Aminothiazole compound and application thereof as brain-permeable histamine H2 receptor agonist

Abstract

The invention discloses an aminothiazole compound and application thereof as a brain-permeable histamine H2 receptor stimulant, and belongs to the field of medicines. The structural general formula of the aminothiazole compound provided by the invention is as shown in formula (I), and the aminothiazole compound comprises pharmaceutically acceptable salts. The aminothiazole compound disclosed by the invention has histamine H2 receptor agonistic activity and excellent blood-brain barrier permeability. Therefore, the compound can be applied to preparation of drugs for treating diseases such as schizophrenia, mania, attention deficit hyperactivity disorder, autism or greedy neurosis, autism, Parkinson's disease, ischemic brain injury and the like. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medicine, and particularly to aminothiazole compounds or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing such compounds, and their use as brain-penetrant histamine H2 receptor agonists. Background Art

[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. There are mainly three types of histamine receptors in the central nervous system, all of which are G protein-coupled receptors. Among them, H1 and H2 receptors are distributed on the postsynaptic membrane, while the H3 receptor is mainly present in the presynaptic part, negatively regulating the synthesis and release of histamine. At present, most of the known functions of the histaminergic system are mediated by the H1 receptor. Similar to the H1 receptor, the H2 receptor is also widely distributed in the brain, but the function of the H2 receptor has been less reported. In recent years, the role of the H2 receptor in neuropsychiatric diseases has attracted more attention. Studies have found that the deletion of the H2 receptor may play a key role in the occurrence of brain diseases such as schizophrenia, mania, attention deficit hyperactivity disorder, Parkinson's disease, and ischemic brain injury. The H2 receptor may become a drug target for these neuropsychiatric diseases.

[0003] For example, schizophrenia is a severe mental illness that affects about 1% of the global population, bringing a heavy burden to society and the economy. The traditional view is that abnormal glutamate synaptic transmission related to the insufficient function of N-methyl-D-aspartic acid receptor (NMDAR) will cause positive symptoms (such as hallucinations, delusions, etc.), negative symptoms (such as emotional deficit, aphasia, etc.) and cognitive dysfunction in schizophrenia. However, the development of glutamate-based antipsychotic drugs faces many challenges. Further exploring the glutamate-related neural mechanisms in schizophrenia and finding new drugs that regulate the function of glutamatergic neurons are of great significance for the treatment of schizophrenia. Studies have found that the deletion of the histamine H2 receptor in glutamatergic neurons in the medial prefrontal cortex will cause schizophrenia-like behaviors, and overexpression of the H2 receptor can improve schizophrenia-related behaviors in mice; local injection of histamine H2 receptor agonists betazole and amthamine into the brain 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. At the same time, 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] Currently, a number of H2 receptor agonists have been reported, which can be mainly divided into arylethylamines and arylpropylguanidines according to their structural types (the main compound structures are as follows). Among them, the arylethylamine derivative Betazole reported in the literature J.Am.Med.Assoc., 1961, 175(10), 908-909 is clinically used for gastric acid secretion function examination, but it is not highly selective for H1 receptors and cannot penetrate the blood-brain barrier.

[0005] Documents WO 91 / 10656 and Bioorg.Med.Chem.Lett., 1994, 4(16), 1913-1916 reported that amthamine and amselamine derived from the histamine H2 receptor partial agonist Dimaprit contain 2-amino-thiazole and 2-aminoselenazole mother nuclei, respectively, and have H2 receptor agonist activities of pD 2 =6.21, pD 2 =6.41, and showed good selectivity for H1 (>1000), but its pharmacokinetic results showed that ansamine and anselenamine could not penetrate the brain, and are currently only used as tool drugs in research.

[0006] The literature J.Med.Chem., 1992, 35, 3239-3246 reported that the arylpropylguanidine H2 receptor agonists Impromidine and Arpromidine have agonist activities of pD 2 =7.80, pD 2 =8.00. The literature ACS.Omega., 2018, 3, 2865-2882 reported that the further developed biarylpropylguanidine derivatives UR-AK 381 and SK&F 93082 had further improved H2 receptor agonist activity, with agonist activities of pEC 50 =8.11, pEC 50 =7.98, but the strong alkalinity and polarity of the guanidine group prevent the molecule from passing through the blood-brain barrier.

[0007]

[0008] Published partial H2 receptor agonists

[0009] The present invention uses the histamine H2 receptor agonist ansamine as a guide, optimizes the structure of the terminal amino group, and enhances its ability to penetrate the blood-brain barrier, effectively solving the shortcoming of existing H2 receptor agonists that they cannot penetrate the brain. It is expected to be used in the treatment of neuropsychiatric diseases such as schizophrenia, mania, binge eating disorder or bulimia nervosa, autism, Parkinson's disease, ischemic brain damage, etc. Summary of the invention

[0010] The object of the present invention is to provide a histamine H2 receptor agonist that can penetrate the blood-brain barrier and apply it to the treatment of neuropsychiatric diseases involving histamine H2 receptors.

[0011] To achieve the above object, the present invention adopts the following technical solutions:

[0012] The present invention provides an aminothiazole compound having a structure of general formula (I):

[0013]

[0014] n = 1 or 2; NR 1 R 2 is an open-chain amine or a 3- to 8-membered cyclic amine;

[0015] When NR 1 R 2 is an open-chain amine, R 1 is selected from hydrogen, C 1-5 alkyl; R 2 is selected from C 1-5 alkyl, benzyl.

[0016] More specifically, in the aminothiazole compound provided by the present invention, when NR 1 R 2 is an open-chain amine, R 1 is selected from H, Me, Et, n-Pr, i-Pr, i-Bu;

[0017] R 2 is selected from Me, Et, n-Pr, i-Pr, i-Bu,

[0018] When NR 1 R 2 is a 3- to 8-membered cyclic amine, it is selected from

[0019] Among them, the structural formulas of representative aminothiazole compounds are shown in Table 1 below:

[0020] Table 1 Structures of aminothiazole compounds

[0021]

[0022]

[0023] The present invention also provides pharmaceutically acceptable salts of the aminothiazole compounds.

[0024] The term "pharmaceutically acceptable salt" refers to salts prepared by conventional methods, including but not limited to organic acid salts and inorganic acid salts. The organic acid salts include but are not limited to maleate, citrate, succinate, tartrate, oxalate, p-toluenesulfonate, malate, fumarate, mesylate, acetate, etc.; the inorganic acid salts include but are not limited to sulfate, hydrochloride, hydrobromide, phosphate, etc.

[0025] The present invention also provides a pharmaceutical composition, comprising the aminothiazole compound or its pharmaceutically acceptable salt as described in any one of the above, or further comprising a pharmaceutically acceptable excipient, diluent, carrier or auxiliary.

[0026] Specifically, the present invention provides the application of the aminothiazole compound, or its pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of therapeutic drugs for treating neuropsychiatric diseases such as schizophrenia, mania, bulimia or nervosa, autism, Parkinson's disease, ischemic brain injury, etc. It should be noted that the pharmaceutical use of the compound is not limited to the preparation of drugs for the above diseases.

[0027] The therapeutic mechanism of the drug includes: the active ingredient aminothiazole compound reduces the hyperpolarization-activated cyclic adenosine monophosphate-gated (HCN) channel-mediated current Ih on glutamatergic neurons, improves the activity of glutamatergic neurons, and then plays the role of activating the histamine H2 receptor. In particular, it has excellent blood-brain barrier permeability and can be used as a brain-penetrating histamine H2 receptor agonist for the preparation of brain disease drugs.

[0028] The beneficial effects of the present invention:

[0029] The present invention provides a novel class of brain-penetrating histamine H2 receptor agonists of aminothiazole. This class of compounds and their derivatives have obvious agonist activity on the histamine H2 receptor, and show good biological activity in in vitro and in vivo biological evaluations. The H2 receptor agonist activity of multiple compounds is better than or equivalent to that of antazoline, and they show excellent blood-brain barrier permeability in pharmacokinetic experiments. Therefore, this class of compounds can be used as histamine H2 receptor agonists in the treatment of diseases related to the histamine H2 receptor, including but not limited to the application in the preparation of therapeutic drugs for neuropsychiatric diseases such as schizophrenia, mania, attention deficit hyperactivity disorder, bulimia or nervosa, autism, Parkinson's disease, ischemic brain injury, etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 It is the time-concentration curve of compound A-3 under intragastric administration and intravenous injection;

[0031] Figure 2 It is the blood and brain time-concentration curve of compound A-3;

[0032] Figure 3 Compound A-3 improves MK-801-induced schizophrenia-related behaviors in mice, including: (A) total distance traveled by mice in the open field within 2 hours; (B) distance traveled by mice in the open field every 5 minutes; (C) preference index of mice for S1 (familiar mouse) and S2 (strange mouse) in the social novelty test; (D) percentage of cotton weight not torn by mice in the nesting test. n = 8; *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001; ns, no significant difference.

[0033] Figure 4 Compound A-3 improves amphetamine-induced manic-related behaviors in mice, including: (A) total distance traveled within 1 hour after Amph administration; (B) total movement time within 1 hour after Amph administration; (C) total distance traveled within 1 hour after sleep deprivation; (D) total movement speed within 1 hour after sleep deprivation. n = 4 - 9; *P < 0.05, **P < 0.01, ***P < 0.001. Detailed implementation manners

[0034] The technical solutions of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. All other embodiments obtained by those of ordinary skill in the art without creative efforts based on the embodiments of the present invention belong to the scope of protection of the present invention.

[0035] Example 1: Preparation of 4-methyl-5-(2-(methylamino)ethyl)thiazol-2-amine (Compound A-1)

[0036]

[0037] Step 1: Synthesis of 2-(4-oxopentyl)-1H-isoindole-1,3(2H)-dione (Intermediate I-2)

[0038] Dissolve 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) in 160 mL of DMF, stir and react at 80 °C for 5 h under nitrogen protection. Remove the solvent under reduced pressure, extract with ethyl acetate, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. Recrystallize from methanol to obtain 35.3 g of pale yellow solid I-2, with a yield of 92%; 11H 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] + 。

[0039] Step 2: Synthesis of 2-(3-bromo-4-oxopentyl)-1H-isoindole-1,3(2H)-dione (Intermediate I-3)

[0040] N 2 Under N protection, bromine (16.0 g, 99 mmol) was slowly added dropwise to a solution of Intermediate I-2 (23.0 g, 99 mmol) in CCl 4 (115 mL) at room temperature for 3 h. The solvent was removed under reduced pressure, saturated sodium bicarbonate was added, and the mixture was extracted twice with ethyl acetate. The organic layer was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain a crude product, and recrystallized from ethanol to obtain 27.3 g of yellow solid I-3 with a yield of 88%; ESI-MS: m / z = 310.0 [M+H] + 。

[0041] Step 3: Synthesis of 2-(2-(2-amino-4-methylthiazol-5-yl)ethyl)isoindole-1,3(2H)-dione (Intermediate I-4)

[0042] 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 the mixture was heated to 80 °C and reacted for 5 h. The reaction system was cooled, filtered by suction, the solvent was removed under reduced pressure from the filtrate, 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 purified by column chromatography to obtain 10.4 g of yellow solid I-4 with a yield of 78%; 1 1H 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] + 。

[0043] Step 4: Synthesis of 5-(2-aminoethyl)-4-methylthiazol-2-amine (Ansamitocin I-5)

[0044] At room temperature, 80% hydrazine hydrate (5.6 g, 90 mmol) was dropped into a solution of intermediate I-4 (13.0 g, 45 mmol) in ethanol (100 mL). The temperature was raised to 70 °C and the reaction was carried out for 5 h. The reaction system was cooled, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain 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] + 。

[0045] Step 5: Preparation of 4-methyl-5-(2-(methylamino)ethyl)thiazol-2-amine (Compound A-1)

[0046] At room temperature, ansamine I-5 (157 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. The temperature was raised to 50 °C and the reaction was carried out for 3 h. An appropriate amount of water was added, and the mixture was extracted with dichloromethane three times. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 91 mg of 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] + 。

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

[0048]

[0049] At room temperature, ansamine I-5 (157 mg, 1.0 mmol), sodium carbonate (212 mg, 2.0 mmol), and ethyl bromide (108 mg, 1.0 mmol) were dissolved in 5 mL of DMF. The temperature was raised to 55 °C and the reaction was carried out for 3 h. An appropriate amount of water was added, and the mixture was extracted with dichloromethane three times. The organic layers were combined, washed with saturated brine, dried over anhydrous Na 2 SO 4 sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 109 mg of orange solid A-2 with a yield of 59%; 1 H NMR (500 MHz, DMSO-d 6)δ6.73(s,2H),2.99 - 2.89(m,4H),2.88 - 2.79(m,2H),2.01(s,3H),1.17(t,J=7.5Hz,3H); ESI-MS: m / z=186.1[M + H] + 。

[0050] Example 3: Preparation of 5-(2-(dimethylamino)ethyl)-4-methylthiazol-2-amine (Compound A-3)

[0051]

[0052] At room temperature, anthramycin I-5 (157 mg, 1.0 mmol), sodium bicarbonate (168 mg, 2.0 mmol), and methyl iodide (142 mg, 2.0 mmol) were dissolved in 5 mL of DMF. The temperature was raised to 60 °C and the reaction was carried out for 3 h. An appropriate amount of water was added, and the mixture was extracted with dichloromethane three times. The organic layers were combined, washed with saturated brine, and dried over anhydrous Na 2 SO 4 dried, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 115 mg of pale yellow solid A-3, with a yield of 62%; 1 H NMR (500 MHz, DMSO-d 6 )δ6.58(s,2H),2.72(t,J=7.5Hz,2H),2.56(s,2H),2.41 - 2.28(m,6H),1.99(s,3H); ESI-MS: m / z=186.1[M + H] + 。

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

[0054]

[0055] At room temperature, anthramycin I-5 (157 mg, 1.0 mmol), cesium carbonate (652 mg, 2.0 mmol), and ethyl bromide (216 mg, 2.0 mmol) were dissolved in 5 mL of DMF. The temperature was raised to 50 °C and the reaction was carried out for 3 h. An appropriate amount of water was added, and the mixture was extracted with dichloromethane three times. The organic layers were combined, washed with saturated brine, and dried over anhydrous Na 2 SO 4 dried, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain a pale yellow solid, with a yield of 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 = 7.0 Hz, 6H); ESI-MS: m / z = 214.1 [M + H] + 。

[0056] Example 5: Preparation of 4-methyl-5-(2-(propylamino)ethyl)thiazol-2-amine (Compound A-5)

[0057]

[0058] Referring to the synthesis of Compound A-1, replacing methyl iodide with propyl iodide gave 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] + 。

[0059] Example 6: Preparation of 5-(2-(dipropylamino)ethyl)-4-methylthiazol-2-amine (Compound A-6)

[0060]

[0061] Referring to the synthesis of Compound A-3, replacing methyl iodide with propyl iodide gave 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] + 。

[0062] Example 7: Preparation of 4-methyl-5-(2-(pyrrolidin-1-yl)ethyl)thiazol-2-amine (Compound A-7)

[0063]

[0064] At room temperature, ansamycin I-5 (157 mg, 1.0 mmol), potassium carbonate (276 mg, 2.0 mmol), and 1,4-dichlorobutane (127 mg, 1.0 mmol) were dissolved in 5 mL of DMF, and the temperature was raised to 65 °C and reacted for 3 h. An appropriate amount of water was added, and the mixture was extracted with dichloromethane three times. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 156 mg of pale yellow solid A-7, with a yield of 74%; 1 H NMR(500MHz,DMSO-d 6 )δ6.51(s,2H),2.64(t,J=7.5Hz,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] + 。

[0065] Example 8: Preparation of 4-(2-(benzylamino)ethyl)-4-methylthiazol-2-amine (Compound A-8)

[0066]

[0067] At room temperature, ansamycin 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 temperature was raised to 45 °C and reacted for 3 h. An appropriate amount of water was added, and the mixture was extracted with dichloromethane three times. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 208 mg of white solid A-8, with a yield of 84%; 1 H NMR(500MHz,DMSO-d 6 )δ7.38(dd,J=12.0,6.0Hz,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] + 。

[0068] Example 9: Preparation of 5-(2-(ethyl(methyl)amino)ethyl)-4-methylthiazol-2-amine (Compound A-9)

[0069]

[0070] At room temperature, compound A-2 (185 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 temperature was raised to 45 °C and reacted for 2 h. An appropriate amount of water was added, and the mixture was extracted with dichloromethane three times. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 78 mg of 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] + .

[0071] Example 10: Preparation of 5-(2-(isopropylamino)ethyl)-4-methylthiazol-2-amine (Compound A-10)

[0072]

[0073] At room temperature, acetone (58 mg, 1.0 mmol) and acetic acid (0.1 mL) were added to a methanol (5 mL) solution of ansamycin I-5 (157 mg, 1.0 mmol). The temperature was raised to 50 °C and reacted for 0.5 h. Sodium cyanoborohydride (75 mg, 1.2 mmol) was added to the system and the reaction continued for 2 h. The solvent was removed under reduced pressure, an appropriate amount of water was added, and the mixture was extracted with dichloromethane twice. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 114 mg of white solid A-10, 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] + .

[0074] Example 11: Preparation of 5-(2-(isopropyl(methyl)amino)ethyl)-4-methylthiazol-2-amine (Compound A-11)

[0075]

[0076] 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 temperature was raised to 40 °C and reacted for 2 h. An appropriate amount of water was added, and dichloromethane was used for extraction twice. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 87 mg of pale orange solid A-11, with a yield of 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] + 。

[0077] Example 12: Preparation of 5-(2-(ethyl(isopropyl)amino)ethyl)-4-methylthiazol-2-amine (Compound A-12)

[0078]

[0079] Referring to the synthesis of compound A-11, methyl iodide was replaced with ethyl bromide to obtain a pale yellow solid with a yield of 45%; 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] + 。

[0080] Example 13: Preparation of 5-(2-(isobutylamino)ethyl)-4-methylthiazol-2-amine (Compound A-13)

[0081]

[0082] At room temperature, isobutyraldehyde (72 mg, 1.0 mmol) and acetic acid (0.1 mL) were added to a methanol (5 mL) solution of ansamycin I-5 (157 mg, 1.0 mmol). The temperature was raised to 45 °C and the reaction was carried out for 0.5 h. Sodium triacetoxyborohydride (254 mg, 1.2 mmol) was added to the system and the reaction was continued for 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 purified by column chromatography to obtain 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] + 。

[0083] Example 14: Preparation of 4-methyl-5-(3-(methylamino)propyl)thiazol-2-amine (Compound A-14)

[0084]

[0085] Step 1: Synthesis of 2-(5-oxooxo)isoindoline-1,3-dione (Intermediate I-8)

[0086] 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, and the mixture was stirred at 75 °C for 5 h under nitrogen protection. The solvent was removed under reduced pressure, an appropriate amount of water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain a crude product, and recrystallized from methanol to obtain 22.1 g of 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] + 。

[0087] Step 2: Synthesis of 2-(4-bromo-5-oxooxo)isoindoline-1,3-dione (Intermediate I-9)

[0088] N 2 Under protection, bromine (16.0 g, 100 mmol) was slowly added dropwise to a solution of intermediate I-8 (24.5 g, 100 mmol) in CCl 4 (120 mL). 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 organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. Recrystallization from ethanol gave 25.8 g of solid I-9 in a yield of 80%; ESI-MS: m / z = 324.0 [M+H] + .

[0089] Step 3: Synthesis of 2-(3-(2-amino-4-methylthiazol-5-yl)propyl)isoindoline-1,3-dione (intermediate I-10)

[0090] 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. The temperature was raised to 75 °C and the reaction was carried out for 5 h. The reaction system was cooled, filtered, and the solvent was removed under reduced pressure from the filtrate. An appropriate amount of water was added, and the mixture was extracted three times with dichloromethane. The organic layers were collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized to obtain 22.6 g of yellow solid I-10 in 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] + .

[0091] Step 4: Synthesis of 5-(3-aminopropyl)-4-methylthiazol-2-amine (intermediate I-11)

[0092] At room temperature, 80% hydrazine hydrate (6.3 g, 100 mmol) was added dropwise to a solution of intermediate I-10 (15.1 g, 50 mmol) in methanol (120 mL). Then the temperature was raised to 70 °C and the reaction was carried out for 5 h. After cooling, suction filtration was carried out, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain 12.1 g of orange solid I-11 in a yield of 71%; 1 H NMR (500 MHz, DMSO-d 6)δ6.51(s,2H),2.81(tt,J=6.5,4.5Hz,2H),2.72-2.55(m,2H),2.35(s,2H),1.96(s,3H);ESI-MS:m / z=172.1[M+H] + 。

[0093] Step Five: Preparation of 4-methyl-5-(3-(methylamino)propyl)-1,3-thiazol-2-amine (Compound A-14)

[0094] 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. The temperature was raised to 70 °C and the reaction was carried out for 3 h. An appropriate amount of water was added, and the mixture was extracted with dichloromethane three times. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 89 mg of pale orange solid A-14, with a yield of 48%; 1 H NMR(500MHz,DMSO-d 6 )δ6.58(s,2H),2.79(qd,J=4.9,4.2Hz,1H),2.72(q,J=4.7Hz,2H),2.65(t,J=7.5Hz,2H),2.46(d,J=4.9Hz,3H),2.34(s,3H),1.92(tt,J=7.5,4.9Hz,2H);ESI-MS:m / z=186.1[M+H] + 。

[0095] Example 15: Preparation of 5-(3-(dimethylamino)propyl)-4-methyl-1,3-thiazol-2-amine (Compound A-15)

[0096]

[0097] 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. The temperature was raised to 65 °C and the reaction was carried out for 3 h. An appropriate amount of water was added, and the mixture was extracted with dichloromethane three times. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain a pale yellow solid with a yield of 56%; 1 H NMR(500MHz,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 = 7.5 Hz, 2H); ESI-MS: m / z = 200.1 [M+H] + 。

[0098] Example 16: Preparation of 5-(3-(ethyl(methyl)amino)propyl)-4-methylthiazol-2-amine (Compound A-16)

[0099]

[0100] 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. The temperature was raised to 45 °C and the reaction was carried out for 2 h. An appropriate amount of water was added, and the mixture was extracted with dichloromethane three times. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 77 mg of 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] + 。

[0101] Example 17: Histamine H2 Receptor Agonist Activity of Aminothiazole Compounds

[0102] Detection principle: The active ingredient, aminothiazole compounds, can increase the activity of glutamatergic neurons by reducing the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel-mediated current Ih on glutamatergic neurons. Furthermore, the H2 receptor can activate its activity through the downstream Gs protein.

[0103] Detection method: cAMP experiment: After the synthesis of the target molecule and its binding, the change in intracellular cAMP level was detected by the cAMP experiment to reflect the activation of the Gs signaling pathway downstream of the H2 receptor. The H2 receptor and cAMP biosensor plasmids were transfected into HEK293T cells. After 24 h, the cells were seeded into 384-well plates; overnight, the cells were starved with PBS, incubated with a fluorescent substrate, and then gradient-diluted agonists were added. The fluorescence values were detected using a microplate reader. The data were processed to obtain a curve of fluorescence value versus agonist concentration to reflect the G-protein pathway agonist activity of the synthesized target molecule.

[0104] Test results: As shown in Table 2, most compounds showed strong H2 receptor agonist activity, and the activities of multiple compounds were equivalent to or better than those of amxanox.

[0105] Table 2 Histamine H2 receptor agonist activities of representative compounds

[0106]

[0107]

[0108] "++++" represents > 8; "+++" represents 6 - 8; "++" represents 5 - 6;

[0109] Example 18: In vivo pharmacokinetic study of the active preferred compound

[0110] 1) Study on the administration method:

[0111] Research method: Using SD rats as experimental animals, they were fasted but not water - deprived for 12 h before the experiment. The compound was dissolved in a suitable solvent or suspended in a 0.5% sodium carboxymethylcellulose (CMCNa) solution (10 mg / mL), and then intravenously injected at a dose of 1.0 mg / kg and orally administered at a dose of 5.0 mg / kg respectively. Blood samples (400 μL) were taken 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, 100 μL of the supernatant was taken, 400 μL of the internal standard compound solution was added, and then centrifuged at 13000 rpm for 10 min. 200 μL of the supernatant was taken and analyzed for the compound concentration in plasma by LC - MS / MS method. The pharmacokinetic parameters after administration were calculated using WinNonLin 7.0 pharmacokinetic software, and the concentration - time curve was processed by Graphpad Prism software. The bioavailability was calculated by the formula: Bioavailability F%=(AUCp.o.×Di.v.) / (AUCi.v.×Dp.o.)×100%.

[0112] Research results: The results are as Figure 1 shown in Table 3. Under intravenous injection, compound A - 3 was metabolized relatively fast, while oral administration had good effects, with a large drug exposure, an AUC reaching 1982.52 h*ng / mL, a relatively long half - life, T 1 / 2 of 7.21 hours, and an oral bioavailability of approximately 100%. Therefore, further evaluation of blood - brain barrier permeability was carried out by oral administration.

[0113] Table 3 Pharmacokinetic parameters of compound A - 3

[0114]

[0115] 2) Evaluation of blood-brain barrier permeability:

[0116] Evaluation method: Sprague-Dawley (SD) mice were used as experimental animals. They were fasted for 12 h before the experiment with free access to water. The SD mice were weighed and grouped. According to the dosing time points, they were divided into a blank group and six experimental groups (3 mice in each group). Each experimental group of mice was gavaged with the candidate compound at a dose of 30 mg / kg, and the mice in the blank group were given physiological saline instead. At the set time points (0.5, 1, 2, 3, 4, 6 hours after dosing), the animals were anesthetized with 10% chloral hydrate, and 0.5 mL of blood samples were collected by orbital blood collection. The blood samples were added to an EP tube containing the anticoagulant disodium EDTA, shaken, and centrifuged at 6,000 rpm for 10 min to separate the plasma. After perfusion with physiological saline, the brain tissues were dissected, labeled, and stored frozen at -20 °C for further analysis. The plasma was processed. To each 100 μL of plasma, 300 μL of ice-cold methanol containing an internal standard of 200 ng / ml was added, vortexed for 1 min, centrifuged at 14,500 rpm for 10 min, and the process was repeated twice. The supernatant was taken for direct injection. The brain tissues were processed. The brain tissues were weighed, minced, and homogenized with 3 times the weight of physiological saline on ice; to each 100 ml of homogenate, 300 μL of methanol containing an internal standard of 200 ng / ml was added, vortexed for 1 min, centrifuged at 14,500 rpm for 10 min, and the process was repeated twice. The supernatant was taken for direct injection. The concentrations of the test substances in the plasma and brain tissues were determined by LC / MS method. The pharmacokinetic parameters after dosing were calculated using the non-compartmental model of DAS 2.0 software. The concentration-time curve was obtained by processing with Graphpad Prism 9 software.

[0117] Evaluation results: Since the histamine H2 receptor agonist amthamine is strongly basic (pKa = 12.24) and has low lipophilicity (clogP = 0.53), the content of amthamine in the brains of SD mice was not detected after gavage administration. Therefore, amthamine cannot penetrate the blood-brain barrier by gavage administration.

[0118] After the structural optimization of compound A-3, its basicity (pKa = 9.64) further decreased and its lipophilicity (clogP = 1.14) further increased. Therefore, it showed excellent blood-brain barrier permeability. As Figure 2 shown in Table 4, with the passage of the dosing time, the content of A-3 in the brains of mice gradually increased, while the content in the blood gradually decreased, and the brain-blood ratio at different times was greater than 2.

[0119] Table 4 Brain-blood ratio of compound A-3

[0120]

[0121] In addition, the brain-blood ratios of multiple representative aminothiazole compounds were detected at administration times of 0.5 h and 2 h respectively, and the results are shown in Table 5. After structural optimization, the liposolubility of the aminothiazole compounds was further improved, and all of them could cross the blood-brain barrier.

[0122] Table 5 Brain-blood ratios of some representative aminothiazole compounds

[0123]

[0124] Therefore, while maintaining the histamine H2 receptor agonist activity, the compounds of the present invention 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 schizophrenia, mania, attention deficit hyperactivity disorder, binge eating disorder or bulimia nervosa, autism, Parkinson's disease, ischemic brain injury and other diseases.

[0125] Example 19: Pharmacodynamic evaluation of the active preferred compound

[0126] 1) Pharmacodynamic evaluation of schizophrenia

[0127] Evaluation method: A schizophrenia drug research model induced by chronic MK-801 (0.2 mg / kg / d, 7 days) was used, and two different doses of compound A-3 were given by gavage for treatment, followed by the evaluation of schizophrenia-related behaviors.

[0128] Evaluation results: MK-801 can cause schizophrenia-related behaviors such as increased exercise in the open field test, reduced social novelty preference in the three-chamber test, and weakened nesting ability in the nesting test ( Figure 3 A-D in). Compared with the mice in the MK-801 model group, the exercise of the mice in the A-3 treatment group decreased significantly ( Figure 3 A, B in), the preference for strange mice increased ( Figure 3 C in), and the nesting ability improved ( Figure 3 D in). The above results indicate that administration of A-3 can improve schizophrenia positive and negative symptom-related behaviors such as hyperactivity and social avoidance induced by MK-801, suggesting that A-3 can be a potential drug for the treatment of schizophrenia.

[0129] 2) Pharmacodynamic evaluation of mania

[0130] Evaluation method: Amphetamine (Amph) and sleep deprivation are animal models for inducing manic-like behaviors in mice. After intraperitoneal injection of Amph (3.5 mg / kg) or 24-hour sleep deprivation, different doses of compound A-3 were given by gavage, and the behavioral changes of the mice in the open field test were evaluated.

[0131] Evaluation results: Intraperitoneal injection of Amph can induce hyperactive behavior in mice, manifested as a significant increase in the movement distance and movement time, and this phenotype can be reversed by the classical anti-manic drug Li 2 CO 3 (200 mg / kg, i.g.) ( Figure 4 A, B in). Compound A-3 at a dose of 0.1 mg / kg and above can significantly reduce the hyperactive behavior of mice and show a dose-dependent improvement within the range of 0.1 - 0.3 mg / kg ( Figure 4 A, B in). Sleep deprivation causes an increase in the exercise volume of mice in the open field test, and this phenotype can also be reversed by the classical anti-manic drug Li 2 CO 3 ( Figure 4 C, D in). Compound A-3 at a dose of 0.1 mg / kg and above can significantly reduce the total movement distance and movement speed ( Figure 4 C, D in).

[0132] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. An aminothiazole compound and a pharmaceutically acceptable salt thereof, wherein the compound has the following general structure (I): Where: n=1 or 2; NR1R2 is an open-chain amine or a 3-8-membered cyclic amine; When NR1R2 is an open chain amine, R1 is selected from hydrogen, C 1-5 Alkyl; R2 is selected from C 1-5 Alkyl, benzyl.

2. The aminothiazole compound according to claim 1, characterized in that When NR1R2 is an open-chain amine, R1 is selected from H, Me, Et, n-Pr, i-Pr, i-Bu; R2 selects Me, Et, n-Pr, i-Pr, i-Bu, When NR1R2 is a 3-8 membered cyclic amine, selected from 3. The aminothiazole compound according to claim 1, characterized in that Its structural formula is selected from:

4. A pharmaceutically acceptable salt, characterized in that It is an organic acid salt or an inorganic acid salt of the compound according to any one of claims 1 to 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 the aminothiazole compound according to any one of claims 1 to 3 or the 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, characterized in that The aminothiazole compound, or a pharmaceutically acceptable salt thereof, is used as a brain-penetrating histamine H2 receptor agonist in the preparation of a drug for treating brain diseases such as schizophrenia, mania, attention deficit hyperactivity disorder, binge eating disorder or bulimia nervosa, autism, Parkinson's disease, and ischemic brain damage.

7. A pharmaceutical composition, characterized in that It contains a therapeutically effective amount of one or more aminothiazole compounds or pharmaceutically acceptable salts thereof as described in any one of claims 1 to 3, or further comprises a pharmaceutically acceptable excipient, diluent, carrier or auxiliary material.

8. The pharmaceutical composition according to claim 7, characterized in that: The pharmaceutical composition is in the form of capsules, powders, tablets, granules, pills, injections, syrups, oral solutions, inhalants, ointments, suppositories or patches.

Images