CN107778232B - Tetrahydroisoquinoline salt derivative and preparation method and application of crystal thereof - Google Patents

Tetrahydroisoquinoline salt derivative and preparation method and application of crystal thereof Download PDF

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CN107778232B
CN107778232B CN201610786957.2A CN201610786957A CN107778232B CN 107778232 B CN107778232 B CN 107778232B CN 201610786957 A CN201610786957 A CN 201610786957A CN 107778232 B CN107778232 B CN 107778232B
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crystal
acid
sipi
benzyloxy
salt derivative
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CN107778232A (en
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谢美华
张福利
吴泰志
钟家亮
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Shanghai Institute of Pharmaceutical Industry
China State Institute of Pharmaceutical Industry
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China State Institute of Pharmaceutical Industry
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Priority to PCT/CN2017/099549 priority patent/WO2018041112A1/en
Priority to JP2019512752A priority patent/JP6823714B2/en
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/18—Aralkyl radicals
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    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract

The invention discloses a salt derivative of 1- (3-methanesulfonamido benzyl) -6-methoxy-7-benzyloxy-1, 2,3, 4-tetrahydroisoquinoline shown as a formula I:

Description

Tetrahydroisoquinoline salt derivative and preparation method and application of crystal thereof
Technical Field
The invention relates to a salt derivative of 1- (3-methanesulfonamido benzyl) -6-methoxy-7-benzyloxy-1, 2,3, 4-tetrahydroisoquinoline and a preparation method thereof, and a pharmaceutical composition containing the salt derivative of 1- (3-methanesulfonamido benzyl) -6-methoxy-7-benzyloxy-1, 2,3, 4-tetrahydroisoquinoline.
Background
Sudden Cardiac Death (SCD) is one of the leading causes of death from cardiovascular disease. SCD production is the loss of regular heart rhythm due to myocardial electrophysiological instability, the most severe being persistent Ventricular Tachycardia (VT) and Ventricular Fibrillation (VF).
Antiarrhythmic drugs can be divided into four categories: class I is a sodium channel blocker, of which there are three subclasses, a, b, and c. Ia is a moderate block sodium channel, and represents drugs such as Quinidine (Quinidine); ib is a mild sodium channel blockage drug, which represents a drug such as Lidocaine (Lidocaine); the Ic type is obvious to block sodium channels, and represents drugs such as Flecainide (Flecainide) and the like. Class II is the β adrenoceptor blocker, the representative drug is Propranolol (Propranolol). Class III is a drug that selectively extends the repolarization process, and its Action Potential Duration (APD) and Effective Refractory Period (ERP) are extended, and Amiodarone (Amiodarone) and the like are typical drugs. Class IV is a calcium antagonist, and typical drugs include Verapamil (Verapamul).
Isoquinoline alkaloids widely exist in natural plants, wherein dibenzylisoquinoline alkaloids (such as berbamine, dauricine, tetrandrine, and neferine), monobenzylisoquinoline alkaloids (such as norcoclaurine), and protoberberine (berberine) have anti-arrhythmia cardiovascular activity. Wherein, the berberine shows III-type antiarrhythmic activity and is clinically reported to be used for treating ventricular arrhythmia.
Since 1985, the Shanghai pharmaceutical industry research institute Xiemehua researcher designed and synthesized nearly thousands of derivatives by using higenamine and berberine as lead compounds to carry out structural transformation. The synthesized nearly thousand new compounds are subjected to pharmacodynamic screening test, Ames toxicity test and acute toxicity evaluation related to arrhythmia, combined with pharmacokinetic parameter evaluation, and the optimal 1- (3-methanesulfonamido benzyl) -6-methoxy-7-benzyloxy-1, 2,3, 4-tetrahydroisoquinoline (hereinafter, abbreviated as SIPI-409) is screened out to be used as a candidate new antiarrhythmic drug for preclinical development, and the structure of the candidate new antiarrhythmic drug is shown in a formula (II).
Figure GDA0002970305850000021
Patent ZL200710181295.7 discloses 1- (3-methanesulfonamido benzyl) -6-methoxy-7-benzyloxy-1, 2,3, 4-tetrahydroisoquinoline (SIPI-409) and SIPI-409 hydrochloride structure, preparation method and application.
However, in further studies, the solubility of SIPI-409 and SIPI-409 hydrochloride in water was found to be very low, being only 0.07mg/mL (0.15nmol/mL) and 0.51mg/mL (1.05nmol/mL), respectively. Meanwhile, preliminary pharmacokinetic results show that: injection of SIPI-409 hydrochloride1/2Similar to sotalol, the bioavailability of SIPI-409 hydrochloride orally administered to SD rats is 24%, which is much lower than sotalol (70%), and is caused by too low solubility of SIPI-409 hydrochloride in water.
Therefore, there is an urgent need in the art to provide salt derivatives of the corresponding compounds with good solubility in water, thereby improving the bioavailability and the druggability thereof.
Disclosure of Invention
The invention aims to provide a SIPI-409 salt derivative with better solubility in water and a preparation method thereof.
In a first aspect of the present invention, there is provided a salt derivative of 1- (3-methanesulfonamidobenzyl) -6-methoxy-7-benzyloxy-1, 2,3, 4-tetrahydroisoquinoline represented by formula I:
Figure GDA0002970305850000022
the salt derivative has a solubility in water of not less than 3.0nmol/mL or 1.8 mg/mL.
In another preferred embodiment, HA is selected from sulfuric acid, nicotinic acid, oxalic acid, glycolic acid, benzenesulfonic acid, or orotic acid; x is selected from 1/3, 1/2, or 1.
In another preferred embodiment, the salt derivative of 1- (3-methanesulfonamidobenzyl) -6-methoxy-7-benzyloxy-1, 2,3, 4-tetrahydroisoquinoline is crystalline.
In another preferred embodiment, HA is sulfuric acid; x is selected from 1/2 or 1. More preferably, when X is 1, the crystalline form of the crystal is determined by X-powder diffraction technique (XRPD) and characterized by Bragg2 θ angle (Bragg2-Theta) as follows: 4.9 +/-0.2 °, 7.1 +/-0.2 °, 8.4 +/-0.2 °, 9.7 +/-0.2 °, 12.0 +/-0.2 °, 15.4 +/-0.2 °, 17.0 +/-0.2 °, 19.5 +/-0.2 °, 20.3 +/-0.2 °, 20.9 +/-0.2 °, 21.6 +/-0.2 °, 22.8 +/-0.2 °, 23.6 +/-0.2 °, 24.6 +/-0.2 °, 25.4 +/-0.2 °, 26.0 +/-0.2 ° and 30.8 +/-0.2 °; or a Differential Scanning Calorimetry (DSC) analysis, wherein an endothermic peak exists at 130 +/-5 ℃ in a DSC pattern.
In another preferred embodiment, HA is oxalic acid; x is selected from 1/2 or 1. More preferably, when X is 1, the crystalline form of the crystal is determined by X-powder diffraction technique (XRPD) and characterized by Bragg2 θ angle (Bragg2-Theta) as follows: 3.4 +/-0.2 °, 4.6 +/-0.2 °, 5.5 +/-0.2 °, 7.8 +/-0.2 °, 9.2 +/-0.2 °, 10.2 +/-0.2 °, 10.8 +/-0.2 °, 11.9 +/-0.2 °, 13.1 +/-0.2 °, 13.8 +/-0.2 °, 14.6 +/-0.2 °, 16.4 +/-0.2 °, 17.0 +/-0.2 °, 18.4 +/-0.2 °, 19.0 +/-0.2 °, 20.2 +/-0.2 °, 21.9 +/-0.2 °, 23.6 +/-0.2 °, 25.8 +/-0.2 °, 27.3 +/-0.2 °, 30.0 +/-0.2 ° and 31.9 +/-0.2 °; or when the compound is analyzed by using a Differential Scanning Calorimetry (DSC), an endothermic peak exists at 161 +/-5 ℃ in a DSC spectrum, and a wider endothermic peak exists in the range of 190-210 ℃.
In another preferred embodiment, the crystalline form of the crystals when HA is nicotinic acid is determined by X-powder diffraction technique (XRPD) and characterized by Bragg2-Theta angles (Bragg2-Theta) as follows: 5.0 +/-0.2 °, 5.9 +/-0.2 °, 7.2 +/-0.2 °, 8.2 +/-0.2 °, 10.9 +/-0.2 °, 12.2 +/-0.2 °, 13.4 +/-0.2 °, 14.4 +/-0.2 °, 15.1 +/-0.2 °, 15.5 +/-0.2 °, 17.0 +/-0.2 °, 17.4 +/-0.2 °, 17.8 +/-0.2 °, 18.7 +/-0.2 °, 19.9 +/-0.2 °, 20.5 +/-0.2 °, 20.8 +/-0.2 °, 21.9 +/-0.2 °, 23.1 +/-0.2 °, 23.5 +/-0.2 °, 24.8 +/-0.2 °, 25.1 +/-0.2 °, 25.6 +/-0.2 °, 27.0 +/-0.2 °, 27.6 +/-0.2 °; or when the compound is analyzed by using a Differential Scanning Calorimetry (DSC), an endothermic peak exists in a DSC graph at 152 +/-5 ℃.
In another preferred embodiment, the crystalline form of the crystals when HA is glycolic acid is determined by X-powder diffraction technique (XRPD) and characterized by Bragg2-Theta angles (Bragg2-Theta) as follows: 4.7 +/-0.2 °, 7.5 +/-0.2 °, 9.9 +/-0.2 °, 10.3 +/-0.2 °, 13.7 +/-0.2 °, 14.3 +/-0.2 °, 14.9 +/-0.2 °, 15.3 +/-0.2 °, 16.1 +/-0.2 °, 16.9 +/-0.2 °, 17.6 +/-0.2 °, 18.1 +/-0.2 °, 18.9 +/-0.2 °, 19.3 +/-0.2 °, 20.4 +/-0.2 °, 20.8 +/-0.2 °, 21.8 +/-0.2 °, 22.5 +/-0.2 °, 22.9 +/-0.2 °, 24.3 +/-0.2 °, 24.9 +/-0.2 °, 25.3 +/-0.2 °, 25.9 +/-0.2 °, 27.7 +/-0.2 °; or when the compound is analyzed by using a Differential Scanning Calorimetry (DSC), an endothermic peak exists at 187 +/-5 ℃ in a DSC chart.
In another preferred embodiment, the crystalline form of the crystals when HA is benzenesulfonic acid is determined by X-powder diffraction technique (XRPD) and characterized by Bragg2 θ angle (Bragg2-Theta) as follows: 6.1 +/-0.2 °, 6.8 +/-0.2 °, 8.2 +/-0.2 °, 8.8 +/-0.2 °, 11.5 +/-0.2 °, 12.7 +/-0.2 °, 14.4 +/-0.2 °, 15.0 +/-0.2 °, 15.5 +/-0.2 °, 16.5 +/-0.2 °, 17.0 +/-0.2 °, 17.4 +/-0.2 °, 17.7 +/-0.2 °, 18.7 +/-0.2 °, 19.4 +/-0.2 °, 19.8 +/-0.2 °, 20.3 +/-0.2 °, 21.3 +/-0.2 °, 21.7 +/-0.2 °, 22.6 +/-0.2 °, 23.0 +/-0.2 °, 23.5 +/-0.2 °, 24.2 +/-0.2 °, 29.1 +/-0.2 °; or when analyzed by Differential Scanning Calorimetry (DSC), an endothermic peak exists at 150 +/-5 ℃ and a shoulder peak exists near 160 ℃ in a DSC chart.
In another preferred embodiment, the crystalline form of the crystals when HA is orotic acid is determined by X-powder diffraction technique (XRPD) and characterized by Bragg2 Theta angle (Bragg2-Theta) as follows: 5.8 +/-0.2 °, 8.7 +/-0.2 °, 9.9 +/-0.2 °, 11.2 +/-0.2 °, 12.5 +/-0.2 °, 13.9 +/-0.2 °, 14.1 +/-0.2 °, 15.2 ° +/-0.2 °, 16.2 +/-0.2 °, 17.0 +/-0.2 °, 17.4 +/-0.2 °, 17.8 +/-0.2 °, 18.7 +/-0.2 °, 19.0 +/-0.2 °, 20.4 +/-0.2 °, 21.9 +/-0.2 °, 23.5 +/-0.2 °, 24.0 +/-0.2 °, 24.9 +/-0.2 °, 25.9 +/-0.2 °, 27.6 +/-0.2 °, 29.5 +/-0.2 °, 31.0 +/-0 °, 31.4 +/-0.2 °; or a Differential Scanning Calorimetry (DSC) analysis, wherein an endothermic peak exists at 138 +/-5 ℃ in a DSC chart.
In a second aspect of the present invention, there is provided a method for preparing a salt derivative of 1- (3-methanesulfonamidobenzyl) -6-methoxy-7-benzyloxy-1, 2,3, 4-tetrahydroisoquinoline provided by the present invention as described above, said method comprising the steps of: 1- (3-methanesulfonamido benzyl) -6-methoxy-7-benzyloxy-1, 2,3, 4-tetrahydroisoquinoline reacts with corresponding acid HA to form a salt derivative.
In another preferred example, the method comprises the steps of: 1- (3-methanesulfonamido benzyl) -6-methoxy-7-benzyloxy-1, 2,3, 4-tetrahydroisoquinoline reacts with corresponding acid in an organic solvent to form a salt derivative.
In another preferred example, the method comprises the steps of: when HA is nicotinic acid, oxalic acid, glycolic acid, benzenesulfonic acid or orotic acid, 1- (3-methanesulfonamido benzyl) -6-methoxy-7-benzyloxy-1, 2,3, 4-tetrahydroisoquinoline is dissolved in an organic solvent, then corresponding acid is added, and crystallization is carried out after cooling to obtain the product.
In another preferred example, the method comprises the steps of: when HA is sulfuric acid, 1- (3-methanesulfonamido benzyl) -6-methoxy-7-benzyloxy-1, 2,3, 4-tetrahydroisoquinoline is dissolved in organic solvent, then organic solvent containing corresponding acid is added, and crystallization is carried out after cooling to obtain the product.
In another preferred example, the method further comprises the steps of: washing and drying the precipitated crystal or precipitate.
In another preferred embodiment, the process involves a reaction temperature of 0-80 ℃.
In another preferred example, the organic solvent involved in the process is methanol, ethanol, isopropanol, acetone, 2-butanone, methyl acetate, isopropyl acetate, methyl tert-ether acetonitrile, or toluene.
In the third aspect of the present invention, there is provided a pharmaceutical composition, which comprises an effective amount of the salt derivative of 1- (3-methanesulfonamido-benzyl) -6-methoxy-7-benzyloxy-1, 2,3, 4-tetrahydroisoquinoline provided by the present invention as described above and one or more pharmaceutically acceptable excipients.
In a fourth aspect of the present invention, there is provided an application of the salt derivative of 1- (3-methanesulfonamido-benzyl) -6-methoxy-7-benzyloxy-1, 2,3, 4-tetrahydroisoquinoline provided by the present invention as described above in the preparation of an antiarrhythmic drug.
Accordingly, the invention provides a salt derivative of a corresponding compound with good solubility in water, so that the bioavailability of the salt derivative is improved, and the druggability of the salt derivative is improved.
Drawings
FIG. 1 is an XRPD pattern of SIPI-409 sulfate crystal under experimental conditions using a Cu target radiation source; in the figure, the horizontal axis represents diffraction peak position (2 θ value) and the vertical axis represents diffraction peak intensity.
FIG. 2 is a DSC spectrum of SIPI-409 sulfate crystals; the downward peak is shown as the endothermic peak.
FIG. 3 is an XRPD pattern of SIPI-409 nicotinate crystals under experimental conditions using a Cu target radiation source; in the figure, the horizontal axis represents diffraction peak position (2 θ value) and the vertical axis represents diffraction peak intensity.
Figure 4 is a DSC profile of SIPI-409 nicotinate crystals; the downward peak is shown as the endothermic peak.
FIG. 5 is an XRPD pattern of SIPI-409 oxalate crystals under experimental conditions using a Cu target radiation source; in the figure, the horizontal axis represents diffraction peak position (2 θ value) and the vertical axis represents diffraction peak intensity.
FIG. 6 is a DSC spectrum of SIPI-409 oxalate crystals; the downward peak is shown as the endothermic peak.
Figure 7 is an XRPD pattern of SIPI-409 glycolate crystals under experimental conditions using a Cu target radiation source; in the figure, the horizontal axis represents diffraction peak position (2 θ value) and the vertical axis represents diffraction peak intensity.
Figure 8 is a DSC profile of SIPI-409 glycolate crystals; the downward peak is shown as the endothermic peak.
FIG. 9 is an XRPD pattern of SIPI-409 benzenesulfonate crystals under experimental conditions employing a Cu target radiation source; in the figure, the horizontal axis represents diffraction peak position (2 θ value) and the vertical axis represents diffraction peak intensity.
FIG. 10 is a DSC spectrum of SIPI-409 benzenesulfonate crystals; the downward peak is shown as the endothermic peak.
Figure 11 is an XRPD pattern of SIPI-409 orotate crystals under experimental conditions using a Cu target radiation source; in the figure, the horizontal axis represents diffraction peak position (2 θ value) and the vertical axis represents diffraction peak intensity.
Figure 12 is a DSC profile of SIPI-409 orotate crystals; the downward peak is shown as the endothermic peak.
Figure 13 is a comparison of the XRPD pattern of SIPI-409 after reaction with 14 acids with the XRPD pattern of the SIPI-409 feedstock; wherein,
a is an XRPD pattern of the SIPI-409 raw material and an XRPD pattern of a reaction product of the SIPI-409 raw material and hydrochloric acid;
b is an XRPD pattern of the SIPI-409 raw material and an XRPD pattern of a reaction product of the SIPI-409 raw material and succinic acid;
c is the XRPD pattern of the SIPI-409 feedstock and its reaction product with glycolic acid;
d is an XRPD pattern of the SIPI-409 raw material and an XRPD pattern of a reaction product of the SIPI-409 raw material and oxalic acid;
e is the XRPD pattern of SIPI-409 raw material and the XRPD pattern of the reaction product of the raw material and the orotic acid;
f is the XRPD pattern of the SIPI-409 raw material and the XRPD pattern of the reaction product of the SIPI-409 raw material and fumaric acid;
g is the XRPD pattern of SIPI-409 raw material and the XRPD pattern of the reaction product of the SIPI-409 raw material and tartaric acid;
h is the XRPD pattern of the SIPI-409 raw material and the XRPD pattern of the reaction product of the SIPI-409 raw material and the ethanedisulfonic acid;
i is an XRPD pattern of the SIPI-409 raw material and an XRPD pattern of a reaction product of the SIPI-409 raw material and malic acid;
j is the XRPD pattern of the SIPI-409 raw material and the XRPD pattern of the reaction product of the SIPI-409 raw material and hydrobromic acid;
k is the XRPD pattern of SIPI-409 raw material and the XRPD pattern of the reaction product of the SIPI-409 raw material and nicotinic acid;
l is an XRPD pattern of the SIPI-409 raw material and an XRPD pattern of a reaction product of the SIPI-409 raw material and sulfuric acid;
m is the XRPD pattern of the SIPI-409 raw material and the XRPD pattern of the reaction product of the SIPI-409 raw material and benzene sulfonic acid.
Figure 14 is a perspective view of the single crystal molecule structure of SIPI-409 sulfate crystal.
Figure 15 is a solubility standard curve obtained using SIPI-409 standard; r value 0.999932.
Figure 16 is an XRPD pattern obtained from crystal stability studies of various salt derivatives of SIPI-409; wherein A is an XRPD pattern obtained by stability investigation of the crystal form of SIPI-409 nicotinate;
b is an XRPD pattern obtained by stability investigation of the crystal form of SIPI-409 glycolate;
c is an XRPD pattern obtained by stability investigation of the crystal form of SIPI-409 oxalate;
d is an XRPD pattern obtained from stability study of the crystal form of SIPI-409 orotate;
e is an XRPD pattern obtained by stability investigation of the crystal form of SIPI-409 benzenesulfonate;
f is the XRPD pattern obtained from stability studies of the crystalline form of SIPI-409 sulfate.
Detailed Description
The inventor has found that the solubility of the 1- (3-methanesulfonamido benzyl) -6-methoxy-7-benzyloxy-1, 2,3, 4-tetrahydroisoquinoline salt derivative with the structure shown in the formula I in water is obviously improved compared with the prior SIPI-409 and SIPI-409 hydrochloride, and a further pharmacokinetic experiment shows that the bioavailability of the SIPI-409 salt derivative is obviously improved compared with the prior SIPI-409 hydrochloride.
The invention provides a salt derivative of a compound SIPI-409 shown as a formula (I).
Figure GDA0002970305850000071
Wherein, the salt with SIPI-40 can be common organic acid or inorganic acid; may be selected from the acids described in table 1.
TABLE 1
Figure GDA0002970305850000081
The results of the salt-type prescreening experiments were tested using XRPD, comparing the XRPD patterns of SIPI-409 reacted with hydrochloric acid, succinic acid, fumaric acid, L-tartaric acid, ethanedisulfonic acid, glycolic acid, orotic acid, DL-malic acid, hydrobromic acid, oxalic acid, phosphoric acid, nicotinic acid, sulfuric acid, benzenesulfonic acid, etc., with the XRPD patterns of SIPI-409 starting material, see figure 15. The results show that the XRPD patterns of the 14 reaction products have significant differences from SIPI-409 in diffraction patterns, diffraction angle positions and diffraction intensity, and the salt forming reaction of the 14 acids and the SIPI-409 can be preliminarily judged. Preferably sulfuric acid, nicotinic acid, oxalic acid, glycolic acid, benzenesulfonic acid, or orotic acid, with SIPI-409; more preferably sulfuric acid, nicotinic acid, or oxalic acid.
The SIPI-409 sulfate crystal provided by the invention has the advantages that the ratio of SIPI-409 to sulfuric acid is 1:1 and 2:1, when the ratio of SIPI-409 to sulfuric acid is 1:1, the obtained crystal is analyzed by powder X-ray diffraction, and when Cu target radiation light source experiment conditions are adopted, the 2 theta characteristic diffraction peak is as follows: 4.9 +/-0.2 °, 7.1 +/-0.2 °, 8.4 +/-0.2 °, 9.7 +/-0.2 °, 12.0 +/-0.2 °, 15.4 +/-0.2 °, 17.0 +/-0.2 °, 19.5 +/-0.2 °, 20.3 +/-0.2 °, 20.9 +/-0.2 °, 21.6 +/-0.2 °, 22.8 +/-0.2 °, 23.6 +/-0.2 °, 24.6 +/-0.2 °, 25.4 +/-0.2 °, 26.0 +/-0.2 ° and 30.8 +/-0.2 °; more preferably, the XRPD pattern is as shown in figure 1.
When the SIPI-409 sulfate crystal is analyzed by using Differential Scanning Calorimetry (DSC), an endothermic peak exists at 130 +/-5 ℃ in a DSC chart with the temperature rise speed of 10 ℃/min; more preferably, the DSC pattern is as shown in figure 2.
The SIPI-409 sulfate crystal (C)25H28N2O4S·H2SO4) The single crystal of (A) is colorless transparent block-shaped, and the crystal density is 1.361g/cm3Space group is P-1, cell parameters:
Figure GDA0002970305850000091
Figure GDA0002970305850000093
94.86 ° for α, 106.70 ° for β, 110.95 ° for γ, unit cell volume
Figure GDA0002970305850000092
The number of asymmetric units in the unit cell, Z, is 2. (FIG. 14)
The SIPI-409 nicotinic acid salt crystal provided by the invention uses powder X-ray diffraction analysis, and when Cu target radiation light source experimental conditions are adopted, the 2 theta characteristic diffraction peak is as follows: 5.0 +/-0.2 °, 5.9 +/-0.2 °, 7.2 +/-0.2 °, 8.2 +/-0.2 °, 10.9 +/-0.2 °, 12.2 +/-0.2 °, 13.4 +/-0.2 °, 14.4 +/-0.2 °, 15.1 +/-0.2 °, 15.5 +/-0.2 °, 17.0 +/-0.2 °, 17.4 +/-0.2 °, 17.8 +/-0.2 °, 18.7 +/-0.2 °, 19.9 +/-0.2 °, 20.5 +/-0.2 °, 20.8 +/-0.2 °, 21.9 +/-0.2 °, 23.1 +/-0.2 °, 23.5 +/-0.2 °, 24.8 +/-0.2 °, 25.1 +/-0.2 °, 25.6 +/-0.2 °, 27.0 +/-0.2 °, 27.6 +/-0.2 °; more preferably, the XRPD pattern is as shown in figure 3.
When the SIPI-409 nicotinic acid salt crystal provided by the invention is analyzed by using a Differential Scanning Calorimetry (DSC), an endothermic peak exists at 152 +/-5 ℃ in a DSC graph with the temperature rise speed of 10 ℃/min; more preferably, the DSC pattern is as shown in figure 4.
The SIPI-409 oxalate crystal provided by the invention has the advantages that the ratio of SIPI-409 to oxalic acid is 1:1 or 2:1, when the ratio of SIPI-409 to oxalic acid is 1:1, the obtained crystal is analyzed by powder X-ray diffraction, and when Cu target radiation light source experiment conditions are adopted, the 2 theta characteristic diffraction peak is as follows: 3.4 +/-0.2 °, 4.6 +/-0.2 °, 5.5 +/-0.2 °, 7.8 +/-0.2 °, 9.2 +/-0.2 °, 10.2 +/-0.2 °, 10.8 +/-0.2 °, 11.9 +/-0.2 °, 13.1 +/-0.2 °, 13.8 +/-0.2 °, 14.6 +/-0.2 °, 16.4 +/-0.2 °, 17.0 +/-0.2 °, 18.4 +/-0.2 °, 19.0 +/-0.2 °, 20.2 +/-0.2 °, 21.9 +/-0.2 °, 23.6 +/-0.2 °, 25.8 +/-0.2 °, 27.3 +/-0.2 °, 30.0 +/-0.2 ° and 31.9 +/-0.2 °; more preferably, the XRPD pattern is as shown in figure 5.
When the SIPI-409 oxalate crystal is analyzed by using a Differential Scanning Calorimetry (DSC), an endothermic peak at 161 +/-5 ℃ and a wider endothermic peak at 190-210 ℃ exists in a DSC chart with the temperature rise speed of 10 ℃/min; more preferably, the DSC pattern is as shown in figure 6.
The SIPI-409 glycolate crystal provided by the invention uses powder X-ray diffraction analysis, and when Cu target radiation light source experimental conditions are adopted, the 2 theta characteristic diffraction peak is as follows: 4.7 +/-0.2 °, 7.5 +/-0.2 °, 9.9 +/-0.2 °, 10.3 +/-0.2 °, 13.7 +/-0.2 °, 14.3 +/-0.2 °, 14.9 +/-0.2 °, 15.3 +/-0.2 °, 16.1 +/-0.2 °, 16.9 +/-0.2 °, 17.6 +/-0.2 °, 18.1 +/-0.2 °, 18.9 +/-0.2 °, 19.3 +/-0.2 °, 20.4 +/-0.2 °, 20.8 +/-0.2 °, 21.8 +/-0.2 °, 22.5 +/-0.2 °, 22.9 +/-0.2 °, 24.3 +/-0.2 °, 24.9 +/-0.2 °, 25.3 +/-0.2 °, 25.9 +/-0.2 °, 27.7 +/-0.2 °; more preferably, the XRPD pattern is as shown in figure 7.
When the SIPI-409 glycolate crystal provided by the invention is analyzed by using a Differential Scanning Calorimetry (DSC), an endothermic peak at 187 +/-5 ℃ exists in a DSC spectrum with the temperature rise speed of 10 ℃/min; more preferably, the DSC pattern is as shown in figure 8.
The SIPI-409 benzene sulfonate crystal provided by the invention uses powder X-ray diffraction analysis, and when Cu target radiation light source experimental conditions are adopted, the 2 theta characteristic diffraction peak is as follows: 6.1 +/-0.2 °, 6.8 +/-0.2 °, 8.2 +/-0.2 °, 8.8 +/-0.2 °, 11.5 +/-0.2 °, 12.7 +/-0.2 °, 14.4 +/-0.2 °, 15.0 +/-0.2 °, 15.5 +/-0.2 °, 16.5 +/-0.2 °, 17.0 +/-0.2 °, 17.4 +/-0.2 °, 17.7 +/-0.2 °, 18.7 +/-0.2 °, 19.4 +/-0.2 °, 19.8 +/-0.2 °, 20.3 +/-0.2 °, 21.3 +/-0.2 °, 21.7 +/-0.2 °, 22.6 +/-0.2 °, 23.0 +/-0.2 °, 23.5 +/-0.2 °, 24.2 +/-0.2 °, 29.1 +/-0.2 °; more preferably, the XRPD is as shown in figure 9.
When the SIPI-409 benzenesulfonate crystal provided by the invention is analyzed by using a Differential Scanning Calorimetry (DSC), an endothermic peak exists at 150 +/-5 ℃ in a DSC graph with the temperature rise speed of 10 ℃/min, and a shoulder exists near 160 ℃; more preferably, the DSC pattern is as shown in figure 10.
The SIPI-409 orotate crystal provided by the invention uses powder X-ray diffraction analysis, and when Cu target radiation light source experimental conditions are adopted, the 2 theta characteristic diffraction peak is as follows: 5.8 +/-0.2 °, 8.7 +/-0.2 °, 9.9 +/-0.2 °, 11.2 +/-0.2 °, 12.5 +/-0.2 °, 13.9 +/-0.2 °, 14.1 +/-0.2 °, 15.2 ° +/-0.2 °, 16.2 +/-0.2 °, 17.0 +/-0.2 °, 17.4 +/-0.2 °, 17.8 +/-0.2 °, 18.7 +/-0.2 °, 19.0 +/-0.2 °, 20.4 +/-0.2 °, 21.9 +/-0.2 °, 23.5 +/-0.2 °, 24.0 +/-0.2 °, 24.9 +/-0.2 °, 25.9 +/-0.2 °, 27.6 +/-0.2 °, 29.5 +/-0.2 °, 31.0 +/-0 °, 31.4 +/-0.2 °; more preferably, the XRPD pattern is as shown in figure 11.
When the SIPI-409 orotate crystal provided by the invention is analyzed by using a Differential Scanning Calorimetry (DSC), an endothermic peak exists at 138 +/-5 ℃ in a DSC graph with the temperature rise speed of 10 ℃/min; more preferably, the DSC pattern is as shown in figure 12.
The SIPI-409 salt derivative crystal provided by the invention comprises a single crystal and a polymorphism thereof.
The invention also provides a preparation method of the SIPI-409 salt derivative and the crystal thereof, which comprises the steps of dissolving SIPI-409 in an organic solvent, adding organic or inorganic acid, stirring for reaction, cooling for crystallization, and obtaining the SIPI-409 salt derivative crystal. The above-mentioned solvents include alcohol solvents, ketone solvents, ether solvents, ester solvents, aromatic hydrocarbon solvents, and nitrile solvents. The alcoholic solvent includes methanol, ethanol, and isopropanol; methanol is preferred; the ketone solvent comprises acetone and 2-butanone; the ether solvent includes methyl tertiary ether, tetrahydrofuran, and 2-methyl tetrahydrofuran; the ester solvents include ethyl acetate, methyl acetate, and isopropyl acetate; the aromatic hydrocarbon solvent comprises toluene and xylene; the nitrile solvent is acetonitrile. The reaction temperature for salifying is 0-80 ℃; preferably 10 to 60 ℃; most preferably 40 deg.c. The ratio of SIPI-409 to acid and the manner of addition may be varied adaptively according to the desired salt derivative without departing from the principles of the present invention.
The SIPI-409 salt derivative or the crystal thereof provided by the invention has certain stability, and can be used as an active ingredient to develop an anti-arrhythmia drug in an oral dosage form for clinical use. Common oral administration forms comprise common tablets, capsules, dispersible tablets, pellets and the like, and excipients, lubricants, adhesives and other auxiliary materials in the dosage forms are all common auxiliary materials in the field.
The features mentioned above with reference to the invention, or the features mentioned with reference to the embodiments, can be combined arbitrarily. All the features disclosed in this specification may be combined in any combination, and each feature disclosed in this specification may be replaced by alternative features serving the same, equivalent or similar purpose. Thus, unless expressly stated otherwise, the features disclosed are merely generic examples of equivalent or similar features.
The main advantages of the invention are: the novel SIPI-409 salt derivative and the crystal thereof provided by the invention can obviously improve the water solubility, and further improve the bioavailability and the drug property.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers. All percentages, ratios, proportions, or parts are by weight unless otherwise specified. The weight volume percentage units in the present invention are well known to those skilled in the art and refer to, for example, the weight of solute in a 100 ml solution. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
The XRPD pattern in the experiment related by the invention is obtained under the experimental condition of a Cu target radiation light source.
The DSC chart in the experiment related by the invention shows that the temperature rise speed is 10 ℃/min.
The stability of the SIPI-40 salt derivative refers to the stability of the salt derivative crystal to temperature, humidity, illumination and hygroscopicity in a certain time.
Example 1
SIPI-409 sulfate and preparation of crystal
Taking SIPI-4090.5 g (0.11mmol), placing the SIPI-4090.5 g in a 50mL flask, adding 20mL of methanol solvent, controlling the water bath temperature at 40 ℃, dropwise adding 1.3mL (0.13mmol) of 1M methanol sulfate solution, continuing to keep the temperature at 40 ℃, stirring for 2 hours, cooling to 5-15 ℃, crystallizing, and filtering to obtain 0.54g of SIPI-409 sulfate white solid powder with the yield of 90%, wherein SIPI-409: 1:1 sulfuric acid, and single crystal data are shown in the attached figure. The XRPD pattern is shown in figure 1, and the DSC pattern is shown in figure 2.
Example 2
Preparation of SIPI-409 nicotinate and crystal
Taking SIPI-4090.5 g (0.11mmol), placing in a 50mL flask, adding 20mL methanol solvent, controlling the water bath temperature at 40 ℃, adding 0.16g nicotinic acid (0.13mmol), continuing to keep at 40 ℃, stirring for 2 hours, cooling to 5-15 ℃, crystallizing, and filtering to obtain SIPI-409 nicotinate white solid powder 0.49g with the yield of 78%. The XRPD pattern is shown in figure 3, and the DSC pattern is shown in figure 4.
Example 3
Preparation of SIPI-409 oxalate and crystal
Taking SIPI-4090.5 g (0.11mmol), placing in a 50mL flask, adding 20mL methanol solvent, controlling the water bath temperature at 40 ℃, adding oxalic acid 0.117g (0.13mmol), keeping the temperature at 40 ℃, stirring for 2 hours, cooling to 5-15 ℃, crystallizing, and filtering to obtain SIPI-409 oxalate white solid powder 0.50g, with the yield of 84%. The XRPD pattern is shown in figure 5, and the DSC pattern is shown in figure 6.
Example 4
SIPI-409 glycolate and preparation of crystal
Taking SIPI-4090.5 g (0.11mmol), placing in a 50mL flask, adding 20mL methanol solvent, controlling the water bath temperature at 40 ℃, adding glycolic acid 0.098g (0.13mmol), keeping the temperature at 40 ℃, stirring for 2 hours, cooling to 5-15 ℃, crystallizing, and filtering to obtain SIPI-409 glycolate white solid powder 0.47g with the yield of 81%. The XRPD pattern is shown in figure 7, and the DSC pattern is shown in figure 8.
Example 5
SIPI-409 benzene sulfonate and preparation of crystal
Taking SIPI-4090.5 g (0.11mmol), placing the SIPI-4090.5 g in a 50mL flask, adding 20mL of methanol solvent, controlling the water bath temperature at 40 ℃, adding 0.205g (0.13mmol) of benzenesulfonic acid, keeping the temperature at 40 ℃, stirring for 2 hours, cooling to 5-15 ℃, crystallizing, and filtering to obtain SIPI-409 benzenesulfonate white solid powder 0.57g with the yield of 84%. The XRPD pattern is shown in figure 9, and the DSC pattern is shown in figure 10.
Example 6
Preparation of SIPI-409 orotate and crystal
Taking SIPI-4090.5 g (0.11mmol), placing the SIPI-4090.5 g in a 50mL flask, adding 20mL of methanol solvent, controlling the water bath temperature at 40 ℃, adding 0.226g (0.13mmol) of orotic acid monohydrate, keeping the temperature at 40 ℃, stirring for 2 hours, cooling to 5-15 ℃, crystallizing, and filtering to obtain 0.52g of SIPI-409 orotate white solid powder with the yield of 77%. The XRPD pattern is shown in figure 11, and the DSC pattern is shown in figure 12.
Example 7
Determination of solubility in Water
And (3) measuring the water solubility of the SIPI-409 and the salt derivatives thereof by adopting a liquid chromatography.
The method comprises the following main experimental steps: configuration concentrations of SIPI-409 standard substances of 5g/mL, 10g/mL, 50g/mL, 100g/mL and 200g/mL respectively are prepared into standard curves, and the results are shown in figure 15.
Chromatographic conditions are as follows:
a chromatographic column: phenomenex Luna 5u C18(2)100A 4.6X 200mm
Detection wavelength: 210nm
Mobile phase: acetonitrile/phosphate buffer (0.68g/L potassium dihydrogen phosphate, pH 3.0 adjusted by triethylamine) ═ 68/32
Column temperature: 30 deg.C
Sample introduction amount: 10L
Retention time: about 6.3min
Sample treatment: preparing a sample to be detected into a supersaturated aqueous solution (suspension), placing the supersaturated aqueous solution (suspension) at the temperature of 30 ℃ for 12 hours after shaking, placing the supersaturated aqueous solution in an ultrasonic instrument for 30 seconds, filtering, diluting by a proper multiple, and carrying out HPLC analysis. The test results are shown in Table 2.
Table 2 solubility in water results
Figure GDA0002970305850000141
Figure GDA0002970305850000151
The results show that the water solubility of the SIPI-409 sulfate, SIPI-409 nicotinate, SIPI-409 oxalate, SIPI-409 glycolate, SIPI-409 benzenesulfonate and SIPI-409 orotate of the invention is obviously improved compared with the water solubility of the prior SIPI-409 and SIPI-409 hydrochloride.
Example 8
Stability survey
Temperature stability investigation
SIPI-409 nicotinate, glycolate, oxalate, orotate, benzene sulfonate and sulfate are placed in a 60 ℃ oven, and samples are respectively taken for 0 day, 5 days, 10 days, 20 days and 30 days to carry out XRPD test.
Investigation of humidity stability
Placing SIPI-409 nicotinate, glycolate, oxalate, orotate, benzene sulfonate, and sulfate at 92.5% RH (saturated KNO)3) Samples were taken at 0, 5, 10, 20 and 30 days for XRPD testing.
Investigation of illumination stability
SIPI-409 nicotinate, glycolate, oxalate, orotate, benzene sulfonate and sulfate are placed in a lighting box, and samples are taken for 0 day, 5 days, 10 days, 20 days and 30 days respectively to carry out XRPD test.
Investigation of moisture absorption
In order to further understand the hygroscopicity of the sample, SIPI-409 nicotinate, glycolate, oxalate, orotate, benzenesulfonate, sulfate were placed in a dynamic moisture sorption analyzer (DVS) for hygroscopicity examination.
The results of the stability studies are shown in FIG. 16 and Table 3.
Table 36 evaluation results of SIPI-409 salt forms
Figure GDA0002970305850000161
The results show that in addition to the fact that nicotinic acid salts are not stable to heat and change at high temperature of 60 ℃ within 5 days, other salt derivatives not only have good solubility in water, but also show the expected stability.
The foregoing is merely a preferred embodiment of the invention and is not intended to limit the scope of the invention, which is defined by the claims appended hereto, and any other technical entity or method that is encompassed by the claims as broadly defined herein, or equivalent variations thereof, is contemplated as being encompassed by the claims.

Claims (9)

1. A salt derivative of 1- (3-methanesulfonamido-benzyl) -6-methoxy-7-benzyloxy-1, 2,3, 4-tetrahydroisoquinoline represented by formula I:
Figure FDA0003026679080000011
the solubility of the salt derivative in water is not less than 3.0 nmol/mL; x is 1;
the salt derivative of the 1- (3-methanesulfonamido benzyl) -6-methoxyl, 7-benzyloxy-1, 2,3, 4-tetrahydroisoquinoline is crystal;
HA is sulfuric acid; the crystal form of the crystal is determined by an X-powder diffraction technology and is characterized by the following Bragg2 theta angle: 4.9 +/-0.2 °, 7.1 +/-0.2 °, 8.4 +/-0.2 °, 9.7 +/-0.2 °, 12.0 +/-0.2 °, 15.4 +/-0.2 °, 17.0 +/-0.2 °, 19.5 +/-0.2 °, 20.3 +/-0.2 °, 20.9 +/-0.2 °, 21.6 +/-0.2 °, 22.8 +/-0.2 °, 23.6 +/-0.2 °, 24.6 +/-0.2 °, 25.4 +/-0.2 °, 26.0 +/-0.2 ° and 30.8 +/-0.2 °;
HA is nicotinic acid; the crystal form of the crystal is determined by an X-powder diffraction technology and is characterized by the following Bragg2 theta angle: 5.0 +/-0.2 °, 5.9 +/-0.2 °, 7.2 +/-0.2 °, 8.2 +/-0.2 °, 10.9 +/-0.2 °, 12.2 +/-0.2 °, 13.4 +/-0.2 °, 14.4 +/-0.2 °, 15.1 +/-0.2 °, 15.5 +/-0.2 °, 17.0 +/-0.2 °, 17.4 +/-0.2 °, 17.8 +/-0.2 °, 18.7 +/-0.2 °, 19.9 +/-0.2 °, 20.5 +/-0.2 °, 20.8 +/-0.2 °, 21.9 +/-0.2 °, 23.1 +/-0.2 °, 23.5 +/-0.2 °, 24.8 +/-0.2 °, 25.1 +/-0.2 °, 25.6 +/-0.2 °, 27.0 +/-0.2 °, 27.6 +/-0.2 °;
HA is oxalic acid; the crystal form of the crystal is determined by an X-powder diffraction technology and is characterized by the following Bragg2 theta angle: 3.4 +/-0.2 °, 4.6 +/-0.2 °, 5.5 +/-0.2 °, 7.8 +/-0.2 °, 9.2 +/-0.2 °, 10.2 +/-0.2 °, 10.8 +/-0.2 °, 11.9 +/-0.2 °, 13.1 +/-0.2 °, 13.8 +/-0.2 °, 14.6 +/-0.2 °, 16.4 +/-0.2 °, 17.0 +/-0.2 °, 18.4 +/-0.2 °, 19.0 +/-0.2 °, 20.2 +/-0.2 °, 21.9 +/-0.2 °, 23.6 +/-0.2 °, 25.8 +/-0.2 °, 27.3 +/-0.2 °, 30.0 +/-0.2 ° and 31.9 +/-0.2 °;
HA is glycolic acid; the crystal form of the crystal is determined by an X-powder diffraction technology and is characterized by the following Bragg2 theta angle: 4.7 +/-0.2 °, 7.5 +/-0.2 °, 9.9 +/-0.2 °, 10.3 +/-0.2 °, 13.7 +/-0.2 °, 14.3 +/-0.2 °, 14.9 +/-0.2 °, 15.3 +/-0.2 °, 16.1 +/-0.2 °, 16.9 +/-0.2 °, 17.6 +/-0.2 °, 18.1 +/-0.2 °, 18.9 +/-0.2 °, 19.3 +/-0.2 °, 20.4 +/-0.2 °, 20.8 +/-0.2 °, 21.8 +/-0.2 °, 22.5 +/-0.2 °, 22.9 +/-0.2 °, 24.3 +/-0.2 °, 24.9 +/-0.2 °, 25.3 +/-0.2 °, 25.9 +/-0.2 °, 27.7 +/-0.2 °;
HA is benzenesulfonic acid; the crystal form of the crystal is determined by an X-powder diffraction technology and is characterized by the following Bragg2 theta angle: 6.1 +/-0.2 °, 6.8 +/-0.2 °, 8.2 +/-0.2 °, 8.8 +/-0.2 °, 11.5 +/-0.2 °, 12.7 +/-0.2 °, 14.4 +/-0.2 °, 15.0 +/-0.2 °, 15.5 +/-0.2 °, 16.5 +/-0.2 °, 17.0 +/-0.2 °, 17.4 +/-0.2 °, 17.7 +/-0.2 °, 18.7 +/-0.2 °, 19.4 +/-0.2 °, 19.8 +/-0.2 °, 20.3 +/-0.2 °, 21.3 +/-0.2 °, 21.7 +/-0.2 °, 22.6 +/-0.2 °, 23.0 +/-0.2 °, 23.5 +/-0.2 °, 24.2 +/-0.2 °, 29.1 +/-0.2 °; or
HA is orotic acid; the crystal form of the crystal is determined by an X-powder diffraction technology and is characterized by the following Bragg2 theta angle: 5.8 +/-0.2 °, 8.7 +/-0.2 °, 9.9 +/-0.2 °, 11.2 +/-0.2 °, 12.5 +/-0.2 °, 13.9 +/-0.2 °, 14.1 +/-0.2 °, 15.2 ° +/-0.2 °, 16.2 +/-0.2 °, 17.0 +/-0.2 °, 17.4 +/-0.2 °, 17.8 +/-0.2 °, 18.7 +/-0.2 °, 19.0 +/-0.2 °, 20.4 +/-0.2 °, 21.9 +/-0.2 °, 23.5 +/-0.2 °, 24.0 +/-0.2 °, 24.9 +/-0.2 °, 25.9 +/-0.2 °, 27.6 +/-0.2 °, 29.5 +/-0.2 °, 31.0 +/-0.2 °, 31.4 +/-0.2 °.
2. A salt derivative of 1- (3-methanesulfonamido-benzyl) -6-methoxy-7-benzyloxy-1, 2,3, 4-tetrahydroisoquinoline represented by formula I:
Figure FDA0003026679080000021
the solubility of the salt derivative in water is not less than 1.8 mg/mL; x is 1;
the salt derivative of the 1- (3-methanesulfonamido benzyl) -6-methoxyl, 7-benzyloxy-1, 2,3, 4-tetrahydroisoquinoline is crystal;
HA is sulfuric acid; the crystal form of the crystal is determined by an X-powder diffraction technology and is characterized by the following Bragg2 theta angle: 4.9 +/-0.2 °, 7.1 +/-0.2 °, 8.4 +/-0.2 °, 9.7 +/-0.2 °, 12.0 +/-0.2 °, 15.4 +/-0.2 °, 17.0 +/-0.2 °, 19.5 +/-0.2 °, 20.3 +/-0.2 °, 20.9 +/-0.2 °, 21.6 +/-0.2 °, 22.8 +/-0.2 °, 23.6 +/-0.2 °, 24.6 +/-0.2 °, 25.4 +/-0.2 °, 26.0 +/-0.2 ° and 30.8 +/-0.2 °;
HA is nicotinic acid; the crystal form of the crystal is determined by an X-powder diffraction technology and is characterized by the following Bragg2 theta angle: 5.0 +/-0.2 °, 5.9 +/-0.2 °, 7.2 +/-0.2 °, 8.2 +/-0.2 °, 10.9 +/-0.2 °, 12.2 +/-0.2 °, 13.4 +/-0.2 °, 14.4 +/-0.2 °, 15.1 +/-0.2 °, 15.5 +/-0.2 °, 17.0 +/-0.2 °, 17.4 +/-0.2 °, 17.8 +/-0.2 °, 18.7 +/-0.2 °, 19.9 +/-0.2 °, 20.5 +/-0.2 °, 20.8 +/-0.2 °, 21.9 +/-0.2 °, 23.1 +/-0.2 °, 23.5 +/-0.2 °, 24.8 +/-0.2 °, 25.1 +/-0.2 °, 25.6 +/-0.2 °, 27.0 +/-0.2 °, 27.6 +/-0.2 °;
HA is oxalic acid; the crystal form of the crystal is determined by an X-powder diffraction technology and is characterized by the following Bragg2 theta angle: 3.4 +/-0.2 °, 4.6 +/-0.2 °, 5.5 +/-0.2 °, 7.8 +/-0.2 °, 9.2 +/-0.2 °, 10.2 +/-0.2 °, 10.8 +/-0.2 °, 11.9 +/-0.2 °, 13.1 +/-0.2 °, 13.8 +/-0.2 °, 14.6 +/-0.2 °, 16.4 +/-0.2 °, 17.0 +/-0.2 °, 18.4 +/-0.2 °, 19.0 +/-0.2 °, 20.2 +/-0.2 °, 21.9 +/-0.2 °, 23.6 +/-0.2 °, 25.8 +/-0.2 °, 27.3 +/-0.2 °, 30.0 +/-0.2 ° and 31.9 +/-0.2 °;
HA is glycolic acid; the crystal form of the crystal is determined by an X-powder diffraction technology and is characterized by the following Bragg2 theta angle: 4.7 +/-0.2 °, 7.5 +/-0.2 °, 9.9 +/-0.2 °, 10.3 +/-0.2 °, 13.7 +/-0.2 °, 14.3 +/-0.2 °, 14.9 +/-0.2 °, 15.3 +/-0.2 °, 16.1 +/-0.2 °, 16.9 +/-0.2 °, 17.6 +/-0.2 °, 18.1 +/-0.2 °, 18.9 +/-0.2 °, 19.3 +/-0.2 °, 20.4 +/-0.2 °, 20.8 +/-0.2 °, 21.8 +/-0.2 °, 22.5 +/-0.2 °, 22.9 +/-0.2 °, 24.3 +/-0.2 °, 24.9 +/-0.2 °, 25.3 +/-0.2 °, 25.9 +/-0.2 °, 27.7 +/-0.2 °;
HA is benzenesulfonic acid; the crystal form of the crystal is determined by an X-powder diffraction technology and is characterized by the following Bragg2 theta angle: 6.1 +/-0.2 °, 6.8 +/-0.2 °, 8.2 +/-0.2 °, 8.8 +/-0.2 °, 11.5 +/-0.2 °, 12.7 +/-0.2 °, 14.4 +/-0.2 °, 15.0 +/-0.2 °, 15.5 +/-0.2 °, 16.5 +/-0.2 °, 17.0 +/-0.2 °, 17.4 +/-0.2 °, 17.7 +/-0.2 °, 18.7 +/-0.2 °, 19.4 +/-0.2 °, 19.8 +/-0.2 °, 20.3 +/-0.2 °, 21.3 +/-0.2 °, 21.7 +/-0.2 °, 22.6 +/-0.2 °, 23.0 +/-0.2 °, 23.5 +/-0.2 °, 24.2 +/-0.2 °, 29.1 +/-0.2 °; or
HA is orotic acid; the crystal form of the crystal is determined by an X-powder diffraction technology and is characterized by the following Bragg2 theta angle: 5.8 +/-0.2 °, 8.7 +/-0.2 °, 9.9 +/-0.2 °, 11.2 +/-0.2 °, 12.5 +/-0.2 °, 13.9 +/-0.2 °, 14.1 +/-0.2 °, 15.2 ° +/-0.2 °, 16.2 +/-0.2 °, 17.0 +/-0.2 °, 17.4 +/-0.2 °, 17.8 +/-0.2 °, 18.7 +/-0.2 °, 19.0 +/-0.2 °, 20.4 +/-0.2 °, 21.9 +/-0.2 °, 23.5 +/-0.2 °, 24.0 +/-0.2 °, 24.9 +/-0.2 °, 25.9 +/-0.2 °, 27.6 +/-0.2 °, 29.5 +/-0.2 °, 31.0 +/-0.2 °, 31.4 +/-0.2 °.
3. The salt derivative of 1- (3-methanesulfonamidobenzyl) -6-methoxy, 7-benzyloxy-1, 2,3, 4-tetrahydroisoquinoline according to claim 1 or 2, wherein,
HA is sulfuric acid; when analyzed by using a differential scanning calorimetry technology, an endothermic peak exists at 130 +/-5 ℃ in a DSC chart;
HA is nicotinic acid; when analyzed by using a differential scanning calorimetry technique, an endothermic peak exists in a DSC chart at 152 +/-5 ℃;
HA is oxalic acid; when a Differential Scanning Calorimetry (DSC) technology is used for analysis, an endothermic peak exists in a DSC spectrum at 161 +/-5 ℃, and a wider endothermic peak exists in a range of 190-210 ℃;
HA is glycolic acid; when analyzed by using a differential scanning calorimetry technology, an endothermic peak exists at 187 +/-5 ℃ in a DSC chart;
HA is benzenesulfonic acid; when analyzed by differential scanning calorimetry, an endothermic peak exists at 150 +/-5 ℃ and a shoulder peak exists at 160 ℃ in a DSC chart; or
HA is orotic acid; when analyzed by differential scanning calorimetry, an endothermic peak at 138 + -5 deg.C exists in the DSC chart.
4. A method for preparing a salt derivative of 1- (3-methanesulfonamidobenzyl) -6-methoxy-7-benzyloxy-1, 2,3, 4-tetrahydroisoquinoline according to any one of claims 1 to 3, which comprises: when HA is nicotinic acid, oxalic acid, glycolic acid, benzenesulfonic acid or orotic acid, dissolving 1- (3-methanesulfonamido benzyl) -6-methoxy-7-benzyloxy-1, 2,3, 4-tetrahydroisoquinoline in an organic solvent, then adding corresponding acid, cooling and crystallizing to obtain a product; or
When HA is sulfuric acid, 1- (3-methanesulfonamido benzyl) -6-methoxy-7-benzyloxy-1, 2,3, 4-tetrahydroisoquinoline is dissolved in organic solvent, then organic solvent containing corresponding acid is added, and crystallization is carried out after cooling to obtain the product.
5. The preparation method of the salt derivative of 1- (3-methanesulfonamidobenzyl) -6-methoxy-7-benzyloxy-1, 2,3, 4-tetrahydroisoquinoline according to claim 4, which further comprises: washing and drying the precipitated crystal or precipitate.
6. The method for producing a salt derivative of 1- (3-methanesulfonamidobenzyl) -6-methoxy-7-benzyloxy-1, 2,3, 4-tetrahydroisoquinoline according to claim 4, wherein the temperature of the production method is 0 to 80 ℃.
7. The method for producing a salt derivative of 1- (3-methanesulfonamidobenzyl) -6-methoxy-7-benzyloxy-1, 2,3, 4-tetrahydroisoquinoline according to claim 4, wherein the organic solvent is methanol, ethanol, isopropanol, acetone, 2-butanone, methyl acetate, isopropyl acetate, methyl tert-ether acetonitrile, or toluene.
8. A pharmaceutical composition consisting of an effective amount of the salt derivative of 1- (3-methanesulfonamidobenzyl) -6-methoxy-7-benzyloxy-1, 2,3, 4-tetrahydroisoquinoline as described in any one of claims 1 to 3, and one or more pharmaceutically acceptable excipients.
9. Use of a salt derivative of 1- (3-methanesulfonamidobenzyl) -6-methoxy-7-benzyloxy-1, 2,3, 4-tetrahydroisoquinoline as defined in any one of claims 1 to 3 for the preparation of a medicament for treating arrhythmia.
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