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CN116407539B - Use of epiprazole methyl fatty acid ester - Google Patents

Use of epiprazole methyl fatty acid ester Download PDF

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CN116407539B
CN116407539B CN202111653327.5A CN202111653327A CN116407539B CN 116407539 B CN116407539 B CN 116407539B CN 202111653327 A CN202111653327 A CN 202111653327A CN 116407539 B CN116407539 B CN 116407539B
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plasma
acid
fatty acid
acid ester
pharmaceutically acceptable
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CN116407539A (en
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何军
李钦
王哲烽
刘洁
杨亚妮
蔡鸿铭
王君吉
时云龙
骆佳玉
郭丰年
邓楚夏
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Shanghai Modern Pharmaceutical Engineering Research Center Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

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Abstract

本发明公开了一种依匹哌唑甲基脂肪酸酯的用途。具体公开了一种药物组合物，其包括：(1)如式I所示的依匹哌唑甲基脂肪酸酯及其药学上可接受的盐，和(2)药学上可接受的辅料。还公开了所述如式I所示的依匹哌唑甲基脂肪酸酯及其药学上可接受的盐或所述药物组合物在制备用于预防和/或治疗中枢神经系统疾病的药物中的用途。本发明依匹哌唑甲基脂肪酸酯可作为依匹哌唑的前药，在血浆或全血中代谢解为依匹哌唑，代谢速率较快，进而用于预防和/或治疗中枢神经系统疾病。

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

Use of epiprazole methyl fatty acid ester
Technical Field
The invention relates to application of an epipiprazole methyl fatty acid ester.
Background
Eppiprazole (BPZ) is chemically named 7- (4- (4- (benzo [ b ] benzothien-4-yl) piperazin-1-yl) butanol) quinolin-2 (1H) -one having the chemical formula shown below.
Eperizole was marketed in 2015 and can be used for the adjuvant treatment of schizophrenia and major depression.
(7- (4- (4- (Benzo [ b ] thiophen-4-yl) piperazine-1-yl) butoxy) -2-oxoquinolin-1 (2H) -yl) fatty acid methyl ester, common name: epinastine laurate, abbreviated BPZL, has a structural formula shown below:
The epipiprazole laurate is used as an epipiprazole prodrug and can be used for treating schizophrenia. This structure is disclosed by patent CN 103781783A and is promising for development of long-acting injection products, but the rate of metabolism of epipiprazole laurate to epipiprazole in plasma or whole blood is slow.
Disclosure of Invention
The invention aims to overcome the defect of slow metabolism rate of epipiprazole laurate in the prior art and provides an application of epipiprazole methyl fatty acid ester as an epipiprazole prodrug. The inventive epipiprazole methyl fatty acid ester can be used as epipiprazole prodrug, and can be metabolized into epipiprazole in blood plasma or whole blood, with high metabolism rate, thereby being used for preventing and/or treating central nervous system diseases.
The invention solves the technical problems by the following technical scheme:
the present invention provides a pharmaceutical composition comprising:
(1) An eppiprazole methyl fatty acid ester as shown in formula I and pharmaceutically acceptable salts thereof,
Wherein n is an integer of 4 to 16;
(2) Pharmaceutically acceptable auxiliary materials.
In one embodiment of the invention, n is 4, 8, 10, 14 or 16.
The invention also provides application of the epipiprazole methyl fatty acid ester shown in the formula I and pharmaceutically acceptable salts thereof or the pharmaceutical composition in preparing medicines for preventing and/or treating central nervous system diseases.
In such use, preferably, the central nervous system disorder is selected from the group consisting of schizophrenia, major depression, attention deficit and agitation caused by Alzheimer's disease, and post-traumatic stress disorder.
The term "pharmaceutically acceptable" refers to salts, solvents, excipients, and the like, which are generally non-toxic, safe, and suitable for patient use. The "patient" is preferably a mammal, more preferably a human.
The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention prepared with relatively non-toxic, pharmaceutically acceptable acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts may be obtained by contacting neutral forms of such compounds with a sufficient amount of a pharmaceutically acceptable base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, zinc, bismuth, ammonium, diethanolamine salts. When the compounds of the present invention contain relatively basic functional groups, the acid addition salts may be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in pure solution or in a suitable inert solvent. The pharmaceutically acceptable acids include inorganic acids including, but 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 acids include 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-type citric acid, oleic acid, tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, formic acid, ethanesulfonic acid, pamoic acid (i.e., 4' -methylene-bis (3-hydroxy-2-naphthoic acid)), amino acids (e.g., glutamic acid, arginine), and the like. 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. See, for example, 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).
The term "pharmaceutically acceptable excipients" refers to excipients and additives used in the manufacture of medicaments and formulation prescriptions, and are all substances contained in the pharmaceutical formulation except the active ingredient. See the pharmacopoeia of the people's republic of China (2020 Edition), or Handbook of Pharmaceutical Excipients (Raymond C Rowe,2009Sixth Edition).
The term "treatment" refers to therapeutic therapy. Treatment, where a particular disorder is involved, refers to (1) alleviation of a disease or one or more biological manifestations of a disorder, (2) interference with (a) one or more points in a biological cascade leading to or causing a disorder or (b) one or more biological manifestations of a disorder, (3) amelioration of one or more symptoms, effects or side effects associated with a disorder, or one or more symptoms, effects or side effects associated with a disorder or treatment thereof, or (4) alleviation of progression of a disorder or one or more biological manifestations of a disorder.
The term "preventing" refers to a reduced risk of acquiring or developing a disease or disorder.
The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that:
the inventive epipiprazole methyl fatty acid ester is used as a prodrug of epipiprazole, is metabolized into epipiprazole in blood plasma or whole blood, has high metabolism rate, and can be used for auxiliary treatment of various mental diseases such as attention deficit and agitation caused by schizophrenia, major depression and Alzheimer disease, and post-traumatic stress disorder.
Drawings
FIG. 1 is a graph showing changes in plasma levels of the metabolism of Compound A 3 and epipiprazole laurate in a whole blood metabolism experiment.
FIG. 2 is a graph showing the change in plasma metabolism of compound A 3 and the blood concentration of the metabolism of epinastine laurate.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention.
In the following examples, the purity of the product was determined by HPLC method under the following conditions:
chromatography column, silica gel is bonded by octadecylsilane.
The mobile phase is 0.15% triethylamine solution (PH 3.50) as mobile phase A, pure acetonitrile solution as mobile phase B, and the ratio of mobile phase A to mobile phase B is 1:9.
The flow rate of the mobile phase is 1.5ml/min;
column temperature 35 ℃;
Detection wavelength of 220nm
The sample injection amount is 10 mu L.
Example 1 preparation of Compound A 1 (n=4)
10.02G of epinastine is added into 200mL of dioxane, naH 2.78g is added in batches for reaction for 30min, KI 1.00g is added, 17.22g of chloromethoxy methyl caproate is measured, and the mixture is slowly added dropwise for reaction for 2h. The reaction was quenched with ice water, extracted 3 times with ethyl acetate, the upper solutions were combined, washed twice with saturated brine, dehydrated with anhydrous magnesium sulfate, rotary distilled, weighed, stirred (1.5 times), column chromatographed, and rotary distilled to give compound a 1 with HPLC purity 99.20%.
Example 2 preparation of Compound A 2 (n=8)
10.10G of epipiprazole was added into 200mL of tetrahydrofuran, C 2H5 ONa 2.80g was added in portions, the reaction was carried out for 30min, naI 1.03g was added, 17.20g of chloromethoxy decanoate was measured, and the reaction was carried out for 2h. The reaction was quenched with ice water, extracted 3 times with ethyl acetate, the upper solutions were combined, washed twice with saturated brine, dehydrated with anhydrous magnesium sulfate, rotary distilled, weighed, stirred (1.5 times), column chromatographed, and rotary distilled to give compound a 2 with an HPLC purity of 99.27%.
Example 3 preparation of Compound A 3 (n=10)
10.01G of epipiprazole is added into 200mL of tetrahydrofuran, CH 3 NaO 2.82g is added in batches for reaction for 30min, KI 1.01g is added, 17.23g of chloromethoxy laurate is measured, and the mixture is slowly added dropwise for reaction for 2h. The reaction was quenched with ice water, extracted 3 times with ethyl acetate, the upper solutions were combined, washed twice with saturated brine, dehydrated with anhydrous magnesium sulfate, rotary distilled, weighed, stirred (1.5 times), column chromatographed, and rotary distilled to give compound a 3 with an HPLC purity of 99.38%.
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,1H),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＝7.6Hz,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).
13C 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).
The molecular ion peak of MS detection compound A 3 is m/z 676.38.
Example 4 preparation of Compound A 3 (n=10)
10.02G of epipiprazole is added into 200mL of dioxane, the mixture is heated and stirred in a water bath at 55 ℃ until the epipiprazole is completely dissolved, the heating is turned off, when the temperature is reduced to 40 ℃, the heating is turned on, the temperature is stabilized at 40 ℃, 1.01gNaI is added for catalysis, then C 4H9 ONa is weighed, added in portions rapidly, 2.83g is added totally, the reaction is carried out for 30min, 17.20g of chloromethoxy laurate is measured, and the mixture is slowly added dropwise and is protected by nitrogen for 2h. Quenching the reaction with ice water, extracting with ethyl acetate, mixing the upper solutions, washing with saturated saline water twice, rotary evaporating to obtain crude product, pulping, recrystallizing, filtering to obtain mother liquor, subjecting the mother liquor to column chromatography, rotary evaporating the chromatographic solution to obtain compound A 3 with HPLC purity of 99.49%.
Example 5 preparation of Compound A 4 (n=14)
10.00G of epipiprazole was added to 200mL of tetrahydrofuran, C 4H9 OK2.80g was added in portions, the reaction was carried out for 30min, KI 1.02g was added, 17.23g of chloromethoxy methyl palmitate was measured, and the reaction was carried out for 2h. The reaction was quenched with ice water, extracted 3 times with ethyl acetate, the upper solutions were combined, washed twice with saturated brine, dehydrated with anhydrous magnesium sulfate, rotary distilled, weighed, stirred (1.5 times), column chromatographed, and rotary distilled to give compound a 4 with an HPLC purity of 99.32%.
Example 6 preparation of Compound A 5 (n=16)
10.01G of epipiprazole is added into 200mL of tetrahydrofuran, naH2.83g is added in portions for reaction for 30min, KI 1.00g is added, 17.23g of chloromethoxy methyl stearate is measured, and the mixture is slowly added dropwise for reaction for 2h. The reaction was quenched with ice water, extracted 3 times with ethyl acetate, the upper solutions were combined, washed twice with saturated brine, dehydrated with anhydrous magnesium sulfate, rotary distilled, weighed, stirred (1.5 times), column chromatographed, and rotary distilled to give compound a 5 with HPLC purity of 99.41%.
Effect example 1 comparative test of metabolism of Compound A 1 (n=4) and epipiprazole laurate in plasma
The test example is a comparative test of plasma incubation metabolism of compound a 1, epinastine laurate. The specific test steps are as follows:
(1) Preparation of plasma SD rat whole blood was collected from the orbit in a vacuum blood collection tube containing heparin sodium, centrifuged (12000 rpm,5 min) and the supernatant was collected as plasma.
(2) Blank plasma preparation, namely, taking 100 mu L of plasma in a centrifuge tube, adding 900 mu L of methanol, swirling for 3min, centrifuging (12000 rpm,5 min), and taking supernatant as blank plasma.
(3) The preparation of the medicine stock solution comprises respectively precisely weighing 16.05mg of epinastine laurate (BPZL) and 1 14.93.93 mg of compound A in a 10mL volumetric flask, adding appropriate amount of methanol, performing ultrasonic treatment to dissolve, adding methanol to volume to scale, and shaking to obtain the medicine stock solution.
(4) The preparation of the mixed control solution comprises precisely transferring 100 μl of each drug stock solution into 500 μl of blood plasma, adding 1mL of methanol, swirling for 5min, centrifuging (12000 rpm,7 min), and collecting supernatant to obtain the mixed control solution.
(5) And (3) preparing incubation solutions, namely taking 1.5mL of each plasma, adding 60 mu L of each drug stock solution respectively, and swirling for 5min, and incubating in a shaking table (37 ℃ and 100 rpm) to obtain the incubation solutions.
(6) The detection solution is prepared by sampling 100 μl of the detection solution in a centrifuge tube at 0h, 0.5h, 1h, 2h, 3h, 5h, 8h, 12h, 20h, and 24h, adding 900 μl of methanol, swirling for 3min, centrifuging (12000 rpm,5 min), collecting supernatant, and sampling.
(7) The chromatographic conditions were as follows:
Chromatographic column: LP-C18 4.6*250mm 5μm
Mobile phase (0.15% triethylamine PH 3.50) phase a (neat acetonitrile) phase B = 1:9
Run time of 30min
Sample injection amount 10. Mu.L
Absorption wavelength of 220nm
Flow rate 1.5mL/min
Column temperature 35 ℃.
(8) The results are shown in the following table:
In the table, ND indicates no detection.
Effect example 2 comparative test of metabolism of Compound A 2 (n=8) and epipiprazole laurate in plasma
The test example is a comparative test of plasma incubation metabolism of compound a 2, epinastine laurate. The specific test steps are as follows:
(1) Preparation of plasma SD rat whole blood was collected from the orbit in a vacuum blood collection tube containing heparin sodium, centrifuged (12000 rpm,5 min) and the supernatant was collected as plasma.
(2) Blank plasma preparation, namely, taking 100 mu L of plasma in a centrifuge tube, adding 900 mu L of methanol, swirling for 3min, centrifuging (12000 rpm,5 min), and taking supernatant as blank plasma.
(3) The preparation of the medicine stock solution comprises respectively precisely weighing a proper amount of BPZL 98.97.97 mg and a proper amount of compound A 2 99.74.74 mg in a 10mL volumetric flask, adding a proper amount of methanol, performing ultrasonic treatment to dissolve, adding methanol to a certain volume to scale, and shaking to obtain the medicine stock solution.
(4) The preparation of the mixed control solution comprises precisely transferring 100 μl of each drug stock solution into 500 μl of blood plasma, adding 1mL of methanol, swirling for 5min, centrifuging (12000 rpm,7 min), and collecting supernatant to obtain the mixed control solution.
(5) And (3) preparing incubation solutions, namely taking 1mL of each plasma, adding 40 mu L of each drug stock solution, and swirling for 5min, and incubating in a shaking table (37 ℃ and 100 rpm) to obtain the incubation solution.
(6) The detection solution is prepared by sampling 50 μl of the detection solution into a centrifuge tube at 0min, 10min, 20min, 30min, 60min, 2h, 5h, 8h, 17h, 20h, 25h, adding 250 μl of methanol, swirling for 3min, centrifuging (12000 rpm,5 min), collecting supernatant, and sampling.
(7) The chromatographic conditions were as follows:
Chromatographic column: LP-C18 4.6*250mm 5μm
Mobile phase (0.15% triethylamine PH 3.50) phase a (neat acetonitrile) phase B = 1:9
Run time of 30min
Sample injection amount 10. Mu.L
Absorption wavelength of 220nm
Flow rate 1.5mL/min
Column temperature 35 ℃.
(8) The results are shown in the following table:
Effect example 3 comparative test of Compound A 3 (n=10) and Epiprazole laurate metabolism in plasma
The test example is a comparative test of plasma incubation metabolism of compound a 3, epinastine laurate. The specific test steps are as follows:
(1) Preparation of plasma SD rat whole blood was collected from the orbit in a vacuum blood collection tube containing heparin sodium, centrifuged (12000 rpm,5 min) and the supernatant was collected as plasma.
(2) Blank plasma preparation, namely, taking 100 mu L of plasma in a centrifuge tube, adding 900 mu L of methanol, swirling for 3min, centrifuging (12000 rpm,5 min), and taking supernatant as blank plasma.
(3) The preparation of the medicine stock solution comprises respectively precisely weighing appropriate amount of BPZL16.89mg and compound A 3 18.80.80 mg in a10 mL volumetric flask, adding appropriate amount of methanol, performing ultrasonic treatment to dissolve, adding methanol to volume to scale, and shaking to obtain the medicine stock solution.
(4) The preparation of the mixed control solution comprises precisely transferring 100 μl of each drug stock solution into 500 μl of blood plasma, adding 1mL of methanol, swirling for 5min, centrifuging (12000 rpm,7 min), and collecting supernatant to obtain the mixed control solution.
(5) And (3) preparing incubation solutions, namely taking 1.5mL of each plasma, adding 60 mu L of each drug stock solution respectively, and swirling for 5min, and incubating in a shaking table (37 ℃ and 100 rpm) to obtain the incubation solutions.
(6) The detection solution is prepared by sampling 100 μl of the detection solution in a centrifuge tube at 0h, 0.5h, 1h, 2h, 3h, 5h, 8h, 12h, 20h, and 24h, adding 900 μl of methanol, swirling for 3min, centrifuging (12000 rpm,5 min), collecting supernatant, and sampling.
(7) The chromatographic conditions were as follows:
Chromatographic column: LP-C18 4.6*250mm 5μm
Mobile phase (0.15% triethylamine PH 3.50) phase a (neat acetonitrile) phase B = 1:9
Run time of 30min
Sample injection amount 10. Mu.L
Absorption wavelength of 220nm
Flow rate 1.5mL/min
Column temperature 35 ℃.
(8) The results are shown in the following table and in fig. 2:
effect example 4 comparative test of metabolism of Compound A 3 (n=10) and epipiprazole laurate in Whole blood
The test example is a compound A 3, an epipiprazole laurate whole blood incubation metabolism comparison test. The specific test steps are as follows:
(1) Whole blood preparation, namely, taking SD rat whole blood from the orbit and putting the SD rat whole blood into a vacuum blood collection tube.
(2) The preparation of the medicine stock solution comprises respectively precisely weighing appropriate amount of BPZL99.23mg and compound A 3 104.52mg in a 10mL volumetric flask, adding appropriate amount of methanol, performing ultrasonic treatment to dissolve, adding methanol to volume to scale, and shaking to obtain the medicine stock solution.
(3) The preparation of the mixed control solution comprises precisely transferring 100 μl of each drug stock solution into 500 μl of blood plasma, adding 1mL of methanol, swirling for 5min, centrifuging (12000 rpm,7 min), and collecting supernatant to obtain the mixed control solution.
(4) And (3) preparing an incubation solution, namely taking 1.0mL of whole blood, respectively adding 40 mu L of each drug stock solution, and swirling for 5min, and incubating in a shaking table (37 ℃ and 100 rpm) to obtain the incubation solution.
(5) The detection solution is prepared by sampling 50 μl of the detection solution in a centrifuge tube at 0min, 10min, 20min, 30min, 1h, 2h, 5h, 8h, and 17h, adding 250 μl of methanol, swirling for 3min, centrifuging (12000 rpm,5 min), collecting supernatant, and sampling.
(6) The chromatographic conditions were as follows:
Chromatographic column: C18 4.6*150mm 5μm
Mobile phase (0.15% triethylamine PH 3.50) phase a (neat acetonitrile) phase B = 1:9
Run time of 15min
Sample injection amount 10. Mu.L
Absorption wavelength of 220nm
Flow rate 1.5mL/min
Column temperature 35 ℃.
(7) The results are shown in the following table and in fig. 1:
Effect example 5 comparative test of metabolism of Compound A 4 (n=14) and epipiprazole laurate in plasma
The test example is a comparative test of plasma incubation metabolism of compound a 4, epinastine laurate. The specific test steps are as follows:
(1) Preparation of plasma SD rat whole blood was collected from the orbit in a vacuum blood collection tube containing heparin sodium, centrifuged (12000 rpm,5 min) and the supernatant was collected as plasma.
(2) Blank plasma preparation, namely, taking 100 mu L of plasma in a centrifuge tube, adding 900 mu L of methanol, swirling for 3min, centrifuging (12000 rpm,5 min), and taking supernatant as blank plasma.
(3) The preparation of the medicine stock solution comprises respectively precisely weighing appropriate amount of BPZL120.01mg and compound A 4 137.02mg in a 10mL volumetric flask, adding appropriate amount of methanol, performing ultrasonic treatment to dissolve, adding methanol to volume to scale, and shaking to obtain the medicine stock solution.
(4) The preparation of the mixed control solution comprises precisely removing BPZL. Mu.L of stock solution and 10. Mu.L of compound A 4 in 500. Mu.L of plasma, adding 1mL of methanol, swirling for 5min, centrifuging (12000 rpm,7 min), and collecting supernatant to obtain the mixed control solution.
(5) And (3) preparing incubation solutions, namely taking 1.0mL of each plasma, adding 40 mu L of each drug stock solution, and swirling for 5min, and incubating in a shaking table (37 ℃ and 100 rpm) to obtain the incubation solution.
(6) The detection solution is prepared by sampling 40 μl of the detection solution in centrifuge tubes at 0min, 10min, 20min, 30min, and 60min, adding 240 μl of acetonitrile, swirling for 3min, centrifuging (12000 rpm,5 min), collecting supernatant, and sampling.
(7) The chromatographic conditions were as follows:
Chromatographic column: LP-C18 4.6*250mm 5μm
Mobile phase (0.15% triethylamine PH 3.50) phase a (neat acetonitrile) phase B = 1:9
Run time of 30min
Sample injection amount 10. Mu.L
Absorption wavelength of 220nm
Flow rate 1.5mL/min
Column temperature 35 ℃.
(8) The results are shown in the following table:
Effect example 6 comparative test of metabolism of Compound A 5 (n=16) and epipiprazole laurate in plasma
The test example is a comparative test of plasma incubation metabolism of compound a 5, epinastine laurate. The specific test steps are as follows:
(1) Preparation of plasma SD rat whole blood was collected from the orbit in a vacuum blood collection tube containing heparin sodium, centrifuged (12000 rpm,5 min) and the supernatant was collected as plasma.
(2) Blank plasma preparation, namely, taking 100 mu L of plasma in a centrifuge tube, adding 900 mu L of methanol, swirling for 3min, centrifuging (12000 rpm,5 min), and taking supernatant as blank plasma.
(3) The preparation of the medicine stock solution comprises respectively precisely weighing appropriate amount of BPZL125.85mg and compound A 5 148.47mg in a 10mL volumetric flask, adding appropriate amount of methanol, performing ultrasonic treatment to dissolve, adding methanol to volume to scale, and shaking to obtain the medicine stock solution.
(4) The preparation of the mixed control solution comprises precisely transferring 15 μl of each drug stock solution into 500 μl of blood plasma, adding 1mL of methanol, swirling for 5min, centrifuging (12000 rpm,7 min), and collecting supernatant to obtain the mixed control solution.
(5) And (3) preparing incubation solutions, namely taking 1.0mL of each plasma, adding 40 mu L of each drug stock solution, and swirling for 5min, and incubating in a shaking table (37 ℃ and 100 rpm) to obtain the incubation solution.
(6) The detection solution is prepared by sampling 40 μl of the detection solution into a centrifuge tube at 0min, 10min, 20min, 30min, 60min, 120min, adding 260 μl of acetonitrile, swirling for 3min, centrifuging (12000 rpm,5 min), collecting supernatant, and sampling.
(7) The chromatographic conditions were as follows:
Chromatographic column: LP-C18 4.6*250mm 5μm
Mobile phase (0.15% triethylamine PH 3.50) phase a (neat acetonitrile) phase B = 1:9
Run time of 30min
Sample injection amount 10. Mu.L
Absorption wavelength of 220nm
Flow rate 1.5mL/min
Column temperature 35 ℃.
(8) The results are shown in the following table:
As shown by the in vitro metabolism experiment, the final metabolite of the compound can be the epipiprazole in plasma or whole blood, and the metabolism rate is faster than that of the epipiprazole laurate.

Claims (5)

1.一种药物组合物，其包括：1. A pharmaceutical composition comprising: (1)如式I所示的依匹哌唑甲基脂肪酸酯及其药学上可接受的盐，(1) an epipiprazole methyl fatty acid ester and a pharmaceutically acceptable salt thereof as shown in formula I, 其中，n为4-16的整数；Wherein, n is an integer from 4 to 16; (2)药学上可接受的辅料。(2) Pharmaceutically acceptable excipients. 2.如权利要求1所述的药物组合物，其特征在于，n为4、8、10、14或16。2. The pharmaceutical composition of claim 1, wherein n is 4, 8, 10, 14 or 16. 3.如式I所示的依匹哌唑甲基脂肪酸酯及其药学上可接受的盐或如权利要求1或2所述药物组合物在制备用于预防和/或治疗中枢神经系统疾病的药物中的用途；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; 其中，n为4-16的整数。Here, n is an integer from 4 to 16. 4.如权利要求3所述的用途，其特征在于，n为4、8、10、14或16。4. The method according to claim 3, wherein n is 4, 8, 10, 14 or 16. 5.如权利要求3或4所述的用途，其特征在于，所述中枢神经系统疾病选自精神分裂症、重度抑郁症、阿尔茨海默病导致的注意缺陷和躁动和创伤后应激障碍。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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CN115768407A (en) * 2020-05-21 2023-03-07 江苏先声药业有限公司 Epipiprazole-containing pharmaceutical composition and preparation method thereof

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CN103781783A (en) * 2011-09-08 2014-05-07 大塚制药株式会社 Piperazine-substituted benzothiophene derivatives as antipsychotic agents
CN110218209A (en) * 2018-03-02 2019-09-10 上海现代药物制剂工程研究中心有限公司 It is a kind of according to crystal form A, preparation method and an application for piperazine azoles laurate

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