Compounds and uses thereof in treatment of NMDAR related diseases

Abstract

The invention belongs to the field of medicinal chemistry and the field of autoimmune disease treatment. The invention provides a compound and application thereof in treatment of NMDAR related diseases.

Description

Technical Field

[0001] This application pertains to the fields of medicinal chemistry and the treatment of autoimmune diseases. Specifically, this application provides compounds and their use in the treatment of NMDAR-related diseases. Background Technology

[0002] Memantine hydrochloride, chemically known as 3,5-dimethyl-1-aminoadamantane hydrochloride, also called 3,5-dimethyltricyclo[3.3.1.1.(3.7)]decan-1-amine hydrochloride, has the molecular formula C12H21N·HCl.

[0003] Memantine hydrochloride, developed by Merz AG in Germany, is a novel, low-to-moderate affinity, voltage-dependent, non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist. It non-competitively blocks NMDA receptors, reducing glutamate-induced NMDA receptor over-excitation, preventing apoptosis, and improving memory, making it a next-generation drug for improving cognitive function. In 2002-2003, it was approved by the European Pharmaceutical Patent Committee and the US Food and Drug Administration for the treatment of moderate to severe Alzheimer's disease. Further research has shown that memantine hydrochloride is also effective for mild to moderate Alzheimer's disease.

[0004] Neuropsychiatric systemic lupus erythematosus (NPSLE) is a manifestation of systemic lupus erythematosus (SLE), involving a variety of symptoms in the central and peripheral nervous systems. SLE is an autoimmune disease characterized by the body's immune system mistakenly attacking its own tissues, leading to widespread inflammation and tissue damage, severely impacting patients' quality of life and social functioning.

[0005] In NPSLE patients, studies have found that certain autoantibodies can target NMDAR, leading to alterations in receptor function. These antibodies may affect neuronal function by interfering with normal NMDAR signaling, thereby triggering neuropsychiatric symptoms such as mood disorders and cognitive impairment. Neuroinflammation plays a crucial role in the pathogenesis of NPSLE. NMDAR also plays a role in the inflammatory response; inflammatory mediators can enhance neuronal excitability by activating NMDAR, exacerbating damage to the nervous system. Furthermore, excessive activation of NMDAR may lead to excitotoxicity, further aggravating neuronal damage. NPSLE patients often exhibit symptoms such as depression, anxiety, and memory impairment, which are closely related to NMDAR dysfunction. Research suggests that NMDAR-targeting treatment strategies may provide new interventions for NPSLE patients, improving their mental and cognitive symptoms.

[0006] The NMDA receptor is a glutamate receptor, and glutamate is the main excitatory neurotransmitter in the human brain. The NMDA receptor consists of two NR1 (GluN1) subunits and two NR2 (GluN2A or B) or NR3 (GluN3A or B) subunits. The NR1 subunit binds the co-agonist glycine, while the NR2 subunit binds the neurotransmitter glutamate. The NMDA receptor has a strong calcium ion (Ca) affinity. 2+ Permeability, and is affected by magnesium ions (Mg) 2+ Voltage-dependent inhibition. Summary of the Invention

[0007] Based on the above, the applicant designed and synthesized a series of compounds to antagonize / inhibit NMDA receptors and treat related diseases such as psychogenic lupus erythematosus, Alzheimer's disease, cognitive impairment, and memory loss.

[0008] On the one hand, this application provides compounds represented by formula (I) or formula (II):

[0009]

[0010] R1 is hydrogen, or an unsubstituted or substituted C1-C4 alkyl group;

[0011] R2 is or

[0012] R3 is R4 is hydrogen, or an unsubstituted or substituted C1-C4 alkyl group;

[0013] a = 1-4, R5 is H, halogen, C1-C4 alkyl or C1-C4 alkoxy;

[0014] or,

[0015]

[0016] Furthermore, R5 is a chlorine atom, fluorine atom, bromine atom, iodine atom, C1-C4 alkyl or C1-C4 alkoxy atom.

[0017] Furthermore, R1 is hydrogen or methyl; R4 is hydrogen or methyl.

[0018] Furthermore, in R3, n = 1, m = 3 or 4, a = 1, and / or b = 3.

[0019] Furthermore, any hydrogen atom in the unsubstituted or substituted C1-C4 alkyl group is replaced by a group selected from hydroxyl, amino, or carboxyl groups.

[0020] Furthermore, the compound is selected from the following compounds:

[0021]

[0022]

[0023] In another aspect, this application provides pharmaceutically acceptable salts, stereoisomers, tautomers, prodrugs, amorphous forms, isotopes, polymorphs, or solvates of the aforementioned compounds.

[0024] Furthermore, the pharmaceutically acceptable salt is a hydrochloride salt.

[0025] In another aspect, this application provides the use of the above-mentioned compounds, pharmaceutically acceptable salts, stereoisomers, tautomers, prodrugs, amorphous substances, isotopes, polymorphs, or solvates, in the preparation of medicaments for treating NMDAR-related diseases.

[0026] In another aspect, this application provides the use of the above-mentioned compounds, pharmaceutically acceptable salts, stereoisomers, tautomers, prodrugs, amorphous substances, isotopes, polymorphs, or solvates, in the preparation of NMDAR antagonists.

[0027] In another aspect, this application provides a medicament for treating NMDAR-related diseases, the medicament comprising the above-mentioned compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, amorphous substance, isotope, polymorph, or solvate.

[0028] Furthermore, the amount of the aforementioned compound contained in a unit dose of the drug is lower than the amount of memantine in the same unit dose of a drug containing memantine.

[0029] The unit dose refers to a unit in drug packaging or preparation, such as, but not limited to, a tablet, a capsule, a bottle or other form of packaging of the same volume of liquid preparation, a bag, a box, etc.

[0030] Because the compound of this application achieves better bioavailability than memantine, the compound of this application can achieve similar or better therapeutic effects with a lower dose than memantine.

[0031] On the other hand, this application provides a method for treating NMDAR-related diseases, the method comprising administering the above-mentioned compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, amorphous substance, isotope, polymorph, or solvate, to a patient suffering from NMDAR-related diseases.

[0032] Furthermore, the amount of the above-mentioned compound administered to the patient in the method is lower than the amount of memantine used when treating the same disease with memantine.

[0033] The NMDAR-related diseases are selected from systemic lupus erythematosus, preferably psychogenic lupus erythematosus, Alzheimer's disease, encephalitis, epilepsy, depression, memory loss, learning disability, cognitive impairment, ischemic brain injury, etc.; the types of NMDAR-related diseases may be added as relevant research progresses. For example, current research shows that NMDAR is also associated with pulmonary fibrosis and myocardial disease.

[0034] The aforementioned drugs may be in pharmaceutically acceptable dosage forms, including but not limited to tablets, capsules, pills, granules, oral liquids, suspensions, powders, water injections, powder injections, sprays, suppositories, gels, and creams; oral dosage forms, such as sustained-release oral preparations, are preferred.

[0035] The aforementioned drugs may include pharmaceutically acceptable excipients, including but not limited to fillers, binders, sustained-release agents, controlled-release agents, lubricants, coating agents, flavoring agents, flavor masking agents, coloring agents, solvents, solubilizers, suspending agents, pH adjusters, osmotic pressure adjusters, emulsifiers, chelating agents, thickeners, antioxidants, preservatives, etc. For the use of excipients in various specific dosage forms, please refer to textbooks in the fields of pharmacy or pharmaceutics, such as Remington Pharmacy.

[0036] The therapeutic dose range can be 0.5-50 mg / day, preferably 1-40 mg / day, and particularly preferably 5-20 mg / day; the frequency of use is once a week to three times a day, preferably once a day. Those skilled in the art should understand that the above range is not a strict limitation on the dosage, and the actual dosage may vary according to relevant research and treatment guidelines, for different compounds, different diseases, and different populations.

[0037] On the other hand, this application provides a method for preparing compound MN-1', the method comprising: step (1): taking compound MN-1'... It reacts with AgNO to form a compound

[0038] Step (2): The compound With compounds The reaction produces compounds

[0039]

[0040] Step (3): Place the compound Reaction with KI to form a compound

[0041] Step (4): Place the compound With compounds

[0042] The reaction produces compounds

[0043]

[0044] Step (5): Place the compound With compounds The reaction produces compounds

[0045]

[0046] Step (6) from the compound The reaction of removing tert-butyloxycarbonyl group yields the compound

[0047]

[0048] On the other hand, this application provides a method for preparing compound MN-8', the method comprising: step (1): taking compound MN-8' into a container and placing the container into the container. With compounds

[0049] The reaction produces compounds

[0050]

[0051] Step (2): The compound With compounds

[0052] The reaction produces compounds

[0053]

[0054] Step (3): Place the compound Detert-butyl reaction produces

[0055]

[0056] Beneficial effects:

[0057] The compounds in this application exhibit good stability, bioavailability, and safety, and can effectively antagonize NMDAR and treat related diseases. Attached Figure Description

[0058] Figure 1 The hydrogen NMR spectrum of MN-1' is shown in Figure 1.

[0059] Figure 2 2. NMR hydrogen spectrum of MN-1';

[0060] Figure 3 The LC / MS chromatogram of MN-1';

[0061] Figure 4 Mass spectrum 1 of LC / MS results for MN-1';

[0062] Figure 5 Mass spectrum 2 of MN-1' as obtained by LC / MS;

[0063] Figure 6 Mass spectrum 3 of LC / MS results for MN-1';

[0064] Figure 7 Mass spectrum 4 of MN-1' as obtained by LC / MS;

[0065] Figure 8 The hydrogen NMR spectrum of MN-8';

[0066] Figure 9 Mass spectrum of MN-8' as obtained by LC / MS;

[0067] Figure 10 Mass spectrum 2 of MN-8' as obtained by LC / MS;

[0068] Figure 11 Mass spectrum 3 of MN-8' as a result of LC / MS;

[0069] Figure 12 4. LC / MS mass spectrum of MN-8';

[0070] Figure 13 Mass spectrum of MN-8' obtained by LC / MS;

[0071] Figure 14 Mass spectrum of MN-8' obtained by LC / MS (6);

[0072] Figure 15 The synthetic route diagram for MN-1';

[0073] Figure 16 This is the synthetic route diagram for MN-8'.

[0074] Figure 17 The mean plasma concentration-time curves of MN-8', MN-1', and MN after a single IV and PO administration of MN-8', MN-1', and MN to male SD rats.

[0075] Figure 18 The individual plasma concentration-time curve of MN-8' after a single oral administration of 21 mg / kg to male SD rats.

[0076] Figure 19 The individual plasma concentration-time curve of MN after a single oral administration of 21 mg / kg MN-8' to male SD rats.

[0077] Figure 20 The individual plasma concentration-time curve of MN after a single oral administration of 23 mg / kg MN-1' to male SD rats.

[0078] Figure 21 This is the individual plasma concentration-time curve of MN after a single oral administration of 10 mg / kg MN to male SD rats.

[0079] Figure 22 Individual plasma concentration-time curves of MN after a single intravenous injection of 2 mg / kg MN in male SD rats.

[0080] Figure 23 Mean plasma concentration-time curves after a single oral administration of MN-8', MN-1', and MN to male beagle dogs.

[0081] Figure 24 The plasma concentration-time curve of MN-8' in male beagle dogs after a single oral administration of 6.3 mg / kg MN-8'.

[0082] Figure 25 Individual plasma concentration-time curves of MN following a single oral administration of 6.3 mg / kg MN-8' to male beagle dogs.

[0083] Figure 26 Individual plasma concentration-time curves of MN after a single oral administration of 6.9 mg / kg MN-1' to male beagle dogs.

[0084] Figure 27 Individual plasma concentration-time curves of MN after a single oral administration of 3 mg / kg MN to male beagle dogs. Detailed Implementation

[0085] The technical solution 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.

[0086] Example 1: Preparation of compound MN-1'

[0087] The synthetic route of MN-1' is as follows Figure 15 As shown:

[0088] (1) Preparation of Int 1:

[0089]

[0090] SM1 (5.0 g, 16.48 mmol) was mixed with H2O (80 mL), and then a solution of NaOH (659 mg, 16.48 mmol) in H2O (20 mL) was added. The mixture was stirred at room temperature for 0.5 hours. After filtration, the filtrate was mixed with a solution of AgNO3 (2.8 g, 16.48 mmol) in H2O (20 mL). The mixture was stirred at room temperature for another 0.5 hours. Then, it was filtered, and the filter cake was washed three times with water. Finally, the filter cake was dried to give Int 1 (5.7 g, 84.30% yield) as a white solid.

[0091] (2) Preparation of compound 1

[0092]

[0093] SM2 (11.0 g, 79.07 mmol) was dissolved in ACN (150 mL), followed by the addition of TEA (10.4 g, 102.80 mmol) at 0 °C. Then, SM3 (12.33 g, 94.89 mmol) was dissolved in ACN (50 mL) at 0 °C, and the mixture was stirred at room temperature for 4 hours. After the reaction was complete, the reaction mixture was monitored by thin-layer chromatography (TLC). The reaction mixture was diluted with H2O (500 mL) and extracted with EA (500 mL). The organic layer was washed three times with brine and then concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (PE:EA = 100:1 to 15:1) to give the desired compound 1 (11.2 g, 61.16% yield) as a white solid.

[0094] (3) Preparation of compound 2

[0095]

[0096] Compound 1 (9.2 g, 39.73 mmol) was dissolved in acetone (300 mL), and KI (26.38 g, 158.90 mmol) was added. The mixture was stirred at 60 °C for 2 days. After filtration, the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (PE:EA = 100:1 to 15:1) to give the desired compound 2 (11.5 g, 89.61% yield) as an oil.

[0097] (4) Preparation of compound 3

[0098]

[0099] Compound 2 (7.0 g, 21.67 mmol) and intermediate 1 (8.89 g, 21.67 mmol) were dissolved in toluene (200 mL) and stirred at 60 °C for 4 hours. After the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by pre-partition thin-layer chromatography (Prep-TLC) (PE:EA = 20:1 to 5:1) to give the desired compound 3 (6.5 g, 60.18% yield) as an oil.

[0100] MS(ESI) m / z: 521.0 [M+Na] + .

[0101] 1 H NMR (400MHz, CDCl3) δ8.39–8.22(m,2H),7.48–7.37(m,2H),5.94–5.83(m,2H),5.10(t,J=7.6Hz,1H),4.24(d,J= 5.2Hz,1H),2.65–2.39(m,2H),2.32–2.12(m,1H),1.94(td,J=14.4,8.5Hz,1H),1.50–1.46(s,9H),1.44(s,9H).

[0102] (5) Preparation of compound 4

[0103]

[0104] Compound 3 (6.5 g, 13.04 mmol) was dissolved in ACN (50 mL), and SM4 (2.81 g, 15.65 mmol) and TEA (1.58 g, 15.65 mmol) were added. The mixture was then stirred at 35 °C for 3 hours. After the reaction was complete, the mixture was purified by reversed-phase column chromatography (FA) to give the desired compound 4 (5.3 g, 75.45% yield) as a white solid.

[0105] MS(ESI) m / z: 561.2 [M+Na] + .

[0106] 1 H NMR (400MHz, CDCl3) δ5.68(s,2H),5.06(d,J=7.8Hz,1H),4.75(s,1H),4.21(d,J=5.4Hz,1H),2.54–2.35(m,2H),2.24–2.11(m,2H),1 .95–1.88(m,1H),1.77(s,2H),1.60(d,J=11.9Hz,4H),1.47(s,9H),1.44(s,9H),1.39–1.28(m,4H),1.19–1.10(m,2H),0.85(s,6H).

[0107] (6) Preparation of compound MN1'

[0108]

[0109] Compound 4 (5.5 g, 10.21 mmol) was dissolved in DCM (30 mL) and TFA (15 mL) and stirred overnight at room temperature. After the reaction was complete, monitoring was performed, and the residue was then concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (TFA) to give the desired compound MN1' (2.4 g, 47.35% yield) as a white solid. The structural confirmation spectrum is shown in [reference needed]. Figure 1-7 .

[0110] Synthesis steps of MN-1 100g:

[0111] 1) Synthesis of N-tert-butoxycarbonyl-L-silver glutamate-1-tert-butyl ester

[0112]

[0113] 300.0 g (988.9 mmol) of N-tert-butyloxycarbonyl-L-glutamic acid-1-tert-butyl ester was placed in a 5 L three-necked flask, and 1.5 L of water was added. The mixture was stirred at room temperature to form a suspension. 500 mL of an aqueous solution of sodium hydroxide (39.6 g, 988.9 mmol) was slowly added. The mixture was stirred at room temperature for half an hour, filtered, and the mother liquor was placed in a 5 L three-necked flask. An aqueous solution of silver nitrate (168.0 g, 988.9 mmol) (1.0 L) was slowly added to the solution with stirring. A large amount of white solid precipitated. The mixture was stirred at room temperature for another 5 minutes, filtered, and the filter cake was washed three times with water (1.0 L x 3). The filter cake was dried at 60°C in the dark to obtain the target product (400.0 g, yield 98.6%, white solid), which was stored in the dark.

[0114] 2) Synthesis of 4-chloromethoxycarbonyloxy-1-nitrobenzene

[0115]

[0116] 4-Nitrophenol (150.0 g, 1078.3 mmol) was dissolved in tetrahydrofuran (1.5 L), cooled to 0°C, and stirred. A tetrahydrofuran solution (500 mL) of methyl chloroformate (166.8 g, 1293.9 mmol) was slowly added dropwise at 0°C. Then, triethylamine (130.7 g, 1293.9 mmol) was dissolved in tetrahydrofuran (500 mL) and slowly added dropwise to the above reaction solution at 0°C. After the addition was complete, the reaction solution was stirred at room temperature for 3 hours. TLC showed that the reaction was complete. Add water (1.5 L) to the reaction solution, extract with ethyl acetate (1.5 L), separate the liquid and liquid, wash the organic phase three times with saturated brine (1.5 L x 3), concentrate, and purify the crude product by column chromatography (elution from petroleum ether:ethyl acetate = 100:1 to petroleum ether:ethyl acetate = 15:1) to obtain the target product (230 g, yield 92.1%, white solid).

[0117] 3) Synthesis of 4-iodomethoxycarbonyloxy-1-nitrobenzene

[0118]

[0119] 4-Chloromethoxycarbonyloxy-1-nitrobenzene (230.0 g, 993.1 mmol) was dissolved in acetone (2.0 L), and potassium iodide (494.6 g, 2.98 mol) was added to the reaction solution. The reaction solution was then heated to 60°C and stirred for 2 days. The reaction solution was filtered, and the filtrate was concentrated to dryness. The crude product was purified by column chromatography (eluting from petroleum ether:ethyl acetate = 100:1 to petroleum ether:ethyl acetate = 15:1) to obtain the target product (290 g, yield 90.4%, pale yellow oil).

[0120] 4) Synthesis of 1-(tert-butyl)5-(((4-nitrophenoxycarbonyl)oxy)methyl)(tert-butyloxycarbonyl)-L-glutamic acid

[0121]

[0122] 4-Iodomethoxycarbonyloxy-1-nitrobenzene (400 g, 1.24 mol) was dissolved in toluene (2.5 L), and N-tert-butoxycarbonyl-L-silver glutamate-1-tert-butyl ester (507.9 g, 1.24 mol) was added to the reaction solution. The reaction mixture was heated to 60°C and reacted for 4 hours. TLC showed that the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated to dryness. The crude product was purified by column chromatography (eluting from petroleum ether:ethyl acetate = 20:1 to petroleum ether:ethyl acetate = 5:1) to give the target product (280 g, yield 45.4%, pale yellow oil). MS (ESI) m / z: 521.2 [M+Na] + .

[0123] 5) Synthesis of 1-(tert-butyl)5-(((3,5-dimethyladamantane-1-yl)carbamoyl)oxy)methyl)(tert-butoxycarbonyl)-L-glutamic acid

[0124]

[0125] 1-(tert-butyl)5-(((4-nitrophenoxycarbonyl)oxy)methyl)(tert-butyloxycarbonyl)-L-glutamic acid (280.0 g, 561.7 mmol) was dissolved in acetonitrile (2.0 L). Memantine hydrochloride (127.3 g, 589.8 mmol) and triethylamine (119.4 g, 1.18 mol) were added to the reaction solution. The reaction solution was heated to 40°C and reacted for 4 h. LC-MS showed that the reaction was complete. Water (2.0 L) was added to the reaction solution, and the mixture was extracted with ethyl acetate (2.0 L). The liquid was separated, and the organic phase was washed five times with saturated brine (1.5 L x 5). The solution was concentrated, and the crude product was purified by column chromatography (elution from petroleum ether:ethyl acetate = 20:1 to petroleum ether:ethyl acetate = 6:1) to obtain the target product (195 g, yield 64.5%, pale yellow oil). MS (ESI) m / z: 561.2 [M+Na] + .

[0126] 6) Synthesis of 5-(((3,5-dimethyladamantane-1-yl)carbamoyl)oxy)methyl)-L-glutamic acid trifluoroacetate

[0127]

[0128] 1-(tert-butyl)5-(((3,5-dimethyladamantane-1-yl)carbamoyl)oxy)methyl)(tert-butoxycarbonyl)-L-glutamic acid (160 g, 292.0 mmol) was dissolved in dichloromethane (640 mL), and trifluoroacetic acid (320 mL) was added to the reaction solution. The reaction solution was stirred at room temperature for 36 hours. The reaction solution was concentrated to dryness to obtain a crude product. The crude product was purified twice by reverse-phase chromatography to obtain the target compound (6.13 g) and the crude product (56.0 g). The crude product was purified together with the next batch.

[0129] 1-(tert-butyl)-5-(((3,5-dimethyladamantane-1-yl)carbamoyl)oxy)methyl)(tert-butoxycarbonyl)-L-glutamic acid (195 g, 362.0 mmol) was dissolved in dichloromethane (780 mL), and trifluoroacetic acid (390 mL) was added to the reaction solution. The reaction solution was heated to 40 °C and reacted for 7 hours. LC-MS showed that the reaction was complete. The solution was cooled to room temperature and concentrated to dryness to obtain a crude product. The crude product was purified by repeated reverse-phase reactions to obtain the target compound (86.8 g), a white solid. The total yield of the two batches was 92.93 g, with an overall yield of 28.4%.

[0130] LC / MS method parameters:

[0131] Mobile phase A: 0.03% aqueous solution of TFA; Mobile phase B: 0.03% ACN solution of TFA;

[0132] Gradient: Phase B 5% - 95% - P - 2min;

[0133] Chromatographic column: Agilent Pursuit XRs 5C18 2.0*30mm 5um;

[0134] Flow rate: 1.5 mL / min.

[0135] MS(ESI) m / z: 383.2 [M+H] + .

[0136] HPLC: 99.171% (ELSD).

[0137] 1 H NMR (400MHz, CDCl3): δ7.99(s,3H),5.64(s,2H),5.25(s,1H),4.08(t,J=5.2Hz,1H),2.67(d,J=4.0Hz,2H),2.35– 2.17(m,2H),2.14(s,1H),1.76(s,2H),1.59(d,J=12.7Hz,4H),1.40–1.26(m,4H),1.20–1.10(m,2H),0.85(s,6H).

[0138] 19 F NMR (376MHz, CDCl3): δ-75.51 (s).

[0139] Example 2: Preparation of compound MN-8'

[0140] The synthetic route of MN-8' is as follows: Figure 16 As shown:

[0141] (1) Compound 2 synthesis:

[0142]

[0143] (1r,3R,5S,7r)-3,5-dimethyladamantan-1-amine hydrochloride (5 g, 23.26 mmol, 1 equivalent) and DIPEA (9.07 g, 69.77 mmol, 3 equivalent) were dissolved in dry THF (100 mL), and chloromethyl chlorate (4.5 g, 34.89 mmol, 1.5 equivalent) was slowly added at 0 °C. After addition, the mixture was stirred at room temperature for 3 hours. The mixture was then concentrated and purified by silica gel column chromatography (0-50% EA in PE) to give the title compound as a yellow oil (4 g, 63.5% yield). MS_(M+H + ): found 272.1, calculated 272.1

[0144] (2) Compound 4 synthesis:

[0145]

[0146] Chloromethyl (1r,3R,5S,7r)-3,5-dimethyladamantan-1-ylcarbamate (2.0 g, 7.38 mmol, 1 equivalent) and tetrabutylammonium di-tert-butyl phosphate (4.0 g, 8.85 mmol, 1.2 equivalent) were dissolved in dry CH3CN (50 mL), and KI (1.23 g, 7.38 mmol, 1.0 equivalent) was added at room temperature. The mixture was stirred at 80 °C for 2 hours. The mixture was then concentrated and purified by silica gel column chromatography (0-50% EA in PE) to give the title compound as a white solid (2.28 g, 66% yield).

[0147] MS_(M+Na + Actual value: 468.2, theoretical value: 446.3

[0148] 1 H NMR (400MHz, CDCl3) δ5.52 (d, J = 13.1Hz, 2H), 4.78 (s, 1H), 2.19–2.12 (m, 1H), 1.78 (s, 2H), 1.60–1. 54(m,4H),1.49(s,18H),1.39–1.34(m,2H),1.29(d,J=7.4Hz,2H),1.28–1.23(m,2H),0.85(s,6H).

[0149] (3) Synthesis of compound MN-8':

[0150]

[0151] (Di-tert-butoxyphosphate) hydroxymethyl (1r,3R,5S,7r)-3,5-dimethyladamantan-1-ylcarbamate (2.28 g, 5.12 mmol) was dissolved in dry DCM (30 mL), and TFA (10 mL) was added at 0 °C. The mixture was stirred at 0 °C for 1 hour. LCMS analysis showed that the reaction was complete.

[0152] The mixture was then concentrated and purified by silica gel column chromatography (0-50% MeOH in DCM) over a short period of time to give the title compound as a white solid (1.54 g, 79% yield). Structural confirmation is shown in [link to structural description]. Figure 8-14 .

[0153] Synthesis steps for MN-8 100g:

[0154] Step 1: Formation of amides

[0155]

[0156] Add A (230g, 1.07 moles, 1.0 eq.) and THF (2L) to a 5L reaction flask at 15-25℃.

[0157] Cool to 0-10℃ in an ice-salt bath.

[0158] Add DIPEA (550.81g, 4.26moles, 4.0eq.) all at once at 0-10℃.

[0159] Add B dropwise at 0-10℃ (151.12g, 1.17moles, 1.1eq.).

[0160] Stir overnight at 15-25℃.

[0161] Monitoring: Spotting display (n-heptane / ethyl acetate = 5 / 1, iodine tank color development): No raw material A was found, and one main spot was formed.

[0162] Pour the reaction solution into a stirred container of methyl tert-butyl ether / water (2L / 6L) at room temperature.

[0163] Separate the liquid and wash the organic phase with 5 wt% citric acid solution (2 L), 5 wt% aq. NaHCO3 (2 L), and sat. NaCl (1 L), respectively.

[0164] The organic phase was dried with sodium sulfate and then evaporated by rotary evaporation.

[0165] The crude product was subjected to column chromatography (eluting with petroleum ether / ethyl acetate 20 / 1 to 10 / 1) to give 259 g of a pale yellow oil.

[0166] Yield: 89%

[0167] LCMS: No UV absorption, clean spotting.

[0168] Step 2: Alkylation reaction

[0169] Add C (33g, 0.12 moles, 1.0 eq.) and MeCN (330 mL) to a 1 L reaction flask at 15-25℃.

[0170] Add D (49.4 g, 0.11 moles, 0.9 eq.) and KI (22.2 g, 0.13 moles, 1.1 eq.) at room temperature.

[0171] Heat to 40-50°C and maintain the temperature while stirring for 2 hours. LCMS ELSD showed no C, 40% E, and 59% N. + Bu4.

[0172] Cool to room temperature.

[0173] The reaction solution was filtered directly, and the filter cake was washed with acetonitrile (30 mL x 3).

[0174] The filtrate was evaporated to dryness.

[0175] Add petroleum ether (330 mL) to the evaporated crude product and stir at room temperature for 1 hour.

[0176] Filter, and wash the filter cake with PE (30mL x 3).

[0177] The filtrate was evaporated at 40°C to obtain 52g of a white, oily substance.

[0178] Yield: 96%

[0179] CMS: No UV absorption, clean ELSD

[0180] Considering the poor stability of the product, a total of 300g of product E was obtained from multiple batches of reaction.

[0181] Step 3: Detert-butylation reaction

[0182]

[0183] Add 4M HCl in dioxane (104 mL) to a 250 mL reaction flask.

[0184] Cool to 0-10℃ in an ice-salt bath.

[0185] Add E (33g, 0.12 moles, 1.0 eq.) all at once at 0-10℃ and maintain the temperature while stirring for 1 hour. LCMS ELSD showed no remaining raw material E, 95% product.

[0186] Add PE (150 mL) to the reaction solution at 0-10℃ and stir for 0.5 h.

[0187] Filter, and wash the filter cake with PE (20mL x 3).

[0188] The filter cake was pulped with DCM (100 mL) at 0-10°C for 0.5 h.

[0189] Filter, and wash the filter cake with DCM (10mL x 3).

[0190] The filter cake was pulped with acetonitrile (20 mL) at 0-10°C for 0.5 h.

[0191] Filter and wash the filter cake with acetonitrile (5 mL x 3).

[0192] Combine with filter cakes obtained from other batches (total of 268g of E used).

[0193] 100g of white solid was obtained by drying with nitrogen at room temperature for 16 hours.

[0194] Yield: 50%

[0195] LCMS: No UV absorption, 100% ELSD

[0196] LC / MS method parameters:

[0197] Mobile phase A: 0.01% aqueous solution of TFA; Mobile phase B: 0.01% ACN solution of TFA;

[0198] Gradient: B increases from 5% to 95% within 1.3 minutes, and 95% B is maintained for 1.2 minutes;

[0199] Flow rate: 1.5 mL / min;

[0200] Chromatographic column: Columnpr Poroshel 120EC-C18 3.0X30mm 2.7-Micron;

[0201] Column temperature: 45℃;

[0202] Detection: UV (214, 4nm), MS (ESI, Pos mode, 110 to 1500amu).

[0203] MS_(M+H + Actual value: 334.3, theoretical value: 334.3

[0204] 1 H NMR(400MHz,MeOD)δ5.48(d,J=12.9Hz,2H),2.18–2.06(m,1H),1.80(s,2H),1.57( dt,J=27.0,13.4Hz,4H),1.35(dd,J=28.2,12.4Hz,4H),1.15(s,2H),0.85(s,6H).

[0205] Example 3: Rat Pharmacokinetic Experiment

[0206] 3.1 Test sample and carrier:

[0207] The basic information of the test sample is shown in Table 1:

[0208] Table 1 Basic Information of the Test Sample

[0209]

[0210] Carrier: Physiological saline, Zhejiang Dubang, 2301240106

[0211] 3.2 Experimental animals:

[0212] Sixteen male SD rats, 6-8 weeks old and weighing 210-240 g, were purchased from JH Laboratory Animal Co., Ltd. Qualification number: 20220009023942. Animals were required to acclimatize for at least 5 days prior to inclusion in the study. In the single oral administration groups (G1 to G3), animals were fasted overnight and fed 4 hours after administration; animals in the single intravenous injection group (G4) had free access to food and water.

[0213] 3.3 Preparation of Drug Delivery Formulations

[0214] The first group of drug solutions was MN-8' (target concentration 4.2 mg / mL) prepared with "100% physiological saline".

[0215] The second group of drug solutions was MN-1' (target concentration 4.6 mg / mL) prepared with "100% physiological saline".

[0216] The dosing solutions for groups 3 and 4 were prepared with MN (target concentrations of 2 mg / mL and 0.4 mg / mL) using 100% saline.

[0217] The specific preparation method is as follows:

[0218] Preparation of PO dosing solution of MN-8' (4.2 mg / mL): Accurately weigh 33.94 mg of MN-8' into a clean bottle; add 6.024 mL of physiological saline to the bottle containing the substance; vortex the mixture for 1 minute and sonicate for 10 minutes to obtain a pale white homogeneous suspension of 4.2 mg / mL.

[0219] Preparation of PO dosing solution of MN-1' (4.6 mg / mL): Accurately weigh 38.67 mg of MN-1' into a clean bottle; add 6.422 mL of physiological saline to the bottle containing the substance; vortex the mixture for 1 minute and sonicate for 10 minutes to obtain a pale white homogeneous suspension of 4.6 mg / mL.

[0220] Preparation of MN PO dosing solution (2 mg / mL): Accurately weigh 17.98 mg MN into a clean bottle; add 7.471 mL of physiological saline to the bottle containing the substance; vortex the mixture for 1 minute and sonicate for 10 minutes to obtain a clear and colorless solution of 2 mg / mL.

[0221] Preparation of intravenous administration solution for MN (0.4 mg / mL): Pipette 1.300 mL of a 2 mg / mL solution; transfer the solution from group 3 to a clean bottle; add 5.200 mL of physiological saline to the bottle containing the solution and mix; vortex the mixture for 1 minute to obtain a clear, colorless solution of 0.4 mg / mL.

[0222] The drug formulations in the upper, middle, and lower layers were diluted and analyzed by LC-MS / MS. The measured dose concentrations were within ±30% of the mean nominal concentration (Table 2-4), and PK data were analyzed using the nominal dose.

[0223] Table 2. LC-MS / MS analysis results of the MN-8' single PO administration formulation.

[0224] Note: Average deviation (%) = (Actual concentration - Nominal concentration) / Nominal concentration * 100

[0225] Table 3. LC-MS / MS analysis results of MN-1' single PO administration formulation

[0226] Note: Average deviation (%) = (Actual concentration - Nominal concentration) / Nominal concentration * 100

[0227] Table 4. LC-MS / MS analysis results of MN single-IV and PO dosing formulations

[0228]

[0229] Note: Average deviation (%) = (Actual concentration - Nominal concentration) / Nominal concentration * 100

[0230] 3.4 Drug administration group and sampling point

[0231] Table 5 Grouping and Sampling Scheme

[0232]

[0233] Note: 1. *All animals were fasted overnight before administration and fed 4 hours after administration. 2. Dosage levels refer to the free base form and have been adjusted according to the form and purity of the salt.

[0234] Table 6 Animal Dosage

[0235]

[0236] No abnormal clinical symptoms were observed during the study.

[0237] 3.5 Sample Collection and Storage

[0238] Rat were restrained at the designated sampling point. Approximately 100 μL of blood was collected via the jugular vein into K2EDTA tubes. The blood samples were placed on wet ice and centrifuged at 2000 g for 5 minutes at 4°C to obtain plasma samples within 15 minutes of collection. Subsequently, 40 μL of stabilizer was immediately added to each 40 μL plasma sample, followed by 800 μL of IS (containing 1% FA). The samples were centrifuged at 14000 rpm for 5 minutes at 4°C, and then 800 μL of the supernatant was transferred to a new tube and stored at below -70°C for long-term preservation until LC-MS / MS analysis.

[0239] 3.6 Pharmacokinetic Analysis

[0240] Quality control was performed based on LC-MS / MS analysis results, and a standard curve was plotted. This was done using concentration-time data and dose levels. Professional 8.2 calculates the pharmacokinetic parameters (CL, V) of MN-8', MN-1', and MN in plasma using a non-compartmental analysis model. SS AUC last AU INF MRT, t 1 / 2 C max and T max The formula for calculating the bioavailability of gavage administration is: F(%) = (dose) / (gavage) IV *AUC PO ) / (dose PO *AUC IV )*100.

[0241] Tables 7, 8, and 9 summarize the mean pharmacokinetic parameters of MN-8', MN-1', and MN in rat plasma after IV and PO administration, respectively. Figures 17-22 The mean plasma concentration versus time curves are shown. Individual plasma concentrations, pharmacokinetic parameters, and concentration-time curves for MN-8', MN-1', and MN are shown in Table 10-14.

[0242] Table 7. Mean pharmacokinetic parameters of MN-8' and MN after oral administration to male SD rats (Mean±SD, N=4)

[0243]

[0244] Table 8. Mean pharmacokinetic parameters of MN-1' and MN after oral administration to male SD rats (Mean±SD, N=4)

[0245]

[0246] NA: Unavailable

[0247] Table 9 Mean pharmacokinetic parameters (Mean ± SD, N = 4) after intravenous and oral administration of MN in male SD rats

[0248]

[0249] Table 10. Plasma concentration-time data and pharmacokinetic parameters of MN-8' after a single oral administration of 21 mg / kg MN-8' to male SD rats.

[0250]

[0251] BQL: Below the limit of quantitation (1.00 ng / mL); NA: Not available.

[0252] Table 11 Plasma concentration-time data and pharmacokinetic parameters of MN after a single oral administration of 21 mg / kg MN-8' to male SD rats.

[0253]

[0254] BQL: Below the lower limit of quantitation (1.00 ng / mL); NA: Not applicable. Table 12. Plasma concentration-time data and pharmacokinetic parameters of MN-1' after a single oral administration of 23 mg / kg MN-1' to male SD rats.

[0255] BQL: Below the limit of quantitation (1.00 ng / mL); NA: Not available.

[0256] Table 13 Plasma concentration-time data and pharmacokinetic parameters of MN after a single oral administration of 23 mg / kg MN-1' to male SD rats.

[0257]

[0258] BQL: Below the limit of quantitation (1.00 ng / mL); NA: Not available.

[0259] Table 14. Plasma concentration-time data and pharmacokinetic parameters of MN after a single oral administration of 10 mg / kg MN to male SD rats.

[0260]

[0261] BQL: Below the limit of quantitation (1.00 ng / mL); NA: Not available.

[0262] Table 15 Plasma concentration-time data and pharmacokinetic parameters of MN after a single intravenous injection of 2 mg / kg MN in male SD rats.

[0263] BQL: Below the limit of quantitation (1.00 ng / mL); NA: Not available.

[0264] In male SD rats, after administration of 21 mg / kg MN-8' to PO, the plasma concentration of MN-8' increased with a terminal half-life of 0.978 ± 0.220 hours (t). 1 / 2 ) decrease; C of MN-8' max The value was 158±85.9 ng / mL, and the corresponding T max The value was 0.0830 ± 0.00 hours; the area under the concentration-time curve (AUC) from time 0 to the last quantifiable concentration. last The concentration-time area under the curve (AUC) was 38.3 ± 8.46 h*ng / mL, from 0 to infinity. INF The value was 42.7 ± 9.59 h*ng / mL.

[0265] In male SD rats, after administration of 21 mg / kg MN-8' to PO, the plasma concentration of MN increased with a terminal half-life of 3.02 ± 0.995 hours (t). 1 / 2 ) decrease; C of MN max The value was 474±57.8 ng / mL, and the corresponding T max The value was 0.625 ± 0.250 hours; the area under the concentration-time curve (AUC) from time 0 to the last quantifiable concentration. last The concentration-time area under the curve (AUC) from 0 to infinity was 2229 ± 433 h * ng / mL. INFThe value was 2277±424 hours*ng / mL.

[0266] After oral administration of 23 mg / kg MN-1' to male SD rats, the plasma concentration of MN-1' at all time points was below the limit of quantification of 1.00 ng / mL.

[0267] In male SD rats, after administration of 23 mg / kg MN-1' to PO, the plasma concentration of MN increased with a terminal half-life of 2.62 ± 0.538 hours (t). 1 / 2 ) decrease; C of MN max The value was 483±126 ng / mL, and the corresponding T max The value was 1.25 ± 0.500 hours; the area under the concentration-time curve (AUC) from time 0 to the last quantifiable concentration. last The concentration-time area under the curve (AUC) from 0 to infinity was 2065 ± 382 h * ng / mL. INF The value was 2120±378 hours*ng / mL.

[0268] In male SD rats, after administration of 10 mg / kg MN via PO, the plasma concentration of MN increased with a terminal half-life of 2.85 ± 0.478 hours (t). 1 / 2 ) decrease; C of MN max The value was 592±135 ng / mL, and the corresponding T max The value is 0.500 ± 0.00 hours; the area under the concentration-time curve (AUC) from time 0 to the last quantifiable concentration. last The concentration-time area under the curve (AUC) from 0 to infinity was 2113 ± 246 h * ng / mL. INF The bioavailability of MN via gavage was 2154 ± 258 h* ng / mL. In male SD rats, the gavage bioavailability of MN after administration of 10 mg / kg was 103 ± 12.3%.

[0269] Following intravenous injection of 2 mg / kg MN into male SD rats, the plasma concentration of MN increased with a terminal half-life of 2.20 ± 0.104 hours (t). 1 / 2 () decreased; mean time of stay (MRT) INF) The time to systemic clearance (C1) was 2.68 ± 0.247 hours; the systemic clearance (C1) was 4.82 ± 0.620 L / hr / kg, equivalent to 146% of the rat hepatic blood flow (3.312 L / hr / kg, Davies and Morris, 1993), indicating that MN had a high clearance rate in rat plasma; the steady-state distribution volume (V) was 2.68 ± 0.247 hours. ssThe concentration was 12.9 ± 1.96 L / kg, equivalent to 12.3 times the total body fluid volume of a rat (0.668 L / kg, Davies and Morris, 1993), indicating that MN has a wide extravascular distribution; the area under the concentration-time curve (AUC) from time 0 to the last quantifiable concentration... last The concentration-time area under the curve (AUC) from 0 to infinity was 410 ± 54.7 h*ng / mL. INF The result was 420 ± 56.2 h * ng / mL.

[0270] In male SD rats, after administration of 21 mg / kg of MN-8' and 23 mg / kg of MN-1' to the prodrugs (MN-8' and MN-1'), the prodrugs were almost completely converted to the parent drug (MN).

[0271] After administration of 21 mg / kg MN-8', 23 mg / kg MN-1', and 10 mg / kg MN via PO, the C of MN... max and AUC INF Broadly similar. The AUC of MN at a unit molar dose... INF，MN-8′ / AUC INF，MN The ratio is 0.936, and the AUC of MN is... INF,MN-1′ / AUC INF,MN The ratio is 0.913.

[0272] In male SD rats, the gavage bioavailability of MN after administration of 10 mg / kg was 103 ± 12.3%.

[0273] Example 4: Pharmacokinetic Study in Beagle Dogs

[0274] 4.1 Test sample and carrier:

[0275] Same as Example 3.

[0276] 4.2 Experimental animals:

[0277] Nine non-newborn male Beagles, weighing 8-11 kg, were purchased from Beijing Marshall Biotechnology Co., Ltd. Qualification number: SCXK(BJ)2022-0007, No. 110318231100008774. The animals were acclimatized for at least two weeks before entering the study. In all PO-administered groups, animals were fasted overnight and fed 4 hours after administration.

[0278] 4.3 Preparation of Drug Delivery Formulations

[0279] The first group of drug solutions was MN-8' (target concentration: 1.575 mg / mL) prepared using "100% physiological saline".

[0280] The second group of drug solutions used MN-1' prepared with 100% physiological saline (target concentration: 1.725 mg / mL).

[0281] The third group of drug solutions used MN (target concentration: 0.75 mg / mL) prepared with 100% physiological saline.

[0282] The specific preparation method is as follows:

[0283] Preparation of MN-8' PO dosing solution (1.575 mg / mL): Accurately weigh 279.79 mg MN-8 into a clean bottle; add 132.428 mL of physiological saline to the bottle containing the compound; stir the mixture for 10 minutes and sonicate for 30 minutes to obtain a pale white homogeneous suspension of 1.575 mg / mL. Preparation of MN-1' PO dosing solution (1.725 mg / mL): Accurately weigh 299.08 mg MN-1 into a clean bottle; add 132.453 mL of physiological saline to the bottle containing the compound; stir the mixture for 10 minutes and sonicate for 30 minutes to obtain a white homogeneous suspension of 1.725 mg / mL. Preparation of MN PO dosing solution (0.75 mg / mL): Accurately weigh 121.43 mg of MN into a clean bottle; add 134.548 mL of physiological saline to the bottle containing the compound; stir the mixture for 10 minutes to obtain a clear and colorless solution of 0.75 mg / mL.

[0284] The drug formulations in the upper, middle, and lower layers were diluted and analyzed by LC-MS / MS. The measured dose concentrations were within ±30% of the mean nominal concentration (Tables 16-18), indicating a small mean deviation. PK data analysis was performed using the nominal dose.

[0285] Table 16 MN-8' Single PO Dosing Formulation LC-MS / MS Analysis Results

[0286] Note: Average deviation (%) = (Actual concentration - Nominal concentration) / Nominal concentration * 100

[0287] Table 17 LC-MS / MS Analysis Results of MN-1' Single-Dose PO Administration Formulation

[0288] Note: Average deviation (%) = (Actual concentration - Nominal concentration) / Nominal concentration * 100

[0289] Table 18. LC-MS / MS Analysis and Results of MN Single-Dose PO Administration Formulation

[0290] Note: Average deviation (%) = (Actual concentration - Nominal concentration) / Nominal concentration * 100

[0291] 4.4 Drug administration group and sampling point

[0292] like Figure 19 and Figure 20 As shown:

[0293] Table 19 Grouping and Sampling Scheme

[0294]

[0295] Note: 1. *All animals were fasted overnight before administration and were given food 4 hours after administration.

[0296] 2. The dosage level refers to the free base form and is adjusted according to the form and purity of the salt.

[0297] Table 20 Animal Dosage

[0298]

[0299] #6-8036830: A large amount of loose stool was observed 1 hour after administration. #8-8028616: A small amount of white, foamy, mucous vomit was observed 4 hours after administration. No abnormal clinical symptoms were observed in other animals during the study period.

[0300] 4.5 Sample Collection and Storage

[0301] Secure the dog to the designated sampling point. Collect approximately 500 μL of blood sample via the cephalic vein into a K2EDTA tube. Add 10% 100 mM AEBSF / NaF (40 mg / mL, dissolved in H2O) to the whole blood sample, then centrifuge at 3000 g for 5 minutes at 4°C within 10 minutes after sampling to obtain plasma samples. Immediately add 100 mM phosphate buffer (pH 4.5) (containing 20 mM cOmplete / 20 mM AEBSF / 8 mg / mL NaF) (v / v = 1:1) to each plasma sample and vortex until homogeneous. Rapidly freeze the plasma in dry ice and then transfer to a container below [temperature missing]. It can be stored in a refrigerator for a long time until LC-MS / MS analysis is performed.

[0302] 4.6 Pharmacokinetic Analysis

[0303] Quality control was performed based on LC-MS / MS analysis results, and a standard curve was plotted. This was done using concentration-time data and dose levels. Professional 8.2 calculates the pharmacokinetic parameters (AUC) of MN-8', MN-1', and MN in plasma using a non-compartmental analysis model. last AUINF t 1 / 2 C max and T max ).

[0304] Tables 21, 22, and 23 summarize the mean pharmacokinetic (PK) parameters of MN-8', MN-1', and MN in canine plasma after oral administration of MN-8', MN-1', and MN. Figure 23-27 The mean plasma concentration versus time curves are shown. Individual plasma concentrations, pharmacokinetic parameters, and concentration-time curves for MN-8', MN'-1, and MN are shown in Tables 24-28.

[0305] Table 21 Mean pharmacokinetic parameters of MN-8' and MN after PO administration in male beagle dogs (Mean ± SD, N = 3)

[0306]

[0307] NA: Unavailable

[0308] Table 22 Mean pharmacokinetic parameters of MN-1' and MN after PO administration in male beagle dogs (Mean ± SD, N = 3)

[0309]

[0310] NA: Unavailable

[0311] Table 23 Mean pharmacokinetic parameters of male beagle dogs after PO administration of MN (Mean ± SD, N = 3)

[0312] Table 24 Plasma concentration-time data and pharmacokinetic parameters after a single oral dose of 6.3 mg / kg MN-8' in male beagle dogs

[0313] BQL: Below the limit of quantitation (1.00 ng / mL); NA: Not available.

[0314] Table 25 Plasma concentration-time data and pharmacokinetic parameters after a single oral dose of 6.3 mg / kg MN-8' in male beagle dogs.

[0315] BQL: Below the limit of quantitation (1.00 ng / mL); NA: Not available.

[0316] Table 26 Plasma concentration-time data and pharmacokinetic parameters after a single oral dose of 6.9 mg / kg MN-1' in male beagle dogs

[0317] BQL: Below the limit of quantitation (1.00 ng / mL); NA: Not available.

[0318] Table 27 Plasma concentration-time data and pharmacokinetic parameters of MN after a single oral dose of 6.9 mg / kg MN-1' in male beagle dogs.

[0319] BQL: Below the limit of quantitation (1.00 ng / mL); NA: Not available.

[0320] Table 28 Plasma concentration-time data and pharmacokinetic parameters after a single oral dose of 3 mg / kg MN in male Beagle dogs.

[0321] BQL: Below the limit of quantitation (1.00 ng / mL); NA: Not available.

[0322] Following oral administration of 6.3 mg / kg of MN-8' to male beagles, the C of MN-8' was... max The value was 14.7 ± 5.47 ng / mL, and the corresponding T... max The value was 0.361 ± 0.241 hours; the area under the concentration-time curve (AUC) from 0 to the final quantifiable concentration. last The value was 6.29 ± 2.61 h*ng / mL.

[0323] Following administration of 6.3 mg / kg MN-8' to male beagle dogs via PO, the plasma concentration of MN was determined with a terminal half-life of 7.52 ± 0.645 hours (t). 1 / 2 ) decrease; C of MN max The value was 459±134 ng / mL, and the corresponding T max The value was 1.33 ± 0.577 hours; from time 0 to the last quantifiable concentration (AUC) last The area under the concentration-time curve for ) was 5392 ± 1364 h*ng / mL, and the area under the concentration-time curve from 0 to infinity (AU) INF The value was 5457±1390 h*ng / mL.

[0324] In male beagle dogs, after oral administration of 6.9 mg / kg of MN-1', the plasma concentration of MN-1 at all time points was below the limit of quantification of 1.00 ng / mL.

[0325] Following oral administration of 6.9 mg / kg MN-1' to male beagle dogs, the plasma concentration of MN decreased over time, and its terminal half-life (t) was [not specified]. 1 / 2 The duration of MN was 5.76 ± 0.529 hours; the C of MN was... max The value was 213±82.2 ng / mL, and the corresponding T maxThe value was 1.67 ± 0.577 hours; from time 0 to the last quantifiable concentration (AUC) last The area under the concentration-time curve for ) was 1756 ± 447 h*ng / mL, and the area under the concentration-time curve from 0 to infinity (AU) INF The value was 1854±474 h*ng / mL.

[0326] Following oral administration of 3 mg / kg MN to male beagle dogs, the plasma concentration of MN was determined over a terminal half-life of 7.10 ± 0.886 hours (t). 1 / 2 ) decrease; C of MN max The value is 243 69.9 ng / mL, corresponding T max The value is 1.33 0.577 hours; from time 0 to the last quantifiable concentration (AUC) last The area under the concentration-time curve for ) was 1925 ± 326 hr*ng / mL, and the area under the concentration-time curve from 0 to infinity (AU) INF The value was 2110±296hr*ng / mL.

[0327] In male beagle dogs, after oral administration of 6.3 mg / kg of MN-8' and 6.9 mg / kg of MN-1', the prodrugs (MN-8', MN-1') were almost completely converted to the parent drug (MN).

[0328] Following oral administration of 6.9 mg / kg MN-1' and 3 mg / kg MN, the C of MN was... max and AUC INF Broadly similar. The AUC of MN at a unit molar dose... INF,MN-1′ / AUC INF,MN The ratio is 0.815.

[0329] Compared to a 3 mg / kg dose level of MN, a C-value of MN was observed after administration of 6.3 mg / kg MN-8' via PO. max and AUC INF Significantly higher. The AUC of MN at a unit molar dose... INF,MN-8′ / AUC INF,MN The ratio is 2.29.

[0330] MN-1' (Glu-modified): MN1' connects to glutamate (Glu) via an enzymatically cleavable linker, mimicking the natural NMDA ligand and potentially enhancing its targeting and central penetration of NMDAR. MN-8' (Phosphate-modified): Introducing a phosphate group may improve water solubility and, through the enzymatic action of phosphatases, release memantine in specific tissues (such as brain tissue) for targeted delivery. Furthermore, phosphate modification can alter the distribution and metabolic properties of drugs.

[0331] Both MN-1' and MN-8' are enzyme-activated prodrugs that utilize the specific enzymatic environment of the lesion region to achieve spatially selective release under conditions of blood-brain barrier damage or local activation, thereby enhancing their effect on the central targets of NPSLE and potentially reducing systemic exposure-related adverse reactions. In particular, MN-8' significantly improves the bioavailability of the parent drug, with an AUC ratio of 2.29, allowing for the use of smaller doses to achieve equivalent or better efficacy. It has been developed into a sustained-release oral formulation.

Claims

1. The compound represented by formula (I) or formula (II): R1 is hydrogen, or an unsubstituted or substituted C1-C4 alkyl group; R2 is or R3 is n = 1 - 4; m = 1 - 6; R4 is hydrogen, or an unsubstituted or substituted C1-C4 alkyl group; a = 1-4, R5 is H, halogen, C1-C4 alkyl or C1-C4 alkoxy; or, b＝1-6。 2. The compound according to claim 1, wherein R5 is a chlorine atom, a fluorine atom, a bromine atom, an iodine atom, a C1-C4 alkyl group, or a C1-C4 alkoxy group.

3. The compound according to claim 1 or 2, wherein R1 is hydrogen or methyl; R4 is hydrogen or methyl.

4. The compound according to any one of claims 1-3, wherein in R3 n = 1, m = 3 or 4, a = 1, and / or b = 3.

5. The compound according to any one of claims 1-3, wherein any hydrogen atom in the unsubstituted or substituted C1-C4 alkyl group is substituted by a group selected from hydroxyl, amino, or carboxyl groups.

6. The compound according to claim 1, wherein the compound is selected from the following compounds:

7. A pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, amorphous form, isotope, polymorph, or solvate of the compound according to any one of claims 1-6.

8. The pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, amorphous substance, isotope, polymorph or solvate according to claim 7; wherein the pharmaceutically acceptable salt is a hydrochloride salt.

9. The use of the compound according to any one of claims 1-6, or the pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, amorphous substance, isotope, polymorph or solvate according to claim 9 or 10, in the preparation of a medicament for treating NMDAR-related diseases.

10. The application according to claim 9, wherein the NMDAR-related diseases are selected from systemic lupus erythematosus, preferably psychogenic lupus erythematosus, Alzheimer's disease, encephalitis, epilepsy, depression, memory loss, learning disability, cognitive impairment, and ischemic brain injury.

11. A medicament for treating NMDAR-related diseases, said medicament comprising a compound according to any one of claims 1-6, or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, amorphous substance, isotope, polymorph, or solvate according to claim 9 or 10.

12. The medicament of claim 11, wherein a unit dose of the medicament contains a lower content of the compound according to any one of claims 1-6, or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, amorphous substance, isotope, polymorph, or solvate according to claim 9 or 10, than a unit dose of a medicament containing memantine.

13. The medicament according to claim 11 or 12, wherein the medicament is an oral preparation, preferably a sustained-release oral preparation.

14. A method for treating NMDAR-related diseases, characterized in that, The method includes administering to a patient with NMDAR-related disease a compound according to any one of claims 1-6, or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, amorphous substance, isotope, polymorph, or solvate according to claim 9 or 10.

15. The method of claim 14, wherein the amount of the compound of any one of claims 1-6, or the pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, amorphous substance, isotope, polymorph, or solvate of claim 9 or 10, administered to the patient in a lower amount than that used when treating the same disease with memantine.

16. The method according to claim 15, wherein the NMDAR-related disease is selected from systemic lupus erythematosus, preferably psychogenic lupus erythematosus, Alzheimer's disease, encephalitis, epilepsy, depression, memory loss, learning disability, cognitive impairment, and ischemic brain injury.

17. A method for preparing compound MN-1', characterized in that, The method includes: Step (1): The compound It reacts with AgNO to form a compound Step (2): The compound With compounds The reaction produces compounds Step (3): Place the compound Reaction with KI to form a compound Step (4): Place the compound With compounds The reaction produces compounds Step (5): Place the compound With compounds The reaction produces compounds Step (6) from the compound The reaction of removing tert-butyloxycarbonyl group yields the compound 18. A method for preparing compound MN-8', characterized in that, The method includes: Step (1): The compound With compounds The reaction produces compounds Step (2): The compound With compounds The reaction produces compounds Step (3): Place the compound Detert-butyl reaction produces

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