Class of salt compounds of isosorbide mononitrate derivatives and use thereof

Abstract

The present invention belongs to the field of pharmaceuticals. Disclosed in the present invention are a class of salt compounds of isosorbide mononitrate derivatives and the use thereof. Salts formed by the isosorbide mononitrate derivatives of the present invention and D-cycloserine exhibit dual activities as a nitric oxide donor and a partial NMDA receptor agonist. The present invention further relates to the use of the salts formed by the isosorbide mononitrate derivatives and D-cycloserine in a drug for treating cerebral stroke or the recovery period of cerebral stroke.

Description

Salt compounds of a class of isosorbide mononitrate derivatives and uses thereof

[0001] The present application claims priority to the Chinese patent application No. 2024112985671, filed on September 18, 2024, and entitled "Salt compounds of a class of isosorbide mononitrate derivatives and uses thereof", the entire content of which is incorporated herein by reference. TECHNICAL FIELD

[0002] The present application belongs to the technical field of pharmacy, and specifically relates to salt compounds of a class of isosorbide mononitrate derivatives and uses thereof. BACKGROUND

[0003] Stroke, commonly known as apoplexy, is divided into two types of ischemic stroke and hemorrhagic stroke, which is caused by various reasons leading to damage of cerebral blood vessels, resulting in focal or whole brain tissue damage. The disease has a higher incidence in cold seasons, and the incidence peak usually occurs in the time period close to noon. Stroke has the characteristics of high incidence, disability rate, recurrence rate and mortality, and is the primary cause of death of Chinese residents. Among them, ischemic stroke accounts for 75% to 90% of all strokes, and hemorrhagic stroke accounts for 10% to 25%.

[0004] The present application discloses a salt formed by a class of isosorbide mononitrate derivatives and D-cycloserine, which has dual activity of releasing nitric oxide and partially agonizing NMDA receptors, and can be used for preparing a drug for treating stroke or recovery period of stroke. SUMMARY

[0005] The technical problem solved by the present application is to provide salt compounds of a class of isosorbide mononitrate derivatives and uses thereof, which have dual activity of releasing nitric oxide and partially agonizing NMDA receptors, and can be used for preparing a drug for treating stroke or recovery period of stroke.

[0006] The technical solution is a class of compounds as shown in formula I or pharmaceutically acceptable salts, deuterium compounds and solvates thereof, formula I is as follows:

[0007] wherein A is a nitric oxide donor active molecule;

[0008] n is selected from the numbers 1, 2, 3, 4, 5 and 6.

[0009] A pharmaceutical composition, which comprises A is a nitric oxide donor active molecule and D-cycloserine and deuterium compounds and solvates thereof.

[0010] As a preferred, wherein A is as follows:

[0011] wherein A is selected from the group consisting of ester compounds formed from mononitrate isosorbide and diacid or polyacid or pharmaceutically acceptable salts, deuterium compounds, solvates, racemic mixtures, enantiomers, diastereomers and tautomers thereof;

[0012] The number of protons (H + ) in the polyacid is 3, 4, 5, 6.

[0013] As preferred, the diacid or polyacid is selected from the group consisting of sulfuric acid, phosphoric acid, carbonic acid, sulfurous acid, phosphorous acid, ethanedioic acid, propanedioic acid, butanedioic acid, butenedioic acid, citric acid, malic acid, glutaric acid, adipic acid, heptanedioic acid, octanedioic acid, acidic amino acid.

[0014] As preferred, the diacid or polyacid is selected from the group consisting of sulfuric acid, phosphoric acid, carbonic acid, sulfurous acid, phosphorous acid, ethanedioic acid, propanedioic acid, butanedioic acid, butenedioic acid, citric acid, malic acid, glutaric acid, aspartic acid.

[0015] As preferred, the diacid or polyacid is selected from the group consisting of sulfuric acid, phosphoric acid, carbonic acid, sulfurous acid, and phosphorous acid.

[0016] As preferred, the diacid or polyacid is selected from the group consisting of ethanedioic acid, propanedioic acid, butanedioic acid, butenedioic acid, citric acid, malic acid, glutaric acid, and adipic acid.

[0017] As preferred, the diacid or polyacid is selected from the group consisting of glutamic acid and aspartic acid.

[0018] As preferred, the compound of formula I is selected from the group consisting of:

[0019] S1 is as shown in the above figure;

[0020] S2 is as shown in the above figure;

[0021] S3 is as shown in the above figure;

[0022] S4 is as shown in the above figure;

[0023] S5 is as shown in the above figure.

[0024] S6 is as shown in the above figure;

[0025] S7 is as shown in the above figure;

[0026] S8 is as shown in the above figure;

[0027] S9 is shown in the above figure;

[0028] S10 is shown in the above figure;

[0029] S11 is shown in the above figure.

[0030] The compound according to any one of the above or a pharmaceutically acceptable salt, deuterated compound and solvate thereof, use of the compound in the preparation of a drug for treating stroke or stroke recovery.

[0031] The pharmaceutically acceptable salt of the present application refers to the salt form of the compound which is suitable for contacting with human or animal tissues within the scope of medical judgment, and has no excessive toxicity, irritation, allergic reaction or other problems or complications, and is commensurate with a reasonable benefit / risk ratio. Such salt can be prepared by reacting a free acid or base of the compound with a suitable acid or base, including but not limited to alkali metal salts (such as sodium salt, potassium salt), alkaline earth metal salts (such as calcium salt, magnesium salt), ammonium salts and acid addition salts formed with organic or inorganic acids. Common inorganic acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, etc., and common organic acids include acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, etc. These salts may differ from the parent compound in some physical properties (such as solubility), but retain the biological efficacy of the parent compound without biological adverse effects.

[0032] The "deuterated compound" of the present application refers to a derivative formed by replacing one or more hydrogen atoms (H) in the molecule of the compound of the present application with a deuterium atom (D).

[0033] The deuterium substitution form of the deuterated compound includes mono-substitution, di-substitution, multi-substitution and full substitution; wherein the content of deuterium isotope at each deuterium substitution position meets the following conditions: generally higher than the natural deuterium isotope content (0.015%), preferably higher than 30%, more preferably higher than 50%, further preferably higher than 75%, most preferably higher than 99%.

[0034] Compared with the corresponding non-deuterated compound, the deuterated compound may have differences in chemical properties, in vivo metabolic processes, etc., which can affect the pharmacokinetic parameters, pharmacodynamic activity and bioavailability of the compound, etc., and thus endow the compound with potential pharmaceutical advantages in specific scenarios, such as improving drug stability, reducing in vivo metabolic rate, etc.

[0035] A solvate refers to a specific ratio of a complex formed by the combination of a compound and solvent molecules through non-covalent intermolecular forces (such as hydrogen bonds, Van der Waals forces, etc.), which can be in the form of stoichiometric or non-stoichiometric combination. When the solvent is water, the solvate formed is specifically referred to as "hydrate". The formation of the solvate can change the solubility, stability, melting point, etc. of the compound, which can affect the application of the compound in the preparation and administration of pharmaceutical preparations.

[0036] The preferred "pharmaceutically acceptable solvate" in the present application refers to a solvate form suitable for the preparation and administration of pharmaceutical preparations within the scope of medical judgment; the solvent used should meet the standard of pharmaceutical acceptability, and the combination of the solvent and the compound should not introduce excessive toxicity or other adverse effects.

[0037] The stroke referred to in the present application is also called cerebrovascular accident, which refers to a class of acute cerebrovascular diseases caused by brain tissue damage due to sudden rupture of cerebral blood vessels or blood vessel obstruction. Its pathogenesis mainly includes two categories: hemorrhagic stroke and ischemic stroke. Hemorrhagic stroke is due to the rupture of intracerebral blood vessels, and blood flows into the brain parenchyma or the space around the brain, forming cerebral hemorrhage or subarachnoid hemorrhage; ischemic stroke is due to cerebral vascular obstruction, leading to necrosis of brain tissue due to ischemia, and the common types include cerebral infarction and transient ischemic attack.

[0038] The "stroke recovery period" referred to in the present application refers to the stage after the acute stage of stroke patients, when the disease tends to be stable, and the core of which is functional recovery and rehabilitation treatment.

[0039] The starting time of this stage is when the patient's vital signs are stable and the neurological symptoms no longer progress; the duration varies due to individual differences (such as disease severity, underlying health status, rehabilitation intervention effect, etc.), and usually can last for several months to several years.

[0040] A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt, deuterated compound, and solvate thereof according to any one of the above and a pharmaceutically acceptable carrier.

[0041] The dosage form of the pharmaceutical composition according to the present application includes but is not limited to tablets, capsules, granules, injections, oral liquid preparations, ointments, suppositories, powders, suspensions, emulsions, aerosols, sprays, patches, gels, films, dripping pills, pellets, sustained-release preparations, controlled-release preparations, and targeted preparations.

[0042] The medicine also includes other medicines for treating stroke or recovery period of stroke. The other medicines for treating stroke or recovery period of stroke include, but are not limited to, edaravone, butylphthalide soft capsules, aspirin, ginkgo biloba extract, clopidogrel, atorvastatin, alteplase, urokinase, citicoline, tenecteplase.

[0043] The medicine and the other medicines for treating stroke or recovery period of stroke can exist independently or in mixture, and the dosage forms can be the same or different.

[0044] The present application also provides a method for treating stroke, which comprises administering the medicine.

[0045] The administration of the medicine includes oral administration, intravenous injection, intramuscular injection, subcutaneous injection, intraperitoneal injection, topical administration, etc.

[0046] In the present application, when the medicine comprises the medicine and other therapeutic agents, two or more medicines can be administered simultaneously or sequentially, and the present application does not limit this. Beneficial effects:

[0047] The present application provides a kind of salt compound formed by mononitrate isosorbide derivative and D-cycloserine, which has dual activity of releasing nitric oxide and NMDA receptor partial agonist, and can be used for preparing medicine for treating stroke or recovery period of stroke. DETAILED DESCRIPTION

[0048] The technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the embodiments of the present application. Obviously, the described embodiments are only a part of the embodiments of the present application, not all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application.

[0049] Preparation of intermediates;

[0050] Synthesis of intermediate B1;

[0051] Synthetic route:

[0052] Synthetic process:

[0053] Take (100 mg, 0.53 mmol) mononitrate isosorbide, dissolved with DCM (2 ml), after nitrogen protection, cooling to 0 degrees, take POCl3(87.7 mg, 0.57 mmol) dissolved with (0.5 ml) DCM, slowly drop into the reaction system, after adding, natural rise to room temperature, reaction 6 h, after complete, the system is cooled to 0-5 degrees, 0.25 ml water is added to quench the reaction, the reaction solution is directly concentrated to dryness, preparative liquid phase separation and purification, water and acetonitrile system, freeze-drying to obtain the product (122 mg 85%), colorless oil.

[0054] ESI-MS: 270.0 [M-H]-

[0055] Synthesis of intermediate B2

[0056] Synthesis route:

[0057] Synthesis process:

[0058] Take (100 mg, 0.53 mmol) mononitrate isosorbide, dissolved with DCM (2 ml), after nitrogen protection, cooling to 0 degrees, take oxalyl chloride (71.7 mg, 0.57 mmol) dissolved with (0.5 ml) DCM, slowly drop into the reaction system, after adding, natural rise to room temperature, reaction 6 h, after complete, the system is cooled to 0-5 degrees, 0.25 ml water is added to quench the reaction, the reaction solution is directly concentrated to dryness, preparative liquid phase separation and purification, water and acetonitrile system, freeze-drying to obtain the product (128 mg 92%), white solid.

[0059] ESI-MS: 262.0 [M-H]-

[0060] Synthesis of intermediate B3

[0061] Synthesis route:

[0062] Synthesis process:

[0063] First step:

[0064] Compound B3-1 (300 mg, 1.72 mmol, 1.0 eq) was dissolved in dichloromethane (10 ml

[0065] ) were added successively. The reaction was stirred at room temperature for 16 h. After the reaction was completed, the mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (PE / EA = 100 / 1 ~ 3 / 1) to give compound B3-2 (400 mg, 66%) as a white solid.

[0066] Second step:

[0067] Compound B3-2 (4.0 g, 11.52 mmol, 1.0 eq) was added to 40 ml acetic acid, and then 20 ml water was added. The reaction was stirred at 60 °C for 2 h. After the reaction was completed, the reaction liquid was concentrated, and the crude product was purified by pre-HPLC (C18, formic acid-water / acetonitrile) to give B3 (2.1 g, 59%) as a white solid.

[0068] ESI-MS: 305.80 [M-H]-

[0069] 1H NMR (400 MHz, DMSO-d6) δ 5.47 (td, J = 5.4, 2.2 Hz, 1H), 5.06 (d, J = 3.2 Hz, 1H), 4.93 (t, J = 5.3 Hz, 1H), 4.37 (d, J = 5.0 Hz, 1H), 4.22 (dd, J = 7.8, 5.0 Hz, 1H), 3.98 - 3.88 (m, 2H), 3.86 - 3.73 (m, 2H), 2.68 (dd, J = 15.4, 5.0 Hz, 1H), 2.55 - 2.49 (m, 1H).

[0070] Synthesis of intermediates B4 and B5

[0071] Synthetic route:

[0072] Synthetic procedure:

[0073] First step:

[0074] Anhydrous citric acid B4-1 (19.20 g, 0.10 mol), acetic anhydride (9.01 g, 0.15 mol) and 30 ml acetic acid were weighed. It was heated to 40 °C and stirred until the citric acid was completely consumed. Then the reaction liquid was concentrated and directly used for the next step.

[0075] Second step:

[0076] Dissolve compound B4-2 (33.0 g, 172.4 mmol, 2 eq) in THF (400 ml). Then add mononitrate isosorbide (15.0 g, 86.2 mmol, 1 eq). Stir the reaction at reflux for 16 h. After completion of the reaction, the mixture was purified by Prep-HPLC (C18, HCOOH-H20 / ACN) to give B4 (1.8 g, 4.9%) as colorless oil and B5 (1.9 g, 5.2%) as colorless oil.

[0077] B4 = ESI-MS: 365.75 [M+H]+

[0078] 1 H NMR (400 MHz, DMSO-d6) δ 5.47 (tt, J = 5.6, 1.7 Hz, 1H), 5.03 (dd, J = 4.8, 3.3 Hz, 1H), 4.93 (q, J = 5.6 Hz, 1H), 4.36 (t, J = 5.1 Hz, 1H), 4.01 - 3.69 (m, 4H), 2.82 - 2.53 (m, 4H).

[0079] B5 = ESI-MS: 365.80 [M+H]+

[0080] 1 H NMR (400 MHz, DMSO-d6) δ 5.48 (td, J = 5.5, 2.4 Hz, 1H), 5.05 (d, J = 3.2 Hz, 1H), 4.90 (t, J = 5.3 Hz, 1H), 4.42 (d, J = 5.0 Hz, 1H), 4.06 (s, 1H), 3.99 - 3.74 (m, 4H), 2.77 - 2.55 (m, 4H).

[0081] Synthesis of intermediate B6

[0082] Synthesis route:

[0083] Synthesis procedure:

[0084] First step:

[0085] Dissolve compound B6-1 hydrochloride (500 mg, 3.13 mmol) in DCM (5 mL), cool to -10 degrees, add PCl5 (731 mg, 0.44 mmol), after addition, warm to about 5 degrees, react for 8 h, after completion of the reaction, directly filter to obtain product 490 mg (89% yield), light brown solid.

[0086] ESI-MS: 139.03 [M+H]+

[0087] 1H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 3H), 4.12 (t, J = 11.7 Hz, 2H), 3.81 (s, 3H).

[0088] Second Step:

[0089] The hydrochloride salt of intermediate B6-2 (480 mg 3.54 mmol) was dissolved in 1.4 ml water, cooled to -10 degrees, and solid hydroxylamine hydrochloride (270 mg, 3.89 mmol) was added. After stirring for 5 min, a solution of sodium hydroxide (553 mg, 13.28 mmol, dissolved in 1 ml water) was added dropwise slowly. After the addition was complete, the reaction was maintained for 4 h. Then the temperature was raised to 45 degrees and the reaction was maintained for 30 min. The reaction solution was concentrated, 2.5 ml of methanol was added, and the mixture was stirred at room temperature for 15 min. The mother liquor was collected by filtration. The mother liquor was cooled to -5 degrees, and acetic acid was added to adjust the pH to 6-7. The light brown product was collected by filtration, 50 mg (13.7% yield).

[0090] ESI-MS: 104.05 [M+H]+

[0091] 1H NMR (400 MHz, DMSO-D6) 3.91 (t, J = 7.9 Hz, 1H), 3.84 (dd, J = 8.7, 7.9 Hz, 1H).

[0092] Synthesis of Intermediate B7

[0093] Synthesis Route:

[0094] Synthesis Process:

[0095] First Step:

[0096] The hydrochloride salt of compound B7-1 (1.47 g, 9.08 mmol) was suspended in DCM (15 mL) and cooled to -10 degrees. PCl5 (2.12 g, 9.99 mmol) was added, and the temperature was raised to about 5 degrees. The reaction was maintained for 8 h. The product was collected by filtration directly after the reaction was completed, 1.56 g (97% yield) of light brown solid.

[0097] ESI-MS: 141.04 [M+H]+

[0098] 1H NMR (400 MHz, DMSO-d6) δ 9.16 - 8.64 (m, 3H), 3.80 (s, 3H).

[0099] Second Step:

[0100] The hydrochloride salt of intermediate B7-2 (780 mg, 4.41 mmol) was dissolved in 2.4 ml of water, cooled to -10 degrees, and solid hydroxylamine hydrochloride (337 mg, 4.85 mmol) was added. After stirring for 5 min, a solution of sodium hydroxide (689 mg, 16.54 mmol) in 1.6 ml of water was added dropwise. The reaction was maintained for 4 h at -10 degrees, then warmed to 45 degrees for 30 min. The reaction mixture was concentrated, 4.3 ml of methanol was added, and the mixture was stirred for 15 min at room temperature. The mother liquor was collected by filtration. The mother liquor was cooled to -5 degrees, and the pH was adjusted to 6-7 with acetic acid. The filtered light brown product was 47 mg (10.1% yield).

[0101] ESI-MS: 106.06 [M+H]+

[0102] Example 1: Synthesis of compound S1

[0103] Synthetic route:

[0104] Synthetic process:

[0105] Phosphonate intermediate B1 (1.28 g, 4.72 mmol) was dissolved in methanol (15 ml), and the system was cooled to 0-5 degrees. D-cycloserine (0.48 g, 4.72 mmol) was dissolved in pure water (10 ml) and added slowly to the above reaction solution. After the addition was complete, the system was allowed to warm to room temperature and react for 12 h. THF: MTBE (30 ml + 15 ml) was added, and the mixture was stirred at 5 degrees for 1 h. The solid was filtered off and dried under vacuum to obtain 1.5 g of the target product.

[0106] 1 H NMR (400 MHz, DMSO-d6) δ 5.49 (td, J = 5.4, 2.2 Hz, 1H), 4.92 (t, J = 5.2 Hz, 1H), 4.61 - 4.42 (m, 3H), 4.19 - 4.13 (m, 1H), 4.03 (t, J = 9.0 Hz, 1H), 3.99 - 3.91 (m, 2H), 3.84 (dd, J = 11.4, 5.3 Hz, 1H), 3.68 (ddd, J = 10.0, 3.2, 1.3 Hz, 1H).

[0107] Example 2: Synthesis of compound S2

[0108] Synthetic route:

[0109] Synthetic process:

[0110] Take oxalate intermediate B2 (0.6g, 2.29mmol) with methanol (15ml) to dissolve, the system cooling to 0~5℃. Take D-cycloserine (0.238g, 2.29mmol) with pure water (18ml) to dissolve, slowly drop into the above reaction liquid, add natural to room temperature reaction 12h, THF: MTBE (40ml+20ml) is added, 5℃ stirring 1h, filter out the solid, vacuum drying 0.75g target product.

[0111] 1 H NMR (400 MHz, DMSO-d6) δ 5.51 (m, 1H), 5.01 (m, 1H), 4.96 (m, 1H), 4.51 (m, 1H), 4.38 (m, 1H), 4.09-4.02 (m, 1H), 3.99 (m, 1H), 3.97-3.93 (m, 1H), 3.92-3.87 (m, 1H), 3.86-3.79 (m, 2H).

[0112] Example 3: Synthesis of compound S6

[0113] Synthetic route:

[0114] Synthetic process:

[0115] Take phosphate intermediate B1 (1.28g, 4.72mmol) with methanol (15ml) to dissolve, the system cooling to 0~5℃. Take deuterated D-cycloserine-D1 (0.486g, 4.72mmol) with pure water (10ml) to dissolve, slowly drop into the above reaction liquid, add natural to room temperature reaction 12h, THF: MTBE (30ml+15ml) is added, 5℃ stirring 1h, filter out the solid, vacuum drying 1.55g target product.

[0116] 1 H NMR (400 MHz, DMSO-d6) δ 5.49 (td, J=5.4, 2.2 Hz, 1H), 4.92 (t, J=5.2 Hz, 1H), 4.61-4.42 (m, 2H), 4.19-4.13 (m, 1H), 4.03 (t, J=9.0 Hz, 1H), 3.99-3.91 (m, 2H), 3.84 (dd, J=11.4, 5.3 Hz, 1H), 3.68 (ddd, J=10.0, 3.2, 1.3 Hz, 1H)

[0117] Example 4: Synthesis of compound S7

[0118] Synthetic route:

[0119] Synthesis procedure:

[0120] Take the phosphonate intermediate B1 (1.28 g, 4.72 mmol) with methanol (15 ml) to dissolve, the system cooling to 0-5 ℃. Take deuterium D-cycloserine-D3 (0.495 g, 4.72 mmol) with pure water (10 ml) to dissolve, slowly drop into the above reaction liquid, add natural to room temperature reaction 12 h, add THF: MTBE (30 ml + 15 ml), 5 ℃ stirring 1 h, filter out the solid, vacuum drying 1.6 g of target product.

[0121] 1 H NMR (400 MHz, DMSO-d6) δ 5.49 (td, J = 5.4, 2.2 Hz, 1H), 4.92 (t, J = 5.2 Hz, 1H), 4.61 - 4.42 (m, 2H), 4.03 (t, J = 9.0 Hz, 1H), 3.99 - 3.91 (m, 1H), 3.84 (dd, J = 11.4, 5.3 Hz, 1H), 3.68 (ddd, J = 10.0, 3.2, 1.3 Hz, 1H)

[0122] Example 5: Synthesis of compound S8

[0123] Synthesis route:

[0124] Synthesis procedure:

[0125] Take the malonate intermediate B3 (0.1 g, 0.33 mmol) with methanol (4 ml) to dissolve, the system cooling to 0-5 ℃. Take D-cycloserine (0.035 g, 0.35 mmol) directly added to the above reaction liquid, add 10 degrees for 48 h, directly filter out the solid, vacuum drying 0.13 g of target product.

[0126] 1 H NMR (400 MHz, DMSO-d6) δ 5.49 (td, J = 5.4, 2.2 Hz, 1H), 4.92 (t, J = 5.2 Hz, 1H), 4.61 - 4.42 (m, 2H), 4.03 (t, J = 9.0 Hz, 1H), 3.99 - 3.91 (m, 1H), 3.84 (dd, J = 11.4, 5.3 Hz, 1H), 3.68 (ddd, J = 10.0, 3.2, 1.3 Hz, 1H)

[0127] Example 6: Synthesis of compound S9

[0128] Synthetic route:

[0129] Synthetic procedure:

[0130] The citrate intermediate B4 (0.1 g, 0.27 mmol) was dissolved in methanol (4 ml), the system was cooled to 0-5 °C. D-cycloserine (0.029 g, 0.28 mmol) was directly added to the above reaction solution, and after addition, it was maintained at 10 degrees for 48 h. The solid was directly filtered and dried under vacuum to obtain 0.124 mg of the target product.

[0131] 1 H NMR (400 MHz, DMOS-D6) δ 5.52 (td, J = 5.5, 2.7 Hz, 1H), 5.17 (t, J = 2.7 Hz, 1H), 5.06 (t, J = 5.3 Hz, 1H), 4.63 (m, 2H), 4.54 (t, J = 5.2 Hz, 1H), 4.44 (t, J = 8.0 Hz, 1H), 4.29 (m, 1H), 4.06 - 3.99 (m, 2H), 3.98 - 3.91 (m, 2H), 2.90 - 2.60 (m, 4H).

[0132] Example 7: Synthesis of compound S10

[0133] Synthetic route:

[0134] Synthetic procedure:

[0135] The citrate intermediate B5 (0.2 g, 0.55 mmol) was dissolved in methanol (8 ml), the system was cooled to 0-5 °C. D-cycloserine (0.059 g, 0.58 mmol) was directly added to the above reaction solution, and after addition, it was maintained at 10 degrees for 48 h. The solid was directly filtered and dried under vacuum to obtain 0.25 g of the target product. d H NMR (400 MHz, DMOS-D6) δ 5.52 (td, J = 5.5, 2.7 Hz, 1H), 5.22 (d, J = 3.1 Hz, 1H), 5.04 (t, J = 5.3 Hz, 1H), 4.64 - 4.57 (m, 2H), 4.40 (t, J = 7.9 Hz, 1H), 4.26 (m, 2H), 4.12 - 3.89 (m, 4H), 2.83 - 2.73 (m, 2H), 2.68 - 2.55 (m, 2H).

[0136] Example 8: Evaluation of the release level of NO of the compound in rats

[0137] PK experiment SD rats were respectively given corresponding compounds by gavage, and the collection time points were 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 10, 24 h. Using Griess reagent method, first convert nitrate (NO3-) in plasma samples into nitrite (NO2-), and then generate azo dye through Griess reaction with reagent, and detect the absorbance (540 nm) using an enzyme marker, to determine the total amount of released nitric oxide. The results are shown in Table 1. The results show that isosorbide mononitrate (ISMN), compounds S1, S2, S6, S7, S8 and S9 can release nitric oxide in rats.

[0138] Table 1 Nitric oxide levels released in rat plasma

[0139] Example 9: Pharmacodynamic study of compound S1

[0140] 1. Materials and methods

[0141] 1.1 Animals

[0142] Sprague-Dawley (SD) rats, Shanghai Slek Experimental Animal Co., Ltd.

[0143] 1.2 Reagents and consumables

[0144] 1.3 Preparation of administration preparation and grouping

[0145] On the day of the experiment, an appropriate amount of compound S1, isosorbide mononitrate, D-cycloserine, B1, B1 and D-cycloserine combination group, isosorbide mononitrate and D-cycloserine combination group were weighed, and except for isosorbide mononitrate which was dissolved in 0.5% CMC-Na solution, the rest were dissolved in pure water to prepare the administration preparation of the required concentration.

[0146] The experiment was divided into: sham operation group, model group, isosorbide mononitrate (ISMN) group (4 mg / kg), D-cycloserine (DCS) group (2 mg / kg), B1 group (4 mg / kg), isosorbide mononitrate (ISMN) group (4 mg / kg) and D-cycloserine (DCS) group (2 mg / kg), B1 group (4 mg / kg) and D-cycloserine (DCS) group (2 mg / kg), compound S1 group (7.8 mg / kg), and the sham operation group and model group were added with the same volume of solvent.

[0147] 1.4 Preparation of rat cerebral ischemia model

[0148] Rats were anesthetized with isoflurane using a respiratory anesthetic, and the depth of anesthesia was appropriate for the animal to have a slight response to a severe stimulus. The anesthetized rat was fixed with the limbs and head, and the animal was fixed in a supine position on the operating table. The rat's head was covered with an anesthetic cover to prevent the animal from waking up during the experiment. The rat's neck was shaved with an animal shaver, and the skin was disinfected with alcohol. A midline incision was made in the neck, and the muscle and fascia were separated along the inner edge of the sternocleidomastoid muscle. The left common carotid artery (CCA), external carotid artery (ECA), and internal carotid artery (ICA) were separated, and a thread was hung at the distal and proximal ends of the CCA and at the ECA for later use. The ICA was temporarily clamped with a micro-artery clamp, and then the CCA and ECA were ligated proximally. Then a small opening was made 4 mm from the CCA bifurcation, and a thread was inserted into the ICA. At this time, the thread was gently tied around the distal end of the CCA with a fine thread. The wound was sutured, and the rat was placed in clean feed, and the general condition and respiration were observed until the anesthesia was recovered; food and water were added, and the rats were raised normally.

[0149] Animals that developed abnormal conditions due to anesthesia, surgery, etc. were excluded. According to the above dose setting principle, the rats were administered once a day from 7 to 28 days after the operation. All animals were subjected to sensory motor behavior (mNSS, grid, cylinder test) tests 7 days before the operation, 14, 22, and 30 days after the operation, and Morris water maze tests from 24 to 29 days. After the behavior test, the brain was perfused and the brain tissue was paraffin-embedded for use (for Nissl staining to evaluate the extent of brain injury).

[0150] 1.5 Behavior Evaluation

[0151] Modified Neurological Deficit Severity Score

[0152] Modified Neurological Deficit Severity Score (mNSS) (total score: 18 points)

[0153] I. Motor function test

[0154] Tail suspension lifting (3 points):

[0155] 1 point: forelimb flexion;

[0156] 1 point: hindlimb flexion;

[0157] 1 point: head deviated from vertical axis by > 10 degrees within 30 seconds;

[0158] Put on the floor (0-3 points):

[0159] 0 points: normal walking;

[0160] 1 point: unable to walk in a straight line;

[0161] 2 points: turning to the paralyzed side;

[0162] 3 points: pour on the paralyzed side;

[0163] II. Sensory function testing (2 points)

[0164] 1 point: placing test (visual, tactile detection);

[0165] 1 point: proprioceptive test (deep sensation, paw push table edge stimulates limb muscle contraction);

[0166] III. Balance beam test (0-6 points)

[0167] 0 points: can stand on the balance beam or walk steadily on the balance beam;

[0168] 1 point: hold on to one side of the balance beam;

[0169] 2 points: hold on to the balance beam with one limb off the balance beam;

[0170] 3 points: hold on to the balance beam with two limbs off the balance beam, or spin on the balance beam for > 60 seconds;

[0171] 4 points: try to balance on the balance beam, but fall off in > 40 seconds;

[0172] 5 points: try to balance on the balance beam, but fall off in > 20 seconds;

[0173] 6 points: fall off the balance beam in < 20 seconds, without trying to balance on the balance beam or holding on to the balance beam;

[0174] IV. Lack of reflexes and abnormal movements (4 points)

[0175] 1 point: ear reflex (head shaking when touching the ear canal);

[0176] 1 point: corneal reflex (winking when lightly touching the cornea with cotton);

[0177] 1 point: startle reflex (motor response to the sound of crackling paper);

[0178] 1 point: seizures, muscle spasms, dystonia;

[0179] Note: the balance beam is 100 cm long, 4 cm wide, and 40 cm high from the ground;

[0180] Placing test: fix the animal's body while the animal's head and the injured side of the forelimb are in a relaxed state; place the animal's head close to the edge of the table, with the injured side of the whisker lightly touching the table edge, and observe whether the rat's injured forelimb is raised; repeat ten times and record the number of times the injured forelimb is raised.

[0181] Grid test

[0182] The rats were placed individually on the grid with the size of 50 cm in length, 50 cm in width and 50 cm in height, and the mesh size of 2 cm x 2 cm, and allowed to move spontaneously for 8-10 min. The number of foot-faults and the total steps of the left and right forelimbs were recorded, and the ratio between the number of foot-faults and the total steps was calculated. The foot-fault percentage was calculated by the formula of (foot-faults / total steps) x 100%. The foot-fault percentage was used to evaluate the damage degree of the motor cortex of the experimental animals. The higher the foot-fault percentage, the more serious the damage of the motor cortex of the rats.

[0183] Morris water maze experiment

[0184] The Morris water maze tank had a diameter of 160 cm and a height of 50 cm, and the water depth was 29 cm. The platform had a diameter of 12 cm and a height of 27 cm, and was fixed 2 cm below the water surface in the SE quadrant (target quadrant). A camera lens was placed 2 m above the center of the tank to record the movement trajectory of the rats synchronously. The water temperature was maintained at 22±1℃. The experiment lasted for 6 days, including the platform test, hidden platform test and spatial exploration test. D1 was the platform test, D2-D5 were the hidden platform test, and D6 was the spatial exploration test.

[0185] 1.6 Calculation of cerebral infarction area

[0186] After the behavior test, the brain was perfused and paraffin-embedded for later use (for Nissl staining to evaluate the brain damage area).

[0187] 1.7 Data statistics

[0188] The quantitative data was expressed as mean ± standard error. Except for the water maze escape latency, the single factor analysis of variance was used for each pharmacodynamic index, and the LSD method was used for testing the differences between groups. P<0.05 was defined as significant difference.

[0189] 2 Experimental results

[0190] 2.1 Effect of compound S1 on cerebral infarction area

[0191] The effect of compound S1 on cerebral infarction area is shown in Table 1. The single factor analysis of variance showed that there was a significant difference between the compound S1 group and the model group (p<0.05), and there was no significant difference between the remaining groups.

[0192] Table 2. Effect of compound S1 on cerebral infarction area

[0193] The data is expressed as Mean ± SEM. #### p<0.001, compared with the sham operation group; *p<0.05, compared with the model group.

[0194] 2.2 Effect of compound S1 on the neurological severity score (mNSS)

[0195] The effect of compound S1 on the neurological severity score (mNSS) is shown in Table 2. There were statistically significant differences between each group at 14 days and 28 days after injury by one-way ANOVA. Compared with the model group, compound S1 significantly reduced the mNSS score at 14 days and 28 days after injury. There was no significant difference between the two groups.

[0196] Table 3. Effect of compound S1 on the neurological severity score (mNSS)

[0197] Results are expressed as Mean ± SEM. #### p<0.001, compared with the sham operation group; **P<0.01, ***P<0.001, compared with the model group.

[0198] 2.3 Long-term effect of compound S1 on forelimb function in cerebral ischemia rats

[0199] The effect of compound S1 on the severity of forelimb movement injury is shown in Table 3. There were statistically significant differences between each group at 14 days and 28 days after injury by one-way ANOVA. Compared with the model group, compound S1 significantly reduced the rate of stumbling of the injured forelimb at 14 days and 28 days after injury. There was no statistically significant difference between the two groups compared with the model group.

[0200] Table 4. Long-term effect of compound S1 on forelimb function in cerebral ischemia rats

[0201] Results are expressed as Mean ± SEM. #### p<0.001, compared with the sham operation group; **P<0.01, compared with the model group.

[0202] 2.4 Effect of compound S1 on learning and memory function in cerebral ischemia rats

[0203] The effect of compound S1 on learning and memory is shown in Table 4. There were statistically significant differences in escape latency between each group by two-way ANOVA. Compared with the model group, the escape latency of compound S1 group was significantly shortened at day 4 of the hidden platform test. In the spatial exploration test, there was no statistically significant difference in the target quadrant residence time and the number of original platform crossings between each group.

[0204] Table 5. Effect of compound S1 on escape latency in the Morris water maze in cerebral ischemia rats

[0205] Results are expressed as Mean ± SEM. ##P<0.01, compared with the sham operation group; **P<0.01, compared with the model group.

[0206] Table 6. Effect of compound S1 on spatial exploration of water maze in cerebral ischemia rats

[0207] Results are expressed as Mean ± SEM.

[0208] The results of pharmacodynamic test showed that compound S1 had significant improvement effect on sensory motor function defect and learning and memory function damage after ischemic stroke when administered in recovery period.

[0209] Pharmacodynamic study of compounds S6 and S7

[0210] 1. Materials and methods

[0211] 1.1 Animals

[0212] Sprague-Dawley (SD) rats, male, SPF level, body weight 250-280 g, Shanghai Slek Experimental Animal Co., Ltd.

[0213] 1.2 Reagents and consumables

[0214] 1.3 Preparation of administration preparation and grouping

[0215] On the experimental day, appropriate amount of compound S6, S7, S8, S9, S10, isosorbide mononitrate, B1, B3, B4, B5, D-cycloserine, D-cycloserine-D1, D-cycloserine-D3, B1 and D-cycloserine combination group, B1 and D-cycloserine-D1 combination group, B1 and D-cycloserine-D3 combination group, B3 and D-cycloserine combination group, B4 and D-cycloserine combination group, B5 and D-cycloserine combination group were weighed, except that isosorbide mononitrate was prepared with 0.5% CMC-Na solution, and the rest were prepared with pure water into the required concentration of administration preparation.

[0216] The experiment is divided into: sham operation group, model group, ISMN group (5.1 mg / kg), B1 group (5.1 mg / kg), B3 group (5.1 mg / kg), B4 group (5.1 mg / kg), B5 group (5.1 mg / kg), DCS group (2.7 mg / kg), DCS-D1 group (2.7 mg / kg), DCS-D3 group (2.7 mg / kg), B1 (5.1 mg / kg) and D-cycloserine (2.7 mg / kg) combination group, B1 (5.1 mg / kg) and D-cycloserine-D1 (2.7 mg / kg) combination group, B1 (5.1 mg / kg) and D-cycloserine-D3 (2.7 mg / kg) combination group, B3 (5.1 mg / kg) and D-cycloserine (2.7 mg / kg) combination group, B4 (5.1 mg / kg) and D-cycloserine (2.7 mg / kg) combination group, B5 (5.1 mg / kg) and D-cycloserine (2.7 mg / kg) combination group, compound S6 group (10 mg / kg), compound S7 group (10 mg / kg), compound S8 group (10 mg / kg), compound S9 group (10 mg / kg), compound S10 group (10 mg / kg), and the sham operation group and the model group are added with the same volume of solvent.

[0217] 1.4 Preparation of rat cerebral ischemia model

[0218] The rats were anesthetized with isoflurane using a respiratory anesthetic, and the depth of anesthesia was appropriate for the animal to have a slight response to severe stimulation. The anesthetized rats were fixed with four limbs and head, and the animal was fixed in a supine position on the operating table. The rat's head was covered with an anesthetic cover to prevent the animal from waking up during the experiment. The animal's neck was shaved with a rat hair clipper, and the skin was disinfected with alcohol. A midline incision was made in the neck, and the muscle and fascia were separated along the inner edge of the sternocleidomastoid muscle. The left common carotid artery (CCA), external carotid artery (ECA) and internal carotid artery (ICA) were separated. The CCA was hung with a thread at the distal and proximal ends and at the ECA. The ICA was temporarily clamped with a micro-artery clamp, then the CCA and ECA were ligated proximally. Then a small opening was cut 4 mm away from the CCA bifurcation, and a thread was inserted into the ICA. At this time, the thread was gently tied with a fine thread wrapped around the distal end of the CCA. The wound was sutured, and the rats were placed in clean feed, and the general condition and respiration were observed until the anesthesia was recovered; food and water were added, and the rats were raised normally.

[0219] Animals that appeared abnormal due to anesthesia, surgery, etc. must be excluded. According to the above dose setting principle, the rats were given drugs once a day on the 15th-28th day after the operation. All animals were tested for sensory motor behavior (mNSS, grid, cylinder test) 7 days before the operation, and 14, 29-31 days after the operation. The open field test was performed on the 33rd day. After the behavior test, the brain was perfused and the brain tissue was paraffin-embedded for use (for Nissl staining to evaluate the extent of brain injury).

[0220] 1.5 Behavioral Assessment

[0221] Modified Neurological Severity Score

[0222] Modified Neurological Severity Score (mNSS) (Total score: 18)

[0223] I. Motor Function Assessment

[0224] Tail Suspension Lift (3 points):

[0225] 1 point: forelimb flexion;

[0226] 1 point: hindlimb flexion;

[0227] 1 point: head deviation from vertical axis > 10 degrees within 30 seconds;

[0228] Floor placement (0-3 points):

[0229] 0 points: normal walking;

[0230] 1 point: unable to walk in a straight line;

[0231] 2 points: turning in circles toward the paralyzed side;

[0232] 3 points: falling toward the paralyzed side;

[0233] II. Sensory Function Assessment (2 points)

[0234] 1 point: placing test (visual, tactile detection);

[0235] 1 point: proprioceptive test (deep sensation, pawing at the edge of the table to stimulate limb muscle contraction);

[0236] III. Balance Beam Test (0-6 points)

[0237] 0 points: able to stand on the balance beam or walk on the balance beam smoothly;

[0238] 1 point: holding onto one side of the balance beam;

[0239] 2 points: holding onto the balance beam with one limb off the balance beam;

[0240] 3 points: holding onto the balance beam with two limbs off the balance beam or spinning on the balance beam > 60 seconds;

[0241] 4 points: attempting to balance on the balance beam but falling off within > 40 seconds;

[0242] 5 points: attempting to balance on the balance beam but falling off within > 20 seconds;

[0243] 6 points: falls off the balance beam in < 20 seconds without trying to balance on the beam or holding onto the beam;

[0244] Four, lack of reflex and abnormal movement (4 points)

[0245] 1 point: ear reflex (head shaking when touching the ear canal);

[0246] 1 point: corneal reflex (eyelid blinking when the cornea is lightly touched with cotton);

[0247] 1 point: startle reflex (motor response to the sound of crackling paper);

[0248] 1 point: seizures, muscle spasms, and muscle tone disorders;

[0249] Note: the balance beam is 100 cm long, 4 cm wide, and 40 cm high from the ground;

[0250] Placement test: the animal's body is fixed while the animal's head and the injured forelimb are in a relaxed state; the animal's head is placed near the edge of the table, and the injured side of the whisker lightly touches the table edge to observe whether the rat's injured forelimb is raised; repeat ten times and record the number of times the injured forelimb is raised.

[0251] Grid test

[0252] A grid with a length, width, and height of 50 cm and a mesh size of 2 cm x 2 cm is used. Each rat is placed on the grid individually and allowed to move freely for 8-10 minutes. The number of stumbling steps and the total number of steps of the rat's left and right forelimbs are recorded. The ratio between the number of stumbling steps and the total number of steps is calculated, and the stumbling percentage is calculated as (stumbling steps / total steps) x 100%. The stumbling percentage is used to evaluate the extent of damage to the motor cortex of experimental animals. The higher the stumbling percentage, the more severe the damage to the motor cortex of the rat.

[0253] Cylinder test

[0254] After focal cerebral ischemia, rats exhibit asymmetry in the use of their forelimbs in the cylinder test, and they tend to use their normal forelimbs more during vertical exploration of the cylinder wall. The rats are placed in a transparent resin glass cylinder and allowed to move freely for 5-7 minutes. Their movements are recorded by video. The time spent by the rat's forelimbs touching the left, right, and both sides of the cylinder is recorded during the 5-minute standing period. The asymmetry index of forelimb use after injury is calculated as (uninjured side touch time - injured side touch time) / (uninjured side touch time + injured side touch time + bilateral touch time) x 100%. The asymmetry index is used to assess the motor function of the forelimbs of rodents and can detect motor deficits or spontaneous recovery caused by brain injury.

[0255] Open field test

[0256] Open field test is a classical behavioral test widely used in behavioral neuroscience and pharmacology research, which is mainly used to assess the spontaneous activity, exploratory behavior and anxiety-like behavior of experimental animals. The open field test device is a rectangular box made of non-reflective material (length x width x height: 100 cm x 100 cm x 40 cm). The bottom of the box is virtually divided into a central area and a peripheral area with equal area. The experiment is carried out in a quiet, weak light, soundproof environment. A camera is installed above the box and connected to a computer with behavior analysis software for recording and analyzing the behavior of rats throughout the experiment. During the experiment, the animals are placed in the box and allowed to freely explore for 10 min, and their behavior parameters are recorded by the video tracking system. Anxiety-like behavior: mainly reflected by the central area activity time, the shorter the time, the higher the anxiety level.

[0257] 1.6 Calculation of cerebral infarction area

[0258] After the behavioral test, the brain was perfused and paraffin-embedded for future use (for Nissl staining to evaluate the extent of brain injury).

[0259] 1.7 Data statistics

[0260] Quantitative data are expressed as mean ± standard error, and each pharmacodynamic index is subjected to one-way ANOVA, and LSD test is used to test the differences between groups. P<0.05 is defined as significant difference.

[0261] 2 Experimental results

[0262] 2.1 Effect of compounds S6-S10 on cerebral infarction area

[0263] The effect of compounds S6-S10 on cerebral infarction area is shown in Table 7. One-way ANOVA showed that the compound S6-S10 group had significant difference compared with the model group (P<0.001), and the remaining groups had no significant difference.

[0264] Table 7. Effect of compounds S6-S10 on cerebral infarction area

[0265] Data are expressed as Mean ± SEM. #### P<0.001 compared with the sham operation group; **** P<0.001 compared with the model group.

[0266] Synergy was evaluated according to Kim Jung-jun formula q = E(a+b) / (Ea+Eb-Ea x Eb). In the formula, E(a+b) is the effective rate of combined drugs, Ea and Eb are the effective rates of drug A or drug B alone. E drug group = (X model - X drug) / X model, X is the value of cerebral infarction range.

[0267] 2.2 Effect of compound S6, S7 on the severity score of nerve injury (mNSS)

[0268] The effect of compound S6, S7 on the severity score of nerve injury (mNSS) is shown in Table 8. After single factor analysis of variance, compared with the model group, compound S6, S7 could significantly reduce the mNSS score of animals after injury (P<0.05), and there was no significant change in the three groups of single drugs.

[0269] Table 8. Effect of compound S6, S7 on the severity score of nerve injury (mNSS)

[0270] Results are expressed as Mean ± SEM. #### P<0.001, compared with the sham operation group; ** P<0.01, ** P<0.05, compared with the model group.

[0271] 2.3 Long-term effect of compound S6, S7 on forelimb function of cerebral ischemia rats

[0272] The effect of compound S6, S7 on the severity of forelimb movement injury is shown in Tables 9-10. After single factor analysis of variance, compared with the model group, compound S6, S7 could significantly reduce the rate of stumbling and asymmetric index of injured forelimb at 28 days after injury (P<0.01), and there was no statistical difference between the three groups of single drugs and the model group.

[0273] Table 9. Long-term effect of compound S6, S7 on forelimb function of cerebral ischemia rats

[0274] Results are expressed as Mean ± SEM. #### p<0.001, compared with the sham operation group; ** P<0.01, compared with the model group.

[0275] Table 10. Long-term effect of compound S6, S7 on forelimb function of cerebral ischemia rats

[0276] Results are expressed as Mean ± SEM. #### p<0.001, compared with the sham operation group; *P<0.05, ** P<0.01, compared with the model group.

[0277] 2.4 Effects of compounds S6 and S7 on anxiety behavior of cerebral ischemia rats

[0278] The effects of compounds S6 and S7 on anxiety behavior are shown in Table 11. After single factor analysis of variance, compared with the model group, compounds S6 and S7 could significantly reduce the anxiety behavior after stroke at 32 days after injury (P<0.01), and there was no statistical difference between the single drug group and the model group.

[0279] Table 11. Long-term effects of compounds S6 and S7 on anxiety behavior of cerebral ischemia rats

[0280] Results are expressed as Mean ± SEM. #### P<0.0001, compared with the sham operation group; ** P<0.01, compared with the model group.

[0281] The results of pharmacodynamic test show that compounds S6 and S7 have significant improvement effect on sensory motor function defects and anxiety behavior after ischemic stroke when administered in the recovery period.

[0282] The above are only preferred embodiments of the present application, and it should be pointed out that the above preferred embodiments should not be regarded as limitation of the present application, and the protection scope of the present application should be limited by the scope defined by the claims. For ordinary skilled in the art, several improvements and refinements can be made without departing from the spirit and scope of the present application, and these improvements and refinements should also be regarded as the protection scope of the present application.

Claims

1. A class of compounds represented by Formula I or pharmaceutically acceptable salts, deuterated compounds, and solvates thereof, characterized in that, Formula I is shown below: A is a nitric oxide donor active molecule; n is selected from the numbers 1, 2, 3, 4, 5, and 6.

2. The compound or pharmaceutically acceptable salt, deuterated compound, and solvate thereof according to claim 1, wherein wherein A is as shown below: A is selected from the group consisting of isosorbide mononitrate and a dibasic acid or polybasic acid to form an ester compound or a pharmaceutically acceptable salt, deuterated compound, solvate, racemic mixture, enantiomer, diastereoisomer, and tautomer thereof as shown in formula II: The number of protons (H + ) that can be given off by the polyacid is 3, 4, 5, 6.

3. The compound of claim 2, wherein The dibasic acid or polybasic acid is selected from the group consisting of sulfuric acid, phosphoric acid, carbonic acid, sulfurous acid, phosphorous acid, ethanedioic acid, propanedioic acid, butanedioic acid, butenedioic acid, citric acid, malic acid, pentanedioic acid, hexanedioic acid, glutamic acid, and aspartic acid.

4. The compound of claim 2, wherein The dibasic acid or polybasic acid is selected from the group consisting of sulfuric acid, phosphoric acid, carbonic acid, sulfurous acid, phosphorous acid, ethanedioic acid, propanedioic acid, butanedioic acid, butenedioic acid, citric acid, malic acid, pentanedioic acid, hexanedioic acid, glutamic acid, and aspartic acid.

5. The compound of claim 2, wherein The dibasic acid or polybasic acid is selected from the group consisting of sulfuric acid, phosphoric acid, carbonic acid, sulfurous acid, and phosphorous acid.

6. The compound of claim 2, wherein The dibasic acid or polybasic acid is selected from the group consisting of ethanedioic acid, propanedioic acid, butanedioic acid, butenedioic acid, citric acid, malic acid, pentanedioic acid, and hexanedioic acid.

7. The compound of claim 2, wherein The dibasic acid or polybasic acid is selected from the group consisting of glutamic acid and aspartic acid.

8. The compound of claim 1, or pharmaceutically acceptable salts, deuterated compounds, and solvates thereof, wherein, The compound of formula I is selected from: S1 as shown in the above figure; S2 as shown in the above figure; S3 as shown in the above figure; S4 is shown in the above figure; S5 as shown in the above figure; S6 as shown in the above figure; S7 as shown in the above figure; S8 as shown in the above figure; S9 as shown in the above figure; S10 as shown in the above figure; S11 is shown in the above figure.

9. The compound or pharmaceutically acceptable salt, deuterated compound, and solvate thereof of any one of claims 1-8, wherein The compound is used for preparing a drug for treating stroke or a recovery period of stroke.

10. A pharmaceutical composition, characterized by, The compound or a pharmaceutically acceptable salt, deuterated compound, and solvate thereof according to any one of claims 1-8 and a pharmaceutically acceptable carrier.

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