Nitric Oxide Donor Drugs of Selexipag Metabolites in the Body

Abstract

The present invention provides a nitric oxide donor drug of a selexipag in vivo metabolite represented by Formula I. The drug can specifically bind to a prostaglandin receptor, play a role in relaxing vascular smooth muscle, and treating pulmonary arterial hypertension. The drug further improves the bioavailability of the selexipag in vivo metabolite, improves its pharmacokinetics, can reduce the dosage and administration frequency, and improves the effectiveness and safety of the drug.

Description

Technical Field

[0001] The present invention belongs to the technical field of medicine, and relates to a drug for treating pulmonary arterial hypertension, in particular to a nitric oxide donor drug of a selexipag metabolite in vivo and its application. Background Art

[0002] Pulmonary arterial hypertension (PAH) is a malignant cardiovascular disease in which the pulmonary artery pressure and pulmonary vascular resistance increase progressively, and ultimately can lead to right heart failure and death of patients, with extremely poor prognosis. The pathogenesis of pulmonary arterial hypertension has not been fully clarified. At present, it is considered that the imbalance between vasoconstriction and vasodilation of pulmonary vessels, in-situ thrombosis formation, abnormal proliferation of endothelium and smooth muscle, inflammatory reaction, and remodeling of pulmonary arterioles play important roles. At present, there are three pathways for targeted drugs for PAH, namely the nitric oxide pathway, the endothelin pathway, and the prostacyclin pathway, which mainly achieve therapeutic effects by improving abnormal contraction of pulmonary arteries and inhibiting proliferation of pulmonary artery smooth muscle cells. Commonly used drugs in the prostacyclin pathway in China include treprostinil and selexipag, among which selexipag is an orally administered highly selective prostacyclin (IP) receptor agonist, and its oral administration method greatly improves patient compliance.

[0003] Selexipag is the first approved oral non-prostacyclin prostacyclin receptor agonist targeting the prostacyclin pathway. Both selexipag and its main active metabolite MRE-269 can highly selectively bind to the prostacyclin receptor, and then produce the effects of vasodilation, anti-proliferation of vascular smooth muscle cells, and anti-vascular fibrosis. In vitro experiments show that the effect of the active metabolite MRE-269 of selexipag on activating the prostacyclin receptor is about 37 times stronger than that of selexipag. Even after the blood drug concentration of selexipag reaches a steady state, the prostacyclin receptor activation effect of MRE-269 is still 3-4 times stronger than that of selexipag. Therefore, at present, MRE-269 is considered to be the main contributor to the pharmacological effect of selexipag.

[0004] The main adverse reactions of selexipag treatment are headache, diarrhea, nausea, jaw pain, vomiting, dyspnea, myalgia, flushing, etc., and the adverse reactions are dose-dependent. Therefore, further improving the bioavailability of selexipag metabolites in vivo, improving its pharmacokinetics, and enhancing the effectiveness and safety of the drug are urgent problems to be solved by those skilled in the art. Summary of the Invention

[0005] In view of the problems existing in the prior art, the present invention provides a nitric oxide donor drug of a selexipag metabolite, which exerts a targeted effect on prostaglandin receptors and regulates the role of NO. The drug can be used for the treatment of pulmonary hypertension, further improving the bioavailability of the selexipag metabolite, improving its pharmacokinetics, reducing the dosage and frequency of administration, and enhancing the effectiveness and safety of the drug.

[0006] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0007] The first aspect of the present invention provides a nitric oxide donor drug of a selexipag metabolite, and its structure is shown in Formula I:

[0008]

[0009] Wherein, n is 0, 1, 2, 3 or 4;

[0010] R is -X-ONO 2 , -OC(O)-X-ONO 2 , -O-X-ONO 2 , or Wherein X is a straight-chain or branched-chain C 1 -C 10 alkylene, C 3-7 cycloalkylene, C 6-10 aryl, C 6-10 aryl-C 1 -C 10 alkylene or C 1 -C 10 alkylene-C 6-10 aryl-C 1 -C 10 alkylene; wherein C 1 -C 10 alkylene, C 3-7 cycloalkylene or C 6-10 aryl may be substituted by one or more of the following substituents: halogen atom, hydroxyl group, carboxyl group, cyano group or -(C 1 -C 10 alkylene)-ONO 2 .

[0011] In some embodiments, X is a straight-chain or branched-chain C 1 -C 6 alkylene, C 4-6 cycloalkylene, phenyl, phenyl-C 1 -C 6 alkylene or C 1 -C 6 alkylene-phenyl-C 1 -C 6Alkylene; wherein C 1 -C 6 Alkylene, C 4-6 Cycloalkylene or phenyl may be substituted by one or more of the following substituents: a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, or -(C 1 -C 6 Alkylene)-ONO 2 .

[0012] The second aspect of the present invention provides a pharmaceutical composition comprising a nitric oxide donor drug of a selexipag metabolite of the present invention and a pharmaceutically acceptable excipient.

[0013] In some embodiments, the pharmaceutical composition further comprises an additional therapeutic agent, and the additional therapeutic agent is a drug suitable for treating pulmonary arterial hypertension, including but not limited to bosentan, ambrisentan, sildenafil, etc.

[0014] The third aspect of the present invention provides the use of the nitric oxide donor drug of the selexipag metabolite or the pharmaceutical composition in the preparation of a drug for treating pulmonary arterial hypertension.

[0015] The fourth aspect of the present invention provides the use of the nitric oxide donor drug of the selexipag metabolite in the preparation of a prostacyclin receptor agonist.

[0016] Compared with the prior art, the present invention has the following beneficial effects:

[0017] A series of nitric oxide donor drugs of selexipag metabolites provided by the present invention can specifically bind to prostaglandin receptors, play a role in relaxing vascular smooth muscle and treating pulmonary arterial hypertension. Further improve the bioavailability of selexipag metabolites, improve their pharmacokinetics, can reduce the dosage and administration frequency, and improve the effectiveness and safety of the drug. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 It is the result of in vivo experiments on rats with hypoxic pulmonary arterial hypertension. DETAILED DESCRIPTION OF THE INVENTION

[0019] Definitions and General Terms

[0020] Unless otherwise specified, the terms of the present invention are defined as follows:

[0021] The term "alkylene" refers to a saturated divalent hydrocarbon group obtained by eliminating two hydrogen atoms from a straight-chain or branched-chain saturated hydrocarbon. Examples of alkylene groups include but are not limited to, methylene (-CH 2 -), ethylene (-CH 2 CH 2 ), propylene (-CH2 CH 2 CH 2 -), ethylene (-CH(CH 3 )-), isopropylidene (-CH(CH 3 )CH 2 -), etc.

[0022] The term "cycloalkylene" refers to a saturated divalent cycloalkyl group obtained by removing two hydrogen atoms from a 3- to 7-membered saturated hydrocarbon ring. Examples of cycloalkylene include, but are not limited to etc.

[0023] The term "halogen atom" refers to F, Cl, Br, or I.

[0024] The term "substituted" means that one or more hydrogen atoms in the given structure are replaced by specific substituents. When more than one position in the given structural formula can be substituted by one or more substituents selected from specific groups, the substituents can be the same or different at each position.

[0025] The term "in vivo metabolite" refers to the product obtained by the metabolic action of a specific compound or its salt in vivo.

[0026] The term "bioavailability" refers to the weight percentage of the compounds disclosed herein that are delivered to the systemic circulation of the animals or humans under study. When administered intravenously, the total exposure of the drug (AUC(0-∞)) is usually defined as 100% bioavailability (F%). "Oral bioavailability" refers to the extent to which the compounds disclosed herein are absorbed into the systemic circulation when an oral pharmaceutical composition is administered, compared to intravenous injection.

[0027] Compound

[0028] The present invention relates to a nitric oxide donor drug of a selexipag in vivo metabolite represented by formula I:

[0029]

[0030] wherein n is 0, 1, 2, 3, or 4;

[0031] R is -X-ONO 2 , -OC(O)-X-ONO 2 , -O-X-ONO 2 , or wherein X is a straight-chain or branched-chain C 1 -C 10 alkylene, C 3-7 cycloalkylene, C 6-10 aryl, C 6-10 aryl-C 1 -C10 Alkylene or C 1 -C 10 Alkylene-C 6-10 Aryl-C 1 -C 10 Alkylene; wherein C 1 -C 10 Alkylene, C 3-7 Cycloalkylene or C 6-10 Aryl may be substituted by one or more of the following substituents: a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, or -(C 1 -C 10 Alkylene)-ONO 2 .

[0032] In some embodiments, X is a straight-chain or branched-chain C 1 -C 6 Alkylene, C 4-6 Cycloalkylene, phenyl, phenyl-C 1 -C 6 Alkylene or C 1 -C 6 Alkylene-phenyl-C 1 -C 6 Alkylene; wherein C 1 -C 6 Alkylene, C 4-6 Cycloalkylene or phenyl may be substituted by one or more of the following substituents: a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, or -(C 1 -C 6 Alkylene)-ONO 2 .

[0033] The compounds of formula I according to the present invention include, but are not limited to, the following specific compounds:

[0034]

[0035]

[0036] Composition

[0037] The pharmaceutical composition of the present invention comprises a compound of formula I and a pharmaceutically acceptable excipient.

[0038] The pharmaceutical excipients described above can be those widely used in the field of drug production. Excipients are mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide methods to enable the active ingredient to dissolve at a desired rate after the subject receives the administration, or to promote the effective absorption of the active ingredient after the subject receives the composition administration. The pharmaceutical excipients described above can be inert fillers, or provide certain functions, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredient of the composition. The pharmaceutical excipients can include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesion agents, glidants, wetting agents, gelling agents, absorption retardants, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents and sweetening agents.

[0039] In some embodiments, the pharmaceutical composition of the present invention further comprises an additional therapeutic agent. The additional therapeutic agent is a drug suitable for treating pulmonary arterial hypertension, including but not limited to bosentan, ambrisentan, sildenafil, etc.

[0040] In some embodiments, the pharmaceutical composition of the present invention is any acceptable oral dosage form, including but not limited to tablets, capsules, cachets, pills, lozenges, powders, syrups, elixirs, suspensions, solutions, emulsions, granules or flat capsules and other dosage forms.

[0041] The pharmaceutical composition of the present invention can be prepared by any method known to those skilled in the art according to the disclosed content. For example, conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or lyophilization processes.

[0042] Use of Compounds and Compositions

[0043] The compound or pharmaceutical composition of the present invention can be used to prepare a drug for treating pulmonary arterial hypertension, or to prepare a prostacyclin receptor agonist.

[0044] Pulmonary arterial hypertension is a pathological phenomenon mainly characterized by vasospasm, intimal hyperplasia and remodeling of pulmonary arterioles. In the late stage, it can cause right heart failure and even death. At rest, when the mean pulmonary artery pressure (mPAP) ≥ 25 mmHg and the pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg are measured by a right heart catheter, pulmonary arterial hypertension can be diagnosed.

[0045] The prostacyclin receptor agonist can increase the concentration of prostacyclin, thereby dilating pulmonary artery smooth muscle, inhibiting smooth muscle hyperplasia and inhibiting platelet aggregation, and improving right heart function and hemodynamics.

[0046] The compounds or compositions of the present invention can act as prostacyclin receptor agonists, specifically bind to prostacyclin receptors, and play a role in relaxing vascular smooth muscle and treating pulmonary arterial hypertension.

[0047] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention. Additionally, it is worth noting that the raw materials involved in the present invention are all ordinary commercially available products unless otherwise specified.

[0048] Example 1

[0049]

[0050] Synthesis route:

[0051]

[0052] Synthesis of Example 1

[0053] The in vivo active compound of selexipag, MRE-269 (prepared with reference to Patent CN201911267969.4) (84 mg), was dissolved in 2 mL of anhydrous DMF. A dichloromethane solution of potassium iodide (52 mg), potassium carbonate (50 mg), and 2-bromoethyl nitrate (70 mg) was added dropwise. The mixture was transferred to 50 °C and stirred for 2 h. The reaction was monitored by TLC and was found to be complete. The solvent was evaporated under reduced pressure, and the product was purified by HPLC to obtain Compound 1 with a yield of 66%.

[0054] 1 H NMR (300 MHz, Chloroform-d) δ 7.86 (s, 1H), 7.68 (ddt, J = 14.6, 6.2, 1.5 Hz, 4H), 7.57–7.43 (m, 4H), 7.43–7.30 (m, 2H), 4.67 (t, J = 6.2 Hz, 2H), 4.46 (t, J = 6.1 Hz, 2H), 4.01 (s, 2H), 3.84 (hept, J = 6.5 Hz, 1H), 3.70 (t, J = 6.3 Hz, 2H), 3.47 (t, J = 6.0 Hz, 2H), 1.92–1.62 (m, 4H), 1.32 (d, J = 6.6 Hz, 6H).

[0055] Example 2

[0056]

[0057] Referring to the synthesis method of Example 1, Compound 2 can be prepared.

[0058] 1 1H NMR (300 MHz, Chloroform-d) δ 7.86 (s, 1H), 7.68 (ddt, J = 14.6, 6.2, 1.5 Hz, 4H), 7.56–7.43 (m, 4H), 7.43–7.17 (m, 2H), 4.41 (t, J = 6.0 Hz, 2H), 4.29 (t, J = 6.1 Hz, 2H), 4.12 (s, 2H), 3.84 (hept, J = 6.5 Hz, 1H), 3.70 (t, J = 6.3 Hz, 2H), 3.47 (t, J = 6.0 Hz, 2H), 2.13 (p, J = 6.2 Hz, 2H), 1.87–1.63 (m, 4H), 1.32 (d, J = 6.6 Hz, 6H).

[0059] Example 3

[0060]

[0061] Compound 3 can be prepared by referring to the synthesis method of Reference Example 1.

[0062] 1 1H NMR (300 MHz, Chloroform-d) δ 7.86 (s, 1H), 7.68 (ddt, J = 15.2, 6.2, 1.5 Hz, 4H), 7.58–7.43 (m, 4H), 7.43–7.27 (m, 2H), 4.48–4.25 (m, 2H), 4.24–4.03 (m, 4H), 3.84 (hept, J = 6.5 Hz, 1H), 3.68 (t, J = 6.3 Hz, 2H), 3.46 (t, J = 6.0 Hz, 2H), 2.01–1.59 (m, 8H), 1.31 (d, J = 6.5 Hz, 6H).

[0063] Example 4

[0064]

[0065] Compound 4 can be prepared by referring to the synthesis method of Reference Example 1.

[0066] 11H NMR (300 MHz, Chloroform-d) δ 7.86 (s, 1H), 7.67 (ddt, J = 11.7, 6.2, 1.5 Hz, 4H), 7.48 (ddt, J = 7.8, 6.4, 1.8 Hz, 4H), 7.44–7.31 (m, 2H), 4.27 (t, J = 6.0 Hz, 2H), 4.16–4.03 (m, 4H), 3.84 (hept, J = 6.5 Hz, 1H), 3.68 (t, J = 6.3 Hz, 2H), 3.47 (t, J = 6.0 Hz, 2H), 1.86–1.64 (m, 8H), 1.64–1.51 (m, 2H), 1.32 (d, J = 6.6 Hz, 6H).

[0067] Example 5

[0068]

[0069] Compound 5 can be prepared by referring to the synthesis method of Reference Example 1.

[0070] 1 1H NMR (300 MHz, Chloroform-d) δ 7.86 (s, 1H), 7.67 (ddt, J = 8.0, 6.1, 1.4 Hz, 4H), 7.53–7.43 (m, 6H), 7.43–7.29 (m, 4H), 5.41 (t, J = 1.0 Hz, 2H), 5.18 (t, J = 0.9 Hz, 2H), 4.09 (s, 2H), 3.84 (hept, J = 6.5 Hz, 1H), 3.68 (t, J = 6.3 Hz, 2H), 3.47 (t, J = 6.0 Hz, 2H), 1.93–1.63 (m, 4H), 1.33 (d, J = 6.6 Hz, 6H).

[0071] Example 6

[0072]

[0073] Compound 6 can be prepared by referring to the synthesis method of Reference Example 1.

[0074] 11H NMR (300 MHz, Chloroform-d) δ 7.86 (s, 1H), 7.67 (ddt, J = 8.0, 6.1, 1.4 Hz, 4H), 7.57–7.44 (m, 4H), 7.44–7.27 (m, 4H), 7.15–6.91 (m, 2H), 5.42 (t, J = 1.0 Hz, 2H), 4.25 (t, J = 6.4 Hz, 2H), 4.20–4.00 (m, 2H), 3.84 (hept, J = 6.5 Hz, 1H), 3.68 (t, J = 6.3 Hz, 2H), 3.47 (t, J = 5.9 Hz, 2H), 2.89 (tt, J = 6.5, 1.0 Hz, 2H), 1.87–1.64 (m, 4H), 1.33 (d, J = 6.6 Hz, 6H).

[0075] Example 7

[0076]

[0077] Compound 7 can be prepared by referring to the synthesis method of Reference Example 1.

[0078] 1 1H NMR (300 MHz, Chloroform-d) δ 7.86 (s, 1H), 7.68 (ddt, J = 15.2, 6.2, 1.5 Hz, 4H), 7.58–7.41 (m, 4H), 7.41–7.26 (m, 2H), 4.84 (p, J = 5.5 Hz, 1H), 4.41 (dd, J = 5.5, 1.1 Hz, 2H), 4.01 (q, J = 15.2 Hz, 2H), 3.84 (hept, J = 6.5 Hz, 1H), 3.76–3.59 (m, 2H), 3.56–3.37 (m, 2H), 1.96–1.61 (m, 6H), 1.32 (dd, J = 25.0, 6.5 Hz, 6H), 0.98 (t, J = 7.4 Hz, 3H).

[0079] Example 8

[0080]

[0081] Compound 8 can be prepared by referring to the synthesis method of Reference Example 1.

[0082] 11H NMR (300 MHz, Chloroform-d) δ 7.86 (s, 1H), 7.77–7.59 (m, 4H), 7.48 (ddt, J = 7.8, 6.4, 1.7 Hz, 4H), 7.42–7.24 (m, 2H), 4.40–4.21 (m, 2H), 4.21–4.00 (m, 4H), 3.84 (hept, J = 6.5 Hz, 1H), 3.78–3.61 (m, 2H), 3.47 (t, J = 6.0 Hz, 2H), 2.01–1.84 (m, 3H), 1.84–1.63 (m, 4H), 1.53 (qdd, J = 7.5, 6.2, 3.2 Hz, 2H), 1.32 (dd, J = 25.0, 6.5 Hz, 6H), 0.91 (t, J = 7.3 Hz, 3H).

[0083] Example 9

[0084]

[0085] Compound 9 can be prepared by referring to the synthesis method of Reference Example 1.

[0086] 1 1H NMR (300 MHz, Chloroform-d) δ 7.86 (s, 1H), 7.67 (ddt, J = 8.0, 6.1, 1.4 Hz, 4H), 7.59–7.42 (m, 4H), 7.42–7.27 (m, 2H), 4.63 (p, J = 5.5 Hz, 1H), 4.10 (s, 2H), 4.04 (d, J = 6.2 Hz, 2H), 3.84 (hept, J = 6.5 Hz, 1H), 3.68 (t, J = 6.3 Hz, 2H), 3.47 (t, J = 6.0 Hz, 2H), 1.95–1.58 (m, 13H), 1.32 (d, J = 6.6 Hz, 6H).

[0087] Example 10

[0088]

[0089] Compound 10 can be prepared by referring to the synthesis method of Reference Example 1.

[0090] 11H NMR (300 MHz, Chloroform-d) δ 7.86 (s, 1H), 7.67 (ddt, J = 11.6, 6.2, 1.5 Hz, 4H), 7.48 (ddt, J = 7.8, 6.5, 1.8 Hz, 4H), 7.44–7.30 (m, 2H), 4.93 (p, J = 6.3 Hz, 1H), 4.14 (s, 2H), 4.03 (d, J = 6.1 Hz, 2H), 3.84 (hept, J = 6.5 Hz, 1H), 3.68 (t, J = 6.3 Hz, 2H), 3.46 (t, J = 6.0 Hz, 2H), 2.23–1.99 (m, 5H), 1.92–1.64 (m, 4H), 1.32 (d, J = 6.6 Hz, 6H).

[0091] Example 11

[0092]

[0093] Compound 11 can be prepared by referring to the synthesis method of Reference Example 1.

[0094] 1 1H NMR (300 MHz, Chloroform-d) δ 7.86 (s, 1H), 7.68 (ddt, J = 15.2, 6.2, 1.5 Hz, 4H), 7.57–7.42 (m, 4H), 7.42–7.29 (m, 2H), 5.13 (s, 2H), 4.62 (t, J = 6.2 Hz, 2H), 4.08 (s, 2H), 3.86 (dt, J = 13.8, 6.4 Hz, 3H), 3.68 (t, J = 6.3 Hz, 2H), 3.47 (t, J = 6.0 Hz, 2H), 1.89–1.64 (m, 4H), 1.32 (d, J = 6.6 Hz, 6H).

[0095] Example 12

[0096]

[0097] Compound 12 can be prepared by referring to the synthesis method of Reference Example 1.

[0098] 11H NMR (300 MHz, Chloroform-d) δ 7.86 (s, 1H), 7.67 (ddt, J = 11.6, 6.2, 1.5 Hz, 4H), 7.56–7.43 (m, 4H), 7.43–7.30 (m, 2H), 4.57 (t, J = 6.2 Hz, 2H), 4.31 (t, J = 6.2 Hz, 2H), 4.02 (s, 2H), 3.93–3.76 (m, 3H), 3.70 (dt, J = 23.1, 6.2 Hz, 4H), 3.47 (t, J = 6.0 Hz, 2H), 1.88–1.63 (m, 4H), 1.32 (d, J = 6.6 Hz, 6H).

[0099] Example 13

[0100]

[0101] Compound 13 can be prepared by referring to the synthesis method of Reference Example 1.

[0102] 1 1H NMR (300 MHz, Chloroform-d) δ 7.86 (s, 1H), 7.77–7.59 (m, 4H), 7.58–7.42 (m, 4H), 7.42–7.26 (m, 2H), 4.57 (t, J = 6.2 Hz, 2H), 4.17 (t, J = 6.1 Hz, 2H), 4.10 (s, 2H), 3.84 (hept, J = 6.5 Hz, 1H), 3.76 (t, J = 6.2 Hz, 2H), 3.68 (t, J = 6.3 Hz, 2H), 3.45 (dt, J = 10.3, 6.0 Hz, 4H), 1.97 (p, J = 6.2 Hz, 2H), 1.88–1.62 (m, 4H), 1.32 (d, J = 6.6 Hz, 6H).

[0103] Example 14

[0104]

[0105] Compound 14 can be prepared by referring to the synthesis method of Reference Example 1.

[0106] 11H NMR (300 MHz, Chloroform-d) δ 7.86 (s, 1H), 7.75–7.61 (m, 4H), 7.48 (ddt, J=7.8, 6.4, 1.8 Hz, 4H), 7.42–7.31 (m, 2H), 4.97 (s, 2H), 4.48–4.32 (m, 4H), 4.01 (s, 2H), 3.84 (hept, J=6.5 Hz, 1H), 3.68 (t, J=6.3 Hz, 2H), 3.46 (t, J=6.0 Hz, 2H), 1.93–1.63 (m, 4H), 1.32 (d, J=6.6 Hz, 6H).

[0107] Example 15

[0108]

[0109] Referring to the synthesis method of Reference Example 1, Compound 15 can be prepared.

[0110] 1 1H NMR (300 MHz, Chloroform-d) δ 7.86 (s, 1H), 7.67 (ddt, J=11.6, 6.2, 1.5 Hz, 4H), 7.57–7.42 (m, 4H), 7.42–7.26 (m, 2H), 5.89 (s, 2H), 5.00 (s, 2H), 4.11 (s, 2H), 3.84 (hept, J=6.5 Hz, 1H), 3.68 (t, J=6.3 Hz, 2H), 3.47 (t, J=6.0 Hz, 2H), 1.93–1.64 (m, 4H), 1.32 (d, J=6.6 Hz, 6H).

[0111] Example 16

[0112]

[0113] Referring to the synthesis method of Reference Example 1, Compound 16 can be prepared.

[0114] 11H NMR (300 MHz, Chloroform-d) δ 7.86 (s, 1H), 7.67 (ddt, J = 7.9, 6.1, 1.4 Hz, 4H), 7.56–7.43 (m, 4H), 7.43–7.27 (m, 2H), 4.62 (t, J = 7.1 Hz, 2H), 4.28–4.08 (m, 6H), 3.84 (hept, J = 6.5 Hz, 1H), 3.68 (t, J = 6.2 Hz, 2H), 3.47 (t, J = 6.0 Hz, 2H), 2.78 (t, J = 7.1 Hz, 2H), 2.05 (p, J = 6.0 Hz, 2H), 1.90–1.62 (m, 4H), 1.32 (d, J = 6.6 Hz, 6H).

[0115] Example 17

[0116]

[0117] Compound 17 can be prepared by referring to the synthesis method of Reference Example 1.

[0118] 1 1H NMR (300 MHz, Chloroform-d) δ 7.86 (s, 1H), 7.72–7.53 (m, 4H), 7.53–7.41 (m, 6H), 7.41–7.21 (m, 4H), 5.41 (t, J = 1.0 Hz, 2H), 5.18 (s, 2H), 4.54 (t, J = 1.0 Hz, 2H), 4.08 (s, 2H), 3.84 (hept, J = 6.5 Hz, 1H), 3.68 (t, J = 6.3 Hz, 2H), 3.47 (t, J = 6.0 Hz, 2H), 1.93–1.59 (m, 4H), 1.33 (d, J = 6.5 Hz, 6H).

[0119] Example 18

[0120]

[0121] Compound 18 can be prepared by referring to the synthesis method of Reference Example 1.

[0122] 11H NMR (300 MHz, Chloroform-d) δ 7.86 (s, 1H), 7.63 (ddt, J = 19.9, 6.2, 1.5 Hz, 4H), 7.52–7.41 (m, 6H), 7.41–7.29 (m, 2H), 7.29–7.10 (m, 2H), 5.90 (s, 2H), 5.42 (t, J = 0.9 Hz, 2H), 4.20–3.97 (m, 2H), 3.84 (hept, J = 6.5 Hz, 1H), 3.68 (t, J = 6.3 Hz, 2H), 3.58 (t, J = 1.0 Hz, 2H), 3.47 (t, J = 6.0 Hz, 2H), 1.89–1.60 (m, 4H), 1.33 (d, J = 6.5 Hz, 6H).

[0123] Example 19

[0124]

[0125] Synthesis method

[0126]

[0127] Dissolve MRE-269 (80 mg), chloromethylfurazan N-oxide, DMAP, and TEA in 2 mL of anhydrous dichloromethane. After stirring at room temperature for four hours, dilute the reaction solution with 3 mL of dichloromethane, wash it twice with 10% hydrochloric acid, once with saturated brine, filter, concentrate the filtrate, and purify it by HPLC to obtain Compound 19 with a yield of 60%.

[0128] 1 1H NMR (300 MHz, Chloroform-d) δ 7.95–7.80 (m, 3H), 7.68–7.55 (m, 5H), 7.55–7.42 (m, 6H), 7.42–7.31 (m, 2H), 6.03 (s, 2H), 4.08 (s, 2H), 3.88 (hept, J = 6.5 Hz, 1H), 3.68 (t, J = 6.3 Hz, 2H), 3.47 (t, J = 6.0 Hz, 2H), 1.95–1.60 (m, 4H), 1.33 (d, J = 6.5 Hz, 6H).

[0129] Example 20

[0130]

[0131] Referring to the synthesis method of Example 19, Compound 20 can be prepared.

[0132] 11H NMR (300 MHz, Chloroform-d) δ 7.86 (s, 1H), 7.72–7.43 (m, 13H), 7.43–7.24 (m, 2H), 4.68–4.38 (m, 4H), 4.01 (s, 2H), 3.88 (hept, J = 6.5 Hz, 1H), 3.68 (t, J = 6.3 Hz, 2H), 3.46 (t, J = 6.0 Hz, 2H), 1.93–1.55 (m, 4H), 1.33 (d, J = 6.5 Hz, 6H).

[0133] Example 21

[0134]

[0135] Referring to the synthesis method of Reference Example 19, Compound 21 can be prepared.

[0136] 1 1H NMR (300 MHz, Chloroform-d) δ 7.92–7.76 (m, 3H), 7.66–7.53 (m, 5H), 7.53–7.42 (m, 6H), 4.38 (t, J = 6.1 Hz, 2H), 4.21 (t, J = 6.1 Hz, 2H), 4.10 (s, 2H), 3.88 (hept, J = 6.5 Hz, 1H), 3.68 (t, J = 6.3 Hz, 2H), 3.46 (t, J = 6.0 Hz, 2H), 2.15 (p, J = 6.1 Hz, 2H), 1.85–1.63 (m, 4H), 1.33 (d, J = 6.5 Hz, 6H).

[0137] Test Example 1

[0138] In vivo test on rats with hypoxic pulmonary hypertension

[0139] (I) Experimental instruments and materials

[0140] HX-200 animal ventilator. All male SD rats used in the experiment were purchased from Yangzhou University, and normal saline was used. All control groups were raised in a normal environment, while the intervention group and the model group were raised in a low-pressure and low-oxygen chamber (air pressure 50 kPa, oxygen concentration 10%).

[0141] (II) Experimental procedures

[0142] Compound 1 was dissolved in DMSO / solutol / water (10 / 10 / 80) to prepare a clear solution. In the intervention group, starting from the second day of hypoxia, compound 1 was administered by gavage at a dose of 5 mg / kg. All rats were weighed weekly, and their survival status was recorded. After four weeks, the pulmonary artery pressure was measured. The rats were anesthetized with chloral hydrate (100 g / L) (3 mL / kg), fixed in the supine position, tracheotomized, and assisted with respiration using a small animal ventilator (frequency 60 times / min, tidal volume 5 mL, inhalation-exhalation ratio 4:5). The left 3rd rib was dissected free, and a catheter connected to a tension transducer at one end was inserted into the pulmonary artery. The mean pulmonary artery pressure (mPAP) was recorded using a BL-420E biological function experimental system. The pleural effusion and ascites were examined and collected, and finally, the rats were sacrificed by drawing blood from the abdominal aorta.

[0143] (III) Experimental results

[0144] See Appendix Figure 1 , compared with the control group, the mPAP of the rats in the model group was significantly increased, and the mPAP of the intervention group administered compound 1 was lower than that of the model group.

[0145] Test Example 2

[0146] Pharmacokinetic experiment of the compound

[0147] (I) Experimental instruments and materials

[0148] High-speed refrigerated centrifuge, vortex oscillator (Vortex Genius3), high-speed centrifuge (Eppendorf5415D), disposable syringe, pipette (Eppendorf). All male SD rats used in the experiment were purchased from Yangzhou University. EDTA-K2 vacuum blood collection tubes and normal saline were used. All rats in the oral administration group were fasted for 12 h before drug administration, allowed free access to water, and free access to food and water during drug administration.

[0149] (II) Experimental procedures

[0150] The compounds of the embodiments of the present invention were dissolved in DMSO / solutol / water (10 / 10 / 80) to prepare a clear solution. The dose of the compound administered by gavage was 25 mg / kg, and the dose of the compound administered via the tail vein was 5 mg / kg. At 2 min, 10 min, 30 min, 1 h, 2 h, 3 h, 5 h, 8 h, 12 h, 16 h, and 24 h after tail vein administration, 0.5 mL of blood was continuously collected from the fundus venous plexus into heparin tubes. At 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 5 h, 8 h, 12 h, 16 h, and 24 h after gavage administration, 0.5 mL of blood was continuously collected from the fundus venous plexus into heparin tubes. After centrifuging the samples at 8000 r at 4 °C for 10 min, 0.15 mL of the upper plasma was taken and stored at -20 °C, and then LC-MS / MS analysis was performed. The data was analyzed by the WinNolin non-compartmental model to obtain the key pharmacokinetic parameters.

[0151] (III) Experimental Results

[0152] Table 1 Pharmacokinetic Parameters of the Compound

[0153]

[0154] From the above experimental results, it can be found that compared with the peak time (1.8 h) and half-life (3 h) of selexipag, the compounds of the present invention significantly prolonged the peak time and half-life, and have excellent potential for long-acting administration and good potential for oral administration.

[0155] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than a limitation on the protection scope of the present invention. Any simple modification or equivalent replacement of the technical solution of the present invention by those of ordinary skill in the art does not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A nitric oxide donor drug of a selexipag in vivo metabolite as shown in Formula I: (Formula I); Wherein, n is 0, 1, 2, 3 or 4; R is -X-ONO 2 , -OC(O)-X-ONO 2 , -O-X-ONO 2 , or ; wherein X is a straight-chain or branched-chain C 1 -C 6 alkylene, C 4-6 cycloalkylene or phenyl-C 1 -C 6 alkylene.

2. The nitric oxide donor drug of the selexipag in vivo metabolite according to claim 1, characterized in that, The compound of Formula I is selected from the following structures: 。 3. A pharmaceutical composition comprising the nitric oxide donor drug of the selexipag in vivo metabolite according to any one of claims 1-2 and a pharmaceutically acceptable excipient.

4. The pharmaceutical composition according to claim 3, characterized in that, The composition further comprises an additional therapeutic agent, and the additional therapeutic agent is bosentan, ambrisentan and / or sildenafil.

5. The pharmaceutical composition according to claim 3 or 4, characterized in that, The pharmaceutical composition is an oral dosage form.

6. The pharmaceutical composition according to claim 5, wherein the oral dosage form includes tablets, capsules, pills, powders, syrups, suspensions, solutions, emulsions or granules.

7. Use of the nitric oxide donor drug of the selexipag in vivo metabolite according to any one of claims 1-2 or the pharmaceutical composition according to any one of claims 3-6 in the preparation of a drug for treating pulmonary arterial hypertension.

8. Use of the nitric oxide donor drug of the selexipag in vivo metabolite according to any one of claims 1-2 or the pharmaceutical composition according to any one of claims 3-6 in the preparation of a prostacyclin receptor agonist.

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