Preparation and application of new compounds for the treatment of methamphetamine addiction and cognitive impairment

Abstract

The present invention discloses a compound for treating methamphetamine addiction and cognitive impairment, its preparation method and application. The new compound NBU513-1 for treating methamphetamine addiction and cognitive impairment induced by the present invention can significantly improve the addictive behavior of mice for methamphetamine, has a therapeutic effect on the cognitive dysfunction caused by methamphetamine, and can be used to prepare a medicine for treating methamphetamine addiction and cognitive impairment induced by methamphetamine. The present invention provides a total synthesis route of compound NBU513-1. Compared with the preparation method of similar compounds in the prior art, the method of the present invention does not need to react with sodium azide, does not produce powerful explosives and highly toxic substances, has high stability and low reaction risk; the method has mild reaction conditions, simple scheme, safe and reliable production and can prepare target products with higher yields, and is suitable for industrial production.

Description

Technical Field

[0001] The present application belongs to the technical field of medicinal chemistry, and specifically relates to a compound for treating methamphetamine addiction and its induced cognitive impairment, as well as a preparation method and application thereof. Background Art

[0002] Methamphetamine (METH) is a drug with a chemical formula of C 10 H 15 N, known in Chinese as N-methyl-1-phenyl-propane-2-amine, is a central nervous system stimulant in the amphetamine class. It exhibits multiple pharmacological and toxicological effects, including central nervous system excitation and appetite suppression, and is a controlled psychoactive drug. METH is toxic to both dopaminergic and non-dopaminergic neurons, and long-term use can severely impair motor and cognitive function. The incidence of cognitive impairment in methamphetamine-addicted patients is 30%-40%. Factors influencing cognitive impairment in methamphetamine-addicted patients include age of onset, lesion location, frequency, duration, and type of attacks, medication effects, surgical interventions, and psychosocial factors, with the influence of methamphetamine itself being crucial. The precise mechanism of cognitive impairment in methamphetamine-addicted patients remains unclear, but it may be related to abnormalities in cerebral cortical development and synaptic horn structure. Research into the neurotoxic mechanisms of METH and related interventional treatments are currently critical and urgently needed.

[0003] The applicant organization has long been engaged in the development of drugs to treat methamphetamine addiction and cognitive impairment caused by methamphetamine addiction (see CN104940196A, CN105726530A, CN105920034A, etc.). In the present invention, the inventors have discovered a novel compound. Through behavioral experiments, they found that it has a good therapeutic effect on methamphetamine addiction and cognitive impairment. They have also fully optimized the total synthesis route of this compound, and thus proposed the present invention. Summary of the Invention

[0004] The present invention aims to provide a novel pharmaceutical compound, NBU513-1, for treating methamphetamine addiction and its induced cognitive impairment, which can significantly improve methamphetamine addiction and its induced cognitive impairment. Another object of the present invention is to provide a total synthetic route for preparing NBU513-1. By optimizing the reaction conditions of each step and designing the structures of related intermediates, the synthesis of NBU513-1 can be conveniently and efficiently achieved in high yield under economical, safe, and efficient conditions.

[0005] According to the present invention, a compound for treating methamphetamine addiction and cognitive impairment is provided, and its structure is as follows:

[0006]

[0007] As another aspect of the present invention, the present invention provides a method for preparing compound NBU513-1, and the synthetic route is as follows:

[0008]

[0009] Compound 6 and compound 7 were reacted in the presence of sodium hydroxide, and N,N-dimethylacetamide (DMAc) was added as a solvent. The reaction was stirred at room temperature until the starting material disappeared. Lithium hydroxide was then added and stirred until the reaction was complete. The intermediate compound 8 was obtained after purification.

[0010] The intermediate compound 8 was deprotected by removing the trityl protecting group in the presence of hydrochloric acid, and the target product NBU513-1 was obtained after purification.

[0011] As another aspect of the present invention, the present invention provides an intermediate compound 8 having the following structure:

[0012]

[0013] As another aspect of the present invention, the present invention provides an intermediate compound 6 having the following structure, whose Chinese name is 5-((4′-bromomethyl)-4,5-difluoro-[1,1′-biphenyl]-2-yl)-1-trityl-1H-tetrazole:

[0014]

[0015] As another aspect of the present invention, the present invention provides a method for synthesizing intermediate compound 6, which specifically comprises the following steps:

[0016] 5-(4,5-difluoro-4′-methyl-[1,1′-biphenyl]-2-yl)-1-trityl-1H-tetrazole (Compound 5) is added to dichloromethane and stirred to dissolve. Azobisisobutyronitrile (AIBN) is added as a catalyst, followed by N-bromosuccinimide. The temperature is raised and the reaction is continued until the starting material disappears. After the reaction is completed, a saline solution is added, stirred, allowed to stand and separate into layers, and the aqueous layer is extracted with dichloromethane. The organic phase is dried, filtered, and concentrated under reduced pressure to remove the solvent. The residue is then separated by column chromatography to obtain 5-((4′-bromomethyl)-4,5-difluoro-[1,1′-biphenyl]-2-yl)-1-trityl-1H-tetrazole. The reaction formula is as follows:

[0017]

[0018] As another aspect of the present invention, the present invention provides a method for synthesizing intermediate compound 5, which specifically comprises the following steps:

[0019] 5-(4,5-difluoro-4′-methyl-[1,1′-biphenyl]-2-yl)-1H-tetrazole (Compound 4) is added to dichloromethane, dissolved, and then triphenylmethane is added. Then, an alkali source is added at 0°C and the temperature is raised to react until the starting material disappears. After the reaction is completed, the reaction solution is added to an aqueous sodium bicarbonate solution, stirred, and allowed to stand for stratification. The aqueous layer is extracted with dichloromethane, and the organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue is separated by chromatography to obtain 5-(4,5-difluoro-4′-methyl-[1,1′-biphenyl]-2-yl)-1-trityl-1H-tetrazole. The reaction formula is as follows:

[0020]

[0021] In this step, dichloromethane is used as a solvent instead of ether generally used in the prior art, thereby reducing potential safety hazards.

[0022] Preferably, the alkali source in this step is at least one of triethylamine, cesium carbonate, potassium carbonate, sodium carbonate and potassium tert-butoxide; more preferably triethylamine.

[0023] Preferably, in this step, the molar ratio of the alkaline source to 5-(4,5-difluoro-4′-methyl-[1,1′-biphenyl]-2-yl)-1H-tetrazole (Compound 4) is 3 to 7:1, preferably 5:1.

[0024] Preferably, the temperature of the temperature-raising reaction in this step is 30-50°C, preferably 40°C.

[0025] As another aspect of the present invention, the present invention provides a method for synthesizing intermediate compound 4, which specifically comprises the following steps:

[0026] A catalyst and a nitrogen source are added to 4,5-difluoro-4′-methyl-[1,1′-biphenyl]-2-carbonitrile (Compound 3), stirred and reacted. After the reaction is completed, the reaction solution is separated, and the organic phase is washed. The organic phase is dried, filtered, and concentrated under reduced pressure, and then recrystallized to obtain 5-(4,5-difluoro-4′-methyl-[1,1′-biphenyl]-2-yl)-1H-tetrazole (Compound 4); the reaction formula is as follows:

[0027]

[0028] Preferably, the nitrogen source in this step is at least one of sodium azide, trimethylsilyl azide, p-toluenesulfonyl azide, tributyltin azide, tetrabutylammonium azide, and diphenylphosphoryl azide; preferably trimethylsilyl azide. Trimethylsilyl azide (TMSN3) can be considered a substitute for metal azides. By adjusting the reaction conditions, partial reaction of the metal azide can occur, making the reaction easier to control.

[0029] Preferably, the catalyst in this step is tetrabutylammonium fluoride trihydrate.

[0030] As another aspect of the present invention, the present invention provides a method for synthesizing intermediate compound 3, which specifically comprises the following steps:

[0031] Potassium 4-methylphenyltrifluoroborate, 4,5-difluoro-2-bromobenzonitrile, an alkali source, and a catalyst are added to a reaction vessel, and then a solvent is added, stirred, and reacted. After the reaction is completed, the reaction solution is added to brine, extracted, and the organic phase is dried, filtered, and concentrated under reduced pressure to remove the solvent. The residue is separated by chromatography to obtain 4,5-difluoro-4′-methyl-[1,1′-biphenyl]-2-carbonitrile; the reaction formula is as follows:

[0032]

[0033] Preferably, the alkali source is at least one of potassium carbonate, cesium carbonate, sodium carbonate, and tripotassium phosphate; more preferably, it is potassium carbonate.

[0034] In order to accelerate the reaction, preferably, the catalyst is at least one of copper acetate, palladium acetate, bistriphenylphosphine palladium dichloride, nickel acetate and bistricyclohexylphosphine palladium dichloride; more preferably, it is palladium acetate.

[0035] As another aspect of the present invention, behavioral experiments of the present invention showed that mice were treated with the compound NBU513-1 of the present invention, then given an intraperitoneal injection of methamphetamine, and then tested for addictive behavior and cognitive function using a conditioned place preference model. The results showed that NBU513-1 can significantly improve mice's addictive behavior for methamphetamine and significantly increase mice's preference for new objects. At the same time, mice treated with NBU513-1 showed significant differences in their preference index for new objects, indicating that the compound NBU513-1 of the present invention has a therapeutic effect on cognitive dysfunction caused by methamphetamine. Therefore, the compound NBU513-1 of the present invention can be used to prepare drugs for treating methamphetamine addiction and cognitive impairment.

[0036] Compared with the prior art, the present invention has the following advantages:

[0037] 1) This invention reports for the first time that the new compound NBU513-1 can significantly improve methamphetamine addiction behavior in mice and has a therapeutic effect on cognitive dysfunction caused by methamphetamine. It can be used to prepare drugs for treating methamphetamine addiction and its induced cognitive dysfunction.

[0038] 2) The present invention provides a total synthetic route for compound NBU513-1. Compared with existing methods for preparing similar compounds, the method of the present invention does not require a sodium azide reaction, does not produce strong explosives and highly toxic substances, has high stability, and reduces reaction risks. The method also has mild reaction conditions, a simple scheme, is safe and reliable in production, and can produce the target product in high yield, making it suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 This is the establishment of the methamphetamine addiction model in Experimental Example 1 of the present invention.

[0040] Figure 2 This is the therapeutic effect of NBU513-1 on cognitive impairment caused by methamphetamine in Test Example 2 of the present invention. DETAILED DESCRIPTION

[0041] The present invention is further described in detail below with reference to specific embodiments.

[0042] Example 1

[0043]

[0044] To a Schlenk flask were added potassium 4-methylphenyltrifluoroborate (118.8 mg, 0.6 mmol), 4,5-difluoro-2-bromobenzonitrile (109.0 mg, 0.5 mmol), potassium carbonate (82.8 mg, 0.6 mmol), and palladium acetate (1.1 mg, 1.0 mol%). A mixture of ethanol and water was added as a solvent (EtOH / H2O, 2 mL / 2 mL). The reaction was stirred at 25°C for 12 h. The reaction progress was monitored by TLC until the starting material disappeared. After the reaction was completed, the reaction solution was added to brine and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography to obtain the target product 3: 4,5-difluoro-4′-methyl-[1,1′-biphenyl]-2-carbonitrile; the yield of the target product 3 was 98%.

[0045] Example 2

[0046] Sodium carbonate was used instead of potassium carbonate, and the other conditions were the same as in Example 1. The yield of the target product 3 was 81%.

[0047] Example 3

[0048] Cesium carbonate was used instead of potassium carbonate, and the other conditions were the same as those in Example 1. The yield of the target product 3 was 82%.

[0049] Example 4

[0050] Potassium carbonate was replaced by tripotassium phosphate, and the other conditions were the same as those in Example 1. The yield of the target product 3 was 61%.

[0051] Example 5

[0052] The amount of potassium carbonate used was 0.5 mmol, and the other conditions were the same as in Example 1. The yield of the target product 3 was 91%.

[0053] Example 6

[0054] The amount of potassium carbonate used was 0.75 mmol, and the other conditions were the same as in Example 1. The yield of the target product 3 was 93%.

[0055] Example 7

[0056] Bistriphenylphosphine palladium dichloride was used instead of palladium acetate. Other conditions were the same as those in Example 1. The yield of the target product 3 was 51%.

[0057] Example 8

[0058] Bis(tricyclohexylphosphine)palladium dichloride replaced palladium acetate, and the other conditions were the same as in Example 1. The yield of the target product 3 was 42%.

[0059] Example 9

[0060] Anhydrous copper acetate replaced palladium acetate, and the other conditions were the same as in Example 1. The yield of the target product 3 was 34%.

[0061] Example 10

[0062] Anhydrous cobalt acetate replaced palladium acetate, and the other conditions were the same as in Example 1. The yield of the target product 3 was 38%.

[0063] Example 11

[0064] Nickel acetate replaced palladium acetate, and the other conditions were the same as in Example 1. The yield of the target product 3 was 73%.

[0065] Example 12

[0066] Ethanol replaced EtOH / H2O, and the other conditions were the same as in Example 1. The yield of the target product 3 was 68%.

[0067] Example 13

[0068] EtOH / H2O with a ratio of ethanol to water of 2:1 was used instead of EtOH / H2O with a ratio of 1:1. Other conditions were the same as those in Example 1, and the yield of the target product 3 was 78%.

[0069] Example 14

[0070] EtOH / H2O with a ratio of 1:2 of ethanol and water was substituted for EtOH / H2O with a ratio of 1:1. The other conditions were the same as those in Example 1, and the yield of the target product 3 was 61%.

[0071] It can be seen from the above Examples 1-14 that the optimal reaction conditions are the reaction conditions of Example 1, that is, the alkaline source is potassium carbonate (1.2 equiv.), the catalyst is palladium acetate (1.0 mol%), the solvent is EtOH:H2O (1:1), the reaction temperature is 25°C, and the reaction time is: stirring and reacting for 12 h.

[0072] Example 15

[0073]

[0074] A Schlenk flask was charged with 4,5-difluoro-4′-methyl-[1,1′-biphenyl]-2-carbonitrile (114.5 mg, 0.5 mmol), tetrabutylammonium fluoride trihydrate (TBAF·3H2O, 67.7 mg, 0.6 mmol), and trimethylsilylazide (TMSN3, 230.4 mg, 2.0 mmol). The reaction was then stirred at 120°C for 18 h. The reaction progress was monitored by TLC until the starting material disappeared. After completion, the reaction mixture was transferred to a separatory funnel containing 20 mL of ethyl acetate, and the organic phase was washed with 1M aqueous HCl. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was then recrystallized from diethyl ether to yield the desired product 4: 5-(4,5-difluoro-4′-methyl-[1,1′-biphenyl]-2-yl)-1H-tetrazole. The yield of the desired product 4 was 86%.

[0075] Example 16

[0076] Sodium azide was used instead of TMSN3, and the other conditions were the same as those in Example 15. The yield of the target product 4 was 73%.

[0077] Example 17

[0078] p-Toluenesulfonyl azide (TsN3) replaced TMSN3, and the other conditions were the same as those in Example 15. The yield of the target product 4 was 32%.

[0079] Example 18

[0080] Diphenylphosphoryl azide ((PhO)2PON3) was used instead of TMSN3. Other conditions were the same as those in Example 15. The yield of the target product 4 was 31%.

[0081] Example 19

[0082] Tetrabutylammonium azide (TBAN3) was used instead of TMSN3. Other conditions were the same as those in Example 15. The yield of the target product 4 was 78%.

[0083] Example 20

[0084] Tributyltin azide (TBSnN3) was used instead of TMSN3, and the other conditions were the same as those in Example 15. The yield of the target product 4 was 41%.

[0085] Example 21

[0086] The amount of TMSN3 used was 1.0 mmol. Other conditions were the same as those in Example 15, and the yield of the target product 4 was 78%.

[0087] Example 22

[0088] The amount of TMSN3 used was 2.5 mmol. Other conditions were the same as those in Example 15, and the yield of the target product 4 was 82%.

[0089] Example 23

[0090] The amount of TBAF·3H2O used was 0.5 mmol. Other conditions were the same as those in Example 15. The yield of the target product 4 was 79%.

[0091] Example 24

[0092] The amount of TBAF·3H2O used was 0.75 mmol. Other conditions were the same as those in Example 15, and the yield of the target product 4 was 82%.

[0093] Example 25

[0094] The reaction temperature was 110° C., and the other conditions were the same as in Example 15. The yield of the target product 4 was 80%.

[0095] Example 26

[0096] The reaction temperature was 130° C., and the other conditions were the same as in Example 15. The yield of the target product 4 was 85%.

[0097] It can be seen from the above Examples 15-26 that the optimal reaction conditions are the reaction conditions of Example 15, namely TBAF·3H2O (1.2 equiv.), TMSN3 (4.0 equiv.), the reaction temperature is 120°C, and the reaction time is: placing in the reactor and stirring and reacting for 18 hours.

[0098] Example 27

[0099]

[0100] In a Schlenk flask, 5-(4,5-difluoro-4′-methyl-[1,1′-biphenyl]-2-yl)-1H-tetrazole (136.0 mg, 0.5 mmol) was added to 2 mL of dichloromethane and stirred to dissolve. Triphenylmethane (Ph3CC1, 167.3.0 mg, 0.6 mmol) was added, followed by triethylamine (Et3N, 253.0 mg, 2.5 mmol) at 0°C. The temperature was raised to 40°C and the reaction was allowed to react for 2 h. The reaction progress was monitored by TLC until the starting material disappeared. After completion of the reaction, the reaction solution was added to aqueous sodium bicarbonate solution, stirred, and allowed to stand for separation. The aqueous layer was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography to obtain the target product 5: 5-(4,5-difluoro-4′-methyl-[1,1′-biphenyl]-2-yl)-1-trityl-1H-tetrazole; the yield of the target product 5 was 75%.

[0101] The product structure was confirmed to be correct by H NMR and C NMR characterization, and the analytical data are as follows: 1 H NMR (500MHz, CDCl3) δ: 7.66-7.63 (m, 1H), 7.36-7.30 (m, 7H), 7.29-7.24 (m, 8H), 6.93-6.88 (m, 8H), 2.27 (s, 3H); 13 C NMR (126MHz, CDCl3) δ: 163.2 (d, J C-F =2.65Hz), 162.7, 160.7, 141.1(2), 141.0, 138.3(d, J C-F =3.53Hz), 137.2, 137.1, 136.5, 132.4 (d, J C-F =8.19Hz), 130.3, 130.2(2), 129.1, 128.9, 128.7, 128.6, 128.4, 128.3, 128.2 , 128.0, 127.9, 127.8, 127.6(2), 127.2, 117.0, 116.8(2), 116.7, 83.0, 21.1; 19 F NMR (471MHz, CDCl3) δ: -115.25.

[0102] Example 28

[0103] Cesium carbonate was used instead of triethylamine, and the other conditions were the same as those in Example 27. The yield of the target product 5 was 51%.

[0104] Example 29

[0105] Potassium carbonate was used instead of triethylamine, and the other conditions were the same as those in Example 27. The yield of the target product 5 was 55%.

[0106] Example 30

[0107] Sodium carbonate was used instead of triethylamine, and the other conditions were the same as in Example 27. The yield of the target product 5 was 43%.

[0108] Example 31

[0109] Potassium tert-butoxide was used instead of triethylamine, and the other conditions were the same as in Example 27. The yield of the target product 5 was 11%.

[0110] Example 32

[0111] The amount of triethylamine used was 2.0 mmol, and the other conditions were the same as in Example 27. The yield of the target product 5 was 68%.

[0112] Example 33

[0113] The amount of triethylamine used was 3.0 mmol, and the other conditions were the same as in Example 27. The yield of the target product 5 was 72%.

[0114] Example 34

[0115] The reaction temperature was 30°C, and the other conditions were the same as in Example 27. The yield of the target product 5 was 71%.

[0116] Example 35

[0117] The reaction temperature was 50°C, and the other conditions were the same as in Example 27. The yield of the target product 5 was 74%.

[0118] It can be seen from the above Examples 27-35 that the optimal reaction conditions are the reaction conditions of Example 27, namely Ph3CCl (1.2 equiv.), triethylamine (5.0 equiv.), reaction temperature of 40°C, and reaction time of reflux stirring for 2 h.

[0119] Example 36

[0120]

[0121] In a Schlenk flask, add 5-(4,5-difluoro-4′-methyl-[1,1′-biphenyl]-2-yl)-1-trityl-1H-tetrazole (257.1 mg, 0.5 mmol) to 2 mL of dichloromethane and stir to dissolve. Azobisisobutyronitrile (82.1 mg, 0.5 mmol) was added as a catalyst, followed by N-bromosuccinimide (NBS, 97.9 mg, 0.55 mmol) at 0°C. The temperature was raised to 40°C and the reaction was allowed to react for 12 h. The reaction progress was monitored by TLC until the starting material disappeared. After the reaction was complete, saline solution was added, the mixture was stirred, and the layers were allowed to stand for separation. The aqueous layer was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography to obtain the target product 6: 5-(4′-bromomethyl)-4,5-difluoro-[1,1′-biphenyl]-2-yl)-1-trityl-1H-tetrazole; the yield of the target product 6 was 85%. 1 H NMR (500MHz, CDCl3) δ: 7.66-7.63 (m, 1H), 7.36-7.30 (m, 7H), 7.29-7.24 (m, 8H), 6.93-6.88 (m, 8H), 2.27 (s, 3H); 13 C NMR (126MHz, CDCl3) δ: 163.2 (d, J C-F =2.65Hz), 162.7, 160.7, 141.1(2), 141.0, 138.3(d, J C-F =3.53Hz), 137.2, 137.1, 136.5, 132.4 (d, J C-F =8.19Hz), 130.3, 130.2(2), 129.1, 128.9, 128.7, 128.6, 128.4, 128.3, 128.2 , 128.0, 127.9, 127.8, 127.6(2), 127.2, 117.0, 116.8(2), 116.7, 83.0, 21.1; 19 F NMR (471MHz, CDCl3) δ: -115.25.

[0122] Example 37

[0123]

[0124] To a Schlenk flask were added 6 (0.5 mmol), 7 (0.6 mmol), and sodium hydroxide (0.75 mmol, 1.5 equivalents), followed by N,N-dimethylacetamide (DMAc) as a solvent (4 mL). The reaction was then stirred at 25°C for 12 hours, and the reaction progress was monitored by TLC until the starting material disappeared. After completion of the reaction, lithium hydroxide (0.75 mmol, 1.5 equivalents) was added to the reaction tube, and stirring was continued at 25°C for 12 hours until the reaction was complete. The reaction solution was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography to obtain the target product 8; the yield of the target product 8 was 82%.

[0125] Example 38

[0126]

[0127] To a Schlenk flask were added 8 (0.5 mmol), hydrochloric acid (1.5 equivalents), and N,N-dimethylacetamide (DMAc) as a solvent (2 mL). The reaction was then stirred at 25°C for 12 h. The reaction progress was monitored by TLC until the starting material disappeared. After completion of the reaction, the reaction solution was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue was isolated by column chromatography to obtain the desired product 9; the yield of the desired product 9 was 87%. 1 H NMR (400MHz, DMSO-D6) δ: 7.66 (dd, J=11.2, 8.4Hz, 1H), 7.50 (dd, J=11.6, 8.0 Hz, 1H), 7.18 (s, 1H), 7.06 (d, J=8.0Hz, 2H), 6.89 (d, J=8.0Hz, 2H), 5.64 (s, 2H), 2.5 6(t, J=4.4Hz, 2H), 1.56 (dd, J=15.0, 7.5Hz, 2H), 1.50 (s, 6H), 0.87 (t, J=7.3Hz, 3H); 13 C NMR (100MHz, DMSO-D6) δ: 161.4, 156.0, 152.1, 150.0 (d, J C-F =12.3Hz), 149.1, 148.9 (d, J C-F =12.5Hz), 147.5(d, J C-F =12.3Hz), 146.4(d, J C-F =12.3Hz), 137.5(m), 136.8, 136.5, 128.5, 125.1, 124.4(m), 118.9, 118.6(m), 69.7, 46.2, 29.3, 27.5, 19.9, 13.0;19 F NMR (376MHz, DMSO-D6) δ: -137.7, -140.4; LCMS m / z calcd for C 24 H 25 F2N603([M+H] + )483.2, found 483.3.

[0128] Test example

[0129] The methamphetamine used in the test examples of the present invention is a standard product obtained from the Narcotics Control Detachment of the Ningbo Public Security Bureau.

[0130] Mice were treated with intraperitoneal injections of compound 1 (10 mg / kg / day) for 20 minutes, followed by intraperitoneal injections of methamphetamine (2.5 mg / kg / day). Addiction behavior tests using a conditioned place preference model and cognitive function tests using novel object recognition were performed. The results showed that NBU513-1 significantly improved methamphetamine addiction in mice and increased their preference for novel objects.

[0131] Experimental Example 1: Experimental Model of Methamphetamine-Induced Addictive Behavior

[0132] The Conditioned Place Preference (CPP) model is an experimental model for evaluating addictive behavior. This model is used to judge the addictive behavior caused by the use of psychotropic drugs.

[0133] Twenty-three male mice (C57BL / 6J, 6-8 weeks old, weighing 18-20 g) were housed in an SPF animal room and, after one week of adaptive feeding, were randomly divided into methamphetamine + DMSO (9 mice), saline + DMSO (7 mice), and methamphetamine + NBU513-1 (7 mice).

[0134] Conduct the conditioned place preference test as follows:

[0135] The details are as follows: On day 1, all mice were allowed to freely acclimate to the conditioned place preference model box for 30 minutes. On day 2, all mice were allowed to freely acclimate to the CPP box for 15 minutes, and the time the mice spent in both boxes was recorded using a camera (AniLab Software Instrument Co., Ltd., Ningbo, China). On days 3, 5, 7, and 9, the methamphetamine + DMSO group and the methamphetamine + NBU513-1 group were given an intraperitoneal injection of DMSO and NBU513-1 (10 mg / kg), respectively, 30 minutes before the injection, followed by an intraperitoneal injection of methamphetamine (2.5 mg / kg / day) 20 minutes later. They were then allowed to acclimate to the CPP-containing box for 30 minutes. On days 4, 6, 8, and 10, the methamphetamine + saline group and the methamphetamine + NBU513-1 group were given an intraperitoneal injection of DMSO and NBU513-1 (10 mg / kg), respectively, 30 minutes before the injection, followed by an intraperitoneal injection of saline 20 minutes later. They were then allowed to acclimate to the CPP-free box for 30 minutes. On day 11, all mice were allowed to move freely in the conditioned place preference model box for 15 minutes. The time the mice spent in the two boxes was recorded using a camera. The primary outcome measure was the CPP score, which was calculated as the time spent in the drug-containing box minus the time spent in the drug-free box.

[0136] like Figure 1 As shown in the conditioned place preference experiment, NBU513-1 can significantly improve methamphetamine-induced addictive behavior.

[0137] Test Example 2: The therapeutic effect of NBU513-1 on cognitive impairment caused by methamphetamine.

[0138] The following method was used to establish a mouse model of cognitive impairment:

[0139] Twenty-three male mice (C57BL / 6J, 6-8 weeks old, weighing 18-20 g) were housed in an SPF animal room and, after one week of adaptive feeding, were randomly divided into methamphetamine + DMSO (9 mice), saline + DMSO (7 mice), and methamphetamine + NBU513-1 (7 mice) groups.

[0140] The details are as follows: Mice that have completed the conditioned place preference in Example 1 are used. On the 12th day, the mice are allowed to move freely in a device without objects for 10 minutes. On the 13th day, two identical objects A and B are placed in the device, and the mice are allowed to explore for 10 minutes. The time the mice stay on each object is recorded by a camera (AniLab Software Instrument Co., Ltd., Ningbo, China). On the 14th day, one of the two identical objects is replaced with a different one and placed in the device. The mice are allowed to explore for 10 minutes, and the time spent on each object is recorded. Before conducting the next set of experiments, alcohol is used to eliminate odor cues. The main outcome indicators are the preference index and exploration time for new objects. Preference index = (new object detection time - old object detection time) / (new object detection time + old object detection time) * 100%.

[0141] like Figure 2 As shown, there was a significant difference in the preference index for novel objects between methamphetamine + DMSO and methamphetamine + NBU513-1, indicating that 10 mg / kg / day intraperitoneal injection of NBU513-1 has a therapeutic effect on cognitive dysfunction caused by methamphetamine.

Claims

1. A compound NBU513-1 for treating methamphetamine addiction and its induced cognitive impairment, having the following structure:

2. The method for preparing the compound NBU513-1 according to claim 1, characterized in that: The synthetic route is as follows: Compound 6 and compound 7 were reacted in the presence of sodium hydroxide, and N,N-dimethylacetamide (DMAc) was added as a solvent. The reaction was stirred at room temperature until the starting material disappeared. Lithium hydroxide was then added and stirred until the reaction was complete. The intermediate compound 8 was obtained after purification. The intermediate compound 8 was deprotected by removing the trityl protecting group in the presence of hydrochloric acid, and the target product NBU513-1 was obtained after purification.

3. An intermediate compound 8 having the following structure:

4. An intermediate compound 6 having the following structure:

5. The preparation method according to claim 2, characterized in that The synthesis method of compound 6 comprises the following steps: 5-(4,5-difluoro-4′-methyl-[1,1′-biphenyl]-2-yl)-1-trityl-1H-tetrazole (Compound 5) was added to dichloromethane and stirred to dissolve. Azobisisobutyronitrile (AIBN) was added as a catalyst, followed by N-bromosuccinimide. The temperature was raised and the reaction was continued until the starting material disappeared. After the reaction, a saline solution was added, the mixture was stirred, allowed to stand and the layers were separated. The aqueous layer was extracted with dichloromethane. The organic phase was dried, filtered, and concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography to obtain Compound 6. The reaction formula is as follows:

6. The preparation method according to claim 5, characterized in that The synthesis method of compound 5 comprises the following steps: 5-(4,5-difluoro-4′-methyl-[1,1′-biphenyl]-2-yl)-1H-tetrazole (Compound 4) is added to dichloromethane, and triphenylmethane is added after dissolution. Then, an alkali source is added at 0°C, and the temperature is raised to react until the starting material disappears. After the reaction is completed, the reaction solution is added to a sodium bicarbonate aqueous solution, stirred, and allowed to stand for stratification. The aqueous layer is extracted with dichloromethane, and the organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue is separated by chromatography to obtain 5-(4,5-difluoro-4′-methyl-[1,1′-biphenyl]-2-yl)-1-trityl-1H-tetrazole (Compound 5); the reaction formula is as follows: Wherein, the alkaline source is triethylamine; the molar ratio of the alkaline source to 5-(4,5-difluoro-4′-methyl-[1,1′-biphenyl]-2-yl)-1H-tetrazole (compound 4) is 3 to 7:

1.

7. The preparation method according to claim 6, characterized in that The synthesis method of compound 4 comprises the following steps: A catalyst and a nitrogen source are added to 4,5-difluoro-4′-methyl-[1,1′-biphenyl]-2-carbonitrile (Compound 3), stirred and reacted. After the reaction is completed, the reaction solution is separated, and the organic phase is washed. The organic phase is dried, filtered, and concentrated under reduced pressure, and then recrystallized to obtain 5-(4,5-difluoro-4′-methyl-[1,1′-biphenyl]-2-yl)-1H-tetrazole (Compound 4); the reaction formula is as follows: The nitrogen source is at least one of sodium azide, trimethylsilyl azide, p-toluenesulfonyl azide, tributyltin azide, tetrabutylammonium azide, and diphenylphosphoryl azide; and the catalyst is tetrabutylammonium fluoride trihydrate.

8. The preparation method according to claim 7, characterized in that The nitrogen source is trimethylsilane.

9. The preparation method according to claim 6, characterized in that The synthesis method of compound 3 comprises the following steps: Potassium 4-methylphenyl trifluoroborate, 4,5-difluoro-2-bromobenzonitrile, an alkali source, and a catalyst are added to a reaction vessel, and then a solvent is added, stirred, and reacted. After the reaction is completed, the reaction solution is added to brine, extracted, and the organic phase is dried, filtered, and concentrated under reduced pressure to remove the solvent. The residue is separated by chromatography to obtain 4,5-difluoro-4′-methyl-[1,1′-biphenyl]-2-carbonitrile; the reaction formula is as follows: Wherein, the alkali source is at least one of potassium carbonate, cesium carbonate, sodium carbonate, and tripotassium phosphate; and the catalyst is palladium acetate.

10. Use of the compound NBU513-1 according to claim 1 for preparing a medicament for treating methamphetamine addiction and cognitive impairment.

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