91 - 1.81 (m, 1H), 1.71 (s, 3H), 1.70 (s, 3H), 1.61 - 1.51 (m, 4H), 1.10 (d, J = 7.2 Hz, 3H) ppm.

[0087] 13C NMR (100MHz, CDCl3): δ=213.1,201.7,146.7,145.0,142.3,134.8,112.8,112 .0,50.3,46.9,42.5,42.0,40.3,35.3,28.0,27.0,21.5,21.1,16.1,11.9ppm.

[0088] ESI-HRMS (m / z): C 20 H 28 O2[M+H] + , 301.2162.

[0089]

[0090] The yield was 18%, white solid;

[0091] 1 H NMR (400MHz, CDCl3): δ = 6.80 (d, J = 5.3Hz, 1H), 4.97 (s, 1H), 4.83 (s, 1H), 4 .70(s,1H),4.62(s,1H),2.92-2.84(m,2H),2.61-2.50(m,2H),2.41-2.31( m,2H),2.22-2.14(m,2H),1.88-1.84(m,1H),1.82(s,3H),1.74-1.71(m,1 H), 1.70 (s, 3H), 1.64 (s, 3H), 1.34-1.23 (m, 1H), 1.14 (d, J = 6.4Hz, 3H) ppm.

[0092] 13 C NMR (100MHz, CDCl3): δ=212.1,201.5,147.4,145.0,144.7,136.8,112.5,110 .0,48.1,46.8,46.4,45.1,45.0,43.5,34.0,28.5,22.5,20.4,16.1,12.2ppm.

[0093] ESI-HRMS (m / z): C 20 H 28 O2[M+H] + , 301.2160.

[0094]

[0095] Yield: 15%, oily;

[0096] 1H NMR (400MHz, CDCl3): δ=6.71-6.67(m,1H),4.80(s,1H),4.79(t,J=3.6Hz,1H),4.76(s, 2H),3.32(dq,J=13.1,6.6Hz,1H),2.84-2.74(m,2H),2.59-2.51(m,3H),2.46-2.38(m, 1H),2.30-2.21(m,1H),1.97(ddd,J=13.5,10.9,5.2Hz,1H),1.79-1.76(m,1H),1.75(t ,J=1.2Hz,3H),1.67(s,3H),1.63(s,3H),1.62-1.60(m,1H),1.04(d,J=6.4Hz,3H)ppm.

[0097] 13 C NMR (100MHz, CDCl3): δ=213.7,201.5,147.1,144.8,143.5,136.3,114.5,112 .0,48.3,47.5,47.2,44.6,40.3,38.7,31.4,27.1,22.4,17.9,16.0,12.1ppm.

[0098] ESI-HRMS (m / z): C 20 H 28 O2[M+H] + , 301.2158.

[0099] Example 2 Synthesis of Compounds II-3 to II-5

[0100]

[0101] Step 1: L-carvone coupling reaction. Refer to the reaction in Example 1, and the obtained intermediate product is set aside;

[0102] Step 2: The intermediate product (1.0 g, 3.33 mmol) obtained in the first step was dissolved in methanol (10 mL), stirred at -10 ° C for 10 min, sodium borohydride (31.4 mg, 0.83 mmol, 0.25 equiv) was added, and the reaction was stirred for 30 minutes, and then the reaction was quenched with saturated ammonium chloride (10 mL), ethyl acetate (10 mL) was added to the reactant, the layers were separated, the aqueous layer was extracted with ethyl acetate (10 mL × 2), the organic layers were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by flash chromatography and separated (eluent and volume ratio: n-hexane: ethyl acetate = 20:1) to obtain compound II-3, compound II-4, compound II-5,

[0103]

[0104] Yield 15%, white solid.

[0105] 1 H NMR (400MHz, CDCl3): δ = 6.49 (dd, J = 3.2, 1.6Hz, 1H), 4.79 (t, J = 1.6Hz, 1H), 4.74 (s, 1H), 4.70 (s, 1H), 4.68 (t ,J=1.6Hz,1H),3.90(dt,J=10.4,4.4Hz,1H),2.82(dd,J=6.0,3.2Hz,1H),2.68(dd,J=10.0,3.6Hz,1H),2.60 -2.50(m,1H),2.40-2.39(m,1H),2.36-2.31(m,1H),2.28-2.18(m,1H),1.93-1.86(m,1H),1.77-1.73(m,1H) ,1.71(s,9H),1.59-1.52(m,1H),1.49-1.40(m,1H),1.24(dt,J=14.0,4.0Hz,1H),1.02(d,J=8.0Hz,3H)ppm.

[0106] 13 C NMR (100MHz, CDCl3): δ=202.0,149.7,145.9,141.3,134.9,112.4,108.9,69. 7,50.5,43.1,39.0,38.0,35.7,34.1,27.8,27.4,21.6,21.6,16.3,13.5ppm.

[0107] ESI-HRMS (m / z): C 20 H 30 O2[M+H] + , 303.2315.

[0108]

[0109] Yield: 25%, oil.

[0110] 1H NMR (400MHz, CDCl3): δ = 6.71 (dt, J = 5.6, 2.1Hz, 1H), 4.98 (s, 1H), 4.82 (s, 1H), 4.63 (t, J = 2.4Hz, 1H), 4.57 (s, 1H), 3.15-3.01(m,1H),2.91(d,J=5.7Hz,1H),2.84(dt,J=11.5,5.5Hz,1H),2.58(ddt,J=19.2,11.8,2.5Hz,1H),2.26( dt,J=19.2,4.8Hz,2H),1.99-1.93(m,1H),1.86(tt,J=12.1,3.1Hz,6H),1.77(dd,J=2.8,1.5Hz,1H),1.73(s,3H), 1.65-1.55(m,1H),1.44-1.35(m,2H),1.13(d,J=5.6Hz,3H),1.11-1.01(m,1H),0.81(dd,J=24.4,12.0Hz,1H)ppm.

[0111] 13 C NMR (100MHz, CDCl3): δ=202.1,149.1,145.1,144.6,136.7,112.1,108.9,75. 7,46.0,45.3,42.8,42.6,41.2,40.4,34.2,28.5,22.7,20.8,16.1,15.6ppm.

[0112] ESI-HRMS (m / z): C 20 H 30 O2[M+H] + ,303.2314.

[0113]

[0114] The yield was 18%, white solid;

[0115] 1H NMR (400MHz, CDCl3): δ = 6.63-6.59 (m, 1H), 4.79 (s, 2H), 4.76 (s, 2H), 2.81 (ddd, J = 11 .1,9.7,5.0Hz,1H),2.68(dd,J=11.2,3.2Hz,1H),2.45(t,J=4.8Hz,1H),2.42-2.32(m ,1H),2.25(dtd,J=18.4,5.4,1.5Hz,1H),2.19-2.08(m,2H),1.71(q,J=2.0Hz,2H),1. 67(s,6H),1.66-1.51(m,3H),1.40(tt,J=10.0,3.6Hz,1H),1.00(d,J=6.4Hz,3H)ppm.

[0116] 13 C NMR (100MHz, CDCl3): δ=201.6,147.3,145.5,142.6,136.1,113.9,110.3,72. 5,48.5,46.4,42.0,38.2,38.1,37.0,30.9,27.4,22.6,18.5,16.0,15.7ppm.

[0117] ESI-HRMS (m / z): C 20 H 30 O2[M+H] + , 303.2315.

[0118] Example 3 Synthesis of Compounds II-6 to II-9

[0119]

[0120] Step 1: L-carvone coupling reaction. Refer to the reaction in Example 1, and the obtained intermediate product is set aside;

[0121] Step 2: The intermediate product (1.0 g, 3.33 mmol) obtained in the first step was dissolved in methanol (10 mL), and hydroxylamine hydrochloride (254.3 mg, 3.66 mmol, 1.1 equiv) and sodium bicarbonate (409.3 mg, 4.99 mmol, 1.5 equiv) were added, and stirred at 70 ° C overnight, then cooled to room temperature, dichloromethane (15 mL) and water (15 mL) were added to the reactants, and the layers were separated. The aqueous phase was extracted with dichloromethane (15 mL × 2), and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated by flash chromatography (eluent and volume ratio: n-hexane: ethyl acetate = 1:1) to obtain compound II-6, compound II-7, compound II-8 and compound II-9.

[0122]

[0123] Yield 8%, white solid;

[0124] 1 H NMR (600MHz, DMSO-d6): δ = 10.41 (s, 1H), 6.61 (t, J = 4.0Hz, 1H), 4.72 (s, 1H), 4 .69(s,2H),4.60(s,1H),3.67(dd,J=13.6,7.4Hz,1H),2.88(d,J=3.6Hz,1H),2 .68(ddt,J=20.1,6.2,2.9Hz,1H),2.42-2.31(m,2H),2.27-2.24(m,1H),2.16- 2.06(m,2H),1.92(d,J=7.2Hz,1H),1.66-1.59(m,10H),1.13-1.06(m,4H)ppm.

[0125] 13 C NMR (150MHz, DMSO-d6): δ=201.0,159.0,148.5,146.1,142.2,133.3,111.1,10 9.1,51.3,41.9,39.5,39.1,31.8,28.5,28.1,26.3,21.7,20.6,16.5,15.8ppm.

[0126] ESI-HRMS (m / z): C 20 H 29 NO2[M+H] + , 316.2269.

[0127]

[0128] Yield 20%, white solid;

[0129] 1H NMR (600MHz, DMSO-d6): δ = 10.41 (s, 1H), 6.61 (t, J = 4.0Hz, 1H), 4.72 (s, 1H), 4.69(s,2H),4.60(s,1H),3.67(q,J=4.8Hz,1H),2.88(d,J=3.6Hz,1H),2.68 (ddt,J=20.1,6.2,2.9Hz,1H),2.42-2.31(m,2H),2.27-2.24(m,1H),2.16-2 .06(m,2H),1.92(d,J=7.2Hz,1H),1.66-1.59(m,10H),1.13-1.06(m,4H)ppm.

[0130] 13 C NMR (150MHz, DMSO-d6): δ=201.0,159.0,148.5,146.1,142.2,133.3,111.1,10 9.1,51.3,41.9,39.5,39.1,31.8,28.5,28.1,26.3,21.7,20.6,16.5,15.8ppm.

[0131] ESI-HRMS (m / z): C 20 H 29 NO2[M+H] + :316.2271.

[0132]

[0133] Yield 9%, white solid;

[0134] 1H NMR (600MHz, DMSO-d6): δ=10.43(s,1H),6.90-6.80(m,1H),4.97(s,1H),4.88(s,1H),4.67(s,1H),4.63(s,1 H),3.19(dq,J=13.2,1.8Hz,1H),2.90-2.85(m,2H),2.65-2.53(m,1H),2.28(d,J=19.8,4.8Hz,1H),2.20(dq, J=12.9,6.5Hz,1H),1.80(tt,J=12.0,4.8Hz,1H),1.75-1.73(m,1H),1.71(s,3H),1.70(s,3H),1.62(s,3H),1 .43(td,J=11.8,3.9Hz,1H),1.37(t,J=12.6Hz,1H),1.12(d,J=6.6Hz,3H),0.92(dd,J=24.6,12.3Hz,1H)ppm.

[0135] 13 C NMR (150MHz, DMSO-d6): δ=200.8,159.3,148.3,145.3,144.9,135.4,112.1,109. 4,45.8,44.2,43.4,43.3,39.6,34.0,28.7,27.9,22.2,20.4,15.7,14.0ppm.

[0136] ESI-HRMS (m / z): C 20 H 29 NO2[M+H] + :316.2272.

[0137]

[0138] Yield 12%, white solid;

[0139] 1H NMR (600MHz, DMSO-d6): δ = 10.39 (s, 1H), 6.80 (s, 1H), 4.83 (s, 2H), 4.71 (s, 1H), 4.70 (t, J = 1.8Hz, 1 H),3.24-3.21(m,1H),2.87(td,J=9.6,5.4Hz,1H),2.52(d,J=11.4Hz,1H),2.49-2.47(m,1H),2.44 -2.37(m,1H),2.26(dt,J=18.6,4.8Hz,1H),1.91-1.84(m,2H),1.68(s,9H),1.77(m,1H),1.44(t,J=12.6Hz,1H),0.95(d,J=6.6Hz,3H)ppm.

[0140] 13 C NMR (150MHz, DMSO-d6): δ=199.7,159.6,148.5,147.0,144.4,134.5,113.4,10 9.5,51.2,45.6,44.6,43.9,38.0,35.5,30.7,28.9,20.2,19.2,15.9,14.9ppm.

[0141] ESI-HRMS (m / z): C 20 H 29 NO2[M+H] + ,316.2268.

[0142] Example 4 Synthesis of Compound II-10 to Compound II-11

[0143]

[0144] Step 1: L-carvone coupling reaction. Refer to the reaction in Example 1, and the obtained intermediate product is set aside;

[0145] Step 2: The intermediate product (1.0 g, 3.33 mmol) obtained in the first step, sodium cyanoborocyanide (251.1 mg, 3.99 mmol, 1.2 equiv), and ammonium acetate (385.0 mg, 4.99 mmol, 1.5 equiv) were added to a mixed solution of methanol: acetonitrile (volume ratio of 5:1, 10 mL) and stirred at room temperature for 72 hours. After the reaction was completed, dichloromethane (15 mL) and saturated ammonium chloride (15 mL) were added to the reactants, and the organic layer was separated. The aqueous phase was extracted with dichloromethane (15 mL × 2), and the organic layers were combined, washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by flash chromatography (eluent and volume ratio: n-hexane: ethyl acetate: triethylamine = 1:1:0.01) to separate compound II-10 and compound II-11:

[0146]

[0147] Yield 10%, oily;

[0148] 1 H NMR (400MHz, CDCl3): δ = 6.72 (td, J = 3.0, 1.6Hz, 1H), 4.80 (s, 1H), 4.70-4.66 (m, 3H), 3.05 (d, J = 11 .6Hz,1H),2.82(d,J=6.0Hz,1H),2.75(dd,J=10.9,1.9Hz,1H),2.66-2.56(m,1H),2.44-2.31(m,2H ),2.09(t,J=6.4Hz,1H),1.94-1.86(m,1H),1.75-1.70(m,9H),1.63(dd,J=12.8,4.4Hz,1H),1.40 (dd,J=13.9,4.6Hz,1H),1.31(d,J=12.2Hz,1H),1.19(d,J=14.2Hz,1H),1.02(d,J=6.8Hz,3H)ppm.

[0149] 13 C NMR (100MHz, CDCl3): δ=202.0,149.8,146.0,140.8,134.7,111.9,108.5, 50.6,48.5,42.4,40.1,38.4,35.4,27.8,26.7,22.3,21.3,16.3,13.0ppm.

[0150] ESI-HRMS (m / z): C 20 H 31 NO[M+H] +,302.2478.

[0151]

[0152] Yield 15%, oily;

[0153] 1 H NMR (600MHz, CDCl3): δ = 6.68, (td, J = 4.2, 1.2Hz, 1H), 4.83 (t, J = 1.8Hz, 1H), 4.81 (s, 1H), 4. 67(s,2H),3.06(s,1H),2.86(dt,J=9.6,6.6Hz,1H),2.35-2.31(m,3H),2.23(tt,J=12.6,3. 0Hz,1H),2.06(tt,J=12.0,2.4Hz,1H),1.88(s,1H),1.78(d,J=7.2Hz,1H),1.76-1.73(m,3H ), 1.71 (s, 3H), 1.68 (s, 3H), 1.64-1.58 (m, 1H), 1.50-1.42 (m, 2H), 0.89 (d, J = 6.6Hz, 3H) ppm. 13 C NMR (150MHz, CDCl3): δ=201.4,150.2,147.5,143.4,136.2,113.5,108.7, 53.1,51.9,45.6,39.4,39.0,37.8,36.9,31.4,21.0,19.7,17.8,16.3ppm.

[0154] ESI-HRMS (m / z): C 20 H 31 NO[M+H] + ,302.2474.

[0155] Example 5 Synthesis of Compound III-1

[0156] The mixture of compound II-3, compound II-4 and compound II-5 prepared in Example 2 (400.0 mg, 1.32 mmol) was dissolved in CHCl3 (10 mL), p-toluenesulfonic acid (44.8 mg, 0.26 mmol, 0.2 equiv) was added at 0°C, the reaction was stirred for 120 minutes, water (10 mL) was added to quench the reaction, and dichloromethane (10 mL) was added to separate the organic layer, the aqueous layer was extracted with dichloromethane (10 mL×2), the organic phases were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography, the eluent volume ratio was: n-hexane: ethyl acetate = 100: 1, to obtain compound III-1, yield: 56%, oily.

[0157]

[0158] 1 H NMR (400MHz, CDCl3): δ = 6.65 (ddd, J = 6.1, 2.4, 1.3, 1H), 4.87 (d, J = 2.0Hz, 1H), 4.83 (t, J = 1.6Hz, 1H), 4.00 (dd,J=6.4,1.2Hz,1H),2.80(ddd,J=13.2,11.3,4.5Hz,1H),2.51(dd,J=13.2,2.0Hz,1H),2.48-2.40(m,1H ),2.32-2.17(m,3H),1.91(d,J=11.3Hz,1H),1.89-1.85(m,1H),1.74(dt,J=2.8,1.2Hz,3H),1.71,(dd,J= 1.4,0.7Hz,3H),1.66-1.59(m,1H),1.54-1.43(m,2H),1.21(s,3H),1.15(s,3H),0.88(d,J=6.4Hz,3H)ppm.

[0159] 13 C NMR (100MHz, CDCl3): δ=201.8,145.8,143.0,136.4,114.2,81.7,81.4,49.2 ,47.9,42.9,39.0,37.0,36.3,31.9,30.3,26.8,22.9,18.2,17.3,16.2ppm.

[0160] ESI-HRMS (m / z): C 20 H 30 O2[M+H] + , 303.2315.

[0161] Example 6 Synthesis of Compound III-2

[0162] The compound III-1 (300.0 mg, 0.99 mmol) prepared in Example 5 was dissolved in CH2Cl2 (5 mL), stirred at 0°C, and N-chlorosuccinimide (NCS, 145.5 mg, 1.09 mmol) was added in batches. The resulting mixture was stirred at 0°C for 2 hours. Dichloromethane (10 mL) and water (10 mL) were added to the reaction system, the organic layer was separated, the aqueous layer was extracted with dichloromethane (10 mL×2), the organic layers were combined, washed with brine (20 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and the residue was purified by flash chromatography, the eluent volume ratio was: ethyl acetate: petroleum ether = 1:50, and compound III-2 was obtained, with a yield of 40%, in the form of an oil.

[0163]

[0164] 1 H NMR (600MHz, CDCl3): δ = 6.67 (dt, J = 6.0, 1.8Hz, 1H), 4.98 (s, 1H), 4.90 (t, J = 1.8Hz, 1H), 4.11 (dd, J = 6.6, 1.2Hz, 1H), 3. 65(dd,J=10.8,1.2Hz,1H),3.43(d,J=10.8Hz,1H),2.82(ddd,J=13.3,11.4,4.5Hz,1H),2.51(dd,J=13.2,2.4Hz,1H),2 .51-2.43(m,1H),2.34-2.21(m,3H),2.14(q,J=3.6Hz,1H),1.97(d,J=11.4Hz,1H),1.80-1.77(m,1H),1.74(dt,J=2.6, 1.3Hz,3H),1.73(s,3H),1.50(ddd,J=13.1,11.6,3.6Hz,1H),1.46-1.41(m,1H),1.31(s,3H),0.88(d,J=6.6Hz,3H)ppm.

[0165] 13 C NMR (150MHz, CDCl3): δ=201.6,145.8,143.3,136.3,114.4,84.1,82.7,48.8 ,48.1,47.9,41.2,38.7,37.5,36.0,31.6,25.8,25.7,18.1,17.2,16.1ppm.

[0166] ESI-HRMS (m / z): C 20 H 29 ClO2[M+H] + , 337.1927.

[0167] Example 7 Synthesis of Compound III-3

[0168] By replacing N-chlorosuccinimide in Example 6 with N-bromosuccinimide and keeping other conditions unchanged, compound III-3 can be prepared with a yield of 45% in the form of an oil.

[0169]

[0170] 1 H NMR (600MHz, CDCl3): δ=6.68-6.66(m,1H),5.0(s,1H),4.90(t,J=1.2Hz,1H),4.14(d,J=6.6,1.8Hz,1H),3.52( d,J=10.2Hz,1H),3.33(d,J=9.6Hz,1H),2.83(ddd,J=13.3,11.5,4.4Hz,1H),2.50(dd,J=13.3,1.8Hz,1H),2.51 -2.44(m,1H),2.35-2.21(m,3H),2.16(q,J=3.0Hz,1H),1.97(q,J=11.4Hz,1H),1.83-1.78(m,1H),1.74(t,J=2 .4Hz,3H),1.73(s,3H),1.50(td,J=11.4,3.6Hz,1H),1.47-1.42(m,1H),1.36(s,3H),0.88(d,J=6.6Hz,3H)ppm.

[0171] 13 C NMR (150MHz, CDCl3): δ=201.6,145.8,143.3,136.3,114.5,83.6,83.0,48.7 ,47.9,41.5,38.7,37.6,37.3,36.1,31.6,26.3,25.8,18.1,17.2,16.1ppm.

[0172] ESI-HRMS (m / z): C 20 H 29 BrO2[M+H] + , 381.1423.

[0173] Example 8 Biological Experiment

[0174] Experimental steps:

[0175] (1) Culture and plating of cardiomyocytes: Human AC16 cardiomyocyte cell line (cell source: purchased from Wuhan Shane Biotechnology Co., Ltd., cell number SNL-483) uses 1% Penicillin-Streptomycin, 15% FBS high-glucose DMEM culture medium and is cultured in a 37°C carbon dioxide cell culture incubator with 95% O2 and 5% CO2. When the cell fusion reaches 80-90%, the cells are passaged and digested with 0.25% trypsin digestion solution for 1-2 minutes. After the cells are observed to become round and bright under the microscope, the trypsin is sucked out with a 1mL range pipette tip, and the pipette tip is immediately changed to absorb the DMEM culture medium containing FBS, and the cells are gently blown to make a cell suspension. The cells are then passaged at a subculture ratio of 1:3; some cells are subcultured at a ratio of 4*10 4 Density plated into 96-well plates for growth.

[0176] (2) Construction of hypoxia-reoxygenation (H / R) model: The H / R model was constructed according to the conventional methods reported in references 1 and 2, laboratory experience, and actual conditions. When the cell density of the 96-well plate reached 70-80%, the cells were washed twice with PBS, replaced with sugar-free and serum-free culture medium, and placed in a hypoxic environment (1% O2, 94% N2, 5% CO2) for 4 h of hypoxia, and then replaced with conventional DMEM culture medium (containing sugar and serum) (95% O2, 5% CO2) for reoxygenation for 2 h;

[0177] (3) Treatment with the compounds of the present invention: This experiment adopted a full-course drug addition treatment (prevention + treatment): after the cells in the 96-well plate adhered for 6-7 hours, the compounds of the present invention prepared in advance were added at a certain working concentration for pretreatment for 16-17 hours, followed by hypoxia-reoxygenation treatment (during which the compounds of the present invention were always used for treatment);

[0178] (4) CCK-8 cell activity assay: After the end of hypoxia and reoxygenation, the cells were washed once with PBS, 100 μl (containing 10 μl CCK-8) solution was added to all wells, and the cells were incubated in a carbon dioxide cell culture incubator for 2.5 h. The 450 nm light absorption value (OD value) was measured using an ELISA reader. The CCK-8 kit was purchased from MCE, catalog number HY-K0301.

[0179] References:

[0180] 1. Liu Q, Wang J, Liang Q, et al. Sparstolonin B attenuates hypoxia-reoxygenation-induced cardiomyocyte inflammation. Exp Biol Med (Maywood). 2014; 239(3):376-384.1550.

[0181] 2. Sun MY, Ma DS, Zhao S, et al. Salidroside mitigates hypoxia / reoxygenation injury by alleviating endoplasmic reticulum stress-induced apoptosis in H9c2 cardiomyocytes. Mol Med Rep. 2018; 18(4): 3760-3768.

[0182] Table 1: OD values ​​of the compounds of the present invention on myocardial cells

[0183]

[0184] Table 1 shows that AC16 cells under normal culture conditions, after being treated with the compounds of the present invention, showed enhanced cell activity (cell activity was measured by CCK-8 method); compared with Blank control (%), * P<0.05, ** P<0.01, *** P < 0.001, **** P<0.0001, N=5, one-way ANOVA.

[0185] Table 2: OD values ​​of the compounds of the present invention on the activity of myocardial cells after hypoxia-reoxygenation treatment

[0186]

[0187] Compared with the Blank control group (percentage), the cell activity in the H / R group was significantly decreased, indicating that the hypoxia-reoxygenation injury model was successfully established.

[0188] Table 2 shows that after AC16 cells were treated with the compounds of the present invention under hypoxia-reoxygenation conditions, compared with the H / R group (%), the compounds II-10 and II-11 of the present invention showed a protective effect on cell hypoxia-reoxygenation injury (cell activity was enhanced); #### P<0.0001vs.Blank control, * P<0.05, ** P<0.01 vs. H / R, N=5, one-wayANOVA.

[0189] The above experimental conclusions indicate that the compounds of the present invention have therapeutic effects on diseases related to myocardial cell damage.

Claims

1. A compound represented by formula I or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof: in: Ring A is selected from 6-9 membered cycloalkyl or 7-9 membered oxacyclic group; R 1 Independently selected from =O, -OH, -NH2, =N-OH, C1-C6 alkyl, C2-C6 alkenyl, wherein the C1-C6 alkyl is optionally further substituted by one or more halogen atoms; n is 1, 2, 3 or 4; and, The compounds of formula I do not include 2. The compound according to claim 1 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is a compound or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof represented by formula II: in, R 2 Independently selected from =O, -OH, -NH2, =N-OH, C1-C6 alkyl, C2-C6 alkenyl, wherein the C1-C6 alkyl is optionally further substituted by one or more halogen atoms; m is 1, 2 or 3.

3. The compound according to claim 2, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is a compound or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof represented by formula II-a: in, R 2 Selected from =O, -OH, -NH2, =N-OH or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally further substituted by one or more atoms selected from F, Cl, Br.

4. The compound according to claim 1 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is a compound represented by formula III or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof: in, X is selected from -O-; R 3 Independently selected from =O, -OH, -NH2, =N-OH, C1-C6 alkyl, C2-C6 alkenyl, wherein the C1-C6 alkyl is optionally further substituted by one or more halogen atoms; p is 1, 2 or 3.

5. The compound according to claim 4, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is a compound represented by formula III-a, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: in, R 4 The C1-C6 alkyl group is optionally further substituted by one or more atoms selected from Cl, Br or I.

6. The compound according to claim 1 or its stereoisomer, tautomer or pharmaceutically acceptable salt, wherein the specific structure of the compound comprises:

7. A pharmaceutical composition comprising an effective dose of the compound according to any one of claims 1 to 6 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

8. Use of the compound according to any one of claims 1 to 6 or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to claim 7 in the preparation of a medicament for treating cardiovascular diseases, wherein the cardiovascular diseases are selected from myocardial hypertrophy, myocardial ischemia, coronary artery syndrome, angina pectoris, myocardial infarction and heart failure.

9. A pharmaceutical composition comprising an effective dose of a compound of formula (1) or (2) and at least one pharmaceutically acceptable carrier or excipient, 10. Use of the pharmaceutical composition according to claim 9 in the preparation of a drug for treating cardiovascular diseases, wherein the cardiovascular diseases are selected from the group consisting of myocardial hypertrophy, myocardial ischemia, coronary artery syndrome, angina pectoris, myocardial infarction, and heart failure.

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