CN107778232A - A kind of salt derivative of tetrahydroisoquinoline and its preparation method and application of crystal - Google Patents
A kind of salt derivative of tetrahydroisoquinoline and its preparation method and application of crystal Download PDFInfo
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- CN107778232A CN107778232A CN201610786957.2A CN201610786957A CN107778232A CN 107778232 A CN107778232 A CN 107778232A CN 201610786957 A CN201610786957 A CN 201610786957A CN 107778232 A CN107778232 A CN 107778232A
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- benzyl
- methoxyl groups
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- benzyloxy
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention discloses a kind of 1 (3 methylsulfonyl amido benzyl) 6 methoxyl groups shown in formula I, the salt derivative of the tetrahydroisoquinoline of 7 benzyloxy 1,2,3,4：
Description
Technical field
The present invention relates to a kind of 1- (3- methylsulfonyl amidos benzyl) -6- methoxyl groups, 7- benzyloxy -1,2,3,4- Tetrahydroisoquinoli-s
Salt derivative of quinoline and preparation method thereof, and comprising 1- (3- methylsulfonyl amidos benzyl) -6- methoxyl groups, 7- benzyloxies -1,2,
The drug component of the salt derivative of 3,4- tetrahydroisoquinolines.
Background technology
Sudden cardiac death (SCD) is one of angiocardiopathy main causes of death.It is due to myocardium electricity that SCD, which is produced,
Physiology is unstable and causes the regular rhythm of the heart to disappear, and the most serious is Continuous Ventricular speed (VT, ventricular
Tachycardia) quivered (VF, vetricalar fibrillation) with room.
Antiarrhymic can be divided into four classes：I classes are sodium channel blocking agent, wherein there is tri- subclass of a, b, c.Ia classes are suitable
Block sodium channels are spent, representing medicine has quinindium (Quinidine) etc.；Ib classes are slight block sodium channels, and it is favourable to represent medicine
More cacaines (Lidocaine) etc.；Ic classes are obvious block sodium channels, and representing medicine has Flecainide (Flecainide) etc..II classes
For beta-2 adrenoceptor blocking agent, medicine is represented as Propranolol (Propranolol).Group III is selectively extension multipole mistake
The medicine of journey, its over reach potential duration (APD) and ERP (ERP), representing medicine has amiodarone (Amiodarone)
Deng.IV classes are calcium antagonist, and representing medicine has Verapamil (Verapamil) etc..
Morphinane alkaloid is widely present in natural plants, and wherein bisbenzylisoquinoline alkaloid is (such as：Berbamine,
Dauricine, Tet, mufangchine, neferine), monobenzyl morphinane alkaloid is (such as：Demethyl coclaurine) and it is former
Jamaicin (berberine) etc. has the cardiac vascular activities such as anti-arrhythmia.Wherein, jamaicin is presented Group III anti-arrhythmia and lived
Property, clinical report is used for Ventricular Arrhythmias.
Shanghai Institute of Pharmaceutical Industry Xie Meihua researcher was since 1985, based on demethyl coclaurine and jamaicin
Compound carries out structure of modification, has designed and synthesized nearly thousand derivatives.Above-mentioned nearly thousand noval chemical compounds of synthesis are through the anti-rhythm of the heart
Not normal relevant Pharmacodynamics screening experiment, Ames toxicity tests and acute toxicity evaluation, with reference to medicine for parameter evaluation, filter out most
Good 1- (3- methylsulfonyl amidos benzyl) -6- methoxyl groups, 7- benzyloxy -1,2,3,4- tetrahydroisoquinolines (use abbreviation SIPI- below
409) preclinical exploitation is carried out as candidate's Antiarrhythmic Agent, shown in its structure such as formula (II).
Patent ZL200710181295.7 discloses 1- (3- methylsulfonyl amidos benzyl) -6- methoxyl groups, 7- benzyloxy -1,2,
The structure and preparation method and application of 3,4- tetrahydroisoquinolines (SIPI-409) and SIPI-409 hydrochlorides.
But found in further research, solubility of the SIPI-409 and SIPI-409 hydrochlorides in water is very low,
Respectively it is only 0.07mg/mL (0.15nmol/mL) and 0.51mg/mL (1.05nmol/mL).Simultaneously preliminary pharmacokinetics
As a result show：The t of drug administration by injection SIPI-409 hydrochlorides1/2It is similar with Sotalol, SD Oral Administration in Rats administration bioavilability
SIPI-409 hydrochlorides are 24%, far below Sotalol (70%), for SIPI-409 hydrochlorides in water the too low institute of solubility
Cause.
Therefore, this area is there is an urgent need to provide the salt derivative of the respective compound that solubility is good in water, and then improves
Its bioavilability, improve its druggability.
The content of the invention
The present invention is intended to provide one kind preferable SIPI-409 salt derivatives of solubility and preparation method thereof in water.
In the first aspect of the present invention, there is provided 1- (3- methylsulfonyl amidos benzyl) -6- methoxyl groups shown in Formulas I, 7- benzyls
Oxy-1, the salt derivative of 2,3,4- tetrahydroisoquinolines：
The solubility of the salt derivative is not less than 3.0nmol/mL or 1.8mg/mL.
In another preference, HA is selected from sulfuric acid, nicotinic acid, oxalic acid, glycolic, benzene sulfonic acid or orotic acid；X be selected from 1/3,
1/2 or 1.
In another preference, described 1- (3- methylsulfonyl amidos benzyl) -6- methoxyl groups, 7- benzyloxies -1,2,3,4-
The salt derivative of tetrahydroisoquinoline is crystal.
In another preference, HA is sulfuric acid；X is selected from 1/2 or 1.More preferably, when X is 1, the crystal formation of the crystal leads to
X- powder diffraction techniques (XRPD) are crossed to determine and be characterized as below with the θ angles (Bragg2-Theta) of Prague 2：4.9±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°、30.8±0.2°；Or during using differential canning calorimetry (DSC) analysis, exist in DSC collection of illustrative plates in the presence of an endothermic peak
At 130 ± 5 DEG C.
In another preference, HA is oxalic acid；X is selected from 1/2 or 1.More preferably, when X is 1, the crystal formation of the crystal leads to
X- powder diffraction techniques (XRPD) are crossed to determine and be characterized as below with the θ angles (Bragg2-Theta) of Prague 2：3.4±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°、31.9±0.2°；Or use
An endothermic peak when differential canning calorimetry (DSC) is analyzed, in DSC collection of illustrative plates be present at 161 ± 5 DEG C, and 190~
A wider endothermic peak be present in 210 DEG C of scopes.
In another preference, the crystal formation of the crystal when HA is nicotinic acid is determined simultaneously by X- powder diffraction techniques (XRPD)
It is characterized as below with the θ angles of Prague 2 (Bragg 2-Theta)：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 during using differential canning calorimetry (DSC) analysis, an endothermic peak be present at 152 ± 5 DEG C in DSC collection of illustrative plates.
In another preference, the crystal formation of the crystal when HA is glycolic is determined by X- powder diffraction techniques (XRPD)
And it is characterized as below with the θ angles of Prague 2 (Bragg 2-Theta)：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 make
An endothermic peak be present at 187 ± 5 DEG C when being analyzed with differential canning calorimetry (DSC), in DSC collection of illustrative plates.
In another preference, the crystal formation of the crystal when HA is benzene sulfonic acid is determined by X- powder diffraction techniques (XRPD)
And it is characterized as below with the θ angles of Prague 2 (Bragg 2-Theta)：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 make
An endothermic peak be present at 150 ± 5 DEG C when being analyzed with differential canning calorimetry (DSC), in DSC collection of illustrative plates, and it is attached at 160 DEG C
Closely an acromion be present.
In another preference, the crystal formation of the crystal when HA is orotic acid is determined by X- powder diffraction techniques (XRPD)
And it is characterized as below with the θ angles of Prague 2 (Bragg 2-Theta)：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°；Or make
An endothermic peak be present at 138 ± 5 DEG C when being analyzed with differential canning calorimetry (DSC), in DSC collection of illustrative plates.
In the second aspect of the present invention, there is provided a kind of 1- (3- methylsulfonyl aminocarbonyl phenylmethyls provided by the invention as described above
Base) -6- methoxyl groups, 7- benzyloxies -1,2, the preparation method of the salt derivative of 3,4- tetrahydroisoquinolines, methods described is including walking
Suddenly：By 1- (3- methylsulfonyl amidos benzyl) -6- methoxyl groups, 7- benzyloxy -1,2,3,4- tetrahydroisoquinolines and corresponding sour HA are anti-
Salt derivative should be formed.
In another preference, methods described includes step：By 1- (3- methylsulfonyl amidos benzyl) -6- methoxyl groups, 7- benzyls
Oxy-1, reaction forms salt derivative to 2,3,4- tetrahydroisoquinolines in organic solvent with corresponding acid.
In another preference, methods described includes step：HA is nicotinic acid, oxalic acid, glycolic, benzene sulfonic acid or orotic acid
When, 1- (3- methylsulfonyl amidos benzyl) -6- methoxyl groups, 7- benzyloxies -1,2,3,4- tetrahydroisoquinolines are dissolved in organic solvent,
Then corresponding acid is added, crystallization obtains product after cooling.
In another preference, methods described includes step：When HA is sulfuric acid, by 1- (3- methylsulfonyl amidos benzyl)-
6- methoxyl groups, 7- benzyloxies -1,2,3,4- tetrahydroisoquinolines are dissolved in organic solvent, then add organic molten containing respective acids
Agent, crystallization obtains product after cooling.
In another preference, methods described also includes step：By the crystallization of precipitation or washing of precipitate, drying.
In another preference, the temperature for the reaction that methods described is related to is 0-80 DEG C.
In another preference, the organic solvent being related in methods described is methanol, ethanol, isopropanol, acetone, 2- fourths
The tertiary ether acetonitrile of ketone, methyl acetate, isopropyl acetate, first or toluene.
In the third aspect of the present invention, there is provided a kind of pharmaceutical composition, carried by the present invention as described above of effective dose
1- (3- methylsulfonyl amidos benzyl) -6- methoxyl groups of confession, the salt derivative and one kind of 7- benzyloxy -1,2,3,4- tetrahydroisoquinolines
Or a variety of pharmaceutically acceptable auxiliary material compositions.
In the fourth aspect of the present invention, there is provided a kind of 1- (3- methylsulfonyl aminocarbonyl phenylmethyls provided by the invention as described above
Base) -6- methoxyl groups, the salt derivative of 7- benzyloxy -1,2,3,4- tetrahydroisoquinolines is in antiarrhythmic medicine is prepared
Using.
Accordingly, the invention provides a kind of salt derivative of the good respective compound of solubility in water, and then it is improved
Bioavilability, improve its druggability.
Brief description of the drawings
Fig. 1 is XRPD collection of illustrative plates of the SIPI-409 vitriols under the conditions of using Cu target emanation light source experimentals；It is horizontal in figure
Axle is diffraction maximum position (2 θ values), and the longitudinal axis is diffraction peak intensity.
Fig. 2 is the DSC collection of illustrative plates of SIPI-409 vitriols；The peak being wherein directed downward is expressed as endothermic peak.
Fig. 3 is XRPD collection of illustrative plates of the SIPI-409 nicotinic acid salt crystal under the conditions of using Cu target emanation light source experimentals；It is horizontal in figure
Axle is diffraction maximum position (2 θ values), and the longitudinal axis is diffraction peak intensity.
Fig. 4 is the DSC collection of illustrative plates of SIPI-409 nicotinic acid salt crystals；The peak being wherein directed downward is expressed as endothermic peak.
Fig. 5 is XRPD collection of illustrative plates of the SIPI-409 oxalic acid salt crystal under the conditions of using Cu target emanation light source experimentals；It is horizontal in figure
Axle is diffraction maximum position (2 θ values), and the longitudinal axis is diffraction peak intensity.
Fig. 6 is the DSC collection of illustrative plates of SIPI-409 oxalic acid salt crystals；The peak being wherein directed downward is expressed as endothermic peak.
Fig. 7 is XRPD collection of illustrative plates of the SIPI-409 glycollates crystal under the conditions of using Cu target emanation light source experimentals；In figure
Transverse axis is diffraction maximum position (2 θ values), and the longitudinal axis is diffraction peak intensity.
Fig. 8 is the DSC collection of illustrative plates of SIPI-409 glycollate crystal；The peak being wherein directed downward is expressed as endothermic peak.
Fig. 9 is XRPD collection of illustrative plates of the SIPI-409 benzenesulfonate crystallines under the conditions of using Cu target emanation light source experimentals；In figure
Transverse axis is diffraction maximum position (2 θ values), and the longitudinal axis is diffraction peak intensity.
Figure 10 is the DSC collection of illustrative plates of SIPI-409 benzenesulfonate crystallines；The peak being wherein directed downward is expressed as endothermic peak.
Figure 11 is XRPD collection of illustrative plates of the SIPI-409 Orotates crystal under the conditions of using Cu target emanation light source experimentals；In figure
Transverse axis is diffraction maximum position (2 θ values), and the longitudinal axis is diffraction peak intensity.
Figure 12 is the DSC collection of illustrative plates of SIPI-409 Orotate crystal；The peak being wherein directed downward is expressed as endothermic peak.
Figure 13 is the comparison of the XRPD collection of illustrative plates of the XRPD collection of illustrative plates and SIPI-409 raw materials after SIPI-409 and 14 kinds of acid reactions；
Wherein,
A is the XRPD collection of illustrative plates of SIPI-409 raw materials and its XRPD collection of illustrative plates with hydrochloric acid reaction product；
B is the XRPD collection of illustrative plates of SIPI-409 raw materials and its XRPD collection of illustrative plates with succinic acid reaction product；
C is the XRPD collection of illustrative plates of SIPI-409 raw materials and its XRPD collection of illustrative plates with glycolic reaction product；
D is the XRPD collection of illustrative plates of SIPI-409 raw materials and its XRPD collection of illustrative plates with oxalic acid reaction product；
E is the XRPD collection of illustrative plates of SIPI-409 raw materials and its XRPD collection of illustrative plates with orotic acid reaction product；
F is the XRPD collection of illustrative plates of SIPI-409 raw materials and its XRPD collection of illustrative plates with fumaric acid reaction product；
G is the XRPD collection of illustrative plates of SIPI-409 raw materials and its XRPD collection of illustrative plates with tartaric acid reaction product；
H is the XRPD collection of illustrative plates of SIPI-409 raw materials and its XRPD collection of illustrative plates with ethionic acid reaction product；
I is the XRPD collection of illustrative plates of SIPI-409 raw materials and its XRPD collection of illustrative plates with malic acid reaction product；
J is the XRPD collection of illustrative plates of SIPI-409 raw materials and its XRPD collection of illustrative plates with hydrobromic acid reaction product；
K is the XRPD collection of illustrative plates of SIPI-409 raw materials and its XRPD collection of illustrative plates with nicotinic acid reaction product；
L is the XRPD collection of illustrative plates of SIPI-409 raw materials and its XRPD collection of illustrative plates with sulfuric acid reaction product；
M is the XRPD collection of illustrative plates of SIPI-409 raw materials and its XRPD collection of illustrative plates with benzene sulfonic acid reaction product.
Figure 14 is the monocrystalline molecule stereo structure perspective view of SIPI-409 vitriols.
Figure 15 is the solubility criteria curve obtained using SIPI-409 standard items；R values 0.999932.
Figure 16 is that the various salt derivative crystal stabilities of SIPI-409 investigate the XRPD collection of illustrative plates obtained；Wherein,
A is the XRPD collection of illustrative plates that the study on the stability of the crystal formation of SIPI-409 nicotinates obtains；
B is the XRPD collection of illustrative plates that the study on the stability of the crystal formation of SIPI-409 glycollates obtains；
C is the XRPD collection of illustrative plates that the study on the stability of the crystal formation of SIPI-409 oxalates obtains；
D is the XRPD collection of illustrative plates that the study on the stability of the crystal formation of SIPI-409 Orotates obtains；
E is the XRPD collection of illustrative plates that the study on the stability of the crystal formation of SIPI-409 benzene sulfonates obtains；
F is the XRPD collection of illustrative plates that the study on the stability of the crystal formation of SIPI-409 sulfate obtains.
Embodiment
Inventor by in-depth study extensively, find 1- (3- methylsulfonyl amido benzyl) of the structure as shown in formula I-
6- methoxyl groups, solubility more existing SIPI-409 of the 7- benzyloxy -1,2,3,4- tetrahydroisoquinoline salt derivatives in water and
SIPI-409 hydrochlorides have significant raising, and further pharmacokinetic studies show the SIPI-409 of present invention salt
The more existing SIPI-409 hydrochloric acid of bioavilability of derivative, which has, to be significantly improved.
The invention provides compound SIPI-409 of the one kind as shown in formula (I) salt derivative.
Wherein, with SIPI-40 into salt can be common are machine acid or inorganic acid；It may be selected from the acid described in table 1.
Table 1
Tested using the XRPD results tested to salt form primary dcreening operation, by SIPI-409 and hydrochloric acid, succinic acid, anti-butylene two
Acid, L-TARTARIC ACID, ethionic acid, glycolic, orotic acid, DL-malic acid, hydrobromic acid, oxalic acid, phosphoric acid, nicotinic acid, sulfuric acid, benzene sulphur
As a result the reacted XRPD collection of illustrative plates such as acid is shown in accompanying drawing 15 compared with the XRPD collection of illustrative plates of SIPI-409 raw materials.As a result in display
Significance difference be present with SIPI-409 in diffraction pattern, diffraction Angle Position and diffracted intensity in the XRPD collection of illustrative plates for stating 14 kinds of reaction products
It is different, it can tentatively judge that there occurs salt-forming reaction with SIPI-409 for above-mentioned 14 kinds of acid.Preferably sulfuric acid, nicotinic acid, oxalic acid, glycolic, benzene
Sulfonic acid or orotic acid and SIPI-409 are into salt；More preferably sulfuric acid, nicotinic acid or oxalic acid.
SIPI-409 vitriols provided by the invention, wherein SIPI-409 and sulfuric acid ratio are 1:1,2:1, wherein when
SIPI-409 and sulfuric acid ratio are 1:When 1, obtain crystal and analyzed using powder x-ray diffraction, using Cu target emanation light source experimentals
During condition, its 2 θ characteristic diffraction peak is：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°、30.8±0.2°；It is highly preferred that its XRPD schemes
Spectrum is as shown in Figure 1.
Above-mentioned SIPI-409 vitriols, when being analyzed using differential canning calorimetry (DSC), show as programming rate
An endothermic peak in 10 DEG C/min DSC collection of illustrative plates to be present at 130 ± 5 DEG C；It is highly preferred that its DSC collection of illustrative plates is as shown in Figure 2.
Above-mentioned SIPI-409 vitriols (C25H28N2O4S·H2SO4) monocrystalline it is block for water white transparency, crystalline density
1.361g/cm3, space group P-1, cell parameter： α=
94.86 °, β=106.70 °, γ=110.95 °, unit cell volumeAsymmetry unit number Z=2 in structure cell.
(accompanying drawing 14)
SIPI-409 nicotinic acid salt crystal provided by the invention, is analyzed using powder x-ray diffraction, using Cu target emanation light
During the experiment condition of source, its 2 θ characteristic diffraction peak is：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°；It is more excellent
Selection of land, its XRPD collection of illustrative plates are as shown in Figure 3.
SIPI-409 nicotinic acid salt crystal provided by the invention, when being analyzed using differential canning calorimetry (DSC), show as
An endothermic peak be present at 152 ± 5 DEG C in the DSC collection of illustrative plates that programming rate is 10 DEG C/min；It is highly preferred that its DSC collection of illustrative plates is such as
Shown in Fig. 4.
SIPI-409 oxalic acid salt crystal provided by the invention, wherein SIPI-409 and oxalic acid ratio are 1:1 or 2:1, wherein
When SIPI-409 and oxalic acid ratio are 1:When 1, obtain crystal and analyzed using powder x-ray diffraction, it is real using Cu target emanations light source
When testing condition, its 2 θ characteristic diffraction peak is：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°、31.9±0.2°；It is highly preferred that its XRPD collection of illustrative plates is as shown in Figure 5.
Above-mentioned SIPI-409 oxalic acid salt crystal, when being analyzed using differential canning calorimetry (DSC), show as programming rate
For in 10 DEG C/min DSC collection of illustrative plates exist an endothermic peak 161 ± 5 DEG C at, and 190~210 DEG C of scopes in the presence of one compared with
Wide endothermic peak；It is highly preferred that its DSC collection of illustrative plates is as shown in Figure 6.
SIPI-409 glycollates crystal provided by the invention, is analyzed using powder x-ray diffraction, using Cu target emanations
During light source experimental condition, its 2 θ characteristic diffraction peak is：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°；It is highly preferred that
Its XRPD collection of illustrative plates is as shown in Figure 7.
SIPI-409 glycollates crystal provided by the invention, when being analyzed using differential canning calorimetry (DSC), performance
An endothermic peak in DSC collection of illustrative plates that programming rate is 10 DEG C/min to be present at 187 ± 5 DEG C；It is highly preferred that its DSC collection of illustrative plates
As shown in Figure 8.
SIPI-409 benzenesulfonate crystallines provided by the invention, are analyzed using powder x-ray diffraction, using Cu target emanations
During light source experimental condition, its 2 θ characteristic diffraction peak is：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°；It is highly preferred that its
XRPD is as shown in Figure 9.
SIPI-409 benzenesulfonate crystallines provided by the invention, when being analyzed using differential canning calorimetry (DSC), performance
An endothermic peak in DSC collection of illustrative plates that programming rate is 10 DEG C/min to be present 150 ± 5 DEG C at, and at 160 DEG C nearby in the presence of one
Individual acromion；It is highly preferred that its DSC collection of illustrative plates is as shown in Figure 10.
SIPI-409 Orotates crystal provided by the invention, is analyzed using powder x-ray diffraction, using Cu target emanations
During light source experimental condition, its 2 θ characteristic diffraction peak is：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°；It is highly preferred that its
XRPD collection of illustrative plates is as shown in figure 11.
SIPI-409 Orotates crystal provided by the invention, when being analyzed using differential canning calorimetry (DSC), performance
An endothermic peak in DSC collection of illustrative plates that programming rate is 10 DEG C/min to be present at 138 ± 5 DEG C；It is highly preferred that its DSC collection of illustrative plates
As shown in figure 12.
SIPI-409 salt derivatives crystal of the present invention includes monocrystalline, also including its polymorphic.
Present invention also offers the preparation method of SIPI-409 salt derivative and its crystal, is to be dissolved in SIPI-409
In organic solvent, organic or inorganic acid is added, after stirring reaction, cooling crystallization, obtains SIPI-409 salt derivative crystal.On
Stating described solvent includes alcohols solvent, ketones solvent, ether solvent, esters solvent, aromatic hydrocarbon solvent, and nitrile solvents.Institute
Stating alcohols solvent includes methanol, ethanol, and isopropanol；It is preferred that methanol；The ketones solvent includes acetone and 2- butanone；The ether
Class solvent includes the tertiary ether of first, tetrahydrofuran, and 2 methyltetrahydrofurans；The esters solvent includes ethyl acetate, methyl acetate,
And isopropyl acetate；The aromatic hydrocarbon solvent includes toluene and dimethylbenzene；The nitrile solvents are acetonitrile.Into the reaction temperature of salt
Spend for 0-80 DEG C；It is preferred that 10-60 DEG C；Most preferably 40 DEG C.The ratio and feed way of SIPI-409 and acid can be according to required
The derivative of salt and do the change of adaptability, without departing from the present invention principle.
SIPI-409 salt derivatives or its crystal provided by the invention have certain stability, active component can be used as to develop
The antiarrhythmic drug of peroral dosage form supplies Clinical practice.Common oral delivery form includes, conventional tablet, capsule, disperses
The auxiliary materials such as piece, micropill etc., the excipient described in above-mentioned formulation, lubricant, adhesive are auxiliary material common in the field.
The features described above that the present invention mentions, or the feature that embodiment is mentioned can be in any combination.Disclosed in this case specification
All features can be used in combination with any combinations thing form, each feature disclosed in specification, can with it is any provide it is identical,
The alternative characteristics substitution of impartial or similar purpose.Therefore except there is special instruction, disclosed feature is only impartial or similar spy
The general example of sign.
Main advantages of the present invention are：New SIPI-409 provided by the invention salt derivative and its crystal, can be obvious
It is water-soluble to improve it, and then improves its bioavilability and druggability.
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate the present invention
Rather than limitation the scope of the present invention.The experimental method of unreceipted actual conditions in the following example, generally according to conventional strip
Part or according to the condition proposed by manufacturer.Unless otherwise indicated, otherwise all percentage, ratio, ratio or number is pressed
Weight meter.The unit in percent weight in volume in the present invention is well-known to those skilled in the art, such as is referred to 100
The weight of solute in the solution of milliliter.Unless otherwise defined, all specialties used in text are ripe with this area with scientific words
It is identical to practice meaning known to personnel.In addition, any method similar or impartial to described content and material all can be applied to
In the inventive method.Preferable implementation described in text only presents a demonstration with material to be used.
XRPD collection of illustrative plates is using being obtained under the conditions of Cu target emanation light source experimentals in experiment of the present invention.
DSC collection of illustrative plates shows as the collection of illustrative plates that programming rate is 10 DEG C/min in experiment of the present invention.
The stability of SIPI-40 salt derivatives of the present invention refers within a certain period of time, the salt derivative crystal
To temperature, humidity, light durability and hygroscopicity.
Embodiment 1
The preparation of SIPI-409 sulfate and crystal
SIPI-409 0.5g (0.11mmol) are taken, are put in 50mL flasks, add 20mL methanol solvates, bath temperature control
At 40 DEG C, 1M methanolic solution 1.3mL (0.13mmol) is added dropwise, after continuing to keep 40 DEG C of stirrings 2 hours, it is cooled to 5~
15 DEG C of crystallizations, filtering, obtain SIPI-409 sulfate white solid powder 0.54g, yield 90%, SIPI-409 in the crystal：
Sulfuric acid=1:1, single crystal data such as accompanying drawing.Its XRPD collection of illustrative plates is as shown in figure 1, DSC collection of illustrative plates is as shown in Figure 2.
Embodiment 2
The preparation of SIPI-409 nicotinates and crystal
SIPI-409 0.5g (0.11mmol) are taken, are put in 50mL flasks, add 20mL methanol solvates, bath temperature control
At 40 DEG C, 0.16g nicotinic acid (0.13mmol) is added, continues after being kept for 40 DEG C stir 2 hours, is cooled to 5~15 DEG C of crystallizations, mistake
Filter, obtains SIPI-409 nicotinate white solid powder 0.49g, yield 78%.Its XRPD collection of illustrative plates as shown in figure 3, DSC collection of illustrative plates such as
Shown in Fig. 4.
Embodiment 3
The preparation of SIPI-409 oxalates and crystal
SIPI-409 0.5g (0.11mmol) are taken, are put in 50mL flasks, add 20mL methanol solvates, bath temperature control
At 40 DEG C, oxalic acid 0.117g (0.13mmol) is added, continues after being kept for 40 DEG C stir 2 hours, is cooled to 5~15 DEG C of crystallizations, mistake
Filter, obtains SIPI-409 oxalates white solid powder 0.50g, yield 84%.Its XRPD collection of illustrative plates as shown in figure 5, DSC collection of illustrative plates such as
Shown in Fig. 6.
Embodiment 4
The preparation of SIPI-409 glycollates and crystal
SIPI-409 0.5g (0.11mmol) are taken, are put in 50mL flasks, add 20mL methanol solvates, bath temperature control
At 40 DEG C, glycolic 0.098g (0.13mmol) is added, continues after being kept for 40 DEG C stir 2 hours, is cooled to 5~15 DEG C of crystallizations,
Filtering, obtains SIPI-409 glycollate white solid powder 0.47g, yield 81%.Its XRPD collection of illustrative plates is as shown in fig. 7, DSC schemes
Spectrum is as shown in Figure 8.
Embodiment 5
The preparation of SIPI-409 benzene sulfonates and crystal
SIPI-409 0.5g (0.11mmol) are taken, are put in 50mL flasks, add 20mL methanol solvates, bath temperature control
At 40 DEG C, benzene sulfonic acid 0.205g (0.13mmol) is added, continues after being kept for 40 DEG C stir 2 hours, is cooled to 5~15 DEG C of crystallizations,
Filtering, obtains SIPI-409 benzene sulfonate white solid powder 0.57g, yield 84%.Its XRPD collection of illustrative plates is as shown in figure 9, DSC schemes
Spectrum is as shown in Figure 10.
Embodiment 6
The preparation of SIPI-409 Orotates and crystal
SIPI-409 0.5g (0.11mmol) are taken, are put in 50mL flasks, add 20mL methanol solvates, bath temperature control
At 40 DEG C, orotic acid monohydrate 0.226g (0.13mmol) is added, continues after being kept for 40 DEG C stir 2 hours, is cooled to 5~15
DEG C crystallization, filtering, obtains SIPI-409 Orotate white solid powder 0.52g, yield 77%.Its XRPD collection of illustrative plates such as Figure 11 institutes
Show, DSC collection of illustrative plates is as shown in figure 12.
Embodiment 7
The measure of solubility in water
Enter the measure of solubility in water-filling to SIPI-409 and its salt derivative using liquid chromatography.
Major experimental step：Configuration concentration distinguishes 5g/mL, 10g/mL, 50g/mL, 100g/mL, 200g/mL SIPI-
409 standard items prepare standard curve, as a result see Figure 15.
Chromatographic condition：
Chromatographic column：Phenomenex Luna 5u C18(2)100A 4.6×200mm
Detection wavelength：210nm
Mobile phase：(0.68g/L potassium dihydrogen phosphates, triethylamine adjust pH as 3.0)=68/32 to acetonitrile/phosphate buffer solution
Column temperature：30℃
Sample size：10L
Retention time：About 6.3min
Sample treatment：Supersaturated aqueous solution (suspension) is made in testing sample, after shaking 12h under the conditions of putting 30 DEG C, is put
Ultrasonic 30s in Ultrasound Instrument, filtering, appropriate multiple is diluted, carry out HPLC analyses.Test result is shown in Table 2.
Solubility results in the water of table 2
As a result show, SIPI-409 sulfate of the invention, SIPI-409 nicotinates, SIPI-409 oxalates, SIPI-
409 glycollates, SIPI-409 benzene sulfonates, SIPI-409 Orotates water in the more existing SIPI-409 of solubility and
SIPI-409 hydrochlorides have significant raising.
Embodiment 8
Study on the stability
Temperature stability is investigated
SIPI-409 nicotinates, glycollate, oxalates, Orotate, benzene sulfonate, sulfate are put into 60 DEG C of baking ovens
Interior, respectively at 0 day, 5 days, 10 days, 20 days, sampling in 30 days carried out XRPD tests.
Humidity stability is investigated
SIPI-409 nicotinates, glycollate, oxalates, Orotate, benzene sulfonate, sulfate are put into 92.5%RH
(saturation KNO3) in, respectively at 0 day, 5 days, 10 days, 20 days, sampling in 30 days carried out XRPD tests.
Light durability is investigated
SIPI-409 nicotinates, glycollate, oxalates, Orotate, benzene sulfonate, sulfate are put in lighting box,
Respectively at 0 day, 5 days, 10 days, 20 days, sampling in 30 days carried out XRPD tests.
Hygroscopicity is investigated
In order to further appreciate that the moisture absorption implementations of sample, by SIPI-409 nicotinates, glycollate, oxalates, whey
Hydrochlorate, benzene sulfonate, sulfate, which are placed in dynamic moisture content Sorption Analyzer (DVS), carries out hygroscopicity investigation.
Study on the stability result is shown in accompanying drawing 16 and table 3.
The evaluation result of 36 kinds of SIPI-409 salt form of table
As a result show, except nicotinate is to thermally labile, under 60 DEG C of hot conditions, change within 5 days, other salt spread out
Not only dissolubility is good in water for biology, is also demonstrated by the stability expected.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not limited to the substantial technological content model of the present invention
Enclose, substantial technological content of the invention is broadly to be defined in the right of application, any technology that other people complete
Entity or method, if with the right of application defined in it is identical, also or a kind of equivalent change, will
It is considered as being covered by among the right.
Claims (20)
1. 1- (3- methylsulfonyl amidos benzyl) -6- methoxyl groups shown in Formulas I, the salt of 7- benzyloxy -1,2,3,4- tetrahydroisoquinolines
Derivative：
The solubility of the salt derivative is not less than 3.0nmol/mL or 1.8mg/mL.
2. 1- (3- methylsulfonyl amidos benzyl) -6- methoxyl groups according to claim 1,7- benzyloxy -1,2,3,4- tetrahydrochysenes
The salt derivative of isoquinolin, wherein, HA is selected from sulfuric acid, nicotinic acid, oxalic acid, glycolic, benzene sulfonic acid or orotic acid；X is selected from 1/3,1/
2 or 1.
3. 1- (3- methylsulfonyl amidos benzyl) -6- methoxyl groups according to claim 1 or 2,7- benzyloxies -1,2,3,4- four
The salt derivative of hydrogen isoquinoline is crystal.
4. 1- (3- methylsulfonyl amidos benzyl) -6- methoxyl groups according to claim 2,7- benzyloxy -1,2,3,4- tetrahydrochysenes
The salt derivative of isoquinolin, HA are sulfuric acid；X is selected from 1/2 or 1.
5. 1- (3- methylsulfonyl amidos benzyl) -6- methoxyl groups according to claim 2,7- benzyloxy -1,2,3,4- tetrahydrochysenes
The salt derivative of isoquinolin, HA are oxalic acid；X is selected from 1/2 or 1.
6. 1- (3- methylsulfonyl amidos benzyl) -6- methoxyl groups according to claim 4,7- benzyloxy -1,2,3,4- tetrahydrochysenes
The salt derivative of isoquinolin, when X is 1, the crystal formation of the crystal is determined by X- powder diffraction techniques (XRPD) and with Bradley
The θ angles of lattice 2 (Bragg 2-Theta) are characterized as below：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°、30.8±0.2°；Or use differential scanning
An endothermic peak be present at 130 ± 5 DEG C when Calorimetric Techniques (DSC) are analyzed, in DSC collection of illustrative plates.
7. 1- (3- methylsulfonyl amidos benzyl) -6- methoxyl groups according to claim 3,7- benzyloxy -1,2,3,4- tetrahydrochysenes
The salt derivative of isoquinolin, the crystal formation of the crystal when HA is nicotinic acid are determined by X- powder diffraction techniques (XRPD) and with Bradley
The θ angles of lattice 2 (Bragg 2-Theta) are characterized as below：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 make
An endothermic peak be present at 152 ± 5 DEG C when being analyzed with differential canning calorimetry (DSC), in DSC collection of illustrative plates.
8. 1- (3- methylsulfonyl amidos benzyl) -6- methoxyl groups according to claim 5,7- benzyloxy -1,2,3,4- tetrahydrochysenes
The salt derivative of isoquinolin, when X is 1, the crystal formation of the crystal is determined by X- powder diffraction techniques (XRPD) and with Bradley
The θ angles of lattice 2 (Bragg 2-Theta) are characterized as below：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°、31.9±0.2°；Or during using differential canning calorimetry (DSC) analysis, DSC
A wider endothermic peak be present at 161 ± 5 DEG C, and in 190~210 DEG C of scopes in the presence of an endothermic peak in collection of illustrative plates.
9. 1- (3- methylsulfonyl amidos benzyl) -6- methoxyl groups according to claim 3,7- benzyloxy -1,2,3,4- tetrahydrochysenes
The salt derivative of isoquinolin, the crystal formation of the crystal when HA is glycolic are determined by X- powder diffraction techniques (XRPD) and with cloth
The θ angles of glug 2 (Bragg 2-Theta) are characterized as below：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 use differential
When scanning Calorimetric Techniques (DSC) analysis, an endothermic peak be present at 187 ± 5 DEG C in DSC collection of illustrative plates.
10. 1- (3- methylsulfonyl amidos benzyl) -6- methoxyl groups according to claim 3,7- benzyloxy -1,2,3,4- tetrahydrochysenes
The salt derivative of isoquinolin, the crystal formation of the crystal when HA is benzene sulfonic acid are determined by X- powder diffraction techniques (XRPD) and with cloth
The θ angles of glug 2 (Bragg 2-Theta) are characterized as below：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 use differential
An endothermic peak be present at 150 ± 5 DEG C when scanning Calorimetric Techniques (DSC) analysis, in DSC collection of illustrative plates, and nearby exist at 160 DEG C
One acromion.
11. 1- (3- methylsulfonyl amidos benzyl) -6- methoxyl groups according to claim 3,7- benzyloxy -1,2,3,4- tetrahydrochysenes
The salt derivative of isoquinolin, the crystal formation of the crystal when HA is orotic acid are determined by X- powder diffraction techniques (XRPD) and with cloth
The θ angles of glug 2 (Bragg 2-Theta) are characterized as below：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°；Or use differential
When scanning Calorimetric Techniques (DSC) analysis, an endothermic peak be present at 138 ± 5 DEG C in DSC collection of illustrative plates.
12. 1- (3- methylsulfonyl amidos benzyl) -6- methoxyl groups according to claim any one of 1-11,7- benzyloxy -1,
The preparation method of the salt derivative of 2,3,4- tetrahydroisoquinolines, it includes：By 1- (3- methylsulfonyl amidos benzyl) -6- methoxyl groups,
7- benzyloxy -1,2,3,4- tetrahydroisoquinolines react to form salt derivative with corresponding sour HA.
13. 1- (3- methylsulfonyl amidos benzyl) -6- methoxyl groups according to claim 12,7- benzyloxies -1,2,3,4- four
The preparation method of the salt derivative of hydrogen isoquinoline, it includes：By 1- (3- methylsulfonyl amidos benzyl) -6- methoxyl groups, 7- benzyloxies -
Reaction forms salt derivative to 1,2,3,4- tetrahydroisoquinolines in organic solvent with corresponding acid.
14. 1- (3- methylsulfonyl amidos benzyl) -6- methoxyl groups according to claim 13,7- benzyloxies -1,2,3,4- four
The preparation method of the salt derivative of hydrogen isoquinoline, it includes：, will when HA is nicotinic acid, oxalic acid, glycolic, benzene sulfonic acid or orotic acid
1- (3- methylsulfonyl amidos benzyl) -6- methoxyl groups, 7- benzyloxies -1,2,3,4- tetrahydroisoquinolines are dissolved in organic solvent, then
Corresponding acid is added, crystallization obtains product after cooling.
15. 1- (3- methylsulfonyl amidos benzyl) -6- methoxyl groups according to claim 13,7- benzyloxies -1,2,3,4- four
The preparation method of the salt derivative of hydrogen isoquinoline, it includes：When HA is sulfuric acid, by 1- (3- methylsulfonyl amidos benzyl) -6- first
Epoxide, 7- benzyloxies -1,2,3,4- tetrahydroisoquinolines are dissolved in organic solvent, then add the organic solvent containing respective acids,
Crystallization obtains product after cooling.
16. 1- (3- methylsulfonyl amidos benzyl) -6- methoxyl groups according to claims 14 or 15,7- benzyloxy -1,2,3,
The preparation method of the salt derivative of 4- tetrahydroisoquinolines, it also includes：By the crystallization of precipitation or washing of precipitate, drying.
17. 1- (3- methylsulfonyl amidos benzyl) -6- methoxyl groups according to claim any one of 12-16,7- benzyloxy -1,
The preparation method of the salt derivative of 2,3,4- tetrahydroisoquinolines, it is characterised in that the reaction temperature of the reaction is 0-80 DEG C.
18. 1- (3- methylsulfonyl amidos benzyl) -6- methoxyl groups according to claim any one of 13-16,7- benzyloxy -1,
The preparation method of the salt derivative of 2,3,4- tetrahydroisoquinolines, it is characterised in that the organic solvent is methanol, ethanol, isopropyl
The tertiary ether acetonitrile of alcohol, acetone, 2- butanone, methyl acetate, isopropyl acetate, first or toluene.
19. a kind of pharmaceutical composition, as the 1- (3- methylsulfonyl amidos benzyl) described in the claim any one of 1-11 of effective dose-
6- methoxyl groups, the salt derivative of 7- benzyloxy -1,2,3,4- tetrahydroisoquinolines and one or more pharmaceutically acceptable auxiliary materials
Composition.
20. 1- (3- methylsulfonyl amidos benzyl) -6- methoxyl groups described in a kind of any one of claim 1-11,7- benzyloxy -1,
The salt derivative of 2,3,4- tetrahydroisoquinolines, the application in antiarrhythmic medicine is prepared.
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| PCT/CN2017/099549 WO2018041112A1 (en) | 2016-08-31 | 2017-08-30 | Salt derivative of tetrahydroisoquinoline and crystalline thereof and preparation method therefor and application thereof |
| US16/329,685 US10676442B2 (en) | 2016-08-31 | 2017-08-30 | Salt derivative of tetrahydroisoquinoline and crystalline thereof and preparation method therefore and application thereof |
| EP17845414.6A EP3508478B1 (en) | 2016-08-31 | 2017-08-30 | Salt derivative of tetrahydroisoquinoline and crystalline thereof and preparation method therefor and application thereof |
| KR1020197009017A KR102346338B1 (en) | 2016-08-31 | 2017-08-30 | Preparation and application of salt derivatives of tetrahydroisoquinoline and crystals thereof |
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| CN101619038A (en) * | 2008-07-04 | 2010-01-06 | 上海医药工业研究院 | Isoquinoline compound or salt thereof, medicinal composition, preparation method and application thereof |
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| CN113456639B (en) * | 2020-03-31 | 2024-01-26 | 江苏康缘药业股份有限公司 | Anti-arrhythmia pharmaceutical composition and preparation method thereof |
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