CN1769272A - Tetrahydroisoquinoline derivative, its preparation method and pharmaceutical composition - Google Patents
Tetrahydroisoquinoline derivative, its preparation method and pharmaceutical composition Download PDFInfo
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Abstract
The invention discloses the novel optical isomer of tetrahydrochysene isoquinoline derivation, (R)-2-[1-( p - Toluenesulphonamido phenoxy)-2- hydroxyl group- propyl group]-6, 7- dimethoxy-1,2,3,4- tetrahydrochysene isoquinoline or (S)-2-[1-( p - Toluenesulphonamido phenoxy)-2- hydroxyl group- propyl group]-6, 7- dimethoxy-1,2,3,4- tetrahydrochysene isoquinoline. The invention also discloses the method for preparation of the compound and the antiarrhythmics which comprises the said compound as active constituent. In the invention, the rat takes the reagent 40mg*kg-1*d-1 and the positive drug Mexiletine 80mg*kg-1*d-1 orally for three days, and it can resist the arrhythmia caused by perfusing the aconitine. The cavy takes the reagent 20mg*kg-1*d-1 and the positive drug Sotalol 30.8mg*kg -1*d-1 orally for three days, and it can resist the arrhythmia caused by perfusing the Ouabain.
Description
Technical field
The present invention relates to a kind of heterogeneous ring compound, relate to a kind of derivative, its preparation method of tetrahydroisoquinoline in particular and be the pharmaceutical composition of the anti-heart disorder of active ingredient with this compound with six-membered ring.
Background technology
Now, cardiovascular disorder has become one of principal disease that threatens human body health, and irregular pulse is again common a kind of cardiovascular disorder.Existing anti-arrhythmic as: though Quinidine, lignocaine, Tamboar, encainide, propafenone, Xin Dean, amiodarone have certain curative effect, ubiquity that toxicity is big, drug effect is low, the synthetic high different shortcomings of cost.Chinese invention patent 95196531.X, notification number 1167485, name is called " tetrahydro isoquinoline derivative and the pharmaceutical preparation that contains them ", a kind of tetrahydro isoquinoline derivative is disclosed, this invention is inhibited to the gathering that is caused by Fibrinogen, can be effective as antithrombotic agent or anticoagulant.But the tetrahydro isoquinoline derivative with optical isomer of good antiarrhythmic activity is not seen in report as yet.
Summary of the invention
Technical problem to be solved by this invention provides the pure tetrahydro isoquinoline derivative of a kind of stereochemistry, the chirality synthetic method of this compound, and this compound is in the application of preparation treatment antiarrhythmic Agents Composition Aspects.
The technical solution adopted in the present invention: (R)-2-[1-(to the methanesulfonamido the phenoxy group)-2-hydroxyl-propyl group of general formula (I) expression]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline or (S)-2-[1-(to the methanesulfonamido phenoxy group)-2-hydroxyl-propyl group]-6,7-dimethoxy-1,2,3, the 4-tetrahydroisoquinoline
Preparation method with tetrahydro isoquinoline derivative of general formula (I) comprises the following steps: that (a) makes the reaction of the compound of the compound of formula (III) and formula (IV), obtains the compound of formula (II),
(b) compound of formula (II) obtains the compound of formula (I) through reduction, substitution reaction
The compound of step (a) Chinese style (IV) is (R)-(-)-2-(p-nitrophenyl oxygen base) propylene oxide, the compound of step (b) Chinese style (II) is (R)-2-[1-(to the methanesulfonamido phenoxy group)-2-hydroxyl-propyl group through the compound that reduction, substitution reaction obtain formula (I)]-6,7-dimethoxy-1,2,3, the 4-tetrahydroisoquinoline.
The compound of step (a) Chinese style (IV) is (S)-(-)-2-(p-nitrophenyl oxygen base) propylene oxide, the compound of step (b) Chinese style (II) is (S)-2-[1-(to the methanesulfonamido phenoxy group)-2-hydroxyl-propyl group through the compound that reduction, substitution reaction obtain formula (I)]-6,7-dimethoxy-1,2,3, the 4-tetrahydroisoquinoline.
The compound of step (a) Chinese style (III) prepares through the following steps: with 3, and the 4-dimethoxy-phenylethylamine, Paraformaldehyde 96 and formic acid mix, stir 1-2h in 30-40 ℃, be chilled to room temperature, remove formic acid under reduced pressure, get oily matter, add water, transfer about PH8 with ammoniacal liquor, methylene dichloride extracts for 3 times, 3 washings of water, use anhydrous magnesium sulfate drying, remove solvent under reduced pressure, get oily matter, with ethyl acetate 30ml dissolving, in the ice bath cooling down, add EtOH-HCl, separate out white solid, the filter collection, the ethyl acetate washing, drying.
The compound of step (a) Chinese style (IV) prepares through the following steps: p-NP, pyridine a little, (R)-(-)-epoxy chloropropane places reaction flask, behind the 60-120 ℃ of stirring 4-8h, evaporated under reduced pressure adds acetone and 3N aqueous sodium hydroxide solution, behind the stirring at room 0.5-1.5h, remove acetone under reduced pressure, use the 500ml dichloromethane extraction, washing, anhydrous magnesium sulfate drying, remove solvent under reduced pressure, methanol crystallization gets light brown crystal.
The compound of step (a) Chinese style (II) prepares through the following steps: the compound of formula (III), (IV) is dissolved in Virahol or N, dinethylformamide, ethanol or chloroform, behind the backflow 2-5h, be chilled to room temperature, add a little sherwood oil, separate out solid, add the gac reflux decolour with Virahol, this solid is carried out recrystallization, obtain yellow square crystal.
The compound of step (b) Chinese style (I) prepares through the following steps: with the crystal of formula (II) compound, iron powder and NH
4C drops in the three-necked bottle, adds 75% tetrahydrofuran aqueous solution, and backflow 2-4h is chilled to room temperature, adds NaHCO
3And ethyl acetate, stirring 30min, the filtering insolubles removes tetrahydrofuran (THF) and ethyl acetate under reduced pressure, extracts for 3 times with ethyl acetate, and anhydrous magnesium sulfate drying removes ethyl acetate under reduced pressure, is directly used in next step reaction; Above-claimed cpd is dissolved in the 10ml pyridine, adds trimethylchlorosilane under stirring at room, stirring reaction 6-10h adds Methanesulfonyl chloride, and stirring at room 7h adds a little H
2O transfers about PH1 with concentrated hydrochloric acid, transfers about PH8 with ammoniacal liquor again, and methylene dichloride extracts for 3 times, washing, and anhydrous magnesium sulfate drying is used alcohol crystal after the evaporated under reduced pressure, and obtaining compound is (I).
The pharmaceutical composition of anti-heart disorder, tetrahydro isoquinoline derivative (R)-2-[1-(to the methanesulfonamido the phenoxy group)-2-hydroxyl-propyl group that wherein contains claim 1]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline or (S)-2-[1-(to the methanesulfonamido phenoxy group)-2-hydroxyl-propyl group]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline or its pharmaceutical salts be as effective constituent, and contain conventional pharmaceutical carrier.The pharmaceutical salts pharmacy here goes up acceptable salt, for example with the salt of mineral acids formation such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid or the salt that forms with organic acids such as citric acid, succsinic acid, tartrate, methylsulfonic acids.
The invention has the beneficial effects as follows: (R)-2-[1-(to the methanesulfonamido phenoxy group)-2-hydroxyl-propyl group that stereochemistry provided by the invention is pure]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline or (S)-2-[1-(to the methanesulfonamido phenoxy group)-2-hydroxyl-propyl group]-6,7-dimethoxy-1,2,3, the 4-tetrahydroisoquinoline has the active effect of better medicament, rat oral test medicine 40mg*kg-1*d-1 and positive drug mexiletine 80mg*kg-1*d-1, continuous three days, can resist the irregular pulse due to the napelline perfusion, cavy oral test medicine 20mg*kg-1*d-1 and the Ta Luoer 30.8mg*kg-1*d-1 of positive drug institute, continuous three days, can resist the irregular pulse due to the ouabain perfusion.The present invention utilizes raw material commonly used and easy operational path to have the optical activity product by synthetic having made of chirality, has avoided low, the shortcomings such as optical purity is poor, wastage of material of traditional method for splitting yield.The pharmacological effect that has anti-heart disorder with the present invention as the pharmaceutical composition of effective constituent.
Embodiment
Below in conjunction with specific embodiment the present invention is described in further detail: (R)-2-[1-(to the methanesulfonamido the phenoxy group)-2-hydroxyl-propyl group of general formula (I) expression]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline or (S)-2-[1-(to the methanesulfonamido phenoxy group)-2-hydroxyl-propyl group]-6,7-dimethoxy-1,2,3, the 4-tetrahydroisoquinoline
Have the preparation method of the tetrahydro isoquinoline derivative of general formula (I), comprise the following steps:
(a) make the reaction of the compound of the compound of formula (III) and formula (IV), obtain the compound of formula (II),
(b) compound of formula (II) obtains the compound of formula (I) through reduction, substitution reaction
The compound of step (a) Chinese style (IV) is (R)-(-)-2-(p-nitrophenyl oxygen base) propylene oxide, the compound of step (b) Chinese style (II) is (R)-2-[1-(to the methanesulfonamido phenoxy group)-2-hydroxyl-propyl group through the compound that reduction, substitution reaction obtain formula (I)]-6,7-dimethoxy-1,2,3, the 4-tetrahydroisoquinoline.
The compound of step (a) Chinese style (IV) is (S)-(-)-2-(p-nitrophenyl oxygen base) propylene oxide, the compound of step (b) Chinese style (II) is (S)-2-[1-(to the methanesulfonamido phenoxy group)-2-hydroxyl-propyl group through the compound that reduction, substitution reaction obtain formula (I)]-6,7-dimethoxy-1,2,3, the 4-tetrahydroisoquinoline.
The compound of step (a) Chinese style (III) prepares through the following steps: with 3, and the 4-dimethoxy-phenylethylamine, Paraformaldehyde 96 and formic acid mix, stir 1-2h in 30-40 ℃, be chilled to room temperature, remove formic acid under reduced pressure, get oily matter, add water, transfer about PH8 with ammoniacal liquor, methylene dichloride extracts for 3 times, 3 washings of water, use anhydrous magnesium sulfate drying, remove solvent under reduced pressure, get oily matter, with ethyl acetate 30ml dissolving, in the ice bath cooling down, add EtOH-HCl, separate out white solid, the filter collection, the ethyl acetate washing, drying.
The compound of step (a) Chinese style (IV) prepares through the following steps: p-NP, pyridine a little, (R)-(-)-epoxy chloropropane places reaction flask, behind the 60-120 ℃ of stirring 4-8h, evaporated under reduced pressure adds acetone and 3N aqueous sodium hydroxide solution, behind the stirring at room 0.5-1.5h, remove acetone under reduced pressure, use the 500ml dichloromethane extraction, washing, anhydrous magnesium sulfate drying, remove solvent under reduced pressure, methanol crystallization gets light brown crystal.
The compound of step (a) Chinese style (II) prepares through the following steps: the compound of formula (III), (IV) is dissolved in Virahol or N, dinethylformamide, ethanol or chloroform, behind the backflow 2-5h, be chilled to room temperature, add a little sherwood oil, separate out solid, add the gac reflux decolour with Virahol, this solid is carried out recrystallization, obtain yellow square crystal.
The compound of step (b) Chinese style (I) prepares through the following steps: with the crystal of formula (II) compound, iron powder and NH
4C drops in the three-necked bottle, adds 75% tetrahydrofuran aqueous solution, and backflow 2-4h is chilled to room temperature, adds NaHCO
3And ethyl acetate, stirring 30min, the filtering insolubles removes tetrahydrofuran (THF) and ethyl acetate under reduced pressure, extracts for 3 times with ethyl acetate, and anhydrous magnesium sulfate drying removes ethyl acetate under reduced pressure, is directly used in next step reaction; Above-claimed cpd is dissolved in the 10ml pyridine, adds trimethylchlorosilane under stirring at room, stirring reaction 6-10h adds Methanesulfonyl chloride, and stirring at room 7h adds a little H
2O transfers about PH1 with concentrated hydrochloric acid, transfers about PH8 with ammoniacal liquor again, and methylene dichloride extracts for 3 times, washing, and anhydrous magnesium sulfate drying is used alcohol crystal after the evaporated under reduced pressure, and obtaining compound is (I).
The pharmaceutical composition of anti-heart disorder, tetrahydro isoquinoline derivative (R)-2-[1-(to the methanesulfonamido the phenoxy group)-2-hydroxyl-propyl group that wherein contains claim 1]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline or (S)-2-[1-(to the methanesulfonamido phenoxy group)-2-hydroxyl-propyl group]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline or its pharmaceutical salts be as effective constituent, and contain conventional pharmaceutical carrier.The pharmaceutical salts pharmacy here goes up acceptable salt, for example with the salt of mineral acids formation such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid or the salt that forms with organic acids such as citric acid, succsinic acid, tartrate, methylsulfonic acids.
Embodiment 1
Preparation (R)-2-[1-(to the methanesulfonamido phenoxy group)-2-hydroxyl-propyl group-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and hydrochloride thereof comprise the following steps:
(a) preparation 6,7-dimethoxy-1,2,3, the 4-four hydrogen isoquinoline hydrochloric acid salt: with 3,4-dimethoxy-phenylethylamine 1.8g, Paraformaldehyde 96 0.30g and formic acid 20ml mix, and in 30-40 ℃ of stirring 1-2h, are chilled to room temperature, remove formic acid under reduced pressure, get oily matter, add water 20ml, transfer about PH8 with ammoniacal liquor, extract methylene dichloride 20ml * 3, water 10ml * 3 washings, anhydrous magnesium sulfate drying removes solvent under reduced pressure, gets oily matter, with ethyl acetate 30ml dissolving, in the ice bath cooling down, add EtOH-HCl, separate out white solid, filter collection, ethyl acetate washing, dry, heavy 2.10g, yield 90.0%, m.p.255-256 ℃.
1HNMR in CDCl
3：3.00(2H，t)，3.41(2H，t)，3.80(6H，s)，4.22(2H，s)，6.75(1H，s)，6.78(1H，s)。
(b) preparation (R)-(-)-2-(p-nitrophenyl oxygen base) propylene oxide: p-NP 50.0g (0.36mol), pyridine a little, 26.7ml (R)-(-)-epoxy chloropropane places the 250ml reaction flask, behind the 60-120 ℃ of stirring 4-8h, evaporated under reduced pressure, the 3N aqueous sodium hydroxide solution of adding 200ml acetone and 150ml is behind the stirring at room 0.5-1.5h, remove acetone under reduced pressure, use the 500ml dichloromethane extraction, washing, anhydrous magnesium sulfate drying, remove solvent under reduced pressure, methanol crystallization gets light brown crystal 3 4.6g, yield 53.7%, m.p.76-78 ℃, [α]
D 20-6.19 (c=1, in CHCl
3),
1HNMR in CDCl
3:: 2.78 (1H), 2.94 (1H), 3.38 (1H), 4.01 (1H), 4.37 (1H), 6.99 (2H), 8.20 (2H).
(c) preparation (R)-(+)-2-[1-(p-nitrophenyl oxygen base)-2-hydroxyl-propyl group-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline: above-mentioned 6,7-dimethoxy-1,2,3, the free alkali 2.12g (0.011mol) of 4-four hydrogen isoquinoline hydrochloric acid salt, 1.99g (0.012mol) (R)-(-)-2-(p-nitrophenyl oxygen base) propylene oxide is dissolved in 20 milliliters of Virahols, also can use N, dinethylformamide, ethanol or chloroform are behind the backflow 2-5h, be chilled to room temperature, add a little sherwood oil, separate out solid, add the gac reflux decolour with Virahol, this solid is carried out recrystallization, obtain yellow square crystal.Get 1.1g, yield: 59.4%, fusing point 117-122 ℃, MS:388, [α]
D 20+ 11.36 (c=1, in CHCl
3).
1HNMR in CDCl
3：2.73(2H)，2.78(1H)，2.86(2H)，2.97(1H)，3.62-3.80(5H)，3.84(3H)，3.86(3H)，4.14(2H)，4.10-4.26(3H)，6.53(1H)，6.62(1H)，7.01(2H)，8.20(2H)
13CNMR in CDCl
3：28.6(1C)，51.3(1C)，55.7(1C)，56.0(1C)，56.1(1C)，59.9(1C)，65.7(1C)，71.1(1C)，109.6(1C)，111.6(1C)，114.7(3C)，125.9(2C)，126.0(1C)，141.8(1C)，147.5(1C)，147.9(1C)，163.8(1C)
IR(cm
-1)：3490，3094，2950，2834，1519，1334，867，754。
(d) preparation (R)-2-[1-(to the methanesulfonamido phenoxy group)-2-hydroxyl-propyl group-6,7-dimethoxy-1,2,3, the 4-tetrahydroisoquinoline: with above-mentioned crystal 0.80g (2.06mmol), iron powder 1.0g (15mmol) and NH
4Cl 0.5g (9.2mmol) drops in the 200ml three-necked bottle, adds 75% tetrahydrofuran aqueous solution 60ml, and backflow 2-4h is chilled to room temperature, adds NaHCO
32.4g with ethyl acetate 50ml, stir 30min, the filtering insolubles removes tetrahydrofuran (THF) and ethyl acetate under reduced pressure, extract ethyl acetate 50ml * 3, and anhydrous magnesium sulfate drying removes ethyl acetate under reduced pressure, is directly used in next step reaction.
Above-claimed cpd 0.5g (1.4mmol) is dissolved in the 10ml pyridine, adds trimethylchlorosilane 2.0ml (16.0mmol) under stirring at room, stirring reaction 6-10h adds Methanesulfonyl chloride 0.23ml (2.6mmol), stirring at room 7h.Add a little H
2O transfers about PH1 with concentrated hydrochloric acid, transfers about PH8 with ammoniacal liquor again, and extract methylene dichloride 30ml * 3, washing, and anhydrous magnesium sulfate drying is used alcohol crystal after the evaporated under reduced pressure, get 0.32g, yield 48.5%, 148 ℃ of fusing points, MS:M+437, [α]
D 20-6.99 (c=0.5, in CHCl
3),
1HNMR in CDCl
3：2.71-2.94(9H)，3.60(1H)，3.78(1H)，3.84(3H)，3.85(3H)，4.01(2H)，4.20(1H)，6.52(1H)，6.61(1H)，6.92(2H)，7.18(2H)
13CNMR in CDCl
3：28.6(1C)，39.1(1C)，51.3(1C)，55.8(1C)，56.0(1C)，56.1(1C)，60.1(1C)，65.9(1C)，70.8(1C)，109.6(1C)，111.6(1C)，115.6(2C)，124.8(2C)，126.0(1C)，126.2(1C)，129.5(1C)，147.5(1C)，147.8(1C)，157.4(1C)
IR(cm
-1)：3373，3288，2929，2850，1510，1321，1147，841
The above-claimed cpd thermosol is transferred PH3-4 with concentrated hydrochloric acid in 10ml ethanol, leave standstill, separate out the hydrochloride of this compound, be white crystalline powder, fusing point 192-194 ℃, [α]
D 20+ 12.5 (c=1, inEtOH).
Under the identical situation of reactions steps among the embodiment 1, condition, change the consumption of reactant, reaction product does not change.For example, Paraformaldehyde 96 0.10g (3.3mmol), 0.20g (6.7mmol), 0.40g (13.3mmol) and formic acid 1.8g in the step (a), 2.1g, 2.2g, obtain 6,7-dimethoxy-1,2,3, the yield of 4-four hydrogen isoquinoline hydrochloric acid salt is respectively 77.1%, 90.0% and 94.3%.P-NP 50.0g (0.36mol) in the step (b), pyridine a little, respectively with 25ml, 30ml, 35ml (R)-(-)-epichlorohydrin reaction obtains light brown crystal 3 0g, 40g, the 48g of (R)-(-)-2-(p-nitrophenyl oxygen base) propylene oxide, and yield is respectively 46.6%, 62.1%, 74.5%.In the step (c) 6,7-dimethoxy-1,2,3, the free alkali 2.12g of 4-four hydrogen isoquinoline hydrochloric acid salt, (R)-(-)-and 2-(p-nitrophenyl oxygen base) propylene oxide 1.99g reaction, reaction obtains product (R)-(+)-2-[1-(p-nitrophenyl oxygen base)-2-hydroxyl-propyl group-6,7-dimethoxy-1 in Virahol, chloroform, ethylene dichloride respectively, 2,3,4-tetrahydroisoquinoline 1.2g, 1.4g, 1.4g, yield is respectively 64.8%, 75.6%, 75.6%.Step (d) is middle with (R)-(+)-2-[1-(p-nitrophenyl oxygen base)-2-hydroxyl-propyl group-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline crystal 0.80g (2.06mmol) is respectively with iron powder 0.4g (6mmol), 0.6g (9mmol), 0.8g (12mmol) and NH
4Cl0.2g (3.7mmol), 0.3g (5.5mmol), 0.4g (7.4mmol) reaction add NaHCO
30.96g, 1.4g, 1.9g, product and trimethylchlorosilane 1.0ml (8.0mmol), 1.5ml (12.0mmol), 2.0ml (16.0mmol) react (R)-2-[1-(to the methanesulfonamido phenoxy group)-2-hydroxyl-propyl group-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline 0.36g, 0.42g, 0.45g, yield is respectively 54.6%, 63.7%, 68.2%.
Embodiment 2
Preparation (S)-2-[1-(to the methanesulfonamido phenoxy group)-2-hydroxyl-propyl group-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and hydrochloride thereof comprise the following steps:
(a) preparation 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 formic acid 20ml mix, and in 30-40 ℃ of stirring 1-2h, are chilled to room temperature, remove formic acid under reduced pressure, get oily matter, add water 20ml, transfer about PH8 with ammoniacal liquor, extract methylene dichloride 20ml * 3, water 10ml * 3 washings, anhydrous magnesium sulfate drying removes solvent under reduced pressure, gets oily matter, with ethyl acetate 30ml dissolving, in the ice bath cooling down, add EtOH-HCl, separate out white solid, the filter collection, ethyl acetate washing, drying, heavy 2.10g, m.p.255-256 ℃.
1HNMR in CDCl
3：3.00(2H，t)，3.41(2H，t)，3.80(6H，s)，4.22(2H，s)，6.75(1H，s)，6.78(1H，s)
(b) preparation (S)-(+)-2-(p-nitrophenyl oxygen base) propylene oxide: p-NP 50.0g (0.36mol), pyridine a little, 26.7ml (S)-(+)-epoxy chloropropane places the 250ml reaction flask, behind the 60-120 ℃ of stirring 4-8h, evaporated under reduced pressure, the 3N aqueous sodium hydroxide solution of adding 200ml acetone and 150ml is behind the stirring at room 0.5-1.5h, remove acetone under reduced pressure, use the 500ml dichloromethane extraction, washing, anhydrous magnesium sulfate drying, remove solvent under reduced pressure, methanol crystallization gets light brown crystal 3 4.6g, yield 53.7%, m.p.75-77 ℃, [α]
D 20+ 6.80.
1HNMR in CDCl
3：2.78(1H)，2.94(1H)，3.38(1H)，4.01(1H)，4.37(1H)，6.99(2H)，8.20(2H)
(c) preparation (S)-(-)-2-[1-(p-nitrophenyl oxygen base)-2-hydroxyl-propyl group-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline: above-mentioned 6,7-dimethoxy-1,2,3, the free alkali 2.12g (0.011mol) of 4-four hydrogen isoquinoline hydrochloric acid salt, 1.99g (0.012mol) (S)-(+)-2-(p-nitrophenyl oxygen base) propylene oxide is dissolved in 20 milliliters of Virahols, also can be N, dinethylformamide, in ethanol or the chloroform, behind the backflow 2-5h, be chilled to room temperature, add a little sherwood oil, separate out solid, add the gac reflux decolour with Virahol, this solid is carried out recrystallization, obtain yellow square crystal.Get 1.1g, yield: 59.4%, fusing point 118-123 ℃, MS:388, [α]
D 20-11.19 (c=1, in CHCl
3).
1HNMR in CDCl
3：2.73(2H)，2.78(1H)，2.86(2H)，2.97(1H)，3.62-3.80(5H)，3.84(3H)，3.86(3H)，4.14(2H)，4.10-4.26(3H)，6.53(1H)，6.62(1H)，7.01(2H)，8.20(2H)
13CNMR in CDCl
3：28.6(1C)，51.3(1C)，55.7(1C)，56.0(1C)，56.1(1C)，59.9(1C)，65.7(1C)，71.1(1C)，109.6(1C)，111.6(1C)，114.7(3C)，125.9(2C)，126.0(1C)，141.8(1C)，147.5(1C)，147.9(1C)，163.8(1C)
IR(cm
-1)：3490，3094，2950，2834，1519，1334，867，754
(d) preparation (S)-2-[1-(to the methanesulfonamido phenoxy group)-2-hydroxyl-propyl group-6,7-dimethoxy-1,2,3, the 4-tetrahydroisoquinoline: with above-mentioned crystal 0.80g (2.06mmol), iron powder 1.0g (15mmol) and NH
4Cl 0.5g (9.2mmol) drops in the 200ml three-necked bottle, adds 75% tetrahydrofuran aqueous solution 60ml, and backflow 2-4h is chilled to room temperature, adds NaHCO
32.4g with ethyl acetate 50ml, stir 30min, the filtering insolubles removes tetrahydrofuran (THF) and ethyl acetate under reduced pressure, extract ethyl acetate 50ml * 3, and anhydrous magnesium sulfate drying removes ethyl acetate under reduced pressure, is directly used in next step reaction.
Above-claimed cpd 0.5g (1.4mmol) is dissolved in the 10ml pyridine, adds trimethylchlorosilane 2.0ml (16.0mmol) under stirring at room, stirring reaction 6-10h adds Methanesulfonyl chloride 0.23ml (2.6mmol), stirring at room 7h.Add a little H
2O transfers about PH1 with concentrated hydrochloric acid, transfers about PH8 with ammoniacal liquor again, and extract methylene dichloride 30ml * 3, washing, and anhydrous magnesium sulfate drying is used alcohol crystal after the evaporated under reduced pressure, get 0.32g, yield 48.5%, 148 ℃ of fusing points, MS:M+437, [α]
D 20+ 6.75 (c=0.5, in CHCl
3).
1HNMR in CDCl
3：2.71-2.94(9H)，3.60(1H)，3.78(1H)，3.84(3H)，3.85(3H)，4.01(2H)，4.20(1H)，6.52(1H)，6.61(1H)，6.92(2H)，7.18(2H)
13CNMR in CDCl
3：28.6(1C)，39.1(1C)，51.3(1C)，55.8(1C)，56.0(1C)，56.1(1C)，60.1(1C)，65.9(1C)，70.8(1C)，109.6(1C)，111.6(1C)，115.6(2C)，124.8(2C)，126.0(1C)，126.2(1C)，129.5(1C)，147.5(1C)，147.8(1C)，157.4(1C)
IR(cm
-1)：3373，3288，2929，2850，1510，1321，1147，841
The above-claimed cpd thermosol is transferred PH3-4 with concentrated hydrochloric acid in 10ml ethanol, leave standstill, separate out the hydrochloride of this compound, be white crystalline powder, fusing point 192-194 ℃, [α]
D 20-12.76 (c=1, in EtOH).
Under the identical situation of reactions steps among the embodiment 2, condition, change the consumption of reactant, reaction product does not change equally.
Embodiment 3
The arrhythmogenic effect of pharmacological evaluation one, general formula (I) compound antagonism napelline.Rat oral test medicine 40mg*kg
-1* d
-1And positive drug mexiletine 80mg*kg
-1* d
-1, continuous three days, can resist the irregular pulse due to the napelline perfusion, increase and occur that ventricular premature contraction, chamber speed, chamber quiver, dead napelline consumption, data see Table 1.
Table 1. sample is to the arrhythogenic influence of napelline (n=8, x ± s)
| Group | Dosage (mg/kg) | The dosage (μ g/kg) of various irregular pulse appearance and dead used napelline | |||
| Ventricular premature contraction | Chamber speed | Quiver in the chamber | Dead | ||
| Model control group | -- | 66.4± 16.4 | 88.3±30.7 | 154.5± 36.8 | 280.5± 110.0 |
| The mexiletine group | 80 | 131.0± 64.3* | 177.9± 64.8** | 282.0± 116.9** | 546.3± 116.0** |
| (R)-and 2-[1-(to the methanesulfonamido phenoxy group)-2-hydroxyl-propyl group]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline | 40 | 83.2± 24.3 | 121.7± 26.1* | 204.9± 38.4* | 470.0± 151.9* |
| (S)-2-[1-(to the methanesulfonamido phenoxy group)-2-hydroxyl-third | 40 | 148.2± 48.3** ##￥￥ | 196.5± 61.6** ##￥ | 254.7± 85.1** ￥ | 550.9± 112.8** |
| Base]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline |
* p＜0.05; * p＜0.01VS model control group ##p＜0.01VS HQ08 group
$P＜0.05;
*P＜0.01 VS HQ07 group.
The arrhythogenic effect of pharmacological evaluation two, general formula (I) compound antagonism ouabain.Cavy oral test medicine 20mg*kg
-1* d
-1And the Ta Luoer 30.8mg*kg of positive drug institute
-1* d
-1, continuous three days, can resist the irregular pulse due to the ouabain perfusion, increase and occur that ventricular premature contraction, chamber speed, chamber quiver, dead ouabain consumption, data see Table 2.
The arrhythogenic influence of table 2. sample antagonism ouabain (n=8, x ± s)
| Group | Dosage (mg/kg) | The dosage (μ g/kg) of various irregular pulse appearance and dead used ouabain | |||
| Ventricular premature contraction | Chamber speed | Quiver in the chamber | Dead | ||
| Model control group | -- | 184.1± 79.5 | 236.5± 90.1 | 275.7± 95.3 | 300.4±91.8 |
| The sotalol group | 30.86 | 332.2± 58.1** | 406.1± 64.8** | 453.2± 60.7** | 495.4± 64.5** |
| (R)-2-[1-(to the methanesulfonamido phenoxy group)-2-hydroxyl-propyl]-6,7-dimethoxy | 20 | 290.9± 72.8* | 330.6± 69.4* | 346.0± 67.9 | 418.6± 63.7** |
| -1,2,3, the 4-tetrahydroisoquinoline | |||||
| (S)-and 2-[1-(to the methanesulfonamido phenoxy group)-2-hydroxyl-propyl group]-6,7-dimethoxy-1,2,3, the 4-tetrahydroisoquinoline | 20 | 308.9± 41.0** | 347.3± 44.6** | 370.9± 42.8* | 424.2± 69.0** |
*p＜0.05；**p＜0.01
Above said content only is the basic explanation of the present invention under conceiving, and according to any equivalent transformation that technical scheme of the present invention is done, all should belong to protection scope of the present invention.
Claims (9)
1. (R)-2-[1-(to the methanesulfonamido the phenoxy group)-2-hydroxyl-propyl group of general formula (I) expression]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline or (S)-2-[1-(to the methanesulfonamido phenoxy group)-2-hydroxyl-propyl group]-6,7-dimethoxy-1,2,3, the 4-tetrahydroisoquinoline
2. the described preparation method with tetrahydro isoquinoline derivative of general formula (I) of claim 1 comprises the following steps:
(a) make the reaction of the compound of the compound of formula (III) and formula (IV), obtain the compound of formula (II)
(b) compound of formula (II) obtains the compound of formula (I) through reduction, substitution reaction
3. the preparation method of tetrahydro isoquinoline derivative according to claim 2, it is characterized in that: the compound of step (a) Chinese style (IV) is (R)-(-)-2-(p-nitrophenyl oxygen base) propylene oxide, the compound of step (b) Chinese style (II) is (R)-2-[1-(to the methanesulfonamido phenoxy group)-2-hydroxyl-propyl group through the compound that reduction, substitution reaction obtain formula (I)]-6,7-dimethoxy-1,2,3, the 4-tetrahydroisoquinoline.
4. the preparation method of tetrahydro isoquinoline derivative according to claim 2, it is characterized in that: the compound of step (a) Chinese style (IV) is (S)-(-)-2-(p-nitrophenyl oxygen base) propylene oxide, the compound of step (b) Chinese style (II) is (S)-2-[1-(to the methanesulfonamido phenoxy group)-2-hydroxyl-propyl group through the compound that reduction, substitution reaction obtain formula (I)]-6,7-dimethoxy-1,2,3, the 4-tetrahydroisoquinoline.
5. the preparation method of tetrahydro isoquinoline derivative according to claim 2, it is characterized in that: the compound of step (a) Chinese style (III) prepares through the following steps: with 3, the 4-dimethoxy-phenylethylamine, Paraformaldehyde 96 and formic acid mix, and in 30-40 ℃ of stirring 1-2h, are chilled to room temperature, remove formic acid under reduced pressure, get oily matter, add water, transfer about PH8 with ammoniacal liquor, methylene dichloride extracts for 3 times, anhydrous magnesium sulfate drying is used in 3 washings of water, removes solvent under reduced pressure, get oily matter, with ethyl acetate 30ml dissolving, in the ice bath cooling down, add EtOH-HCl, separate out white solid, the filter collection, ethyl acetate washing, drying.
6. the preparation method of tetrahydro isoquinoline derivative according to claim 2, it is characterized in that: the compound of step (a) Chinese style (IV) prepares through the following steps: p-NP, pyridine a little, (R)-(-)-epoxy chloropropane places reaction flask, behind the 60-120 ℃ of stirring 4-8h, evaporated under reduced pressure, add acetone and 3N aqueous sodium hydroxide solution, behind the stirring at room 0.5-1.5h, remove acetone under reduced pressure, use the 500ml dichloromethane extraction, washing, anhydrous magnesium sulfate drying removes solvent under reduced pressure, methanol crystallization gets light brown crystal.
7. the preparation method of tetrahydro isoquinoline derivative according to claim 2, it is characterized in that: the compound of step (a) Chinese style (II) prepares through the following steps: the compound of formula (III), (IV) is dissolved in Virahol or N, dinethylformamide, ethanol or chloroform, behind the backflow 2-5h, be chilled to room temperature, add a little sherwood oil, separate out solid, add the gac reflux decolour with Virahol, this solid is carried out recrystallization, obtain yellow square crystal.
8. the preparation method of tetrahydro isoquinoline derivative according to claim 2, it is characterized in that: the compound of step (b) Chinese style (I) prepares through the following steps: with the crystal of formula (II) compound, iron powder and NH
4C drops in the three-necked bottle, adds 75% tetrahydrofuran aqueous solution, and backflow 2-4h is chilled to room temperature, adds NaHCO
3And ethyl acetate, stirring 30min, the filtering insolubles removes tetrahydrofuran (THF) and ethyl acetate under reduced pressure, extracts for 3 times with ethyl acetate, and anhydrous magnesium sulfate drying removes ethyl acetate under reduced pressure, is directly used in next step reaction;
Above-claimed cpd is dissolved in the 10ml pyridine, adds trimethylchlorosilane under stirring at room, stirring reaction 6-10h adds Methanesulfonyl chloride, and stirring at room 7h adds a little H
2O transfers about PH1 with concentrated hydrochloric acid, transfers about PH8 with ammoniacal liquor again, and methylene dichloride extracts for 3 times, washing, and anhydrous magnesium sulfate drying is used alcohol crystal after the evaporated under reduced pressure, and obtaining compound is (I).
9. the pharmaceutical composition of anti-heart disorder, tetrahydro isoquinoline derivative (R)-2-[1-(to the methanesulfonamido the phenoxy group)-2-hydroxyl-propyl group that wherein contains claim 1]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline or (S)-2-[1-(to the methanesulfonamido phenoxy group)-2-hydroxyl-propyl group]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline or its pharmaceutical salts be as effective constituent, and contain conventional pharmaceutical carrier.
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| US6562837B1 (en) * | 1998-10-21 | 2003-05-13 | Korea Institute Of Science & Technology | Use of tetrahydroisoquinoline compounds for the treatment of septicemia |
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