CN1040320C - Secoaporphine compound, its preparation method and pharmaceutical composition containing the compound - Google Patents
Secoaporphine compound, its preparation method and pharmaceutical composition containing the compound Download PDFInfo
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Abstract
The invention provides a compound with a secoaporphine structure shown as a formula . Wherein R is1、R2、R4Is hydrogen, C1-8Alkyl radical, R3Is allyl, benzyl, C1-8Alkyl and CN. The compounds have an inhibitory effect on acute arrhythmia caused by ouabain , have better effect than Lidocaine (Lidocaine), and can be clinically preferred antiarrhythmic drugs.
Description
The pharmaceutical composition that the present invention relates to Secoaporphine compound, its preparation method and contain this compound, this compound has antiarrhythmic effect.
The kinds of Diseases of human cardiovascular aspect are various, and cause of disease complexity, and wherein hypertension, cardiac failure, stenocardia and irregular pulse all are common diseases.The not outer sodium channel inhibitor of medicine (the 1st class), suprarenin antagonist (the 2nd class) of treatment cardiovascular disease, polar prolongation (the 3rd class), calcium pipeline inhibitor antiarrhythmic drugs such as (the 4th classes) again, adrenergic blocker, nitrate, foxglove or anti-coagulant, diuretic(s), hyperlipidemia inhibitor and so on medicine.Some patient suffers from two or more cardiovascular diseases simultaneously clinically, for example existing cardiac failure disease, the irregular pulse phenomenon is also arranged, treat this patient and should not only adopt the 4th class calcium pipeline inhibitor, also should not adopt the 1st class such as Quinidine and so on to have the inhibiting antiarrhythmic drug of very strong calcium pipeline.But for there being the stenocardia and the atrium rhythm of the heart patient that overruns then can adopt calcium pipeline inhibitor simultaneously, coronary artery is loosened, the rhythm of the heart slightly slows down to reduce the purpose that the heart oxygen-consumption reaches the allevating angina pectoris symptom.
But nature papaveracease, Sapindaceae all contain officials' aporphine (secoaporphine) Alkaloid, but the structure of department's aporphine (secoaporphine) compounds belongs to aminobenzyl isoquinoline 99.9, the amido benzylisoquinoline often produces by the approach of the synthetic isoquinoline 99.9 of tyrosine (tyrosine) in vivo, for example morphine, morphine monomethyl ether.The amido benzylisoquinoline also can be at Sodium Nitrite (NaNO
2) exist and to utilize the generation of Pschorr synthetic method down.
But department's aporphine (secoaporphine) is no matter compounds morphine, morphine monomethyl ether, pharmacologically active that apomorphine presented are analgesia, cough-relieving or emetic action mostly, and this compounds seldom presents the effectiveness of cardiovascular aspect.The present invention mainly is with Boldina (Boldine) but is that initial compounds synthesizes a series of departments aporphines (secoaporphine) analog derivative, and inquires into this compounds for the activity of cardiovascular and apply to clinical.
The general formula of The compounds of this invention is as follows:
R wherein
1, R
2, R
4Be hydrogen, C
1-8Alkyl, R
3Be allyl group, benzyl, C
1-8Alkyl, CN.If but substituting group is following arbitrary situation; Work as R
1, R
2, R
3, R
4Be methyl, or R
1, R
2, R
4Be methyl, R
3Be benzyl, ethyl group, or R
1, R
2, R
3Be hydrogen, R
4Be methyl, or R
1, R
2Be hydrogen, R
3Be benzyl, R
4Be methyl, or R
1, R
2Be hydrogen, R
3Be CN, R
4Be methyl, and other substituting groups are when being hydrogen, then these compounds all do not belong within the present invention's formula (I) scope.
But the people such as the previous T.Kametani of department's aporphine (secoaporphine) compounds that belong to amido benzylisoquinoline structure are published in the synthesis mode of the 3667th page of Tetrahedron in 1969 the 25th volume shown in reaction formula I, are initial compounds with the amido benzylisoquinoline.
The present invention carries out Huffman (Hofmann) reaction by Secoaporphine compound Boldina (Boldine) and alkyl halide compounds, and the azo-cycle that contains of Secoaporphine compound is untied.But the present invention also can be at the aromatic nucleus the 3rd of department's Boldina (Secoboldine) of open loop, 7 replace, or replace at the 13rd nitrogen base, preparation method shown in reaction formula (II) is decided to be initiator with bohr, Boldina is dissolved in the N of capacity, in the dinethylformamide solution, react down at 100-180 ℃ with an amount of allyl bromide 98 (allyl bromide), can get compound (1) after products therefrom is purified but allyl group department Boldina (N-allylsecoboldine), the structure of this compound is that Boldina contains azo-cycle and unties the 14th and go up to link allyl group (allyl group), or change allyl bromide 98 into benzyl chloride and after reacting, with products therefrom purified again and compound (5) but benzyl department Boldina (N-benzylsecoboldine).Can get other product with diazomethane reaction again from compound (1) or compound (5).Measure respectively after the gained compound is purified uv-absorbing (UV), infrared spectra (IR), hydrogen nuclear magnetic resonance spectrum (
1H-NMR), mass spectrum physical datas such as (EIMS).
Reaction formula (1)
Reaction formula (2)
Reaction formula (2 ')
Suitable compound of the present invention is shown in table (1):
Table (1) compound R
1R
2R
3(1) H H pi-allyl (2) H H H (3) H Me pi-allyl (4) Me Me pi-allyl (5) H H benzyl (6) H Me benzyl (7) Me Me benzyl (8) Me Me Me (9) H Me Me (10) Me H Me (11) H H Et (12) H Me Et (13) Me Me Et (14) H H n-Bu
(15) Me Me n-Bu
(16) H Me n-Bu
(17) H H i-Bu
(18) H Me i-Bu
(19) Me Me i-Bu
(20) H H n-Hex
(21) H Me n-Hex
(22) Me Me n-Hex
(23) H H n-Pr
(24) H Me n-Pr
(25) Me Me n-Pr
(26) H H CN
(27) H Me CN
(28) Me Me CN
Compound shown in the formula of the present invention (1) has been carried out the rat heart muscle convergent force, heartbeat is restrained frequently, the influence experiment of action potential and membrane current, whether the membrane current by rat myocardial cell is suppressed, whether the action potential cycle prolongs is come the entry evaluation medicine whether to have antiarrhythmic effect, and this experiment also further gives toxic dose ouabain (Ouabain) class cardiac drug to guinea pig atrium sample and intends the mensuration medicine again to cause the irregular pulse phenomenon, whether the caused acute irregular pulse of ouabain (Ouabain) produced restraining effect and contrast to assess these medicines, and assess its effect whether than know to have an antergic lignocaine (Lidocaine) good.
But department's aporphine (secoaporpnine) compounds is to the influence of rat heart convergent force and palmic rate
Method:
Rat with after the Sodital anesthesia, is taken out heart left atrium, right atrium and right ventricle branch are opened in the 10ml container, and the right atrium is directly write down its autorhymicity and is shunk, and left atrium and right ventricle then take second place with per second 2 to stimulate to cause contraction.
The result:
Compound (1; 3; 4; 5; 7) shown in figure (3); And the compound (8; 9; 26) of table (2) all can make the autorhymicity heartbeat of rat right atrium subtract but its convergent force all increases; when these medicines are at concentration 3-30 μ M in the left atrium of constant stimulus frequency stimulation and right ventricle sample convergent force is increased and compound （ 1 ） during at concentration 9 μ M for the autorhymicity heartbeat of rat right atrium, the situation of left atrium irriate is shown in table （ 3 ） . （ 2 ） （ 1 ） （ N-allylsecoboldine ） （ 3 ） （ N-allylsecopredicentrine ） （ 4 ） （ N-allylsecoglaucine ） （ 5 ） （ N-benzylsecoboldine ） （ 7 ） （ N-benzylsecoglaucine ） （ 8 ） （ N-methylsecoglaucine ） （ 9 ） （ N-methylsecopredicentrine ） （ 26 ） （ N-cyanosecoboldine ） （ 3 ） ：； Left atrium and right ventricle:the contraction that 2 electricity irritation of per second cause
| But allyl group department Boldina 9 μ M | ||
| Preparation | Convergent force (%) | H.R.(％) |
| The right atrium | 164±14 ** | 58.5±3.4 ** |
| The left atrium | 126.6±6.3 ** | --- |
| Right ventricle | 126±7.3 * | --- |
To rat and guinea pig myocardial cell electrophysiology effect experiment
Method:
Place example to put microscopically in the cell of rat and guinea pig Ventricular dissociation, carry out membrane current and the fixed experiment of membrane potential pincers, observe the influence of medicine myocardial action potential and membrane current in electrode sucking mode.
The result:
Influence to action potential: compound (1) but allyl group department Boldina (N-allylse-coboldine) just can make myocardial cell's lengthening of action potential when 1 μ M, when 3 μ M, can make action potential duration prolong 5 times.In addition compound (1) but the action potential depolarize rate action that slows down of allyl group department Boldina is similar to Quinidine, but Quinidine be little before handling the amplitude ratio administration of its action potential of back, and compound (1) but allyl group department bohr rule makes the potential amplitude increase as scheming shown in (2) on the contrary.Other derivative such as compound (4) but allyl group department glaucine (N-allylsecoglaucine) to the influence of action potential to compound (1) but allyl group department Boldina similar.
Influence to potassium current: compound (5) but benzyl department Boldina (N-benzylsecob-ldine) just has the effect of the inhibition moment outflow potassium current (Ito) stronger than Quinidine to rat ventricle cell when 3 μ M, its result is shown in figure (3).Under same concentrations, Quinidine can make moment outflow potassium current reduce about 60%, as for compound (1) but allyl group department Boldina can reduce moment outflow potassium current under 0.6 μ M concentration about 40 to 50%, the derivative that other table (1) shows can both have very strong restraining effect to the moment potassium current that outflows.Shown in table (4).
Table (4) is to the restraining effect of rat ventricle cell moment outflow potassium current
Compound concentration moment outflow potassium current (26) but cyanogen department Boldina (Ito) N-cyanosecoboldine 6 μ M reduce 80% (9) methyl Si Kepeiniting N-methyl-secopredicentrine, 6 μ M reduce about 60% (8) but the glaucine N-methyl-secoglaucine of methyl department 6 μ M minimizing 70%
In addition, compound (1) but allyl group department Boldina outflows potassium current (Ito) though inhibition is arranged to maximum instantaneous, but its current potential-electric current that presents moment outflow potassium current does not activate relation curve and moves right on the contrary, shown in figure (4), this result shows compound (1) but allyl group department Boldina can not strengthened not activating of moment outflow potassium current.In fact compound (1) but allyl group department Boldina not only also has restraining effect to rat ventricle cell moment outflow potassium current (Ito), for the outflow of the property opened the late potassium current (IK) of guinea pig restraining effect is also arranged, shown in figure (5).Compound (1) but allyl group department Boldina has the restraining effect of 20-30% approximately when 1 μ M, when 3 μ M, have 50-60% to suppress approximately, when 9 μ M, have 70-80% to suppress effect approximately.And compound (5) but the benzyl department Boldina outflow of the property opened late potassium current to guinea pig when 1 μ M also has 30% restraining effect.
Influence to sodium current: compound (1) but allyl group department Boldina just can produce 25% to guinea pig atrium cell or rat ventricle cell when 0.9 to 1.2 μ M suppress the sodium current effect, shown in figure (6).And the resume speed that does not activate the back sodium channel is had slow effect, and its t1/2 is prolonged to 100ms shown in figure (7) by 50ms approximately.If compound (1) but the concentration of allyl group department Boldina increases the electric current that then can make sodium current to 3 μ M and 9 μ M that activating rate and membrane potential relation curve are not moved to the left, V1/2 is become-70.8mV by-60.9mV when 3 μ M, when 9 μ M V1/2 become-85.9mV is shown in figure (8).This result be illustrated in higher concentration compound (1) but allyl group department Boldina to sodium channel except direct inhibition, the sodium channel ratio of active state is not increased, shown in figure (8D, E).
Influence to calcium current: with the compound (1) of 3 μ M but allyl group department Boldina does not have restraining effect for the calcium current (Ica) of rat ventricle cell, and the calcium current of rat ventricle cell reduces to and is about original 71% when concentration increases to 12 μ M, even since do not add any medicine unicellular experiment after 6 minutes its calcium current can nature eliminate and be original 79%, if after revising so then calcium current in fact only be suppressed about 9%, shown in figure (9).
But department's aporphine (secoaporphine) compounds suppresses the ARR experiment of guinea pig that ouabain (Ouabain) causes
Method:
Give 0.6 μ M ouabain (Ouabain) in the guinea pig left atrium, observe its convergent force, and after 5-20 minute, give 15 to 30 μ M Secoaporphine compounds and lignocaine (Lidocaine), observed and survey its current potential again.
The result:
The convergent force that gives guinea pig left atrium, 0.6 μ M ouabain (Ouabain) back increases gradually, but in 5-20 minute, can produce ARR phenomenon, if give 15 to 20 μ M concentration compound (1) but allyl group department Boldina, compound (5) but benzyl department Boldina, or the compound (3) of 30 μ M concentration but allyl group Si Peiniting, then the ARR phenomenon of guinea pig can be suppressed, but the effect of the enhancing guinea pig myocardial contraction that ouabain causes still exists.Especially with the compound (1) of 20 μ M concentration but the handled sample of allyl group department Boldina, before not only can suppressing irregular pulse that ouabain brings out but also guinea pig myocardial contraction reinforced effects and also reaching administration 4 to 6 times.If bring out ARR medicine with benefit cacaine (Lidocaine) as handling the antagonism ouabain, then the dosage of lignocaine must could suppress irregular pulse during 30 μ M, and this moment, cardiac contractile force only was the twice that does not give before the ouabain, as scheming shown in (10).
The compounds of this invention adds various vehicle, behind Magnesium Stearate, lactose, starch etc., can be made into tablet or other solid preparations, can be made into injection or other liquid preparations and various formulation and regulate potential of hydrogen with the phosphoric acid salt damping fluid.The permissible acid salt of medicine of formula of the present invention (1) compound, with and medicine on the pharmaceutical preparation of permissible acid salt all can reach antiarrhythmic drug effect, general dosage can need allotment with symptom, is generally everyone each 50 to 300mg, every day 3 times.
1g Boldina (boldine) is dissolved in the N of 30ml, in the dinethylformamide solution, reacted 2 hours down at 100-110 ℃ with 1.2ml allyl bromide 98 (allyl bromide), can get compound (1) after products therefrom is purified but allyl group department Boldina, productive rate is 56%, and measures the physical data of compound.
Uv-absorbing (UV) λ max (EtOH, log ε):
356(3.11)，339(3.28)，311(4.15)，299(4.12)，
278(4.49)，256(4.88)nm。
Infrared spectra (IR) ν max (KBr):
3425，2950，2825，1660，1510，1460，
1439，1419，1275，1220，1159，1100，
1091，995， 880，785cm-1。
Hydrogen nuclear magnetic resonance spectrum (
1H-NMR, CDCl
3):
δ8.93(s，H-5)，7.73(d，J＝6.6Hz，H-14)，
7.45(d，J＝9.1Hz，H-9)，7.28(s，H-8)，7.13(s，H-2)，
5.93(ddt，J＝17.0，10.2，6.6Hz，H-15)，
5.21(br d，J＝17.0Hz，Hz-16)，
5.17(br d，J＝10.2Hz，HE-16)，4.05(s，6-OMe)，
3.82(s，4-OMe)， 3.23(m，2H，H-11)，
3.16(br d，J＝6.6Hz，H-14)， 2.41(s，13-Me)，
2.75(m，2H，H-12)。
Mass spectrum (EIMS, 70eV) m/z (rel.int.) M+}:
367 (press C
22H
25NO
4Calculate) (2), 283 (1), 84 (100).The preparation of embodiment 2 compounds (3) allyl group Si Kepeiniting (N-allylsecopredicentrine):
With initial compounds (1) but allyl group department Boldina is dissolved in the methyl alcohol that reaction is after 24 hours down at 4 ℃ with diazomethane, purified compound (3) the allyl group Si Kepeiniting that obtains, productive rate are 16%, and measure the physical data of compound.
Uv-absorbing (UV) λ max (EtOH, log ε): 356 (2.98), 339 (3.12), 311 (3.98), 299 (3.95), 277 (4.26), 255 (4.68) nm.
Infrared spectra (IR) ν max (KBr): 3420,2960,2850,1590,1510,1470,1410,1360,1325,1260,1220,1150,1090,1035,995,885,840,810cm-1.
Hydrogen nuclear magnetic resonance spectrum (
1H-NMR, CDCl
3): δ 8.93 (s, H-5), 7.78 (d, J=9.1Hz, H-10), 7.53 (d, J=9.1Hz, H-9), 7.18 (s, H-2), 7.18 (s, H-8), 6.01 (ddt, J=16.0,11.7,7.2Hz, H-15), 5.35 (br d, J=11.7Hz, HE-16), 5.34 (br d, J=16.0Hz, Hz-16), 4.04 (s, 6-OMe), 4.02 (s, 7-OMe), 3.82 (s, 4-OMe), 3.44 (m, 2H, H-11), 3.40 (br d, J=7.2Hz, H-14), 2.98 (m, 2H, H-12), 2.59 (s, 13-Me)
{ M+}:381 (presses C to mass spectrum EIMS (70eV) m/z (rel.int)
23H
27NO
4Calculate) (1), 297 (0.5), 84 (100), 41 (25).Embodiment 3 compounds (4) but the preparation of allyl group department glaucine (N-allylsecoglaucine):
With initial compounds (1) but allyl group department Boldina according to the described methods reaction of embodiment 2 24 hours, obtain compound (4) but allyl group department glaucine after purified, productive rate is 72%, and the physical data of mensuration compound.
Uv-absorbing (UV) λ max (EtOH, log ε):
355(3.10)，339(3.25)，313(4.03)，302(4.03)
278(4.28)，257(4.79)nm。
Infrared spectra (IR) ν max (KBr):
2960，1600，1510，1470，1420，1110，
1085，1035，990，890cm-1。
Hydrogen nuclear magnetic resonance spectrum (
1H-NMR, CDCl
3):
δ9.25(s，H-5)，7.72(d，J＝9.1Hz，H-10)，
7.50(d，J＝9.1Hz，H-9)，7.18(s，H-8)，
7.16(s，H-2)，
5.92(ddt，J＝17.0，10.2，6.6Hz，H-15)，
5.21(br d，J＝17.0Hz，Hz-16)，
5.17(br d，J＝10.2Hz，HE-16)，
4.05(s，6-OMe)，4.01(s，7-ONe)，
4.01(s，3-OMe)，3.90(s，4-OMe)，
3.26(m，2H，H-11)，3.14(br d，J＝6.6Hz，H-14)，
2.75(m，2H，H-12)，2.40(s，13-Me)。
Mass spectrum EIMS (70eV) m/z (rel.int) M+.}:
395 (press C
24H
29NO
4Calculate) (7), 311 (3), 84 (100),
41(93)。Embodiment 4 compounds (5) but the preparation of N-benzyl department Boldina (N-benzylsecoboldine):
1g Boldina (boldine) is dissolved in the N of 30ml, in the dinethylformamide solution, according to embodiment 1 described should the reaction 2 hours, can gets compound (5) but benzyl department Boldina after purified, productive rate is 74%, and measures the physical data of compound.
Uv-absorbing (UV) λ max (EtOH, log ε):
357(2.98)，339(3.15)，311(3.99)，299(3.96)，
278(4.39)，257(4.72)nm。
Infrared spectra (IR) ν max (KBr):
3380，2925，1590，1505，1470，1455，
1430，1410，1260，1220，1150，1080，
990，870，775，690cm-1。
Hydrogen nuclear magnetic resonance spectrum (
1H-NMR, CDCl
3):
δ8.92(s，H-5)，7.66(d，J＝9.1Hz，H-10)，
7.42(d，J＝9.1Hz，H-9)，7.28(s，H-8)，
7.27(m，5H，Ph-H)，7.12(s，H-2)，
4.05(s，6-OMe)，3.82(s，4-OMe)，
3.63(s，H-14)，3.24(m，2H，H-11)，
2.77(m，2H，H-12)，2.39(s，13-Me)。
Mass spectrum EIMS (70eV) m/z (rel.int) M+.}:
417 (press C
26H
27NO
4Calculate 4) (6), 283 (10), 134 (100),
91(56)。The preparation of embodiment 5 compounds (6) benzyl Si Kepeiniting (N-benzylsecopredicentrine):
With initial compounds (1) but allyl group department Boldina according to the described methods reaction of embodiment 2 24 hours, after purified compound (6) benzyl Si Kepeiniting, productive rate is 45%, and measures the physical data of compound.
Uv-absorbing (UV) λ max (EtOH, log ε):
356(3.15)，339(3.29)，311(3.99)，299(3.99)，
278(4.31)，256(4.74)nm。
Infrared spectra (IR) ν max (KBr):
3425，2930，1600，1510，1470，1455，
1430，1410，1265，1230，1150，1080，
990，740，700cm-1。
Hydrogen nuclear magnetic resonance spectrum (
1H-NMR, CDCl
3):
δ8.93(s，H-5)，7.68(d，J＝9.1Hz，H-10)，
7.46(d，J＝9.1Hz，H-9)，7.27(m，5H，ph-H)，
7.18(s，H-8)，7.14(s，H-2)，4.05(s，6-OMe)，
4.03(7-OMe)，3.82(s，4-OMe)，3.66(s，H-14)，
3.26(m，2H，H-11)，2.79(m，2H，H-12)，
2.40(s，13-Me)。
{ M+.}:431 (presses C to mass spectrum EIMS (70eV) m/z (rel.int)
27H
29NO
4Calculate) (1), 297 (1), 134 (100), 91 (82).Embodiment 6 compounds (7) but the preparation of benzyl department glaucine (N-benzylsecoglaucine):
With initial compounds (1) but allyl group department Boldina according to the described methods reaction of embodiment 2 24 hours, after purified compound (7) but benzyl department glaucine, productive rate is 29%, and the physical data of mensuration compound.
Uv-absorbing (UV) λ max (EtOH, log ε):
355(2.76)，339(2.90)，313(3.65)，302(3.65)，
277(3.92)，257(4.39)nm。
Infrared spectra (IR) ν max (KBr):
3000，2925，1610，1595，1500，1470，
1460，1440，1415，1360，1270，1258，
1230，1189，1150，1100，1080，990，
845，760，715，685cm-1。
Hydrogen nuclear magnetic resonance spectrum (
1H-NMR, CDCl
3):
δ9.25(s，H-5)，7.66(d，J＝9.1Hz，H-10)，
7.47(d，J＝9.1Hz，H-9)，7.27(m，5H，Ph-H)，
7.18(s，H-8)，7.15(s，H-2)，
4.05(s，6-OMe)，4.02(7-OMe)，4.00(s，3-OMe)，
3.90(s，4-OMe)，3.65(s，H-14)，
3.30(m，2H，H-11)，2.80(m，2H，H-12)，
2.40(s，13-Me)。
Mass spectrum EIMS (70eV) m/z (rel.int) M+.}:
445 (press C
28H
31NO
41Calculate) (1), 311 (1), 134 (100), 91
(76)。Embodiment 7 compounds (1) but allyl group department Boldina (N-allylsecoboldeine) preparation
Gross weight 50mg
Lactose 30mg
Starch 4mg
Magnesium Stearate 6mg
Semen Maydis powder 10mg
Can make according to above-mentioned prescription and to contain compound (1) but allyl group department Boldina tablet.
Description of drawings:
The compound that figure (1) exerts an influence for rat heart convergent force and palmic rate
Figure (2) but Quinidine and allyl group department Boldina (N-allylsecoboldine) to the comparison of rat action potential effect
Figure (3) but benzyl department Boldina (N-benzylsecoboldine) to the outflow influence of electric current of rat moment
Figure (4) but allyl group department Boldina to outflow current potential-electric current activatory relation curve not of potassium current of maximum instantaneous
Figure (5) but allyl group department Boldina (N-allylsecoboldine) in the outflow of the property opened the late potassium current effect of guinea pig
Figure (6) but allyl group department Boldina in guinea pig atrium cell or the effect of rat ventricle cell inhibiting sodium current
Figure (7) but allyl group department Boldina at guinea pig atrium cell to not activating the carryover effects of the resume speed of sodium channel afterwards
Figure (8) but allyl group department Boldina at the electric current of guinea pig atrium cellular sodium electric current not activating rate and membrane potential relation curve
Figure (9) but allyl group department Boldina for the calcium current of rat ventricle cell
The ARR antagonism effect that figure (10) causes ouabain (Quabain)
Claims (7)
1, a kind of compound and its esters, wherein R with following general formula (I) structure
1, R
2, R
4Be hydrogen, C
1-8Alkyl, R
3Be allyl group, benzyl, C
1-8Alkyl, CN, but its substituting group must not be under conditions: R
1, R
2, R
3, R
4Be methyl; Or R
1, R
2, R
4Be methyl, R
3Be benzyl, ethyl group; Or R
1, R
2, R
3Be hydrogen, R
4Be methyl; Or R
1, R
2Be hydrogen, R
3Be benzyl, R
4Be methyl; Or R
1, R
2Be hydrogen, R
3Be CN, R
4Be methyl.
2, press the compound of Formula I and its esters of claim 1, wherein R
1, R
2, R
4Be hydrogen, methyl, R
3Be allyl group, benzyl, C
1-8Alkyl, CN.
3, the method for compound and its esters shown in a kind of formula (I) of making claim 1, its method is to be decided to be initiator with bohr, carries out Hofmann reaction with an amount of halohydrocarbon, or carries out diazotization reaction again, R in formula (I) compound
1, R
2, R
4Be hydrogen, C
1-8Alkyl, R
3Be allyl group, benzyl, C
1-8Alkyl, CN, but its substituting group must not be under conditions: R
1, R
2, R
3, R
4Be methyl; Or R
1, R
2, R
4Be methyl, R
3Be benzyl, ethyl group; Or R
1, R
2, R
3Be hydrogen, R
4Be methyl; Or R
1, R
2Be hydrogen, R
3Be benzyl, R
4Be methyl; Or R
1, R
2Be hydrogen, R
3Be CN, R
4Be methyl.
4, press manufacturing formula (I) compound and the method for its esters, the wherein R of claim 3
1, R
2, R
4Be hydrogen, methyl, R
3Be allyl group, benzyl, C
1-8Alkyl, CN.
5, the method for the described preparation formula of claim 3 (I) compound and its esters, wherein this halohydrocarbon is an allyl bromide 98.
6, a kind of antiarrhythmic pharmaceutical composition comprises a kind of formula by claim 1 (I) compound or its salt class and necessary additional excipient, R in formula (I) compound
1, R
2, R
4Be hydrogen, C
1-8Alkyl, R
3Be allyl group, benzyl, C
1-8Alkyl, CN, but its substituting group must not be under conditions: R
1, R
2, R
3, R
4Be methyl; Or R
1, R
2, R
4Be methyl, R
3Be benzyl, ethyl group; Or R
1, R
2, R
3Be hydrogen, R
4Be methyl; Or R
1, R
2Be hydrogen, R
3Be benzyl, R
4Be methyl; Or R
1, R
2Be hydrogen, R
3Be CN, R
4Be methyl.
7, press the pharmaceutical composition of claim 6, the R in its Chinese style (I) compound
1, R
2, R
4Be hydrogen, methyl, R
3Be allyl group, benzyl, C
1-8Alkyl, CN.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN93112825A CN1040320C (en) | 1993-12-14 | 1993-12-14 | Secoaporphine compound, its preparation method and pharmaceutical composition containing the compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN93112825A CN1040320C (en) | 1993-12-14 | 1993-12-14 | Secoaporphine compound, its preparation method and pharmaceutical composition containing the compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1103863A CN1103863A (en) | 1995-06-21 |
| CN1040320C true CN1040320C (en) | 1998-10-21 |
Family
ID=4990293
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN93112825A Expired - Fee Related CN1040320C (en) | 1993-12-14 | 1993-12-14 | Secoaporphine compound, its preparation method and pharmaceutical composition containing the compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1040320C (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1884265A (en) * | 2005-06-20 | 2006-12-27 | 美时化学制药股份有限公司 | Apofen and subapofen compounds for treating diabetes |
-
1993
- 1993-12-14 CN CN93112825A patent/CN1040320C/en not_active Expired - Fee Related
Non-Patent Citations (1)
| Title |
|---|
| TETRAHEDRON * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1103863A (en) | 1995-06-21 |
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