JPS60136566A - 1,2,3,4-tetrahydroisoquinoline derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:A 1,2,3,4-tetrahydroisoquinoline derivative expressed by formula I (R<1> is trimethyoxyphenyl) or a pharmacologically acceptable acid addition salt thereof. EXAMPLE:threo-1-( 3',4',5'-Trimethoxy-alpha-methylbenzyl )-5,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline. USE:A vasodilator, capable of acting selectively on adrenergic beta2-receptors, and having little side effects such as increase in heart rate, etc. PREPARATION:An isoquinoline derivative expressed by formula III (R<2> is protecting group) is subjected to the partial reductive reaction step of the isoquinoline skeleton and eliminative step of the protecting group in an optional order, and if necessary the reaction product is converted into a pharmacologically acceptable acid addition salt thereof to afford the aimed compound expressed by formula I .

Description

[Detailed description of the invention]

The present invention relates to a 1,2,3,4-tetrahydroisoquinoline derivative represented by the general formula (wherein G represents a trimethoxyphenyl group) and a method for producing the same. Compound (I) of the present invention is a new compound and is a useful pharmaceutical compound with excellent bronchodilator action. In particular, the compound of the present invention (IJ selectively acts on adrenergic β2 receptors) and has excellent characteristics as a bronchodilator with few side effects such as increased heart rate. According to the present invention, The target compound ('I) is obtained by partially reducing the inquinoline skeleton of the inquinoline derivative represented by the general formula (wherein R2 represents a protecting group and R1 has the same meaning as above) as shown in the reaction formula below. It can be produced by subjecting it to the reaction step and the elimination step of the acetate in the given order. The method will be explained in detail. As the protecting group R2 in compound (II) in the above reaction formula, it is preferable to use a group that can be eliminated by catalytic reduction. Examples of such protecting groups include benzyl group, P −
Examples include substituted or unsubstituted benzyl MI such as methoxybenzyl M, 3,4-dimethoxybenzyl group, and substituted or unsubstituted benzyloxycarbonyl groups such as benzyloxycarbonyl group and P-methoxycarbonyl group. Removal of protecting groups of starting compound (II) and compound (old)
When using a group that can be removed by catalytic reduction as a protecting group, it can be carried out by catalytically reducing, for example, compound (III) or compound (III) in the presence of a catalyst in a hydrogen gas stream. - Preferred examples include palladium-carbon, palladium black, Raney nickel, etc. This catalytic reduction reaction can be suitably carried out in a suitable solvent at normal temperature and pressure.As a solvent, for example, meta/-
Ruethanol-tetrahydrofuran, dioxane, water, or a mixed solvent thereof can be used. Further, the partial reduction reaction of the isoquinoline skeleton of the starting compound (n) and the compound (III) can be carried out according to a conventional method. For example, it is suitably carried out by reducing compound (II) or compound (III) in a solvent using a platinum-based catalyst such as platinum dioxide, rhodium-alumina, palladium-carbon, etc. under normal pressure or pressurization. As a solvent, methanol, ethanol, tetrahydro7ran, dioxane,
Examples include water or a mixed solvent thereof. This reaction was carried out at 20-100°C. It is particularly preferable to carry out the process at a temperature of 20 to 50°C, and the process is preferably carried out in an acidic soil having a suitable level of soil, such as a salt or acidic soil. The n61.2.3.4-tetrahuman isomer thus obtained can be obtained by reacting the mixture of stereoisomers with a reactive derivative of the carboxyl group of trifluoroacetic acid and then with benzyl halide. general formula

[However, R3 represents a benzyl group, and R1 has the same meaning as above. ] After preparing the compound represented by the formula, one of the stereoisomers of compound (IV) is separated using the difference in solubility between the stereoisomers, and further protection is obtained from the one stereoisomer thus obtained. It can be obtained by removing the group C. The reaction formula for this is as follows. ([) ([V) Represents a gen atom. That is, the compound ([) is reacted with a reactive derivative of the carboxyl group of trifluoroacetic acid in a solvent. This reaction is 20~
50PC- (can be carried out. As a solvent,
Chloroform, methylene chloride. tetrahydrofuran,
Examples include dioxane. Examples of reactive derivatives of trifluoroacetic acid include trifluoroacetic acid halide, trifluoroacetic anhydride, and the like. After the above reaction, the compound ([V]) can be prepared by reacting the reaction product with benzyl/1-lide in a solvent. Examples of the solvent include dimethyl sulfoxide, dimethylformamide, methanol-ethanol, etc. This reaction is preferably carried out at 20 to 30°C in the presence of a deoxidizing agent. Potassium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, etc. are preferably used as the deoxidizing agent. Good results are obtained especially when this reaction is carried out in the presence of sodium iodide.Separation of the 2m stereoisomer of the compound (IT) thus obtained is as follows:
This can be carried out by taking advantage of the solubility difference between the two stereoisomers, and if necessary, it can also be carried out in combination with 9.III. Methyl acetate is used when performing a separation operation utilizing the mutual solubility of the two stereoisomers of compound (IV). Ethyl acetate, methanol, ethanol, tetrahydro7
Solvents such as Ran, n-hexane, etc. can generally be used.91 For example, when the operation is carried out using a mixed solvent of ethyl acetate and n-hexane, the erythro form of compound (IV) is isolated as a crystal, and the compound The threo form is dissolved in its mother liquor. Furthermore, if the threo isomer of compound (V) is recovered from the mother liquor by silica gel chromatography treatment, it is possible to remove the threo isomer of compound (■) and the erythro present in a small amount in the mother liquor. For example, the trifluoroacetyl group serving as the N-position protecting group of compound ([V)' can be removed by hydrolysis, and the benzyl group serving as the 0-position protecting group can be removed by catalytic reduction. Among these, hydrolysis can be preferably carried out in the presence of a base,
As the base yarn, for example, potassium hydroxide or hydroxyl can be used. As the solvent, it is preferable to use methanol, ethanol, tetrahydrofuran, dioxane, isopropyl alcohol, water or a mixed solvent thereof. In addition, the benzyl group, which is the 0-position protecting group, can be removed by catalytic reduction in the presence of a catalyst in a hydrogen gas stream. can be administered. As the catalyst, for example, palladium-carbon, palladium black, Raney nickel, etc. can be used. Unconnected 1
The QIk reduction reaction can be carried out in a suitable solvent at room temperature and pressure, and it is desirable to use, for example, methanol, ethanol, tetrahydrofuran, water, or their base solvents as the solvent. Compound (I) of the present invention, which is obtained by evaporation, is a medical bronchodilator that selectively acts on adrenergic β2 receptors, and is effective in treating obstructive pulmonary diseases such as bronchial asthma and chronic bronchitis. It can be used to treat and prevent symptoms of heart disease. Furthermore, the compound (I) of the present invention is a useful pharmaceutical compound since it can be used for a long period of time and administered intravenously. The daily administration of the compound (f) of the present invention or its theoretically acceptable acid addition salt is based on the patient's age, zero body weight,
Although it varies depending on the condition, the usual daily dosage is about 0.03 to 500 μg per gram of body weight. Preferably, 0.1 to 200 μm is appropriate. The compound (I) of the present invention can be used for pharmaceutical purposes in the form of Yuura base or any of its pharmacologically acceptable acid addition salts. Salts of inorganic acids such as fumaric acid, maleic acid, succinic acid, para-toluenesulfonic acid, methanesulfonic acid, malic acid. Salts of organic acids such as N-acylamino acids can be used. When the compound (I) of the present invention is administered as a medicine, it can be administered orally (orally) (it can also be administered parenterally). It may be a solid agent, solution, suspension,
It may also be a modification such as a milky lotion. Moreover, when administered parenterally, it can also be used as an injection or a drip injection. Note that the starting material compound (III) is a new compound and can be cleaved according to the following reaction formula, for example.The following is a detailed explanation of the present invention from Experimental Examples, Reference Examples, and Examples. 1 Cats with body i2.1 to 4.5 were intoxicated with bendoparbital sodium salt (4O2ηz14, i, pJ) and garamin trithiodide (511+j/pJ) under artificial respiration.
/L4-N,V,). Over time, the Gletsoyer transducer established the internal pressure and measured the heart rate at the same time. Bronchodilator serotonin creanan (20 μ7
Immediately before the intravenous administration of the 1λ compound (2 minutes before for the pleasure compound 1, 1 minute before for the test compound 2), a physiological saline solution of the Vζ specimen was administered intravenously, and the efficacy of each 1λ form was examined. Qi・A Zhangsakuto [](
adrenaline ρ2 receptor stimulating effect) and heart rate increasing effect (adrenaline β1 receptor stimulating effect)
From the d-action curve, the internal pressure of Qi J due to serotonin creatinine sulfate U Ho (qi d'
Sample administration required to suppress M) by 50% [1 (L strike,
gDso・] and heart rate 1 or 1ii1/1
It is necessary to increase fλ by 5 beats.
Rls). The results are shown in Table 1.
α-Simethylbennal)-5,7-cyhydroxyl. 2, 3.4-Tetrahytroinquinoline hydrochloride 2,
Inglotele/-Salt Sensitive Salt Example 1 ill l -(3', 4', 5'-) 1J l to4-cya'-J tilbenzyl)-5,7-dibenzyloxyin quinoline 535~ Dissolve in 30% of a mixture of ethanol and tetrahydrofuran (2:1) and catalytically reduce the mixture in the presence of 200η of palladium and carbon at room temperature for 2 hours. After the reaction, the catalyst is filtered off and washed with ethanol. Filtrate and the washing liquid were combined and distilled off under reduced pressure.The remaining residue was treated with 10<ethanol and hydrochloric acid, and recrystallized from a mixture of ethanol and diethyl ether to give 1-(3
', 4<5'-trimethoxy-α-methylbenzyl)-
5,7-hydroxyisoqui/phosphorus hydrochloride 360'f
is obtained as yellow prismatic crystals. (21 (1-(3:4?5'-trimethoxy-α-methylbenzyl)-5,7-cyhydroxyisoquinoline hydrochloride 5.09F obtained in 11) was mixed with ethanol and water (10
:1) Dissolve 110 rnlK of the mixture and catalytically reduce it in the presence of 1.5 g of platinum dioxide under 3.5 atm for 4 hours. After the reaction, the catalyst is filtered off and washed with ethanol. The filtrate and washing liquid were combined and the solvent was distilled off under pressure to obtain l -(3?
4?5'-trimethoxy-α-methylbenzyl)-5,
7-Sihydroxy-1.2.3.4-tetrahydroisoquinoline (diastereomeric mixture 35.10F is obtained as a yellow caramel. Yield: quantitative maas tm/e): 359 (M+) Example 2 +11 1- (3 :4:5'-1-liftoxy-α-
methylbenzyl)-5,7-cyhydroxy 1.2.3
．． Dissolve 5.17 liters of tetrahydroisoquinoline in 50 chloroform, add 4.21 liters of trifluoroacetic anhydride with stirring at room temperature, and stir for 3 hours. After the reaction, the solvent is distilled off under pressure. Remaining methanol 50
ffl/ and left at room temperature for 3 hours. Next, methanol was distilled off under reduced pressure, and the remaining benzene 5O
In addition to rnl, methanol and trifluoroacetic acid are distilled off under reduced pressure. The residue thus obtained was dissolved in dimethyl sulfoxide 50I71, and 3.81S' of K benzyl chloride, 6.9QI of potassium carbonate and 20"QI of sodium iodide were added at 50-60°C. Heat for 4 hours. Extract the reaction solution with benzene, wash with water, 1% sodium hydroxide solution and saturated saline,
dry. Then, it is treated with activated carbon and the benzene is removed under reduced pressure F.
To leave. The remaining residue was dissolved in ethyl acetate/n-hexane (1:2)
Crystal from mixed solution”””f6nWJ=Qx IJX C
+ -1-(3,'4.'5'-t-17/Toxie α
-methylbenzyl)-2-triful 4-tetrahydroisoquinoline 3.94'. The crystallization mother liquor was concentrated under reduced pressure, and the residue was separated using silica gel gel chromatography (development tgWL; ethyl acetate di-n-hexane = l2-4).
, 7-dipenzyloxy-1.2.3.4-tetrahytroinquinoline 2.02P as pale yellow caramel and its erythro form 0.24! i' is obtained as an I nail color prism product. Yield: engineering, lithro form; 50.6% threo form; 24.5% erythro form; mp, 155-156.5°mag, s
(s/e): 635 (M+)IR(CHC
;13): 1680 rhythmic font; m88B(m
/θ):635(It)IR(CHCL3): l
6 B 2 cm (2-() (1) Tetl lettuce L
/ O 1- + 3: 4z5'-trimethoxy-α-methylbenzyl)-2-trifluoroacetate W-5
,7-dibenzyloxy-1,2,3,4-tetrahytroinquinoline 1.91F was mixed with ethanol/water (12:1
) Dissolved in mixture 75- and added 1.7 g of potassium hydroxide.
, force) and reflux for 1 hour. After the reaction, the solvent was distilled off under reduced pressure, and the residue was made acidic with dilute hydrochloric acid, and then extracted with chloroform. After drying the extract, the chloroform was distilled off under reduced pressure, and the crystalline residue was washed with methanol and diethyl nylon. Threo-1-c3H4' was obtained by recrystallization from the mixed solution. 5'-trimethoxy-〇-methylbenzyl)-5,7-
Dipenzyloxy-1.2.3,4-tetrahydroxyisoquinoline hydrochloride 1.53SJ is obtained as a colorless prism product. Yield: 89<mP, 217-221'l 51'? ) mass (
m/θ) : 539 (Id+3I R(Nujol
l(c+i”l: 1608.2400-2800(
Erythro 1-c 3' obtained by 2-mouth J (1),
4',5'-trimethoxy-α-methylbenzyl]-
2-trifur τ loacetyl-5,7-dibenzyloxy-1,2,3,4-tetrahydroisobo/phosphorus 3.81
was dissolved in a mixture of ethanol and water (15:l), 3.371 i' of potassium hydroxide was added thereto, and the mixture was refluxed for 1 hour. By treating in the same manner as in (2-a) below, erythro 1- (3:4jh'-)rimethoxy〇-methylbenzyl)'-5+ 7-dibenzyloxy-1121314-tetroE-droisoquinoline.
The hydrochloride salt 3.35!7 is obtained as colorless needles. yield:
97 width mP-215-218゜mass (m/s): 539 (IJ+)IR
(Nujol) (c+i”l:250tl-2800
(3-a) The slino-1-(process 4) obtained in (2-a)
Add 9 to 1 phosphorus hydrochloride 2881 to 22 m of a mixture of ethanol, tetrahydrofuran, and water (5:5:1), and add 10
In the presence of % palladium on carbon 150 II', the mixture was subjected to catalytic reduction at room temperature and pressure for 3 hours. After the reaction, the catalyst is filtered off and washed with ethanol. Combine the filtrate and washing liquid and reduce the solvent by 1E.
Ding leaves. By crystallizing the residue from a mixture of ethanol and diethyl ether, threo-1-(3co4',s
'-trimethoxy-α-methylbenzyl-5,7-cyhydroky! , 2.3.4-Tetrahydroisoquinoline salt 140η is crushed as colorless needle crystals. Yield near 0.7 hmp, 245-248° (decomposition) mass (m/e): 359 (M+)IR (
NujOll(cii'): 351) 0, 3:2
60.2400-270QNMR (D20.δ): 1
．． 44 (d, J=7! IZ, 3H) p 2.7-
4.0 (mI2”) + J, 25-3.63 (m, 3H
), 3.78 (s, 9H). 5.142 (d, J=2.5Hz, 1 old, 6.38
(d, J=2.587., LH), 6.47 (El,
2H) (ko3-+:+3 (:J-obtained by the 4-rule)
(alpha-methylbenzyl)-5゜7-dipenzyloxy-1.2.3.4-tetrahydroisoquinoline salt
Tetrahydrofuran/water (4:4:l) mixture 45rnl
The presence of 10% palladium-carbon Zoo'η dissolved in -
Then, leave it in contact for 3 hours at room temperature and pressure. Here it is. Process in the same way as (, 3-a).
xy-α-methylbenzyl)-5,7
-Shihydroxy-1.2.3.4-tetrahydroin 1,2/phosphorus salt Di-packed 360-"r is obtained as colorless prism crystals. , Yield: 81.4% +11P, 253-256° (9;4)IR(N
ujol) (i”) 23+ 53.3 Niji00,L
60 0Nl(R(Dzo, δl: 1.45(t
, J=ji, 5Hz, 3H), 2.64-3.0(+a
. '1Il), 3°2-3.5(m, 3H1,3,8(s
, 3H), 3°84(3,6H), (3,48(d
, J-3+1z, lH). 6.52 (d, J=2Hz, IH), 6.62 (s, 2
H). 1.2Ht, J=71(z, 3H), 3.39(q, J
=7Hz. 2 ■ () Reference example 1 (1) Dissolve 222 chloride of selenium dioxide in 0.5 - of water,
Then 10rnl of dioxane and i-(3',4',
Add 5'-trimethoxybenzyl)-5,7-dibenzyloxyin quinoline 521"'i and reflux for 2 hours while stirring. Remove the reaction strain and solvent by volume and remove the remaining residue with chloroform. Extract. The extract is washed sequentially with sodium hydroxide and saturated saline, and then dried. Chloroform is distilled off under reduced pressure. The remaining blood is purified by silica gel column chromatography (developing solvent: chloroform).
Further, by recrystallizing from ethyl #acid, 1-(3'4
ζ51-trimethoxybenzoyl)-5,7-dibenzyloxyisoquinoline 460~ is obtained as colorless needles. Yield: 86% mp, 169.5-171゜ma88 (m/e): 535 (M+11 R(
Nujoll (C7+1 2 : 1662NMR(C
DC13) ε: 3.79 (s, 6H), 3.90 (s
, 3H). 5.04 (8,2H), 5.17 (8,2 old, 6.8
5(d, J=2H2,1H). 7.2-7.6 (m, 1H), 8.15 (d, J=6H
z,lHJ. 847 (d, J = 6Hz, 1H1) (2) Suspend 150g of magnesium in 10% anhydrous ether, add 720"P of methyl iodine, and stir to dissolve methylmagnesium iodide. The suspension The liquid was cooled to below 10°C, and l −(3?4?
10 ml of tetrahydrofuran containing 5'-trimethoxybenzoyl)-5,7-dipenzyloxyisoquinoline 5351'9 was added dropwise and stirred for 1 hour. After the reaction, add 1% ammonium chloride aqueous solution under cooling to decompose excess methylmagnesium iodide, and extract with ethyl acetate. The extract is washed with brine, dried, and ethyl acetate is distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: chloroform) to obtain
(3te415'-trimethoxy-α-hydroxy-α-
325 mg of methylbenzyl)-5,7-dibenzyloxyisoquinoline are obtained as a yellow oil. Yield: 59
%mass (m/e): 551 (M+1NM
R (CDC13) ε: 1.94 (Sunday, 3H), 3.7
3 (9,6HJ. 3.81 (s, 3H), 4.74 (s, 2H), 5.1
7 (ε:, 2H). 6.608.2HJ, 6.72 (broad 8.2
)1), 7. : U3 (s, 5H). 7.43 (a, 50), 8.05 (d, J=6
Hz, 11 (+. 8.37 (d, J = 6 Hz, 1H) +31 (1 obtained in 21 -(3', 475'-trimethythc α-hydroxy-α-methylbenzyl)-
Dissolve 276η of 5,7-dibenzyloxyisoquinoline in a mixture of tetrahydrofuran-10% hydrochloric acid + 5:1), gently stir and reflux, add 750μ of zinc powder little by little, and stir for 30 minutes.・Reflux. After the reaction,
Excess zinc was filtered off and washed with tetrahydrofuran.
o After combining the filtrate and washing liquid and distilling off the solvent under reduced pressure,
The residue was neutralized with 10% sodium hydroxide solution and extracted with ethyl acetate. The extract is washed with saturated brine, dried, and ethyl acetate is distilled off under pressure. The residue was purified by silica gel column chromatography [developing medium: chloroform] to obtain crystals (14), and further recrystallized from a mixture of ethyl acetate and beef sanitation. )
190 η of dimethoxy-α-methylbenzyl)-5,7-dibenzyloxyisoquinoline is obtained as colorless needles. Yield near 1% mP, l 45-146゜mass (+n/e): 535 (+4+3N
MR (CDG13) ε: 1.82 (d, J=7Hz
, 3H), 3.76 (s-6H), 3.80
(s, 3HJ -4,6@-4,81+ ITl
, 1klJ. 4.96 and 5.10 (dd, J=llHyp, 6
tIH). 6.50(8,2)1), 6.74(d, J=2H
z, lHJ. 7.0) 5(d, J=2fiZ, 11(), 7.2-7
．． 6 (I!1.1OH).

Claims (1)

[Scope of Claims] 1. 1. 2.3.4-Tetrahytroinquinoline derivative or a pharmacologically acceptable acid addition salt thereof represented by the general formula (wherein R1 represents a trimethoxyphenyl group) 2. ,
Threo-1-L pressure +', 5'-i-rimethoxy α
-Methylbenzyl J-5,7-cyhydroxy 1.2.
3゜4-tetrahydroinky/phosphorus Compound 3 according to claim 1, general formula (wherein R1 represents a trimethoxyphenyl group, R2
represents a protecting group. ) The isoquinoline derivative represented by is subjected to a partial reduction reaction step of the isoquinoline skeleton and a protective group elimination step in an arbitrary order of order, and if necessary, the product is produced in a manner that is pharmacologically acceptable. A 1,2% 3,4-tetrahydroisoquinoline derivative represented by the general formula (wherein R1 has the same meaning as above) or a pharmacologically acceptable derivative thereof Method for producing acid addition salts. 4, with the general formula Ho ], Z, 3. A mixture of 21 stereoisomers of a 4-tetrahydroisoquinoline derivative is reacted with a reactive derivative of trifluoroacetic acid at the carboxyl 7A & then reacted with benzyl halide to give the formula (However, R
1 represents benzyl weir, and R1 has the same meaning as above. ] After forming a compound represented by the above formula, one stereoisomer of the compound ([V) is converted into an addition salt with the difference in solubility between the stereoisomers (wherein R1 is the same as above) A method for producing a threo- or erythro 1.2.3.4-tetrahydroisoquinoline derivative or a pharmacologically acceptable acid addition salt thereof.