N-phenyl formate vothioxetine prodrug derivative as well as pharmaceutical composition and application of N-phenyl formate vothioxetine prodrug derivative

Abstract

The invention belongs to the technical field of medicines, and particularly relates to an N-phenyl formate vothioxetine prodrug derivative, a pharmaceutical composition thereof and application of the N-phenyl formate vothioxetine prodrug derivative in preparation of medicines for preventing or treating diseases related to 5-hydroxytryptamine receptors. The invention develops a new application of the compound with the structure as shown in the formula (I) as the prodrug of the votioxetine, the compound is injected in a composition form, and generates the votioxetine through enzyme metabolism in vivo, so that the blood concentration of the votioxetine can be maintained for a long time, the action time of the drug can be effectively prolonged to be more than 28 days, the fluctuation of the blood concentration is small, and the effect of the votioxetine is improved. The administration frequency can be reduced, and the compliance of a patient and the treatment effect on depression diseases are improved. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and specifically relates to N-phenylformate vortioxetine prodrug derivatives, pharmaceutical compositions thereof and use thereof in preparing drugs for preventing or treating diseases related to 5-hydroxytryptamine receptors. Background Art

[0002] Depression is a common persistent and serious mental illness in clinical practice. It is a disease caused by various reasons with low mood or mood and loss of interest as the core symptoms. It may be accompanied by slow thinking, sleep disorders, executive dysfunction and abnormal social function. In more serious cases, suicidal ideation may be seen. According to statistics from the World Health Organization (WHO), about 322 million people in the world are suffering from depression, and depression has inevitably become the largest single factor causing non-fatal health loss. In recent years, due to the expansion of the patient scale and people's attention to mental health, the government has successively promulgated policies to invest more resources in mental health, which has effectively promoted the progress and development of the field of mental health, and also formed a market space with huge demand for antidepressants.

[0003] Vortioxetine is a new type of selective serotonin reuptake inhibitor and an antidepressant with multiple mechanisms. It not only acts on 5-HT transporters, but also binds to multiple 5-HT receptors. It is a 5-HT1A agonist, a 5-HT1B partial agonist, and an antagonist of 5-HT1D, 5-HT7 and 5-HT3. It exerts its pharmacological effects by binding to corresponding transporters and receptors. The marketed dosage form is tablets, which were jointly developed by Lundbeck Pharmaceuticals and Takeda Pharmaceuticals.

[0004] The Chinese invention patent with publication number CN109851573B discloses an amino acid amide compound of vortioxetine. This type of amidated modified compound is stable in gastric juice and intestinal juice, which can reduce the promoting effect of vortioxetine on gastrointestinal motility and thus reduce the incidence of adverse reactions such as nausea and vomiting. The PCT invention patent application with publication number WO2017162536A1 discloses a series of vortioxetine amide derivatives and alkyl carbonate derivatives, with the purpose of enhancing the lipid solubility of vortioxetine, improving the blood-brain barrier passage rate, and prolonging its metabolic time.

[0005] The treatment of depression usually requires a long-term process. As the only antidepressant drug that can significantly improve patients' cognitive function, if its long-acting drug can be developed, the dosing interval can be greatly extended, thereby improving the treatment effect of depression. Summary of the invention

[0006] In view of the deficiencies in the above-mentioned prior art, the present invention provides an N-phenylformate vortioxetine prodrug derivative, a pharmaceutical composition thereof and use thereof in the preparation of a drug for preventing or treating diseases related to serotonin receptors. By conducting a pharmacokinetic test on the derivative in rats, it is found that vortioxetine can be stably released for a long time. The derivative is developed as a long-acting prodrug of vortioxetine, which can significantly extend the dosing interval and improve the therapeutic effect of depression.

[0007] The specific technical solutions are as follows: The first object of the present invention is to provide a compound having a structure represented by formula (I) for use in the preparation of a drug for preventing or treating diseases related to 5-hydroxytryptamine receptors, wherein the structure of formula (I) is: .

[0008] Furthermore, the disease includes depression.

[0009] The second object of the present invention is to provide a method for preparing a compound, wherein the compound is a compound having a structure shown in formula (I) in the above-mentioned use, comprising the following steps: cooling triphosgene and dichloroethane in an ice-water bath, adding phenol, and then dripping triethylamine, continuing to stir in an ice-water bath after the dripping is completed, then heating and stirring overnight, adding vortioxetine, heating to react, adding water after the reaction is completed, separating the liquids, and purifying the organic phase by column chromatography to obtain a white solid, namely the compound.

[0010] Further, phenol was added at 0-5°C, and then triethylamine was slowly added dropwise. After the addition was completed, stirring was continued in an ice-water bath for 30 minutes, and then the temperature was raised to 50°C and stirred overnight. Vortioxetine was added, and the temperature was raised to 75-85°C for reaction for 8 hours. In the column chromatography operation, the elution ratio of the eluent was pure petroleum ether gradually transitioned to a volume ratio of petroleum ether to ethyl acetate of 90:10, that is, petroleum ether / ethyl acetate (90 / 10, V / V).

[0011] The present invention synthesizes a compound of formula (I), and performs pharmacokinetic screening on the compound in rats, and finds that the compound can maintain sustained release of vortioxetine for more than 28 days in vivo, and the fluctuation of vortioxetine drug concentration is small, which can significantly extend the administration interval of vortioxetine, improve patient compliance and the therapeutic effect on depression.

[0012] The third object of the present invention is to provide a N-phenylformate vortioxetine prodrug derivative, including the compound used in the above-mentioned purpose and a pharmaceutically acceptable salt of the compound.

[0013] Pharmaceutically acceptable salts refer to inorganic and organic acid salts that are suitable for contact with human and animal tissues within the scope of reasonable medical judgment and have no excessive toxicity, irritation, or allergic reaction. Inorganic acids that form salts with the amino group of the compound of formula (I) include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, perchloric acid, boric acid, nitric acid, and the like. Organic acids that form salts with the amino group of the compound of formula (I) include, but are not limited to, formic acid, acetic acid, butyric acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, lactic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphoric acid, camphorsulfonic acid, benzoic acid, fumaric acid, glycerophosphoric acid, gluconic acid, malic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, nicotinic acid, oxalic acid, oleic acid, palmitic acid, pamoic acid, and the like.

[0014] The fourth object of the present invention is to provide a pharmaceutical composition comprising the N-phenylformate vortioxetine prodrug derivative as described above.

[0015] Furthermore, the pharmaceutical composition is administered in a parenteral form, including an oil solution or a nanocrystalline form.

[0016] Furthermore, the pharmaceutical composition is administered by injection.

[0017] Furthermore, the pharmaceutical composition is administered in the form of intramuscular injection or subcutaneous injection.

[0018] The fifth object of the present invention is to provide a use of the N-phenylformate vortioxetine prodrug derivative as described above and the pharmaceutical composition as described above in the preparation of a drug for preventing or treating diseases related to 5-hydroxytryptamine receptors.

[0019] Furthermore, the present invention provides a use of the N-phenylformate vortioxetine prodrug derivative as described above in the preparation of a drug for preventing or treating depression-related diseases.

[0020] Compared with the prior art, the present invention has the following beneficial effects: The present invention develops a new use of a compound of formula (I) as a prodrug of vortioxetine. The compound is administered by injection in the form of a composition, and is metabolized by enzymes in the body to produce vortioxetine, so that the blood concentration of vortioxetine is maintained for a long time, and the drug action time can be effectively extended to more than 28 days. The blood concentration fluctuates little, and the number of administrations can be reduced, thereby improving patient compliance and the therapeutic effect on depression. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 The graph is a blood concentration-time curve of vortioxetine produced by the metabolism of compound (I) in vivo. DETAILED DESCRIPTION

[0022] The principles and features of the present invention are described below in conjunction with examples, which are only used to explain the present invention and are not intended to limit the scope of the present invention in any form. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art, and may be made including but not limited to changes and modifications related to the chemical structures, substituents, derivatives, formulations and / or methods of the present invention without departing from the spirit of the present invention and the scope of the appended claims.

[0023] Example 1: Preparation of compound (I)

[0024] 1.60g triphosgene, 40g dichloroethane, cool in an ice-water bath. At 0℃, add 1.58g phenol, and slowly drop 1.70g triethylamine. After the dropwise addition, continue stirring in an ice-water bath for 30 minutes, then heat to 50℃ and stir overnight.

[0025] 2.0 g of vortioxetine was added, and the temperature was raised to 75°C for reaction for 8 h. After the reaction, 60 g of water was added, and the mixture was separated and the organic phase was purified by column chromatography. The elution ratio of the eluent was gradually transitioned from pure petroleum ether to petroleum ether / ethyl acetate (90 / 10, V / V), and 0.98 g of a white solid was obtained, namely compound (I).

[0026] HPLC purity 95.79%. mp: 61.6-62.8℃. ESI-MS (m / z): 419.15 [M+H] + . 1 H NMR(400MHz, CDCl3) δ 7.40 – 7.35 (m, 3H), 7.23 – 7.20 (m, 1H), 7.20 – 7.13 (m,3H), 7.11 – 7.02 (m, 3H), 6.93 – 6.87 (m, 1H), 6.56 (dd, J = 7.9, 1.3 Hz,1H), 3.82 (s, 4H), 3.16 – 3.06 (m, 4H), 2.37 (s, 3H), 2.34 (s, 3H). Example 2: Preparation of Compound (I)

[0027] 1.60g triphosgene, 40g dichloroethane, cool in an ice-water bath. At 5°C, add 1.58g phenol, and slowly drop 1.70g triethylamine. After the dropwise addition, continue stirring in an ice-water bath for 30 minutes, then heat to 50°C and stir overnight.

[0028] 2.0 g of vortioxetine was added, and the temperature was raised to 85°C for reaction for 8 h. After the reaction, 60 g of water was added, and the mixture was separated. The organic phase was purified by column chromatography, and the elution ratio of the eluent was gradually transitioned from pure petroleum ether to petroleum ether / ethyl acetate (90 / 10, V / V), to obtain 0.90 g of white solid, i.e., compound (I). HPLC purity was 96.30%.

[0029] Example 3: Preparation of Compound (I) Oil Solution The compound (I) prepared in Example 1 was dissolved in soybean oil for injection to prepare an oil solution of 40 mg / mL (calculated as vortioxetine).

[0030] Example 4: Preparation of an aqueous suspension of compound (I) CMC-Na and Tween 20 were dissolved in ultrapure water to prepare an aqueous solution containing 1.5% CMC-Na and 0.4% Tween 20. After passing the compound (I) prepared in Example 2 through a 200-mesh sieve, an appropriate amount was added to the above aqueous solution to prepare a 40 mg / mL (based on vortioxetine) suspension.

[0031] Experiment: Pharmacokinetic behavior of compound (I) in rats Experimental animals: Male SD rats, purchased from Jinan Pengyue Experimental Animal Breeding Co., Ltd., weighing 180-220 g, 3 rats in each group.

[0032] Each group of rats was intramuscularly injected with compound (I) oil solution and compound (I) aqueous suspension at a dose of 20 mg / kg, and blood was collected from the eye socket before administration and 15 minutes, 1 hour, 6 hours, 1 day, 2 days, 3 days, 5 days, 7 days, 9 days, 11 days, 14 days, 21 days, 25 days, and 28 days after administration. 0.25 mL of blood was collected each time and placed in an EP tube pre-treated with heparin. The blood was centrifuged at 12000 rpm for 5 minutes, and the plasma was frozen at -80°C for detection.

[0033] Biological sample pretreatment: 50 μL of drug-containing plasma was added with 50 μL of internal standard (agomelatine, 2 ng / mL) and 150 μL of methanol, vortexed for 1 min, centrifuged at 12000 rpm for 5 min, and the supernatant was taken for sample analysis.

[0034] Testing instruments: Ultra-high performance liquid chromatography system: Ultimate3000 (Thermo Corporation, USA) Triple quadrupole tandem chromatograph: TSQ Quantiva (Thermo Corporation, USA) Data acquisition: Xcalibur (Thermo Fisher Scientific, USA) Mass spectrometry conditions: ion source: electrospray ionization source (ESI); ionization voltage: 5000 V; temperature: 500°C; sheath gas: 50 Arb; auxiliary gas: 50 Arb; positive ion mode detection, scan time: 200 ms.

[0035] The drug concentration-time curve of vortioxetine produced by the metabolism of compound (I) in vivo is shown in Table 1. Figure 1 .

[0036] Table 1 Data on the time-dependent changes in drug concentration of vortioxetine produced by the metabolism of compound (I) in vivo

[0037] Note: The drug concentration of each compound in the table is the average drug concentration in the blood of three rats.

[0038] From Table 1 and Figure 1 It can be seen that the maximum drug concentration of the oil solution of compound (I) is 83.2 ng / mL, which is higher than the maximum drug concentration of 61.8 ng / mL of the aqueous suspension of compound (I). Both can effectively maintain the sustained release of vortioxetine (>10 ng / mL) for >28 days, and the aqueous suspension of compound (I) releases the drug more smoothly than the oil solution of compound (I).

[0039] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. Use of a compound in the preparation of a drug for preventing or treating a disease related to 5-hydroxytryptamine receptors, characterized in that: The structural formula of the compound is shown in formula (I): 。 2. The use according to claim 1, characterized in that The diseases include depression.

3. A method for preparing a compound, characterized in that: The compound is a compound having a structure shown in formula (I) in the use described in claim 1 or 2, comprising the following steps: cooling triphosgene and dichloroethane in an ice-water bath, adding phenol, then dripping triethylamine, continuing to stir in an ice-water bath after the dripping is completed, then heating and stirring overnight, adding vortioxetine, heating to react, adding water after the reaction is completed, separating the liquids, and purifying the organic phase by column chromatography to obtain a white solid, namely the compound.

4. The method for preparing the compound according to claim 3, characterized in that: Phenol was added at 0-5°C, and then triethylamine was added dropwise. After the addition was completed, stirring was continued in an ice-water bath for 30 minutes, and then the temperature was raised to 50°C and stirred overnight. Vortioxetine was added, and the temperature was raised to 75-85°C for reaction for 8 hours. In the column chromatography operation, the elution ratio of the eluent was a transition from petroleum ether to a volume ratio of petroleum ether to ethyl acetate of 90:

10.

5. A N-phenylformate vortioxetine prodrug derivative, characterized in that: The invention comprises the compound for use as claimed in claim 1 or 2 and a pharmaceutically acceptable salt of the compound.

6. A pharmaceutical composition, characterized in that The invention comprises the N-phenylformate vortioxetine prodrug derivative as claimed in claim 5.

7. The pharmaceutical composition according to claim 6, characterized in that Administer in parenteral form.

8. Use of the N-phenylformate vortioxetine prodrug derivative as claimed in claim 5, and the pharmaceutical composition as claimed in claim 6 or 7 in the preparation of a medicament for preventing or treating diseases related to 5-hydroxytryptamine receptors.

9. The use according to claim 8, characterized in that The diseases include depression.

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