CN101468992B - Isoquinolinium compound or salts thereof, pharmaceutical composition containing the same, preparation and use thereof - Google Patents
Isoquinolinium compound or salts thereof, pharmaceutical composition containing the same, preparation and use thereof Download PDFInfo
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- CN101468992B CN101468992B CN2007101736972A CN200710173697A CN101468992B CN 101468992 B CN101468992 B CN 101468992B CN 2007101736972 A CN2007101736972 A CN 2007101736972A CN 200710173697 A CN200710173697 A CN 200710173697A CN 101468992 B CN101468992 B CN 101468992B
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Abstract
The invention discloses isoquinolin compounds shown as a formula I and salts thereof, wherein R1 refers to H, -CH3 or Br. The invention also discloses a preparation method for the compounds, which comprises the step of reacting compounds shown as III under the action of a condensing agent in halogenated alkane or benzene. The invention also discloses a medicine composition containing the compounds, and application of the compounds to preparing medicines for treating arrhythmia. The isoquinolin compounds and the salts thereof have good antiarrhythmic activity and certain function of strengthening myocardial contraction force.
Description
Technical field
The present invention relates to the new compound of a class, and the pharmaceutical composition, its preparation method and the application that contain it, be specifically related to Isoquinolinium compound or its salt, and the pharmaceutical composition, its preparation method and the application that contain it.
Background technology
Sudden cardiac death (SCD) is one of cardiovascular disorder main causes of death.The generation of SCD is to cause owing to cardiac electrophysiology is unstable clocklike that the rhythm of the heart disappears, and the most serious is continues chamber speed (VT, vetricular tachycardia) and chamber quiver (VF, vetricalar fibrillation).
At present, existing numerous anti-arrhythmic is as sodium channel inhibitor, beta-blocker, calcium channel blocker and potassium channel blocking agent etc.In the clinical application, need antiarrhythmic drug energy reducing heart rate, and simultaneously myocardial contraction is had influence or enhancing.But existing anti-arrhythmic generally all has stronger restraining effect to myocardial contraction.As the verapamil of widespread use clinically, it has restraining effect to myocardial contraction in reducing heart rate, its IC
50=0.138 μ M.
Isoquinoline alkaloid extensively is present in the natural phant, and many have an important physical activity, and especially the effect aspect cardiovascular is noticeable.Bisbenzylisoquinoline alkaloid in the natural phant, as Berbamine, dauricine, Tetrrine, kukoline and Neferine, and monobenzyl isoquinoline 99.9 biology, as demethyl coclaurine and Berberine (berberine) etc., it is active in functions such as hypotensive, platelet aggregation-against, cardiac stimulant, diuresis and anti-arrhythmias all to have obvious cardiovascular.Wherein, demethyl coclaurine (Uigenamine) (major ingredient with beta-receptor agonism that extracts from the Chinese medicine monkshood) can strengthen myocardial contraction, but heart rate is accelerated, and myocardial oxygen consumption increases, thereby has limited its clinical use.
Summary of the invention
Problem to be solved by this invention is in order to overcome the existing antiarrhythmic drug defective stronger to the restraining effect of cardiac contractile force; and provide a class new have an antiarrhythmic activity; and myocardial contraction is presented isoquinoline compound or its salt of certain enhancement and the pharmaceutical composition, preparation method and the application that contain it.
Isoquinoline compound of the present invention is suc as formula shown in the I:
Formula I
Wherein, R
1For H ,-CH
3Or Br.
The salt of isoquinoline compound of the present invention is inorganic acid salt or organic acid salt.Wherein, what described inorganic acid salt was preferable is hydrochloride, preferred 6,7-methylene-dioxy-1-(2-thenyl)-3,4-dihydro-isoquinoline hydrochloride.
Preparation method suc as formula the isoquinoline compound shown in the I of the present invention comprises the steps: in halogenated alkane or benzene, under the effect of condensing agent, the compound shown in formula III is reacted, and gets final product.
Formula III formula I
Wherein, R
1For H ,-CH
3Or Br.
That wherein, described condensing agent is preferable is POCl
3, the consumption of described condensing agent is preferable is 1～2 times of compound molar weight shown in formula III.What the temperature of described reaction was preferable is 50～80 ℃, and better is the reflux temperature of solvent.What described halogenated alkane was preferable is chloroform.Reaction times can be by a plate reaction monitoring, with reactant consumption intact till.
Among the present invention, described compound shown in formula III can be made by in the following dual mode any:
(1) under temperature of reaction is 150～180 ℃ condition, will carry out dehydration condensation, get final product suc as formula the homopiperony lamine shown in the II with suc as formula the 2-5 ' shown in the V-substituting group-thiophene acetic acid.Do not have particular requirement suc as formula the homopiperony lamine shown in the II with suc as formula the amount ratio of the 2-5 ' shown in the V-substituting group thiophene acetic acid, preferable is 1: 1.Reaction times can be by a plate reaction monitoring, with reactant consumption intact till.
Formula II formula V formula III
Wherein, R
1For H ,-CH
3Or Br.
(2) will be suc as formula the 2-5 ' shown in the V-substituting group-thiophene acetic acid and SOCl
2Reaction makes 2-5 '-substituting group thiophen acetyl chloride.What the temperature of reaction was preferable is room temperature～80 ℃.2-thiophene acetic acid and SOCl
2Amount ratio do not have particular requirement, preferable is 1: 1.
Then, in the halogenated alkane solvent, with 2-5 '-substituting group thiophen acetyl chloride with carry out condensation reaction suc as formula the homopiperony lamine shown in the II, get final product.What the temperature of described condensation reaction was preferable is 0～10 ℃.5-substituting group-2-thiophen acetyl chloride with do not have particular requirement suc as formula the homopiperony lamine amount ratio shown in the II, preferable is 1: 1.The preferred ethylene dichloride of described halogenated alkane.
Formula II formula III
Wherein, R
1For H ,-CH
3Or Br.
The preparation method of the salt suc as formula the isoquinoline compound shown in the I of the present invention comprises the steps: compound shown by formula I is dissolved in the organic solvent, adds acid and carries out acidifying and get final product.What described organic solvent was preferable is alcoholic solvent, preferred alcohol.The consumption of organic solvent is advisable with solubilizing reaction thing at least.Described acid can be organic acid or mineral acid, as halogen acid.What the consumption of acid was preferable is 1～2 consumption for making solution system pH, can make that acidifying is complete.What acidifying was preferable at room temperature carries out, and preferable stirring makes it to separate out precipitation and gets final product.
Compound of the present invention can be made pharmaceutical composition with various typical additives pharmaceutically.According to therapeutic purpose, pharmaceutical composition can be made various types of administration unit dosage, as tablet, pill, pulvis, liquid, suspension, emulsion, granule, capsule, suppository and injection (solution and suspension) etc.
For the pharmaceutical composition that makes tablet form is shaped, can use any known and widely used vehicle in this area.For example, carrier is as lactose, white sugar, sodium-chlor, glucose, urea, starch, lime carbonate, kaolin, crystalline cellulose and silicic acid etc.; Tackiness agent is as water, ethanol, propyl alcohol, common syrup, glucose solution, starch solution, penetrating judgment solution, carboxymethyl cellulose, lac, methylcellulose gum and potassiumphosphate, polyvinylpyrrolidone etc.; Disintegrating agent, as dry starch, sodiun alginate, agar powder and sea-tangle powder, fatty acid ester, sodium lauryl sulphate, stearic acid monoglycerides, starch and the lactose etc. of sodium bicarbonate, lime carbonate, polyethylene anhydro sorbitol; The disintegration inhibitor is as white sugar, tristearin, Oleum Cocois and winterized stearin; Adsorption enhancer is as quaternary amine alkali and sodium lauryl sulphate etc.; Wetting agent is as glycerine, starch etc.; Sorbent material is as starch, lactose, kaolin, wilkinite and colloid silicic acid etc.; And lubricant, as purified talcum, stearate, boric acid powder and polyoxyethylene glycol etc.If necessary, can also with common be coated with the stain material make tablet as sugar coated tablet, be coated with gelatin film tablet, enteric coated tablets, film coated tablets, duplicature tablet and multilayer tablet.
For the pharmaceutical composition that makes pill is shaped, can use any known and widely used excipient in this area, for example, and carrier, as lactose, starch, Oleum Cocois, hardened vegetable oils, kaolin and talcum etc.; Tackiness agent, as gum arabic powder, yellow work rubber powder, gelatin and ethanol etc.; Disintegrating agent is as agar and sea-tangle powder etc.
For the pharmaceutical composition that makes suppository form is shaped, can use any known and widely used excipient in this area, for example, polyoxyethylene glycol, Oleum Cocois, higher alcohols, the ester of higher alcohols, gelatin and semisynthetic glyceryl ester etc.
In order to prepare the pharmaceutical composition of injection form, solution and suspension can be sterilized, and preferably add proper amount of sodium chloride, glucose or glycerine etc. are made and the isotonic injection of blood.When the preparation injection, also can use any carrier commonly used in this area.For example, water, ethanol, propylene glycol, the isooctadecanol of ethoxylation, the fatty acid ester of the isooctadecanol of polyoxyization and polyethylene anhydro sorbitol etc.In addition, also can add common solvating agent, buffer reagent and pain killer etc.
Among the present invention, the medication of described pharmaceutical composition does not have particular restriction.Can select the preparation administration of various formulations according to patient age, sex and other condition and symptom.For example, tablet, pill, solution, suspension, emulsion, granule and capsule are oral administrations; Injection can be individually dosed, perhaps carries liquid (as glucose solution and amino acid solution) to be mixed into the row vein injection with injection, if necessary can be merely carries out injecting in muscle, intracutaneous, the subcutaneous or abdomen with injection; Suppository is for being administered into rectum.The amount of application of this discovery can change according to the type of route of administration, patient's age, body weight, disease and severity etc., and common dosage can be: per daily dose 0.1～10mg/kg body weight.
The present invention is raw materials used and reagent is all commercially available gets.
The invention still further relates to the application in the antiarrhythmic medicine of preparation treatment of isoquinoline compound of the present invention or its salt.
Positive progressive effect of the present invention is: isoquinoline compound of the present invention or its salt have antiarrhythmic activity preferably, and myocardial contraction is presented certain enhancement.
Embodiment
Mode below by embodiment further specifies the present invention, but does not therefore limit the present invention among the described scope of embodiments.
Reference example 1 N-2-thiophene acetyl-3,4-methylene-dioxy phenylethylamine
2-thiophene acetic acid 1.4g (10mmol) and homopiperony lamine 1.5g (10mmol) were mixed, in 150～160 ℃ of reacting by heating 2.5 hours.Add the ethylene dichloride dissolving after being chilled to room temperature, use 5wt%HCl respectively, H
2O, 1NNaOH, H
2The O washing, anhydrous magnesium sulfate drying removes solvent under reduced pressure, gets N-2-thiophene acetyl-3,4-methylene-dioxy phenylethylamine 2.46g, yield 85.0%, benzene-hexane recrystallization, fusing point 91.6-92.6 ℃.
Ultimate analysis: C
15H
15NO
3S: calculated value %:C62.26, H5.23, N4.84
Experimental value %:C62.37, H5.31, N5.00
1H?NMR(DMSO)δ：3.45(S，2H，O＝C-C
H 2)
Embodiment 16,7-methylene-dioxy-1-(2-thenyl)-3,4-dihydro-isoquinoline
With 2.75g (10mmol) N-2-thiophene acetyl-3,4-methylene-dioxy phenylethylamine is dissolved in the 60ml chloroform, drips 2ml (20mmol) POCl
3, finishing, reflux removes excessive POCl under reduced pressure to putting plate reaction and display reactant consumption (about 3 hours) fully
3And chloroform, residuum solidifies with 1: 1 benzene-hexane wash, filter collect crude product, methyl alcohol-ether (volume ratio 1: 1) recrystallization, 6,7-methylene-dioxy-1-(2-thenyl)-3,4-dihydro-isoquinoline 2.89g, yield 98.8%.
Embodiment 26,7-methylene-dioxy-1-(2-thenyl)-3,4-dihydro-isoquinoline hydrochloride
With 2.75g (10mmol) N-2-thiophene acetyl-3,4-methylene-dioxy phenylethylamine is dissolved in the 60ml chloroform, drips 1ml (10mmol) POCl
3, finish, be heated to 50 ℃, to putting plate reaction and display reactant consumption (about 3 hours) fully, remove excessive POCl under reduced pressure
3And chloroform, residuum solidifies with 1: 1 benzene-hexane wash, the filter collect crude product, methyl alcohol-ether (volume ratio 1: 1) recrystallization is collected crystal, is dissolved in ethanol, the ethanolic soln that splashes into saturated HCl is to pH=1, get 6,7-methylene-dioxy-1-(2-thenyl)-3,4-dihydro-isoquinoline hydrochloride 2.0g, yield 68%, fusing point 201.8-203.0 ℃.
Ultimate analysis: C
15H
14ClNO
2S: calculated value %:C58.53, H4.58, N4.55, Cl11.52
Experimental value %:C58.29, H4.76, N4.90, Cl11.40
1H NMR (DMSO) δ: 4.70 (S, 2H, C
H 2-thienyl)
Embodiment 36,7-methylene-dioxy-1-(2-thenyl)-3,4-dihydro-isoquinoline tartrate
With 2.75g (10mmol) N-2-thiophene acetyl-3,4-methylene-dioxy phenylethylamine is dissolved in the 60ml benzene, drips 1.5ml (15mmol) POCl
3, finish, be heated to 80 ℃, reactant disappears (about 3 hours), removes excessive POCl under reduced pressure
3And chloroform, residuum solidifies with 1: 1 benzene-hexane wash, filter collect crude product, methyl alcohol-ether (volume ratio 1: 1) recrystallization is collected crystal, gets 6,7-methylene dichloride base-1-(2-thenyl)-3, the 4-dihydro-isoquinoline is dissolved in the ethyl acetate, drip the tartaric ethyl acetate solution of saturated 8wt%, to pH=1.5, stir and separate out crystal, filter, filter cake washs with ethyl acetate, drying, get 6,7-methylene dichloride base-1-(2-thenyl)-3,4-dihydro-isoquinoline tartrate.
Reference example 2 N-2--5 '-methyl-thiophene acetyl-3,4-methylene-dioxy phenylethylamine
2--5 '-methyl-thiophene acetic acid 1.54g (10mmol) and homopiperony lamine 1.5g (10mmol) were mixed, in 150～160 ℃ of reacting by heating 2.5 hours.Add the ethylene dichloride dissolving after being chilled to room temperature, use 5wt%HCl respectively, H
2O, 1N NaOH, H
2The O washing, anhydrous magnesium sulfate drying removes solvent under reduced pressure, gets N-2-5 '-methyl-thiophene acetyl-3,4-methylene-dioxy phenylethylamine.
Embodiment 46,7-methylene-dioxy-1-(2-5 '-methyl-thenyl)-3, the 4-dihydro-isoquinoline hydrochloride
With 2.89g (10mmol) N-2-5 '-methyl-thiophene acetyl-3,4-methylene-dioxy phenylethylamine is dissolved in the 60ml chloroform, drips 2ml (20mmol) POCl
3, finish, be heated to 50 ℃, to putting plate reaction and display reactant consumption (about 3 hours) fully, remove excessive POCl under reduced pressure
3And chloroform, residuum was with 1: 1 benzene-hexane wash, solidify, filter collect crude product, methyl alcohol-ether (volume ratio 1: 1) recrystallization is collected crystal, get 6,7-methylene-dioxy-1-(2-5 '-methyl-thenyl)-3, the 4-dihydro-isoquinoline is dissolved in ethanol with it, the ethanolic soln that splashes into saturated HCl is to pH=1.5, remove solvent under reduced pressure, residuum gets 6 with methyl alcohol-ether (volume ratio 1: 1) recrystallization, 7-methylene-dioxy-1-(2-5 '-methyl-thenyl)-3, the 4-dihydro-isoquinoline hydrochloride, yield 90.1%, 211.6～212.0 ℃ of fusing points.
MS?285；
1H-NMR(DMSO)δ：4.66(S.2H
)
Reference example 3 N-2--5 '-bromo-thiophene acetyl-3,4-methylene-dioxy phenylethylamine
2-5 '-bromo-thiophene acetic acid 2.19g (10mmol) and homopiperony lamine 1.5g (10mmol) were mixed, in 150～160 ℃ of reacting by heating 2.5 hours.Add the ethylene dichloride dissolving after being chilled to room temperature, use 5wt%HCl respectively, H
2O, 1N NaOH, H
2The O washing, anhydrous magnesium sulfate drying removes solvent under reduced pressure, gets N-2-5 '-bromo-thiophene acetyl-3,4-methylene-dioxy phenylethylamine.
Embodiment 56,7-methylene-dioxy-1-(2-5 '-the bromo-thenyl)-3, the 4-dihydro-isoquinoline hydrochloride
With 3.54g (10mmol) N-2-5 '-methyl-thiophene acetyl-3,4-methylene-dioxy phenylethylamine is dissolved in the 60ml chloroform, drips 2ml (20mmol) POCl
3, finish, be heated to 50 ℃, to putting plate reaction and display reactant consumption (about 3 hours) fully, remove excessive POCl under reduced pressure
3And chloroform, residuum was with 1: 1 benzene-hexane wash, solidify, filter collect crude product, methyl alcohol-ether (volume ratio 1: 1) recrystallization is collected crystal, get 6,7-methylene-dioxy-1-(2-5 '-the bromo-thenyl)-3, the 4-dihydro-isoquinoline is dissolved in ethanol with it, the ethanolic soln that splashes into saturated HCl is to pH1～2, remove solvent under reduced pressure, residuum gets 6 with methyl alcohol-ether (volume ratio 1: 1) recrystallization, 7-methylene-dioxy-1-(2-5 '-the bromo-thenyl)-3, the 4-dihydro-isoquinoline hydrochloride, yield 63.4%, 80.8～81.6 ℃ of fusing points.
MS：350，
1H-NMR(DMSO)δ：4.10(S，2H，
)
Effect embodiment
Carry out following compound according to a conventional method electricity irritation is caused the effect experiment that the spontaneous dancing of guinea pig in vitro left atrium convergent force and right atrium influences.
Table 1 pair electricity irritation causes the spontaneous dancing influence of guinea pig in vitro left atrium convergent force and right atrium
-right atrium is spontaneous beats in order to increase
As seen from the above table, demethyl coclaurine (Uigenamine) makes heart rate accelerate when strengthening myocardial contraction, and myocardial oxygen consumption is increase, thereby has limited its clinical use.Verapamil has restraining effect to myocardial contraction in reducing heart rate, its IC
50=0.138 μ M.Spontaneous dancing has certain enhancement, EC to the convergent force of left atrium simultaneously and compound of the present invention is in the right atrium of slowing down
50=19.7 μ M.And the isoquinoline 99.9 that corresponding phenyl ring replaces is bigger to left atrium convergent force restraining effect, IC
50=78.8 μ M.
Above experimental result shows that isoquinoline compound of the present invention or its salt have antiarrhythmic activity preferably, and myocardial contraction is presented certain enhancement.
Claims (16)
1. a class is suc as formula the isoquinoline compound shown in the I or its salt;
Formula I
Wherein, R
1For H ,-CH
3Or Br.
2. as claimed in claim 1 suc as formula the isoquinoline compound shown in the I or its salt, it is characterized in that: described salt is inorganic acid salt or organic acid salt.
3. as claimed in claim 2 suc as formula the isoquinoline compound shown in the I or its salt, it is characterized in that: described inorganic acid salt is a hydrochloride.
4. as claimed in claim 3 suc as formula the isoquinoline compound shown in the I or its salt, it is characterized in that: described hydrochloride is: 6, and 7-methylene-dioxy-1-(2-thenyl)-3,4-dihydro-isoquinoline hydrochloride.
5. the preparation method suc as formula the isoquinoline compound shown in the I as claimed in claim 1 is characterized in that: in halogenated alkane or benzene, under the effect of condensing agent, the compound shown in formula III is reacted, get final product;
Formula III formula I
Wherein, R
1For H ,-CH
3Or Br.
6. preparation method as claimed in claim 5 is characterized in that: described condensing agent is POCl
3
7. preparation method as claimed in claim 5 is characterized in that: the consumption of described condensing agent is 1～2 times of the compound molar weight shown in formula III.
8. preparation method as claimed in claim 5 is characterized in that: the temperature of described reaction is 50～80 ℃.
9. preparation method as claimed in claim 5 is characterized in that: the temperature of described reaction is the reflux temperature of solvent.
10. preparation method as claimed in claim 5 is characterized in that: described halogenated alkane is a chloroform.
11. the preparation method of the salt suc as formula the isoquinoline compound shown in the I as claimed in claim 1 is characterized in that comprising the steps: compound shown by formula I is dissolved in the organic solvent, adds acid and carries out acidifying and get final product.
12. preparation method as claimed in claim 11 is characterized in that: described organic solvent is an alcohol reagent.
13. preparation method as claimed in claim 12 is characterized in that: described alcohol reagent is an ethanol.
14. preparation method as claimed in claim 11 is characterized in that: the consumption of described acid is that to make solution system pH be 1～2 consumption.
15. contain the treatment significant quantity as each described pharmaceutical composition in the claim 1～4 suc as formula the isoquinoline compound shown in the I or its salt.
16. as each described application in the ARR medicine of preparation treatment of claim 1～4 suc as formula the isoquinoline compound shown in the I or its salt.
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| CN101468992B true CN101468992B (en) | 2010-12-08 |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1566098A (en) * | 2003-07-02 | 2005-01-19 | 上海医药工业研究院 | Isoquinoline compound, preparation method and application of salt thereof |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1566098A (en) * | 2003-07-02 | 2005-01-19 | 上海医药工业研究院 | Isoquinoline compound, preparation method and application of salt thereof |
Non-Patent Citations (3)
| Title |
|---|
| JUDITH A. BOSSON et al.THE CHEMICAL CONSTITUENTS OF AUSTRALIAN FLINDERSIA SPECIES XVII. THE STRUCTURE OF IFFLAIAMINE.《Austrilian Journal of Chemistry》.1963,第16卷480-490. * |
| 冉崇昭等.1-苄基-2-( 4′-甲磺酰基-1-羟基-苯乙基)-1 ,2 ,3 ,4-四氢异喹啉类化合物的合成及其抗心律失常活性.《中国药物化学杂志》.2007,第17卷(第2期),65-71. |
| 冉崇昭等.1-苄基-2-( 4′-甲磺酰基-1-羟基-苯乙基)-1,2,3,4-四氢异喹啉类化合物的合成及其抗心律失常活性.《中国药物化学杂志》.2007,第17卷(第2期),65-71. * |
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Effective date of registration: 20161019 Address after: 222001 Jiangsu city of Lianyungang Province Economic and Technological Development Zone Jiangning industrial city Kanion Road No. 58 Patentee after: Kangyuan Pharmceutical Co., Ltd. Patentee after: Shanghai Institute of pharmaceutical industry Address before: 200040 Beijing West Road, Shanghai, No. 1320 Patentee before: Shanghai Institute of pharmaceutical industry |