CN1566098A - Isoquinoline compound, preparation method and application of salt thereof - Google Patents
Isoquinoline compound, preparation method and application of salt thereof Download PDFInfo
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Abstract
The invention discloses an isoquinoline compound, preparation method and use use in preparing medicament for treating arrhythmia. The compound provided by the invention possesses strong arrhythmia resistance.
Description
Technical field
The present invention relates to the preparation method of a kind of isoquinoline compound and salt thereof, and the application in preparation treatment anti-arrhythmia disease medicine.
Background technology
Sudden cardiac death (SCD) is one of cardiovascular disorder main causes of death.It is to cause clocklike that the rhythm of the heart disappears because cardiac electrophysiology is unstable that SCD produces, and the most serious is continues chamber speed (VT is vetriculartachycardia) with chamber quiver (VF, vetricalar fibrillation).
Anti-arrhythmic can divide four classes: the I class is to be the sodium channel inhibitor of representative with the Quinidine, and they mainly treat supraventricular tachycardia, and flecainide of IC class, lorcainide etc. are also effective to ventricular premature contraction, but they all have restraining effect to cardiac muscle.Extensive clinical study at CAST (Cardiac arrhthmia Suppresion Trials) finds that the medication group mortality ratio (7.7%) of such medicine is higher than control group (3.0%).This result enlightens people for the validity of antiarrhythmic drug and the revaluation of security.The II class is a beta-blocker, is mainly used in the irregular pulse that the beta-receptor hyperfunction causes, cardiac muscle is also had certain restraining effect.The IV class is a calcium channel blocker, and it suppresses flow of calcium ions and makes decreased heart rate, and cardiac muscle is also had restraining effect, and this external enwergy reflectivity causes sympathetic activation, and accelerates heart rate.III class anti-arrhythmic has over reach current potential time-histories (APD action potential duration) and effective refractory period (ERD effective refractoryperidod), to the ventricular arrhythmia treatment effectively, especially life-threatening chamber speed and chamber are quivered effectively.So the emphasis of antiarrhythmic drug research turns to III class antiarrhythmic drug.
Britylium (Bretylium tosylate) is to be used for the treatment of the medicine that the chamber is fast and quiver in the chamber sixties, but it is a quaternary ammonium salt, and is oral invalid.Atlansil is the medicine that is used for the treatment of the intractable ventricular arrhythmia seventies, but because multiple side effect, clinical application is placed restrictions on.Because the complicacy of the irregular pulse cause of disease, and clinical requirement to security are so III class antiarrhythmic drug progress is slow.
From the method for applied genetics such as Tempel in 1987 and molecular cloning, from the Shaker fruit bat, clone the mutator gene of potassium channel first, almost the ligands specific of potassium channel also is found simultaneously.In addition, cell patch tongs technology application and development, so that myocardial cell's potassium channel had more comprehensively and deep understanding, thus started the upsurge of potassium channel molecular level research.Recent study finds that the myocardial cell has 8 kinds of potassium channel hypotypes, wherein export-oriented Delayed Rectifier Potassium Current (I
k) retardance can over reach current potential time-histories and effective refractory period, be the main target site of III class antiarrhythmic drug.
Sotalol (Sotalol) is the nonselective beta-blocker of listing in 1974, and it has the electric physilogical characteristics of over reach current potential time-histories and effective refractory period, presents retardance I
kEffect.In the research of ESVEM (Eiectrophysiloyic Versus Electrocardiongraphic Monitoring) examination bed, sotalol can reduce mortality ratio, so FDA is used for the treatment of irregular pulse in approval in 1992.The new purposes of sotalol has been started the research of the III class antiarrhythmic drug of class novel action mechanism-potassium channel retardation.
Further investigation shows I
kPassage has two types, i.e. I
Kr(fast passage) and I
Ks(slow pathway).For I
kRetarding agent treatment irregular pulse wishes to block simultaneously I
KrAnd I
KsBecause simple I
KrRetarding agent such as sotalol, it has contrary use dependency (Reverse use-dependence RVD) and causes arrhythogenic side effect, promptly when heart rate is fast, the effect that prolongs APD slows down, and when heart rate is slow, prolong the APD effect to strengthen, therefore cause APD excessively to prolong.Block I simultaneously
KrAnd I
KsCan eliminate the contrary dependency of using.
Isoquinoline alkaloid extensively is present in the natural phant, and many have an important physical activity, and especially the effect aspect cardiovascular is noticeable.It is active in functions such as hypotensive, platelet aggregation-against, cardiac stimulant, diuresis and anti-arrhythmias that bisbenzylisoquinoline alkaloid in the natural phant such as Berbamine, dauricine, Tetrandrine, cocculine, Neferine and monobenzyl morphinane alkaloid demethyl coclaurine and Berberine (berberine) etc. all have obvious cardiovascular.Wherein Berberine presents III class antiarrhythmic activity, clinically is used for the treatment of intractable chamber speed and chamber morning, and total effective rate reaches more than 60%, but it is a quaternary ammonium salt, and oral absorption is poor, and irregular.
In sum, to be used to prepare treatment anti-arrhythmia disease medicine be that people institute is very expected to the new isoquinoline compound of research and development.
Summary of the invention
One of technical issues that need to address of the present invention are open Isoquinolinium compound and salt thereof:
Two of the technical issues that need to address of the present invention provide the preparation method of above-mentioned isoquinoline compound;
Another technical problem that the present invention need solve is to disclose the application of described compound in preparation treatment anti-arrhythmia disease medicine, to satisfy people's needs.
Compound of the present invention is compound and the salt thereof with one of following general structure, comprises inorganic acid salt or organic acid salt, preferably hydrochloride:
Wherein, R1, R2, R3 represent H, OH, OCH
3, OCH
2Ph, OCH
2O, F, Cl or Br;
R4, R5, R6 represent H, CN, NH
2, NO
2, NHSO
2CH
3, OH, OCH
3, CH
2OCH
2
Above-mentioned each substituting group is at the A ring and B ring different positions is single, double or three replacements;
R7 represents C
1～C
6Alkyl, preferably comprise CH
3, CH
2CH
3, CH (CH
3)
2Or CH
2CH (CH
3)
2In a kind of;
The R8 representative
Or
Wherein, R ' 8 represents C
1～C
6Alkyl, CH preferably
3, CH
2CH
3Or CH
2Ph;
R9 represents C
1～C
6Alkyl, preferably H, CH
3, CH
2CH
3, CH (CH
3)
2
Y＝S，O，N，n＝1，2。
Preferred compound comprises:
1-(2, the 5-dimethoxy-benzyl)-6,7-methylene-dioxy-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (SIPI 926);
1-(4-methoxy-benzyl)-6-methoxyl group-7-benzyloxy-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (SIPI 1124);
1-(3-methylsulfonyl amido benzyl)-6,7-methylene-dioxy-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (C-391);
1-(3-methylsulfonyl amido benzyl)-6-methoxyl group, 7-benzyloxy-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (C409);
1-(2, the 5-dimethoxy-benzyl)-4-sec.-propyl-6,7-dimethoxy-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (C312);
2-[1-(to a Toluidrin phenoxyl)-2-hydroxyl-propyl group]-6,7-dimethoxy-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (C602);
2-[1-(right-the amido phenoxy group)-2-hydroxyl-propyl group]-6-methoxyl group-7-benzyloxy-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (C491).
The preparation method of above-claimed cpd I or II and salt thereof comprises the steps:
1. be raw material with substituted phenyl ethylamine (1) and substituted phenylacetic acid (2), in 170～180 ℃ of direct dehydrating condensations or substituted phenylacetic acid SOCl
2Being prepared into acyl chlorides, is solvent and substituted phenyl ethylamine (1) condensation then with the ethylene dichloride, and preparation has the compound shown in the general structure (3), and reaction expression is:
2. the compound (3) that step (1) is obtained is solvent and POCl with the chloroform
3Reflux and reacted 2～6 hours down, obtain to have the compound shown in the general structure (4), reaction expression is:
3. the compound (4) that step (2) is obtained is solvent and NaBH with methyl alcohol
4Reacted 0.5～4 hour, and obtained to have the compound shown in the general structure (5), reaction expression is:
4. in compound (5) dissolving and ethanol that step (3) is obtained, under room temperature, add EtOH-HX then, obtain to have the salt of the compound shown in the formula I to acid; Wherein, X is a halogen;
Or the compound (5) that 4.-1. step (3) is obtained is at N, under the existence of N dimethyl oxygen yl pyridines, being solvent and general structure with the methylene dichloride is the compound back flow reaction of (6) 8～12 hours, obtains to have general structure and is the compound shown in (7), and reaction expression is:
General structure can adopt the commercially available prod for the compound of (6);
4.-2. the compound and the general structure that with general structure are (7) are R ' 8NH
2The commercially available prod be solvent refluxing reaction 8～12 hours with the pyridine, can obtain the compound shown in the formula II, reaction expression is:
Or
4.-3. compound (5) that step (3) is obtained and general structure are that the commercially available lsothiocyanates of R ' 8NCS is solvent with acetone, and back flow reaction 12～18 hours can obtain the compound shown in the formula H;
Compound I or II stir under room temperature with EtOH-HX and separate out precipitation and be converted into corresponding salt.
The preparation method of above-claimed cpd III or IV and salt thereof comprises the steps:
1. be lead compound with compound (8) and compound (9), preparation has the compound shown in the general structure (10), and reaction expression is:
In the compound (9), n=1,2, can adopt the commercially available prod; Reaction conditions is identical with the method for above-claimed cpd (3);
2. the compound that 1. step is obtained (10) prepares compound (11) according to the synthetic method of compound (4), i.e. compound III, and reaction expression is:
3. the compound that 2. step is obtained (11) in methanol solution with NaBH
4React, can obtain compound IV of the present invention, the same compound of reaction conditions (5), reaction expression is:
The preparation method of above-claimed cpd V and VI and salt thereof comprises the steps:
1. being raw material with compound (12), is solvent with formic acid, reacts 1～5 hour with (HCHO) n and HCOOH down in 40～60 ℃, obtains to have the compound of general structure for (13), and reaction expression is:
2. the compound that 1. step is obtained (13) in EtOH solution with have general structure and be the compound of (14), with K
2CO
3For arm acid agent, be solvent with EtOH, under the catalysis of KI, back flow reaction 6～10 hours obtains the compound of V of the present invention, and is converted into salt, and reaction expression is:
The compound VI of being addressed and the preparation method of salt thereof comprise the steps:
1. will have general structure for the compound of (15) with have general structure for the compound of (16) reaction conditions according to compound V reacts, obtain to have the compound of general structure for (17), reaction expression is:
2. the compound that 1. step is obtained (17) is solvent with methyl alcohol, uses NaBH
4Be reductive agent, at room temperature reacted 2～6 hours, obtain compound VI, be converted into salt then, reaction expression is:
The preparation method of above-claimed cpd VII and salt thereof comprises the steps:
1. will have general structure for the compound of (13) and general structure for (19) or general structure be (20) at K
2CO
3Existence under, be solvent with ethanol, KI is a catalyzer, reaction under refluxing, obtaining general structure is the compound of (21), reaction expression is:
Document wyrick can be adopted in compound (19) and (20), S.D.et al.J Med chem, and 1978,21 (4), 386 disclosed methods are prepared;
2. compound (21) is reacted in EtOH-HX solution, obtain the salt of the compound of VII of the present invention;
The preparation method of above-claimed cpd VIII and salt thereof comprises the steps:
1. will have general structure and react according to above-mentioned reaction conditions for (19) or the general structure compound for (20) for the compound of (15) and general structure, the acquisition general structure is the compound of (23), and reaction expression is:
2. compound (23) is reacted in EtOH-HX solution, obtain the salt of the compound of VIII of the present invention.
Compound of the present invention and hydrochloride thereof, mineral acid or organic acid salt can be used for preparing antiarrhythmic medicine.Test-results shows that The compounds of this invention presents very strong antiarrhythmic activity, especially have the retardance potassium channel activity and present the not normal effect of anti-chamber property rule.
(1) electricity irritation is caused that shrink the guinea pig in vitro left atrium and the spontaneous dancing influence in right atrium (seeing Table 1);
(2) the guinea pig left atrium myoelectricity that exsomatizes is stimulated the influence (seeing Table 2) that causes FRP (FRP);
(3) chamber that causes of anti-ouabain early, a short battle array chamber speed, the quiver effect (seeing Table 3) of cavy whole animal model of chamber speed and chamber;
(4) use patch clamp technique, carry out the research (seeing Table 4) of potassium channel blocking effect;
Compound of the present invention can composition the mode of form by oral, vein, Transdermal absorption be applied to the patient that need treat.Said composition contains the arbitrary described compound of the general structure I～VIII that treats significant quantity, and one or more pharmaceutically acceptable carriers, said carrier is meant the carrier of medicine and pharmacology field routine, for example, thinner such as water etc., weighting agent such as starch etc., tackiness agent such as derivatived cellulose etc., or other sweeting agents, flavouring agent etc.
Amount of application of the present invention can change according to the type of route of administration, patient's age, body weight, disease and severity etc., and its per daily dose is generally 0.1～10mg/kg body weight.
Table 1 pair electricity irritation causes that the guinea pig left atrium that exsomatizes is shunk and the influence of the spontaneous jumping in right atrium
From the visible compound S IPI926 of last table, 1123,1127 and 1124 have the spontaneous dancing activity in the right atrium of inhibition, IC
50Value is respectively: 7.09,3.91,3.72 and 6.3 μ M.The restraining effect that compares the left atrium with verapamil (Verapamie) is little.1127 pairs of left atrium convergent forces of compound S IPI have certain enhancement.
Table 2 compound stimulates the influence that causes FRP (FRP) to the guinea pig left atrium myoelectricity that exsomatizes
*-effective refractory period shortens.
From last table visible Compound C-391, C-409, C-312, C-602, C-491 compare with sotalol with SIPI 926 has the activity that prolongs effective refractory period.
The anti-ouabain of table 3 causes the test of cavy ventricular arrhythmia
| Sample | Dosage mg (mmol)/kg | Ouabain dosage (μ g/lg) | |||
| Ventricular premature contraction | Short battle array chamber speed | Chamber speed | Quiver in the chamber | ||
| Physiological saline | ????2m/kg | ????144.8 | ????156.1 | ????167.4 | ????189.3 |
| Sotalol | ????6.17(0.02) | ????206.3 | ????230.4 | ????240.2 | ????298.7 |
| SIPS-926 | ????3.6(0.01) | ????183.4 | ????188.1 | ????192.7 | ????232.9 |
| C-391 | ????3.9(0.01) | ????200.1 | ????240.3 | ????248.6 | ????291.0 |
| C-409 | ????9.7(0.02) | ????208.5 | ????219.6 | ????245.3 | ????308.0 |
| C-602 | ????8.7(0.02) | ????202.1 | ????222.6 | ????234.1 | ????283.4 |
| C-312 | ????4.2(0.01) | ????177.3 | ????194.1 | ????210.2 | ????253.8 |
| C-491 | ????10.15(0.02) | ????187.0 | ????212.9 | ????237.8 | ????292.2 |
From the visible compound S IPI-926 of last table, C-391, C-409, C-602, C-312 compares with sotalol with C-491, presents significant anti-ventricular arrhythmia activity.
SIPI-926 all shows good antiarrhythmic activity, and in the whole animal model discrimination, finds that it has III class antiarrhythmic activity in suppressing the ventricular arrhythmia model that spontaneous dancing model in right atrium and anti-ouabain cause.In order to inquire into its mechanism of antiarrhythmic action, utilize patch clamp technique, and compare with sotalol, carried out the research of potassium channel blocking effect.The results list is as follows:
Table 4-1sotatol 100 μ mol/l are to Delayed Rectifier Potassium Current (I
Kr) process action time (pA)
| ????control | ?????????????????Sotalol | |||
| ????1min | ????2min | ????3min | ||
| ????1 | ????27.01 | ????20.45 | ????16.19 | ????10.75 |
| ????2 | ????21.24 | ????13.44 | ????9.21 | ????5.37 |
| ????3 | ????33.47 | ????25.9 | ????18.21 | ????12.11 |
| ????4 | ????26.85 | ????23.14 | ????19.74 | ????15.32 |
| ????M | ????27.14 | ????20.73 | ????15.84 | ????11.14 |
| ????P | ????0.138 | ????0.016 | ????0.003 | |
Table 4-2SIPI-926 100 μ mol/L are to I
KrProcess action time (pA)
| ????control | ?????????????SIPI?926 | |||
| ????1min | ????2min | ????3min | ||
| ????1 | ????19.0 | ????9.5 | ????0 * | ????0 * |
| ????2 | ????31.2 | ????12.5 | ????0 * | ????0 * |
| ????3 | ????31.2 | ????15.6 | ????0 * | ????0 * |
| ????M | ????27.1 | ????12.5 | ||
| ????P | ????0.03 | ????0.03 | ????0.02 | |
*0 is all to block potassium current, and cell is not dead.
Table 4-3SIPI-926 is to I
KsConcentration dependent effect (pA)
| ????control | ?????????????????????SIP-926 | |||
| ????1×10 -4M | ????1×10 -5M | ????1×10 -6M | ||
| ????1 | ????925 | ????412 | ????710 | ????770 |
| ????2 | ????632 | ????357 | ????566 | ????589 |
| ????3 | ????721 | ????388 | ????531 | ????651 |
| ????4 | ????895 | ????400 | ????634 | ????547 |
| ????M | ????793 | ????389 | ????610 | ????639 |
| ????P | ????0.006 | ????0.02 | ????0.1127 | |
Conclusion: SIPI-926 is to I
KrRetardation is arranged, and have time-dependent manner.When 100 μ mol concentration, SIPI-926 is when 1min, to I
KrInhibiting rate and suitable during sotalol 4min, and when 2min, suppress I fully
Kr, illustrate that SIPI-926 is to I
KrRestraining effect stronger than sotalol.What is more important SIPI-926 is to I
KsAlso present the dependent retardation of tangible solubility.SIPI-926 is to I
KrAnd I
KsRetardation is all arranged, and this is that current III class antiarrhythmic drug is desirable.And sotalol only blocks I
Kr, prompting is on the mechanism of action, and SIPI-926 is more superior than sotalol.
As can be seen from the above results, the antiarrhythmic effect of SIPI-926 is because it has blocked I
KrAnd I
KsThereby over reach current potential time-histories and effective refractory period show its III class antiarrhythmic drug effect.From the introduction of front as can be known, block I simultaneously
KrAnd I
Ks, can eliminate the contrary dependency of using, significantly reduce the proarrhythmia side effect, be one of main direction of current antiarrhythmic drug research.
Embodiment
Embodiment 1
1-(2, the 5-dimethoxy-benzyl)-6,7-methylene-dioxy-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt SIPI 926
(1) 16.3g (0.1mol) homopiperony lamine and 19.0g (0.1mol) 2.5-dimethoxyphenylacetic acid are mixed, in 170-180 ℃ of heating 4 hours, cooling, after being dissolved in chloroform, use 2NHCl successively, 2NNaOH and water washing, anhydrous magnesium sulfate drying removes solvent under reduced pressure, residuum EtOH-H
2The O recrystallization gets 22.1gN-(3,4-methylene-dioxy styroyl)-3,4-dimethoxy phenylacetamide, yield 65%, fusing point 119-120 ℃.
Ultimate analysis C
19H
21NO
5Calculated value %:C 66.74, H 5.87, and N 4.07
Measured value %:C 66.46, H 6.16, and N 4.08
(2) above-mentioned acid amides 17g (0.05mol) is dissolved in the dry chloroform, add the 26ml phosphorus oxychloride, refluxed 4 hours, remove solvent and excessive phosphorus oxychloride under reduced pressure, the residuum petroleum ether, obtain solid, ethyl alcohol recrystallization gets 13.8g 1-(2, the 5-Dimethoxyphenyl)-6.7-methylene-dioxy-3, the 4-dihydro-isoquinoline hydrochloride, yield 85%, fusing point 197-198 ℃ (decomposition).
Ultimate analysis C
19H
20NO
4Cl calculated value %:C 63.03, H 5.56, and N 4.07, and C1 9.74
Measured value %:C 63.07, H 5.57, and N 3.87, and C1 9.80
(3) above-mentioned dihydro-isoquinoline hydrochloride 9.6g (0.03mole) is dissolved in the 200ml methyl alcohol, is chilled to 5 ℃, divide 3 each 1g to add sodium borohydride, finish, stirring at room 1-2 hour, remove solvent under reduced pressure, add 100ml water, chloroform extraction, washing, anhydrous magnesium sulfate drying, the chloroformic solution of filtering siccative drips EtOH-HCl to PH1-2, remove solvent under reduced pressure, use 95% ethyl alcohol recrystallization, get 7.3g SIPI 926, yield 75%, fusing point 237-240 ℃ (decomposition)
Ultimate analysis C
19H
22NO
4Cl calculated value %:C 62.72, H 6.09, and N 3.85, and C1 9.74
Measured value %:C 62.91, H 6.38, and N 3.99, and C1 9.88
Embodiment 2
1-(4-methoxy-benzyl)-6-methoxyl group-7-benzyloxy-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt SIPI 1124
(1) be that raw material makes corresponding amide by example one (1) operation with 3-methoxyl group-4-benzyloxy phenylethylamine and 4-methoxyphenylacetic acid.
(2) be that raw material makes corresponding dihydro-isoquinoline hydrochloride by embodiment 1 (2) operation with above-mentioned acid amides
(3) be that raw material makes SIPI 1124, fusing point 176-177 ℃ by example one (3) operation with above-mentioned dihydro-isoquinoline hydrochloride.
Ultimate analysis C
25H
28NO
3ClH
2O calculated value %:C 67.63, H6.81, N3.16, C17.99
Measured value %:C 67.93, H7.00, N2.85, C18.19
Embodiment 3
1-(3-methylsulfonyl amido benzyl)-6,7-methylene-dioxy-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt C-391
(1) 8.5g (0.047mol) 3-nitrophenyl-acetic acid, 16ml SOCl
2, 16ml benzene is mixed, behind the reflux 4h, removes solvent and excessive SOCl under reduced pressure
2Get 3-oil of mirbane Acetyl Chloride 98Min..
8g (0.04mol) homopiperony lamine is dissolved in the 60ml ethylene dichloride,, drips 10% the NaOH solution and the dichloroethane solution of 7.8g (0.039mol) 3-oil of mirbane Acetyl Chloride 98Min. simultaneously in 0～5 ℃, control PH8-9 finishes, stirring at room reaction 4h, separate out solid, filter collection, 5%HCl washing, washing, drying, ethyl alcohol recrystallization, get 12.5g N-(3,4-methylene-dioxy styroyl)-and 3-oil of mirbane ethanamide, yield 86%, fusing point 128-130 ℃.
(2) 10g iron powder and 5% NH
4Cl solution 50ml is mixed, in 100 ℃ of stirrings 20 minutes, is chilled to 60 ℃ then, adds 10g (0.03mol) N-(3,4-methylene-dioxy styroyl)-3-oil of mirbane ethanamide and 10ml ethanolic soln.In 60 ℃ of stirring reactions 3 hours.Be chilled to room temperature, add 5%NaHCO
320ml, methylene dichloride 60ml, continuation was stirred 10 minutes, filtered, and divide and get organic layer, washing, drying removes solvent under reduced pressure, gets 8.0g N-(3,4-methylene-dioxy styroyl)-3-amido phenylacetamide, yield 90%, fusing point 155-157 ℃.
(3) 8.5g (0.028mol) N-(3,4-methylene-dioxy styroyl)-3-amido ethanamide and 20ml pyridine are mixed, are chilled to 0 ℃, drip 3.5g (0.03mol) methylsulfonyl chloride, finish, stirring at room reaction 20 hours, Dropwise 5 %HCl to PH2-3 separates out solid, continues to stir 10 minutes, filter collection solid, washing, drying, ethyl alcohol recrystallization gets 9.7g N-(3,4-methylene-dioxy styroyl)-3-Toluidrin yl acetamide, yield 92.4%, fusing point 144-145 ℃.
(4) 5g N-(3,4-methylene-dioxy styroyl)-3-Toluidrin yl acetamide, 15ml POCl
3Mixed with the 30ml chloroform, reflux 3.5 hours removes solvent and excessive POCl then under reduced pressure
3, the residuum petroleum ether, ethyl alcohol recrystallization gets 1-(3-methylsulfonyl amido benzyl)-6,7-methylene-dioxy-3,4-dihydro-isoquinoline hydrochloride 5.0g, yield 95%, fusing point 241-243 ℃.
(5) 1.0g 1-(3-methylsulfonyl amido benzyl)-6,7-methylene-dioxy-3, the 4-dihydro-isoquinoline is dissolved in the 30ml methyl alcohol, presses example one (3) operation, gradation adds the reduction of 1g sodium borohydride, becomes hydrochloride with EtOH-HCl, makes C-391 0.8g, yield 84.1%, molten some 256-257 ℃, MS:M
+360.
Embodiment 4
1-(3-methylsulfonyl amido benzyl)-6-methoxyl group, 7-benzyloxy-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt C409
(1) be that raw material makes N-(3-methoxyl group-4-benzyloxy styroyl)-3-oil of mirbane ethanamide by embodiment 3-(1) with the condensation of 3-nitrophenyl-acetic acid with 3-methoxyl group-4-benzyloxy phenylethylamine.
(2) above-mentioned acid amides is used Fe-NH by example three-(2)
4The Cl reduction makes N-(3-methoxyl group-4-benzyloxy styroyl)-3-amido phenylacetamide.
(3) above-mentioned acid amides makes N-(3-methoxyl group-4-benzyloxy styroyl)-3-methylsulfonyl amido phenylacetamide by example three-(3) and methylsulfonyl chloride reaction.
(4) above-mentioned acid amides is pressed example three-(4) and POCl
3Reaction makes 1-(3-methylsulfonyl amido benzyl)-6-methoxyl group-7-benzyloxy-3,4-dihydro-isoquinoline hydrochloride.
(5) above-mentioned dihydro-isoquinoline makes 1-(3-methylsulfonyl amido benzyl)-6-methoxyl group-7-benzyloxy-1,2,3,4-tetrahydroisoquinoline by example-(5) through the sodium borohydride reduction.Make hydrochloride C409 with the EtOH-HCl salify, yield 80.3%, fusing point 202-204 ℃, MS:M
+452.
Embodiment 5
1-(2, the 5-dimethoxy-benzyl)-4-sec.-propyl-6,7-dimethoxy-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt C312
(1) α-sec.-propyl-3, the 4-dimethoxybenzeneacetonitrile
30ml 40%NaOH is splashed into 10g (0.057mol) 3 in room temperature, in the mixed solution of 4-dimethoxybenzeneacetonitrile, 26ml methyl-sulphoxide and 9.24g (0.081mol) bromo propane, finish, in stirring at room 4.5 hours, add water 100ml, tell organic layer, water layer extracts with toluene 30ml * 3, merges organic layer, is washed to neutrality, anhydrous magnesium sulfate drying, remove solvent under reduced pressure and get 9.4g, yield 81% is placed after fixing, fusing point 46-48 ℃, MS:M
+219.
(2) 3.4-dimethoxy-β-isopropyl benzene ethamine
With the 100ml tetrahydrofuran (THF), 24.66g (0.18mol) aluminum chloride is mixed, stirs a moment in ice is molten, and adding potassium boron hydrogen 9.95g (0.18mol) was in stirring at room 1 hour.Add 8g (0.0365mol)-α-sec.-propyl-3, the 30ml tetrahydrofuran solution of 4-dimethoxybenzeneacetonitrile.Finish, after 1 hour, back flow reaction is 1 hour again in stirring at room.Remove solvent under reduced pressure, use the 1N hcl acidifying, methylene dichloride 30ml * 3 washings alkalizes to PH11-12 with 20% sodium hydroxide, and extract methylene dichloride 60ml * 3, washing, and anhydrous magnesium sulfate drying removes solvent under reduced pressure, gets 4.32g, yield 53%.Not purifiedly be directly used in the synthetic of following acid amides.
(3) N-(3,4-dimethoxy-β-isopropyl phenyl)-2,5-dimethoxy phenylacetamide
With 2,5-dimethoxyphenylacetic acid 3.46g (0.18mol) is dissolved in the 40ml exsiccant ethylene dichloride, drips 6.3g (0.54mol) sulfur oxychloride in 0 ℃, finishes, and in stirring at room 30 minutes, is warming up to 40-45 ℃ of stirring reaction afterwards 4 hours.Remove solvent and excessive sulfur oxychloride under reduced pressure, get 2,5-dimethoxy Acetyl Chloride 98Min..
The 20ml diethyl ether solution of 1N sodium hydroxide 20ml (0.02mol) and above-mentioned acyl chlorides is splashed into 4g (0.016mol) 3 simultaneously in 0 ℃, in the 20ml diethyl ether solution of 4-dimethoxy-β-isopropyl benzene ethamine, control PH8-9 finishes, in 0 ℃ stir 2 hours after, in stirring at room 4 hours.Separate out solid, the filter collection is washed to neutrality, drying.Heavy 5.1g, yield 59.4%, fusing point 78-80 ℃, MS:M
+401.
(4) 1-(2, the 5-dimethoxy-benzyl)-4-sec.-propyl-6,7-dimethoxy-3,4-dihydro-isoquinoline hydrochloride
4.1g (0.01mol) above acid amides, 60ml ethylene dichloride and 10ml phosphorus oxychloride are mixed, reflux 3.5 hours, remove solvent under reduced pressure, use petroleum ether three times, use the alcohol-ether recrystallization, get 2.1g, 180-181 ℃ of yield 41.5%. fusing point, MS:M
+383.
(5) Compound C 312
2.1g (4.4mmol) above-mentioned dihydro-isoquinoline hydrochloride is dissolved in the 20ml methyl alcohol, the ice bath cooling adds 0.8g (0.02mol) sodium borohydride, stirring at room 4 hours removes solvent under reduced pressure, adds water 100ml, extract with ethylene dichloride 30ml * 3, wash 2 times, anhydrous magnesium sulfate drying removes solvent under reduced pressure, with EtOH-HCl solution salify, the filter collection, heavy 1.2g, yield 58.1%.Molten some 178-179 ℃, MS:M
+385.
Embodiment 6
2-[1-(to a Toluidrin phenoxyl)-2-hydroxyl-propyl group]-6,7-dimethoxy-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt C602
(1) 6,7-dimethoxy-1,2,3, the 4-four hydrogen isoquinoline hydrochloric acid salt
With 3,4-dimethoxy-phenylethylamine 1.8g (10mmol), Paraformaldehyde 96 0.30g (10mmol) and 98% formic acid 20ml mix, in 40～60 ℃ of stirring reaction 1.5h, be chilled to room temperature, remove formic acid under reduced pressure, get oily matter, add water 20ml, transfer PH8-9 with ammoniacal liquor, extract methylene dichloride 20ml * 3, water 10ml * 3 washings, anhydrous magnesium sulfate drying, remove the appearance agent under reduced pressure, get oily matter, with ethyl acetate 30ml dissolving, down in the ice bath cooling, add EtOH-HCl, fold white solid, filter collection, ethyl acetate washing, dry, heavy 2.10g, yield 90.0%, 255～256 ℃ of fusing points.
(2) 2-[1-(right-nitro-phenoxy)-2-hydroxyl-propyl group]-6,7-dimethoxy-1,2,3,4---four hydrogen isoquinoline hydrochloric acid salt
Above-mentioned hydrochloride 1.0g (4.36mmol) 1-chloro-2-(right-nitro-phenoxy)-2-propyl alcohol 1.0g (4.36mmol) and K
2CO
31.2g (8.72mmol), KI0.7g (4.36mmol) and 50ml ethanol mixture, refluxed 8 hours, be chilled to room temperature, filtering is not tolerant, steams and removes ethanol, adds 30ml water, extract chloroform 30ml * 3, washing, anhydrous magnesium sulfate drying is used the EtOH-HCl salify, get 1.1g, yield 59.4%, 122～124 ℃ of fusing points, MS:388.
(3) 2-[1-(right-the amido phenoxy group)-2-hydroxyl-propyl group]-6,7-dimethoxy-1,2,3,4---four hydrogen isoquinoline hydrochloric acid salt
With free alkali 0.8g (2.06mmol), the iron powder 1.0g (15mmol) of above-mentioned hydrochloride, NH
4Cl 0.5g (9.2mmol) puts in the 250ml three-necked bottle, adds 75% aqueous ethanolic solution 60ml, and backflow 4h is chilled to room temperature, adds Na
2CO
31.5g and acetate acetate 50ml, support was mixed 30 minutes, and the filtering insolubles removes ethanol and ethyl acetate under reduced pressure, extract ethyl acetate 50ml * 3, anhydrous magnesium sulfate drying removes ethyl acetate under reduced pressure, and the post layer separates (or directly using the EtOH-HCl salify), get 0.61g, yield 85.9%, mp214～216 ℃, MS:M
+358.
(4)C602
The free alkali 0.5g (1.4mmol) of above-mentioned hydrochloride is dissolved in the 20ml dry pyridine, adds trimethylchlorosilane 2.0ml (16.0mmol) under stirring at room, stirring reaction 10 hours added methylsulfonyl chloride 0.23ml (2.6mmol) stirring at room 7 hours.Add H
2O 2ml transfers PH1～2 with concentrated hydrochloric acid, uses NH again
4OH transfers PH8-9, CH
2Cl
2Extract 30ml * 3, washing, and anhydrous magnesium sulfate drying, the post layer separates, (eluent ethyl acetate).Use the EtOH-HCl salify, get 0.32g, yield 48.5%, 209～212 ℃ of fusing points, MS:M
+437.
(5) 1-chloro-2-(right-nitro-phenoxy)-2-propyl alcohol
Get to nitre phenol 28.0g (0.2mol) sodium hydroxide 8.0g (0.2mol) and H
2O 75ml places the 250ml reaction flask, and behind the backflow 4h, solid all dissolves, and drips 1-epichlorohydrin 32ml (0.4mol) down in refluxing, add in the 1h, continue back flow reaction 4h, be chilled to room temperature, use ethyl acetate 200ml, extract 100ml * 2, washing, anhydrous magnesium sulfate drying, decompression.Steaming desolventizes.The post layer separates (eluent CH
2Cl
2: sherwood oil (30～60 ℃)=3: 1), get 25.4g (oily matter), yield 55.0%.
Embodiment 7
2-[1-(right-the amido phenoxy group)-2-hydroxyl-propyl group]-6-methoxyl group-7-benzyloxy-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt C491
(1) be that raw material makes 6-methoxyl group-7-benzyloxy-1,2,3 by example 6-(1) with 3-methoxyl group-4-benzyloxy phenylethylamine, 4-four hydrogen isoquinoline hydrochloric acid salt, yield 65%, fusing point 214-215 ℃.
(2) be raw material with above-mentioned hydrochloride, make 2-[1-(p-nitrophenyl oxygen base)-2-hydroxyl-propyl group by embodiment 6-(2)]-6-methoxyl group-7-benzyloxy-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt, yield 86.5%, MS:M
+465.Fusing point 158-161 ℃.
(3) be that raw material prepares C491 by embodiment 6-(3) with above-mentioned hydrochloride, yield 84,8% (contains 2H
2O and 1HCl salt).Fusing point 208-211 ℃ (decomposition), MS:M
+435.
Contain compound of the present invention, add the multiple formulation that different auxiliary material is made tablet, capsule, preparation capable of permeating skin, sustained release preparation and injection.With different route of administration medications, to satisfy clinical needs.
Embodiment 8
Injection
Prescription SIPI926 2.5～5g
Phenylcarbinol 9～18g
Water for injection adds to 1000ml
Preparation technology: accurately take by weighing SIPI926 by recipe quantity and place a container, add an amount of water for injection, stirring makes molten entirely, presses recipe quantity and adds phenylcarbinol, adds to the full amount of water for injection, and solution is through 0.45 μ m filtering with microporous membrane.The solution embedding is (1ml contains main ingredient 2mg) in glass ampoule, and preparation was through flowing steam sterilization 30 minutes.
Embodiment 9
Capsule
Prescription SIPI926 30mg
Starch 40mg
Lactose 120mg
Talcum powder 10mg
Preparation technology: SIPI 926 is worn into fine powder, cross 100 order nylon mesh.Former, auxiliary material fine powder are fully mixed evenly, after 60 mesh sieve secondaries.To mix during former uniformly, auxiliary material fine powder incapsulates, every capsules contains main ingredient 30mg.
Embodiment 10
Slow releasing tablet
Prescription: immediate release section slow-released part
SIPI?926??????15g????????????SIPI?926??????15g
Lactose 60 dextrin 3g
Starch 20g gum arabic 1g
The low hydroxyl cane sugar powder 1g that replaces
Propyl cellulose 10g starch 15g
An amount of Magnesium Stearate 15g of 7% starch slurry
Magnesium Stearate 1g shellac solution 20ml
Ethanol is an amount of
It is an amount of to heat up in a steamer water
Preparation technology:
Raw material SIPI 926 is worn into fine powder, cross 100 mesh sieves.The fine powder of raw material and auxiliary material is evenly mixed, cross 60 mesh sieve secondaries, add 7% starch slurry, make particle with 20 mesh sieves, in 50～55 ℃ of convection oven dryings, make the immediate release section dried particles.By the same method slow-released part is made dried particles.The dried particles of quick-release and slowly-releasing two parts is mixed, sieve 2 times through 16 mesh sieves, add the Magnesium Stearate mixing, compressing tablet, every contains main ingredient 5mg, 10mg, 15mg.
Claims (8)
1. Isoquinolinium compound and salt thereof is characterized in that, described compound is the compound with one of following general structure:
Wherein, R1, R2, R3 represent H, OH, OCH
3, OCH
2Ph, OCH
2O, F, Cl or Br; R4, R5, R6 represent H, CN, NH
2, NO
2, NHSO
2CH
3, OH, OCH
3, CH
2OCH
2
Above-mentioned each substituting group is at the A ring and B ring different positions is single, double or three replacements;
R7 represents C
1～C
6Alkyl;
The R8 representative
Or
Wherein, R ' 8 represents C
1～C
6Alkyl;
R9 represents C
1～C
6Alkyl;
Y＝S，O，N，n＝1，2。
2. compound according to claim 1 is characterized in that R7 comprises CH
3, CH
2CH
3, CH (CH
3)
2Or CH
2CH (CH
3)
2In a kind of; R ' 8 represents CH
3, CH
2CH
3Or CH
2Ph; R9 represents H, CH
3, CH
2CH
3, CH (CH
3)
2
3. the described compound of claim 1 is characterized in that, described salt comprises inorganic acid salt or organic acid salt.
4. compound according to claim 3 is characterized in that, described salt is hydrochloride.
5. compound according to claim 3 is characterized in that the salt of the compound of being addressed is:
1-(2, the 5-dimethoxy-benzyl)-6,7-methylene-dioxy-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (SIPI 926);
1-(4-methoxy-benzyl)-6-methoxyl group-7-benzyloxy-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (SIPI 1124);
1-(3-methylsulfonyl amido benzyl)-6,7-methylene-dioxy-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (C-391);
1-(3-methylsulfonyl amido benzyl)-6-methoxyl group, 7-benzyloxy-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (C409);
1-(2, the 5-dimethoxy-benzyl)-4-sec.-propyl-6,7-dimethoxy-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (C312);
2-[1-(right-the Toluidrin phenoxyl)-2-hydroxyl-propyl group]-6,7-dimethoxy-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (C602);
2-[1-(right-the amido phenoxy group)-2-hydroxyl-propyl group]-6-methoxyl group-7-benzyloxy-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (C491).
6. the preparation method of described compound of claim 1 and salt thereof is characterized in that, Compound I or II comprise the steps:
1. be raw material with substituted phenyl ethylamine (1) and substituted phenylacetic acid (2), in 170～180 ℃ of direct dehydrating condensations or substituted phenylacetic acid SOCl
2Being prepared into acyl chlorides, is solvent and substituted phenyl ethylamine (1) condensation then with the ethylene dichloride, and preparation has the compound shown in the general structure (3), and reaction expression is:
2. the compound (3) that step (1) is obtained is solvent and POCl with the chloroform
3Reflux and react down, obtain to have the compound shown in the general structure (4), reaction expression is:
3. the compound (4) that step (2) is obtained is solvent and NaBH with methyl alcohol
4React, obtain to have the compound shown in the general structure (5), reaction expression is:
4. in compound (5) dissolving and ethanol that step (3) is obtained, under room temperature, add EtOH-HX then, obtain to have the salt of the compound shown in the formula I to acid; Wherein, X is a halogen;
Or the compound (5) that 4.-1. step (3) is obtained is at N, under the existence of N dimethyl oxygen yl pyridines, is solvent and the general structure compound back flow reaction for (6) with the methylene dichloride, obtains to have general structure and is the compound shown in (7), and reaction expression is:
4.-2. the compound and the general structure that with general structure are (7) are R ' 8NH
2The commercially available prod be solvent refluxing reaction with the pyridine, can obtain the compound shown in the formula II, reaction expression is:
Or
4.-3. compound (5) that step (3) is obtained and general structure are that the commercially available lsothiocyanates of R ' 8NCS is solvent with acetone, and back flow reaction can obtain the compound shown in the formula II;
Mixture I or II stir under room temperature with EtOH-HX and separate out precipitation and be converted into corresponding salt;
The preparation method of III or IV and salt thereof comprises the steps:
1. be lead compound with compound (8) and compound (9), preparation has the compound shown in the general structure (10), and reaction expression is:
In the compound (9), n=1,2;
2. the compound that 1. step is obtained (10) prepares compound (11) according to the synthetic method of compound (4), i.e. compound III, and reaction expression is:
3. the compound that 2. step is obtained (11) in methanol solution with NaBH
4React, can obtain compound IV of the present invention, reaction expression is:
The preparation method of compound V and VI and salt thereof comprises the steps:
1. being raw material with compound (12), is solvent with formic acid, reacts with (HCHO) n and HCOOH, obtains to have the compound of general structure for (13), and reaction expression is:
2. the compound that 1. step is obtained (13) in EtOH solution with have general structure and be the compound of (14), with K
2CO
3For arm acid agent, be solvent with EtOH, under the catalysis of KI, back flow reaction obtains the compound of V of the present invention, and is converted into salt, and reaction expression is:
The preparation method of compound VI and salt thereof comprises the steps:
1. will have general structure for the compound of (15) with have general structure for the compound of (16) reaction conditions according to compound V reacts, obtain to have the compound of general structure for (17), reaction expression is:
2. the compound that 1. step is obtained (17) is solvent with methyl alcohol, uses NaBH
4Be reductive agent, obtain compound VI, be converted into salt then, reaction expression is:
The preparation method of compound VI I and salt thereof comprises the steps:
1. will have general structure for the compound of (18) and general structure for (7) or general structure be (20) at K
2CO
3Existence under, be solvent with ethanol, KI is a catalyzer, reaction under refluxing, obtaining general structure is the compound of (21), reaction expression is:
2. compound (21) is reacted in EtOH-HX solution, obtain the salt of the compound of VII of the present invention;
The preparation method of compound VIII and salt thereof comprises the steps:
1. will have general structure and react according to above-mentioned reaction conditions for (19) or the general structure compound for (20) for the compound of (15) and general structure, the acquisition general structure is the compound of (23), and reaction expression is:
2. compound (23) is reacted in EtOH-HX solution, obtain the salt of the compound of VIII of the present invention.
7. contain claim 1～5 each the described compound and the salt thereof for the treatment of significant quantity, and the pharmaceutical composition of pharmaceutically acceptable carrier.
8. each described compound of claim 1～5 and salt thereof the application in the antiarrhythmic medicine of preparation treatment.
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200710165708A CN100595195C (en) | 2003-07-02 | 2003-07-02 | Preparation method and application of isoquinoline componds and salts thereof |
| CNB031296599A CN100404509C (en) | 2003-07-02 | 2003-07-02 | Isoquinoline compound, preparation method and application of salt thereof |
| CNB2007101812957A CN100422156C (en) | 2003-07-02 | 2003-07-02 | Isoquinolinium compound, producing method and application of its salt |
| CNB2007101657078A CN100572360C (en) | 2003-07-02 | 2003-07-02 | The preparation method of Isoquinolinium compound and salt thereof and application |
| CNB2007101812942A CN100494180C (en) | 2003-07-02 | 2003-07-02 | Preparation method and uses of isoquinolinium compound and its salt |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB031296599A CN100404509C (en) | 2003-07-02 | 2003-07-02 | Isoquinoline compound, preparation method and application of salt thereof |
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| CNB2007101657078A Division CN100572360C (en) | 2003-07-02 | 2003-07-02 | The preparation method of Isoquinolinium compound and salt thereof and application |
| CNB2007101812942A Division CN100494180C (en) | 2003-07-02 | 2003-07-02 | Preparation method and uses of isoquinolinium compound and its salt |
| CN200710165708A Division CN100595195C (en) | 2003-07-02 | 2003-07-02 | Preparation method and application of isoquinoline componds and salts thereof |
| CNB2007101812957A Division CN100422156C (en) | 2003-07-02 | 2003-07-02 | Isoquinolinium compound, producing method and application of its salt |
Publications (2)
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|---|---|
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| CN100404509C CN100404509C (en) | 2008-07-23 |
Family
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| CN200710165708A Expired - Fee Related CN100595195C (en) | 2003-07-02 | 2003-07-02 | Preparation method and application of isoquinoline componds and salts thereof |
| CNB2007101657078A Expired - Lifetime CN100572360C (en) | 2003-07-02 | 2003-07-02 | The preparation method of Isoquinolinium compound and salt thereof and application |
| CNB2007101812942A Expired - Fee Related CN100494180C (en) | 2003-07-02 | 2003-07-02 | Preparation method and uses of isoquinolinium compound and its salt |
| CNB031296599A Expired - Lifetime CN100404509C (en) | 2003-07-02 | 2003-07-02 | Isoquinoline compound, preparation method and application of salt thereof |
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| CNB2007101657078A Expired - Lifetime CN100572360C (en) | 2003-07-02 | 2003-07-02 | The preparation method of Isoquinolinium compound and salt thereof and application |
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| CN101468993B (en) * | 2007-12-28 | 2010-10-13 | 上海医药工业研究院 | Isoquinolinium compound or its salts, pharmaceutical composition containing the same, preparation and use thereof |
| CN101468992B (en) * | 2007-12-28 | 2010-12-08 | 上海医药工业研究院 | Isoquinolinium compound or salts thereof, pharmaceutical composition containing the same, preparation and use thereof |
| CN101468995B (en) * | 2007-12-28 | 2011-04-06 | 上海医药工业研究院 | Isoquinolinium compound or its salts, pharmaceutical composition containing the same, preparation and use thereof |
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| CN1045785A (en) * | 1989-03-21 | 1990-10-03 | 国家医药管理局上海医药工业研究院 | There are isoquinoline 99.9, quinazolone and the protoberberine derivative of the effect of treatment cardiovascular disorder synthetic |
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| KR20190040069A (en) * | 2016-08-31 | 2019-04-16 | 차이나 스테이트 인스티튜트 오브 파마수티컬 인더스트리 | Tetrahydroisoquinoline Salt Derivatives and Their Crystallization Methods and Applications |
| JP2019526594A (en) * | 2016-08-31 | 2019-09-19 | チャイナ ステート インスティチュート オブ ファーマスーティカル インダストリー | Tetrahydroisoquinoline salt derivative and its production method and use |
| US10676442B2 (en) | 2016-08-31 | 2020-06-09 | China State Institute Of Pharmaceutical Industry | Salt derivative of tetrahydroisoquinoline and crystalline thereof and preparation method therefore and application thereof |
| CN107778232B (en) * | 2016-08-31 | 2021-05-28 | 上海医药工业研究院 | Tetrahydroisoquinoline salt derivative and preparation method and application of crystal thereof |
| CN107778232A (en) * | 2016-08-31 | 2018-03-09 | 上海医药工业研究院 | A kind of salt derivative of tetrahydroisoquinoline and its preparation method and application of crystal |
| KR102346338B1 (en) * | 2016-08-31 | 2022-01-03 | 차이나 스테이트 인스티튜트 오브 파마수티컬 인더스트리 | Preparation and application of salt derivatives of tetrahydroisoquinoline and crystals thereof |
| WO2021196982A1 (en) * | 2020-03-31 | 2021-10-07 | 江苏康缘药业股份有限公司 | Anti-arrhythmic pharmaceutical composition and preparation method therefor |
| CN113456639A (en) * | 2020-03-31 | 2021-10-01 | 江苏康缘药业股份有限公司 | Anti-arrhythmia pharmaceutical composition and preparation method thereof |
| JP2023524625A (en) * | 2020-03-31 | 2023-06-13 | 江蘇康縁薬業股▲ぶん▼有限公司 | Antiarrhythmic drug composition and manufacturing method |
| 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 |
| JP7547495B2 (en) | 2020-03-31 | 2024-09-09 | 江蘇康縁薬業股▲ぶん▼有限公司 | Antiarrhythmic drug compositions and methods of manufacture |
Also Published As
| Publication number | Publication date |
|---|---|
| CN100404509C (en) | 2008-07-23 |
| CN100494180C (en) | 2009-06-03 |
| CN101407494A (en) | 2009-04-15 |
| CN100595195C (en) | 2010-03-24 |
| CN100572360C (en) | 2009-12-23 |
| CN101153021A (en) | 2008-04-02 |
| CN101153022A (en) | 2008-04-02 |
| CN101407495A (en) | 2009-04-15 |
| CN100422156C (en) | 2008-10-01 |
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