Oxayohimbine compounds and pharmaceutical uses thereof

Abstract

The application belongs to the technical field of medicine, and discloses a kind of oxaevodiamine compounds and pharmaceutical use thereof, and specifically provides a kind of oxaevodiamine compounds shown in formula (I), and their physiologically acceptable salts and pharmaceutical compositions.The compounds can effectively inhibit the proliferation of pulmonary artery smooth muscle cells caused by PDGF-BB, and can be used for preventing or treating pulmonary arterial hypertension.

Description

Technical Field

[0001] This invention relates to a class of oxa-evodiamine compounds of general formula (I), and their physiologically acceptable salts. It also relates to the use of these compounds in the preparation of medicaments for the prevention or treatment of pulmonary arterial hypertension, and pharmaceutical compositions containing said compounds. Background Technology

[0002] Pulmonary arterial hypertension (PAH) is a clinical and pathophysiological syndrome characterized by progressively increasing pulmonary vascular resistance due to various causes. The 2022 ESC / ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension define the hemodynamic criteria for PAH as a resting mean pulmonary artery pressure >20 mmHg, pulmonary arteriole wedge pressure ≤15 mmHg, and pulmonary vascular resistance >2 Wood units. PAH belongs to the first of the five major categories of pulmonary hypertension (PH). The development of PAH, accompanied by increased pulmonary vascular resistance, leads to increased cardiac workload, resulting in right ventricular hypertrophy, heart failure, and death, characterized by high mortality and poor prognosis.

[0003] The pathogenesis of pulmonary hypertension is complex, but all share the same pathological basis: pulmonary vascular remodeling. Remodeling of the medial aspect and intima of the pulmonary artery thickens the vessel wall, increasing pulmonary vascular resistance, and subsequently elevating mean pulmonary artery pressure. Pulmonary vascular remodeling is inseparable from the phenotypic transformation of pulmonary artery smooth muscle cells, mainly manifested as abnormal proliferation and resistance to apoptosis. This phenotypic transformation of pulmonary artery smooth muscle cells is related to various signaling molecules, such as platelet-derived growth factor (PDGF). PDGF is a dimeric glycoprotein; abnormal PDGF signaling leads to abnormal vascular remodeling, stimulating the phenotypic transformation of pulmonary artery smooth muscle cells from contractile to secretory types.

[0004] Currently, treatments for pulmonary hypertension primarily target and constrict blood vessels through the prostacyclin, endothelin, and nitric oxide / cyclic guanosine monophosphate pathways, promoting pulmonary vasodilation and restoring normal blood flow to the heart and lungs. However, studies show that these medications have not significantly improved patient survival rates. Therefore, developing drugs that inhibit pulmonary artery smooth muscle cell proliferation and effectively improve vascular remodeling is urgently needed. Summary of the Invention

[0005] The purpose of this invention is to provide a novel type of oxa-evodia alkaloid compound represented by general formula (I).

[0006] Another object of the present invention is to provide the use of the compound represented by general formula (I) in a medicament for the prevention or treatment of pulmonary hypertension, and a pharmaceutical composition containing said compound.

[0007] To achieve the objectives of this invention, the technical solution adopted by this invention is to provide a compound represented by general formula (I) or a physiologically acceptable salt thereof:

[0008]

[0009] Wherein, n is selected from 1, 3, 4, 5, 6, 7; R is selected from C2-C4 alkyl groups containing secondary amine groups, aryl groups containing substituents or not containing substituents;

[0010] The secondary amine group is selected from dimethylamine, diethylamine, piperidine, and pyrrole;

[0011] The substituents are selected from halogens, trifluoromethyl, methoxy, dimethylamino, morpholine, and piperidine.

[0012] Another object of the present invention is to provide a compound having the following structure or a physiologically acceptable salt thereof, characterized in that the compound is selected from:

[0013]

[0014]

[0015]

[0016] To prepare a pharmaceutical preparation, a compound of general formula (I) may be mixed with a suitable pharmaceutical carrier substance, flavoring agent, flavoring agent and pigment by a known method and made into a tablet or coated tablet, or suspended or dissolved in water or oil with other additives.

[0017] The present invention also relates to a pharmaceutical composition comprising an effective dose of a compound as described in general formula I and a pharmaceutically acceptable carrier.

[0018] The compounds of this invention can be administered orally or via non-gastrointestinal routes. Oral administration may include tablets, capsules, or coated formulations; non-gastrointestinal dosage forms include injections and suppositories. These formulations are prepared according to methods well known to those skilled in the art. The excipients used in the manufacture of tablets, capsules, and coated formulations are conventionally used adjuvants, such as starch, gelatin, gum arabic, silica, and polyethylene glycol; solvents used in liquid dosage forms include, for example, water, ethanol, propylene glycol, and vegetable oils such as corn oil, peanut oil, and olive oil. Formulations containing the compounds of this invention may also contain other adjuvants, such as surfactants, lubricants, disintegrants, preservatives, flavoring agents, and colorants.

[0019] Beneficial technical effects:

[0020] The compounds of this invention can effectively inhibit the proliferation of pulmonary artery smooth muscle cells induced by PDGF-BB, effectively improve vascular remodeling, and significantly improve the survival rate of rats with pulmonary hypertension, and are expected to provide a safe and effective treatment for pulmonary hypertension. Attached Figure Description

[0021] Appendix Figure 1 Treatment of pulmonary hypertension rats with TM-20 Detailed Implementation

[0022] The invention will be further described below with reference to the embodiments, but these embodiments do not limit the scope of the invention.

[0023] The structure of the compound was determined by nuclear magnetic resonance (NMR), mass spectrometry (MS), or high-resolution mass spectrometry (HRMS). NMR shifts (δ) are given in parts per million (ppm). mp represents the melting point in °C, uncorrected for temperature. Column chromatography typically uses 200–300 mesh silica gel as the support. NMR measurements were performed using an INOVA-400 analyzer with CDCl3 and DMSO-d6 as solvents and TMS as the internal standard. Chemical shifts are given in ppm. MS measurements were performed using an Agilent LC / MSD TOF liquid chromatography-mass spectrometry system.

[0024] Example 1: Preparation of TM-1

[0025]

[0026] 1) Tryptophan (4.8 g, 30 mmol) was dissolved in ethyl formate (11.1 g, 15 mmol), and the mixture was refluxed at 60 °C for 20 h. After the reaction was complete, the solvent was evaporated, and the product was obtained by column chromatography, yielding 3.8 g of the product (79% yield).

[0027] 2) N-(2-(1H-indol-3-yl)ethyl)formamide (3.8 g, 20 mmol) was dissolved in 50 mL of anhydrous dichloromethane. The solution was cooled to approximately 5 °C using a cold hydrazine filter. POCl3 (15.5 g, 101 mmol) was slowly added dropwise using a constant pressure funnel. The reaction was carried out in an ice bath for 2 h, followed by a further increase in temperature to room temperature for 2 h. After the reaction was complete, most of the solvent was evaporated, and 10% glacial acetic acid was added dropwise until no more bubbles were observed. The filtrate was collected by suction filtration, and ammonia was added. The solid was collected by suction filtration again. The product was washed several times with water and dried to obtain 2.9 g of product, with a yield of 76%.

[0028] 3) 4,9-dihydro-3H-pyrido[3,4-b]indole (510 mg, 3 mmol), salicylic acid (414 mg, 3 mmol), and EDCI (864 mg, 4.5 mmol) were dissolved in 30 mL of anhydrous dichloromethane and reacted at room temperature for 12 h. After the reaction was complete, salicylic acid was removed with NaHCO3, and EDCI was removed with water. After extraction with dichloromethane and water, the product was obtained by column chromatography, yielding 444 mg of the product (87% yield).

[0029] 4) 7,8,13,13b-tetrahydro-5H-benzo[5',6'][1,3]oxazino[3',2':1,2]pyrido[3,4-b]indol-5-one (290 mg, 1 mmol) was dissolved in 10 mL of anhydrous DMF, followed by the addition of NaH (100 mg, 4.2 mmol). The mixture was kept under argon protection at room temperature for 10 min, then ethyl 4-bromobutyrate (390 mg, 2 mmol) was added, and the reaction was carried out at 100 °C for 6 h. After the reaction was complete, most of the solvent was evaporated, and the mixture was extracted with ethyl acetate and water. Column chromatography yielded 246 mg of the product, with a yield of 68%.

[0030] 5) Ethyl 4-((5-oxo-8,13b-dihydro-5H-benzo[5',6'][1,3]oxazine[3',2':1,2]pyridin[3,4-b]indol-13(7H)-yl)methyl)butyrate (139 mg, 0.34 mmol) was dissolved in 5 ml of a mixed solution (THF:MeOH:H2O = 3:1:1), and 35 mg of lithium hydroxide monohydrate was added. The reaction was carried out at room temperature. After the reaction was complete, the solvent was evaporated, and hydrochloric acid was added to precipitate the product, giving 81 mg of the product, with a yield of 58%.

[0031] 6) 4-((5-oxo-8,13b-dihydro-5H-benzo[5',6'][1,3]oxazine[3',2':1,2]pyridin[3,4-b]indol-13(7H)-yl)methyl)butyric acid (106 mg, 0.26 mmol), EDCI (192 mg, 1 mmol), DMAP 12 mg, and aniline 25 mg were added to 10 mL of dichloromethane and reacted at room temperature. After the reaction was complete, the mixture was extracted with dichloromethane, and the organic phase was collected. Sodium bicarbonate solution was added to remove excess acid. The product was obtained by column chromatography in 59% yield. mp: 196-198℃. 1H NMR(400MHz,DMSO-d6)δ9.88(s,1H),7.88–7.83(m,1H),7.61–7.55(m,2H),7.53–7 .47(m,3H),7.27–7.16(m,4H),7.16–7.11(m,1H),7.11–7.06(m,1H),7.01–6.95(m ,1H),6.79(s,1H),4.72–4.65(m,1H),4.35–4.26(m,2H),3.18–3.10(m,1H),2.97– 2.79(m,2H),2.44–2.38(m,2H),2.18–2.06(m,2H).HR-ESI-MS: m / z=452.1957[M+H] + calcd for C 28 H 26 O3N3:452.1969.

[0032] Example 2: Preparation of TM-2

[0033]

[0034] Its synthesis method and operation are the same as TM-1, except that o-chloroaniline is replaced with aniline, with a yield of 45%. mp: 171-173℃. 1 H NMR(400MHz,DMSO-d6)δ9.64–9.46(m,1H),7.95–7.88(m,1H),7.65–7.52(m,4H),7.50–7.45(m,1H),7.32–7.10(m,6H),6.84(s,1H),4.83–4 .70(m,1H),4.43–4.30(m,2H),3.24–3.15(m,1H),3.01–2.83(m,2H),2.61–2.54(m,2H),2.22–2.12(m,2H).HR-ESI-MS:m / z=486.1582[M+H] + calcd for C 28 H 25 O3N3Cl: 486.1579.

[0035] Example 3: Preparation of TM-3

[0036]

[0037] Its synthesis method and operation are the same as TM-1, except that m-chloroaniline is replaced with aniline, with a yield of 95%. mp: 188-190℃. 1H NMR (400MHz, DMSO-d6) δ10.26–10.01(m,1H),7.92–7.88(m,1H),7.80–7.76(m,1H ),7.65–7.58(m,2H),7.57–7.51(m,1H),7.41–7.36(m,1H),7.33–7.20(m,3H),7. 20–7.06(m,3H),4.87–4.67(m,1H),4.44–4.24(m,2H),3.22–3.13(m,1H),3.01–2 .82(m,2H),2.48–2.43(m,2H),2.20–2.10(m,2H).HR-ESI-MS:m / z=486.1576[M+H] + calcd forC 28 H 25 O3N3 Cl: 486.1579.

[0038] Example 4: Preparation of TM-4

[0039]

[0040] Its synthesis method and operation are the same as TM-1, except that p-methoxyaniline is replaced with aniline, with a yield of 98%. mp: 193-195℃. 1 H NMR(400MHz,DMSO-d6)δ9.88–9.68(m,1H),7.93–7.88(m,1H),7.65–7.58(m,2H),7.58–7 .53(m,1H),7.48–7.42(m,2H),7.31–7.21(m,2H),7.21–7.16(m,1H),7.15–7.10(m,1H),6 .87–6.81(m,3H),4.85–4.69(m,1H),4.40–4.24(m,2H),3.71(s,3H),3.23–3.13(m,1H), 3.01–2.82(m,2H),2.44–2.38(m,2H),2.20–2.10(m,2H).HR-ESI-MS:m / z=482.2078[M+H] + calcd for C 29 H 28 O4N3:482.2074.

[0041] Example 5: Preparation of TM-5

[0042]

[0043] The synthesis method and operation are the same as TM-1, except that p-trifluoromethylaniline is replaced with aniline, with a yield of 96%. mp: 204-206℃. 1 H NMR(400MHz,DMSO-d6)δ10.37–10.20(m,1H),7.91–7.88(m,1H),7.79–7.74(m,2 H),7.66–7.59(m,4H),7.56–7.51(m,1H),7.30–7.20(m,2H),7.18–7.10(m,2H), 6.82(s,1H),4.83–4.67(m,1H),4.46–4.24(m,2H),3.23–3.14(m,1H),3.00–2.8 2(m,2H),2.49–2.47(m,2H),2.22–2.12(m,2H).HR-ESI-MS:m / z=520.1852[M+H] + calcd forC 29 H 25 O3N3F3:520.1843.

[0044] Example 6: Preparation of TM-6

[0045]

[0046] Its synthesis method and operation are the same as TM-1, except that p-dimethylaminoaniline is replaced with aniline, with a yield of 41%. mp: 208-210℃. 1 H NMR(400MHz,DMSO-d6)δ9.69–9.57(m,1H),7.93–7.88(m,1H),7.65–7.53(m,3H),7 .37–7.32(m,2H),7.30–7.17(m,3H),7.16–7.10(m,1H),6.83(s,1H),6.68–6.63(m ,2H),4.79–4.69(m,1H),4.40–4.26(m,2H),3.23–3.14(m,1H),3.01–2.86(m,2H), 2.83(s,6H),2.42–2.35(m,2H),2.19–2.10(m,2H).HR-ESI-MS:m / z=495.2391[M+H] + calcdfor C 30 H 31 O3N4:495.2391.

[0047] Example 7: Preparation of TM-7

[0048]

[0049] Its synthesis method and operation are the same as TM-1, except that p-morpholinoaniline is replaced with aniline, with a yield of 88%. mp: 210-212℃. 1 H NMR(400MHz,DMSO-d6)δ9.77–9.64(m,1H),7.87–7.84(m,1H),7.59–7.47(m,3H) ,7.38–7.33(m,2H),7.25–7.05(m,4H),6.83–6.76(m,3H),4.73–4.65(m,1H),4.3 8–4.22(m,2H),3.70–3.66(m,4H),3.18–3.09(m,1H),3.01–2.95(m,4H),2.95–2. 77(m,2H),2.38–2.34(m,2H),2.15–2.06(m,2H).HR-ESI-MS: m / z=537.2512[M+H] + calcd for C 32 H 33 O4N4: 537.2496.

[0050] Example 8: Preparation of TM-8

[0051]

[0052] Its synthesis method and operation are the same as TM-1, except that 4-pyridinylamine is replaced with aniline, with a yield of 28%. mp: 214-216℃. 1 H NMR(400MHz,DMSO-d6)δ10.40–10.20(m,1H),8.41–8.38(m,2H),7.93–7.88(m,1 H),7.65–7.59(m,2H),7.57–7.49(m,3H),7.30–7.21(m,2H),7.19–7.10(m,2H), 6.83(s,1H),4.81–4.66(m,1H),4.45–4.29(m,2H),3.22–3.14(m,2H),3.00–2.8 5(m,2H),2.49–2.47(m,1H),2.21–2.11(m,2H).HR-ESI-MS:m / z=453.1926[M+H] + calcd for C 27 H 25 O3N4:453.1921.

[0053] Example 9: Preparation of TM-9

[0054]

[0055] Its synthesis method and operation are the same as TM-1, except that 4-aminopyrimidine is replaced with aniline, with a yield of 56%. mp: 215-217℃. 1 H NMR(400MHz,DMSO-d6)δ10.98–10.87(m,1H),8.86–8.82(m,1H),8.63–8.59(m,1H),8.00– 7.97(m,1H),7.92–7.89(m,1H),7.63–7.52(m,3H),7.31–7.19(m,2H),7.17–7.09(m,2H), 6.82(s,1H),4.77–4.70(m,1H),4.40–4.26(m,2H),3.23–3.13(m,1H),3.00–2.91(m,1H), 2.91–2.87(m,1H),2.60–2.55(m,2H),2.18–2.10(m,2H).HR-ESI-MS:m / z=454.1886[M+H] + calcd for C 26 H 24 O3N5:454.1874.

[0056] Example 10: Preparation of TM-10

[0057]

[0058] Its synthesis method and operation are the same as TM-1, except that 1-naphthylamine is replaced with aniline, with a yield of 75%. mp: 200-202℃. 1 H NMR(400MHz,DMSO-d6)δ10.14(s,1H),8.26(s,1H),7.91–7.87(m,1H),7.85–7.80(m,2H),7.79– 7.75(m,1H),7.65–7.60(m,2H),7.56–7.44(m,3H),7.42–7.37(m,1H),7.32–7.26(m,1H),7.23– 7.17(m,2H),7.16–7.11(m,1H),6.85(s,1H),4.80–4.66(m,1H),4.46–4.33(m,2H),3.24–3.14( m,2H),3.00–2.86(m,2H),2.55–2.53(m,1H),2.24–2.16(m,2H).HR-ESI-MS:m / z=502.2121[M+H] + calcd for C 32 H 28O3N3: 502.2125.

[0059] Example 11: Preparation of TM-11

[0060]

[0061] Its synthesis method and operation are the same as TM-1, except that 3-chloro-4-fluoroaniline is replaced with aniline, with a yield of 95%. mp: 163-165℃. 1 H NMR(400MHz,DMSO-d6)δ10.07(s,1H),7.86–7.80(m,2H),7.58–7.54(m,2H),7 .52–7.47(m,1H),7.38–7.32(m,1H),7.31–7.15(m,3H),7.14–7.05(m,2H),6.7 6(s,1H),4.75–4.64(m,1H),4.36–4.26(m,2H),3.15–3.08(m,1H),2.95–2.82 (m,2H),2.42–2.34(m,2H),2.13–2.07(m,2H).HR-ESI-MS: m / z=504.1486[M+H] + calcd for C 28 H 24 O3N3ClF:504.1485.

[0062] Example 12: Preparation of TM-12

[0063]

[0064] Its synthesis method and operation are the same as TM-1, except that dimethylaminoethylamine is replaced with aniline, with a yield of 73%. mp: 157-159℃. 1 H NMR(400MHz,DMSO-d6)δ7.89–7.85(m,1H),7.77–7.70(m,1H),7.60–7.51(m,3 H),7.26–7.13(m,3H),7.10–7.05(m,1H),6.75(s,1H),4.76–4.66(m,1H),4.2 9–4.15(m,2H),3.19–3.02(m,3H),2.96–2.77(m,2H),2.25–2.21(m,2H),2.16 –2.12(m,2H),2.09(s,6H),2.05–1.97(m,2H).HR-ESI-MS:m / z=447.2390[M+H] + calcd for C 26 H 31O3N4:447.2391.

[0065] Example 13: Preparation of TM-13

[0066]

[0067] The synthesis method and operation are the same as TM-1, except that 4-methylpiperazine aniline is replaced with aniline, with a yield of 79%. mp: 199-201℃. 1 H NMR(400MHz,DMSO-d6)δ9.74–9.64(m,1H),7.93–7.88(m,1H),7.61(m,2H),7.58–7.53(m,1H) ),7.41–7.36(m,2H),7.30–7.21(m,2H),7.20–7.09(m,2H),6.88–6.81(m,3H),4.79–4.68(m ,1H),4.40–4.29(m,2H),3.31–3.11(m,1H),3.09–3.04(m,4H),3.00–2.85(m,2H),2.48–2.4 3(m,4H),2.43–2.37(m,2H),2.22(s,3H),2.17–2.11(m,2H).HR-ESI-MS:m / z=550.2812[M+H] + calcd for C 33 H 36 O3N5: 550.2813.

[0068] Example 14: Preparation of TM-14

[0069]

[0070] Its synthesis method and operation are the same as TM-1, except that 3-dimethylaminopropylamine is replaced with aniline, with a yield of 58%. mp: 114-116℃. 1H NMR(400MHz,DMSO-d6)δ7.94–7.84(m,2H),7.65–7.56(m,3H),7.30–7.17(m,3H),7.14– 7.09(m,1H),6.79(s,1H),4.78–4.69(m,1H),4.31–4.20(m,2H),3.23–3.13(m,1H),3.0 6–3.00(m,1H),3.00–2.93(m,2H),2.90–2.81(m,1H),2.43–2.35(m,2H),2.25(s,6H),2 .22–2.15(m,2H),2.10–2.00(m,2H),1.59–1.49(m,2H).HR-ESI-MS:m / z=461.2547[M+H] + calcd for C 27 H 33 O3N4:461.2547.

[0071] Example 15: Preparation of TM-15

[0072]

[0073] Its synthesis method and operation are the same as TM-1, except that 2-diethylaminoethylamine is replaced with aniline, with a yield of 82%. mp: 104-106℃. 1 H NMR(400MHz,DMSO-d6)δ7.94–7.89(m,1H),7.77–7.71(m,1H),7.64–7.54(m,3H),7.29–7.23(m,2H ),7.23–7.17(m,1H),7.14–7.08(m,1H),6.79(s,1H),4.84–4.66(m,1H),4.37–4.13(m,2H),3.24–3 .14(m,1H),3.10–3.02(m,2H),3.01–2.92(m,1H),2.93–2.81(m,1H),2.48–2.39(m,4H),2.39–2.3 4(m,2H),2.21–2.15(m,2H),2.10–2.00(m,2H),0.95–0.86(m,6H).HR-ESI-MS:m / z=475.2706[M+H] + calcd for C 28 H 35 O3N4: 475.2704.

[0074] Example 16: Preparation of TM-16

[0075]

[0076] The synthesis method and operation are the same as TM-1, except that ethyl 6-bromohexanoate is replaced with ethyl 4-bromobutyrate and 2-dimethylaminoethylamine is replaced with aniline, with a yield of 37%. mp: 104-106℃. 1 H NMR(400MHz,Chloroform-d)δ8.07–8.02(m,1H),7.61–7.56(m,1H),7.52–7.46(m,1H),7.38–7.34(m,1H),7 .32–7.24(m,1H),7.19–7.11(m,2H),7.05–7.00(m,1H),6.49(s,1H),6.46–6.40(m,1H),5.00–4.86(m,1H),4 .34–4.10(m,2H),3.38–3.31(m,2H),3.27–3.17(m,1H),3.05–2.92(m,2H),2.55–2.48(m,2H),2.30(s,6H), 2.21–2.15(m,2H),1.96–1.87(m,2H),1.74–1.65(m,2H),1.49–1.38(m,2H).HR-ESI-MS: m / z=475.2705[M+H] + calcd for C 28 H 35 O3N4: 475.2704.

[0077] Example 17: Preparation of TM-17

[0078]

[0079] Its synthesis method and operation are the same as TM-1, except that 2-pyrroleethylamine is replaced with aniline, with a yield of 30%. mp: 108-110℃. 1H NMR(400MHz,Chloroform-d)δ8.08–8.00(m,1H),7.60–7.56(m,1H),7.52–7.44(m,2H),7.29(m,1H),7. 25–7.20(m,1H),7.19–7.13(m,2H),7.13–7.08(m,1H),6.55(s,1H),4.98–4.89(m,1H),4.45–4.31(m,1H ),4.31–4.18(m,1H),3.51–3.39(m,2H),3.30–3.18(m,1H),3.06–2.95(m,2H),2.94–2.89(m,4H),2.88 –2.83(m,2H),2.38–2.31(m,2H),2.31–2.18(m,2H),1.98–1.91(m,4H).HR-ESI-MS:m / z=473.2547[M+H] + calcd for C 28 H 33 O3N4: 473.2547.

[0080] Example 18: Preparation of TM-18

[0081]

[0082] Its synthesis method and operation are the same as TM-1, except that 2-piperidineethylamine is replaced with aniline, with a yield of 55%. mp: 130-132℃. 1 H NMR(400MHz,DMSO-d6)δ7.95–7.90(m,1H),7.87–7.77(m,1H),7.64–7.55(m,3H),7.30–7 .22(m,2H),7.22–7.17(m,1H),7.14–7.09(m,1H),6.79(s,1H),4.79–4.68(m,1H),4.32–4 .22(m,2H),3.24–3.11(m,3H),3.01–2.82(m,2H),2.70–2.52(m,2H),2.46–2.31(m,4H), 2.23–2.16(m,2H),2.11–2.00(m,2H),1.60–1.33(m,6H).HR-ESI-MS:m / z=487.2705[M+H] + calcd for C 29 H 35 O3N4: 487.2704.

[0083] Example 19: Preparation of TM-19

[0084]

[0085] The synthesis method and operation are the same as TM-1, except that ethyl 8-bromooctanoate is replaced with ethyl 4-bromobutyrate, and 2-dimethylaminoethylamine is replaced with aniline, with a yield of 48%. mp: 130-132℃. 1 H NMR(400MHz,Chloroform-d)δ8.09–8.00(m,1H),7.59–7.54(m,1H),7.51–7.44(m,1H),7.37–7,32(m,1H),7 .30–7.21(m,1H),7.19–7.09(m,2H),7.02–6.96(m,1H),6.47(s,1H),6.18–6.08(m,1H),4.96–4.88(m,1H),4 .33–4.05(m,2H),3.34–3.27(m,2H),3.24–3.15(m,1H),3.04–2.90(m,2H),2.46–2.38(m,2H),2.22(s,6H), 2.17–2.07(m,2H),1.91–1.82(m,2H),1.63–1.53(m,2H),1.42–1.20(m,6H).HR-ESI-MS: m / z=433.2129[M+H] + calcd for C 26 H 29 O4N2:433.2122.

[0086] Example 20: Preparation of TM-20

[0087]

[0088] The synthesis method and operation are the same as TM-1, except that ethyl 1-bromoethyl acetate is replaced with ethyl 4-bromobutyrate and 2-dimethylaminoethylamine is replaced with aniline, with a yield of 71%. mp: 126-128℃. 1 H NMR(400MHz,DMSO-d6)δ7.98–7.93(m,1H),7.88–7.85(m,1H),7.60–7.53 (m,2H),7.51–7.47(m,1H),7.24–7.16(m,2H),7.14–7.05(m,2H),6.68(s ,1H),5.02–4.83(m,2H),4.81–4.64(m,1H),3.18–3.10(m,3H),2.98–2.7 9(m,2H),2.25–2.19(m,2H),2.03(s,6H).HR-ESI-MS:m / z=419.2068[M+H]+ calcd forC 24 H 27 O3N4:419.2078. Pharmacological experiments:

[0089] Experiment Example 1: Cell proliferation inhibition activity test

[0090] The effect of the compound on PASMC proliferation was detected using the CCK-8 assay. Primary PASMCs in logarithmic growth phase were seeded at 5000 cells / well, with 100 μL per well in a 96-well plate. PASMCs were divided into three groups: control group, PDGF-BB (20 ng / mL) intervention model group, and compound-intervention PDGF-BB model group. After cell adhesion at 37°C for 24 h, the model groups were added to complete medium containing 20 ng / mL PDGF-BB. The prepared compound stock solution (prepared with DMSO) was diluted with complete medium containing 20 ng / mL PDGF-BB and added to each well at a concentration of 10 μM (final DMSO concentration less than 0.1%). A well with 0.1% DMSO was used as a control group. The cells were incubated at 37°C for 24 hours. Fresh culture medium was then added and 10% volume of CCK-8 was added. After incubation at 37°C for 1-2 hours, the absorbance of each well at 450 nm was measured using a microplate reader. The experiment was repeated three times. The results are shown in Table 1.

[0091] Table 1. Cell proliferation inhibitory activity of the compounds

[0092]

[0093]

[0094] Experimental Example 2: In vivo rat experiment

[0095] Forty healthy male SD rats were randomly divided into four groups of ten each. The experimental groups were (1) control group; (2) model group; (3) sildenafil administration group; and (4) TM-20 administration group. Two hours after administration of the modeling agent, the administration group was given the drug by gavage for 28 consecutive days. The rats were anesthetized by intraperitoneal injection of sodium pentobarbital solution. After the righting reflex disappeared, the rats were fixed on the operating table, and the trachea was bluntly dissected and endotracheal intubation was performed. The ventilator was set with the following parameters: tidal volume 3 mL, frequency 50 breaths / min, and inspiratory-to-expiratory ratio 2:1. After thoracotomy, the pulmonary artery was reached through the right ventricle and a catheter was inserted under direct vision. The pulmonary artery pressure was measured. After systemic perfusion with physiological saline, the pulmonary artery and left lung were taken and fixed in 4% neutral paraformaldehyde solution, embedded in paraffin, serially sectioned, and stained with hematoxylin and eosin (HE). Five fields of view were randomly selected from each sample to detect the pulmonary artery wall thickness and observe the pulmonary artery stenosis. Five pulmonary arterioles with a diameter of 100±50 μm were randomly selected. The ratio of the vessel wall cross-sectional area to the lumen area (WA%) = (TA-IA) / TA was calculated using IPP 6.0 (Image-Pro-Plus 6.0) image processing software to evaluate pulmonary vascular remodeling. The results are as follows: Figure 1 As shown.

Claims

1. A class of oxa-evodiamine compounds represented by the following general formula (I) and their physiologically acceptable salts: in, n is selected from 1, 3, 4, 5, 6, 7; R is selected from C2-C4 alkyl groups containing secondary amine groups, aryl groups containing substituents or not containing substituents; the secondary amine group is selected from dimethylamine, diethylamine, piperidine, pyrrole; the substituent is selected from halogens, trifluoromethyl, methoxy, dimethylamino, morpholine, piperidine.

2. The compound according to claim 1 and its physiologically acceptable salt, characterized in that, The compounds mentioned are selected from:

3. A pharmaceutical composition comprising an effective dose of any one of the compounds as described in any one of claims 1 to 2 and a pharmaceutically acceptable carrier.

4. The pharmaceutical composition according to claim 3, characterized in that, The pharmaceutical composition is selected from tablets, capsules, pills, injections, sustained-release preparations, controlled-release preparations, or various microparticle delivery systems.

5. The use of the compound or a physiologically acceptable salt thereof as described in any one of claims 1 to 2 in the preparation of a medicament for the prevention or treatment of pulmonary hypertension.

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