WO2022199708A1 - Pharmaceutically acceptable salt of lumateperone, and preparation method therefor, pharmaceutical composition containing same, and use thereof - Google Patents

Abstract

Provided are a pharmaceutically acceptable salt of lumateperone, and a preparation method therefor, a pharmaceutical composition containing same, and the use thereof. The pharmaceutically acceptable salt of lumateperone is a salt formed from a lumateperone free base and an organic acid having no less than six carbon atoms. The prepared pharmaceutically acceptable salt of lumateperone has low solubility, is suitable for slow-release administration, has high stability, is convenient to prepare and is suitable for large-scale industrial production.

Description

Lumepirone medicinal salt, preparation method, pharmaceutical composition containing same and application

This application requires that it was submitted to the State Intellectual Property Office of China on March 26, 2021. The patent application number is 202110322805.8, and the name of the invention is the previous application of "Medicinal salt of lumepirone, preparation method, pharmaceutical composition containing it and application" priority. The entirety of this application is incorporated herein by reference.

technical field

The invention belongs to the technical field of medicine, and particularly relates to a medicinal salt of lumepirone, a preparation method, a medicinal composition containing the same and an application.

Background technique

On December 23, 2019, Intra-Cellular Therapies announced that its antipsychotic drug Lumateperone (trade name Caplyta) was approved by the U.S. Food and Drug Administration (FDA) for the treatment of schizophrenia in adults. Lumepirone is the first innovative drug in the field of schizophrenia treatment. It exerts its curative effect by co-regulating the central 5-HT, DA and glutamatergic systems. At present, the drug has not yet been marketed in China.

The chemical name for lumepirone is 1-(4-fluorophenyl)-4-[(6bR,10aS)-2,3,6b,9,10,10a-hexahydro-3-methyl-1H-pyrido [3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl]1-butanone, its chemical structure is as follows:

Lumepirone is a 5-HT _2A receptor ligand with strong affinity for the dopamine D2 receptor and the serotonin transporter, but negligible binding to receptors associated with cognitive and metabolic side effects of antipsychotics.

The industrial production of lumepirone still faces challenges. Lumepirone, the free base form, is an oily, viscous solid. Patent document CN112384218A describes that it is extremely difficult to prepare salts of this compound. The hydrochloride salt form of lumepirone is disclosed in US Patent Document US 7,183,282, which is obtained by precipitation from diethyl ether, but this particular salt form is hygroscopic and exhibits poor stability. The tosylate salt of lumepirone is disclosed in patent documents WO 2009/114181 and US 2011/0112105.

Currently listed is lumepirone p-toluenesulfonate capsule, which is an oral preparation and needs to be administered daily to maintain its blood concentration. However, due to the need for frequent administration, the patient's medication compliance is poor. Therefore, there is an urgent need to develop a pharmaceutically acceptable salt of lumepirone that has low solubility in water or different pH media, is suitable for sustained-release administration, and has stable physical and chemical properties.

SUMMARY OF THE INVENTION

In order to improve the above problems, the present invention provides a pharmaceutically acceptable salt of lumepirone, which is a salt formed by the free base of lumepirone and an organic acid with more than six carbons.

According to an embodiment of the present invention, the organic acid with more than six carbons is a C ₆ -C ₃₀ organic acid, including but not limited to: caproic acid, heptanoic acid, octanoic acid, nonanoic acid, azelaic acid, decanoic acid, tenacic acid Monoalkanoic acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, heptadecanoic acid, stearic acid, nonadecanoic acid, eicosanoic acid, oleic acid, eicosane acid, behenic acid, behenic acid, behenic acid, behenic acid, behenic acid, behenic acid, behenic acid, behenadecanoic acid, Triaconoic acid, triglyceride, lignin, pamoic acid, 1-hydroxy-2 naphthoic acid, pamoic acid (also known as "pamoic acid") and naphthoic acid derivatives. The "naphthoic acid derivatives" include, but are not limited to, naphthoic acid esters, such as naphthoic acid containing a carboxyl group and an additional ester functional group.

According to an embodiment of the present invention, the pharmaceutically acceptable salt of lumepirone is lumepirone hemipamoate, that is, the pamoate of lumepirone, wherein lumepirone and pamoic acid are The molar ratio is 1:0.5 for compound salt formation.

According to an embodiment of the present invention, the pamoic acid is also called Pamoic acid, CAS No. 130-85-8.

According to an embodiment of the present invention, the lumepirone pamoate salt is amorphous.

Amorphous in the present invention refers to the form of an amorphous solid (non-crystalline).

According to an embodiment of the present invention, the X-ray powder diffraction pattern of the amorphous lumepirone hempamoate salt is a dispersion pattern without characteristic peaks, substantially as shown in FIG. 3 .

According to an embodiment of the present invention, the differential scanning calorimetry analysis of the amorphous form of lumepiprone hempamoate shows that it has no distinct melting peak, as shown in FIG. 4 .

According to an embodiment of the present invention, the NMR image of the lumepirone hemipamoate amorphous shows that lumepirone and pamoic acid form a salt in a molar ratio of 1:0.5, as shown in FIG. 5 .

The present invention also provides the preparation method of the pharmaceutical salt of lumepirone, which comprises the following steps: performing a salt-forming reaction between the free base of lumepirone and the organic acid with more than six carbons as described above.

According to an embodiment of the present invention, the preparation method of the amorphous lumepiprone hemipate salt comprises the following steps:

Method (1): dissolving lumepirone p-toluenesulfonate in ethanol to obtain solution A, dissolving pamoic acid in sodium hydroxide ethanol solution to obtain solution B, adding solution B to solution A and stirring; or

Method (2): Dissolve lumepirone and pamoic acid in DMSO, add anti-solvent water, stir and separate out.

According to an embodiment of the present invention, the stirring in methods (1) and (2) is performed at 0˜30°C.

According to an embodiment of the present invention, in method (2), the lumepirone is obtained by dissolving lumepirone p-toluenesulfonate in dichloromethane, and adding 0.2N aqueous sodium hydroxide solution under stirring conditions. Mepirone free base.

The present invention also provides the use of the pharmaceutical salt of lumepirone as described above in the preparation of a medicament for the treatment and/or prevention of schizophrenia, bipolar disorder and acute mania in adults.

According to an embodiment of the present invention, the pharmaceutically acceptable salt of lumepirone is lumepirone hemipamoate.

The present invention also provides a pharmaceutical composition comprising the pharmaceutically acceptable salt of lumepirone as described above.

According to an embodiment of the present invention, the pharmaceutically acceptable salt of lumepirone is lumepirone hemipamoate.

According to an embodiment of the present invention, the pharmaceutical composition may further include pharmaceutically acceptable excipients.

According to an embodiment of the present invention, the pharmaceutically acceptable adjuvant includes one, two or more of physiologically or pharmaceutically acceptable carriers, diluents, vehicles and/or excipients.

The present invention also provides a lumepirone pharmaceutical preparation, which comprises the above-mentioned lumepirone pharmaceutically acceptable salt or pharmaceutical composition.

According to embodiments of the present invention, the dosage forms of the lumepirone pharmaceutical formulation include, but are not limited to, tablets, capsules, solutions, suspensions and semi-solid formulations.

In the present invention, the pharmaceutically acceptable excipients refer to the following substances: within the scope of normal medical judgment, they are suitable for contact with the patient's tissue without inappropriate toxicity, irritation, allergic reaction, etc., and have reasonable Pros and cons ratio, and can be effectively used for its purpose.

The present invention also provides a method for treating and/or preventing schizophrenia, bipolar disorder, and acute mania in adults, comprising adding the above pharmaceutically acceptable salt of lumepirone, or a pharmaceutical composition thereof, or lumepirone A pharmaceutical formulation of the london is administered to a subject in need thereof.

beneficial effect

The medicinal salt of lumepirone prepared by the present invention has low solubility in media with different pH, and the solubility difference is small, indicating that the salt form itself has a sustained-release effect, and the release speed can be minimally dependent on pH, so as to avoid The effect on the release rate of the drug in the pH environment of different regions in the body results in the phenomenon of burst release or excessively high blood drug concentration in local regions of the body, and reduces the drug release variability among individuals. Therefore, it is suitable for preparing long-acting preparations, can reduce the frequency of medication, improve the compliance of patients with medication, and has a good market prospect. In addition, the medicinal salt of lumepirone has high stability, convenient preparation, and is suitable for large-scale industrial production.

Moreover, the present invention adopts lumepirone p-toluenesulfonate as the initial raw material to carry out the subsequent reaction operation, which can effectively avoid the influence of the free base which is used alone as an oily substance and has poor stability on the final product. The operation process is simpler and repeatable.

Description of drawings

Fig. 1 is comparative example 1 lumepirone tosylate XRPD collection of illustrative plates;

Fig. 2 is comparative example 1 lumepirone p-toluenesulfonate DSC collection of illustrative plates;

Fig. 3 is embodiment 1 lumepirone semi-pamoate XRPD collection of illustrative plates;

Fig. 4 is embodiment 1 lumepirone semi-pamoate DSC collection of illustrative plates;

Fig. 5 is the ¹ H-NMR spectrum of embodiment 2 lumepirone semi-pamoate;

Figure 6 is the XRPD spectrum of the lumepirone hemipamate salt of Example 2.

Detailed ways

The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following examples are only for illustrating and explaining the present invention, and should not be construed as limiting the protection scope of the present invention. All technologies implemented based on the above content of the present invention are covered within the intended protection scope of the present invention.

Unless otherwise stated, the starting materials and reagents used in the following examples are commercially available or can be prepared by known methods.

Nuclear magnetic resonance ( ¹ H-NMR), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and high performance liquid chromatography (HPLC) were used to test the salt compounds of the examples and comparative examples, respectively. The instrument parameters used for the test are as follows:

(1) The ¹ H-NMR test was carried out in Bruker Advance III 500M nuclear magnetic resonance spectrometer, the measurement frequency was 400 Mz, and the solvent used was deuterated DMSO.

(2) The DSC measurement was carried out in a sealed tray device of TA Instruments model Q2000, and the test method was as follows: the sample (about 1-2 mg) was weighed in an aluminum tray, and then transferred to the instrument for measurement. The test parameters are as follows: the instrument is equilibrated at 30°C, heated to 300°C at a rate of 10°C/min, and the experimental atmosphere is nitrogen.

(3) XRPD measurements were performed on a Bruker model D8Advance X-ray powder diffractometer using a circular zero-background single-crystal silicon sample stage. The scanning parameters are as follows: voltage 40kv, current 40mA, scanning range 3°-45°, scanning step size 0.02°, and scanning mode is continuous scanning.

(4) Instruments and related detection parameters used for the detection of HPLC content and related substances

Content test:

Content gradient elution program table:

time (min)	Mobile phase A (volume fraction %)	Mobile phase B (volume fraction %)
0.0	90	10
8.0	10	90
12.0	10	90
12.1	90	10
15.0	90	10

Related Substance Testing:

instrument	high performance liquid chromatography
Column	Welch Xtimate C18 4.6×150mm, 5μm
Detection wavelength	214nm
flow rate	1.0mL/min
column temperature	30℃
Injection volume	10μL
mobile phase A	Volume fraction 0.05% trifluoroacetic acid aqueous solution
mobile phase B	Acetonitrile
solvent	60% acetonitrile in water

For the gradient elution program table:

time (min)	Mobile phase A (volume fraction %)	Mobile phase B (volume fraction %)
0.0	90	10
10.0	20	80
15.0	20	80
15.1	90	10
25.0	90	10

Comparative Example 1 Solid-phase characterization and detection of lumepirone p-toluenesulfonate

The commercially available lumepirone p-toluenesulfonate was subjected to solid phase characterization and detection, and the test items were ¹ H-NMR, DSC and XRPD.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 9.10 (s, 1H), 8.07-8.03 (m, 2H), 7.48 (d, 2H), 7.37 (t, 3H), 7.11 (d, 2H) ), 6.60(t, 1H), 6.51(d, 2H), 6.42(d, 2H), 3.61-3.57(m, 1H), 3.47-3.39(m, 3H), 3.23-2.98(m, 6H), 2.81(s,3H), 2.74-2.68(m,1H), 2.64-2.53(m,1H), 2.26(d,4H), 2.12-1.97(m,3H).

The X-ray powder diffraction pattern of the crystalline form of lumepirone p-toluenesulfonate is shown in Figure 1. Specifically, the X-ray powder diffraction pattern at 2θ is about 5.643°, 8.428°, 11.310°, 12.077°, 13.284° , 15.787°, 16.041°, 16.421°, 17.030°, 17.507°, 18.173°, 18.985°, 19.243°, 19.873°, 20.742°, 21.650°, 22.594°, 22.812°, 23.429°, 23.740°, 24.294° There are diffraction peaks at °, 26.007°, 26.941°, 27.269°, 29.700°, 31.594°, 34.869°, 37.551° and 39.523° with an error range of ±0.2°.

The differential scanning calorimetry curve (DSC) shows that the peak value of the endothermic peak of the crystalline form of lumepirone p-toluenesulfonate is 179.03° C. The specific test results are shown in Figure 2 .

Embodiment 1 The preparation method 1 of lumepirone hemipamoate

100 mg (0.175 mmol) of lumepirone p-toluenesulfonate was dissolved in 3 mL of ethanol, and 34 mg (0.088 mmol) of pamoic acid was dissolved in 0.92 mL of 7.5 mg/mL sodium hydroxide 90% ethanol-water solution Obtained clear sodium hydroxide solution of pamoic acid (sodium hydroxide concentration is 7.5mg/mL of 90% ethanol-aqueous solution is prepared in the following manner: ethanol and water are made into a volume fraction of 90 with a volume ratio of 9/1. % ethanol aqueous solution, and then sodium hydroxide was dissolved in the solution to make a concentration of 7.5 mg/mL). 0.92 mL of pamoic acid sodium hydroxide solution was added to 3 mL of lumepirone p-toluenesulfonic acid solution under stirring at room temperature, the product was isolated by filtration and washed with water to obtain a gray solid filter cake. The filter cake was dried in a vacuum drying oven at 40°C for 12 hours, and the obtained samples were detected by ¹ H-NMR, XRPD and DSC. ¹ H-NMR results show that the obtained sample is lumepirone hemipate (base:acid molar ratio is 1:0.5), and the nuclear magnetic test results are as follows:

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 8.19 (d, 2H), 8.04-8.02 (m, 2H), 7.65 (d, 1H), 7.32 (t, 2H), 7.13-7.11 (m) , 1H), 7.01(t, 1H), 6.59(s, 1H), 6.51(d, 1H), 6.41(d, 1H), 4.69(s, 1H), 3.12(t, 3H), 2.80(s, 3H), 2.71 (t, 1H), 2.17 (s, 1H), 2.08 (s, 1H), 2.01 (s, 2H).

The XRPD and DSC spectra of lumepirone hemipamoate are shown in Figures 3 and 4, respectively, and the results show that lumepirone hemipamoate is amorphous.

Embodiment 2 The preparation method 2 of lumepirone hemipamoate

Dissolve 1.44 g (2.546 mmol) of lumepirone p-toluenesulfonate in 15 mL of dichloromethane, add 0.2 N aqueous sodium hydroxide solution under stirring, separate layers, discard the aqueous layer, and concentrate under reduced pressure to remove the solvent to obtain Lumepirone free base. The above-mentioned lumepirone free base and 0.49g (1.273mmol) pamoic acid were dissolved in 20mL DMSO, ultrasonically dissolved, 50mL water was added, a solid was precipitated, stirred, suction filtered, washed with a large amount of water, and dried under reduced pressure to obtain 1.33g Light yellow solid, yield 89.26%.

The obtained sample was detected by ¹ H-NMR and XRPD, and the result of ¹ H-NMR showed that the obtained sample was lumepirone hemipamoate (base:acid molar ratio was 1:0.5), and the results were as follows:

¹ H-NMR (400MHz, DMSO-d ₆ ): δ 8.22-8.18(t, 2H), 8.05-8.01(m, 2H), 7.67-7.65(d, 1H), 7.34-7.29(t, 2H) , 7.16-7.12(t,1H), 7.04-7.00(t,1H), 6.61-6.57(t,1H), 6.53-6.51(d,1H), 6.42-6.40(d,1H), 4.70(s, 1H), 3.50-3.44(m, 2H), 3.41-3.30(m, 7H), 3.23(s, 1H), 3.15-3.12(t, 3H), 2.80(s, 3H), 2.18-1.98(m, 4H).

The NMR test results showed that lumepirone and pamoic acid formed a salt with a molar ratio of 1:0.5.

Its X-ray powder diffraction pattern is shown in Figure 6, which shows that lumepirone hemipate is amorphous.

Example 3 Solubility Comparison

Get the lumepirone p-toluenesulfonate of Comparative Example 1 and the lumepirone semi-pamoate obtained in Examples 1 and 2 respectively, and three kinds of substances are added to the corresponding medium respectively (the test results are shown in Table 1, Wherein pH3 is acetate buffer solution, pH5, pH7 and pH9 are phosphate buffer solution), the obtained solution was shaken at 37°C for 24 hours, filtered using a 0.45 μm aqueous filter, and the filtrate was collected. The solubility of the three substances in the test medium was determined by high performance liquid chromatography.

Table 1 shows that the solubility of lumepirone hemi-pamoate prepared by the present invention in water and different pH media is significantly lower than that of lumepirone p-toluenesulfonate, and lumepirone hemi-pamoate in water Its solubility is 7-8 μg/mL, which is equivalent to about 1/200 of that of lumepirone p-toluenesulfonate. And in each pH medium, the solubility of lumepirone hemipamoate is low, and the solubility difference is small, indicating that the salt form itself has a sustained release effect, and the release rate can be minimally dependent on pH, thereby avoiding The influence of the pH environment on the drug release rate in different regions of the body, resulting in the phenomenon of burst release or excessively high blood drug concentration in local regions of the body, as well as reducing the variability of drug release between individuals, so it is suitable for the preparation of long-acting preparations, which can reduce the The frequency of medication is improved, and the compliance of patients with medication is improved, and the market prospect is good.

Table 1 Solubility Comparison Results

Embodiment 4 Related substance content and stability comparison

Take lumepirone p-toluenesulfonate and the lumepirone hemipamoate obtained in Example 2 and place them under accelerated conditions (40°C/75%RH), and take samples at 0 days, 1 month, and 3.5 months respectively. Conduct related substance testing.

The test results of related substances under accelerated conditions are shown in Table 2. Table 2 shows that the lumepirone semi-pamoate of the present invention and the commercially available lumepirone p-toluenesulfonate are in 1 month, and the impurity type and impurity content increase are equivalent, but the related substance RRT in 3.5 months. .83 and RRT1.06 content and total impurity content changes, the lumepirone semipamoate of the present invention has obvious advantages over commercially available lumepirone p-toluenesulfonate, namely lumepirone of the present invention Hemipamoate is more stable.

Table 2 Test results of related substances

Note: ND = not detected; the last column "Total Change" is the increase in the content of related substances relative to the 0th day.

Claims (10)

1. A medicinal salt of lumepirone, characterized in that it is a salt formed by the free base of lumepirone and an organic acid with more than six carbons.
2. The medicinal salt of lumepirone according to claim 1, characterized in that: the "organic acid with more than six carbons" is an organic acid of _C6 - _C30 ; the " _C6 - _C30 ""organicacid" is selected from: caproic acid, heptanoic acid, caprylic acid, nonanoic acid, azelaic acid, capric acid, undecanoic acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, Heptadecanoic acid, stearic acid, nonadecanoic acid, eicosanoic acid, oleic acid, behenic acid, behenic acid, behenic acid, tetracosanoic acid, pentadecanoic acid acid, hexadecanoic acid, heptanoic acid, octacosanoic acid, nonacosanoic acid, triaconoic acid, triglyceride, lignin, pamoic acid, 1-hydroxy-2naphthalene Formic acid, pamoic acid and naphthoic acid derivatives.
3. The medicinal salt of lumepirone as claimed in claim 1, wherein the medicinal salt of lumepirone is lumepirone semi-pamoate, wherein lumepirone and pamoic acid are The molar ratio is 1:0.5 for compound salt formation.
4. The medicinal salt of lumepirone according to claim 3, wherein: the lumepirone pamoate is amorphous;

   Preferably, the amorphous X-ray powder diffraction pattern of the lumepirone hemipamoate is substantially as shown in FIG. 3 .
5. The preparation method of the medicinal salt of lumepirone according to any one of claims 1-4, characterized in that: comprising the steps of: salifying the free base of lumepirone with the above-mentioned organic acid having more than six carbons reaction.
6. The preparation method of claim 5, wherein: the amorphous preparation method of the lumepiprone semi-pamoate salt comprises the steps:

   Method (1): dissolving lumepirone p-toluenesulfonate in ethanol to obtain solution A, dissolving pamoic acid in sodium hydroxide ethanol solution to obtain solution B, adding solution B to solution A and stirring; or

   Method (2): Dissolve lumepirone and pamoic acid in DMSO, add anti-solvent water, stir and separate out.
7. Use of the medicinal salt of lumepirone according to any one of claims 1-4 in the preparation of a medicament for the treatment and/or prevention of schizophrenia, bipolar disorder and acute mania in adults.
8. The use according to claim 7, wherein the medicinal salt of lumepirone is lumepirone hemipamoate.
9. A pharmaceutical composition comprising the pharmaceutically acceptable salt of lumepirone according to any one of claims 1-4;

   Preferably, the pharmaceutical composition includes pharmaceutically acceptable excipients;

   Preferably, the pharmaceutically acceptable adjuvants include one, two or more of physiologically or pharmaceutically acceptable carriers, diluents, vehicles and/or excipients.
10. A lumepirone pharmaceutical preparation, comprising the lumepirone medicinal salt according to any one of claims 1-4;

    Preferably, the dosage form of the lumepirone pharmaceutical preparation is selected from the group consisting of tablets, capsules, solutions, suspensions and semi-solid preparations.

Images