Nitric oxide donor type beraprost derivative as well as pharmaceutical composition and application thereof

Abstract

The invention discloses a series of novel compounds which contain beraprost and a nitric oxide donor and are shown in the following formula I. The invention relates to the series of compounds as well as pharmaceutical compositions and application thereof. The beraprost sodium and NO donor combined drug provided by the invention overcomes the defects that the beraprost sodium is short in clearing half-life period, the number of times of administration per day is large, the curative effect has a saturated capping effect, and NO is a gas which is rapidly decomposed and metabolized in a solution and is short in half-life period, and the new compound reduces the dosage and the administration frequency of original beraprost administration, improves the curative effect of the beraprost sodium and the NO donor, and improves the curative effect of the beraprost sodium and the NO donor. Meanwhile, by utilizing the smooth muscle relaxation effect caused by NO molecules released by the compound in vivo, the synergistic effect of the two drugs is exerted through the dual effects, and the effectiveness and safety of the drug are improved.

Description

[0001] This application is a divisional application of an application with an application date of November 18, 2021, application number 202111366683.9, and invention name “A nitric oxide donor-type beraprost derivative, its pharmaceutical composition and use”. Technical Field

[0002] The present invention belongs to the field of biomedicine, and specifically relates to a nitric oxide donor type beraprost derivative or a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof and uses thereof. Background Art

[0003] Pulmonary hypertension (PH, including pulmonary arterial hypertension, PAH) is a disease characterized by increased pulmonary vascular resistance and right ventricular failure. After being diagnosed, patients have a short survival period and a high mortality rate. It is a malignant disease.

[0004] Currently, the main drugs used in clinical treatment of pulmonary arterial hypertension include endothelin receptor antagonists (such as bosentan), phosphatase 5 inhibitors (such as sildenafil), guanylate cyclase agonists (riociguat), prostacyclin analogs (such as beprostaglandin) and prostacyclin receptor agonists (celecoxib). The mechanism of action of these drugs ultimately involves nitric oxide (NO) and cGMP pathways to dilate endothelial vessels.

[0005] Among these drugs, prostaglandin analogs are the most effective and classic drugs, among which beraprost sudiam is the oral preparation mainly used in clinical practice. However, due to its pharmacokinetic defects, it needs to be administered multiple times a day. Therefore, some researchers have improved the preparation (such as the successful launch of the sustained-release tablet Careload in Japan) and structure (the failure of the phase III clinical study of beraprost optical body Esuberaprost) of beraprost.

[0006] Since NO plays the most critical role in the entire pathway, but is difficult to administer due to its gaseous characteristics and rapid metabolism, the use of a NO donor model is a new attempt to develop new drugs. For example, long-acting inhalers of liposome aerosols prepared with NO donors are used to treat PAH (Nahar K, et al., Pharma Res. 2016); the latanoprost nitrate developed by Valeant Pharma is composed of latanoprost acid butanediol mononitrate, which has a dual mechanism of action in the treatment of glaucoma: latanoprost acid (a marketed drug) can act on the uveoscleral pathway to promote the discharge of aqueous humor; butanediol mononitrate can release nitric oxide (NO) to promote the discharge of aqueous humor through the trabecular meshwork and Schlemm's canal. This two-pronged new treatment method has been verified in clinical trials: compared with the single administration of latanoprost, latanoprost nitrate can more significantly reduce intraocular pressure and show better clinical advantages. The product was approved by the FDA for marketing in 2017 (trade name VYZULTA). Therefore, the use of prostaglandins plus the modification of the NO donor mode can increase the effectiveness of the drug through two pharmacological pathways, which is a more convenient new drug development path.

[0007] In addition to being used for the treatment of pulmonary hypertension, beprostaglandin sodium has also been tried for malignant tumor metastasis (developed by United Therap, USA), atherosclerosis (developed by Kaken Pharma, Japan), hypertension (developed by Kaken Pharma, Japan and United Therap, USA), diabetic neuropathy (developed by Kaken Pharma, Japan), as well as nephritis and renal failure, cerebrovascular dementia (CN 112691109A), alcoholic fatty liver (HK1219665A) and other diseases. At the same time, NO donor drugs are also used to develop a variety of diseases such as anti-inflammatory and cardiovascular disease treatment (Megson IL & Webb DJ, Expert Opin Investig Drugs, 2002; Knox CD et al., MK5108, JAm Heart Assoc, 2016). Therefore, beprostaglandin sodium and NO donors have the possibility of developing a variety of therapeutic drugs.

[0008] The present invention is a drug developed from a series of nitric oxide donor-type beraprost derivatives or pharmaceutically acceptable salts thereof. After entering the body, the series of compounds decompose into beraprost and generate nitric oxide (NO), which can produce dual pharmacological effects. On the one hand, beraprost can specifically bind to prostaglandins receptors to play a role in relaxing vascular smooth muscle. On the other hand, NO molecules released by these compounds in the body also play a role in relaxing blood vessels through the cGMP pathway of endothelial cells. The two mechanisms synergistically enhance the therapeutic effect.

[0009] These series of compounds can be used as therapeutic drugs for the treatment of pulmonary hypertension, myocardial infarction, kidney disease, peripheral vascular diseases such as occlusive arteriosclerosis, and ophthalmic diseases (such as diabetic retinopathy, glaucoma, etc.), osteoporosis, thromboangiitis, thromboembolic diseases and many other diseases. Summary of the invention

[0010] The present application provides a new series of compounds of beraprost sodium combined with NO donors to address the defects of beraprost sodium, such as short elimination half-life, high number of daily dosing times, saturation capping effect of therapeutic effect, and short half-life of NO being a gas that is rapidly decomposed and metabolized in solution.

[0011] In order to achieve the above object, the present invention provides a nitric oxide donor-type beraprost derivative or a pharmaceutically acceptable salt thereof as shown in the following formula I:

[0012]

[0013] n is 0, 1, 2, 3 or 4;

[0014] R is -X-ONO2, -RC(O)-X-ONO2, -OX-ONO2, or Where X is a straight or branched C1-C 10 Alkyl, cycloalkyl or -C1-C 10 Alkyl-aromatic ring-; wherein C1-C 10 Alkyl, C 5-7 The cycloalkyl group or aromatic ring may be substituted by one or more of the following substituents: halogen atoms, hydroxyl groups, carboxyl groups, cyano groups or -(C1-C 10 Alkyl)-ONO2.

[0015] The cycloalkyl group is preferably C 5-7 Cycloalkyl, aromatic ring is C 5-10 Aromatic ring.

[0016] Further, the compound includes any one of the following specific structures:

[0017]

[0018]

[0019] The pharmaceutically acceptable salt of the nitric oxide donor beraprost derivatives mentioned in the present invention can be an acidic salt or an alkaline salt. Acidic salts such as hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid or nitric acid, or bisulfate, or acid addition salts formed with the following organic acids: formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, persulfate, 3- Phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, aminosulfonic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptanoic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid or thiocyanic acid. Basic salts such as sodium ion, potassium ion, N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, dicyclohexylamine, 1,6-hexanediamine, ethanolamine, glucosamine, meglumine, sarcosine, serinol, trishydroxymethylaminomethane, aminopropanediol, 1-amino-2,3,4-butanetriol.

[0020] Another technical solution of the present application provides a pharmaceutical composition containing the above-mentioned nitric oxide donor-type beraprost derivatives, which includes a compound with a structure shown in general formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0021] The carrier is any one of a sustained-release agent, an excipient, a filler, a binder, a wetting agent, a disintegrant, an absorption promoter, an adsorption carrier, a surfactant and a lubricant, or a mixture of two or more thereof.

[0022] The pharmaceutical composition is preferably any one of an external preparation, an oral preparation and an injection preparation.

[0023] The oral preparation is any one of granules, capsules and tablets.

[0024] The pharmaceutical composition of the nitric oxide donor beraprost derivatives of the present invention includes its application as a procyclist analog.

[0025] The pharmaceutical composition of the nitric oxide donor beraprost derivatives of the present invention includes its use in preparing therapeutic drugs for treating pulmonary hypertension, myocardial infarction, kidney disease, peripheral vascular diseases such as occlusive arteriosclerosis, and ophthalmic diseases (such as diabetic fundus lesions, glaucoma, etc.), osteoporosis, thromboangiitis, thromboembolic diseases and other diseases.

[0026] Beneficial effects: Compared with the prior art, the present invention has the following advantages:

[0027] The present invention provides a class of beraprost sodium and NO donor combination drugs, which solve the defects of beraprost sodium, such as short elimination half-life, multiple daily administration times, saturation capping effect of therapeutic effect, and short half-life of NO being a gas that is rapidly decomposed and metabolized in solution. The new compound reduces the original beraprost sodium administration dosage and frequency of administration, and at the same time utilizes the effect of relaxing smooth muscles caused by the release of NO molecules in the body by the compound. Through the dual effects, the synergistic effect of the two drugs is exerted, thereby improving the effectiveness and safety of the drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 It indicates the therapeutic effect of compound 15 on hypoxic pulmonary hypertension in mice;

[0029] Figure 2 represents the bone density measurement data of mice after treatment with compound 15;

[0030] Figure 3 It shows the effect of compound 15 on the proliferation of renal tubular epithelial cells in acute renal failure. DETAILED DESCRIPTION

[0031] The present invention will be further described below with reference to the embodiments.

[0032] Example 1

[0033]

[0034] Synthesis route:

[0035]

[0036] Synthesis of Example 1

[0037] Concentrated sulfuric acid (13 mmol) was dissolved in dichloromethane, and fuming nitric acid (14 mmol) was slowly added dropwise at 0°C. After the reaction was continued for 20 min, 2-bromoethanol (6 mmol) was added to the above reaction solution. The reaction was continued at 0°C for 4 hours, and the reaction solution was slowly poured into ice water, extracted twice with dichloromethane (50 mL), and the organic phase was collected, washed once with water and once with saturated brine, and then dried to obtain the product 2-bromoethyl nitrate.

[0038] Beraprost (60 mg) was dissolved in 2 mL of anhydrous DMF, and a dichloromethane solution of potassium iodide (75 mg), potassium carbonate (62 mg) and 2-bromoethyl nitrate (80 mg) was added dropwise. The mixture was stirred at 50° C. for 2 h. The reaction was complete when detected by TLC. The solvent was dried and purified by HPLC to obtain Example 1 in a yield of 67%. 1 HNMR(300MHz,DMSO-d)δ7.38–7.22(m,2H),7.00(d,J=5.8Hz,1H),5.85(d,J=9.5Hz ,2H),4.63–4.51(m,2H),4.38(d,J=12.5Hz,1H),4.23–4.15(m,2H),3.49–3.36(m, 2H),2.95–2.76(m,2H),2.61(dq,J=12.5,2.0Hz,1H),2.56–2.39(m,4H),2.28(d,J =13.0Hz,1H),2.01–1.99(m,1H),1.95–1.76(m,5H),1.03(d,J=5.5Hz,3H).ESI-MS m / z:510.2[M+Na] + .

[0039] Example 2

[0040]

[0041] Referring to the synthesis method of Example 1, Example 2 can be prepared. 1 H NMR (300MHz, DMSO-d) δ7.35–7.24(m,2H),7.04(ddd,J=3.7,2.7,1.4Hz,1H),5.88(s,1H),5.82(s,1H),4.71–4.52(m,3H),4.35–4.10(m,6H),2. 86(qd,J=12.3,0.9Hz,2H),2.61(dq,J=12.5,2.0Hz,1H),2.51–2.37(m, 4H),2.36–2.15(m,3H),1.94–1.74(m,6H),1.00(d,J=5.7Hz,3H).ESI-MS m / z:524.2[M+Na] + .

[0042] Example 3

[0043]

[0044] Referring to the synthesis method of Example 1, Example 3 can be prepared. 1H NMR(300MHz, Methanol-d4)δ7.39–7.22(m,2H),7.04(d,J=3.1Hz,1H),5.69–5.46 (m,2H),4.69–4.52(m,3H),4.31–4.09(m,5H),4.01(d,J=12.5Hz,1H),2.86(qd,J= 12.3,0.9Hz,2H),2.70(dq,J=12.5,2.0Hz,1H),2.55(dq,J=12.3,1.9Hz,1H),2.4 9–2.38(m,3H),2.28(d,J=13.0Hz,1H),2.09–1.78(m,10H),1.02(d,J=5.3Hz,3H).

[0045] Example 4

[0046]

[0047] Referring to the synthesis method of Example 1, Example 4 can be prepared. 1 H NMR (300MHz, DMSO-d4) δ7.41–7.24(m,1H),7.07(d,J=7.4Hz,1H),5.85(d,J=7.5Hz,1H),4.71–4.51(m,2H),4.28–4.00(m,3H),2.94–2.77(m ,1H),2.66(dq,J=12.5,2.0Hz,1H),2.56–2.37(m,2H),2.28(d,J=13.0Hz,1H),1.94–1.78(m,5H),1.68–1.54(m,1H),1.02(d,J=5.5Hz,2H).

[0048] Example 5

[0049]

[0050] Referring to the synthesis method of Example 1, Example 5 can be prepared. 1H NMR(300MHz,DMSO-d4)δ7.37(t,J=7.5Hz,1H),7.24(dd,J=7.5,2.0Hz,1H), 7.02(d,J=7.7Hz,1H),5.65–5.42(m,2H),4.71–4.52(m,3H),4.32–4.02(m,6 H),2.93–2.77(m,2H),2.66(dq,J=12.4,2.0Hz,1H),2.52–2.26(m,5H),1.9 5–1.81(m,5H),1.68–1.59(m,4H),1.53–1.35(m,4H),1.00(d,J=6.5Hz,3H).

[0051] Example 6

[0052]

[0053] Synthesis of Example 6

[0054] Beraprost (60 mg) was dissolved in 2 mL of anhydrous acetonitrile, potassium iodide (75 mg) and potassium carbonate (62 mg) were added, and the mixture was stirred at room temperature for 10 min. 2-chloromethyl ethyl nitrate (15 mg) was added, and the mixture was reacted at 60° C. for 8 h. The reaction was stopped, the solvent was dried by spin drying, dichloromethane was added, the mixture was washed with water twice, washed with saturated brine once, the organic phase was concentrated, and the mixture was purified by HPLC to obtain Example 6 with a yield of 42%. 1 H NMR(300MHz,DMSO-d)δ7.11–7.01(m,2H),6.95(dq,J=7.7,1.2Hz,1H),5.90–5.6 8(m,2H),5.09(s,2H),4.66–4.56(m,2H),4.22–4.09(m,2H),3.87(t,J=6.2Hz,2 H),2.88–2.68(m,3H),2.46(t,J=7.1Hz,2H),2.21(dp,J=6.2,2.0Hz,2H),2.11( t,J=4.7Hz,2H),2.05–1.85(m,3H),1.65(t,J=2.0Hz,3H),1.02(d,J=6.8Hz,3H).

[0055] Example 7

[0056]

[0057] Referring to the synthesis method of Example 6, Example 7 can be prepared. 1H NMR(300MHz,DMSO-d)δ7.28–7.08(m,2H),7.05(dq,J=7.7,1.2Hz,1H),5.89–5.58(m,2H) ,5.06(q,J=2.7Hz,2H),4.94(q,J=4.5Hz,1H),4.37(t,J=6.1Hz,2H),4.22–4.04(m,2H), 3.59(t,J=6.1Hz,2H),3.43(dd,J=5.5,4.2Hz,1H),2.92–2.66(m,3H),2.46(t,J=7.1Hz, 2H),2.27–2.16(m,2H),2.16–1.85(m,7H),1.65(t,J=2.0Hz,3H),1.01(d,J=6.5Hz,3H).

[0058] Example 8

[0059]

[0060] Referring to the synthesis method of Example 6, compound 8 can be obtained. ESI-MS m / z: 513.3 [M+H] + . 1 H NMR(300MHz,DMSO-d)δ7.25–7.04(m,2H),7.00(dq,J=7.7,1.0Hz,1H),5.91–5.66(m,2H),4.94( q,J=4.5Hz,1H),4.57(t,J=6.2Hz,2H),4.30–4.04(m,4H),3.82(t,J=6.2Hz,2H),3.72(t,J=6.2 Hz,2H),3.43(dd,J=5.5,4.2Hz,1H),2.86–2.68(m,3H),2.41(t,J=7.0Hz,2H),2.21(dp,J=6.2, 2.0Hz,2H),2.18–2.07(m,2H),2.07–1.85(m,3H),1.66(t,J=2.0Hz,3H),1.01(d,J=6.9Hz,3H).

[0061] Example 9

[0062]

[0063] Referring to the synthesis method of Example 6, Example 9 can be prepared. 1H NMR(300MHz,DMSO-d)δ7.16–7.02(m,2H),6.95(dq,J=7.7,1.2Hz,1H),5.98–5.66(m ,4H),5.11–4.87(m,3H),4.24–4.03(m,2H),3.43(dd,J=5.5,4.2Hz,1H),2.77(dqd, J=30.2,6.5,6.1,1.1Hz,3H),2.46(t,J=7.1Hz,2H),2.21(dp,J=6.2,2.0Hz,2H),2. 11(t,J=4.7Hz,2H),2.02–1.87(m,3H),1.55(t,J=2.0Hz,3H),1.02(d,J=6.8Hz,3H).

[0064] Example 10

[0065]

[0066] Referring to the synthesis method of Example 6, Example 10 can be prepared. 1 H NMR(300MHz,Chloroform-d)δ7.16–7.02(m,2H),6.95(ddt,J=6.0,2.7,0.9Hz,1 H),5.93–5.61(m,4H),4.76–4.42(m,3H),4.29–4.04(m,2H),3.92(d,J=5.5Hz,1H ),3.43(dd,J=5.5,4.2Hz,1H),2.96–2.63(m,5H),2.45(td,J=7.0,0.9Hz,2H),2. 30–2.06(m,4H),2.06–1.84(m,3H),1.57(t,J=2.0Hz,3H),1.00(d,J=6.2Hz,3H).

[0067] Embodiment 11

[0068]

[0069] Referring to the synthesis method of Example 1, Example 11 can be prepared. 1H NMR(300MHz,DMSO-d)δ7.49–7.30(m,2H),7.18–7.02(m,4H),6.97(ddt,J=7.0,1 .9,1.0Hz,1H),5.78(qd,J=15.6,6.2Hz,2H),5.52–5.24(m,2H),4.80(d,J=6.2H z,1H),4.39–4.02(m,5H),3.42(dd,J=5.5,4.2Hz,1H),2.89–2.56(m,5H),2.40( t,J=7.1Hz,2H),2.26–1.85(m,9H),1.61(t,J=2.0Hz,3H),1.01(d,J=6.7Hz,3H).

[0070] Example 12

[0071]

[0072] Referring to the synthesis method of Example 1, Example 12 can be prepared. 1 H NMR(300MHz,DMSO-d)δ7.13–7.02(m,2H),6.95(ddt,J=5.5,3.3,0.9Hz,1H) ,5.89–5.57(m,4H),4.94(dt,J=5.1,4.3Hz,1H),4.42(qt,J=10.4,6.1Hz,2H ),4.24–4.06(m,2H),3.43(dd,J=5.5,4.2Hz,1H),2.94–2.63(m,3H),2.63–2 .39(m,4H),2.26–1.79(m,9H),1.62(t,J=2.0Hz,3H),0.99(d,J=6.8Hz,3H).

[0073] Example 13

[0074]

[0075] Referring to the synthesis method of Example 1, Example 13 can be prepared. 1H NMR(500MHz,Chloroform-d)δ7.51–7.30(m,2H),7.19–7.05(m,4H),6.97(ddt,J=7.0,2.0,1.0Hz,1H) ,5.78(qd,J=15.6,6.2Hz,2H),5.52–5.31(m,2H),4.94(dt,J=5.1,4.2Hz,1H),4.22–4.05(m,5H),3.4 2(dd,J=5.5,4.2Hz,1H),2.87–2.68(m,3H),2.62(tq,J=6.5,1.0Hz,2H),2.40(t,J=7.1Hz,2H),2.21( dp,J=5.9,2.0Hz,2H),2.16–2.01(m,2H),2.01–1.87(m,3H),1.81–1.60(m,7H),1.02(d,J=6.7Hz,3H).

[0076] Embodiment 14

[0077]

[0078] Referring to the synthesis method of Example 1, compound 14 can be prepared. 1 H NMR(300MHz,DMSO-d)δ7.22–6.99(m,2H),6.97(ddt,J=7.3,1.8,0.9Hz,1H),5.78 (qd,J=15.6,6.2Hz,2H),4.94(dt,J=5.0,4.2Hz,1H),4.29–4.15(m,3H),4.15–4. 03(m,3H),3.42(dd,J=5.5,4.2Hz,1H),2.89–2.66(m,3H),2.40(t,J=7.0Hz,2H), 2.31–2.18(m,2H),2.18–1.84(m,6H),1.76–1.33(m,14H),1.04(d,J=6.1Hz,3H).

[0079] Embodiment 15

[0080]

[0081] Referring to the synthesis method of Example 1, compound 15 can be prepared. 1H NMR(300MHz,DMSO-d)δ7.21–7.05(m,2H),6.97(ddt,J=5.6,3.5,1.1Hz,1H),5.78(qd,J=15 .6,6.2Hz,2H),4.94(dt,J=5.0,4.2Hz,1H),4.34–4.10(m,5H),3.75(dd,J=10.5,6.3Hz,1H ),3.42(dd,J=5.5,4.2Hz,1H),2.89–2.66(m,3H),2.41(t,J=7.1Hz,2H),2.21(dp,J=6.2,2 .0Hz,2H),2.17–1.82(m,7H),1.82–1.59(m,5H),1.59–1.39(m,6H),1.01(d,J=6.7Hz,3H).

[0082] Example 16

[0083]

[0084] Referring to the synthesis method of Example 6, compound 16 can be prepared. 1 H NMR(300MHz,DMSO-d)δ7.13–7.04(m,2H),6.97(ddt,J=5.7,3.5,1.1Hz,1H),5 .87–5.62(m,4H),4.94(dt,J=5.1,4.3Hz,1H),4.32(t,J=6.0Hz,2H),4.23–4. 05(m,2H),3.92(d,J=5.5Hz,1H),2.91–2.66(m,3H),2.51–2.32(m,4H),2.26– 2.17(m,2H),2.17–1.75(m,9H),1.62(t,J=2.0Hz,3H),0.99(d,J=6.1Hz,3H).

[0085] Embodiment 17

[0086]

[0087] Referring to the synthesis method of Example 6, compound 17 can be prepared. 1H NMR(300MHz,DMSO-d)δ7.13–7.00(m,2H),6.96(ddt,J=6.2,2.9,1.1Hz,1H),5.8 9–5.63(m,2H),5.04–4.83(m,3H),4.69(d,J=6.2Hz,1H),4.48–4.28(m,4H),4.22 –4.03(m,2H),3.92(d,J=5.5Hz,1H),2.93–2.60(m,3H),2.40(t,J=7.1Hz,2H),2. 25–2.07(m,4H),2.07–1.86(m,3H),1.57(t,J=2.0Hz,3H),1.00(d,J=6.2Hz,3H).

[0088] Embodiment 18

[0089]

[0090] Referring to the synthesis method of Example 6, compound 18 can be prepared. 1 H NMR(300MHz,DMSO-d)δ7.18–7.02(m,2H),6.97(ddt,J=5.6,3.5,1.1Hz,1H),5.78(q d,J=15.6,6.2Hz,2H),4.94(dt,J=5.0,4.2Hz,1H),4.71–4.52(m,2H),4.23–4.04(m, 6H),3.43(dd,J=5.5,4.2Hz,1H),2.92–2.66(m,5H),2.40(t,J=7.1Hz,2H),2.21(dp ,J=6.2,2.0Hz,2H),2.18–1.85(m,7H),1.60(t,J=2.0Hz,3H),1.04(d,J=6.8Hz,3H).

[0091] Embodiment 19

[0092]

[0093] Referring to the synthesis method of Example 6, compound 19 can be prepared. 1H NMR(300MHz,DMSO-d)δ7.15–7.02(m,2H),6.97(ddt,J=7.0,1.9,1.0Hz,1H),5.78(qd,J=1 5.6, 6.2Hz, 2H), 4.94 (dt, J=5.1, 4.2Hz, 1H), 4.61 (t, J=7.1Hz, 2H), 4.26–4.04 (m, 6H), 3. 42(dd,J=5.5,4.2Hz,1H),2.89–2.67(m,5H),2.39(t,J=7.0Hz,2H),2.21(dp,J=6.2,2.0H z,2H),2.17–1.87(m,5H),1.87–1.73(m,4H),1.60(t,J=2.0Hz,3H),0.98(d,J=6.7Hz,3H).

[0094] Embodiment 20

[0095]

[0096] Referring to the synthesis method of Example 6, compound 20 can be prepared. 1 H NMR(300MHz, DMSO-d)δ7.13–7.02(m,2H),6.96(ddt,J=5.5,3.3,1.0Hz,1H),5.78(qd,J= 15.6,6.2Hz,2H),4.94(dt,J=5.0,4.2Hz,1H),4.71–4.51(m,2H),4.40–4.26(m,4H),4.26 –4.05(m,2H),3.43(dd,J=5.5,4.2Hz,1H),2.91–2.63(m,5H),2.40(t,J=7.1Hz,2H),2.2 1(dp,J=6.2,2.0Hz,2H),2.20–1.85(m,5H),1.65(t,J=2.0Hz,3H),1.02(d,J=6.7Hz,3H).

[0097] Embodiment 21

[0098]

[0099] Referring to the synthesis method of Example 6, compound 21 can be prepared. 1H NMR(300MHz,DMSO-d)δ7.20–7.10(m,2H),7.01(ddt,J=5.5,3.3,1.0Hz,1H),5.78(qd,J=15.6,6.2Hz ,2H),5.25(q,J=6.6Hz,1H),4.94(dt,J=5.1,4.3Hz,1H),4.52–4.41(m,2H),4.41–4.26(m,2H),4.26 –4.05(m,2H),3.43(dd,J=5.5,4.2Hz,1H),2.91–2.67(m,3H),2.40(t,J=7.0Hz,2H),2.21(dp,J=6.2 ,2.0Hz,2H),2.17–1.84(m,5H),1.65(t,J=2.0Hz,3H),1.47(d,J=6.6Hz,3H),1.00(d,J=6.2Hz,3H).

[0100] Embodiment 22

[0101]

[0102] Referring to the synthesis method of Example 6, compound 22 can be prepared. 1 H NMR(300MHz,DMSO-d)δ7.21–7.08(m,2H),7.00(ddt,J=6.9,1.9,1.0Hz,1H),5.78(qd,J=1 5.6,6.2Hz,2H),4.94(dt,J=5.0,4.2Hz,1H),4.54–4.31(m,2H),4.22–4.03(m,6H),3.42( dd,J=5.5,4.2Hz,1H),2.91–2.62(m,3H),2.49(t,J=7.0Hz,2H),2.40(t,J=7.1Hz,2H),2. 21(dp,J=6.2,2.0Hz,2H),2.18–1.82(m,9H),1.55(t,J=2.0Hz,3H),1.00(d,J=6.2Hz,3H).

[0103] Embodiment 23

[0104]

[0105] Referring to the synthesis method of Example 6, compound 23 can be prepared. 1H NMR(300MHz,DMSO-d)δ7.17–7.08(m,2H),7.00(ddt,J=5.6,3.5,1.1Hz,1H),5.78 (qd,J=15.6,6.2Hz,2H),5.09–4.87(m,3H),4.27–4.05(m,6H),3.43(dd,J=5.5,4. 2Hz,1H),2.86–2.67(m,3H),2.38(t,J=7.1Hz,2H),2.21(dp,J=6.2,2.0Hz,2H),2 .17–1.87(m,5H),1.87–1.72(m,4H),1.61(t,J=2.0Hz,3H),1.01(d,J=6.7Hz,3H).

[0106] Embodiment 24

[0107]

[0108] Referring to the synthesis method of Example 6, compound 24 can be prepared. 1 H NMR(300MHz,DMSO-d)δ7.54–7.38(m,2H),7.30–7.15(m,2H),7.15–7.02(m,2H),6.97(ddt,J=7 .0,2.0,1.0Hz,1H),5.97–5.70(m,4H),5.50–5.26(m,2H),4.94(dt,J=5.1,4.2Hz,1H),4.80(d, J=6.2Hz,1H),4.26–4.04(m,3H),3.62(q,J=0.8Hz,2H),2.77(dqd,J=31.3,6.5,6.1,1.1Hz,3H ),2.43(td,J=7.1,1.0Hz,2H),2.27–1.82(m,7H),1.60(t,J=2.0Hz,3H),1.04(d,J=6.6Hz,3H).

[0109] Embodiment 25

[0110]

[0111] Referring to the synthesis method of Example 6, compound 25 can be prepared. 1H NMR (300MHz, DMSO-d) δ8.04(tt,J=2.2,1.0Hz,1H),7.92(ddd,J=7.7,2.2,1.1Hz,1H),7.57(ddq,J=7.9,2.2,1.1Hz,1H),7.47(t,J=7 .8Hz,1H),7.20–7.02(m,2H),6.97(ddt,J=7.0,2.0,1.0Hz,1H),5.89–5.70(m,2H),5.45(t,J=1.0Hz,2H),4.94(dt,J=5.0,4.2Hz,1H ),4.80(d,J=6.2Hz,1H),4.46(td,J=6.0,0.8Hz,2H),4.37(td,J=6.0,0.8Hz,2H),4.26–4.04(m,3H),3.42(dd,J=5.5,4.2Hz,1H),2. 93–2.62(m,3H),2.41(t,J=7.0Hz,2H),2.21(dp,J=5.9,2.0Hz,2H),2.16–1.84(m,5H),1.65(t,J=2.0Hz,3H),1.02(d,J=6.6Hz,3H).

[0112] Embodiment 26

[0113]

[0114] Referring to the synthesis method of Example 6, Compound 26 can be prepared. 1 H NMR(300MHz,DMSO-d)δ8.11–7.84(m,2H),7.65–7.37(m,2H),7.13–7.01(m,2H),6.97(ddt,J =7.0,2.0,1.0Hz,1H),5.92–5.62(m,2H),4.94(dt,J=5.0,4.2Hz,1H),4.80(d,J=6.2Hz,1H) ,4.32–3.95(m,7H),3.45(dd,J=5.6,4.3Hz,1H),2.89–2.67(m,3H),2.40(t,J=7.1Hz,2H),2 .21(dp,J=5.9,2.0Hz,2H),2.18–1.85(m,7H),1.61(t,J=2.0Hz,3H),1.00(d,J=6.8Hz,3H).

[0115] Embodiment 27

[0116]

[0117] Referring to the synthesis method of Example 6, compound 27 can be prepared. 1 H NMR(300MHz,DMSO-d)δ8.05–7.89(m,2H),7.58–7.35(m,2H),7.17–7.04(m,2H),6.97(ddt, J=6.9,2.0,1.0Hz,1H),5.90–5.65(m,2H),4.94(dt,J=5.1,4.2Hz,1H),4.80(d,J=6.2Hz,1 H),4.30–4.02(m,7H),3.45(dd,J=5.6,4.3Hz,1H),2.88–2.66(m,3H),2.49–2.31(m,2H),2 .21(dp,J=5.9,2.0Hz,2H),2.18–1.73(m,9H),1.61(t,J=2.2Hz,3H),1.01(d,J=6.4Hz,3H).

[0118] Embodiment 28

[0119]

[0120] Referring to the synthesis method of Example 6, compound 28 can be prepared. 1 H NMR(300MHz,DMSO-d)δ7.22–7.06(m,2H),7.00(dtt,J=5.7,3.5,1.0Hz,1H),5.7 8(qd,J=15.6,6.2Hz,2H),4.94(dt,J=5.1,4.3Hz,1H),4.62–4.40(m,4H),4.29–4 .05(m,4H),3.43(dd,J=5.5,4.2Hz,1H),2.87–2.67(m,3H),2.55–2.39(m,3H),2. 26–2.16(m,2H),2.16–1.85(m,5H),1.66(t,J=2.1Hz,3H),1.00(d,J=6.5Hz,3H).

[0121] Embodiment 29

[0122]

[0123] Referring to the synthesis method of Example 1, compound 29 can be prepared. 1H NMR(300MHz,DMSO-d)δ7.19–7.07(m,2H),7.01(ddt,J=6.9,1.9,1.0Hz,1H),5.7 8(qd,J=15.6,6.2Hz,2H),4.94(dt,J=5.0,4.2Hz,1H),4.56–4.36(m,4H),4.29– 4.01(m,4H),3.92(d,J=5.5Hz,1H),2.91–2.65(m,3H),2.40(t,J=7.0Hz,2H),2. 33–2.17(m,3H),2.17–1.81(m,7H),1.60(t,J=1.9Hz,3H),0.99(d,J=6.2Hz,3H).

[0124] Embodiment 30

[0125]

[0126] Referring to the synthesis method of Example 6, compound 30 can be prepared. 1 H NMR(300MHz, DMSO-d)δ7.21–7.07(m,2H),7.00(ddt,J=6.9,1.9,1.0Hz,1H),5.78(qd,J=15.6,6.2 Hz,2H),5.28–5.02(m,3H),4.94(dt,J=5.1,4.2Hz,1H),4.74(dd,J=21.4,5.9Hz,3H),4.23–4.05(m ,2H),3.93(dd,J=5.5,3.9Hz,3H),3.42(dd,J=5.5,4.2Hz,1H),2.87–2.67(m,3H),2.43(t,J=7.1Hz ,2H),2.21(dp,J=6.2,2.0Hz,2H),2.18–1.84(m,5H),1.60(t,J=2.2Hz,3H),1.00(d,J=6.6Hz,3H).

[0127] Embodiment 31

[0128]

[0129] Referring to the synthesis method of Example 6, compound 31 can be prepared. 1H NMR(300MHz, DMSO-d)δ7.15–7.04(m,2H),6.97(ddt,J=6.9,1.9,1.0Hz,1H),5.78(qd,J=15.6 ,6.2Hz,2H),5.11(p,J=5.6Hz,1H),4.94(dt,J=5.0,4.2Hz,1H),4.68(d,J=5.6Hz,2H),4.27–4 .02(m,5H),3.84(d,J=5.5Hz,2H),3.56–3.29(m,3H),2.86–2.63(m,3H),2.40(t,J=7.1Hz,2H) ,2.21(dp,J=5.9,2.0Hz,2H),2.17–1.88(m,7H),1.61(t,J=2.2Hz,3H),0.99(d,J=6.6Hz,3H).

[0130] Embodiment 32

[0131]

[0132] Synthesis method

[0133]

[0134] Beraprost (60 mg), chloromethylfurazan N-oxide, DMAP and TEA were dissolved in 2 mL of anhydrous dichloromethane. After stirring at room temperature for four hours, 3 mL of dichloromethane was added to the reaction solution for dilution. The solution was washed twice with 10% hydrochloric acid and once with saturated brine, filtered, and the filtrate was concentrated and purified by HPLC to obtain Example 32 in a yield of 40%. 1 H NMR(300MHz,DMSO-d)δ7.94–7.73(m,2H),7.69–7.50(m,3H),7.13–7.02(m,2H),6.97(ddt,J=7.0 ,2.0,1.0Hz,1H),6.11–5.95(m,2H),5.89–5.64(m,2H),4.94(dt,J=5.0,4.2Hz,1H),4.80(d,J=6 .2Hz,1H),4.22–4.03(m,3H),3.45(dd,J=5.6,4.3Hz,1H),2.88–2.65(m,3H),2.43(t,J=7.1Hz,2 H),2.21(dp,J=5.9,2.0Hz,2H),2.18–1.84(m,5H),1.61(t,J=2.1Hz,3H),1.00(d,J=6.2Hz,3H).

[0135] Embodiment 33

[0136]

[0137] Referring to the synthesis method of Example 32, Compound 33 can be prepared. 1 H NMR(300MHz,DMSO-d)δ8.04–7.90(m,2H),7.73–7.49(m,3H),7.17–7.02(m,2H),6.97(ddt,J =7.0,2.0,1.0Hz,1H),5.93–5.61(m,2H),4.94(dt,J=5.0,4.2Hz,1H),4.63(td,J=6.2,1.0H z,2H),4.43(t,J=6.2Hz,2H),4.27–4.00(m,3H),3.45(dd,J=5.6,4.3Hz,1H),2.88–2.62(m, 3H), 2.40 (t, J = 7.1Hz, 2H), 2.29–1.86 (m, 7H), 1.55 (t, J = 2.1Hz, 3H), 1.01 (d, J = 6.2Hz, 3H).

[0138] Embodiment 34

[0139]

[0140] Referring to the synthesis method of Example 32, Compound 34 can be prepared. 1 H NMR(300MHz,DMSO-d)δ8.12–7.91(m,2H),7.70–7.54(m,3H),7.17–7.04(m,2H),6.97(ddt ,J=7.0,2.0,1.0Hz,1H),5.89–5.63(m,2H),4.94(dt,J=5.0,4.2Hz,1H),4.80(d,J=6.2Hz, 1H),4.43(t,J=6.1Hz,2H),4.24–4.03(m,5H),3.45(dd,J=5.6,4.3Hz,1H),2.88–2.67(m,3 H),2.40(t,J=7.1Hz,2H),2.27–1.85(m,9H),1.57(t,J=1.9Hz,3H),0.99(d,J=6.6Hz,3H).

[0141] Embodiment 35

[0142]

[0143] Referring to the synthetic method of Example 32, Compound 35 can be prepared. 1H NMR(300MHz,DMSO-d)δ8.04–7.84(m,2H),7.70–7.52(m,3H),7.16–7.04(m,2H),6.97(ddt,J=7 .3,1.8,0.9Hz,1H),5.90–5.63(m,2H),4.94(dt,J=5.1,4.2Hz,1H),4.47–4.31(m,2H),4.24–4. 00(m,5H),3.45(dd,J=5.6,4.3Hz,1H),2.89–2.62(m,3H),2.48–2.34(m,2H),2.21(dp,J=5.9, 2.0Hz,2H),2.20–1.87(m,5H),1.87–1.72(m,4H),1.62(t,J=1.8Hz,3H),0.99(d,J=6.2Hz,3H).

[0144] Test Example 1: In vitro NO release test of compounds

[0145] The Griess method uses the released NO to be instantly oxidized in aqueous solution to form NO2 - , NO2 - It forms a complex with Griess reagent, and this complex has strong ultraviolet absorption at 540nm, thereby determining the amount of NO released by the compound.

[0146] 1) Solution preparation: Blank solution: 10 mL DMSO and 190 mL PBS were mixed; Griess reagent: sulfonamide (4.0 g), N-(1-naphthyl)ethylenediamine dihydrochloride (0.2 g) and 10 mL 85% H3PO4 were dissolved in 90 mL distilled water and stirred to a clear solution; L-cysteine ​​solution: After accurately weighing L-cysteine, a certain amount of PBS was added to prepare a 200 μM solution; Test compound solution: The test compound was accurately weighed, dissolved in DMSO and diluted to a concentration of 1 mM, and then diluted with PBS to a concentration of 200 μM.

[0147] 2) Preparation of standard curve equation: Use blank solution to prepare sodium nitrite standard solution concentrations: 0, 0.78, 1.56, 3.13, 6.25, 12.5, 25, 50, 100 μmol / L, take 150 μL of each concentration each time, add 50 μL of Griess reagent and mix well, incubate in a 37°C constant temperature shaker for 30 minutes, measure the absorbance of each tube at 540 nm with an enzyme reader, subtract the blank solution reading and regress to obtain the standard curve equation.

[0148] 3) Test of test compound: 2.5 mL of the prepared test compound solution and L-cysteine ​​solution were mixed, and incubated in a constant temperature shaker at 37°C for 120 min. 150 μL of the mixed solution was taken every 15 min, and 50 μL of Griess reagent was added to mix. After incubation in a constant temperature shaker at 37°C for another 30 min, the absorbance of each tube was measured at 540 nm by an enzyme marker, and the blank solution reading was subtracted and the value was substituted into the standard curve equation to obtain the NO release amount.

[0149] Through testing, the data of some compounds of the present invention are shown in Table 1. The test results show that the nitric oxide donor-type beraprost derivatives or pharmaceutically acceptable salts thereof of the present invention have good NO release effect.

[0150] Table 1. NO release effect of the compounds in the examples

[0151]

[0152]

[0153] Test Example 2: In vivo test in rats with hypoxic pulmonary hypertension

[0154] 1) Experimental instruments and materials: HX-200 animal ventilator and SD male rats used in the experiment were purchased from Yangzhou University. All control groups were raised in normal environment, and the drug intervention group and model group were raised in a low-pressure hypoxia chamber (air pressure 50 kPa, oxygen concentration 10%).

[0155] 2) Experimental procedures: Compound 15 was dissolved in DMSO / solutol / water (10 / 10 / 80) to prepare a clear solution. The drug intervention group was gavaged with compound 15 at a dose of 5 mg / kg starting from the second day of hypoxia. All rats were weighed weekly, and the survival status was recorded. The pulmonary artery pressure was measured four weeks later. Rats were anesthetized with chloral hydrate (100 g / L) (3 ml / kg), fixed in the supine position, tracheotomy, and assisted breathing with a small animal ventilator (frequency 60 times / min, tidal volume 5 ml, respiratory ratio 4:5). The third rib on the left side was freed, and a catheter with a tension transducer at one end was sent to the pulmonary artery, and the mean pulmonary artery pressure (mPAP) was recorded by the BL-420E biofunctional experimental system. Pleural effusion and ascites were examined and collected, and finally blood was drawn from the abdominal aorta to kill the rats.

[0156] 3) Experimental results showed that compared with the control group, the mPAP of the model group rats was significantly increased, and the mPAP of the intervention group treated with compound 15 was lower than that of the model group, which had a good therapeutic effect on hypoxic pulmonary hypertension. Figure 1 The results showed that the nitric oxide donor beraprost derivative compound 15 had therapeutic effect on hypoxic pulmonary hypertension in mice in vivo.

[0157] Test Example 3: Therapeutic Effect on Osteoporosis

[0158] 1) Experimental materials: 1. Animal clean-grade C57BL / 6 strain, 8-10-week-old non-pregnant female mice were purchased from Yangzhou University. 2. Main reagents and instruments: Progynova (estradiol valerate tablets, Bayer); mouse osteocalcin (OC) enzyme-linked immunosorbent assay kit, alkaline phosphatase (ALP) test kit, tartrate-resistant acid phosphatase (StrACP) test kit (all the above kits were purchased from Nanjing Jiancheng). Dual-energy X-ray bone densitometer (HOLOGIC); ECLIPSE 50i microscope (Nikon); MUTISKANMK3 microplate reader (Thermo); tissue sectioning equipment (including KD-TS3D1 biological tissue automatic dehydrator (Zhejiang Kedi), TB-718 biological tissue automatic embedding machine (Hubei Taiwei), R138 rotary slicer (Hubei Taiwei), TK-212 automatic constant temperature slide floater (Hubei Taiwei), TK-213 automatic constant temperature slide drying machine (Hubei Taiwei) etc.).

[0159] 2) Experimental methods: a Animal grouping: Female mice were randomly divided into 4 groups, namely, sham operation group, model group, positive drug group, and test drug group. b Preparation of postmenopausal osteoporosis mouse model: After anesthetizing mice with chloral hydrate, the ovaries were removed in a supine position. In the sham operation group, only the same volume of fat tissue near the ovaries was removed. Vaginal smear examination was performed on the 4th to 8th day after ovariectomy to determine whether the ovariectomy was complete. c Administration method: Administration was performed on the 3rd day after surgery, positive control drug (0.1mL / 10g of Progynova was administered by oral gavage), and the sham operation group and model group were given an equal volume of 0.9% sodium chloride solution, which was continuously administered by oral gavage for 28 days. d Result test: Blood and bone tissue were collected after the 28th day. The following indicators were tested: (1) Determination of bone density: lumbar vertebrae L4-6 were taken to measure bone density using dual-energy X-ray absorptiometry. (2) Observation of bone tissue morphology. Tibia HE staining was used to observe the changes in bone tissue morphology. The trabecular volume ratio (bone volume / tissue volume, BV / TV), trabecular bone number (trabecular bone number, Tb.N) and trabecular separation (trabecular separation, Tb.sp) were mainly tested as quantitative evaluation indicators. (3) Determination of the content of biological markers ALP, StrACP, OC, and E2 in mouse serum. Blood was collected by enucleation and assayed using a kit and enzyme-linked reaction adsorption method. All data were analyzed using SPSS20.0 software.

[0160] 3) Experimental results: Compared with the model group, the test compound can effectively increase the various indicators of lumbar bone density in mice, and the osteocalcin content is significantly reduced; the levels of alkaline phosphatase and acid phosphatase in serum are significantly reduced, indicating that the compound can improve the relevant indicators in estrogen deficiency-induced osteoporosis.

[0161] in, Figure 2 The data of bone density determination of mice after treatment with nitric oxide donor beraprost derivative compound 15 are shown. Table 2 and Table 3 show the data of quantitative indexes of bone morphology and bone metabolism indexes in serum of mice after treatment with compound 15.

[0162] Table 2. Quantitative index data of bone morphology

[0163]

[0164] Table 3. Bone metabolism indexes in mouse serum

[0165]

[0166] Test Example 4: Protective effect of renal tubules in acute renal failure

[0167] 1) Experimental materials, glycerol (McLean); CCK-8 kit, Annexin V-PE apoptosis detection kit, superoxide dismutase activity detection kit, malondialdehyde detection kit (Biyuntian Biotechnology Co., Ltd.); primary antibodies against caspases, caspase3 and 9, B lymphoma-2 gene, Bcl-2 associated X protein (BAX, anti-rabbit), TGF-β1, smad3 (Abcam, USA). Protein gel imager, microplate reader and flow cytometer (Beckman Coulter, CytoFLEX model). Clean grade SD rats were purchased from Yangzhou University.

[0168] 2) Experimental method: establish a rat hind limb injection of glycerol acute renal failure model. After 24 hours, the BUN and Cr levels in the rat serum increased, and the renal interstitial vascular necrosis and inflammatory cell infiltration were considered to be successful. Take part of the renal tissue of the model animal for in vitro culture, separate and identify the renal tubular epithelial cells, and add the test drug for co-culture (0-24 hours), and measure the changes in various biochemical indicators and apoptosis. All data were analyzed statistically.

[0169] 3) Experimental results: Compared with the control group, the OD of the model animal cells after culture (3, 6, 12, 24h) 450, MDA activity, and BCL2 protein levels were decreased, while SOD activity, cell apoptosis rate, and caspase3, caspase9, BAX, TGF-b1, and Smad3 protein levels were increased; compared with the model group, the test compound could cause OD 450 The test compound can promote the proliferation of renal tubular epithelial cells in rats with acute renal failure, inhibit apoptosis, inhibit oxidative stress, and slow down the damage of renal tubular epithelial cells in acute renal failure by inhibiting the expression of pro-apoptotic proteins.

[0170] in Figure 3 The results show the tubular proliferation of mice with acute renal failure treated with compound 15. Tables 4 and 5 show the effects of compound 15 on MDA, SOD and apoptosis rate, apoptotic proteins, TGF-β1 and Smad3 of renal tubular cells in mice with acute renal failure treated with acute renal failure.

[0171] Table 4. Effects of compound 15 on MDA, SOD and apoptosis rate of renal tubular epithelial cells in acute renal failure

[0172]

[0173] Table 5. Effects of compound 15 on apoptotic proteins, TGF-β1 and Smad3 in renal tubular epithelial cells in acute renal failure

[0174] Group Caspase3 Caspase9 BCL2 BAX TGF-β1 Smad3 Control group 0.31±0.08 0.39±0.12 1.07±0.13 0.29±0.09 0.33±0.02 0.11±0.01 Model Group 1.27±0.19 0.88±0.2 0.08±0.02 1.17±0.17 0.91±0.09 0.57±0.08 200 μg / mL Compound 15 group 0.28±0.06 0.48±0.1 0.56±0.11 0.32±0.12 0.24±0.05 0.19±0.07

[0175] Test Example 5: Antiplatelet Aggregation Effect

[0176] 1) Experimental materials: ADP, adrenaline, collagen (Baili Biotechnology)

[0177] 2) Experimental method: Blood samples provided by healthy subjects were mixed with 3.8% citric acid solution and centrifuged at 160r / min to obtain platelet-rich plasma. For calibration data, the obtained platelet-rich plasma was further centrifuged at 2000r / min to obtain platelet-poor plasma, which was stored in a refrigerator at -20°C for later use. The test was performed using Bornl's turbidity method. 225μL of platelet-rich plasma was added to the reaction cup, the example compound was configured into a 50nM solution (25mM Tris-acetate and 120mM NaCl), 25μL of the example compound solution was added, and after incubation at 37°C for 2min, 5μL of ADP (final concentration 2μM) was added to induce platelet aggregation. In order to evaluate the degree of platelet aggregation, the maximum absorbance was taken from the blank group 10min after ADP was added, so as to calculate the inhibition rate of each example compound in inhibiting ADP-induced platelet aggregation. It can be seen from the data in Table 6 below that the compounds described in the examples of the present application all have a good effect of inhibiting ADP-induced platelet aggregation.

[0178] Table 6. Inhibition of ADP-induced platelet aggregation by the example compounds

[0179] Compound Platelet aggregation inhibition rate (%) Compound Platelet aggregation inhibition rate (%) 1 78 19 69 2 66 20 45 3 57 21 81 4 43 22 52 5 64 23 56 6 39 24 47 7 44 25 35 8 61 26 22 9 52 27 35 10 54 28 47 11 67 29 56 12 42 30 52 13 61 31 67 14 48 32 55 15 92 33 82 16 81 34 35 17 59 35 44 18 66

[0180] For those skilled in the art, the present disclosure is not limited to the foregoing illustrative embodiments, but can be embodied in other specific forms without departing from its essential attributes. It is therefore intended that all aspects be considered as illustrative and not restrictive, that reference is made to the embodiments of the appended claims rather than to the foregoing embodiments, that references are made only to the appended claims rather than to the foregoing examples, and that all changes that come within the meaning and scope of equivalents of the claims are therefore intended to be included herein.

[0181] All patents, patent applications, and literature references cited in this specification are hereby incorporated by reference in their entirety. In the event of inconsistency, the present disclosure, including the definitions, will control.

Claims

1. A nitric oxide donor beraprost derivative or a pharmaceutically acceptable salt thereof, characterized in that: It is selected from the following structures:

2. Use of the nitric oxide donor-type beraprost derivative or a pharmaceutically acceptable salt thereof according to claim 1 as a procyclist analog.

3. Use of the nitric oxide donor beraprost derivative or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a drug for treating pulmonary hypertension, myocardial infarction, kidney disease, occlusive arteriosclerosis, diabetic retinopathy, glaucoma, osteoporosis, thromboangiitis, and thromboembolic diseases.

4. A pharmaceutical composition, characterized in that The invention comprises the nitric oxide donor type beraprost derivative or a pharmaceutically acceptable salt thereof as claimed in claim 1 and a pharmaceutically acceptable carrier.

5. The pharmaceutical composition according to claim 4, characterized in that The carrier is any one of a sustained-release agent, an excipient, a filler, a binder, a wetting agent, a disintegrant, an absorption accelerator, an adsorption carrier, a surfactant and a lubricant, or a mixture of two or more thereof.

6. The pharmaceutical composition according to claim 5, characterized in that The pharmaceutical composition is any one of an external preparation, an oral preparation and an injection preparation.

7. A pharmaceutical composition according to claim 6, characterized in that: The oral preparation is any one of granules, capsules and tablets.

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