CN101468995A - Isoquinolinium compound, pharmaceutical composition containing the same, preparation and use thereof - Google Patents
Isoquinolinium compound, pharmaceutical composition containing the same, preparation and use thereof Download PDFInfo
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- CN101468995A CN101468995A CNA2007101737212A CN200710173721A CN101468995A CN 101468995 A CN101468995 A CN 101468995A CN A2007101737212 A CNA2007101737212 A CN A2007101737212A CN 200710173721 A CN200710173721 A CN 200710173721A CN 101468995 A CN101468995 A CN 101468995A
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Abstract
The invention discloses isoquinolin compounds shown as a formula I and salts thereof. The invention also discloses a preparation method for the compounds, which comprises the step of reacting compounds shown as IV under the action of a reducing agent in an alcohol solvent. 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 no influence on myocardial contraction force.
Description
Technical field
The present invention relates to a kind of new compound, and the pharmaceutical composition, its preparation method and the application that contain it, be specifically related to a kind of isoquinoline 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, Tetrandrine, cocculine 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 a kind of new antiarrhythmic activity that has is provided; and myocardial contraction there are not isoquinoline compound or its salt of influence 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
The salt of isoquinoline compound of the present invention is inorganic acid salt or organic acid salt.What wherein, described inorganic acid salt was preferable is hydrochloride.
Preparation method suc as formula the isoquinoline compound shown in the I of the present invention comprises the steps: in alcoholic solvent, under the effect of reductive agent, will react suc as formula the compound shown in the IV, gets final product.
Formula IV formula I
That wherein, described reductive agent is preferable is NaBH
4The consumption of described reductive agent is preferable is suc as formula the compound molar weight shown in the IV 1～2 times.What the temperature of reaction was preferable is 20～40 ℃.What described alcoholic solvent was preferable is methyl alcohol.Reaction times can be by a plate reaction monitoring, with reactant consumption intact till.
Among the present invention, described suc as formula preferable the making of the compound shown in the IV: as in halogenated alkane or benzene, under the effect of condensing agent, the compound shown in formula III to be reacted, get final product by following method.
Formula III formula I
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 homopiperony lamine shown in the II and 2-pyridylacetic acid(HPAC).Amount ratio suc as formula homopiperony lamine shown in the II and 2-pyridylacetic acid(HPAC) does not have particular requirement, and that preferable is 1:1.Reaction times can be monitored by thin-layer chromatography, till finishing with reactant consumption.
Formula II formula III
(2) with 2-pyridylacetic acid(HPAC) and SOCl
2Reaction makes 2-pyridine Acetyl Chloride 98Min..What the temperature of reaction was preferable is room temperature～80 ℃.2 pyridylacetic acid(HPAC)s and SOCl
2Amount ratio do not have particular requirement, that preferable is 1:1.
Then, in the halogenated alkane solvent, with 2-pyridine Acetyl Chloride 98Min. 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 ℃.2-pyridine Acetyl Chloride 98Min. with do not have particular requirement suc as formula the homopiperony lamine amount ratio shown in the II, that preferable is 1:1.The preferred ethylene dichloride of described halogenated alkane.
Formula II formula III
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 not had influence.
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 N-2-pyridine ethanoyl-3,4-methylene-dioxy phenylethylamine
2-pyridylacetic acid(HPAC) 1.67g (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-pyridine ethanoyl-3,4-methylene-dioxy phenylethylamine.
Embodiment 16,7-methylene-dioxy-1-(2-picolyl)-3,4-dihydro-isoquinoline
With 3.02g (10mmol) N-2-pyridine ethanoyl-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-picolyl)-3,4-dihydro-isoquinoline, yield 98%.
Embodiment 26,7-methylene-dioxy-1-(2-picolyl)-3,4-dihydro-isoquinoline
With 3.02g (10mmol) N-2-pyridine ethanoyl-3,4-methylene-dioxy phenylethylamine is dissolved in the 60ml chloroform, drips 1ml (10mmol) POCl
3, finish, be heated to 50 ℃, to reactant disappearance (about 3 hours), remove 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, 6,7-methylene-dioxy-1-(2-picolyl)-3,4-dihydro-isoquinoline, yield 96%.
Embodiment 36,7-methylene-dioxy-1-(2-picolyl)-3,4-dihydro-isoquinoline
With 3.02g (10mmol) N-2-pyridine ethanoyl-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, 6,7-methylene-dioxy-1-(2-picolyl)-3,4-dihydro-isoquinoline, yield 95%.
Embodiment 46,7-methylene dichloride base-1-(2-picolyl)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt
With 10.04g (30mmol) 6,7-methylene-dioxy-1-(2-picolyl)-3, the 4-dihydro-isoquinoline is dissolved in the 20ml methyl alcohol, is chilled to below 5 ℃, and gradation adds 2.22g (60mmol) NaBH
4Finish, 25 ℃ of stirrings of room temperature are spent the night.Remove methyl alcohol next day under reduced pressure, adds 20ml water, uses chloroform extraction, washing, anhydrous magnesium sulfate drying, filtering MgSO
4After chloroformic solution, the ethanolic soln that drips saturated HCl is to pH1～2.Remove solvent under reduced pressure, residuum gets 6,7-methylene dichloride base-1-(2-picolyl)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt, yield 81.2%, fusing point 205.4-206.2 ℃ with methyl alcohol-ether (volume ratio 1:1) recrystallization.
Ultimate analysis: C
16H
18Cl
2N
2O
2: calculated value %:C 56.32, H 5.32, N 8.21 cl 20.78
Experimental value %:C 56.30, H 5.23, and N 8.19, and cl 20.52
1H?NMR(DMSO)S：3.50(T，1H，CH)
Embodiment 56,7-methylene dichloride base-1-(2-picolyl)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt
With 10.04g (30mmol) 6,7-methylene-dioxy-1-(2-picolyl)-3, the 4-dihydro-isoquinoline is dissolved in the 20ml methyl alcohol, is chilled to below 5 ℃, and gradation adds 1.11g (30mmol) NaBH
4Finish, 40 ℃ of stirrings are spent the night.Remove methyl alcohol next day under reduced pressure, adds 20ml water, uses chloroform extraction, washing, anhydrous magnesium sulfate drying, filtering MgSO
4After chloroformic solution, the ethanolic soln that drips saturated HCl is to the pH=1.Remove solvent under reduced pressure, residuum gets 6,7-methylene dichloride base-1-(2-picolyl)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt 6.5g, yield 70.4% with methyl alcohol-ether (volume ratio 1:1) recrystallization.
Embodiment 66,7-methylene dichloride base-1-(2-picolyl)-1,2,3,4-tetrahydroisoquinoline tartrate
With 10.04g (30mmol) 6,7-methylene-dioxy-1-(2-picolyl)-3, the 4-dihydro-isoquinoline is dissolved in the 20ml methyl alcohol, is chilled to below 5 ℃, and gradation adds 1.665g (45mmol) NaBH
4Finish, 20 ℃ of stirrings are spent the night.Remove methyl alcohol next day under reduced pressure, adds 20ml water, uses chloroform extraction, washing, anhydrous magnesium sulfate drying, filtering MgSO
4After chloroformic solution, remove solvent under reduced pressure, 6,7-methylene dichloride base-1-(2-picolyl)-1,2,3, the 4-tetrahydroisoquinoline, be dissolved in the ethyl acetate, drip the tartaric ethyl acetate solution of saturated 8wt%, to pH=1.5, crystal is separated out in stirring, filters, and filter cake washs with ethyl acetate, drying gets 6,7-methylene dichloride base-1-(2-picolyl)-1,2,3,4-tetrahydroisoquinoline tartrate.
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 does not have influence to the convergent force of left atrium simultaneously and compound of the present invention is in the right atrium of slowing down.And the isoquinoline 99.9 that corresponding phenyl ring replaces is bigger to left atrium convergent force restraining effect, IC
50=91.5 μ M.
Above experimental result shows that isoquinoline compound of the present invention or its salt have antiarrhythmic activity preferably, and myocardial contraction is not had influence.
Claims (20)
1. a class is suc as formula the isoquinoline compound shown in the I or its salt.
Formula I
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. the preparation method of compound as claimed in claim 1 is characterized in that comprising the steps: in alcoholic solvent, under the effect of reductive agent, will react suc as formula the compound shown in the IV, gets final product.
Formula IV formula I
5. preparation method as claimed in claim 4 is characterized in that: described reductive agent is NaBH
4
6. preparation method as claimed in claim 4 is characterized in that: the consumption of described reductive agent is 1～2 times suc as formula the compound molar weight shown in the IV.
7. preparation method as claimed in claim 4 is characterized in that: the temperature of described reaction is 20～40 ℃.
8. preparation method as claimed in claim 4 is characterized in that: described alcoholic solvent is a methyl alcohol.
9. preparation method as claimed in claim 4 is characterized in that: describedly made by following method suc as formula the compound shown in the IV: 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 IV
10. preparation method as claimed in claim 9 is characterized in that: described condensing agent is POCl
3
11. preparation method as claimed in claim 9 is characterized in that: the consumption of described condensing agent is 1～2 times of the compound molar weight shown in formula III.
12. preparation method as claimed in claim 9 is characterized in that: the temperature of described reaction is 50～80 ℃.
13. preparation method as claimed in claim 9 is characterized in that: the temperature of described reaction is the reflux temperature of solvent.
14. preparation method as claimed in claim 9 is characterized in that: described halogenated alkane is a chloroform.
15. the preparation method of the salt of compound shown by formula I as claimed in claim 1 is characterized in that comprising the steps: compound shown by formula I is dissolved in the organic solvent, adding acid is carried out acidifying and is got final product.
16. preparation method as claimed in claim 15 is characterized in that: described organic solvent is an alcohol reagent.
17. preparation method as claimed in claim 16 is characterized in that: described alcohol reagent is an ethanol.
18. preparation method as claimed in claim 15 is characterized in that: the consumption of described acid is that to make solution system pH be 1～2 consumption.
19. contain the pharmaceutical composition as each described compound and salt thereof in the claim 1～3 for the treatment of significant quantity.
20. as the application of each described compound or its salt of claim 1～3 in the antiarrhythmic medicine of preparation treatment.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103351338A (en) * | 2013-06-17 | 2013-10-16 | 张家港威胜生物医药有限公司 | Simple preparation process of higenamine hydrochloride |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN100494180C (en) * | 2003-07-02 | 2009-06-03 | 上海医药工业研究院 | Preparation method and uses of isoquinolinium compound and its salt |
| CN1328263C (en) * | 2004-11-01 | 2007-07-25 | 上海汇伦生命科技有限公司 | Tetrahydroisoquinoline derivative, its preparation method and pharmaceutical composition |
-
2007
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103351338A (en) * | 2013-06-17 | 2013-10-16 | 张家港威胜生物医药有限公司 | Simple preparation process of higenamine hydrochloride |
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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 |