Aminothiazoles and their use as brain-permeable histamine h2 receptor agonists

Abstract

The application discloses an amino thiazole compound and use thereof as a brain-permeable histamine H2 receptor agonist, and belongs to the field of medicines. The amino thiazole compound provided by the application has a structural general formula as shown in formula (I) and includes pharmaceutically acceptable salts. The amino thiazole compound has histamine H2 receptor agonistic activity and excellent blood-brain barrier permeability. Therefore, the amino thiazole compound can be applied to preparation of a medicine for treating diseases such as schizophrenia, mania, attention deficit hyperactivity disorder, binge eating or bulimia nervosa, autism, Parkinson's disease, ischemic brain injury and the like.

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, and more particularly to aminothiazole compounds or pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing such compounds, for use as brain-penetrating histamine H2 receptor agonists. Background Technology

[0002] Histamine is an important neurotransmitter and neuromodulator in the central nervous system, participating in the regulation of various physiological functions such as wakefulness, feeding, learning, and memory. Central histamine primarily has three receptors, all of which are G protein-coupled receptors. H1 and H2 receptors are located on the postsynaptic membrane, while H3 receptors are mainly located presynaptic, negatively regulating histamine synthesis and release. Currently, most known histaminergic system functions are mediated by H1 receptors. While H2 receptors are similar to H1 receptors and widely distributed in the brain, their function has been less reported. In recent years, the role of H2 receptors in neuropsychiatric disorders has attracted considerable attention. Studies have found that H2 receptor deficiency may play a crucial role in the development of brain diseases such as schizophrenia, mania, attention deficit hyperactivity disorder, Parkinson's disease, and ischemic brain injury. H2 receptors may become drug targets for these neuropsychiatric disorders.

[0003] Schizophrenia is a severe mental illness affecting approximately 1% of the global population, imposing a heavy burden on society and the economy. Traditional views hold that abnormal glutamate synaptic transmission, associated with insufficient N-methyl-D-aspartate receptor (NMDAR) function, causes positive symptoms (such as hallucinations and delusions), negative symptoms (such as loss of emotion and aphasia), and cognitive impairment in schizophrenia. However, the development of glutamate-based antipsychotic drugs faces many challenges. Further exploration of the glutamatergic neural mechanisms involved in schizophrenia and the search for novel drugs that regulate glutamatergic neural function are of great significance for the treatment of schizophrenia. Studies have found that the absence of histamine H2 receptors in glutamatergic neurons in the medial prefrontal cortex induces schizophrenia-like behavior, and overexpression of H2 receptors can improve schizophrenia-related behaviors in mice. Local intracerebral injection of the histamine H2 receptor agonists betahistazole and azamine can increase the activity of glutamatergic neurons and improve schizophrenia-like behaviors in animals; therefore, H2 receptor agonists have great potential for the treatment of schizophrenia. Meanwhile, preclinical studies have also found that H2 receptor agonists can improve brain diseases such as mania, attention deficit hyperactivity disorder, Parkinson's disease, and ischemic brain injury.

[0004] Several H2 receptor agonists have been reported so far. Based on their structural type, they can be mainly divided into arylethylamines and arylpropylguanidines (the main compound structures are shown below). Among them, the arylethylamine derivative Betazole, reported in J. Am. Med. Assoc., 1961, 175(10), 908-909, is used clinically for gastric acid secretion function testing. However, it has low selectivity for H1 receptors and cannot cross the blood-brain barrier.

[0005] Literature WO 91 / 10656 and Bioorg. Med. Chem. Lett., 1994, 4(16), 1913-1916 reported Amthamine and Amselamine, derived from the histamine H2 receptor partial agonist Dimaprit. They contain 2-aminothiazole and 2-aminoselenoazole cores, respectively, and have H2 receptor agonist activities of pD2 = 6.21 and pD2 = 6.41, respectively. They also show good selectivity for H1 (>1000). However, their pharmacokinetic results show that Amthamine and Amselamine cannot penetrate the brain and are currently only used as research tools.

[0006] The literature J. Med. Chem., 1992, 35, 3239-3246 reported the arylpropylguanidine H2 receptor agonists Impromidine and Arpromidine, with agonistic activities of pD2 = 7.80 and pD2 = 8.00, respectively. The literature ACS. Omega., 2018, 3, 2865-2882 reported the further developed biarylpropylguanidine derivatives UR-AK 381 and SK&F93082, which showed further enhanced H2 receptor agonistic activities, with agonistic activities of pEC... 50 = 8.11, pEC 50 = 7.98, but the strong basicity and polarity of the guanidine group prevent the molecule from crossing the blood-brain barrier.

[0007]

[0008] This invention uses the histamine H2 receptor agonist ansaramine as a lead agent, and optimizes the structure of the terminal amino group to enhance its ability to cross the blood-brain barrier. This effectively solves the shortcomings of existing H2 receptor agonists that cannot penetrate the brain, and is expected to be used in the treatment of neuropsychiatric diseases such as schizophrenia, mania, bulimia nervosa or bulimia nervosa, autism, Parkinson's disease, and ischemic brain injury. Summary of the Invention

[0009] The purpose of this invention is to provide a histamine H2 receptor agonist that can cross the blood-brain barrier and apply it to the treatment of neuropsychiatric diseases involving histamine H2 receptors.

[0010] To achieve the above objectives, the present invention adopts the following technical solution: This invention provides an aminothiazole compound having the structure of general formula (Ⅰ):

[0011] (I) n = 1 or 2; NR1R2 is an open-chain amine or a 3-8 member cyclic amine; When NR1R2 is an open-chain amine, R1 is selected from hydrogen, C 1-5 Alkyl group; R2 is selected from C 1-5 Alkyl, benzyl.

[0012] More specifically, in the aminothiazole compounds provided by this invention, when NR1R2 is an open-chain amine, R1 is selected from H, Me, Et, n -Pr、 i -Pr、 i -Bu; R2 is selected from Me, Et, n -Pr、 i -Pr、 i -Bu、 ; When NR1R2 is a 3-8 membered cyclic amine, it is selected from... , .

[0013] The structural formulas of representative aminothiazole compounds are shown in Table 1 below: Table 1. Structures of aminothiazole compounds

[0014] The present invention also provides pharmaceutically acceptable salts of the aforementioned aminothiazole compounds.

[0015] The term "pharmaceutically acceptable salt" refers to salts prepared by conventional methods, including but not limited to organic acid salts and inorganic acid salts. Organic acid salts include, but are not limited to, maleates, citrates, succinates, tartrates, oxalates, p-toluenesulfonates, malates, fumarates, methanesulfonates, acetates, etc.; inorganic acid salts include, but are not limited to, sulfates, hydrochlorides, hydrobromic acids, phosphates, etc.

[0016] The present invention also provides a pharmaceutical composition comprising an aminothiazole compound as described in any of the preceding claims or a pharmaceutically acceptable salt thereof, or further comprising a pharmaceutically acceptable excipient, diluent, carrier or excipient.

[0017] Specifically, this invention provides the use of the aforementioned aminothiazole compounds, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of remedies for treating neuropsychiatric disorders such as schizophrenia, mania, bulimia nervosa, autism, Parkinson's disease, and ischemic brain injury. It is worth noting that the pharmaceutical use of these compounds is not limited to the preparation of remedies for the aforementioned diseases.

[0018] The therapeutic mechanism of the drug includes: its active ingredient, aminothiazole compounds, increases the activity of glutamatergic neurons by reducing the current Ih mediated by hyperpolarized activated cyclic adenosine monophosphate (HCN) channels on glutamatergic neurons, thereby stimulating histamine H2 receptors. In particular, it has excellent blood-brain barrier permeability and can be used as a brain-penetrating histamine H2 receptor agonist in the preparation of drugs for brain diseases.

[0019] The beneficial effects of this invention are as follows: This invention provides a novel class of aminothiazole-based histamine H2 receptor agonists that can penetrate the brain. These compounds and their derivatives exhibit significant agonistic activity against histamine H2 receptors, demonstrating good biological activity in both in vitro and in vivo biological evaluations. Several compounds show H2 receptor agonistic activity superior to or equivalent to that of arsamine, and exhibit excellent blood-brain barrier permeability in pharmacokinetic studies. Therefore, these compounds can be used as histamine H2 receptor agonists in the treatment of diseases related to histamine H2 receptors, including but not limited to the use in the treatment of neuropsychiatric disorders such as schizophrenia, mania, attention deficit hyperactivity disorder, bulimia nervosa, autism, Parkinson's disease, and ischemic brain injury. Attached Figure Description

[0020] Figure 1 The following are the drug efficacy curves for compound A-3 administered by gavage and intravenous injection, as well as the blood and brain efficacy curves for compound A-3 administered by gavage. Among them, (A) drug efficacy curve for compound A-3 administered by gavage (5 mg / kg); (B) drug efficacy curve for compound A-3 administered by intravenous injection (1 mg / kg); (C) brain efficacy curve for compound A-3 administered by gavage (30 mg / kg); (D) blood efficacy curve for compound A-3 administered by gavage (30 mg / kg).

[0021] Figure 2 The following are the drug-time curves of compound A-15 after gavage and intravenous injection, as well as the blood and brain drug-time curves of compound A-15 after gavage. Among them, (A) drug-time curve of compound A-15 after gavage (5 mg / kg); (B) drug-time curve of compound A-15 after intravenous injection (1 mg / kg); (C) brain drug-time curve of compound A-15 after gavage (20 mg / kg); (D) blood drug-time curve of compound A-15 after gavage (20 mg / kg).

[0022] Figure 3 The following are the drug-time curves of compound A-17 after gavage and intravenous injection, as well as the blood and brain drug-time curves of compound A-17 after gavage. Among them, (A) drug-time curve of compound A-17 after gavage (5 mg / kg); (B) drug-time curve of compound A-17 after intravenous injection (1 mg / kg); (C) brain drug-time curve of compound A-17 after gavage (20 mg / kg); (D) blood drug-time curve of compound A-17 after gavage (20 mg / kg).

[0023] Figure 4 The following are drug-time curves for compound A-18 administered by gavage and intravenous injection, as well as blood and cerebral drug-time curves for compound A-18 administered by gavage. Among them, (A) drug-time curve for compound A-18 administered by gavage (5 mg / kg); (B) drug-time curve for compound A-18 administered by intravenous injection (1 mg / kg); (C) cerebral drug-time curve for compound A-18 administered by gavage (20 mg / kg); (D) blood drug-time curve for compound A-18 administered by gavage (20 mg / kg).

[0024] Figure 5 To improve MK-801-induced schizophrenia-related behaviors in mice, compound A-3 was used, where (A) the total distance mice traveled in an open field over 2 hours; (B) the distance mice traveled every 5 minutes in the open field; (C) the preference index of mice for S1 (familiar mice) and S2 (unfamiliar mice) in a social novelty test; and (D) the percentage of cotton weight not torn by mice in a nesting test. n=8; * P <0.05; ** P <0.01; *** P <0.001; **** P <0.0001; ns, no significant difference.

[0025] Figure 6 To improve amphetamine-induced manic-related behaviors in mice, compound A-3 was used to determine the following: (A) total distance traveled within 1 hour after amphetamine administration; (B) total time of movement within 1 hour after amphetamine administration; (C) total distance traveled within 1 hour after sleep deprivation; and (D) total speed of movement within 1 hour after sleep deprivation. n=4-9; * P <0.05,** P <0.01, *** P <0.001. Detailed Implementation

[0026] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. 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 of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0027] Example 1: Preparation of 4-methyl-5-(2-(methylamino)ethyl)thiazole-2-amine (Compound A-1)

[0028] Step 1: Synthesis of 2-(4-oxopentyl)-1H-isoindole-1,3(2H)-dione (intermediate I-2) 5-Chloro-2-pentanone I-1 (20.0 g, 166 mmol), phthalimide (24.4 g, 166 mmol), potassium iodide (5.5 g, 33 mmol), and potassium carbonate (34.4 g, 249 mmol) were dissolved in 160 mL of DMF. o The reaction was stirred at C for 5 hours under nitrogen protection. The solvent was removed under reduced pressure, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Recrystallization from methanol gave 35.3 g of a pale yellow solid I-2, with a yield of 92%. 1 H NMR (500 MHz, Chloroform- d ) δ 7.82 (dd, J = 5.0, 3.0 Hz, 2H), 7.74 (dd, J = 5.0, 3.0 Hz, 2H), 3.73 (t, J = 7.0 Hz, 2H), 2.58 (t, J = 8.0 Hz, 2H), 2.16 (s, 3H), 1.98(p, J = 7.0 Hz, 2H); ESI-MS: m / z = 232.1 [M+H] + .

[0029] Step 2: Synthesis of 2-(3-bromo-4-oxopentyl)-1H-isoindole-1,3(2H)-dione (intermediate I-3) Under N2 protection, liquid bromine (16.0 g, 99 mmol) was slowly added dropwise to a CCl4 (115 mL) solution of intermediate I-2 (23.0 g, 99 mmol), and the reaction was carried out at room temperature for 3 h. The solvent was removed under reduced pressure, and the mixture was extracted twice with ethyl acetate by adding saturated sodium bicarbonate. The organic layer was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Recrystallization from ethanol gave 27.3 g of yellow solid I-3, yield 88%, ESI-MS: m / z = 310.0 [M+H]. + .

[0030] Step 3: Synthesis of 2-(2-(2-amino-4-methylthiazolyl-5-yl)ethyl)isoindole-1,3(2H)-dione (intermediate I-4) Intermediate I-3 (14.4 g, 46 mmol), thiourea (3.4 g, 49 mmol), and triethylamine (9.4 g, 93 mmol) were dissolved in 100 mL of dioxane and heated to 80°C. o The reaction was carried out at C for 5 h. The reaction system was cooled, filtered, and the solvent was removed from the filtrate under reduced pressure. An appropriate amount of water was added, and the mixture was extracted three times with dichloromethane. The organic layer was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography to obtain 10.4 g of yellow solid I-4, with a yield of 78%. 1 H NMR (500 MHz, Chloroform- d ) δ 7.88-7.83 (m, 4H), 6.59 (s, 2H), 3.67 (t, J = 6.8 Hz, 2H), 2.86 (t, J = 7.0 Hz, 2H), 1.88 (s, 3H); ESI-MS: m / z = 288.1 [M+H] + .

[0031] Step 4: Synthesis of 5-(2-aminoethyl)-4-methylthiazol-2-amine (Ansarmin I-5) At room temperature, 80% hydrazine hydrate (5.6 g, 90 mmol) was added dropwise to a 100 mL ethanol solution of intermediate I-4 (13.0 g, 45 mmol), and the solution was heated to 70°C. o The reaction was carried out at C for 5 hours. The reaction system was cooled, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography to give 5.4 g of yellow solid I-5, with a yield of 75%. 1 H NMR (500 MHz, DMSO- d 6) δ 6.54 (s, 2H), 2.65-2.58 (m, 2H), 2.57-2.53 (m, 2H), 1.98 (s, 3H); ESI-MS: m / z = 158.1 [M+H] + .

[0032] Step 5: Preparation of 4-methyl-5-(2-(methylamino)ethyl)thiazole-2-amine (Compound A-1) At room temperature, dissolve ansaramine I-5 (157 mg, 1.0 mmol), potassium carbonate (276 mg, 2.0 mmol), and methyl iodide (142 mg, 1.0 mmol) in 5 mL of DMF, and heat to 50°C. o The reaction was carried out at C for 3 h. A suitable amount of water was added, and the mixture was extracted three times with dichloromethane. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography to give 91 mg of a pale yellow solid A-1, with a yield of 53%. 1 H NMR (500 MHz, DMSO- d 6 ) δ 6.69 (s, 2H), 2.81 (m,4H), 2.46 (s, 3H), 2.00 (s, 3H); ESI-MS: m / z = 172.1 [M+H] + .

[0033] Example 2: Preparation of 5-(2-(ethylamino)ethyl)-4-methylthiazol-2-amine (Compound A-2)

[0034] At room temperature, ansaramine I-5 (157 mg, 1.0 mmol), sodium carbonate (212 mg, 2.0 mmol), and bromoethane (108 mg, 1.0 mmol) were dissolved in 5 mL of DMF, and the solution was heated to 55°C. o The reaction was carried out at C for 3 h. A suitable amount of water was added, and the mixture was extracted three times with dichloromethane. The combined organic layers were washed with saturated brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was subjected to column chromatography to give 10⁹ mg of orange solid A-2, with a yield of 59%. 1 H NMR (500 MHz, DMSO- d 6 ) δ 6.73 (s, 2H), 2.99-2.89 (m,4H), 2.88-2.79 (m, 2H), 2.01 (s, 3H), 1.17 (t, J= 7.5 Hz, 3H); ESI-MS: m / z =186.1 [M+H] + .

[0035] Example 3: Preparation of 5-(2-(dimethylamino)ethyl)-4-methylthiazol-2-amine (Compound A-3)

[0036] At room temperature, dissolve ansaramine I-5 (157 mg, 1.0 mmol), sodium bicarbonate (168 mg, 2.0 mmol), and methyl iodide (142 mg, 2.0 mmol) in 5 mL of DMF, and heat to 60°C. o The reaction was carried out at C for 3 h. A suitable amount of water was added, and the mixture was extracted three times with dichloromethane. The combined organic layers were washed with saturated brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and the residue was subjected to column chromatography to give 115 mg of a pale yellow solid A-3, with a yield of 62%. 1 H NMR (500 MHz, DMSO- d 6 ) δ 6.58 (s, 2H), 2.72 (t, J =7.5 Hz, 2H), 2.56 (s, 2H), 2.41-2.28 (m, 6H), 1.99 (s, 3H); ESI-MS: m / z =186.1 [M+H] + .

[0037] Example 4: Preparation of 5-(2-(diethylamino)ethyl)-4-methylthiazol-2-amine (Compound A-4)

[0038] At room temperature, ansaramine I-5 (157 mg, 1.0 mmol), cesium carbonate (652 mg, 2.0 mmol), and bromoethane (216 mg, 2.0 mmol) were dissolved in 5 mL of DMF, and the solution was heated to 50°C. o React at C for 3 h. Add an appropriate amount of water, extract three times with dichloromethane, combine the organic layers, wash with saturated brine, dry with anhydrous Na2SO4, concentrate under reduced pressure, and the residue is subjected to column chromatography to give a pale yellow solid, yield 61%; 1 H NMR (500 MHz, DMSO- d 6 ) δ 5.72 (s, 2H), 2.96-2.92 (m, 2H), 2.86-2.82 (m, 2H), 2.59 (q, J= 7.0 Hz, 4H), 2.35 (s, 2H), 1.02 (t, J = 7.0Hz, 6H); ESI-MS: m / z = 214.1 [M+H] + .

[0039] Example 5: Preparation of 4-methyl-5-(2-(propylamino)ethyl)thiazole-2-amine (Compound A-5)

[0040] Following the synthesis of compound A-1, iodomethane was replaced with iodopropane to give a yellow solid in 62% yield. 1 H NMR (500 MHz, DMSO-) d 6 ) δ 6.64 (s, 2H), 2.84-2.68 (m, 6H), 2.00 (s, 3H), 1.51 (p, J = 7.5 Hz, 2H), 0.89 (t, J = 7.5 Hz, 3H); ESI-MS: m / z = 200.1 [M+H] + .

[0041] Example 6: Preparation of 5-(2-(dipropylamino)ethyl)-4-methylthiazol-2-amine (Compound A-6)

[0042] Following the synthesis of compound A-3, iodomethane was replaced with iodopropane to give a pale yellow solid in 66% yield; 1 HNMR (500 MHz, DMSO- d 6 ) δ 6.59 (s, 2H), 2.77-2.57 (m, 8H), 1.99 (s, 3H), 1.53-1.43 (m, 4H), 0.87 (t, J = 7.5 Hz, 6H); ESI-MS: m / z = 242.2 [M+H] + .

[0043] Example 7: Preparation of 4-methyl-5-(2-(pyrrolidone-1-yl)ethyl)thiazole-2-amine (Compound A-7)

[0044] At room temperature, dissolve ansaramine I-5 (157 mg, 1.0 mmol), potassium carbonate (276 mg, 2.0 mmol), and 1,4-dichlorobutane (127 mg, 1.0 mmol) in 5 mL of DMF, and heat to 65°C. o The reaction was carried out at C for 3 h. A suitable amount of water was added, and the mixture was extracted three times with dichloromethane. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography to give 156 mg of a pale yellow solid A-7, with a yield of 74%. 1 H NMR (500 MHz, DMSO- d 6 )δ 6.51 (s, 2H), 2.64 (t, J = 7.5 Hz, 2H), 2.50-2.40 (m, 6H), 1.97 (s, 3H), 1.70-1.65 (m, 4H); ESI-MS: m / z = 212.1 [M+H] + .

[0045] Example 8: Preparation of 4-(2-(benzylamino)ethyl)-4-methylthiazol-2-amine (Compound A-8)

[0046] At room temperature, ansaramine I-5 (157 mg, 1.0 mmol), cesium carbonate (652 mg, 2.0 mmol), and benzyl bromide (171 mg, 1.0 mmol) were dissolved in 5 mL of DMF, and the solution was heated to 45°C. o The reaction proceeded at C for 3 h. A suitable amount of water was added, and the mixture was extracted three times with dichloromethane. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was then subjected to column chromatography to give 208 mg of a white solid A-8, with a yield of 84%. 1 H NMR (500 MHz, DMSO- d 6 )δ 7.38 (dd, J = 12.0, 6.0 Hz,4H), 7.34-7.31 (m, 1H), 6.61 (s, 2H), 3.92 (s, 2H), 2.76 (s, 4H), 1.99 (s,3H); ESI-MS: m / z = 248.1 [M+H] + .

[0047] Example 9: Preparation of 5-(2-(ethyl(methyl)amino)ethyl)-4-methylthiazol-2-amine (Compound A-9)

[0048] At room temperature, compound A-2 (185 mg, 1.0 mmol), potassium carbonate (276 mg, 2.0 mmol), and iodomethane (142 mg, 1.0 mmol) were dissolved in 5 mL of DMF, and the solution was heated to 45°C. o The reaction proceeded at C for 2 hours. A suitable amount of water was added, and the mixture was extracted three times with dichloromethane. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was then subjected to column chromatography to give 78 mg of a pale yellow solid A-9, with a yield of 39%. 1 H NMR (500 MHz, DMSO- d 6 )δ 6.59 (s, 2H), 2.70-2.60 (m,6H), 2.35 (s, 3H), 1.99 (s, 3H), 1.05 (t, J = 7.0 Hz, 3H); ESI-MS: m / z = 200.1[M+H] + .

[0049] Example 10: Preparation of 5-(2-(isopropylamino)ethyl)-4-methylthiazol-2-amine (Compound A-10)

[0050] At room temperature, acetone (58 mg, 1.0 mmol) and acetic acid (0.1 mL) were added to a methanol (5 mL) solution of ansaramine I-5 (157 mg, 1.0 mmol), and the mixture was heated to 50°C. o After reacting at C for 0.5 h, sodium cyanoborohydride (75 mg, 1.2 mmol) was added to the system, and the reaction was continued for another 2 h. The solvent was removed under reduced pressure, an appropriate amount of water was added, and the mixture was extracted twice with dichloromethane. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography to give a white solid A-10 of 114 mg, with a yield of 57%. 1 H NMR (500 MHz, DMSO- d 6 ) δ 6.53 (s, 2H), 2.76-2.72 (m, 1H), 2.61 (s, 4H), 1.98 (s, 3H), 0.97 (d, J = 6.0 Hz, 6H); ESI-MS: m / z = 200.1 [M+H] + .

[0051] Example 11: Preparation of 5-(2-(isopropyl(methyl)amino)ethyl)-4-methylthiazol-2-amine (Compound A-11)

[0052] At room temperature, compound A-10 (200 mg, 1.0 mmol), sodium carbonate (212 mg, 2.0 mmol), and methyl iodide (142 mg, 1.0 mmol) were dissolved in 5 mL of DMF, and the solution was heated to 40 °C. o React at C for 2 h. Add appropriate amounts of water and dichloromethane twice, combine the organic layers, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and the residue is subjected to column chromatography to give 87 mg of pale orange solid A-11, yield 41%. 1 H NMR (500 MHz, DMSO- d 6 )δ 6.50 (s, 2H), 2.91-2.81 (m, 1H), 2.62 (t, J = 7.5 Hz, 2H), 2.48 (d, J = 7.5 Hz, 2H), 2.19 (s, 3H), 1.98 (s,3H), 0.96 (d, J = 6.5 Hz, 6H); ESI-MS: m / z = 214.1 [M+H] + .

[0053] Example 12: Preparation of 5-(2-(ethyl(isopropyl)amino)ethyl)-4-methylthiazol-2-amine (Compound A-12)

[0054] Following the synthesis of compound A-11, replacing iodomethane with bromoethane yielded a pale yellow solid in 45% yield. 1 HNMR (500 MHz, DMSO- d 6 ) δ 6.50 (s, 2H), 2.59 (t, J = 7.0 Hz, 2H), 2.37 (t, J =7.0 Hz, 2H), 2.15 (s, 3H), 2.05 (d, J = 7.5 Hz, 2H), 1.97 (s, 3H), 1.70-1.68(m, 1H), 0.84 (d, J= 6.5 Hz, 6H); ESI-MS: m / z = 228.2 [M+H] + .

[0055] Example 13: Preparation of 5-(2-(isobutylamino)ethyl)-4-methylthiazol-2-amine (Compound A-13)

[0056] At room temperature, isobutyraldehyde (72 mg, 1.0 mmol) and acetic acid (0.1 mL) were added to a methanol (5 mL) solution of ansaramine I-5 (157 mg, 1.0 mmol), and the mixture was heated to 45°C. o After reacting at C for 0.5 h, sodium triacetoxyborohydride (254 mg, 1.2 mmol) was added to the system, and the reaction was continued for another 2 h. The solvent was removed under reduced pressure, an appropriate amount of water was added, and the mixture was extracted twice with dichloromethane. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography to give 175 mg of white solid A-13, with a yield of 82%. 1 H NMR (500 MHz, DMSO- d 6 )δ 6.61 (s, 2H), 2.75 (s, 4H), 2.53 (s, 2H), 2.00 (s, 3H), 1.80-1.78 (m, 1H), 0.90 (d, J = 7.0 Hz, 6H); ESI-MS: m / z = 214.1 [M+H] + .

[0057] Example 14: Preparation of 4-methyl-5-(3-(methylamino)propyl)thiazole-2-amine (Compound A-14)

[0058] Step 1: Synthesis of 2-(5-oxooxy)isoindoline-1,3-dione (intermediate I-8) 6-Chloro-2-hexanone I-7 (13.5 g, 100 mmol), phthalimide (14.7 g, 100 mmol), potassium iodide (1.7 g, 33 mmol), and potassium carbonate (20.7 g, 150 mmol) were dissolved in 110 mL of acetonitrile. oThe reaction was stirred at C for 5 h under nitrogen protection. The solvent was removed under reduced pressure, and an appropriate amount of water was added. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Recrystallization from methanol yielded 22.1 g of a yellow solid I-8, with a yield of 90%. 1 H NMR (500 MHz, Chloroform- d ) δ 7.85 (dd, J = 5.5, 3.0 Hz, 2H), 7.73 (dd, J = 5.5, 3.0 Hz, 2H), 3.71 (t, J = 7.0 Hz, 2H), 2.51 (t, J = 7.0 Hz, 2H), 2.15(s, 3H), 1.77-1.57 (m, 4H); ESI-MS: m / z = 246.1 [M+H] + .

[0059] Step 2: Synthesis of 2-(4-bromo-5-oxooxy)isoindoline-1,3-dione (intermediate I-9) Under N2 protection, liquid bromine (16.0 g, 100 mmol) was slowly added dropwise to a CCl4 (120 mL) solution of intermediate I-8 (24.5 g, 100 mmol), and the reaction was carried out at room temperature for 3 h. Saturated sodium bicarbonate was added, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Recrystallization from ethanol gave solid I-9 25.8 g, yield 80%, ESI-MS: m / z = 324.0 [M+H] + .

[0060] Step 3: Synthesis of 2-(3-(2-amino-4-methylthiazolyl-5-yl)propyl)isoindoline-1,3-dione (intermediate I-10) Intermediate I-9 (16.2 g, 50 mmol), thiourea (3.8 g, 53 mmol), and N,N-diisopropylethylamine (12.9 g, 100 mmol) were dissolved in 110 mL of dioxane and heated to 75°C. o The reaction was carried out at C for 5 h. The reaction system was cooled, filtered, and the solvent was removed from the filtrate under reduced pressure. An appropriate amount of water was added, and the mixture was extracted three times with dichloromethane. The organic layer was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized to give 22.6 g of yellow solid I-10, with a yield of 75%. 1 H NMR (500 MHz, DMSO- d 6)δ 7.82 (dd, J = 5.0, 3.0 Hz, 2H), 7.74 (dd, J = 5.0, 3.0 Hz, 2H), 5.71 (s,2H), 3.86 (t, J = 5.5 Hz, 2H), 2.76-2.57 (m, 2H), 2.17 (tt, J = 8.0, 5.5 Hz,2H); ESI-MS: m / z =302.1 [M+H] + .

[0061] Step 4: Synthesis of 5-(3-aminopropyl)-4-methylthiazol-2-amine (Intermediate I-11) At room temperature, 80% hydrazine hydrate (6.3 g, 100 mmol) was added dropwise to a methanol (120 mL) solution of intermediate I-10 (15.1 g, 50 mmol), and then the temperature was raised to 70°C. o The reaction was carried out at C for 5 h, cooled, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography to give 12.1 g of orange solid I-11, with a yield of 71%. 1 H NMR (500 MHz, DMSO- d 6 ) δ 6.51 (s, 2H), 2.81 (tt, J = 6.5, 4.5 Hz, 2H), 2.72-2.55 (m, 2H), 2.35 (s, 2H), 1.96 (s,3H); ESI-MS: m / z = 172.1 [M+H] + .

[0062] Step 5: Preparation of 4-methyl-5-(3-(methylamino)propyl)thiazole-2-amine (Compound A-14) At room temperature, intermediate I-11 (171 mg, 1.0 mmol), potassium carbonate (276 mg, 2.0 mmol), and methyl iodide (142 mg, 1.0 mmol) were dissolved in 5 mL of DMF, and the solution was heated to 70°C. o The reaction was carried out at C for 3 h. A suitable amount of water was added, and the mixture was extracted three times with dichloromethane. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography to give 89 mg of a pale orange solid A-14, with a yield of 48%. 1 H NMR (500 MHz, DMSO- d 6)δ 6.58 (s, 2H), 2.79 (qd, J =4.9, 4.2 Hz, 1H), 2.72 (q, J = 4.7 Hz, 2H), 2.65 (t, J = 7.5 Hz, 2H), 2.46(d, J = 4.9 Hz, 3H), 2.34(s, 3H), 1.92 (tt, J = 7.5, 4.9 Hz, 2H); ESI-MS: m / z= 186.1 [M+H] + .

[0063] Example 15: Preparation of 5-3-(dimethylamino)propyl)-4-methylthiazol-2-amine (Compound A-15)

[0064] At room temperature, intermediate I-11 (171 mg, 1.0 mmol), potassium carbonate (276 mg, 2.0 mmol), and methyl iodide (142 mg, 2.0 mmol) were dissolved in 5 mL of DMF, and the solution was heated to 65°C. o The reaction was carried out at C for 3 h. A suitable amount of water was added, and the mixture was extracted three times with dichloromethane. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography to give a pale yellow solid, with a yield of 56%. 1 H NMR (500 MHz, DMSO- d 6 )δ 6.62 (s, 2H), 2.65 (t, J = 7.5 Hz, 2H), 2.54 (d, J = 7.5 Hz, 2H), 2.45 (s, 6H), 1.97 (s, 3H), 1.70 (p, J = 7.5Hz, 2H); ESI-MS: m / z = 200.1 [M+H] + .

[0065] Example 16: Preparation of 5-(3-(ethyl(methyl)amino)propyl)-4-methylthiazol-2-amine (Compound A-16)

[0066] At room temperature, compound A-14 (185 mg, 1.0 mmol), potassium carbonate (276 mg, 2.0 mmol), and bromoethane (109 mg, 1.0 mmol) were dissolved in 5 mL of DMF, and the solution was heated to 45°C. o The reaction proceeded at C for 2 hours. A suitable amount of water was added, and the mixture was extracted three times with dichloromethane. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was then subjected to column chromatography to give 77 mg of a pale yellow solid, A-16, with a yield of 36%. 1 H NMR (500 MHz, DMSO- d 6 ) δ 6.58 (s, 2H), 2.72-2.51 (m,6H), 2.33 (s, 3H), 1.97 (s, 3H), 1.66 (m, 2H), 1.05 (t, J = 7.0 Hz, 3H); ESI-MS: m / z = 214.1 [M+H] + .

[0067] Example 17: Preparation of 4-methyl-5-(2-(cyclobutan-1-yl)ethyl)thiazol-2-amine (Compound A-17)

[0068] Step 1: Synthesis of 5-(2-chloroethyl)-4-methylthiazol-2-amine (Intermediate I-13) Liquid bromine (1.6 g, 10 mmol) was slowly added dropwise to a carbon tetrachloride (30 mL) solution of compound I-1 (1.2 g, 10 mmol), and the reaction was carried out at room temperature for 3 h. The solvent was removed under reduced pressure, and the residue was extracted three times with saturated sodium bicarbonate and ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Recrystallization from methanol yielded 1.1 g of solid I-12. Intermediate I-12 (1.1 g, 5.6 mmol), thiourea (450 mg, 5.9 mmol), and triethylamine (1.1 g, 11.2 mmol) were dissolved in dioxane (30 mL), and the solution was heated to 80°C. o The reaction was carried out at C for 5 h. The reaction system was cooled, filtered, and the solvent was removed from the filtrate under reduced pressure. An appropriate amount of water was added, and the mixture was extracted three times with dichloromethane. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized to give 1.08 g of yellow solid I-13. The two-step yield was 38%. 1 H NMR (500 MHz, DMSO- d 6 ) δ6.72 (s, 2H), 3.67 (t,J = 7.0 Hz, 2H), 2.95 (t, J = 7.0 Hz, 2H), 2.00 (s,3H); ESI-MS: m / z = 177.0 [M+H] + .

[0069] Step 2: Preparation of 4-methyl-5-(2-(cyclobutan-1-yl)ethyl)thiazol-2-amine (Compound A-17) At room temperature, intermediate I-13 (500 mg, 2.84 mmol), potassium carbonate (785 mg, 5.68 mmol), and aziridine hydrochloride (266 mg, 2.84 mmol) were dissolved in acetonitrile (20 mL), and the mixture was heated to 60°C under N2 protection. o The reaction was carried out at C for 6 h. The mixture was filtered, and the solvent was removed from the filtrate under reduced pressure. The residue was subjected to column chromatography to give 106 mg of a pale yellow solid A-17, with a yield of 19%. 1 H NMR (500 MHz, DMSO-) d 6 ) δ 6.54 (s, 2H), 3.25 (t, J = 7.2 Hz, 4H), 2.48-2.44 (m,2H), 2.04-1.98 (m, 2H), 1.96 (s, 3H), 1.47-1.40 (m, 2H); ESI-MS: m / z = 198.1[M+H] + .

[0070] Example 18: Preparation of 4-methyl-5-(3-(cyclobutan-1-yl)propyl)thiazol-2-amine (Compound A-18)

[0071] Step 1: Synthesis of 5-(3-chloropropyl)-4-methylthiazol-2-amine (Intermediate I-15) Following the synthesis of intermediate I-13, I-1 was replaced with I-7 to obtain intermediate I-14, which in turn yielded a yellow solid I-15, with a two-step yield of 36%. 1 H NMR (500 MHz, DMSO- d 6 ) δ 6.68 (s, 2H), 3.62 (t, J =6.5 Hz, 2H), 2.64 (t, J= 7.0 Hz, 2H), 1.99 (s, 3H), 1.83–1.91 (m, 2H); ESI-MS: m / z = 191.0 [M+H] + .

[0072] Step 2: Preparation of 4-methyl-5-(3-(cyclobutan-1-yl)propyl)thiazol-2-amine (Compound A-18) Following the synthesis of compound A-17, intermediate I-13 was replaced with I-15, yielding 234 mg of a pale yellow solid, with a yield of 39%. 1 H NMR (500 MHz, DMSO- d 6 ) δ 6.57 (s, 2H), 3.37 (t, 4H), 2.61-2.45 (m, 4H), 2.11 -2.01 (m, 2H), 1.96 (s, 3H), 1.51-1.42 (m, 2H); ESI-MS: m / z = 212.1 [M+H] + .

[0073] Example 19: Histamine H2 receptor agonist activity of aminothiazole compounds Detection Principles: cAMP Assay: Aminothiazole compounds activate adenylate cyclase through H2 receptor-mediated Gs protein signaling, increasing intracellular cAMP levels. The cAMP assay uses a fluorescence reporter system to monitor cAMP levels in real time, thus reflecting the agonistic activity of the compound on the H2 receptor-Gs pathway. BRET Assay: After aminothiazole compounds bind to the H2 receptor, β-arrestin (βarr) is recruited to the receptor. The BRET assay uses bioluminescent resonance energy transfer (BRET) technology to detect the interaction between the H2 receptor and β-arrestin in real time, quantitatively reflecting the degree to which the H2 receptor recruits βarr.

[0074] Detection methods: cAMP assay: HEK293T cells were transfected with H2 receptor and cAMP biosensor plasmid. After 24 h, the cells were seeded into 96-well plates. Overnight, the cells were starved with PBS buffer, incubated with equilibration buffer containing fluorescent substrate, and then serially diluted agonists were added. Fluorescence values ​​were detected using a microplate reader. Data were processed to obtain a curve showing the change in fluorescence value with agonist concentration to reflect the G protein pathway agonist activity of aminothiazole compounds. BRET assay: HEK293T cells were transfected with H2 receptor fused with the RLUC8 tag at the C-terminus and β-arrestin1 plasmid fused with the Venus tag at the N-terminus. After 24 h, the cells were seeded into 96-well plates. Overnight, the cells were starved with D-HANKS buffer, incubated with equilibration buffer containing fluorescent substrate, and then serially diluted agonists were added. Fluorescence values ​​in the 460-480 nm and 515-535 nm channels were detected using a microplate reader. The data were processed to obtain a curve showing the ratio of dual fluorescence values ​​as a function of agonist concentration, which reflects the βarr pathway agonist activity of aminothiazole compounds.

[0075] Detection results: As shown in Table 2, most compounds exhibited strong H2 receptor agonist activity, and the activity of several compounds was equivalent to or better than that of ansaramine; some compounds showed G protein bias.

[0076] Table 2. Histamine H2 receptor agonistic activity of representative compounds

[0077] "++++" represents >8; "+++" represents 6-8; "++" represents 5-6; "+" represents <5; Example 20: In vivo pharmacokinetic study of the preferred active compound Administration method study: Methods: SD rats were used as experimental animals. They were fasted for 12 hours but allowed free access to water before the experiment. The compound was dissolved in a suitable solvent or suspended in 0.5% sodium carboxymethyl cellulose (CMCNa) solution (10 mg / mL), and administered intravenously at 1.0 mg / kg and orally at 5.0 mg / kg, respectively. Blood samples of 400 μL were collected at 10 min, 20 min, 30 min, 1 h, 2 h, 4 h, 8 h, and 24 h after administration. The blood samples were centrifuged at 6000 rpm for 10 min, and 100 μL of the supernatant was collected. 400 μL of the internal standard compound solution was added, and the mixture was centrifuged at 13000 rpm for 10 min. 200 μL of the supernatant was collected, and the plasma compound concentration was analyzed using LC-MS / MS. Pharmacokinetic parameters after administration were calculated using WinNonLin 7.0 pharmacokinetic software. The drug-time curves were obtained by Graphpad Prism software. Bioavailability was calculated using the formula: Bioavailability F% = (AUCp.o. × Di.v.) / (AUCi.v. × Dp.o.) × 100%.

[0078] Research results: The results are as follows Figure 1 As shown in Table 3, compound A-3 is metabolized rapidly after intravenous administration, while oral administration via gavage is more effective and results in higher drug exposure, with an AUC of 1747.08 h*ng / mL. max The concentration reached 373.32 ng / mL, with rapid absorption. (T) max =1h, relatively long half-life, T 1 / 2 The time is 6.22 hours, and the oral bioavailability is approximately 100%.

[0079] Table 3 Pharmacokinetic parameters of compound A-3

[0080] The results are as follows Figure 2 As shown in Table 4, compound A-15 is metabolized rapidly after intravenous administration, while oral administration via gavage is more effective and results in higher drug exposure, with an AUC of 1012.99 h*ng / mL. max The concentration reached 409.89 ng / mL, with rapid absorption. (T) max =0.67h, the half-life is relatively short, T 1 / 2 The time to absorption is 1.92 hours, and the oral bioavailability is approximately 50%.

[0081] Table 4 Pharmacokinetic parameters of compound A-15

[0082] The results are as follows Figure 3As shown in Table 5, compound A-17 is metabolized rapidly after intravenous administration, while oral administration via gavage is more effective and results in higher drug exposure, with an AUC of 3615.52 h*ng / mL. max Reaching 1412.97 ng / mL, it is absorbed relatively quickly, T max =0.5h, relatively long half-life, T 1 / 2 The time is 5.45 hours, and the oral bioavailability is approximately 75%.

[0083] Table 5 Pharmacokinetic parameters of compound A-17

[0084] The results are as follows Figure 4 As shown in Table 6, compound A-18 is metabolized slowly when administered intravenously, and has moderate efficacy and drug exposure when administered orally via gavage, with an AUC of 666.10 h*ng / mL. max The concentration reached 152.21 ng / mL, with rapid absorption. (T) max =1.17h, relatively long half-life, T 1 / 2 It takes approximately 10.00 hours, and the oral bioavailability is approximately 25%.

[0085] Table 6 Pharmacokinetic parameters of compound A-18

[0086] 2) Evaluation of blood-brain barrier permeability: Evaluation Methods: SD rats were used as experimental animals. They were fasted for 12 hours prior to the experiment, but allowed free access to water. The SD rats were weighed and divided into one control group and three to four experimental groups (n=3 per group) according to the drug administration time points. Each experimental group received the candidate compound via gavage at 30 mg / kg or 20 mg / kg. The control group received physiological saline instead. At the designated time points (0.5, 1, 2, and 4 hours after drug administration), the animals were anesthetized with 10% chloral hydrate. 0.5 mL of blood was collected from the orbital cavity and added to an EP tube containing disodium EDTA (an anticoagulant). The tube was shaken and centrifuged at 6,000 rpm for 10 min to separate the plasma. After perfusion with physiological saline, brain tissue was dissected, labeled, and stored at -20°C. oCryopreservation for later testing. For plasma, 300 μL of ice-cold methanol containing 200 ng / ml internal standard was added to every 100 μL of plasma. The mixture was vortexed for 1 min, centrifuged at 14,500 rpm for 10 min, and repeated twice. The supernatant was then directly injected into the sample. For brain tissue, the tissue was weighed, minced, and homogenized with 3 times its weight of physiological saline. The process was performed on ice. 300 μL of methanol containing 200 ng / ml internal standard was added to every 100 ml of homogenate. The mixture was vortexed for 1 min, centrifuged at 14,500 rpm for 10 min, and repeated twice. The supernatant was then directly injected into the sample. The concentrations of the test substance in plasma and brain tissue were determined by LC / MS. Pharmacokinetic parameters after administration were calculated using a non-compartmental model in DAS 2.0 software. The pharmacokinetic curves were obtained using Graphpad Prism 9 software.

[0087] Evaluation results: Due to the strong basicity (pKa = 12.24) and low lipid solubility (clogP = 0.53) of the histamine H2 receptor agonist ansaramine, it was not detected in the brains of SD rats after gavage administration, indicating that ansaramine cannot cross the blood-brain barrier via gavage. However, compounds A-3, A15, A17, and A18, after structural optimization, showed significantly improved lipid solubility and excellent blood-brain barrier permeability.

[0088] like Figure 1 As shown in Table 7 (C and D), within 0.5–4 hours, the A-3 content in the rat brain gradually increased with the passage of time after drug administration, while the drug content in the plasma gradually decreased.

[0089] The brain-blood ratios at 0.5 hours, 1 hour, 2 hours, and 4 hours were 2.2, 3.8, 7.6, and 17.7, respectively, demonstrating excellent blood-brain barrier permeability.

[0090] Table 7. Brain and blood concentrations and brain-blood ratio of compound A-3

[0091] like Figure 2 As shown in Table 8 (C and D), within 1-4 hours, the A-15 content in the rat brain gradually increased with the passage of time after drug administration, while the drug content in the plasma gradually decreased.

[0092] The brain-blood ratios at 1 hour, 2 hours, and 4 hours were 0.8, 1.1, and 3.3, respectively, demonstrating excellent blood-brain barrier permeability.

[0093] Table 8. Brain and blood concentrations and brain-blood ratio of compound A-15

[0094] like Figure 3 As shown in Table 9 (C and D), within 1-4 hours, the A-17 content in the rat brain generally showed a gradually increasing trend with the passage of time after drug administration, while the drug content in the plasma showed a gradually decreasing trend.

[0095] The brain-blood ratios at 1 hour, 2 hours, and 4 hours were 0.9, 3.2, and 4.3, respectively, demonstrating excellent blood-brain barrier permeability.

[0096] Table 9. Brain and blood concentrations and brain-blood ratio of compound A-17

[0097] like Figure 4 As shown in Table 10 (C and D), within 1-4 hours, the A-18 content in the rat brain remained relatively stable as the administration time progressed, while the drug content in the plasma showed a gradual decreasing trend.

[0098] The blood-brain ratios at 1 hour, 2 hours, and 4 hours were 0.2, 0.4, and 0.3, respectively. Although the blood-brain ratios were low, they still showed a certain degree of blood-brain barrier permeability.

[0099] Table 10. Brain and blood concentrations and brain-blood ratio of compound A-18

[0100] In addition, the blood-brain ratio of several representative aminothiazole compounds was tested at administration times of 0.5 h and 2 h. The results are shown in Table 11. The aminothiazole compounds A-1, A-2, A-7, A-9, and A-14, after structural optimization, showed improved lipid solubility and were able to cross the blood-brain barrier, exhibiting good blood-brain ratios at 0.5 h and 2 h.

[0101] Table 11. Cerebral-blood ratio of some representative aminothiazole compounds

[0102] Therefore, the compounds described in this invention, while maintaining histamine H2 receptor agonist activity, also have excellent blood-brain barrier permeability, and can be used as histamine H2 receptor agonists in the treatment of neuropsychiatric diseases related to histamine H2 receptors, including but not limited to the treatment of schizophrenia, mania, attention deficit hyperactivity disorder, bulimia nervosa or bulimia nervosa, autism, Parkinson's disease, ischemic brain injury and other diseases.

[0103] Example 21: Pharmacodynamic evaluation of preferred active compounds 1) Pharmacodynamic evaluation of schizophrenia Evaluation method: A chronic MK-801 (0.2 mg / kg / d, 7 days)-induced schizophrenia drug research model was used, and two different doses of compound A-3 were administered by gavage, followed by evaluation of schizophrenia-related behaviors.

[0104] Evaluation results: MK-801 can induce schizophrenia-related behaviors in mice, such as increased activity in the open field test, decreased social novelty preference in the three-box test, and weakened nesting ability in the nesting test. Figure 5 AD). Compared with the MK-801 model group, the A-3 treatment group showed a significant decrease in motor activity. Figure 5 A, B), increased preference for unfamiliar mice ( Figure 5 C), Improved nest-building ability ( Figure 5 D). The above results indicate that administration of A-3 can improve behaviors associated with positive and negative symptoms of schizophrenia, such as MK-801-induced hypermotility and social avoidance, suggesting that A-3 may be a potential drug for the treatment of schizophrenia.

[0105] 2) Pharmacodynamic evaluation of mania Evaluation methods: Amphetamine (Amph) and sleep deprivation are animal models for inducing manic-like behavior in mice. Mice were administered different doses of compound A-3 via gavage after intraperitoneal injection of Amph (3.5 mg / kg) or 24-hour sleep deprivation, and behavioral changes in the open field were evaluated.

[0106] Evaluation results: Intraperitoneal injection of Amph induced hyperactivity in mice, manifested as a significant increase in movement distance and duration. This phenotype could be reversed by the classic antimanic drug Li2CO3 (200 mg / kg, ig). Figure 6 A, B). Compound A-3 significantly reduced hyperactivity in mice at doses of 0.1 mg / kg and above, exhibiting a dose-dependent improvement in the range of 0.1–0.3 mg / kg. Figure 6 A, B). Sleep deprivation induced increased activity in mice during the open field test, and this phenotype could be reversed by the classic antimanic drug Li2CO3 (A, B). Figure 6 C, D). Compound A-3 at doses of 0.1 mg / kg and above can significantly reduce total distance and speed of movement (C, D). Figure 6 C, D).

[0107] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. An aminothiazole compound and its pharmaceutically acceptable salt, said compound having the following general formula (I): In the formula: n = 1 or 2; NR1R2 is an open-chain amine or a 3-8 member cyclic amine; When NR1R2 is an open-chain amine, R1 is selected from hydrogen, C 1-5 Alkyl group; R2 is selected from C 1-5 Alkyl, benzyl.

2. The aminothiazole compound according to claim 1, characterized in that, when NR1R2is a cyclic amine, R1is selected from the group consisting of H, Me, Et, n -Pr, i -Pr, i -Bu; R2is selected from Me, Et, n -Pr, i -Pr, i -Bu, ; when NR1R2is a 3-8 membered cyclic amine, is selected from , .

3. The aminothiazole compound according to claim 1, wherein Its structural formula is selected from: 。 4. A pharmaceutically acceptable salt, characterized in that, The organic acid salt or inorganic acid salt of the compound according to any one of claims 1-3; the organic acid salt includes, but is not limited to, maleate, citrate, succinate, tartrate, oxalate, p-toluenesulfonate, malate, fumarate, methanesulfonate, and acetate; the inorganic acid salt includes, but is not limited to, sulfate, hydrochloride, hydrobromide, and phosphate.

5. Use of an aminothiazole compound according to any one of claims 1 to 3 or a salt according to claim 4, characterized in that, Application in the preparation of brain-penetrating histamine H2 receptor agonists.

6. The use according to claim 5, wherein the compound is ###0002### The use of the aforementioned aminothiazole compounds, or pharmaceutically acceptable salts thereof, as brain-penetrating histamine H2 receptor agonists in the preparation of medicaments for the treatment of brain diseases such as schizophrenia, mania, attention deficit hyperactivity disorder, bulimia nervosa, autism, Parkinson's disease, and ischemic brain injury.

7. A pharmaceutical composition, characterized by, It contains a therapeutically effective amount of one or more aminothiazole compounds as described in any one of claims 1-3 or a pharmaceutically acceptable salt thereof, or further includes pharmaceutically acceptable excipients, diluents, carriers or excipients.

8. The pharmaceutical composition of claim 7, wherein: The pharmaceutical composition is formulated in the form of capsules, powders, tablets, granules, pills, injections, syrups, oral liquids, inhalers, ointments, suppositories, or patches.

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