Use of epipiprazole methyl fatty acid ester

Abstract

The present invention discloses a use of epiriprazole methyl fatty acid ester. Specifically disclosed is a pharmaceutical composition, which comprises: (1) epiriprazole methyl fatty acid ester as shown in formula I and a pharmaceutically acceptable salt thereof, and (2) a pharmaceutically acceptable excipient. Also disclosed is the use of the epiriprazole methyl fatty acid ester as shown in formula I and a pharmaceutically acceptable salt thereof or the pharmaceutical composition in the preparation of a drug for preventing and / or treating central nervous system diseases. The epiriprazole methyl fatty acid ester of the present invention can be used as a prodrug of epiriprazole, and is metabolized to epiriprazole in plasma or whole blood, and has a fast metabolic rate, and is further used for preventing and / or treating central nervous system diseases.

Description

Technical Field

[0001] The invention relates to application of epiprazole methyl fatty acid ester. Background Art

[0002] Brexpiprazole (BPZ), chemically named 7-(4-(4-(benzo[b]thiophen-4-yl)piperazine-1-yl)butanol)quinoline-2(1H)-one, has a chemical structure as shown below.

[0003]

[0004] Ipiriprazole was launched in 2015 and can be used as an adjunctive treatment for schizophrenia and major depressive disorder.

[0005] (7-(4-(4-(Benzo[b]thiophen-4-yl)piperazine-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl) fatty acid methyl ester, commonly known as epipiprazole laurate, referred to as BPZL, has the following structural formula:

[0006]

[0007] As a prodrug of irinotecan, lauric acid ester of irinotecan can be used to treat schizophrenia. The structure is disclosed in patent CN 103781783 A, and this structure is very promising to be developed into a long-acting injection product, but the rate at which irinotecan lauric acid ester is metabolized to irinotecan in plasma or whole blood is relatively slow. Summary of the invention

[0008] The technical problem to be solved by the present invention is to overcome the defect of the slow metabolic rate of epiriprazole laurate in the prior art, and to provide a use of epiriprazole methyl fatty acid ester as an epiriprazole prodrug. The epiriprazole methyl fatty acid ester of the present invention can be used as a prodrug of epiriprazole, and is metabolized into epiriprazole in plasma or whole blood, and has a fast metabolic rate, and is further used for preventing and / or treating central nervous system diseases.

[0009] The present invention solves the above technical problems through the following technical solutions:

[0010] The present invention provides a pharmaceutical composition comprising:

[0011] (1) an epipiprazole methyl fatty acid ester and a pharmaceutically acceptable salt thereof as shown in formula I,

[0012]

[0013] Wherein, n is an integer from 4 to 16;

[0014] (2) Pharmaceutically acceptable excipients.

[0015] In one embodiment of the present invention, n is 4, 8, 10, 14 or 16.

[0016] The present invention also provides the use of the epiprazole methyl fatty acid ester as shown in formula I and its pharmaceutically acceptable salt or the pharmaceutical composition in the preparation of drugs for preventing and / or treating central nervous system diseases.

[0017] In the use, preferably, the central nervous system disease is selected from schizophrenia, major depression, attention deficit and agitation caused by Alzheimer's disease and post-traumatic stress disorder.

[0018] The term "pharmaceutically acceptable" means that salts, solvents, excipients, etc. are generally non-toxic, safe, and suitable for use by patients. The "patient" is preferably a mammal, more preferably a human.

[0019] The term "pharmaceutically acceptable salt" refers to a salt prepared from a compound of the present invention and a relatively nontoxic, pharmaceutically acceptable acid or base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting a neutral form of such compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, and diethanolamine salts. When the compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting a neutral form of such compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. The pharmaceutically acceptable acid includes an inorganic acid, and the inorganic acid includes, but is not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like. The pharmaceutically acceptable acid includes organic acids, including but not limited to acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid, tannic acid, pantothenic acid, bitartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (i.e., 4,4'-methylene-bis(3-hydroxy-2-naphthoic acid)), amino acids (e.g., glutamic acid, arginine), etc. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0020] The term "pharmaceutically acceptable excipients" refers to excipients and additives used in the production of drugs and the preparation of prescriptions. It is all substances contained in drug preparations except active ingredients. Please refer to the Pharmacopoeia of the People's Republic of China (2020 Edition) or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).

[0021] The term "treat" refers to therapeutic treatment. When referring to a specific condition, treatment means: (1) ameliorating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade leading to or causing the condition or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition.

[0022] The term "prevent" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0023] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0024] The reagents and raw materials used in the present invention are commercially available.

[0025] The positive and progressive effects of the present invention are:

[0026] The methyl fatty acid ester of epiliprazole of the present invention is used as a prodrug of epiliprazole, which is metabolized into epiliprazole in plasma or whole blood with a fast metabolic rate, and can be used for the auxiliary treatment of various mental illnesses such as schizophrenia, major depression, attention deficit and agitation caused by Alzheimer's disease, and post-traumatic stress disorder. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 In the whole blood metabolism experiment, compound A 3 The blood concentration curve of the drug metabolized with epirinotecan laurate.

[0028] Figure 2 In the plasma metabolism experiment, compound A 3 The blood concentration curve of the drug metabolized with epirinotecan laurate. DETAILED DESCRIPTION

[0029] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples.

[0030] In the following examples, the purity of the product was determined by HPLC under the following conditions:

[0031] Chromatographic column: octadecylsilane bonded silica gel.

[0032] Mobile phase: 0.15% triethylamine solution (PH 3.50) was used as mobile phase A, and pure acetonitrile solution was used as mobile phase B; the ratio of mobile phase A to mobile phase B was 1:9.

[0033] Mobile phase flow rate: 1.5 ml / min;

[0034] Column temperature: 35°C;

[0035] Detection wavelength: 220nm

[0036] Injection volume: 10 μL.

[0037] Example 1: Compound A 1 Preparation of (n=4)

[0038] 10.02 g of epiriprazole was added to 200 mL of dioxane, 2.78 g of NaH was added in batches, and the mixture was reacted for 30 min. 1.00 g of KI was added, and 17.22 g of methyl chloromethoxyhexanoate was measured and slowly added dropwise, and the mixture was reacted for 2 h. The reaction was quenched with ice water, and the mixture was extracted with ethyl acetate for 3 times. The upper layer solutions were combined and washed twice with saturated brine, and dehydrated with anhydrous magnesium sulfate, and then rotary evaporated, weighed, mixed (1.5 times), and subjected to column chromatography. The chromatographic solution was rotary evaporated to obtain compound A. 1 ,HPLC purity is 99.20%.

[0039] Example 2: Compound A 2 Preparation of (n=8)

[0040] Add 10.10 g of epipiprazole to 200 mL of tetrahydrofuran and add C 2 H 5 ONa 2.80g, react for 30min, add NaI 1.03g, measure 17.20g of methyl chloromethoxydecanoate, slowly add dropwise, react for 2h. Quench the reaction with ice water, extract with ethyl acetate 3 times, combine the upper solution, wash twice with saturated brine, remove water with anhydrous magnesium sulfate, rotary evaporate, weigh, mix (1.5 times), column chromatography, rotary evaporate the chromatographic solution, and obtain compound A 2 ,HPLC purity is 99.27%.

[0041] Example 3: Compound A 3 Preparation of (n=10)

[0042] Add 10.01 g of epiprazole to 200 mL of tetrahydrofuran and add CH 3 NaO 2.82g, react for 30min, add KI 1.01g, weigh 17.23g of methyl chloromethoxylaurate, slowly add dropwise, react for 2h. Quench the reaction with ice water, extract with ethyl acetate 3 times, combine the upper solution, wash twice with saturated brine, remove water with anhydrous magnesium sulfate, rotary evaporate, weigh, mix (1.5 times), column chromatography, rotary evaporate the chromatographic solution, and obtain compound A 3 ,HPLC purity is 99.38%.

[0043] 1H NMR (400MHz, CDCl3) δ7.62(d,J=9.5Hz,1H),7.56(d,J=8.0Hz,1H),7.49–7.38(m,1H),7.28(t,J=7. 8Hz,1H),6.99(s,1H),6.91(d,J=7.6Hz,1H),6.85(d,J=8.6Hz,1H),6.52(d,J=9.4Hz,1H),5.90(s,1 H),5.44(s,1H),4.12(t,J=6.0Hz,1H),3.25(s,1H),2.81(s,1H),2.65–2.58(m,1H),2.22(t,J=7.6H z,1H),1.98–1.87(m,1H),1.87–1.78(m,1H),1.57–1.48(m,1H),1.27(s,4H),0.90(t,J=6.6Hz,1H).

[0044] 13 C NMR(101MHz, CDCl3)δ172.68(s),162.58(s),161.06(s),147.79(s),140.68(s),140.29(s),139.90(s),133 .60(s),129.55(s),124.59(s),121.34(s),117.60(s),116.69(s),114.27(s),111.81(s),110.70(s),99.49 (s),86.50(s),70.41(s),67.66(s),57.64(s),52.96(s),51.34(s),33.73(s),31.47(s),29.26(s),29.15(t ,J=12.3Hz),29.01(s),28.90(s),28.80(s),28.62(s),26.71(s),24.11(s),22.70(s),22.25(s),13.70(s).

[0045] MS detection of compound A 3 The molecular ion peak is m / z 676.38.

[0046] Example 4: Compound A 3 Preparation of (n=10)

[0047] Add 10.02g of epiriprazole to 200mL of dioxane, heat in a 55℃ water bath and stir until completely dissolved, turn off the heating, wait until the temperature drops to 40℃, turn on the heating and stabilize the temperature at 40℃, add 1.01g of NaI as a catalyst, and then weigh C 4 H9 ONa was added in batches quickly, and a total of 2.83 g was added. The reaction lasted for 30 min. 17.20 g of methyl chloromethoxylaurate was measured and slowly added dropwise under nitrogen protection for 2 h. The reaction was quenched with ice water, extracted with ethyl acetate, and the upper layer solutions were combined and washed twice with saturated brine. The crude product was rotary evaporated to obtain a crude product. The crude product was pulped, recrystallized, and filtered to obtain a mother liquor. The mother liquor was subjected to column chromatography, and the chromatographic liquid was rotary evaporated to obtain compound A. 3 ,HPLC purity is 99.49%.

[0048] Example 5: Compound A 4 Preparation of (n=14)

[0049] Add 10.00 g of epipiprazole to 200 mL of tetrahydrofuran and add C 4 H 9 OK2.80g, react for 30min, add KI 1.02g, weigh 17.23g chloromethoxy palmitic acid methyl ester, slowly dropwise add, react for 2h. Quench the reaction with ice water, extract with ethyl acetate 3 times, combine the upper solution, wash twice with saturated brine, remove water with anhydrous magnesium sulfate, rotary evaporate, weigh, mix (1.5 times), column chromatography, rotary evaporate the chromatographic solution, and obtain compound A 4 ,HPLC purity is 99.32%.

[0050] Example 6: Compound A 5 Preparation of (n=16)

[0051] 10.01 g of epiriprazole was added to 200 mL of tetrahydrofuran, 2.83 g of NaH was added in batches, the reaction was continued for 30 min, 1.00 g of KI was added, 17.23 g of methyl chloromethoxy stearate was measured, and the mixture was slowly added dropwise for 2 h. The reaction was quenched with ice water, extracted with ethyl acetate for 3 times, the upper layer solutions were combined and washed twice with saturated brine, and dehydrated with anhydrous magnesium sulfate, and then rotary evaporated, weighed, mixed (1.5 times), column chromatographed, and the chromatographic solution was rotary evaporated to obtain compound A. 5 ,HPLC purity is 99.41%.

[0052] Effect Example 1: Compound A in plasma 1 (n=4) Comparative study on metabolism of epriprazole laurate

[0053] This test example is compound A 1 , plasma incubation metabolism comparison test of ipiprazol laurate. The specific test steps are as follows:

[0054] (1) Preparation of plasma: Whole blood was collected from SD rats via the eye socket and placed in a vacuum blood collection tube containing sodium heparin. The blood was centrifuged (12000 rpm, 5 min) and the supernatant was taken as plasma.

[0055] (2) Preparation of blank plasma: 100 μL of plasma was placed in a centrifuge tube, 900 μL of methanol was added, vortexed for 3 min, centrifuged (12000 rpm, 5 min), and the supernatant was taken as blank plasma.

[0056] (3) Preparation of drug stock solution: Accurately weigh appropriate amounts of 16.05 mg of epiridol laurate (BPZL), compound A 1 14.93 mg was placed in a 10 mL volumetric flask, and an appropriate amount of methanol was added to dissolve by sonication. The volume was fixed to the mark with methanol and shaken to obtain the stock solution of each drug.

[0057] (4) Preparation of mixed control solution: Accurately pipette 100 μL of each drug stock solution into 500 μL of plasma, add 1 mL of methanol, vortex for 5 min, centrifuge (12000 rpm, 7 min), and take the supernatant to obtain the mixed control solution.

[0058] (5) Preparation of incubation solution: Take 1.5 mL of plasma, add 60 μL of each drug stock solution, vortex for 5 min, and incubate in a shaker (37° C., 100 rpm) to obtain the incubation solution.

[0059] (6) Preparation of detection solution: Take 100 μL of sample at 0 h, 0.5 h, 1 h, 2 h, 3 h, 5 h, 8 h, 12 h, 20 h, and 24 h and put it into a centrifuge tube. Add 900 μL of methanol, vortex for 3 min, centrifuge (12000 rpm, 5 min), take the supernatant, and inject it.

[0060] (7) The chromatographic conditions are as follows:

[0061] Chromatographic column: LP-C18 4.6*250mm 5μm

[0062] Mobile phase: (0.15% triethylamine pH 3.50) Phase A: (pure acetonitrile) Phase B = 1:9

[0063] Running time: 30 minutes

[0064] Injection volume: 10 μL

[0065] Absorption wavelength: 220nm

[0066] Flow rate: 1.5mL / min

[0067] Column temperature: 35°C.

[0068] (8) The results are shown in the following table:

[0069]

[0070] In the table, ND means not detected.

[0071] Effect Example 2: Compound A in plasma 2 (n=8) Metabolism comparison study with epiridol laurate

[0072] This test example is compound A 2 , plasma incubation metabolism comparison test of ipiprazol laurate. The specific test steps are as follows:

[0073] (1) Preparation of plasma: Whole blood was collected from SD rats via the eye socket and placed in a vacuum blood collection tube containing sodium heparin. The blood was centrifuged (12000 rpm, 5 min) and the supernatant was taken as plasma.

[0074] (2) Preparation of blank plasma: 100 μL of plasma was placed in a centrifuge tube, 900 μL of methanol was added, vortexed for 3 min, centrifuged (12000 rpm, 5 min), and the supernatant was taken as blank plasma.

[0075] (3) Preparation of drug stock solution: Accurately weigh appropriate amounts of BPZL 98.97 mg, compound A 2 99.74 mg was placed in a 10 mL volumetric flask, and an appropriate amount of methanol was added to dissolve by sonication. The volume was fixed to the mark with methanol and shaken to obtain the stock solution of each drug.

[0076] (4) Preparation of mixed control solution: Accurately pipette 100 μL of each drug stock solution into 500 μL of plasma, add 1 mL of methanol, vortex for 5 min, centrifuge (12000 rpm, 7 min), and take the supernatant to obtain the mixed control solution.

[0077] (5) Preparation of incubation solution: Take 1 mL of plasma, add 40 μL of each drug stock solution, vortex for 5 min, and incubate on a shaker (37° C., 100 rpm) to obtain the incubation solution.

[0078] (6) Preparation of detection solution: Take 50 μL of sample at 0 min, 10 min, 20 min, 30 min, 60 min, 2 h, 5 h, 8 h, 17 h, 20 h, and 25 h and put it into a centrifuge tube. Add 250 μL of methanol, vortex for 3 min, centrifuge (12000 rpm, 5 min), take the supernatant, and inject it.

[0079] (7) The chromatographic conditions are as follows:

[0080] Chromatographic column: LP-C18 4.6*250mm 5μm

[0081] Mobile phase: (0.15% triethylamine pH 3.50) Phase A: (pure acetonitrile) Phase B = 1:9

[0082] Running time: 30 minutes

[0083] Injection volume: 10 μL

[0084] Absorption wavelength: 220nm

[0085] Flow rate: 1.5mL / min

[0086] Column temperature: 35°C.

[0087] (8) The results are shown in the following table:

[0088]

[0089]

[0090] Effect Example 3. Compound A in plasma 3 (n=10) Comparative study on metabolism of epiridol laurate

[0091] This test example is compound A 3 , plasma incubation metabolism comparison test of ipiprazol laurate. The specific test steps are as follows:

[0092] (1) Preparation of plasma: Whole blood was collected from SD rats via the eye socket and placed in a vacuum blood collection tube containing sodium heparin. The blood was centrifuged (12000 rpm, 5 min) and the supernatant was taken as plasma.

[0093] (2) Preparation of blank plasma: 100 μL of plasma was placed in a centrifuge tube, 900 μL of methanol was added, vortexed for 3 min, centrifuged (12000 rpm, 5 min), and the supernatant was taken as blank plasma.

[0094] (3) Preparation of drug stock solution: Accurately weigh appropriate amounts of BPZL 16.89 mg and compound A 3 18.80 mg was placed in a 10 mL volumetric flask, and an appropriate amount of methanol was added to dissolve by sonication. The volume was fixed to the mark with methanol and shaken to obtain the stock solution of each drug.

[0095] (4) Preparation of mixed control solution: Accurately pipette 100 μL of each drug stock solution into 500 μL of plasma, add 1 mL of methanol, vortex for 5 min, centrifuge (12000 rpm, 7 min), and take the supernatant to obtain the mixed control solution.

[0096] (5) Preparation of incubation solution: Take 1.5 mL of plasma, add 60 μL of each drug stock solution, vortex for 5 min, and incubate in a shaker (37° C., 100 rpm) to obtain the incubation solution.

[0097] (6) Preparation of detection solution: Take 100 μL of sample at 0 h, 0.5 h, 1 h, 2 h, 3 h, 5 h, 8 h, 12 h, 20 h, and 24 h and put it into a centrifuge tube. Add 900 μL of methanol, vortex for 3 min, centrifuge (12000 rpm, 5 min), take the supernatant, and inject it.

[0098] (7) The chromatographic conditions are as follows:

[0099] Chromatographic column: LP-C18 4.6*250mm 5μm

[0100] Mobile phase: (0.15% triethylamine pH 3.50) Phase A: (pure acetonitrile) Phase B = 1:9

[0101] Running time: 30 minutes

[0102] Injection volume: 10 μL

[0103] Absorption wavelength: 220nm

[0104] Flow rate: 1.5mL / min

[0105] Column temperature: 35°C.

[0106] (8) The results are shown in the following table and Figure 2 As shown:

[0107]

[0108] Effect Example 4: Compound A in whole blood 3 (n=10) Comparative study on metabolism of epiridol laurate

[0109] This test example is compound A 3 , whole blood incubation metabolism comparison test of ipriprazole laurate. The specific test steps are as follows:

[0110] (1) Preparation of whole blood: Whole blood of SD rats was collected from the eye socket and placed in a vacuum blood collection tube.

[0111] (2) Preparation of drug stock solution: Accurately weigh appropriate amounts of BPZL 99.23 mg and compound A 3 104.52 mg was placed in a 10 mL volumetric flask, and an appropriate amount of methanol was added to dissolve by sonication. The volume was fixed to the mark with methanol and shaken to obtain the stock solution of each drug.

[0112] (3) Preparation of mixed control solution: Accurately pipette 100 μL of each drug stock solution into 500 μL of plasma, add 1 mL of methanol, vortex for 5 min, centrifuge (12000 rpm, 7 min), and take the supernatant to obtain the mixed control solution.

[0113] (4) Preparation of incubation solution: Take 1.0 mL of whole blood, add 40 μL of each drug stock solution, vortex for 5 min, and incubate in a shaker (37° C., 100 rpm) to obtain the incubation solution.

[0114] (5) Preparation of detection solution: Take 50 μL of sample at 0 min, 10 min, 20 min, 30 min, 1 h, 2 h, 5 h, 8 h, and 17 h and put it into a centrifuge tube. Add 250 μL of methanol, vortex for 3 min, centrifuge (12000 rpm, 5 min), take the supernatant, and inject it.

[0115] (6) The chromatographic conditions are as follows:

[0116] Chromatographic column: C18 4.6*150mm 5μm

[0117] Mobile phase: (0.15% triethylamine pH 3.50) Phase A: (pure acetonitrile) Phase B = 1:9

[0118] Run time: 15 minutes

[0119] Injection volume: 10 μL

[0120] Absorption wavelength: 220nm

[0121] Flow rate: 1.5mL / min

[0122] Column temperature: 35°C.

[0123] (7) The results are shown in the following table and Figure 1 As shown:

[0124]

[0125]

[0126] Effect Example 5: Compound A in plasma 4 (n=14) Comparative study on metabolism of epriprazole laurate

[0127] This test example is compound A 4 , plasma incubation metabolism comparison test of ipiprazol laurate. The specific test steps are as follows:

[0128] (1) Preparation of plasma: Whole blood was collected from SD rats via the eye socket and placed in a vacuum blood collection tube containing sodium heparin. The blood was centrifuged (12000 rpm, 5 min) and the supernatant was taken as plasma.

[0129] (2) Preparation of blank plasma: 100 μL of plasma was placed in a centrifuge tube, 900 μL of methanol was added, vortexed for 3 min, centrifuged (12000 rpm, 5 min), and the supernatant was taken as blank plasma.

[0130] (3) Preparation of drug stock solution: Accurately weigh appropriate amounts of BPZL120.01 mg and compound A 4 137.02 mg was placed in a 10 mL volumetric flask, and an appropriate amount of methanol was added to dissolve by sonication. The volume was fixed to the mark with methanol and shaken to obtain the stock solution of each drug.

[0131] (4) Preparation of mixed control solution: Accurately pipette 10 μL of BPZL stock solution and compound A 4 15 μL was added to 500 μL plasma, 1 mL of methanol was added, vortexed for 5 min, centrifuged (12000 rpm, 7 min), and the supernatant was taken to obtain a mixed control solution.

[0132] (5) Preparation of incubation solution: Take 1.0 mL of plasma, add 40 μL of each drug stock solution, vortex for 5 min, and incubate in a shaker (37° C., 100 rpm) to obtain the incubation solution.

[0133] (6) Preparation of detection solution: 40 μL of sample was taken at 0 min, 10 min, 20 min, 30 min, and 60 min respectively and placed in a centrifuge tube. 240 μL of acetonitrile was added. The mixture was vortexed for 3 min and centrifuged (12000 rpm, 5 min). The supernatant was collected and injected.

[0134] (7) The chromatographic conditions are as follows:

[0135] Chromatographic column: LP-C18 4.6*250mm 5μm

[0136] Mobile phase: (0.15% triethylamine pH 3.50) Phase A: (pure acetonitrile) Phase B = 1:9

[0137] Running time: 30 minutes

[0138] Injection volume: 10 μL

[0139] Absorption wavelength: 220nm

[0140] Flow rate: 1.5mL / min

[0141] Column temperature: 35°C.

[0142] (8) The results are shown in the following table:

[0143]

[0144] Effect Example 6: Compound A in plasma 5 (n=16) Comparative study on metabolism of epiridol laurate

[0145] This test example is compound A5 , plasma incubation metabolism comparison test of ipiprazol laurate. The specific test steps are as follows:

[0146] (1) Preparation of plasma: Whole blood was collected from SD rats via the eye socket and placed in a vacuum blood collection tube containing sodium heparin. The blood was centrifuged (12000 rpm, 5 min) and the supernatant was taken as plasma.

[0147] (2) Preparation of blank plasma: 100 μL of plasma was placed in a centrifuge tube, 900 μL of methanol was added, vortexed for 3 min, centrifuged (12000 rpm, 5 min), and the supernatant was taken as blank plasma.

[0148] (3) Preparation of drug stock solution: Accurately weigh appropriate amounts of BPZL 125.85 mg and compound A 5 148.47 mg was placed in a 10 mL volumetric flask, and an appropriate amount of methanol was added to dissolve by sonication. The volume was fixed to the mark with methanol and shaken to obtain the stock solution of each drug.

[0149] (4) Preparation of mixed control solution: Accurately pipette 15 μL of each drug stock solution into 500 μL of plasma, add 1 mL of methanol, vortex for 5 min, centrifuge (12000 rpm, 7 min), and take the supernatant to obtain the mixed control solution.

[0150] (5) Preparation of incubation solution: Take 1.0 mL of plasma, add 40 μL of each drug stock solution, vortex for 5 min, and incubate in a shaker (37° C., 100 rpm) to obtain the incubation solution.

[0151] (6) Preparation of detection solution: 40 μL of sample was taken at 0 min, 10 min, 20 min, 30 min, 60 min, and 120 min respectively and placed in a centrifuge tube. 260 μL of acetonitrile was added. The mixture was vortexed for 3 min and centrifuged (12000 rpm, 5 min). The supernatant was collected and injected.

[0152] (7) The chromatographic conditions are as follows:

[0153] Chromatographic column: LP-C18 4.6*250mm 5μm

[0154] Mobile phase: (0.15% triethylamine pH 3.50) Phase A: (pure acetonitrile) Phase B = 1:9

[0155] Running time: 30 minutes

[0156] Injection volume: 10 μL

[0157] Absorption wavelength: 220nm

[0158] Flow rate: 1.5mL / min

[0159] Column temperature: 35°C.

[0160] (8) The results are shown in the following table:

[0161]

[0162]

[0163] The above in vitro metabolism experiments show that the final metabolite of the compound of the present invention in plasma or whole blood is epiriprazole, and the metabolic rate is faster than epiriprazole laurate.

Claims

1. A pharmaceutical composition comprising: (1) an epipiprazole methyl fatty acid ester and a pharmaceutically acceptable salt thereof as shown in formula I, Wherein, n is an integer from 4 to 16; (2) Pharmaceutically acceptable excipients.

2. The pharmaceutical composition according to claim 1, characterized in that n is 4, 8, 10, 14 or 16.

3. Use of the epiriprazole methyl fatty acid ester and its pharmaceutically acceptable salt as shown in formula I or the pharmaceutical composition as claimed in claim 1 or 2 in the preparation of a medicament for preventing and / or treating central nervous system diseases; in, n is an integer from 4 to 16.

4. The use according to claim 3, characterized in that n is 4, 8, 10, 14 or 16.

5. The use according to claim 3 or 4, characterized in that The central nervous system disease is selected from schizophrenia, major depressive disorder, attention deficit and agitation caused by Alzheimer's disease and post-traumatic stress disorder.

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