A compound containing an anthraquinone ring parent nucleus, its preparation method and application

Abstract

The application discloses a compound containing an anthraquinone ring mother nucleus, a preparation method and application thereof, and a structural general formula (I) and (II) are as follows: The compound containing the anthraquinone ring mother nucleus has better proteasome agonist activity and good myocardial hypoxia protection activity. The compound provided by the application has the advantages of easy availability of a synthesis raw material, simple synthesis route, mild reaction condition, high yield of each step and simple operation.

Description

Technical Field

[0001] This invention relates to the field of pharmaceuticals, and more specifically, to a new class of anthraquinone-containing cyclic core compounds, their preparation methods and applications, as well as the application of said compounds in the preparation of drugs for treating cardiovascular diseases. Background Technology

[0002] Maintaining protein homeostasis has been proven to be a key factor in cellular health. Protein homeostasis is achieved through the precise coordination of cellular activities by a protein homeostasis system, which consists of protein synthesis mechanisms, protein folding and modification, and two protein hydrolysis systems. Approximately 80% of proteins in the body are degraded via the proteasome; therefore, maintaining stable proteasome levels is crucial for overall health.

[0003] The proteasome is a giant protein complex in the body that plays a vital role in degrading misfolded, unwanted, or damaged proteins within cells and maintaining intracellular protein homeostasis. Studies have confirmed a close link between proteasome dysfunction and various diseases, including cancer, cardiovascular disease, immune diseases, and neurodegenerative diseases, thus making it a promising ideal drug target.

[0004] Although research on proteasome agonists has made steady progress in recent years, and many potential structures with development value have been discovered, the field still faces significant challenges. For example, currently reported agonists have simple structures, unclear structure-activity relationships, and poor activity. Efficacy studies on agonists are limited, mostly remaining at the molecular level. Research on pathogenic IDPs mainly focuses on neurodegenerative disease-related proteins such as Aβ and tau, while research on cardiovascular diseases caused by hypoxia-induced damage is scarce. Furthermore, current cardiovascular drug development primarily revolves around the development of targeted drugs and new drug targets. Proteasome agonists, as novel mechanisms, can compensate for the shortcomings of existing drugs and have broad research value. Summary of the Invention

[0005] To address the shortcomings of existing technologies, the technical problem this invention aims to solve is to design and synthesize a novel class of small-molecule 20S proteasome agonists, and to evaluate the proteasome agonist activity and hypoxia protective activity of these compounds. The results show that these compounds possess good proteasome agonist activity and hypoxia protective activity, and as a novel class of small-molecule 20S proteasome agonists, they hold promise as an effective option for the clinical treatment of cardiovascular diseases.

[0006] Terminology definition:

[0007] As used in this invention, the term "aryl" refers to a monocyclic or fused polycyclic group with 5-12 carbon atoms, possessing a fully conjugated π-electron system. Non-limiting examples of aromatic rings include benzene and naphthalene rings. Aromatic rings can be substituted or unsubstituted. Substituents in aromatic rings are selected from halogens, nitro groups, and C6 groups. 1-4 Alkyl, C 1-4 Alkyl group.

[0008] As used in this invention, the term "heterocyclic aryl" refers to an unsaturated carbon ring with 5-6 ring atoms, wherein one or more carbon atoms are replaced by heteroatoms such as oxygen, nitrogen, sulfur, etc. Specific heterocyclic aryl groups can be: pyridinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, and isoxazolyl, etc.

[0009] The term "heterocyclic group" as used in this invention refers to a monocyclic group having 4-6 ring atoms, wherein at least one or two ring atoms are selected from nitrogen, oxygen, and sulfur heteroatoms, and the remaining ring atoms are carbon atoms. Specific heterocyclic groups can be piperidinyl, piperazine, pyrrolidinyl, tetrahydropyranyl, oxocyclic butyl, etc.

[0010] The term "alkoxy group" as used in this invention refers to an -O-alkyl group. Specific alkoxy groups can be methoxy, ethoxy, tert-butoxy, etc.

[0011] As used in this invention, the term "heteroatom" refers to an atom composed of elements other than carbon. Specific heteroatoms can be nitrogen (N), sulfur (S), oxygen (O), etc.

[0012] As used in this invention, the term "hydrophilic group" refers to an atomic group that is soluble in water or readily affinity for water. Specific hydrophilic groups can be carboxylic acid groups, sulfonic acid groups, phosphate groups, amino groups, quaternary ammonium groups, ether bonds, and hydroxyl groups, etc.

[0013] The purpose of this invention is to provide a compound having the general formula (Ⅰ):

[0014]

[0015] in:

[0016] R1 is selected from aryl, heterocyclic aryl, alkyl, cycloalkyl-substituted amino groups, or amino groups substituted with C. 1-4 Alkyl, C 1-4 Amino groups that are substituted with alkoxy, aralkyl, or heterocyclic aryl groups in any way;

[0017] R2 is selected from C 1-6 Alkyl or cycloalkyl-substituted amino groups;

[0018] X is selected from heteroatoms.

[0019] Preferably, R1 is selected from amino groups substituted with phenyl, pyridyl, piperidinyl, or cyclopropyl, or amino groups substituted with p-tolyl, o-tolyl, m-tolyl, p-methoxyphenyl, p-morpholinephenyl, or p-methylpiperazinephenyl.

[0020] R2 is selected from amino groups substituted with propyl, isobutyl, hydroxyethyl, 2-morpholinoethyl, or isobutyl (methyl);

[0021] X is selected from oxygen.

[0022] Furthermore, the preparation method of the compound represented by general formula (Ⅰ) includes the following: using 1-amino-2,4-dibromoanthraquinone as a raw material, cyclization with sodium nitrite, concentrated sulfuric acid, and sodium azide yields 3,5-dibromo-6-anthraphen[1,9-cd]isoxazole-6-one intermediate; after substitution reaction of R1 in the intermediate with AlCl3, substitution of R2 with the corresponding amine finally yields, for example, compounds A1-A11.

[0023]

[0024] More specifically, the preferred compounds of the present invention having the general formula (I) structure are:

[0025] 3-(isobutylamino)-5-(m-toluamino)-6H-anthra[1,9-cd]isoxazole-6-one (A1);

[0026] 3-(isobutylamino)-5-(p-toluamino)-6H-anthra[1,9-cd]isoxazol-6-one (A2);

[0027] 3-(isobutylamino)-5-(o-tolylamino)-6H-anthra[1,9-cd]isoxazol-6-one (A3);

[0028] 3-(isobutylamino)-5-(p-methoxyphenylamino)-6H-anthra[1,9-cd]isoxazol-6-one (A4);

[0029] 3-(isobutylamino)-5-((4-morpholinophenyl)amino)-6H-anthra[1,9-cd]isoxazol-6-one (A5);

[0030] 3,5-Di(piperidin-1-yl)-6H-anthra[1,9-cd]isoxazol-6-one (A6);

[0031] 3-(isobutylamino)-5-(cyclopropylamino)-6H-anthra[1,9-cd]isoxazole-6-one (A7);

[0032] 3-((2-hydroxyethyl)amino)-5-(m-toluidine)-6H-anthracite[1,9-cd]isoxazole-6-one (A8);

[0033] 3-((2-morpholinoethyl)amino)-5-(m-toluidine)-6H-anthracite[1,9-cd]isoxazol-6-one (A9);

[0034] 3-(isobutyl(methyl)amino)-5-(m-toluidine)-6H-anthracite[1,9-cd]isoxazol-6-one (A10);

[0035] 3-(propylamino)-5-(m-toluamino)-6H-anthra[1,9-cd]isoxazole-6-one (A11).

[0036] Another object of the present invention is to provide a compound having the general formula (II):

[0037]

[0038] Wherein: Z is selected from O, NH, NHR, CO, CONH, NHCO;

[0039] R3 is selected from aryl, heterocyclic aryl, alkyl, heteroalkyl, heterocyclic alkyl, or aryl or heterocyclic aryl that is substituted by any of the following: cycloalkyl, C1-4 alkyl, or C1-4 alkoxy.

[0040] R4 is selected from hydrophilic groups containing heteroatoms that are substituted at any position on the hydrogen or benzene ring;

[0041] Y is selected from hydrophilic groups containing heteroatoms.

[0042] Preferably, Z is selected from NH, CO, and CONH;

[0043] R3 is selected from p-tolyl, 4-methoxyphenyl, m-tolyl, isobutyl, 4-morpholinophenyl, 4-(4-methylpiperazin-1-yl)phenyl, 2-morpholinoethyl, 4-phenylpiperidine, N-methylphenylethyl, 1,2,3,4-tetrahydroisoquinoline, thiazolyl-2-ylpiperazine, and 4-benzylpiperazine.

[0044] R4 is selected from hydrogen or hydroxyl groups;

[0045] Y is selected from hydroxyl or amino groups;

[0046] In this case, the positions of Y and R4 can be interchanged, and Z-R3 are located at any position on the same benzene ring as Y, and the number can be 1-2.

[0047] Furthermore, the preparation method of the compound represented by general formula (II) includes the following:

[0048] There are two methods. The first method involves ring-opening reactions of A2 and A4 with hydrazine hydrate and target carbon to obtain the corresponding A12 and A13. The second method involves condensing rhein and the corresponding amine with HATU and DIPEA to obtain compounds such as A14-A24.

[0049] More specifically, the preferred compounds of the present invention having the general formula (II) structure are:

[0050] 1-Amino-2-(isobutylamino)-4-(p-toluamino)anthracene-9,10-dione (A12);

[0051] 1-Amino-2-(isobutylamino)-4-((4-methoxyphenyl)amino)anthracene-9,10-dione (A13);

[0052] 4,5-Dihydroxy-9,10-dioxo-N-(m-tolyl)-9,10-dihydroanthracene-2-carboxamide (A14);

[0053] 4,5-Dihydroxy-N-isobutyl-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide (A15);

[0054] 4,5-Dihydroxy-N-(4-methoxyphenyl)-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide (A16);

[0055] 4,5-Dihydroxy-N-(4-morpholinophenyl)-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide (A17);

[0056] 4,5-Dihydroxy-N-(4-(4-methylpiperazin-1-yl)phenyl)-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide (A18);

[0057] 4,5-Dihydroxy-N-(2-morpholinoethyl)-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide (A19);

[0058] 1,8-Dihydroxy-3-(4-phenylpiperidin-1-carbonyl)anthracene-9,10-dione (A20);

[0059] 4,5-Dihydroxy-N-methyl-9,10-dioxo-N-phenylethyl-9,10-dihydroanthracene-2-carboxamide (A21);

[0060] 1,8-Dihydroxy-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)anthracene-9,10-dione (A22);

[0061] 1,8-Dihydroxy-3-(4-(thiazolyl-2-yl)piperazin-1-carbonyl)anthracene-9,10-dione (A23);

[0062] 3-(4-Benzylpiperazine-1-carbonyl)-1,8-dihydroxyanthracene-9,10-dione (A24).

[0063] Another object of the present invention is to provide a pharmaceutical composition comprising at least one compound in any of the forms described above, wherein a stereoisomer of the compound or a pharmaceutically acceptable salt thereof is an active component, and comprising one or more pharmaceutically acceptable carriers or excipients.

[0064] The pharmaceutical composition described in this invention can be formulated into various pharmaceutical dosage forms, such as oral, injection, inhalation, and implantation. Injection and oral administration are preferred, for example, injections, lyophilized powder injections, tablets, capsules, or granules.

[0065] The pharmaceutical compositions of the present invention and various formulations thereof can be prepared using conventional pharmaceutical carriers.

[0066] Another object of the present invention is to provide the pharmaceutical use of compounds of general formula (I) and (II) or pharmaceutical compositions containing said compounds. Specifically, the present invention provides the use of compounds of general formula (I) and (II) or pharmaceutical compositions containing said compounds in the preparation of proteasome agonists, and also provides their use in the preparation of medicaments for treating cardiovascular diseases.

[0067] Furthermore, the cardiovascular diseases mentioned are selected from ischemic heart disease, stroke, cardiomyopathy, rheumatic heart disease, hypertensive heart disease, endocarditis, arrhythmia, aortic disease, peripheral artery disease, and other cardiovascular and circulatory system diseases.

[0068] Experiments have demonstrated that the anthraquinone-containing ring-based compound of this invention possesses excellent proteasome agonist activity and protects cells from hypoxia-induced damage. The raw materials required for the synthesis of this compound are readily available, the route is rationally designed, the reaction conditions are mild, the yields at each step are high, the operation is simple, and it is suitable for industrial production. Attached Figure Description

[0069] Figures 1(a) to 1(h) This is a graph showing the test results of the hypoxic myocardial protective activity of different anthraquinone-containing ring-based compounds in this invention. Detailed Implementation

[0070] The present invention will be further described in conjunction with the embodiments. The following embodiments are only illustrative of the present invention and are not intended to limit the present invention in any way.

[0071] Example A1 Preparation of 3-(isobutylamino)-5-(m-toluamino)-6H-anthra[1,9-cd]isoxazole-6-one

[0072]

[0073] Concentrated sulfuric acid (5 mL) was heated at 30-40 °C for 10 min, and then NaNO2 (199 mg, 1.1 eq) was added and stirred for 30 min. Compound 1 (1 g, 1.0 eq) was gradually added, and the mixture was stirred overnight at 50-55 °C. After the reaction was complete by TLC, the reaction system was poured directly into ice water, filtered, and the solid was washed successively with ice water and a 1:1 mixture of ethanol and diethyl ether to obtain a yellow solid. NaN3 (273 mg, 1.6 eq) was dissolved in water, and the yellow solid was added and stirred overnight at room temperature. After the reaction was complete by TLC, the mixture was filtered, and the solid was washed successively with water and a 9:1 mixture of acetone and water to obtain a yellow solid. The yellow solid was placed in toluene (10 mL) and stirred overnight at 70 °C. After the reaction was complete by TLC, the reaction system was cooled to room temperature, filtered, and the solid was washed with diethyl ether to obtain yellow solid 2 (yield 32.4%). 1H NMR (400MHz, DMSO) δ8.29(d,J=5.6Hz,2H),8.16(d,J=7.6Hz,1H),7.93(t,J=7.6Hz,1H),7.81(t,J=7.6Hz,1H).

[0074] m-Toluene (423.5 mg, 3.0 eq) was dissolved in nitrobenzene (3 mL). AlCl3 (439.5 mg, 2.5 eq) was added under vigorous stirring. After 5 min, compound 2 (500 mg, 1.0 eq) was added, and the mixture was stirred at room temperature for 3 h. After the reaction was complete by TLC, the reaction system was added dropwise to water, and a solid precipitated. The precipitate was filtered. The solid was recrystallized from toluene to give red solid 3 (yield 65.2%). 1 H NMR (500MHz, DMSO) δ11.30(s,1H),8.39(d,J=8.0Hz,1H),8.14(d,J=7.6Hz,1H),7.89(t,J=7.6Hz,1H),7.74(t ,J=7.6Hz,1H),7.68(s,1H),7.44(t,J=8.0Hz,1H),7.33(d,J=6.0Hz,2H),7.21(d,J=7.6Hz,1H),2.39(s,3H).

[0075] Compound 3 (207.8 mg, 1.0 eq) and isobutylamine (94.0 mg, 2.5 eq) were dissolved in acetonitrile and reacted at 70–80 °C for 3 h. After the reaction was complete by TLC, the reaction system was cooled to room temperature and then stirred at -15 °C for 1 h, resulting in the precipitation of a solid. The solid was filtered and washed with cold acetonitrile to give a red solid A1 (yield 54.7%). 1H NMR (400MHz, DMSO) δ11.73 (s, 1H), 8.69 (s, 1H), 8.46 (d, J = 8.0Hz, 1H), 8.15 (d, J=7.6Hz,1H),7.81(t,J=7.4Hz,1H),7.68(t,J=7.6Hz,1H),7.40(t,J=7.6Hz,1H ),7.27(d,J=8.0Hz,2H),7.13(d,J=7.2Hz,1H),6.12(s,1H),3.17-2.87(m,2H) ,2.38(s,3H),2.08-1.89(m,1H),0.94(d,J=6.0Hz,6H).HRMS(ESI)calcd.for[C 25 H 24 N3O2] + ([M+H)) + ):m / z 398.1863,found:398.1859.

[0076] Examples A2 to A11 were synthesized using similar procedures to Example A1, with corresponding reagents.

[0077] Example A2

[0078]

[0079] This example uses a similar operation to Example A1, except that p-methylaniline is used instead of m-methylaniline.

[0080] 1 H NMR (400MHz, DMSO) δ11.70(s,1H),8.63(s,1H),8.48(d,J=8.0Hz,1H),8.17(d,J=7.6Hz,1H),7.82(t,J=7.2Hz,1H),7.70(t,J=7.6Hz,1H),7.37(d, J=8.0Hz,2H),7.33(d,J=8.0Hz,2H),6.09(s,1H),3.13-2.92(m,2H),2.37(s,3H),2.07-1.88(m,1H),0.93(d,J=6.4Hz,6H).HRMS(ESI)calcd.for[C 25 H 24N3O2] + ([M+H)) + ):m / z 398.1863,found:398.1865. Example A3

[0081]

[0082] This example uses a similar operation to Example A1, except that o-methylaniline is used instead of m-methylaniline.

[0083] 1 H NMR (400MHz, DMSO) δ11.63(s,1H),8.67(s,1H),8.50(d,J=7.6Hz,1H),8.19(d,J=7 .6Hz,1H),7.83(t,J=7.2Hz,1H),7.70(t,J=7.6Hz,1H),7.52(d,J=7.2Hz,1H),7.4 4(d,J=7.2Hz,1H),7.37(t,J=7.6Hz,1H),7.28(t,J=7.2Hz,1H),5.84(s,1H),3.07 -2.84(s,2H),2.35(s,3H),2.00-1.86(s,1H),0.90(m,6H).HRMS(ESI)calcd.for[C 25 H 24 N3O2] + ([M+H)) + ):m / z 398.1863,found:398.1868.

[0084] Example A4

[0085]

[0086] This example uses a similar operation to Example A1, except that p-methoxyaniline is used instead of m-methylaniline.

[0087] 1 H NMR (400MHz, CF3COOD) δ8.60(d,J=8.0Hz,2H),8.13(t,J=7.6Hz,1H),8.05(t,J=7.6Hz,1H),7.53(d,J=8.4Hz,2H),7.31(d,J =8.4Hz,2H),4.09(s,3H),3.32(d,J=3.6Hz,2H),2.17(dd,J=13.6,6.8Hz,1H),1.08(d,J=6.8Hz,6H).HRMS(ESI)calcd.for[C 25 H 24N3O3] + ([M+H)) + ):m / z 414.1812,found:414.1803.

[0088] Example A5

[0089]

[0090] This example uses a similar operation to Example A1, except that p-morpholinoaniline is used instead of m-methylaniline.

[0091] 1 H NMR(400MHz,CF3COOD)δ8.62(m,2H),8.14(s,1H),8.04(m,3H),7.91(m,2H),4.49( m,4H),4.09(m,4H),3.39(m,2H),2.23(m,1H),1.12(m,6H).HRMS(ESI)calcd.for[C 28 H 29 N4O3] + ([M+H)) + ):m / z 469.2234,found:469.2247.

[0092] Example A6

[0093]

[0094] This example uses a similar operation to Example A1, except that piperidine is used instead of m-methylaniline, and piperidine is used instead of isobutylamine.

[0095] 1 H NMR (400MHz, CDCl3) δ8.58(d,J=8.0Hz,1H),8.07(d,J=7.6Hz,1H),7.66(t,J=7.6Hz,1H),7.56(t,J=7.6Hz,1H),6.09(s,1 H),3.98-3.87(m,4H),3.61-3.49(m,4H),1.95-1.86(m,4H),1.84-1.79(m,4H),1.76-1.72(m,4H).HRMS(ESI)calcd.for[C 28 H 29 N4O3] + ([M+H)) + ):m / z 469.2234,found:469.2247.

[0096] Example A7

[0097]

[0098] This example uses a similar operation to Example A1, except that cyclopropylamine is used instead of m-methylaniline.

[0099] 1 H NMR (400MHz, DMSO) δ9.88(s,1H),8.53(s,1H),8.41(d,J=7.6Hz,1H),8.12(d,J=7.6Hz,1H),7.76(t,J=6.8Hz,1H),7.64(t,J=7.2Hz,1H),6.18(s, 1H),3.30-3.15(m,1H),3.02-2.83(m,2H),2.21-2.00(m,1H),1.00(d,J=6.0Hz,6H),0.97-0.93(m,2H),0.77-0.67(m,2H).HRMS(ESI)calcd.for[C 21 H 22 N3O2] + ([M+H)) + ):m / z 348.1707,found:348.1704. Example A8

[0100]

[0101] This example uses a similar operation to Example A1, except that ethanolamine is used instead of isobutylamine.

[0102] 1 H NMR (400MHz, DMSO) δ11.72 (s, 1H), 8.41 (d, J = 7.6Hz, 1H), 8.35 (s, 1H), 8.10 (d,J=7.6Hz,1H),7.76(t,J=7.2Hz,1H),7.64(t,J=7.6Hz,1H),7.34(t,J=8. 0Hz,1H),7.28-7.19(m,2H),7.07(d,J=7.6Hz,1H),6.36-6.15(m,1H),4.89( t,J=5.2Hz,1H),3.61(q,J=5.2Hz,2H),2.34(s,3H).HRMS(ESI)calcd.for[C 23 H 20 N3O3] + ([M+H)) + ):m / z 386.1499,found:386.1495.

[0103] Example A9

[0104]

[0105] This example uses a similar procedure to Example A1, except that N-(2-aminoethyl)morpholine is used instead of isobutylamine.

[0106] 1 H NMR (400MHz, DMSO) δ11.73 (s, 1H), 8.46 (d, J = 7.6Hz, 1H), 8.38 (s, 1H), 8.16 ( d,J=7.6Hz,1H),7.84-7.78(m,1H),7.73-7.66(m,1H),7.40(dd,J=10.8,5.2H z,1H),7.31(s,2H),7.13(d,J=7.6Hz,1H),6.18(s,1H),3.57-3.49(m,4H),3 .35(s,3H),2.56(t,J=6.8Hz,2H),2.43-2.33(m,6H).HRMS(ESI)calcd.for[C 27 H 27 N4O3] + ([M+H)) + ):m / z455.2078,found:455.2075.

[0107] Example A10

[0108]

[0109] This example uses a similar procedure to Example A1, except that N-methylisobutylamine is used instead of isobutylamine.

[0110] 1 H NMR (400MHz, DMSO) δ11.76(s,1H),8.43(d,J=7.6Hz,1H),8.11(d,J=7.6Hz,1H ),7.80(t,J=7.2Hz,1H),7.68(t,J=7.2Hz,1H),7.37(t,J=7.2Hz,1H),7.33-7. 24(m,2H),7.10(d,J=7.2Hz,1H),6.03(s,1H),2.28-3.12(m,2H),2.51(s,3H), 2.37(s,3H),2.10-2.01(m,1H),0.88(d,J=6.4Hz,6H).HRMS(ESI)calcd.for[C 26 H 26 N3O2] + ([M+H)) +):m / z412.2020,found:412.2027.

[0111] Example A11

[0112]

[0113] This example uses a similar operation to Example A1, except that n-propylamine is used instead of isobutylamine.

[0114] 1 H NMR (400MHz, CF3COOD) δ8.62-8.57(m,2H),8.12(t,J=7.6Hz,1H),8.05(t,J=7.6Hz,1H),7.56(t,J=7.6Hz,1H),7.44(d,J=7.6Hz,1 H),7.35(d,J=11.6Hz,2H),3.47(m,2H),2.53(s,3H),1.91(dd,J=14.4,7.2Hz,2H),1.09(t,J=7.2Hz,3H).HRMS(ESI)calcd.for[C 24 H 22 N3O2] + ([M+H)) + ):m / z 384.1707,found:384.1719.

[0115] Example A12 Preparation of 1-amino-2-(isobutylamino)-4-(p-toluamino)anthracene-9,10-dione

[0116]

[0117] Compound 4 (A2) (50.0 mg, 1.0 eq) was stirred in a mixture of DMF (0.5 mL) and ethanol (0.5 mL), Pd / C (7.5 mg) was added, and hydrazine hydrate (50 μL) was added dropwise. The reaction was refluxed for 1 h. After the reaction was confirmed to be complete by TLC, the reaction system was diluted with EA, extracted with water, and the organic layer was evaporated to dryness and passed through a column to give a purple solid A-12 (yield 80.4%). 1H NMR (400MHz, CDCl3) δ12.60(s,1H),8.34(dd,J=15.2,7.6Hz,2H),7.69(dt,J=23.6,6.8Hz,2H),7.26(s,1H),7.24-7.16(m,3H),6.5 6(s,1H),4.30(s,1H),2.95-2.77(m,2H),2.38(s,3H),1.91(dt,J=13.2,6.4Hz,1H),0.99(d,J=6.4Hz,6H).HRMS(ESI)calcd.for[C 25 H 26 N3O2] + ([M+H)) + ):m / z400.2020,found:400.2018.

[0118] Example A13 uses a similar procedure to Example A12, but synthesizes with the corresponding reagents.

[0119] Example A13

[0120]

[0121] This example uses a similar operation to Example A12, except that A4 is used instead of A2.

[0122] 1 H NMR (400MHz, CDCl3) δ8.31(d,J=6.4Hz,2H),7.72(t,J=7.2Hz,1H),7.64(s,1H),6.96(s,2H),3. 85(s,3H),1.96-1.79(m,2H),1.30-1.23(m,1H),0.98(d,J=6.4Hz,6H).HRMS(ESI)calcd.for[C 25 H 26 N3O3] + ([M+H)) + ):m / z 416.1969,found:416.1970.

[0123] Example A14 Preparation of 4,5-dihydroxy-9,10-dioxo-N-(m-tolyl)-9,10-dihydroanthracene-2-carboxamide

[0124]

[0125] Compound 5 (300.0 mg, 1.0 eq), m-methylaniline (113.0 mg, 1.0 eq), HATU (602.5 mg, 1.5 eq), DIPEA (550.9 μL, 3.0 eq), and DMF (5 mL) were stirred overnight at room temperature. After the reaction was confirmed to be complete by TLC, the reaction mixture was diluted with EA, extracted with water, and the organic layer was evaporated to dryness and column chromatography to give a yellow solid A-13 (yield 53.1%).

[0126] 1 H NMR (400MHz, DMSO) δ11.96(s,2H),10.57(s,1H),8.23(d,J=1.6Hz,1H),7.91(d,J=1.6Hz,1H),7.89-7.84(m,1H),7.79(dd,J=7.6,1.0Hz,1H),7. 65(s,1H),7.61(d,J=8.4Hz,1H),7.44(dd,J=8.4,1.2Hz,1H),7.27(t,J=7.6Hz,1H),6.98(d,J=7.6Hz,1H),2.34(s,3H).HRMS(ESI)calcd.for[C 22 H 16 NO5] + ([M+H)) + ):m / z 374.1023,found:374.1009.

[0127] Examples A15 to A24 were synthesized using similar procedures to Example A14, with corresponding reagents.

[0128] Example A15

[0129]

[0130] This example uses a similar operation to Example A14, except that isobutylamine is used instead of m-methylaniline.

[0131] 1 H NMR (400MHz, DMSO) δ11.94(s,2H),8.94(t,J=5.6Hz,1H),8.16(d,J=1.2Hz,1H),7.86(t,J=8.0Hz,1H),7.80-7.77(m,2H), 7.44(d,J=8.4Hz,1H),3.13(t,J=6.4Hz,2H),1.89(dt,J=13.2,6.8Hz,1H),0.92(d,J=6.8Hz,6H).HRMS(ESI)calcd.for[C 19 H 18NO5] + ([M+H)) + ):m / z 340.1179,found:340.1186.

[0132] Example A16

[0133]

[0134] This example uses a similar procedure to Example A14, except that p-methoxyaniline is used instead of m-methylaniline.

[0135] 1H NMR (400MHz, DMSO) δ12.00(s,2H),10.59(s,1H),8.28(s,1H),7.96(s,1H),7.91(t,J=8.0Hz,1H),7.83(d,J=7.2 Hz,1H),7.77(d,J=8.8Hz,2H),7.48(d,J=8.4Hz,1H),7.02(d,J=8.8Hz,2H),3.83(s,3H).HRMS(ESI)calcd.for[C 22 H 16 NO6] + ([M+H)) + ):m / z390.0972,found:390.0958.

[0136] Example A17

[0137]

[0138] This example uses a similar procedure to Example A14, except that p-morpholinoaniline is used instead of m-methylaniline.

[0139] 1 H NMR (400MHz, DMSO) δ11.76(s,2H),10.48(s,1H),8.22(s,1H),7.89(s,1H),7.85(t,J=8.0Hz,1H),7.77(d,J=7.2Hz,1H),7.66(d, J=8.8Hz,2H),7.43(d,J=8.4Hz,1H),6.96(d,J=8.89Hz,2H),3.74(d,J=4.8Hz,4H),3.08(d,J=4.8Hz,4H).HRMS(ESI)calcd.for[C 25 H 21 N2O6] + ([M+H)) + ):m / z 445.1394,found:445.1390.

[0140] Example A18

[0141]

[0142] This example uses a similar procedure to Example A14, except that 4-(4-methylpiperazine)aniline is used instead of m-methylaniline.

[0143] 1 H NMR (400MHz, DMSO) δ12.23(s,2H),10.50(s,1H),8.23(s,1H),7.90(s,1H),7.88-7.83(m,1H),7.78(d,J=6.4Hz,1H), 7.68(d,J=6.8Hz,2H),7.44(d,J=8.0Hz,1H),7.00(d,J=6.8Hz,2H),3.25(m,4H),2.88(m,7H).HRMS(ESI)calcd.for[C 26 H 24 N3O5] + ([M+H)) + ):m / z 458.1710,found:458.1707.

[0144] Example A19

[0145]

[0146] This example uses a similar procedure to Example A14, except that N-(2-aminoethyl)morpholine is used instead of m-methylaniline.

[0147] 1 H NMR (400MHz, DMSO) δ11.93(s,2H),8.90(s,1H),8.13(s,1H),7.84(t,J=7.6Hz,1H),7.76(d,J=7.2Hz,2H),7.4 2(d,J=8.0Hz,1H),3.59(t,J=8.0Hz,4H),3.45-3.41(m,2H),2.50(m,2H),2.45(m,4H).HRMS(ESI)calcd.for[C 21 H 21 N2O6] + ([M+H)) + ):m / z397.1394,found:397.1388.

[0148] Example A20

[0149]

[0150] This example uses a similar procedure to Example A14, except that 4-phenylpiperidine is used instead of m-methylaniline.

[0151] 1 H NMR (400MHz, DMSO) δ12.02(s,2H),7.90(t,J=8.0Hz,1H),7.80(d,J=7.6Hz,1H),7.74(s,1H), 7.52(s,1H),7.48(d,J=8.4Hz,1H),7.38(d,J=4.4Hz,4H),7.28(dd,J=8.8,4.4Hz,1H),4.71( d,J=12.8Hz,1H),3.69(d,J=12.8Hz,1H),3.32(t,J=11.6Hz,1H),2.97(d,J=4.8Hz,1H),2.94 -2.85(m,1H),1.95(d,J=11.6Hz,1H),1.78(m,2H),1.34-1.29(m,1H).HRMS(ESI)calcd.for[C 26 H 22 NO5] + ([M+H)) + ):m / z 428.1492,found:428.1501.

[0152] Example A21

[0153]

[0154] This example uses a similar procedure to Example A14, except that N-tolueneethylamine is used instead of m-methylaniline.

[0155] 1 H NMR (400MHz, DMSO) δ11.94(s,2H),7.85(s,1H),7.76-7.74(m,1H),7.53(d,J= 1.2Hz,1H),7.42(s,1H),7.35(s,1H),7.32(d,J=1.2Hz,1H),7.26(d,J=1.2Hz ,1H),7.21(d,J=1.2Hz,2H),7.03(d,J=5.2Hz,1H),6.89(d,J=1.2Hz,1H),3.4 7(t,J=6.8Hz,2H),3.08(s,3H),2.95(t,J=7.2Hz,2H).HRMS(ESI)calcd.for[C 24 H 20 NO5]+ ([M+H)) + ):m / z402.1336,found:402.1343.

[0156] Example A22

[0157]

[0158] This example uses a similar procedure to Example A14, except that 1,2,3,4-tetrahydroisoquinoline is used instead of m-methylaniline.

[0159] 1 H NMR (400MHz, DMSO) δ12.01(s,2H),7.91-7.86(m,1H),7.78(d,J=6.0Hz,1H),7.71(d,J=10.8Hz,1H),7.49(d,J=14.0Hz, 2H),7.32(s,1H),7.24(m,3H),4.85(s,1H),4.62(s,1H),3.93(m,1H),3.62(m,1H),2.93(m,2H).HRMS(ESI)calcd.for[C 24 H 18 NO5] + ([M+H)) + ):m / z 400.1170,found:402.1175.

[0160] Example A23

[0161]

[0162] This example uses a similar procedure to Example A14, except that N-thiazopiperazine is used instead of m-methylaniline.

[0163] 1 H NMR (400MHz, DMSO) δ11.96(s,2H),7.84(t,J=8.0Hz,1H),7.76-7.73(m,1H),7.70(d,J=1.2Hz,1H),7.46(d,J=1.2Hz,1H),7. 44-7.41(m,1H),7.20(d,J=3.6Hz,1H),6.91(d,J=3.6Hz,1H),3.80(m,2H),3.56(m,2H),3.47(m,4H).HRMS(ESI)calcd.for[C 22 H 18 N3O5S] + ([M+H)) +):m / z 436.0962,found:436.0949.

[0164] Example A24

[0165]

[0166] This example uses a similar operation to Example A14, except that diphenylmethylpiperazine is used instead of m-methylaniline.

[0167] 1 H NMR (400MHz, DMSO) δ11.92 (s, 2H), 7.82 (t, J = 8.0Hz, 1H), 7.73-7.70 (m, 1H), 7 .59(d,J=1.2Hz,1H),7.45(d,J=7.2Hz,4H),7.40(dd,J=8.4,0.8Hz,1H),7.35( d,J=1.2Hz,1H),7.31(t,J=7.6Hz,4H),7.20(t,J=7.2Hz,2H),4.38(s,1H),3.6 9(m,2H),3.38-3.36(m,2H),2.43(m,2H),2.31(m,2H).HRMS(ESI)calcd.for[C 32 H 27 N2O5] + ([M+H)) + ):m / z519.1914,found:519.1909.

[0168] Experimental Example 1: Test of proteasome agonist activity of anthraquinone cyclic parent compound

[0169] Experimental Methods: The activity of different compounds was detected using the fluorescent substrate Suc-Leu-Leu-Val-Tyr-AMC to preliminarily evaluate their agonistic effects on enzyme activity. The Tyr-AMC sequence in the substrate was hydrolyzed by a proteasome-like protease, releasing AMC. The fluorescence absorption of the hydrolyzed product AMC could be detected under excitation conditions of 355 nm and emission conditions of 460 nm. The agonistic effect of the compounds on 20S proteasome activity was observed, and the results are shown in Table 1.

[0170] Table 1. Agonistaltic activity of compounds against 20S proteasome CT-L

[0171]

[0172]

[0173] Note: NT - Untested

[0174] Experimental Example 2: Hypoxic Cardiac Protective Activity Test of Anthraquinone Cyclic Core Compounds

[0175] Experimental Methods: 1. Cell Seeding: H9C2 cells were prepared into a cell suspension using DMEM culture medium containing 10% fetal bovine serum and seeded at a density of 5000 cells per well (200 μL per well) into a 96-well plate. 2. Cell Culture: The control group was placed in a cell culture chamber with an O2 concentration of 21% and a CO2 concentration of 5%, while the hypoxia group was placed in a hypoxia incubator with an O2 concentration of 1% and a CO2 concentration of 5%. 3. Drug Addition: Different concentrations of the compound were added to the culture medium of each group sequentially. 4. Colorimetric Analysis: After 14 hours of culture, 10 μL of MTT solution (5 mg / ml dissolved in PBS) was added to each well. Incubation was continued for 4 hours, then the culture was terminated, and the culture supernatant was carefully aspirated from the wells. 150 μL of DMSO was added to each well, and the mixture was shaken for 10 minutes to fully dissolve any crystals. 5. Colorimetric Measurement: The absorbance of each well was measured at a wavelength of 490 nm using an ELISA reader, and the results were recorded. Cell viability (%) = (Absorbance of test group / Absorbance of control group) × 100%. Results of the hypoxic cardioprotective activity of some compounds are shown below. Figures 1(a) to 1(h) As shown.

[0176] As can be seen, most of the compounds of this invention possess strong proteasome agonist activity, and some of the more active proteasome agonists exhibit myocardial hypoxia protective activity. The above experiments demonstrate that these compounds have excellent prospects for application in treating cardiovascular diseases, and therefore possess good commercial value.

Claims

1. A compound containing an anthraquinone ring core, characterized in that, The compound is any one of the following: 3-(isobutylamino)-5-(o-tolylamino)-6H-anthra[1,9-cd]isoxazol-6-one; 3-(isobutylamino)-5-(p-methoxyphenylamino)-6H-anthra[1,9-cd]isoxazol-6-one; 3-(isobutylamino)-5-((4-morpholinophenyl)amino)-6H-anthraphen[1,9-cd]isoxazol-6-one; 3-(isobutylamino)-5-(cyclopropylamino)-6H-anthra[1,9-cd]isoxazole-6-one; 3-((2-morpholinoethyl)amino)-5-(m-toluidine)-6H-anthraphen[1,9-cd]isoxazol-6-one; 3-(propylamino)-5-(m-toluamino)-6H-anthra[1,9-cd]isoxazole-6-one; 1-Amino-2-(isobutylamino)-4-((4-methoxyphenyl)amino)anthracene-9,10-dione; 4,5-Dihydroxy-N-(4-morpholinophenyl)-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide; 4,5-Dihydroxy-N-(4-(4-methylpiperazin-1-yl)phenyl)-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide; 1,8-Dihydroxy-3-(4-phenylpiperidin-1-carbonyl)anthracene-9,10-dione; 4,5-Dihydroxy-N-methyl-9,10-dioxo-N-phenylethyl-9,10-dihydroanthracene-2-carboxamide; 1,8-Dihydroxy-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)anthracene-9,10-dione; 1,8-Dihydroxy-3-(4-(thiazo-2-yl)piperazin-1-carbonyl)anthracene-9,10-dione.

2. A pharmaceutical composition comprising at least one compound as claimed in claim 1 or a pharmaceutically acceptable salt of said compound as an active ingredient, and comprising one or more pharmaceutically acceptable carriers or excipients.

3. The pharmaceutical composition according to claim 2, characterized in that, The administration route of the pharmaceutical composition is selected from oral, injection, inhalation, and implantation.

4. The pharmaceutical composition according to claim 3, characterized in that, The dosage form of the pharmaceutical composition is injection, tablet, capsule or granule.

5. Use of the compound of claim 1, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 4 in the preparation of a medicament for cardiovascular diseases.

6. The use according to claim 5, characterized in that, The cardiovascular diseases mentioned include ischemic heart disease, stroke, cardiomyopathy, rheumatic heart disease, hypertensive heart disease, endocarditis, arrhythmia, aortic disease, and peripheral artery disease.

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