A hydroxyl-substituted taurine derivative, a synthetic method and application thereof

Abstract

The application provides a hydroxyl-substituted treprostinil derivative, a synthesis method and application thereof, and belongs to the technical field of drugs.The compound is a coupling compound containing treprostinil and a nitric oxide donor, and is shown as follows.The hydroxyl-substituted treprostinil derivative is a combination drug of treprostinil and a NO donor, solves defects of weak curative effect of treprostinil, inconvenience of NO administration, and uncontrollable dosage, and improves the effectiveness of the drug and the compliance of patients through synergistic effect of the two, and the drug effectiveness control is also improved.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a hydroxylated treprostyl derivative, its synthesis method, and its application. Background Technology

[0002] Pulmonary arterial hypertension (PAH) is a malignant disease characterized by increased pulmonary vascular resistance and right ventricular failure. Prostaglandins in the body activate adenylate cyclase by interacting with prostaglandin receptors on platelets or vascular smooth muscle, thereby increasing intracellular cAMP concentration and thus dilating blood vessels.

[0003] Prostacyclin (PGI2) drugs are one of the important types of targeted therapies for the treatment of PAH. Treprositinil, as a prostacyclin analogue, was developed by United Therapeutics and approved by the FDA in 2002. It can specifically bind to the prostacyclin receptor, exerting the effects of relaxing vascular smooth muscle, reducing pulmonary artery pressure, and inhibiting pulmonary artery vascular remodeling and in situ thrombosis. Treprositinil is currently the only prostacyclin drug used for the treatment of PAH that has multiple routes of administration, such as subcutaneous, intravenous, inhalation, or oral subcutaneous / intravenous administration. It has antiplatelet and vasodilatory properties, and its structure is stable with a longer duration of action than other prostacyclins. It is the preferred drug for the treatment of pulmonary arterial hypertension, with strong evidence-based medicine support (Nika Skoro-Sajer, Drugs 2012; James C Coons, et al., Therapeutic Advances in Respiratory Disease, 2021; Steven D Nathan, et al., Lancent Respiratory Medicine, 2021).

[0004] Nitric oxide (NO) is a messenger molecule widely present in the human body with various physiological activities. At physiological concentrations, it can increase intracellular cGMP levels by activating soluble guanylate cyclase in smooth muscle cells, thereby causing vasodilation and regulating blood pressure. NO is also a commonly used drug for pulmonary hypertension and pulmonary embolism (Fernanda Blasina et al., Pulmonary Pharmacology & Therapeutics, 2019; Jeffrey A. Kline, Am Heart J. 2017;), especially advantageous in the treatment of pulmonary hypertension in children and newborns and in the treatment of hospitalized patients with advanced disease (Puthiyachirakkal M et al., Front Pediatr, 2013; Petros AJ and Pierce CM, Paediatr Anaesth, 2006). However, because it is a gas, it must be administered in a hospital and via inhalation. Due to significant individual differences among patients, dosage control is difficult, so its clinical use is gradually decreasing, and it is still used only in hospitalized patients and in critical situations.

[0005] Because the pathogenesis of pulmonary hypertension is complex, combination therapy regimens using two or three drugs with different mechanisms of action have been developed in clinical practice to improve efficacy (White RJ, et al., Am J Respir Crit Care Med, 2020; Verlinden NJ, et al., Pulmonary Circulation 2020). Due to the unique advantages of nitric oxide (NO) and treprostol, which act via two different second messenger pathways (cGMP and cAMP), there is also clinical experience in using combination therapy to improve treatment efficacy (Stacy Mandras, et al., J of Cardiovascular Pharmacol and Therapy, 2021). However, because the two drugs require different administration methods (NO must be inhaled in the hospital, while treprostol can be taken orally, injected, or inhaled), drug use is very inconvenient. Furthermore, the efficacy is weaker, patient compliance is low, and it is difficult to achieve ideal treatment results. Summary of the Invention

[0006] The purpose of this invention is to provide a hydroxylated treprostene derivative, its synthesis method, and its applications. Addressing the weakness in the efficacy of widely used treprostene in clinical practice, this invention provides a NO-conjugated treprostene derivative or its pharmaceutically usable salt. This type of NO-conjugated treprostene derivative or its pharmaceutically usable salt can be used to treat various diseases, including pulmonary hypertension, acute respiratory distress syndrome, arterial occlusive disease, organ fibrosis, kidney disease, eye diseases (such as diabetic retinopathy), osteoporosis, thromboangiitis obliterans, and myocardial infarction.

[0007] The technical solution of this invention is implemented as follows:

[0008] This invention provides a hydroxylated treprostyl derivative having the structure shown in Formula I:

[0009]

[0010] Among them, R1 and R2 are selected from H, Furthermore, R1 and R2 are not both H; where R3 is a straight-chain or branched C1-C chain. 10 Alkyl, C 5-7 cycloalkyl or -C1-C 10 alkyl-aryl ring-, R4 and R5 are straight-chain or branched C1-C 10 Alkyl; wherein C1-C 10 Alkyl, C 5-7 The cycloalkyl or aromatic ring may be substituted with one or more of the following substituents: halogen atom, hydroxyl group, carboxyl group, cyano group, or -(C1-C) group. 10 Alkyl)-ONO2.

[0011] As a further improvement of the present invention, the compound comprises any of the following structures:

[0012]

[0013]

[0014] This invention further protects a method for synthesizing the above-mentioned hydroxylated treprostyl derivative, comprising the following steps:

[0015]

[0016] S1. Starting material A is used to synthesize carboxylic acid nitrate intermediate B via a substitution reaction;

[0017] S2. Raw material C is synthesized via esterification to obtain intermediate D;

[0018] S3. Intermediate C and intermediate B undergo esterification, and three types of substituted intermediates E, F or G are obtained by purification and separation.

[0019] S4. Intermediates E, F, or G undergo deprotection reactions to yield products H, I, or J.

[0020] As a further improvement of the present invention

[0021] The reagents for the S1 substitution reaction include, but are not limited to, silver nitrate and concentrated nitric acid, and the solvents used include, but are not limited to, acetonitrile, dichloromethane, chloroform, acetone, ethyl acetate, toluene, dioxane, etc.

[0022] The condensing agents used in the S2 esterification reaction include, but are not limited to: (1-ethyl-3-(3-dimethylpropylamine)carbodiimide), dicyclohexylcarbodiimide, trifluoromethanesulfonic anhydride, and p-toluenesulfonic acid. The solvents used include, but are not limited to: acetonitrile, dichloromethane, chloroform, acetone, ethyl acetate, toluene, dioxane, etc.

[0023] The condensing agents used in the S3 esterification reaction include, but are not limited to: (1-ethyl-3-(3-dimethylpropylamine)carbodiimide), dicyclohexylcarbodiimide, trifluoromethanesulfonic anhydride, and p-toluenesulfonic acid. The solvents used include, but are not limited to: acetonitrile, dichloromethane, chloroform, acetone, ethyl acetate, toluene, and dioxane.

[0024] The reagents used in the S4 deprotection reaction include, but are not limited to: trifluoroacetic acid, tetrabutylammonium fluoride, tetrabutylammonium iodide, hydrofluoric acid, hydrochloric acid, potassium hydroxide, sodium hydroxide, palladium on carbon, etc., and the solvents used include, but are not limited to: acetonitrile, dichloromethane, chloroform, acetone, ethyl acetate, toluene, dioxane, methanol, ethanol, etc.

[0025] This invention further protects the application of the above-mentioned hydroxylated treprostyl derivative as a procyclosporine analog and nitric oxide coupling.

[0026] This invention further protects the use of the above-mentioned hydroxylated treprostone derivative in the preparation of a therapeutic drug for treating pulmonary hypertension, acute respiratory distress syndrome, arterial occlusive disease, organ fibrosis, nephropathy, diabetic retinopathy, osteoporosis, thromboangiitis obliterans, and myocardial infarction.

[0027] This invention offers the following advantages: It comprises a series of innovative drugs conjugated with treprostyl and NO donors. These drugs combine two key components, treprostyl and NO, and decompose in vivo into treprostyl and NO donors, subsequently producing NO. On one hand, treprostyl provides specific binding to prostaglandin receptors, exerting a vasodilatory effect on vascular smooth muscle. On the other hand, the drug releases NO molecules in vivo, enabling rapid onset of action. Since treprostyl and NO act through different pathways, cGMPS and cAMP respectively, they have a synergistic effect, enhancing vasodilatory efficacy. Furthermore, the drug is easier to administer, addressing patient compliance issues and providing more effective treatment for diseases such as pulmonary hypertension. These compounds can be used in the treatment of various diseases including pulmonary hypertension, acute respiratory distress syndrome, arterial occlusive disease, organ fibrosis, kidney disease, eye diseases (such as diabetic retinopathy), osteoporosis, thromboangiitis obliterans, and myocardial infarction.

[0028] The hydroxylated treprostene derivative of this invention is a class of treprostene and NO donor combination drugs, which solves the defects of weak efficacy of treprostene and inconvenient administration and dosage control of NO. Through the synergistic effect of the two, the efficacy of the drug and patient compliance are improved, and the control of drug efficacy is also improved. Attached Figure Description

[0029] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0030] Figure 1 This is a comparison chart of NO release from different groups of compounds in the experimental examples. Detailed Implementation

[0031] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0032] Example 1: Preparation of Compound 1

[0033]

[0034] The synthesis route is as follows:

[0035]

[0036] The synthesis method is as follows:

[0037] 2-Bromopropionic acid (5 mmol) was dissolved in acetonitrile, and silver nitrate (8 mmol) was added under stirring. The reaction was carried out at 60 °C for 4 hours. The reaction was monitored by TLC until complete. The solvent was evaporated, dichloromethane was added, and the mixture was washed once with water and once with saturated brine. The mixture was then subjected to column chromatography to obtain intermediate 1-B.

[0038] Treprostrinone (100 mg) was dissolved in 10 mL of dichloromethane. 2,4-Dimethylbenzyl alcohol (65 mg), DMAP (25 mg), and EDCI.HCl (66 mg) were added in sequence. The mixture was stirred at room temperature for 14 h. The reaction was confirmed to be complete by TLC. The reaction mixture was diluted with ethyl acetate, washed once with 0.1 M hydrochloric acid aqueous solution, and once with saturated brine. The mixture was purified by column chromatography to obtain intermediate 1-D.

[0039] Intermediate 1-D (0.1 mmol), intermediate 1-B (0.15 mmol), EDCI.HCl (0.2 mmol), and HOBT (0.2 mmol) were dissolved in dichloromethane, stirred at room temperature for 4 hours, and the reaction was monitored by TLC until complete. The solvent was evaporated and purified by column chromatography to obtain intermediate 1-E.

[0040] Intermediate 1-E (0.1 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added and stirred. After reacting at room temperature for 2 hours, the solvent was evaporated and the product was purified by HPLC to obtain compound 1 in 18% yield. 1 H NMR(500MHz,Chloroform-d)δ7.08(t,J=7.9Hz,1H),6.78(dd,J=8.0,1.4Hz,2H),5.05(dt,J=5.6,4. 5Hz,1H),4.80–4.67(m,2H),4.63(t,J=7.1Hz,2H),3.57–3.45(m,1H),3.36(d,J=6.8Hz,1H),2.95(d, J=7.2Hz,2H),2.87–2.71(m,4H),2.32–2.23(m,1H),2.20(dtd,J=7.9,6.2,2.9Hz,1H),2.11–1.96(m ,3H),1.83–1.65(m,2H),1.63–1.51(m,2H),1.47–1.36(m,4H),1.36–1.24(m,4H),0.94–0.80(m,3H).

[0041] Example 2: Preparation of Compound 2

[0042]

[0043] The synthesis route is as follows:

[0044]

[0045] Referring to the synthesis method of intermediate 1-B, intermediate 2-B can be obtained by replacing raw material 1-A with 2-A.

[0046] Intermediate 1-D (0.1 mmol), intermediate 2-B (0.15 mmol), EDCI.HCl (0.2 mmol), and HOBT (0.2 mmol) were dissolved in dichloromethane, stirred at room temperature for 6 hours, and the reaction was monitored by TLC until complete. The solvent was evaporated and purified by HPLC to obtain intermediate 2-C.

[0047] Compound 2 can be prepared by replacing the raw material with 2-C according to the synthesis method of Example 1. 1 H NMR(500MHz,Chloroform-d)δ7.08(t,J=7.9Hz,1H),6.90–6.66(m,2H),4.72(d,J=4.8Hz,2 H),4.58(p,J=5.5Hz,1H),4.32(t,J=5.9Hz,2H),4.04–3.92(m,1H),2.96(d,J=7.2Hz,2H),2 .88–2.61(m,2H),2.46–2.26(m,3H),2.26–2.04(m,2H),1.99–1.72(m,9H),1.66(tdd,J=6. 9,5.5,1.4Hz,2H),1.56(tdd,J=7.2,4.6,1.8Hz,2H),1.44–1.22(m,6H),0.97–0.69(m,3H).

[0048] Example 3: Preparation of Compound 3

[0049]

[0050] Compound 3 can be prepared by replacing the raw material with 4-bromobutyric acid according to the synthesis method of Example 1. 1HNMR(500MHz,Chloroform-d)δ7.08(t,J=7.9Hz,1H),6.94–6.54(m,2H),5.02(ddd,J=5.7,5.0, 4.2Hz,1H),4.88–4.60(m,2H),4.44(td,J=6.1,2.5Hz,2H),3.70–3.45(m,1H),3.36(d,J=6.8Hz ,1H),2.95(d,J=7.2Hz,2H),2.89–2.70(m,2H),2.50(t,J=7.1Hz,2H),2.27(dddd,J=10.8,9.8, 5.4,2.8Hz,1H),2.20(dtd,J=7.9,6.4,2.9Hz,1H),2.13–1.93(m,5H),1.84–1.67(m,2H),1.67–

[0051] 1.50(m,2H),1.45–1.35(m,4H),1.35–1.19(m,4H),0.96–0.70(m,3H).

[0052] Example 4: Preparation of Compound 4

[0053]

[0054] Compound 4 can be prepared by replacing the raw material with 4-bromobutyric acid according to the synthesis method of Example 2. 1 HNMR(500MHz,Chloroform-d)δ7.08(t,J=7.9Hz,1H),6.94–6.66(m,2H),4.81–4.64(m,2H),4.58(p,J= 5.5Hz,1H),4.44(td,J=6.1,2.5Hz,2H),4.08–3.88(m,1H),2.96(d,J=7.2Hz,2H),2.88–2.64(m,2H),2. 49(t,J=7.1Hz,2H),2.39(d,J=5.3Hz,1H),2.23–2.01(m,4H),1.96–1.86(m,2H),1.86–1.72(m,3H),1.6 6(tdd,J=6.6,5.5,1.0Hz,2H),1.56(tdd,J=7.3,4.6,1.8Hz,2H),1.43–1.18(m,6H),1.00–0.60(m,3H).

[0055] Example 5: Preparation of Compound 5

[0056]

[0057] Compound 5 can be prepared by replacing the raw material with 6-bromohexanoic acid, referring to the synthesis method of Example 2. 1 HNMR(500MHz,Chloroform-d)δ7.08(t,J=7.9Hz,1H),6.94–6.68(m,2H),4.72(d,J=4.8Hz,2H),4.5 8(p,J=5.5Hz,1H),4.29(t,J=6.0Hz,2H),4.14–3.80(m,1H),2.96(d,J=7.2Hz,2H),2.87–2.62(m,2 H),2.39(d,J=5.3Hz,1H),2.31(t,J=6.8Hz,2H),2.23–2.04(m,2H),1.99–1.87(m,2H),1.87–1.72( m,5H),1.66(tdd,J=6.9,5.5,1.4Hz,2H),1.62–1.43(m,6H),1.43–1.23(m,6H),0.99–0.72(m,3H).

[0058] Example 6: Preparation of Compound 1

[0059]

[0060] Compound 6 can be prepared by replacing the raw material with 6-bromohexanoic acid, referring to the synthesis method of Example 1. 1 H NMR(500MHz,Chloroform-d)δ7.08(t,J=7.9Hz,1H),6.91–6.64(m,2H),5.14–5.00(m,1H),4 .72(d,J=4.8Hz,2H),4.32(t,J=5.9Hz,2H),3.59–3.42(m,1H),3.36(d,J=6.8Hz,1H),2.95( d,J=7.2Hz,2H),2.89–2.69(m,4H),2.35–2.23(m,1H),2.20(dtd,J=7.9,6.3,2.9Hz,1H),2. 13–1.93(m,3H),1.93–1.65(m,6H),1.65–1.48(m,2H),1.48–1.19(m,8H),0.95–0.70(m,3H).

[0061] Example 7: Preparation of Compound 7

[0062]

[0063] Compound 7 can be prepared by replacing the raw material with 7-bromoheptanoic acid according to the synthesis method of Example 2. 1H NMR(500MHz,Chloroform-d)δ7.07(t,J=7.9Hz,1H),6.88–6.67(m,2H),4.72(d,J=4.8Hz,2H),4.58(p,J=5. 5Hz,1H),4.29(t,J=6.0Hz,2H),4.15–3.89(m,1H),2.96(d,J=7.2Hz,2H),2.87–2.66(m,2H),2.38(d,J=5.3 Hz,1H),2.31(t,J=7.0Hz,2H),2.21–2.06(m,2H),1.98–1.88(m,2H),1.88–1.82(m,1H),1.82–1.74(m,4H), 1.66(tdd,J=6.9,5.5,1.4Hz,2H), 1.56(tdd,J=7.2,4.6,1.8Hz,2H), 1.53–1.25(m,12H), 0.96–0.81(m,3H).

[0064] Example 8: Preparation of Compound 8

[0065]

[0066] Compound 8 can be prepared by replacing the raw material with 7-bromoheptanoic acid according to the synthesis method of Example 1. 1 H NMR(500MHz,Chloroform-d)δ7.08(t,J=7.9Hz,1H),6.92–6.70(m,2H),5.25–4.89(m,1H),4.72( d,J=4.8Hz,2H),4.29(t,J=6.0Hz,2H),3.63–3.44(m,1H),3.36(d,J=6.8Hz,1H),2.95(d,J=7.2H z,2H),2.88–2.68(m,2H),2.37–2.20(m,3H),2.16(dtd,J=7.9,6.4,2.9Hz,1H),2.12–1.93(m,3H ),1.88–1.64(m,4H),1.64–1.46(m,6H),1.46–1.36(m,4H),1.36–1.18(m,4H),1.01–0.83(m,3H).

[0067] Example 9: Preparation of Compound 9

[0068]

[0069] The synthesis route is as follows:

[0070]

[0071] Intermediate 1-D (0.1 mmol), intermediate 1-B (0.3 mmol), EDCI.HCl (0.4 mmol), and HOBT (0.4 mmol) were dissolved in dichloromethane and stirred at room temperature for 6 hours. The reaction was monitored by TLC until complete. The solvent was evaporated and purified by HPLC to obtain intermediate 3-A. Compound 9 can be prepared by referring to the synthesis method in Example 1. 1 H NMR(500MHz,Chloroform-d)δ7.11(t,J=7.8Hz,1H),6.90–6.65(m,2H),5.28–4. 98(m,1H),4.82–4.65(m,2H),4.63–4.26(m,3H),2.96(d,J=7.3Hz,2H),2.89–2. 64(m,6H),2.37–2.21(m,1H),2.16(dtd,J=7.9,6.3,3.0Hz,1H),2.10–1.96(m,3 H),1.82–1.71(m,2H),1.71–1.60(m,4H),1.45–1.19(m,6H),0.96–0.76(m,3H).

[0072] Example 10: Preparation of Compound 10

[0073]

[0074] Compound 10 can be prepared by replacing the raw materials with 8-bromooctanoic acid according to the synthesis method of Example 2. 1 H NMR(500MHz,Chloroform-d)δ7.09(t,J=7.9Hz,1H),6.89–6.65(m,2H),4.88–4.62(m,2H),4.58(p,J=5.5Hz,1H),4 .40–4.14(m,2H),4.02(qd,J=5.5,4.6Hz,1H),2.96(d,J=7.2Hz,2H),2.87–2.62(m,2H),2.38(d,J=5.3Hz,1H),2.3 5–2.24(m,2H),2.22–2.06(m,2H),1.97–1.88(m,2H),1.88–1.71(m,5H),1.66(tdd,J=6.9,5.5,1.4Hz,2H),1.56(t dd,J=7.3,4.6,1.8Hz,2H),1.52–1.45(m,2H),1.42(qd,J=6.7,0.7Hz,2H),1.39–1.22(m,10H),0.94–0.80(m,3H).

[0075] Example 11: Preparation of Compound 11

[0076]

[0077] Compound 11 can be prepared by replacing the raw materials with 9-bromononanoic acid according to the synthesis method of Example 2. 1 H NMR(500MHz,Chloroform-d)δ7.09(t,J=7.9Hz,1H),6.96–6.45(m,2H),4.81–4.65(m,2H),4.58(p,J =5.5Hz,1H),4.29(t,J=6.1Hz,2H),4.02(qd,J=5.5,4.6Hz,1H),2.96(d,J=7.2Hz,2H),2.87–2.65(m ,2H),2.38(d,J=5.3Hz,1H),2.31(t,J=7.1Hz,2H),2.22–2.05(m,2H),1.99–1.87(m,2H),1.87–1.72 (m,5H),1.66(tdd,J=6.9,5.5,1.4Hz,2H),1.60–1.38(m,6H),1.38–1.19(m,12H),1.00–0.73(m,3H).

[0078] Example 12: Preparation of Compound 12

[0079]

[0080] Compound 12 can be prepared by replacing the raw materials with 7-bromoheptanoic acid according to the synthesis method of Example 1. 1 HNMR(500MHz,Chloroform-d)δ7.07(t,J=7.9Hz,1H),6.92–6.60(m,2H),5.14–5.02(m,1H), 4.72(d,J=4.8Hz,2H),4.29(t,J=6.0Hz,2H),3.59–3.41(m,1H),3.37(d,J=6.6Hz,1H),2.95( d,J=7.2Hz,2H),2.87–2.69(m,2H),2.37–2.21(m,3H),2.16(dtd,J=7.9,6.4,2.9Hz,1H),2.1 1–1.92(m,3H),1.84–1.65(m,4H),1.64–1.54(m,2H),1.54–1.20(m,14H),0.99–0.56(m,3H).

[0081] Example 13: Preparation of Compound 13

[0082]

[0083] Compound 13 can be prepared by replacing the raw materials with 10-bromodecanoic acid according to the synthesis method of Example 2. 1 H NMR(500MHz,Chloroform-d)δ7.11(t,J=7.9Hz,1H),6.92–6.57(m,2H),4.80–4.62(m,2H),4.58(p,J=5.5Hz,1 H),4.29(t,J=6.1Hz,2H),4.06(qd,J=5.5,4.6Hz,1H),2.95(dd,J=7.3,1.1Hz,2H),2.83–2.63(m,2H),2.38(d, J=5.3Hz,1H),2.28(t,J=7.0Hz,2H),2.22–2.06(m,2H),1.97–1.87(m,2H),1.86–1.73(m,5H),1.66(tdd,J=6.9 ,5.5,1.4Hz,2H),1.56(tdd,J=7.3,4.6,1.8Hz,2H),1.53–1.39(m,4H),1.39–1.19(m,14H),0.98–0.65(m,3H).

[0084] Example 14: Preparation of Compound 14

[0085]

[0086] Compound 14 can be prepared by replacing the raw material with 6-bromohexanoic acid according to the synthesis method of Example 2. 1 H NMR(500MHz,Chloroform-d)δ7.10(t,J=7.9Hz,1H),6.91–6.59(m,2H),5.09(td,J=5.4,4.2H z,1H),4.83–4.62(m,2H),4.57(p,J=5.6Hz,1H),4.29(t,J=6.1Hz,4H),2.94(d,J=7.2Hz,2H), 2.89–2.60(m,2H),2.34–2.23(m,5H),2.20(dtd,J=8.0,6.2,3.0Hz,1H),2.11–1.95(m,3H),1 .82–1.72(m,6H),1.70–1.61(m,4H),1.61–1.43(m,8H),1.43–1.21(m,6H),1.02–0.72(m,3H).

[0087] Example 15: Preparation of Compound 15

[0088]

[0089] Compound 15 can be prepared by replacing the raw materials with 4-bromocyclohexane-1-carboxylic acid, referring to the synthesis method of Example 2. 1 HNMR(500MHz,Chloroform-d)δ7.07(t,J=7.9Hz,1H),6.88–6.58(m,2H),4.79–4.62( m,3H),4.58(p,J=5.5Hz,1H),4.18–3.76(m,1H),2.96(d,J=7.2Hz,2H),2.86–2.65(m, 2H),2.47–2.31(m,2H),2.21–2.04(m,2H),2.01–1.72(m,13H),1.67(tdd,J=6.9,5.5 ,1.6Hz,2H),1.56(tdd,J=7.2,4.6,1.8Hz,2H),1.43–1.20(m,6H),0.96–0.74(m,3H).

[0090] Example 16: Preparation of Compound 16

[0091]

[0092] Compound 16 can be prepared by replacing the raw materials with 3-bromo-2-methylpropionic acid according to the synthesis method of Example 1. 1 HNMR(500MHz,Chloroform-d)δ7.08(t,J=7.9Hz,1H),6.91–6.66(m,2H),5.00(ddd,J= 5.7,4.9,4.3Hz,1H),4.82–4.63(m,2H),4.37(d,J=6.4Hz,2H),3.61–3.44(m,1H),3.3 6(d,J=6.8Hz,1H),3.02–2.71(m,5H),2.36–2.14(m,2H),2.14–1.92(m,3H),1.87–1.6 5(m,2H),1.65–1.48(m,2H),1.51–1.37(m,4H),1.37–1.17(m,7H),0.96–0.66(m,3H).

[0093] Example 17: Preparation of Compound 17

[0094]

[0095] Compound 17 can be prepared by replacing the raw materials with 2,2-dibromoacetic acid according to the synthesis method of Example 2. 1H NMR(500MHz,Chloroform-d)δ7.09(t,J=7.9Hz,1H),6.91–6.67(m,2H),4.88–4.66(m,2H),4.65– 4.38(m,5H),4.02(qd,J=5.5,4.6Hz,1H),3.10(p,J=6.4Hz,1H),2.96(d,J=7.2Hz,2H),2.88–2.60 (m,2H),2.38(d,J=5.3Hz,1H),2.26–2.05(m,2H),1.98–1.88(m,2H),1.88–1.72(m,3H),1.67(tdd ,J=6.8,5.5,1.2Hz,2H),1.56(tdd,J=7.3,4.6,1.8Hz,2H),1.44–1.21(m,6H),1.04–0.53(m,3H).

[0096] Example 18: Preparation of Compound 18

[0097]

[0098] Compound 18 can be prepared by replacing the raw material with 4-bromo-3-methylbutyric acid according to the synthesis method of Example 2. 1 HNMR(500MHz,Chloroform-d)δ7.08(t,J=7.9Hz,1H),6.90–6.63(m,2H),4.72(d,J=4.8Hz,2H),4.60 (p,J=5.5Hz,1H),4.26–4.14(m,2H),4.10–3.91(m,1H),2.96(d,J=7.2Hz,2H),2.85–2.68(m,2H),2. 42–2.23(m,4H),2.21–2.08(m,2H),1.96–1.87(m,2H),1.87–1.75(m,3H),1.66(tdd,J=6.9,5.5,1.4 Hz,2H),1.56(tdd,J=7.3,4.6,1.8Hz,2H),1.40–1.27(m,6H),1.26–1.20(m,3H),0.96–0.76(m,3H).

[0099] Example 19: Preparation of Compound 19

[0100]

[0101] The synthesis route is as follows:

[0102]

[0103] The synthesis of intermediate 4-A can be found in Molecules, 2012, 17, 7556-7568.

[0104] Intermediate 1-D (0.1 mmol), intermediate 4-A, 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 saline solution. After filtration, the filtrate was concentrated and purified by HPLC to obtain intermediate 4-B.

[0105] Compound 19 can be prepared by referring to the synthesis method of Example 2. 1 H NMR(500MHz,Chloroform-d)δ7.92–7.73(m,2H),7.73–7.49(m,3H),7.10(t,J=7.9Hz,1H),6.7 8(td,J=7.9,1.1Hz,2H),6.11–5.95(m,2H),5.17(td,J=5.4,4.2Hz,1H),4.81–4.64(m,2H),4. 61(p,J=5.5Hz,1H),4.37(d,J=6.4Hz,2H),3.55(s,2H),3.02–2.88(m,2H),2.88–2.66(m,3H), 2.34–1.97(m,5H),1.79–1.68(m,2H),1.68–1.54(m,4H),1.44–1.19(m,9H),0.99–0.73(m,3H).

[0106] Example 20: Preparation of Compound 20

[0107]

[0108] Compound 20 can be prepared by referring to the synthesis method of Example 19. 1HNMR(500MHz,Chloroform-d)δ7.77–7.67(m,2H),7.67–7.55(m,3H),7.10(t,J=7.9Hz,1H),6.78(td,J =7.9,1.2Hz,2H),5.17(td,J=5.4,4.2Hz,1H),4.82–4.68(m,2H),4.68–4.46(m,5H),4.37(d,J=6.4Hz, 2H),3.51(s,2H),3.05–2.88(m,2H),2.88–2.64(m,3H),2.36–2.18(m,2H),2.18–2.09(m,1H),2.09–1. 98(m,2H),1.81–1.68(m,2H),1.65(tdd,J=7.3,6.5,5.1Hz,4H),1.43–1.19(m,9H),0.95–0.77(m,3H).

[0109] Example 21: Preparation of Compound 1

[0110]

[0111] Compound 21 can be prepared by referring to the synthesis method of Example 19. 1 H NMR(500MHz,Chloroform-d)δ7.92–7.74(m,2H),7.69–7.47(m,3H),7.10(t,J=7.9Hz,1H),6.7 8(td,J=7.9,1.1Hz,2H),5.17(td,J=5.4,4.2Hz,1H),4.83–4.65(m,2H),4.61(p,J=5.5Hz,1H) ,4.42–4.32(m,4H),4.21(t,J=6.1Hz,2H),3.51(s,2H),3.06–2.88(m,2H),2.88–2.64(m,3H), 2.36–1.96(m,7H),1.85–1.68(m,2H),1.68–1.55(m,4H),1.46–1.17(m,9H),1.00–0.62(m,3H).

[0112] Experimental Example 1: In vitro NO release test

[0113] Test materials: The blank solution was a mixture of DMSO and PBS; Griess reagent was prepared as follows: sulfonamide (4.0 g), N-(1-naphthyl)ethylenediamine dihydrochloride (0.2 g) and 10 mL of 85% H3PO4 were dissolved in 90 mL of distilled water and stirred until a clear solution was obtained; the test compound (compounds 4, 6, 8, 11, 15 and 21 in this patent example) solution was prepared by accurately weighing the test compound, dissolving it in DMSO and diluting it with PBS to a concentration of 200 μM.

[0114] Experimental method and standard curve equation: 0-100 μmol / L sodium nitrite standard solutions were prepared using blank solutions, mixed with Griess reagent, and incubated in a constant temperature shaker at 37℃ for 30 min. The absorbance was measured at 540 nm, and the standard curve equation was obtained by subtracting the blank solution reading from the absorbance.

[0115] Experimental test: The test compound solution and L-cysteine ​​solution were mixed and incubated in a shaker at 37°C for 120 min. Then, the mixture was mixed with Griess reagent and incubated in a shaker at 37°C for another 30 min. The absorbance at 540 nm was measured, and the NO release was calculated according to the standard curve equation.

[0116] Experimental results: The experimental results are as follows Figure 1 As shown, the compounds in the examples have good NO release effects.

[0117] Experimental Example 2: Antiplatelet Aggregation Effect

[0118] Experimental materials: ADP (adenosine diphosphate), adrenaline, collagen, and platelet aggregation function assay kit (CAT#5393).

[0119] Experimental Methods: Platelet-rich plasma was prepared using blood samples from healthy individuals. Bornl's turbidimetric assay was used for testing. 225 μL of platelet-rich plasma was added to a reaction vessel, followed by 25 μL of a solution of the test compound (the compound in this patent embodiment) prepared as a 1.8-1800 nM solution (25 mM Tris-acetate and 120 mM NaCl). After co-incubation at 37°C for 2 min, ADP was added to a final concentration of 2 μM to induce platelet aggregation. The inhibition rate of the compound against ADP-induced platelet aggregation was evaluated.

[0120] Experimental results: The results are shown in Table 1.

[0121] Table 1. Compounds in the examples inhibit ADP-induced platelet aggregation.

[0122] Compound numbering <![CDATA[Inhibition rate (IC 50 , nM)]]> Compound numbering <![CDATA[Inhibitory rate (IC 50 , nM)]]> 1 15 12 6.4 2 11 13 9.4 3 12 14 6.8 4 9.1 15 7.7 5 9.9 16 5.2 6 4.9 17 9.0 7 5.7 18 4.5 8 10 19 11 9 12 20 18 10 16 21 17 11 13 Pregnant leni 34

[0123] As shown in the table above, the compounds in the examples have a good effect on inhibiting ADP-induced platelet aggregation.

[0124] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A hydroxylated treprostyl derivative, characterized in that, It has the structure shown in Equation I: Formula I; Among them, R1 and R2 are selected from H, or Furthermore, R1 and R2 are not both H; where R3 is a straight-chain or branched C1-C 10 Alkyl, C 5-7 cycloalkyl or -C1-C 10 alkyl-aryl ring-, R4 and R5 are straight-chain or branched C1-C 10 Alkyl; wherein C1-C 10 Alkyl, C 5-7 The cycloalkyl or aromatic ring may be substituted with one or more of the following substituents: halogen atom, hydroxyl group, carboxyl group, cyano group, or -(C1-C) group. 10 Alkyl)-ONO2.

2. The hydroxylated treprostyl derivative according to claim 1, characterized in that, Choose from any of the following structures: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 3. A method for synthesizing a hydroxylated treprostyl derivative as described in claim 1 or 2, characterized in that, Includes the following steps: S1. Starting material A is used to synthesize carboxylic acid nitrate intermediate B via a substitution reaction; S2. Intermediate D is synthesized from raw material C via esterification. S3. Intermediate C and intermediate B undergo esterification, and three types of substituted intermediates E, F, or G are obtained through purification and separation; S4. Intermediates E, F, or G undergo deprotection reactions to yield products H, I, or J.

4. The synthesis method according to claim 3, characterized in that, In the steps described: The reagents for the S1 substitution reaction are selected from silver nitrate or concentrated nitric acid, and the solvents used are selected from acetonitrile, dichloromethane, chloroform, acetone, ethyl acetate, toluene, or dioxane. The condensing agent used in the S2 esterification reaction is selected from (1-ethyl-3(3-dimethylpropylamine)carbodiimide), dicyclohexylcarbodiimide, trifluoromethanesulfonic anhydride or p-toluenesulfonic acid, and the solvent used is selected from acetonitrile, dichloromethane, chloroform, acetone, ethyl acetate, toluene or dioxane. The condensing agent used in the S3 esterification reaction is selected from (1-ethyl-3(3-dimethylpropylamine)carbodiimide), dicyclohexylcarbodiimide, trifluoromethanesulfonic anhydride or p-toluenesulfonic acid, and the solvent used is selected from acetonitrile, dichloromethane, chloroform, acetone, ethyl acetate, toluene or dioxane. The reagents used in the S4 deprotection reaction are selected from trifluoroacetic acid, tetrabutylammonium fluoride, tetrabutylammonium iodide, hydrofluoric acid, hydrochloric acid, potassium hydroxide, sodium hydroxide, or palladium on carbon, and the solvents used are selected from acetonitrile, dichloromethane, chloroform, acetone, ethyl acetate, toluene, dioxane, methanol, or ethanol.

5. The use of a hydroxylated treprostone derivative as described in claim 1 or 2 in the preparation of a therapeutic medicament for treating pulmonary hypertension, acute respiratory distress syndrome, arterial occlusive disease, organ fibrosis, nephropathy, diabetic retinopathy, osteoporosis, thromboangiitis obliterans, or myocardial infarction.

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