Salt of lappaconitine derivative as well as preparation method and application of salt

Abstract

The invention relates to a salt of a lappaconitine derivative as well as a preparation method and application thereof, the salt of the derivative is obtained by reacting (la, 14a, 16beta)-20-ethyl-1, 14, 16-trimethoxyaconitane-4, 8, 9-triol 4-[2-(ethylsulfonylamino)] benzoate with acid, and the acid can be hydrogen bromide, hydrogen chloride, nitric acid, phosphoric acid, p-toluenesulfonic acid or methanesulfonic acid and sulfuric acid. When the acid is hydrogen bromide or hydrogen chloride, the salt of the analogue exists in a crystal form with a crystal form A or a crystal form B. The analogue has the advantages of good solid property, high stability, good solubility, small hygroscopicity and the like, and can be used for preparing medicines for treating cardiovascular and cerebrovascular diseases.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and in particular relates to an acid addition salt, a salt-type crystal and a medical use of a lappaconitine derivative. Background Art

[0002] Lappaconitine is an alkaloid extracted from the root of Aconitum carmichaelii, a plant of the Ranunculaceae family. In my country, it is the first non-addictive, non-opioid analgesic with a strong analgesic effect. Its analgesic effect is 7 times that of the antipyretic analgesic aminopyrine, which is equivalent to pethidine, but not as good as morphine. In Central Asia and Russia, lapaconitine is also a compound with antiarrhythmic effects. Arrhythmia refers to a disease with irregular heart rhythm. Some arrhythmias have no obvious symptoms, but some may cause palpitations, and in severe cases, there will be symptoms of dizziness, chest pain or shortness of breath. When arrhythmias develop to a certain extent, they may cause stroke, heart failure and cardiac arrest, leading to death. Lappaconitine has a strong antiarrhythmic effect. It can regulate the expression of voltage-dependent sodium, potassium and calcium ion channels and related protein genes on the channels to control the generation of action potentials at different stages, reduce the excitability of the cardiac conduction system, and exert its antiarrhythmic effect.

[0003] At present, lappaconitine has been used clinically as an arrhythmia drug in Russia and has been used clinically as an analgesic drug in my country for many years. Unfortunately, LA is highly toxic in clinical use and has side effects such as fever and allergies. In addition, lappaconitine also has defects such as poor water solubility, low bioavailability, and slow onset of analgesic activity, which limits the further clinical application of lappaconitine. In summary, the field urgently needs to develop lappaconitine analogs with stable physical properties and good drugability for the treatment of cardiovascular and cerebrovascular diseases. Summary of the invention

[0004] The purpose of the present invention is to provide a salt of a lappaconitine derivative and a preparation method and use thereof. The salt of the derivative has a structure as shown in formula (I), wherein n is 1, X is hydrogen bromide, hydrogen chloride, nitric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid or a combination thereof; n is 0.5, and X is sulfuric acid. When X is hydrogen bromide or hydrogen chloride, the salt of the derivative exists in the form of crystal form A or crystal form B, has the advantages of good solid properties, high stability, good solubility, low hygroscopicity, etc., and can be used to prepare drugs for treating cardiovascular and cerebrovascular diseases.

[0005] The salt of a lappaconitine derivative described in the present invention has a structural formula (I) of:

[0006]

[0007] Wherein, n is 1, X is hydrogen bromide, hydrogen chloride, nitric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid; n is 0.5, X is sulfuric acid.

[0008] The salt derived from lappaconitine has the structural formula of compound (I)-1:

[0009]

[0010] The compound of formula (I)-1 is a crystal in the form of Form A, and the Form A has at least one of the following characteristics:

[0011] 1) Its XRPD pattern has characteristic peaks at at least 3, 5 or 6 of the following 2θ values: 5.41°±0.20°, 13.48°±0.20°, 14.43°±0.20°, 16.11°±0.20°, 20.86°±0.20° and 27.22±0.20°;

[0012] 2) Its DSC spectrum has an absorption peak at 248±5℃;

[0013] 3) After the mixture is placed at a temperature of 25°C and a relative humidity of 80% to reach equilibrium, the moisture content increases by 0-0.1% of the total weight;

[0014] 4) The solubility in deionized water at 37°C is 3mg / mL-1g / mL;

[0015] The XRPD spectrum of the crystalline form A also has characteristic peaks at at least 3, 5 or 7 of the following 2θ values: 9.68°±0.20°, 12.70°±0.20°, 16.52°±0.20°, 16.87°±0.20°, 19.59°±0.20°, 22.76°±0.20° and 22.93±0.20°.

[0016] The salt of the lappaconitine derivative, the salt has the structural formula (I)-2 compound:

[0017]

[0018] The compound of formula (I)-2 is a crystal in the form of Form B, and the Form B has at least one of the following characteristics:

[0019] 1) Its XRPD spectrum has characteristic peaks at at least 3, 5 or 7 of the following 2θ values: 5.39°±0.20°, 12.80°±0.20°, 13.48°±0.20°, 13.87°±0.20°, 14.65°±0.20°, 16.11°±0.20°, 19.72°±0.20°;

[0020] 2) Its DSC spectrum has an absorption peak at 227±5℃;

[0021] 3) After reaching equilibrium under the conditions of 25°C and RH80%, the water content increases by 0-0.4% of the total weight;

[0022] 4) Its solubility in deionized water at 37°C is 3 mg / mL-1 g / mL;

[0023] The XRPD spectrum of the crystalline form B also has characteristic peaks at at least 3, 5 or 7 of the following 2θ values: 9.68°±0.20°, 9.94°±0.20°, 16.83°±0.20°20.79°±0.20°, 22.84°±0.20°, 24.88±0.20° and 27.21±0.20°.

[0024] A method for preparing a salt of a lappaconitine derivative is carried out according to the following steps:

[0025] a. Dissolve (1a,14a,16β)-20-ethyl-1,14,16-trimethoxyaconitane-4,8,9-triol 4-[2-(ethylsulfonylamino)]benzoate in a mixture of acetonitrile and dichloromethane or a mixture of methanol and dichloromethane at a volume ratio of 3:1, add 1 times the amount of hydrobromic acid solution, 2 mol / L hydrochloric acid solution, 65% nitric acid solution, p-toluenesulfonic acid monohydrate, methanesulfonic acid, 0.95 times the amount of 85% phosphoric acid or 0.45 times the amount of concentrated sulfuric acid at a temperature of 0°C, stir at room temperature for 1 hour, and then evaporate the solvent to obtain a mixture;

[0026] b. Recrystallize the mixture obtained in step a with methanol, or slurry it with acetonitrile, ether or ethyl acetate at a temperature of 40°C for 2 hours, or slurry it with ethanol, ethyl acetate or ether for 2 hours, and filter to obtain solid compound (I)-1(la,14a,16β)-20-ethyl-1,14,16-trimethoxyaconitane-4,8,9-triol 4-[2-ethylsulfonylamino)]benzoate hydrobromide; or compound (I)-2((la,14a,16β)-20-ethyl-1,14,16-trimethoxyaconitane-4,8,9-triol 4-[2-ethylsulfonylamino)]benzoate hydrochloride; or compound (la,14a,16β)-20-ethyl-1,14,16-trimethoxyaconitane-4,8,9-triol 4-[2-ethylsulfonylamino)]benzoate hydrochloride. )] benzoate nitrate; or (la,14a,16β)-20-ethyl-1,14,16-trimethoxyaconitane-4,8,9-triol 4-[2-ethylsulfonylamino)] benzoate p-toluenesulfonate; or (la,14a,16β)-20-ethyl-1,14,16-trimethoxyaconitane-4,8,9-triol 4-[2-ethylsulfonylamino)] benzoate methanesulfonate; or (la,14a,16β)-20-ethyl-1,14,16-trimethoxyaconitane-4,8,9-triol 4-[2-ethylsulfonylamino)] benzoate phosphate; or (la,14a,16β)-20-ethyl-1,14,16-trimethoxyaconitane-4,8,9-triol 4-[2-ethylsulfonylamino)] benzoate sulfate.

[0027] The pharmaceutical composition of the salt of the lappaconitine derivative having the structure of formula (I), (I)-1 and (I)-2, and optional pharmaceutically acceptable excipients, is prepared into oral preparations in the form of tablets, capsules, granules, powders or syrups; the non-oral preparations are self-injections, powder injections, sprays and suppositories.

[0028] Use of the compound or the pharmaceutical composition as claimed in claim 5 in the preparation of drugs for treating cardiovascular and cerebrovascular diseases.

[0029] The cardiovascular diseases include arrhythmia, heart failure, angina pectoris, myocardial ischemia, myocardial injury or myocardial infarction.

[0030] The present invention discloses a salt of a lappaconitine derivative, a preparation method thereof and a use thereof, wherein the structural formula (II) of the raw material (1a,14a,16β)-20-ethyl-1,14,16-trimethoxyaconitane-4,8,9-triol 4-[2-(ethylsulfonylamino)]benzoate in the preparation method of the salt of the lappaconitine derivative is:

[0031]

[0032] (Ⅱ)

[0033] The compound (II) is recorded in Chinese patent application No. 202011276843.6. Experimental tests have shown that this type of compound has significant antiarrhythmic activity. However, compound (II) as a free base has poor water solubility at room temperature, which has a certain impact on the formulation process when used as a pharmaceutical preparation.

[0034] The term pharmaceutically acceptable means that the carrier, vehicle, diluent, excipient and / or formed salt are generally chemically or physically compatible with the other ingredients constituting a pharmaceutical dosage form and physiologically compatible with the receptor.

[0035] The term salt and pharmaceutically acceptable salt refers to a salt formed by a compound with an inorganic and / or organic acid, which may be precipitated in a solution and collected by filtration, or recovered after evaporation of the solvent. The salt in the present invention may be a hydrochloride, sulfate, p-toluenesulfonate, hydrobromide, phosphate, methanesulfonate or nitrate of the compound.

[0036] Pharmaceutical composition: Unless otherwise specified, the pharmaceutical composition described in the present invention comprises at least one compound of the present invention, and optionally a pharmaceutically acceptable excipient.

[0037] The acid addition salt, salt-type crystal and medical use of a lappaconitine analogue described in the present invention have the following beneficial effects: after extensive and in-depth research, the present invention synthesizes and separates the acid addition salt and crystal of a lappaconitine analogue with antiarrhythmic activity, and related physical and chemical property research shows that the acid addition salt and its corresponding crystal form with the advantages of good solid properties, high stability, good solubility, low hygroscopicity, etc. can be developed as a cardiovascular and cerebrovascular therapeutic drug. In addition, the preparation method of the present invention also has the advantages of high product purity, easy storage, simple method and easy repeatability. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 is an XRPD pattern of the present invention in the form of crystals having Form A;

[0039] Figure 2 The DSC spectrum of the present invention in the form of crystals having Form A;

[0040] Figure 3 is an XRPD pattern of the present invention in the form of crystals having Form B;

[0041] Figure 4 This is the DSC spectrum of the present invention in the form of crystals having Form B. DETAILED DESCRIPTION

[0042] Example 1

[0043] Preparation of (1a,14a,16β)-20-ethyl-1,14,16-trimethoxyaconitane-4,8,9-triol 4-[2-(ethylsulfonylamino)]benzoate hydrobromide:

[0044] The raw material compound (II) (la, 14a, 16β)-20-ethyl-1, 14, 16-trimethoxyaconitane-4, 8, 9-triol 4-[2-(ethylsulfonylamino)] benzoate 1.20 g, 1.89 mmol was dissolved in 6 mL of acetonitrile and 2 mL of dichloromethane, 463 mg, 1.89 mmol of 33% hydrobromic acid was added at 0°C, the solvent was evaporated after stirring at room temperature for 1 hour, and the mixture was recrystallized with 10 mL of methanol, filtered and dried to obtain 1.15 g of compound (I)-1 (la, 14a, 16β)-20-ethyl-1, 14, 16-trimethoxyaconitane-4, 8, 9-triol 4-[2-(ethylsulfonylamino)] benzoate hydrobromide in the form of a white solid, with a yield of 85% and a purity of 99.1% according to high performance liquid chromatography (HPLC);

[0045] 1 H NMR(400MHz,dmso-d6)δ9.95(s,1H),8.35(s,1H),7.92(dd,J=8.0,1.6Hz,1H),7.66(ddd,J=8.7,7.2,1.6Hz,1H),7.56(dd,J=8.4,1.2 Hz,1H),7.23(td,J=7.6,1.2Hz,1H),4.90(s,1H),4.63(s,1H),3.93(dd,J=12.3,4.2Hz,1H),3.57(s,1H),3.45(t,J=11.3Hz,1H),3.37 (d,J=4.5Hz,1H),3.33–3.30(m,2H),3.29(s,4H),3.28(s,4H),3.23(s,4H),2.82(dd,J=15.1,7.4Hz,1H),2.65(d,J=7.2Hz,1H),2.47– 2.37(m,2H),2.34–2.10(m,7H),2.02(d,J=14.8Hz,1H),1.82(dd,J=13.4,6.8Hz,1H),1.73(dd,J=15.0,8.1Hz,1H),1.30–1.18(m,7H).

[0046] 13C NMR(101MHz,dmso-d6)δ166.16,139.66,134.88,131.47,123.29,119.26,117.49,88.66,82.08,80.87,79.69,76.53,73.66,6 1.15,57.21,55.90,55.70,55.59,50.21,48.95,46.90,46.21,41.88,41.28,35.69,27.99,26.28,22.55,21.26,10.22,7.89.

[0047] MS: m / z 635.8[M+1] + ;

[0048] X-ray powder diffraction (XRPD) test method:

[0049] Instrument: Bruker D8 advance X-ray multicrystal diffractometer; target: Cu-Kα (40 kV, 40 mA); sample to detector distance: 30 cm; divergence slit: 0.6 mm; voltage and current: 40 Kv, 40 mA; scanning type: two-axis linkage; scanning step width: 0.02°; scanning range: 3-40°; scanning step: 0.1 s;

[0050] The diffraction angle (2θ value) in X-ray powder diffraction (XRPD) may have an error within the range of ±0.2°, so the numerical value of the diffraction angle in the present invention should be understood as a numerical value also included in the range of about ±0.2°; therefore, the present invention not only covers the crystal form that completely matches the characteristic signal peak in the specific X-ray powder diffraction (XRPD) spectrum, but also covers the crystal form that has an error of about ±0.2° with the characteristic signal peak in the specific X-ray powder diffraction (XRPD) spectrum;

[0051] X-ray powder diffraction (XRPD) results showed that the obtained solid was in crystalline form, corresponding to Form A, as shown in Table 1 and Figure 1 As shown:

[0052] Table 1 XRPD data of Form A of Compound (I)-1

[0053]

[0054] DSC test method:

[0055] Instrument: METTLER TOLEDO differential scanning calorimeter; temperature range: 30-300°C; scanning rate: 10°C / min; nitrogen flow rate: 50mL / min;

[0056] The results of differential scanning calorimetry (DSC) showed that the obtained solid began to have an endothermic peak at 244.85 and reached a peak at 248.07°C. Figure 2 shown.

[0057] Example 2

[0058] Preparation of (1a,14a,16β)-20-ethyl-1,14,16-trimethoxyaconitane-4,8,9-triol 4-[2-(ethylsulfonylamino)]benzoate hydrochloride:

[0059] 1.20 g, 1.89 mmol of the raw material compound (II) was dissolved in 6 mL of acetonitrile and 2 mL of dichloromethane, and 0.945 mL, 1.89 mmol of 2 mmol / L hydrochloric acid was added at 0°C. After stirring at room temperature for 1 hour, the solvent was evaporated, and 8 mL of acetonitrile was used for slurrying at 40°C for 2 hours. After filtering, it was dried to obtain 1.2 g of compound (I)-2(1a,14a,16β)-20-ethyl-1,14,16-trimethoxyaconitane-4,8,9-triol 4-[2-(ethylsulfonylamino)]benzoate hydrochloride in the form of a white solid, with a yield of 95% and a purity of 99.3% by high performance liquid chromatography (HPLC);

[0060] 1 H NMR(400MHz,dmso-d6)δ9.99(s,1H),8.43(s,1H),7.92(dd,J=8.0,1.6Hz,1H),7.65(ddd,J=8.7,7.2,1.6Hz,1H),7.57(dd,J=8.4,1.2Hz ,1H),7.23(td,J=7.6,1.2Hz,1H),5.00(s,1H),4.67(s,1H),3.96(dd,J=12.5,4.3Hz,1H),3.56(s,1H),3.49–3.40(m,1H),3.38(d,J=4.5 Hz,1H),3.31(d,J=7.3Hz,1H),3.28(s,4H),3.28(s,4H),3.23(s,5H),2.82(dd,J=15.1,7.4Hz,1H),2.65(d,J=7.2Hz,1H),2.47–2.36(m, 2H),2.33–2.10(m,7H),2.03(d,J=14.9Hz,1H),1.82(dd,J=13.2,6.8Hz,1H),1.73(dd,J=15.0,8.0Hz,1H),1.23(dt,J=17.2,7.4Hz,7H).

[0061] 13C NMR(101MHz,dmso-d6)δ166.15,139.64,134.83,131.44,123.30,119.35,117.64,88.62,82.13,80.93,79.61,76.54,73.64,6 1.00,57.21,55.87,55.63,55.59,50.22,48.98,46.91,46.21,41.87,41.31,35.71,27.97,26.26,22.58,21.30,10.19,7.89.

[0062] MS: m / z 635.8[M+1] + ;

[0063] The X-ray powder diffraction (XRPD) test method was consistent with that in Example 1. The results showed that the obtained solid was in a crystalline form, corresponding to Form B, as shown in Table 2 and Figure 3 As shown;

[0064] Table 2 XRPD data of Form B of Compound (I)-2

[0065]

[0066] The differential scanning calorimetry (DSC) test method was consistent with that in Example 1. The results showed that the obtained solid began to have an endothermic peak at 223.25°C and reached a peak value at 227.62°C. Figure 4 shown.

[0067] Example 3

[0068] Preparation of (1a,14a,16β)-20-ethyl-1,14,16-trimethoxyaconitane-4,8,9-triol 4-[2-(ethylsulfonylamino)]benzoate nitrate:

[0069] 1.20 g, 1.89 mmol of the raw material compound (II) was dissolved in 6 mL of acetonitrile and 2 mL of dichloromethane, and 183 mg, 1.89 mmol of 65% nitric acid was added at a temperature of 0°C. After stirring at room temperature for 1 hour, the solvent was evaporated, and 8 mL of ethanol was used for slurrying for 2 hours. After filtering and drying, 1.18 g of the compound (1a, 14a, 16β)-20-ethyl-1,14,16-trimethoxyaconitane-4,8,9-triol 4-[2-(ethylsulfonylamino)]benzoate nitrate was obtained in the form of a white solid, with a yield of 89 and a purity of 99.2% by high performance liquid chromatography (HPLC);

[0070] 1H NMR(400MHz,dmso-d6)δ9.95(s,1H),8.34(s,1H),7.92(dd,J=8.0,1.6Hz,1H),7.66(ddd,J=8.7,7.2,1.6Hz,1H),7.56(dd,J=8.5,1.2Hz,1 H),7.28–7.19(m,1H),4.90(s,1H),4.64(s,1H),3.90(dd,J=12.5,4.2Hz,1H),3.57(s,1H),3.49–3.40(m,1H),3.36(d,J=4.5Hz,1H),3.33 –3.30(m,1H),3.29(s,4H),3.28(s,4H),3.23(s,4H),3.20–3.11(m,1H),2.83(dd,J=15.2,7.4Hz,1H),2.65(d,J=7.1Hz,1H),2.47–2.37(m ,2H),2.34–2.11(m,6H),2.02(d,J=15.6Hz,1H),1.82(dd,J=14.0,6.7Hz,1H),1.73(dd,J=15.1,8.1Hz,1H),1.23(dt,J=14.8,7.1Hz,7H).

[0071] 13 C NMR(101MHz,dmso-d6)δ166.18,139.68,134.90,131.48,123.30,119.28,117.49,88.69,82.09,80.84,79.75,76.54,73.67,61.2 4,57.22,55.96,55.66,55.60,50.22,48.96,46.88,46.21,41.89,41.29,35.70,28.03,26.30,22.56,21.25,18.55,10.21,7.89.

[0072] MS: m / z 635.8[M+1] + .

[0073] Example 4

[0074] Preparation of (1a,14a,16β)-20-ethyl-1,14,16-trimethoxyaconitane-4,8,9-triol 4-[2-(ethylsulfonylamino)]benzoate p-toluenesulfonate:

[0075] 1.20 g, 1.89 mmol of the raw material compound (II) was dissolved in 6 mL of acetonitrile and 2 mL of dichloromethane, 359 mg, 1.89 mmol of p-toluenesulfonic acid monohydrate was added at 0°C, the solvent was evaporated after stirring at room temperature for 1 hour, slurried with 8 mL of ethyl acetate for 2 hours, filtered and dried to obtain 1.23 g of the compound (1a, 14a, 16β)-20-ethyl-1,14,16-trimethoxyaconitane-4,8,9-triol 4-[2-(ethylsulfonylamino)]benzoate p-toluenesulfonate in the form of a white solid, with a yield of 83% and a high performance liquid chromatography (HPLC) purity of 98.8%;

[0076] 1 H NMR(400MHz,dmso-d6)δ9.95(s,1H),8.33(s,1H),7.92(dd,J=8.0,1.6Hz,1H),7.66(td,J=7.8,1.6Hz,1H),7.56(d,J=8.3Hz,1H),7.47(d,J=8.1 Hz,2H),7.27–7.20(m,1H),7.11(d,J=7.8Hz,2H),4.91(s,1H),4.64(s, 1H),3.89(d,J=12.2Hz,1H),3.57(s,1H),3.44(t,J=11.5Hz,1H),3.36(d ,J=4.5Hz,1H),3.34–3.30(m,1H),3.29(s,4H),3.28(s,4H),3.23(s,4H ),3.20–3.10(m,1H),2.83(dd,J=15.2,7.3Hz,1H),2.64(d,J=7.2Hz,1H) ,2.47–2.37(m,2H),2.28(s,4H),2.27–2.10(m,4H),2.02(d,J=14.3Hz, 1H),1.87–1.79(m,1H),1.73(dd,J=15.2,8.2Hz,1H),1.30–1.18(m,7H).

[0077] 13C NMR(101MHz,dmso-d6)δ166.19,145.71,139.72,137.63,134.93,131.51 ,128.06,125.51,123.31,119.24,117.44,88.68,82.13,80.88,79.72,76 .55,73.68,61.18,57.23,55.97,55.66,55.61,50.24,48.95,46.87,46. 23,41.91,41.28,35.74,28.01,26.31,22.58,21.26,20.78,10.20,7.91.

[0078] MS: m / z 635.8[M+1] + .

[0079] Example 5

[0080] Preparation of (1a,14a,16β)-20-ethyl-1,14,16-trimethoxyaconitane-4,8,9-triol 4-[2-(ethylsulfonylamino)]benzoate methanesulfonate:

[0081] 1.20 g, 1.89 mmol of the raw material compound (II) was dissolved in 6 mL of methanol and 2 mL of dichloromethane, and 182 mg, 1.89 mmol of methanesulfonic acid was added at 0°C. After stirring at room temperature for 1 hour, the solvent was evaporated, and 10 mL of ether was used for slurrying at 40°C for 2 hours. After filtering, it was dried to obtain 1.17 g of the compound (1a, 14a, 16β)-20-ethyl-1,14,16-trimethoxyaconitane-4,8,9-triol 4-[2-(ethylsulfonylamino)]benzoate methanesulfonate in the form of a white solid, with a yield of 85% and a high performance liquid chromatography (HPLC) purity of 98.6%;

[0082] 1H NMR(400MHz,dmso-d6)δ9.95(s,1H),8.33(s,1H),7.92(d,J=8.0Hz,1H),7.66(t,J=7.8Hz,1H),7.56(d,J=8.3Hz,1H),7.2 4(t,J=7.6Hz,1H),5.09–4.46(m,2H),3.90(d,J=11.9Hz,1H),3.57(s,1H),3.50–3.40(m,1H),3.40–3.32(m,2H),3.31(s, 4H),3.29(s,4H),3.23(s,5H),2.83(dd,J=15.2,7.3Hz,1H),2.65(d,J=7.2Hz,1H),2.50(s,1H),2.46–2.36(m,2H),2.31( s,4H),2.27–2.11(m,3H),2.02(d,J=15.0Hz,1H),1.81(d,J=6.5Hz,1H),1.73(dd,J=15.1,8.2Hz,1H),1.30–1.18(m,7H).

[0083] 13 C NMR(101MHz,dmso-d6)δ166.17,139.67,134.90,131.48,123.31,119.29,117.52,88.68,82.12,80.85,79.72,76.54,73.66,6 1.18,57.22,55.95,55.66,55.60,50.23,48.95,46.86,46.21,41.89,41.28,35.71,28.01,26.30,22.57,21.25,10.20,7.90.

[0084] MS: m / z 635.8[M+1] + .

[0085] Example 6

[0086] Preparation of (1a,14a,16β)-20-ethyl-1,14,16-trimethoxyaconitane-4,8,9-triol 4-[2-(ethylsulfonylamino)]benzoate phosphate:

[0087] 1.20 g, 1.89 mmol of the raw material compound (II) was dissolved in 6 mL of methanol and 2 mL of dichloromethane, and 217 mg, 1.89 mmol of 85% phosphoric acid was added at 0°C. After stirring at room temperature for 1 hour, the solvent was evaporated, and 10 mL of ethyl acetate was used for slurrying at room temperature for 2 hours. After filtering and drying, 1.13 g of the compound (1a, 14a, 16β)-20-ethyl-1,14,16-trimethoxyaconitane-4,8,9-triol 4-[2-(ethylsulfonylamino)]benzoate phosphate was obtained in the form of a white solid, with a yield of 81% and a high performance liquid chromatography (HPLC) purity of 98.8%;

[0088] 1 H NMR(400MHz,dmso-d6)δ10.11(s,1H),7.89(dd,J=7.9,1.6Hz,1H),7.64(td,J=7.7,1.6Hz,1H),7.57(d,J=8.3Hz,1H),7.21(t,J=7.6Hz,1H),7.02(br s,5H),3.53(d,J=11.4Hz,1H),3.33–3.27(m,3H),3.26(s,4H),3.22(s,4H),3.20(s,4H),2.97(s,1H),2.81–2.57(m,3H),2.48–2.40( m,1H),2.40–2.34(m,1H),2.29(s,1H),2.20–1.90(m,8H),1.47(dd,J=14.8,8.1Hz,1H),1.19(t,J=7.4Hz,3H),1.08(t,J=7.1Hz,3H).

[0089] MS: m / z 635.8[M+1] + .

[0090] Example 7

[0091] Preparation of (1a,14a,16β)-20-ethyl-1,14,16-trimethoxyaconitane-4,8,9-triol 4-[2-(ethylsulfonylamino)]benzoate sulfate:

[0092] 1.20 g, 1.89 mmol of the raw material compound (II) was dissolved in 6 mL of methanol and 2 mL of dichloromethane, and 83 mg, 0.45 mmol of concentrated sulfuric acid was added at 0°C. After stirring at room temperature for 1 hour, the solvent was evaporated, and 10 mL of ether was used for slurrying at room temperature for 2 hours. After filtering, it was dried to obtain 1.12 g of compound (1a, 14a, 16β)-20-ethyl-1,14,16-trimethoxyaconitane-4,8,9-triol 4-[2-(ethylsulfonylamino)]benzoate sulfate in the form of a white solid, with a yield of 87% and a high performance liquid chromatography (HPLC) purity of 98.4%;

[0093] 1 H NMR(400MHz,cd3od)δ8.02(dd,J=8.0,1.6Hz,1H),7.69(d,J=8.4Hz,1H),7.64–7.57(m,1H),7.17(t,J=7.6Hz, 1H),4.03(d,J=12.5Hz,1H),3.70(d,J=3.0Hz,1H),3.52–3.45(m,2H),3.43(s,4H),3.40(s,4H),3.34(s,4H), 3.31(s,1H),3.25(q,J=7.4Hz,2H),3.03(dd,J=15.6,7.4Hz,1H),2.87(d,J=7.2Hz,1H),2.60–2.25(m,8H),2. 19–2.10(m,1H),2.01–1.89(m,1H),1.83(dd,J=15.5,8.1Hz,1H),1.40(t,J=7.1Hz,4H),1.29(t,J=7.3Hz,3H). 13 C NMR(101MHz,cd3od)δ168.39,142.24,136.37,132.98,124.16,119.38,117.00,90.48,83.91,82.35,82.12,78.26,75.63,63.69 ,58.27,57.95,56.66,56.53,52.14,50.70,50.54,48.49,47.38,43.60,42.95,37.75,29.88,27.92,24.02,22.67,10.88,8.42.

[0094] MS: m / z 635.8[M+1] + .

[0095] Example 8

[0096] Comparison of hygroscopicity of raw material compound (II) and its salt:

[0097] Moisture absorption test method:

[0098] Instrument: British SMS dynamic vapor sorption instrument (DVS); Humidity range: 0-90%; Method: Gradient humidification, the standard is mass increase less than 0.002% / min;

[0099] Table 3 Compound hygroscopicity test

[0100]

[0101] As can be seen from Table 3 above, the hydrobromide salt of the raw material compound (II) is almost non-hygroscopic, the hydrochloride salt, nitrate salt and p-toluenesulfonate salt are slightly hygroscopic, and the methanesulfonate salt, phosphate salt and sulfate salt are extremely hygroscopic.

[0102] Example 9

[0103] The solid-state stability of the raw material compound (II) and its salt is compared:

[0104] Test method: Weigh about 20 mg of each compound, accurately weigh it, put it in a transparent vial, and place it under high temperature 60°C and high humidity 92.5% RH conditions for 0 day and 10 days respectively. After sampling, test it according to the stability test items;

[0105] Note: HH is the code for high humidity, HT is the code for high temperature, and D stands for day;

[0106] Table 4 Solid state stability content results of raw material compound (II)

[0107]

[0108]

[0109] Table 5 Solid-state stability content of hydrochloride salt of raw material compound (II)

[0110]

[0111] Table 6 Solid-state stability content of hydrobromide salt of raw material compound (II)

[0112]

[0113] Table 7 Results of solid state stability of nitrate of raw material compound (II)

[0114]

[0115] Table 8 Solid state stability content results of p-toluenesulfonate of raw material compound (II)

[0116]

[0117] Table 9 Solid state stability content results of the methanesulfonate of the raw material compound (II)

[0118]

[0119]

[0120] Table 10 Phosphate solid state stability content results of raw material compound (II)

[0121]

[0122] Table 11 Sulfate solid state stability content results of raw material compound (II)

[0123]

[0124] It can be seen from Table 4-11 that the sulfate salt of the raw material compound (II) has relatively low stability under high temperature and high humidity conditions, while the other salts are relatively stable.

[0125] Example 10

[0126] Comparison of solubility and solution stability of raw material compound (II) and its salt:

[0127] Solubility test method:

[0128] Weigh 50-60 mg of each compound, accurately add about 15 ml of water, shake in a constant temperature shaker at 37°C, 120 rpm, take about 5 ml of sample at 0 h, 4 h, and 24 h, filter through a 0.45 m aqueous filter membrane, discard 4 ml, take the filtrate, perform HPLC analysis, and calculate the solubility of the test sample in water at 37°C by the external standard method;

[0129] Aqueous solution stability study: Take the test solution at 0h and store it at room temperature to study its solution stability within 48h;

[0130] Table 12 Compound solubility test results

[0131]

[0132]

[0133] As can be seen from Table 12, the solubility of the raw material compound (II) is less than or equal to 0.01 g / 100 g water, which is poorly soluble, while all of its salt compounds were observed to be completely dissolved during the experiment, and the calculated solubility was greater than 0.34 g / 100 g water, and the solubility increased significantly;

[0134] Table 13 Compound solution stability test results

[0135]

[0136] As can be seen from Table 13, the aqueous solutions of all compounds have good stability.

Claims

1. A salt of a lappaconitine derivative, characterized in that The structural formula (I) of the salt is: Wherein, n is 1, X is hydrogen bromide, hydrogen chloride, nitric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid; n is 0.5, X is sulfuric acid.

2. The salt derived from lappaconitine according to claim 1, characterized in that The structural formula of the salt is (I)-1 compound: The compound of formula (I)-1 is a crystal in the form of Form A, and the Form A has at least one of the following characteristics: 1) Its XRPD pattern has characteristic peaks at at least 3, 5 or 6 of the following 2θ values: 5.41°±0.20°, 13.48°±0.20°, 14.43°±0.20°, 16.11°±0.20°, 20.86°±0.20° and 27.22±0.20°; 2) Its DSC spectrum has an absorption peak at 248±5℃; 3) After the mixture is placed at a temperature of 25°C and a relative humidity of 80% to reach equilibrium, the moisture content increases by 0-0.1% of the total weight; 4) The solubility in deionized water at 37°C is 3mg / mL-1g / mL; The XRPD spectrum of the crystalline form A also has characteristic peaks at at least 3, 5 or 7 of the following 2θ values: 9.68°±0.20°, 12.70°±0.20°, 16.52°±0.20°, 16.87°±0.20°, 19.59°±0.20°, 22.76°±0.20° and 22.93±0.20°.

3. The salt of the lappaconitine derivative according to claim 1, characterized in that The salt has the following structural formula (I)-2: The compound of formula (I)-2 is a crystal in the form of Form B, and the Form B has at least one of the following characteristics: 1) Its XRPD spectrum has characteristic peaks at at least 3, 5 or 7 of the following 2θ values: 5.39°±0.20°, 12.80°±0.20°, 13.48°±0.20°, 13.87°±0.20°, 14.65°±0.20°, 16.11°±0.20°, 19.72°±0.20°; 2) Its DSC spectrum has an absorption peak at 227±5℃; 3) After the mixture is placed at a temperature of 25°C and a relative humidity of 80% to reach equilibrium, the moisture content increases by 0-0.4% of the total weight; 4) Its solubility in deionized water at 37°C is 3 mg / mL-1 g / mL; The XRPD spectrum of the crystalline form B also has characteristic peaks at at least 3, 5 or 7 of the following 2θ values: 9.68°±0.20°, 9.94°±0.20°, 16.83°±0.20°20.79°±0.20°, 22.84°±0.20°, 24.88±0.20° and 27.21±0.20°.

4. A method for preparing a salt of a lappaconitine derivative, characterized in that: Follow these steps: a. Dissolve (1a,14a,16β)-20-ethyl-1,14,16-trimethoxyaconitane-4,8,9-triol 4-[2-(ethylsulfonylamino)]benzoate in a mixture of acetonitrile and dichloromethane or a mixture of methanol and dichloromethane at a volume ratio of 3:1, add 1 times the amount of hydrobromic acid solution, 2 mol / L hydrochloric acid solution, 65% nitric acid solution, p-toluenesulfonic acid monohydrate, methanesulfonic acid, 0.95 times the amount of 85% phosphoric acid or 0.45 times the amount of concentrated sulfuric acid at a temperature of 0°C, stir at room temperature for 1 hour, and then evaporate the solvent to obtain a mixture; b. Recrystallize the mixture obtained in step a with methanol, or slurry it with acetonitrile, ether or ethyl acetate at a temperature of 40°C for 2 hours, or slurry it with ethanol, ethyl acetate or ether for 2 hours, and filter to obtain solid compound (I)-1(la,14a,16β)-20-ethyl-1,14,16-trimethoxyaconitane-4,8,9-triol 4-[2-ethylsulfonylamino)]benzoate hydrobromide, or compound (I)-2((la,14a,16β)-20-ethyl-1,14,16-trimethoxyaconitane-4,8,9-triol 4-[2-ethylsulfonylamino)]benzoate hydrochloride, or compound (la,14a,16β)-20-ethyl-1,14,16-trimethoxyaconitane-4,8,9-triol 4-[2-ethylsulfonylamino)]benzoate hydrochloride )] benzoate nitrate; or (la,14a,16β)-20-ethyl-1,14,16-trimethoxyaconitane-4,8,9-triol 4-[2-ethylsulfonylamino)] benzoate p-toluenesulfonate; or (la,14a,16β)-20-ethyl-1,14,16-trimethoxyaconitane-4,8,9-triol 4-[2-ethylsulfonylamino)] benzoate methanesulfonate; or (la,14a,16β)-20-ethyl-1,14,16-trimethoxyaconitane-4,8,9-triol 4-[2-ethylsulfonylamino)] benzoate phosphate; or (la,14a,16β)-20-ethyl-1,14,16-trimethoxyaconitane-4,8,9-triol 4-[2-ethylsulfonylamino)] benzoate sulfate.

5. The pharmaceutical composition of the salt of the lappaconitine derivative having the structure of formula (I), (I)-1 and (I)-2 according to claims 1-3, characterized in that Optional pharmaceutically acceptable excipients are used to make oral preparations into tablets, capsules, granules, powders or syrups; non-oral preparations are self-injections, powder injections, sprays and suppositories.

6. Use of the compound according to any one of claims 1 to 3 or the pharmaceutical composition according to claim 5 in the preparation of a drug for treating cardiovascular and cerebrovascular diseases.

7. The use according to claim 6, wherein the cardiovascular disease is arrhythmia, heart failure, angina pectoris, myocardial ischemia, myocardial injury or myocardial infarction.

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