Oxaevodiamine compound and pharmaceutical application thereof

Abstract

The invention belongs to the technical field of medicines, discloses an oxa-evodiamine compound and a pharmaceutical application thereof, and particularly provides the oxa-evodiamine compound shown as a formula (I), and physiologically acceptable salts and pharmaceutical compositions thereof. The compounds can effectively inhibit proliferation of pulmonary artery smooth muscle cells caused by PDGF-BB, and can be used for preventing or treating pulmonary arterial hypertension. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a class of oxaevodiamine compounds of general formula (I), and their physiologically acceptable salts, the use of these compounds in preparing drugs for preventing or treating pulmonary hypertension, and pharmaceutical compositions containing the compounds. Background Art

[0002] Pulmonary arterial hypertension (PAH) is a clinical and pathophysiological syndrome characterized by a progressive increase in pulmonary circulatory resistance due to a variety of reasons. The 2022 ESC / ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension define the hemodynamic criteria for PAH as resting mean pulmonary artery pressure > 20 mmHg, pulmonary arteriolar 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 occurrence and development of PH is accompanied by an increase in pulmonary vascular resistance, which can increase the cardiac load and lead to right ventricular hypertrophy and failure, resulting in death, and is characterized by high mortality and poor prognosis.

[0003] The pathogenesis of pulmonary hypertension is very complex, but they all have the same pathological basis of pulmonary vascular remodeling. The remodeling of the medial and intimal lining of the pulmonary arteries causes the thickening of the vascular wall, increases pulmonary vascular resistance, and subsequently increases the mean pulmonary artery pressure. Pulmonary vascular remodeling is inseparable from the phenotypic transformation of pulmonary artery smooth muscle cells, which is mainly manifested as abnormal proliferation and apoptosis resistance. The phenotypic transformation of pulmonary artery smooth muscle cells is related to a variety of signaling molecules, such as platelet-derived growth factor. Platelet-derived growth factor (PDGF) is a dimeric glycoprotein. Abnormal PDGF signaling can lead to abnormal vascular remodeling and stimulate the phenotypic transformation of pulmonary artery smooth muscle cells from contractile to secretory.

[0004] At present, the treatment drugs for pulmonary hypertension mainly target vasoconstriction, promote pulmonary vasodilation, and restore normal blood supply to the heart and lungs through the prostacyclin pathway, endothelin pathway, and nitric oxide / cyclic guanosine monophosphate pathway. However, surveys show that the survival rate of patients after taking the drugs has not been greatly improved. Therefore, it is urgent to develop drugs that inhibit the proliferation of pulmonary artery smooth muscle cells and effectively improve vascular remodeling. Summary of the invention

[0005] The object of the present invention is to provide a novel oxaerutaecarpine 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 drugs for preventing or treating pulmonary arterial hypertension, and a pharmaceutical composition containing the compound.

[0007] In order to achieve the purpose of the present invention, the technical solution adopted by the present 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 containing secondary amine group, aryl containing substituent or not containing substituent;

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

[0011] The substituent is selected from halogen, 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] In order to prepare pharmaceutical preparations, the compounds of general formula (I) can be mixed with suitable pharmaceutical carrier materials, aromatics, flavoring agents and pigments by known methods and made into tablets or coated tablets, or suspended or dissolved in water or oil with other additives.

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

[0018] The compounds of the present invention can be administered orally or parenterally. Oral administration can be tablets, capsules, coatings, and parenteral administration forms include injections and suppositories. These preparations are prepared according to methods well known to those skilled in the art. The adjuvants used to make tablets, capsules, and coatings are conventional adjuvants, such as starch, gelatin, gum arabic, silica, polyethylene glycol, and the solvents used in liquid dosage forms include water, ethanol, propylene glycol, and vegetable oils such as corn oil, peanut oil, olive oil, etc. The preparations containing the compounds of the present invention may also contain other adjuvants, such as surfactants, lubricants, disintegrants, preservatives, flavoring agents, pigments, etc.

[0019] Beneficial technical effects:

[0020] The compound of the present invention can effectively inhibit the proliferation of pulmonary artery smooth muscle cells caused by PDGF-BB, effectively improve vascular remodeling, and significantly increase the survival rate of pulmonary hypertension model rats, and is expected to provide a safe and effective treatment for pulmonary hypertension. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Attached Figure 1 :The therapeutic effect of TM-20 on rats with pulmonary hypertension DETAILED DESCRIPTION

[0022] The invention is 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 is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS) or high resolution mass spectrometry (HRMS). NMR shift (δ) is given in parts per million (ppm). mp is the melting point given in °C, and the temperature is not corrected. Column chromatography generally uses 200-300 mesh silica gel as a carrier. NMR determination is performed using INOVA-400, the determination solvent is CDCl3, DMSO-d6, the internal standard is TMS, and the chemical shift is given in ppm. MS determination is performed using an Agilent LC / MSD TOF liquid chromatography-mass spectrometer.

[0024] Example 1: Preparation of TM-1

[0025]

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

[0027] 2) Dissolve N-(2-(1H-indol-3-yl)ethyl)formamide (3.8g, 20mmol) in 50ml of anhydrous dichloromethane, cool to about 5°C with low-temperature cold hydrazine, slowly add POCl3 (15.5g, 101mmol) using a constant pressure funnel, react in an ice bath for 2h, then warm to room temperature for 2h. After the reaction is complete, most of the solvent is dried, and 10% glacial acetic acid is added until no bubbles appear. Filter the filtrate, add ammonia water to the filtrate, and filter the solid again. After washing the product with water several times, dry it to obtain 2.9g of the 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), EDCI (864 mg, 4.5 mmol) were dissolved in 30 ml of anhydrous dichloromethane and reacted at room temperature for 12 hours. After the reaction was complete, salicylic acid was removed with NaHCO3, EDCI was removed with water, and after extraction with dichloromethane and water, 444 mg of the product was obtained by column chromatography with a yield of 87%.

[0029] 4) 7,8,13,13b-tetrahydro-5H-benzo[5',6'][1,3]oxazine[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), argon protection at room temperature for 10 min, and the addition of ethyl 4-bromobutyrate (390 mg, 2 mmol), and the reaction was carried out at 100°C for 6 h. After the reaction was completed, most of the solvent was dried, and the product was extracted with ethyl acetate and water. 246 mg of the product was obtained by column chromatography 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 to react at room temperature. After the reaction was complete, the solvent was dried and hydrochloric acid was added to precipitate the product to obtain 81 mg of the product with a yield of 58%.

[0031] 6) Add 10 ml of dichloromethane to 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)butanoic acid (106 mg, 0.26 mmol), EDCI (192 mg, 1 mmol), DMAP 12 mg, and aniline 25 mg, and react at room temperature. After the reaction is complete, extract with dichloromethane, take the organic phase, add sodium bicarbonate solution, and remove the excess acid. The product is obtained by column chromatography with a yield of 59%. mp: 196-198°C. 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] + Calculate 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 by aniline, and the yield is 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] + Calculate 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 by aniline, and the yield is 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] + Calculate for C 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 by aniline, and the yield is 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] + Calculate for C 29 H 28 O4N3:482.2074.

[0041] Example 5: Preparation of TM-5

[0042]

[0043] Its synthesis method and operation are the same as TM-1, except that p-trifluoromethylaniline is replaced by aniline, and the yield is 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] + Calculate for C 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 by aniline, and the yield is 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-morpholineaniline is replaced by aniline, and the yield is 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] + Calculate 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-pyridylamine is replaced by aniline, and the yield is 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] + Calculate 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 by aniline, and the yield is 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] + Calculate 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 by aniline, and the yield is 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] + Calculate 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 by aniline, and the yield is 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] + Calculate 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 by aniline, and the yield is 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] + Calculate for C 26 H 31O3N4:447.2391.

[0065] Example 13: Preparation of TM-13

[0066]

[0067] Its synthesis method and operation are the same as TM-1, except that 4-methylpiperazineaniline is replaced by aniline, and the yield is 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] + Calculate 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 by aniline, and the yield is 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] + Calculate 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 by aniline, and the yield is 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] + Calculate for C 28 H 35 O3N4:475.2704.

[0074] Example 16: Preparation of TM-16

[0075]

[0076] Its synthesis method and operation are the same as TM-1, except that 6-bromohexanoic acid ethyl ester is replaced by 4-bromobutyric acid ethyl ester, and 2-dimethylaminoethylamine is replaced by aniline, with a yield of 37%. mp: 104-106°C. 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] + Calculate 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-pyrrolethylamine is replaced by aniline, and the yield is 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] + Calculate 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-piperidinylethylamine is replaced by aniline, and the yield is 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] + Calculate for C 29 H 35 O3N4:487.2704.

[0083] Example 19: Preparation of TM-19

[0084]

[0085] Its synthesis method and operation are the same as TM-1, except that 8-bromooctanoic acid ethyl ester is replaced by 4-bromobutyric acid ethyl ester, and 2-dimethylaminoethylamine is replaced by aniline, with a yield of 48%. mp: 130-132°C. 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] + Calculate for C 26 H 29 O4N2:433.2122.

[0086] Example 20: Preparation of TM-20

[0087]

[0088] Its synthesis method and operation are the same as TM-1, except that 1-ethyl bromoacetate is replaced by ethyl 4-bromobutyrate, and 2-dimethylaminoethylamine is replaced by aniline, with a yield of 71%. mp: 126-128°C. 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]+ Calculate for C 24 H 27 O3N4:419.2078.Pharmacological experiments:

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

[0090] The CCK-8 method was used to detect the effect of the compound on PASMC proliferation. The primary PASMC cells in the logarithmic growth phase were inoculated in 96-well plates at 5000 cells / well, 100 μL per well, and the PASMC experimental groups were: control group, PDGF-BB (20 ng / mL) intervention model group, and compound intervention PDGF-BB model group. After culturing in a 37°C cell culture incubator for 24 hours until the cells adhered to the wall, the model group was added with complete medium containing 20 ng / mL PDGF-BB, and 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 (the final DMSO concentration was less than 0.1%), and the wells with a DMSO concentration of 0.1% were set as the control group. The cells were incubated in a 37°C cell culture incubator for 24 h, and fresh culture medium was replaced with 10% volume of CCK-8. After incubation at 37°C for 1-2 h, the absorbance of each well at a wavelength of 450 nm was measured using an ELISA reader. The process was repeated three times. The results are shown in Table 1.

[0091] Table 1 Cell proliferation inhibitory activity of compounds

[0092]

[0093]

[0094] Experimental Example 2: In vivo rat experiment

[0095] Forty healthy SD male rats were randomly divided into four groups, with 10 rats in each group. The experimental groups were (1) control group; (2) model group; (3) sildenafil administration group; (4) TM-20 administration group. Two hours after the administration of the modeling agent, the rats were gavaged and the treatment was continued for 28 consecutive days. The rats were anesthetized by intraperitoneal injection of sodium pentobarbital solution. After the righting reflex disappeared, they were fixed on the operating table, and the trachea was bluntly separated and intubated. The ventilator settings were: tidal volume 3mL, frequency 50 times / min, and respiratory ratio 2:1. After thoracotomy, the pulmonary artery was reached through the right ventricle under direct vision and a catheter was placed to measure the pulmonary artery pressure. After systemic perfusion with normal saline, the pulmonary artery and left lung were fixed in 4% neutral paraformaldehyde solution, embedded in paraffin, and serially sectioned and stained with HE. Five fields of view were randomly selected for each sample to detect the thickness of the pulmonary artery wall and observe the pulmonary artery stenosis. Five pulmonary arteriolar vessels with a diameter of 100±50μm were randomly selected, and 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 the remodeling of pulmonary vessels. Figure 1 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 containing a secondary amine group, aryl containing substituents or not containing substituents; the secondary amine group is selected from dimethylamine, diethylamine, piperidine, pyrrole; the substituent is selected from halogen, trifluoromethyl, methoxy, dimethylamino, morpholine, piperidine.

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

3. A pharmaceutical composition comprising an effective dose of any one of the compounds according to 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. Use of the compound according to any one of claims 1 to 2 or a physiologically acceptable salt thereof in the preparation of a drug for preventing or treating pulmonary arterial hypertension.

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