CN115260190A

CN115260190A - Prapidone prodrug, preparation method and application thereof

Info

Publication number: CN115260190A
Application number: CN202211046523.0A
Authority: CN
Inventors: 郭术涛; 徐遵凯; 姜瑶瑶; 陈志霞
Original assignee: Nankai University
Current assignee: Nankai University
Priority date: 2022-08-30
Filing date: 2022-08-30
Publication date: 2022-11-01

Abstract

The invention provides a paliperidone prodrug, a preparation method and application thereof, wherein the paliperidone prodrug is a compound shown as the following formula (I), a racemate, a stereoisomer, a tautomer or pharmaceutically acceptable salts thereof:

the acidic environment of the administration part triggers the hydrolysis of a ketal bond in the prodrug, so that the paliperidone prodrug can be released in vivo for a long time.

Description

Prapidone prodrug, preparation method and application thereof

Technical Field

The invention belongs to the field of prodrug compounds, and particularly relates to a paliperidone prodrug, a preparation method and application thereof.

Background

Schizophrenia and schizoaffective disorder are two chronic diseases with unknown etiology, and are clinically manifested as syndromes with different symptoms, which relate to various disorders such as sensory perception, thinking, emotion, behavior and the like and uncoordinated mental activities. The course of disease usually continues, with recurrent attacks, gradual exacerbations or exacerbations.

Patients with schizophrenia and schizoaffective disorder require long-term, uninterrupted drug therapy to inhibit disease progression. At present, oral medicines are mainly used for treating the diseases, and the oral medicines need to be taken regularly, so that the compliance of a patient is poor, and the fluctuation of blood concentration in a body is large. Paliperidone (Paliperidone), also known as 9-hydroxyrisperidone (9-hydroxy-risperidone), chemical name: 3- [2- [4- (6-fluoro-1,2-benzooxazol-3-yl) piperidin-1-yl]Ethyl radical]-9-hydroxy-2-methyl-6,7,8,9-tetrahydropyrido [1,2-a]Pyrimidin-4-one of formula C ₂₃ H ₂₇ FN ₄ O ₃ The chemical structural formula is shown as a molecular formula (1), is a second generation (atypical) antipsychotic and is clinically used for treating schizophrenia and schizoaffective disorder. Paliperidone exerts antipsychotic effects mainly by antagonizing 5-hydroxytryptamine 2 (5-HT 2A) receptors and dopamine 2 (D2) receptors, and exhibits higher receptor affinity and better therapeutic effect compared with other atypical antipsychotics.

Paliperidone palmitate is a prodrug molecule which couples paliperidone and palmitic acid through ester bonds, and after administration, the ester bonds in the prodrug can be decomposed by esterase in tissues in vivo to release paliperidone, so that the paliperidone palmitate plays a role in treating schizophrenia and schizoaffective disorder for a long time.

However, the paliperidone palmitate preparation has the following defects: (1) Paliperidone palmitate is formed by connecting paliperidone with palmitic acid through ester bonds, the ester bonds are degraded in vivo by esterase, the prodrug is decomposed into the palmitic acid and the paliperidone, and the esterase content in different patients is different, so that the activation rate of the prodrug is different, and the risk of failure of the activation of the prodrug exists; and (2) the imported drugs are expensive. Therefore, the development of a preparation with stable prodrug activation rate and low drug failure rate is a technical problem to be solved in the field.

Disclosure of Invention

In view of the above, the present invention provides a paliperidone prodrug, a preparation method thereof, and an application thereof, aiming at overcoming the defects in the prior art.

In order to achieve the purpose, the technical scheme of the invention is realized as follows:

in a first object of the present invention, provided are compounds represented by the following formula (I), racemates, stereoisomers, tautomers thereof or pharmaceutically acceptable salts thereof:

wherein R is selected from unsubstituted or optionally substituted by one, two or more R _a Substituted of the following groups: c _1-40 Alkyl radical, C _2-40 Alkenyl radical, C _2-40 Alkynyl, C _3-20 Cycloalkyl, C _3-20 Cycloalkyloxy, 3-20 membered heterocyclyl, 3-20 membered heterocyclyloxy, C _6-20 Aryl radical, C _6-20 Aryloxy, 5-20 membered heteroaryl, 5-20 membered heteroaryloxy.

Preferably, each R is _a Independently selected from C _1-40 Alkyl radical, C _2-40 Alkenyl radical, C _2-40 Alkynyl, C _3-20 Cycloalkyl radical, C _3-20 Cycloalkyloxy, 3-20 membered heterocyclyl, 3-20 membered heterocyclyloxy, C _6-20 Aryl radical, C _6-20 Aryloxy, 5-20 membered heteroaryl, 5-20 membered heteroaryloxy.

Preferably, R is selected from unsubstituted or optionally substituted by one, two or more R _a Substituted C _1-40 One of alkyl groups.

Preferably, R is selected from C _1-40 One of alkyl groups.

Preferably, R is selected from C _1-40 One of linear alkyl groups.

Preferably, R is C ₁₈ A linear alkyl group.

The second object of the present invention is to provide a process for the preparation of the above compound, which comprises reacting paliperidone with the compound of formula (II) to obtain the compound of formula (I):

wherein R is independently selected from any of the ranges described above.

Preferably, the preparation method comprises the following specific steps:

adding paliperidone, the compound shown in the formula (II) and a reaction solvent into a reaction vessel, adding an acid catalyst under the condition of air isolation, carrying out nucleophilic addition reaction on the paliperidone and the compound shown in the formula (II), and adding triethylamine to terminate the reaction after the reaction is completed, thereby obtaining the compound shown in the formula (I).

Preferably, the reaction solvent is any one of dichloromethane, tetrahydrofuran, and toluene.

Preferably, the acid catalyst is any one of 1,2-dichloroacetic acid, p-toluenesulfonic acid, pyridine p-toluenesulfonic acid.

Preferably, the triethylamine after termination reaction further comprises a purification step, wherein the purification step specifically comprises: after the reaction is finished, decompressing and concentrating to remove the solvent, purifying the product by silica gel column chromatography, wherein the developing agent of the silica gel column chromatography is petroleum ether and ethyl acetate; then concentrating and drying to obtain the compound shown in the formula (I).

The third object of the present invention is to provide a preparation containing the compound represented by the above formula (I), wherein the preparation is in the form of tablet, capsule, multilayer tablet, oral sustained release preparation, transdermal delivery system, suppository, micro-formulation, ampoule agent, solution, emulsion, dispersion, powder, nano-formulation, liposome preparation, drop, nasal spray, inhalation spray, aerosol, inhalation powder, micro-crystal preparation, transdermal delivery system or subcutaneous delivery preparation.

Preferably, the formulation is in the form of a microcrystalline formulation.

Preferably, the microcrystalline preparation is prepared by any one or any combination of a medium grinding method, an ultrasonic method, a high-pressure homogenization method, a laser ablation and fragmentation technology, a solvent-anti-solvent precipitation method, a supercritical fluid method, a solvent evaporation method and a spray drying method.

Preferably, the microcrystalline preparation is prepared by the following method:

1) Dissolving the compound shown in the formula (I) by using a good solvent, adding double distilled water into the solution, and volatilizing the solvent to obtain initial microcrystals;

2) Adding a surfactant into the initial microcrystals, and fully swirling to uniformly disperse the microcrystals;

3) Grinding the microcrystal by using a small ball or carrying out ultrasonic treatment on the microcrystal to obtain the microcrystal with the size of 0.1-20 mu m;

4) Adding a stabilizer, and freeze-drying;

5) And (4) re-suspending the freeze-dried powder by using double-distilled water to obtain the microcrystalline preparation.

Preferably, the good solvent is any one or more of C1-C5 lower alkyl alcohol, acetone and DMSO;

preferably, the double distilled water used in step 1) has a pH of between 8 and 9.

Preferably, the surfactant used in step 2) is one or more of polysorbate 20, polysorbate 80, alkyl glucoside, fatty glyceride, sorbitan fatty acid, poloxamer;

preferably, the pellet used in step 3) is one of zirconium pellet, alumina pellet, steel pellet and polytetrafluoroethylene pellet;

preferably, the stabilizer used in step 4) is one or more of methylcellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, polyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, alginate, chitosan, dextran, gelatin, polyoxyethylene ether, polyoxypropylene ether, citric acid monohydrate, sodium dihydrogen phosphate monohydrate, and sodium hydroxide.

The fourth object of the present invention is to provide the use of the compound or microcrystalline preparation represented by the formula (I) in the preparation of a medicament for treating or preventing a psychiatric disease, preferably schizophrenia or schizoaffective disorder.

Compared with the prior art, the invention has the following advantages:

1) The paliperidone acetonide prodrug disclosed by the invention is an acid-sensitive prodrug, and does not depend on the activation of enzymes in a body, after muscle administration, an immune reaction of the body can induce an administration part to form an acidic microenvironment, and the acidic microenvironment can continuously trigger the hydrolysis of a propiophenone bond in the paliperidone prodrug, so that the long-acting release of paliperidone is realized.

2) The acidic microenvironment is generated by the induction of normal immune response of the body, and the expression difference of different patients is small, so the acetonide bond coupled paliperidone prodrug microcrystal has higher medication success rate.

3) The preparation method of the paliperidone acetonide prodrug is mature and efficient, firstly, isopropenyl ether intermediates of different alcohols are constructed through modular reaction, and then the paliperidone prodrugs coupled with acetonide bonds can be obtained through reaction with paliperidone.

4) The paliperidone acetonide prodrug microcrystalline preparation disclosed by the invention is simple in preparation process, and the paliperidone acetonide prodrug molecule can be prepared into the microcrystalline preparation by common methods such as a solvent-antisolvent precipitation method and the like.

5) The hydrolysis product of the pro-drug of paliperidone coupled by the acetonide bond is paliperidone, a modification molecule and acetone, and the acetone naturally exists in vivo, so that the degradation product does not generate toxic or side effect on organisms.

Drawings

FIG. 1 shows the NMR spectrum of SKP (example 1);

FIG. 2 is a nuclear magnetic resonance carbon spectrum of SKP (example 1);

FIG. 3 is a high resolution mass spectrum of SKP (example 1);

FIG. 4 is an X-ray diffraction pattern of SKP (example 1);

FIG. 5 is a differential scan metric heatmap of SKP (example 1);

FIG. 6 is a thermogravimetric plot of SKP (example 1);

FIG. 7 is a graph of the rate of hydrolysis of SKP in pH 5.0 buffer versus time (example 1);

FIG. 8 is a graph of the hydrolysis rate of SKP in pH 5.0 buffer with the equation for the kinetics of hydrolysis of y = -0.0330x +4.6438 (R) ² = 0.9933) (example 1);

FIG. 9 is a graph of the rate of hydrolysis of SKP in pH 7.4 buffer versus time (example 1);

FIG. 10 is a graph of the hydrolysis rate of SKP in pH 7.4 buffer with the kinetic equation for hydrolysis of y = -0.0324x +4.5980 (R) ² = 0.9869) (example 1);

FIG. 11 is a polarization micrograph of initial SKP-MCs (example 2);

FIG. 12 is a scanning electron micrograph of SKP-MCs-6 (example 3);

FIG. 13 is a scanning electron micrograph of SKP-MCs-2 (example 4);

FIG. 14 is a scanning electron micrograph of SKP-MCs-1 (example 5);

FIG. 15 is a graph showing changes in Zeta potential of microcrystalline injection preparations of SKP-MCs-6, SKP-MCs-2 and SKP-MCs-1 (example 7);

FIG. 16 is a graph showing the investigation of drug leakage in vitro of the microcrystalline injection formulation of SKP-MCs-1 (example 7);

FIG. 17 is an X-ray diffraction pattern of a microcrystalline injection formulation of SKP-MCs-2 after intramuscular administration (example 7);

FIG. 18 is a graph of the drug concentration versus time of paliperidone in vivo after administration of SKP-MCs-6, SKP-MCs-2, SKP-MCs-1 and Invega Sustenna microcrystalline injection formulations (example 7) and (b) is a partial magnified view of (a) after 21 days. (ii) a

FIG. 19 is a graph of the drug concentration of the prodrug versus time in vivo following administration of SKP-MCs-6, SKP-MCs-2, SKP-MCs-1, and Invega Sustenna microcrystalline injectable formulations (example 7);

FIG. 20 shows the prodrug hydrolysis rates in blood after administration of SKP-MCs-6, SKP-MCs-2, SKP-MCs-1 and Invega Sustenna microcrystalline injectable formulations (example 7);

FIG. 21 is a graph showing the change in body weight of rats after administration of the microcrystalline injection preparations of SKP-MCs-6, SKP-MCs-2 and SKP-MCs-1 (example 7);

FIG. 22 is a graph showing the conventional evaluation of blood in rats on day 14 after administration of microcrystalline injection preparations of SKP-MCs-6, SKP-MCs-2 and SKP-MCs-1 (example 7);

FIG. 23 is a graph showing the routine evaluation of blood of rats on day 28 after administration of microcrystalline injection preparations of SKP-MCs-6, SKP-MCs-2 and SKP-MCs-1 (example 7);

FIG. 24 is a graph showing biochemical evaluation of blood of rats on day 14 after administration of microcrystalline injection preparations of SKP-MCs-6, SKP-MCs-2 and SKP-MCs-1 (example 7);

FIG. 25 is a graph showing the routine evaluation of blood of rats on day 28 after administration of microcrystalline injection preparations of SKP-MCs-6, SKP-MCs-2 and SKP-MCs-1 (example 7);

Detailed Description

Unless defined otherwise, technical terms used in the following examples have the same meanings as commonly understood by one of ordinary skill in the art to which the present invention belongs. The test reagents used in the following examples, unless otherwise specified, are all conventional biochemical reagents; the experimental methods are all conventional methods unless otherwise specified.

The invention will be described in detail with reference to the following examples.

Example 1

A method for preparing a stearyl alcohol modified paliperidone prodrug coupled via a ketal linkage, comprising the steps of:

1) Preparation of a compound of formula (2):

stearyl alcohol (37mmol, 10g), dimethoxypropene (624mmol, 60mL) and tetrahydrofuran (100 mL) were charged into a 500mL reaction flask, and after all the materials were dissolved, 2,6-dimethylpyridinium salt (1.85mmol, 0.516g) was added to p-toluenesulfonic acid, and the mixture was stirred at room temperature for 4 hours. After the reaction is completed, triethylamine (2 mL) is added into the system to terminate the reaction, the reaction is concentrated, and the molecular weight of 6.1g shown in the molecular formula (2) is obtained by silica gel column chromatography separation with petroleum ether/ethyl acetate as an eluent, and the yield is 53%.

2) Preparation of a Compound represented by the formula (3) (named SKP, the same applies below):

a100 mL reaction flask was charged with paliperidone (1.0 mmol, 0.43g), ultra-dry dichloromethane (20 mL), dichloroacetic acid (1.1mmol, 0.14g) under nitrogen, stirred at room temperature for 0.5h, then added with the molecule of formula (2) (6.0 mmol, 1.86g), and stirred at room temperature for 6h. After the reaction was completed, triethylamine (1 mL) was added to the reaction system to terminate the reaction, and the reaction was concentrated and separated by silica gel column chromatography using petroleum ether/ethyl acetate as an eluent to obtain 0.53g of SKP in a yield of 72%.

The SKP molecules are identified and characterized by adopting a nuclear magnetic resonance technology and a high-resolution mass spectrum, and the specific results are as follows:

¹ H NMR(400MHz,Chloroform-d)δ7.70(dd,J＝8.7,5.1Hz,1H),7.22(dd,J＝8.5,2.1Hz,1H),7.03(td,J＝8.9,2.2Hz,1H),4.76(t,J＝4.1Hz,1H),4.13–3.89(m,2H),3.49(ddd,J＝8.8,7.6,6.4Hz,1H),3.36(dt,J＝8.8,7.1Hz,1H),3.16(dt,J＝11.7,3.4Hz,2H),3.06(dt,J＝10.3,4.9Hz,1H),2.79–2.71(m,2H),2.38–2.21(m,5H),2.20–1.96(m,6H),1.85(tdd,J＝12.8,5.4,3.2Hz,2H),1.52(q,J＝6.3Hz,2H),1.40(d,J＝1.3Hz,6H),1.23(s,32H),0.85(t,J＝6.8Hz,3H).

¹³ C NMR(100MHz,Chloroform-d)δ164.03,163.89,162.91,162.43,161.23,158.65,155.88,122.83,122.72,120.74,117.41,117.40,112.50,112.26,101.80,97.64,97.37,67.49,61.95,56.69,53.51,40.63,34.76,32.03,30.67,30.06,29.81,29.77,29.48,26.91,26.34,26.08,24.07,22.80,21.45,17.67,14.24.

the hydrogen spectrum (FIG. 1) and the carbon spectrum (FIG. 2) show characteristic peaks of SKP at δ 1.4ppm (s, 6H) and δ 101.80ppm, respectively; mass Spectrometry (FIG. 3) shows C ₄₄ H ₆₉ FN ₄ O ₄ [M+H] ⁺ :737.5380,[M+2H] ⁺ :738.5396,[M+3H] ⁺ 739.5480, and the theoretical value [ M + H [ ]] ⁺ :737.5376，[M+2H] ⁺ ：738.5448；[M+2H] ⁺ :739.5521, which shows that the target product is obtained successfully.

SKP is characterized by X-ray diffraction, as shown in figure 4, the spectrum of the compound is obviously changed compared with the raw material spectrum, but still has an obvious characteristic diffraction peak, which indicates that SKP exists in the form of crystal drug.

SKP is characterized by adopting a synchronous thermal analyzer, and differential scanning calorimetry (figure 5) shows that the melting peak of a compound shown by SKP is 95 ℃; the thermogravimetric (fig. 6) shows the SKP decomposition temperature at 180 ℃.

Experimental example 1 acid-responsive hydrolysis test of SKP

Paliperidone stock (1 mM) and SKP stock (1 mM, containing 0.1% triethylamine) were prepared with methanol. The SKP stock solution was diluted with pH 5.0 (40% acetic acid/sodium acetate buffer (50mM, pH 3.7) and 60% acetonitrile (v/v)) buffer and 7.4 (40% phosphate buffer (50mM, pH 6.4) and 60% acetonitrile (v/v)) buffer solutions, respectively, to give a concentration of 50. Mu.M paliperidone after complete hydrolysis of the prodrug. The hydrolysis system was incubated on a shaker (37 ℃ C., 100 rpm). 200. Mu.L of a sample was taken at a predetermined time point, 200. Mu.L (60% phosphate buffer (200mM, pH 8.0) and 40% acetonitrile (v/v), pH 8.7) of a hydrolysis stop solution was added thereto, and the content of paliperidone was measured using high performance liquid chromatography after vortexing.

A chromatographic column: phenomenex, luna C8 column,5 μm, 150X 4.6mm; mobile phase: methanol/acetonitrile (1/1,v/v, containing 0.02% ammonia): ultrapure water (containing 0.02% ammonia); flow rate: 1.8mL/min; ultraviolet detection wavelength: 238nm; column temperature: at 30 ℃.

The hydrolysis rate calculation formula is as follows:

hydrolysis rate (%) = concentration of paliperidone in sample tube/concentration of paliperidone after complete acidolysis of paliperidone prodrug × 100%.

The hydrolysis rate-time curves of SKP at pH =5.0 and 7.4 are shown in fig. 7 and 9, and the hydrolysis kinetics at pH =5.0 and 7.4 are shown in fig. 8 and 10.

SKP hydrolysis showed quasi-first order kinetics with hydrolysis half-lives of 21.0min and 21.4h at pH 5.0 and 7.4, respectively. The above results show that the compound molecule is hydrolyzed at a faster rate under acidic conditions.

Example 2

The preparation of a microcrystalline formulation of a paliperidone prodrug was carried out as an example in example 1:

weighing 35mg of SKP prepared in example 1, dissolving in 3.5mL of ethanol (containing 0.1% of triethylamine), adding 3.5mL of double distilled water with pH of 8, placing in a refrigerator at 4 ℃ to slowly volatilize the ethanol to grow crystals, after 96h, completely volatilizing the ethanol, adding 350 μ L of Tween 20 (accounting for 20wt% of the weight of the SKP), transferring to a 10mL centrifuge tube, supplementing 5mL of the suspension with the double distilled water, and dispersing microcrystals by vortex.

The prepared microcrystals (named initial SKP-MCs) are identified and characterized by a polarization microscope, and as shown in FIG. 11, the prepared crystals are long and rod-shaped and uniform in size.

Example 3

To initial SKP-MCs 5g of zirconia pellets 0.4-0.5mm in diameter were added and vortexed at 3 steps for 1h using a vortexer (Vortex 2, IKA Inc., germany) to obtain crystallites of one size.

The prepared microcrystal (named as SKP-MCs-6) is identified and characterized by a scanning electron microscope, as shown in figure 12, the microcrystal has uniform size and is flat, the major diameter and the minor diameter of the microcrystal are measured by ImageJ software, and the length-width ratio is calculated, so that the result shows that the average major diameter of the microcrystal is 6.4 mu m, and the length-width ratio is 2.7.

Example 4

To initial SKP-MCs 5g of zirconia pellets of diameter 0.4-0.5mm were added and vortexed at 3 stops for 2h using a vortexer (Vortex 2, IKA Inc., germany) to obtain crystallites of another size.

The prepared microcrystals (named as SKP-MCs-2) are identified and characterized by a scanning electron microscope, as shown in FIG. 13, the major and minor diameters of the microcrystals are measured by ImageJ software, and the aspect ratio is calculated, and the result shows that the average major diameter of the microcrystals is 2.2 μm and the aspect ratio is 2.2.

Example 5

The initial SKP-MCs were sonicated at 30 ℃ at 37kHz and 100% power for 2h (Elmasonic P, elma, germany) to obtain crystallites of another size.

The prepared microcrystal (named as SKP-MCs-1) is identified and characterized by a scanning electron microscope, as shown in figure 14, the major axis and the minor axis of the microcrystal are measured by ImageJ software, and the length-width ratio is calculated, so that the result shows that the average major axis of the microcrystal is 1.3 mu m, and the length-width ratio is 1.9.

Example 6

Adding 5mL of mixed solution with pH 8 into SKP-MCs-6, SKP-MCs-2 and SKP-MCs-1, wherein the specific mixture ratio is as follows:

PEG 4000 (20 wt% of SKP), citric acid monohydrate (3.1 wt% of SKP), sodium dihydrogen phosphate monohydrate (2.9 wt% of SKP), and sodium hydroxide (2.9 wt% of SKP), mixing, and lyophilizing.

Example 7

Adding 1mL of double distilled water into certain mass of SKP-MCs-6, SKP-MCs-2 and SKP-MCs-1 freeze-dried powder (46.7 mg, the mass of paliperidone), and mixing to obtain microcrystalline injection.

Experimental example 2 dispersibility test of microcrystalline injection preparations of SKP-MCs-6, SKP-MCs-2 and SKP-MCs-1

Placing the prepared SKP-MCs-6, SKP-MCs-2 and SKP-MCs-1 microcrystalline injection preparations at room temperature, and measuring the Zeta potential of the injection preparations by using a dynamic light scattering instrument on the 0 th day, the 14 th day, the 30 th day and the 100 th day to evaluate the dispersibility of the microcrystalline preparations. As shown in FIG. 15, the Zeta potential of the three microcrystalline injection formulations was maintained between-17.1 mV and-25.4 mV without significant change during storage for 100 days, indicating that the three microcrystalline injection formulations could maintain good dispersibility during storage.

Experimental example 3 evaluation of drug leakage of microcrystalline injection preparation of SKP-MCs-1

The SKP-MCs-1 microcrystalline injection preparation is placed at room temperature for 100 days, and the content of free paliperidone in the injection preparation is analyzed by high performance liquid chromatography. As shown in fig. 16, no paliperidone was detected when the microcrystalline formulation was left at room temperature for 100 days, indicating that the microcrystalline injection formulation did not leak the drug from the crystallites under room temperature storage conditions.

Experimental example 4 melting Point test of SKP-MCs-2 microcrystal

Melting points of paliperidone, SKP and SKP-MCs-2 were measured by a melting point apparatus, as shown in Table 1, and their melting points were 159 ℃,101.5 ℃ and 103 ℃, respectively, which proves that the microcrystals had higher melting points and higher stability, and the microcrystals did not undergo crystal form changes during transportation and storage.

TABLE 1 melting points of paliperidone, SKP, and initial SKP-MCs

Experimental example 5 microcrystalline Crystal form test of microcrystalline injection preparation of SKP-MCs-2

The crystal form change of the SKP-MCs-2 microcrystal in the body is detected by X-ray diffraction, and as shown in figure 17, the samples are SKP-MCs-2 microcrystal freeze-dried powder, SKP-MCs-2 microcrystal freeze-dried powder coated on muscle tissue and SKP-MCs-2 microcrystal injection preparation after 7 days of intramuscular injection respectively. After the microcrystal is injected into the muscle for 7 days, the characteristic peak of the microcrystal can be detected, which shows that the microcrystal can well maintain the crystal form in vivo, and the long-acting release of the medicament is facilitated.

Experimental example 6 evaluation of pharmacokinetics of microcrystalline injection preparations of SKP-MCs-6, SKP-MCs-2 and SKP-MCs-1

Male Wistar rats (350. + -.30 g) were anesthetized with isoflurane and 150. Mu.L of SKP-MCs-6, SKP-MCs-2, SKP-MCs-1 microcrystalline injection formulations and commercial formulation Invega Sustenna were injected intramuscularly to the hindlimb biceps, respectively, at a dosage of 20mg of paliperidone per kg, and then blood plasma concentrations of paliperidone were determined by orbital bleeds at specific time points.

The plasma concentration change and pharmacokinetic parameters of paliperidone are shown in FIG. 18 and Table 2, and in 24h, 20.2, 8.4, 9.0 and 2.1ng/mL of paliperidone was detected by Invega Sustenna, SKP-MCs-1, SKP-MCs-2 and SKP-MCs-6, respectively, indicating that these formulations can rapidly release the drug after administration. Peak concentrations of paliperidone following administration for the Invega Sustenna, SKP-MCs-1, SKP-MCs-2, and SKP-MCs-6 groups (C) _max ) 92.8, 45.5, 45.8 and 40.4ng/mL, respectively. T of four groups _1/2 74.3, 176.2, 366.4 and 494.4h, respectively. The terminal half-life of the SKP-MCs group increases with increasing crystallite size. In addition, the Invega Sustenna group had a lower concentration of paliperidone than the SKP-MCs group at 28 days post-administration; paliperidone was not detected by the Invega Sustenna group after 43 days of dosing, while low concentrations of paliperidone were still detected by the SKP-MCs group. This indicates that the three microcrystals of SKP-MCs show a more gradual, longer-term drug release capacity compared to the commercial formulation Invega Sustenna.

TABLE 2 pharmacokinetic parameters of paliperidone following administration of Invega Sustenna, SKP-MCs-1, SKP-MCs-2 and SKP-MCs-6 microcrystalline formulations determined by non-compartmental analysis

Note t _1/2 Paliperidone terminal half-life; t is t _max Paliperidone concentration peak time; c _max Paliperidone peak concentration; AUC _last The area under the paliperidone concentration-time curve for the period of time from the start of the administration time to the last point; AUC _(0–∞) Total area under the drug concentration-time curve from the start of dosing time to the time when paliperidone is totally eliminated.

In addition, the prodrug concentrations for all four microcrystalline formulations were less than 2.3ng/mL, much lower than the paliperidone concentration (fig. 19), and the ratio of free paliperidone to total paliperidone was calculated to be higher than 0.86 at each time point (fig. 20), indicating that the prodrug was efficiently hydrolyzed in vivo.

Experimental example 7 changes in body weight of rats after administration of microcrystalline preparations of SKP-MCs-6, SKP-MCs-2 and SKP-MCs-1

Male Wistar rats (350 + -30 g) were anesthetized with isoflurane, and 150. Mu.L of SKP-MCs-6, SKP-MCs-2, and SKP-MCs-1 microcrystalline injection preparations were injected intramuscularly to the hind limb biceps according to the administration dose of 20mg of paliperidone per kg, respectively, and then the body weights of the rats were weighed at specific time points.

Body weight change as shown in figure 21, there was no significant change in body weight for the three different size microcrystalline formulation groups compared to the untreated group.

Experiment 8 conventional evaluation of blood after administration of SKP-MCs-6, SKP-MCs-2 and SKP-MCs-1 microcrystalline injection preparations

Male Wistar rats (350 + -30 g) were anesthetized with isoflurane and were given 150 μ L of SKP-MCs-6, SKP-MCs-2, SKP-MCs-1 microcrystalline injections intramuscularly in the hindlimb biceps according to a dose of 20mg of paliperidone per kg, respectively, followed by routine characterization of blood at 14 days and 28 days.

Fig. 22 and 23 show the results of the routine blood treatment on

days

14 and 28, respectively, and it can be seen that the numbers of leukocytes, erythrocytes, platelets, monocytes, neutrophils and lymphocytes are not significantly different from those of the group to which no administration has been made.

Experiment 9 blood biochemical evaluation of SKP-MCs-6, SKP-MCs-2 and SKP-MCs-1 microcrystalline injection preparation after administration

Male Wistar rats (350. + -.30 g) were anesthetized with isoflurane and were given a dose of 20mg of paliperidone per kg by intramuscular injection of 150. Mu.L of microcrystalline injection preparations of SKP-MCs-6, SKP-MCs-2, and SKP-MCs-1 into the hindlimb biceps, respectively, followed by biochemical evaluation of blood at 14 days and 28 days.

FIGS. 24 and 25 show the biochemical results of blood at day 14 and day 28, respectively, and it can be seen that the contents of glucose, creatinine, urea nitrogen, glutamic-pyruvic transaminase and glutamic-oxalacetic transaminase were not significantly different from those of the group without administration.

The examples show that the paliperidone prodrug based on the ketal bond and the microcrystalline preparation thereof have the characteristics of definite structure, simple and efficient preparation method and process, excellent acid responsiveness, excellent long-acting slow-release capability and biological safety, and have high innovation and application prospect.

The above description is only for the purpose of illustrating the preferred embodiments of the present invention and should not be taken as limiting the invention, so that any modifications, equivalents, improvements and the like, which are within the spirit and principle of the present invention, should be included in the scope of the present invention.

Claims

1. A compound represented by the following formula (I), a racemate, a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof:

wherein the content of the first and second substances,r is selected from unsubstituted or optionally substituted by one, two or more R _a Substituted of the following groups: c _1-40 Alkyl radical, C _2-40 Alkenyl radical, C _2-40 Alkynyl, C _3-20 Cycloalkyl radical, C _3-20 Cycloalkyloxy, 3-20 membered heterocyclyl, 3-20 membered heterocyclyloxy, C _6-20 Aryl radical, C _6-20 Aryloxy, 5-20 membered heteroaryl, 5-20 membered heteroaryloxy.

2. The compound of claim 1, wherein: each R _a Independently selected from C _1-40 Alkyl radical, C _2-40 Alkenyl radical, C _2-40 Alkynyl, C _3-20 Cycloalkyl radical, C _3-20 Cycloalkyloxy, 3-20 membered heterocyclyl, 3-20 membered heterocyclyloxy, C _6-20 Aryl radical, C _6-20 Aryloxy, 5-20 membered heteroaryl, 5-20 membered heteroaryloxy.

3. The compound of claim 1, wherein: r is selected from unsubstituted or optionally substituted by one, two or more R _a Substituted C _1-40 One of alkyl groups;

preferably, R is selected from C _1-40 One of alkyl groups;

preferably, R is selected from C _1-40 One of linear alkyl;

preferably, R is C ₁₈ A linear alkyl group.

4. A process for the preparation of a compound according to any one of claims 1 to 3, characterized in that: comprises reacting paliperidone with a compound shown in a formula (II) to obtain a compound shown in a formula (I):

wherein R is independently selected from the ranges recited in any one of claims 1-3;

preferably, the preparation method comprises the following specific steps:

adding paliperidone, a compound shown in a formula (II) and a reaction solvent into a reaction vessel, adding an acid catalyst under the condition of air isolation, carrying out nucleophilic addition reaction on the paliperidone and the compound shown in the formula (II), and adding triethylamine to terminate the reaction after the reaction is completed to obtain a compound shown in the formula (I);

preferably, the reaction solvent is any one of dichloromethane, tetrahydrofuran and toluene;

preferably, the acid catalyst is any one of 1,2-dichloroacetic acid, p-toluenesulfonic acid and pyridine p-toluenesulfonic acid;

5. A pharmaceutical preparation comprising a compound of formula (I) according to any one of claims 1 to 3, characterized in that: the pharmaceutical preparation is in the form of tablet, capsule, multilayer tablet, oral sustained release agent, transdermal delivery system, suppository, micrometer preparation, ampoule agent, solution, emulsion, dispersion, powder, nanometer preparation, liposome preparation, drop, nasal spray, inhalation spray, aerosol, inhalation powder, microcrystalline preparation, transdermal delivery system or subcutaneous delivery preparation.

6. The pharmaceutical formulation of claim 5, wherein: the dosage form of the pharmaceutical preparation is a microcrystalline preparation.

7. A process for preparing a pharmaceutical formulation of a compound of claim 6, characterized in that: the preparation method of the microcrystalline preparation comprises any one or any combination of a medium grinding method, an ultrasonic method, a high-pressure homogenizing method, a laser ablation and crushing technology, a solvent-antisolvent precipitation method, a supercritical fluid method, a solvent evaporation method and a spray drying method.

8. The method of preparing a pharmaceutical formulation according to claim 6, wherein: the microcrystalline preparation is prepared by the following method:

4) Adding a stabilizer, and freeze-drying;

5) And (4) resuspending the microcrystalline freeze-dried powder by using double distilled water to obtain the microcrystalline injection preparation.

9. A method of preparing a formulation of a compound according to claim 8, characterized in that: the good solvent is C ₁ ～C ₅ Any one or more of lower alkyl alcohols, acetone, DMSO;

preferably, the double distilled water used in step 1) has a pH of between 8 and 9;

preferably, the surfactant used in step 2) is one or more of polysorbate 20, polysorbate 80, alkyl glucoside, fatty acid glyceride, fatty acid sorbitan, poloxamer;

10. Use of a compound according to any one of claims 1 to 3 or a pharmaceutical formulation according to claim 5 or 6 in the manufacture of a medicament for the treatment or prevention of a psychotic disorder, preferably schizophrenia or schizoaffective disorder.