JPH03151365A - Isoquinolinol derivative - Google Patents

Abstract

NEW MATERIAL:An isoquinolinol derivative of formula I (R<1> is 2-4C saturated or unsaturated straight or branched chain hydrocarbon; R<2> and R<3> are H or lower alkoxy) or a salt thereof. EXAMPLE:2-Ethyl-4-phenyl-1,2,3,4-tetrahydro-4-isoquinolinol. USE:Useful as a drug exhibiting an antidepressant activity. Low toxic. PREPARATION:A shown in the reaction formula A, a compound of formula II is reduced to provide the compound of formula I. In another method shown in the reaction formula B, a compound of formula III is reacted with a halide, etc., to provide the compound of formula I.

Description

[Detailed description of the invention]

The present invention relates to isoquinolitool derivatives represented by the following general formula CI) and pharmacologically acceptable salts thereof. Here, R' represents a saturated or unsaturated, linear or branched hydrocarbon having 2 to 4 carbon atoms. R2, R3
are the same or different and represent hydrogen or lower alkoxy. The above compound according to the present invention is a novel compound that has not been described in any literature, exhibits antidepressant action, and is useful as a pharmaceutical.

[Conventional technology]

It has been known that drugs that inhibit the oxidase of monoamines in the body, such as tonin and dopamine, are effective. From these clinical facts, the causes of depression are
Absolute or relative depletion of monoamines in specific regions of the brain was thought to be involved. Although powerful counter-arguments have been proposed to this theory, it has been confirmed that drugs that inhibit monoamine uptake have antidepressant effects. Drugs that improve depression by inhibiting the uptake of monoamines include, for example, bicyclic drugs such as desipramine, which relatively selectively inhibits noradrenaline, and non-selective drugs that inhibit noradrenaline, serotonin, and dopamine. Nomifensine, etc., were known to inhibit the disease. Although these drugs have been used as antidepressants, there was a need for a broader range of versatility, and a need for stable compounds with long blood half-life and high bioavailability.

[Problem to be solved by the invention]

The present inventors investigated various compounds for the purpose of solving the above technical problem, and as a result, they discovered that the compound of the present invention has a novel and excellent monoamine uptake inhibiting activity.

[Means to solve the problem]

The gist of the present invention lies in the structure itself of the compound represented by general formula [I]. Among the compounds represented by the general formula [I], the compounds in which R1 is methyl are known compounds described in literature. The compound of the present invention is similar in chemical structure to the compound in which R1 is methyl, but has excellent pharmacological activity and low toxicity (and has a sufficient inventive step. The compound of the present invention will also be described in detail later). Contains an optically active substance as described above.The structure of the compound of the present invention will be explained in detail.In the general formula [■], the hydrocarbon represented by R1 is a straight or branched hydrocarbon having 2 to 4 carbon atoms. is preferable, and examples of saturated ones include ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 5ec-
Butyl, tert-butyl, etc. can be mentioned. Examples of unsaturated substances include vinyl, allyl (a
llyl), propargyl, and the like. Examples of the lower alkoxy represented by R2 and R3 include methoxy, ethoxy, and propoxy. Examples of the salts of the compounds of the present invention include salts of mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, and salts of organic acids such as oxalic acid, tartaric acid, maleic acid, and benzenesulfonic acid. The compound of the present invention can be produced, for example, by the following method. [First manufacturing method] (n) (1) In the formula, R1, R2, and R3 are the same as above. X represents halogen. This reaction can be carried out by reducing the general formula [■]. Examples of the halogen represented by X include chlorine, fluorine, bromine, and iodine. [I
I] can be produced by reacting with a zero-valent transition metal complex such as tetrakistriphenylphosphine nickel or tetrakistriphenylphosphine palladium, or by intramolecular cyclization by an intramolecular Grignard reaction using metallic magnesium or metallic lithium. can. The reaction solvent in this case is not particularly limited, and examples thereof include dimethylformamide, hexamethylphosphortriamide, tetrahydrofuran, diethyl ether, and the like. The reaction temperature, degree and time in this case can be set taking into consideration various conditions. [Second manufacturing method] In the formula, R1, R2, and R3 are the same as above. X represents halogen. The compound of the present invention can be produced by reacting the secondary amine compound represented by formula [III] above with a halide represented by XR'. In this reaction, a small excess of a halide (e.g., alkyl chloride, alkyl bromide, alkyl iodite, etc.) is generally used, and an appropriate inert solvent (e.g., dimethylformamide, acetonitrile, tetrahydrofuran, dioxane, acetone, etc.) is used. The reaction may be carried out in the presence of an appropriate base (eg, various alkalis such as sodium carbonate and potassium carbonate, various amines such as triethylamine) at a temperature range of 0 to 200° C. for several hours to several tens of hours. When administering the compound of the present invention as a medicament, the compound of the present invention may be administered as such or in a pharmaceutically acceptable non-toxic and inert carrier, e.g. 0.1 to 99.5%, preferably 0.5%. It is administered to animals, including humans, as a pharmaceutical composition containing ~90%. As carriers, one or more solid, semisolid, or liquid diluents, fillers, and other formulation auxiliaries are used. Preferably, the pharmaceutical composition is administered in dosage unit form. The pharmaceutical composition of the present invention can be administered orally, intracellularly, locally (transdermally, etc.), or rectally. Of course, it is administered in a dosage form suitable for these administration methods. For example, intravenous administration is particularly preferred. The dosage for antidepressants depends on the patient's condition such as age and weight,
Although it is desirable to make adjustments in consideration of the route of administration, the nature and severity of the disease, etc., the amount of the active ingredient of the present invention for adults is usually in the range of 1 = IQOmg/person per day, preferably A range of 1-10 mg/person is common. In some cases, a lower dose than this may be sufficient, and in other cases, a higher dose may be required. Also 2-3 times a day
It can be administered in divided doses.

【Example】

The present invention will be explained in more detail with reference to Reference Examples, Examples, and Test Examples below, but the present invention is not limited to these Examples. Reference Example I N-ethyl-N-(2-iodobenzyl)phenacylamine 261 mg of phenacyl bromide in 10 ml of dioxane! Add 685 m of N-ethyl-2-iodobenzylamine to the solution.
g of dioxane 10-solution is added and stirred at room temperature for 5 hours. The formed white precipitate was filtered off and the solvent was distilled off to obtain 578 mg of crude product. This was purified by flash chromatography to obtain 418 mg of the target compound as a yellow oil. Mass spectrometry value (C+J, as INO) Calculated value 378
．． 0357 (M-1) φ consolation work OI'l')
11!0I R(KBr) 1682 cm-'(C
=0)'H-NMR (CDCI=, 200MHz,
δ) 7.93 (2H, dd), 7.8HIH
, dd). 7゛, 36-7.58 (4H, m), 7.29 (L
H, ddd). 6.93 (IH, ddd). 3.81. 3.94 (each 2) 1. s). 2.78 (2H, (1), 1.11 (3H, t). Reference Example 2 N-(2-iodobenzyl)-N-(n-propyl)phenacylamine A solution of 706 mg of phenacyl bromide in 15 mj! of dioxane 2-iodo-N-n-propylbenzylamine 1.
Add 952 g of dioxane 15-solution and stir at room temperature for 5 hours. After evaporation of the solvent, 20 cm of benzene was added and allowed to stand, the white precipitate formed was filtered off, and the solvent was evaporated to obtain 1.736 g of a crude product. This was purified by flash chromatography to obtain the target compound as a yellow oil with a concentration of 1.09%.
4g was obtained. Mass spectrometry value (as C,, R2゜INO)! +! Value R
q';! n! 'ill (M-1) Actual value 392.
0503 I R (KBr) 1693 cm-' (C=0)
'H-NMR (C mouth C1s, 200M) Iz,
δ)7.91(2)1. dd), 7.8H
1)1. dd). 7.36-7.58 (4H, m), 7.29 (1)
1. ddd). 6.93 (IH, ddd). 3.83. 3.95 (each 2H, s). 2.66 (2H, t), 1.44-1.63 (2B
, m). 0.85(3)1. t). Similarly, the following compounds were obtained. Reference Example 3 N-(2-iodobenzyl)-N-(isopropyl)nasylamine yellow oil. Mass spectrometry value (as C,,H2゜INO) Calculated value 39
3.0591 Actual value 393.0596 I R (KBr) 1697 cm-1 (C=0)'
)l-NMR (1:Dclg, 200M)lz,
δ) 7.9H2H, dd), 7.75(IH, dd
). Fair 45~7.57 (4H, m>, 7.27 (LH,
ddd). 6.90 (IH, ddd). 3.75. 3.9Heach 2H, s). 2.97-3.16 (IH, m). 1.13(6)1. d). Reference Example 4 N-(n-butyl)-N-(2-iodobenzyl)phenacylamine yellow oil. Mass spectrometry value (C,,) 1.21NO) Calculated value 4
07.0747 Actual value 407.0697 I R (KBr) 1686 cm"' (C=0)
') I-NMR (CDCl2.200M)+2. δ
)7.91(2)1. dd), 7.81 (IH,
dd). 7.36-7.58 (4H, m), ? , 26(1)
1. ddd). 6.93 (II (, ddd). 3.83.3.95 (each 2H, s). 2.70 (2) 1. t), 1.22-1.54 (
4H, m). 0.85 (3H, t). Reference Example 5 Yellow oil. 'LNMR (CDCl2.200MH2, δ)7.81
(II, dd), 7.59 (LH, dd). 7.5HIH,d), 7.28(IH,ddd). 6.93(ill, ddd), 6.84(l)1
．． d). 3.95 (2H, s), 3.1 (3H, s),
3.94 (3H, s). 2.66(1)1. t), 1.56-1.49 (
2H, m). 0.86 (3H, t). Reference Example 6 (1) N-Benzyl-N-(2-iodobenzyl)phenacylamine In a dioxane 10-solution of 549 mg of phenacyl bromide,
N-benzyl-2-iodobenzylamine 1.783g
Dioxane 10mJi! Add the solution and stir at room temperature for 5 hours. After the solvent is distilled off, n-hexane is added and the mixture is left to stand, and the resulting precipitation is removed by filtration. When the solvent is distilled off, crude product 1
．． Obtain 562g. This was purified by flash chromatography, and the calculated amount of yellow oily substance (C22H, as INO) was 44.
1.0590 Actual value 441.0540 I R (KBr): 1692 cm-1 (C=o)
'H-NMR (CDC13,200?J)lz,
δ) 7.77-7.83 (3H, m). 7, 22-7.55 (9H, m). 6.93 (IH, ddd). 3.87 (2H, s), 3.92 (4H, s) 1, 1
80g was obtained. Nickel chloride (NiC12) 588mg, Zinc (Zn) 304mg, ) Riphenylphosphine (
Ph, P) 2437 mg was placed in a two-necked Kolben and replaced with nitrogen. Anhydrous, oxygen-free N,N-dimethylformamide (
Add DMF>30d and stir at 55°C for 5 minutes. (
A solution of 992 mg of the compound obtained in 1) in anhydrous, oxygen-free DMF 5- is added, and the mixture is stirred at 55 to 60°C for 2.5 hours. The reaction mixture was adjusted to pH 2 with 2% hydrochloric acid and washed with ether. The aqueous layer is made alkaline with concentrated ammonia water and extracted with chloroform. Dry the chloroform layer with magnesium sulfate,
After evaporation of the solvent, crude product 552B was obtained. This is preparative TLC (hereinafter referred to as rPLcJ) (At, so
s. Purification with benzene-chloroform (10:1) gave 415 mg of the target compound as a yellow oil. Hydrochloride. Needle-shaped crystals. Melting point: 181-185°C. Elemental analysis value Calculated value as C22H1, No-HCl (
%) C near 5.10H: 6.30 N: 3.98
Actual value (%) C near 5.14H: 6.25 N:
3.96HR-MS Calculated value as C,,H,,NO 315.1622 Actual value 315.1636 I R(KBr): 3482 c+++-'(01
() (free base)'H-NMR (CDC1s, 10
0MHz, δ) (free base): 6.88~? , 6
0 (14)1. m). 3.56.3.96 (each 1N, d). 3.74 (2H, s). 2.78.3.06 (each IH, d). (3) 4-phenyl-1,2,3,4-tetrahydro-
To a solution of 472 mg of the compound obtained from 4-inquinolinol (2) in 7 ml of methanol were added 1.50 mf of IN hydrochloric acid-methanol and 65 mg of 20% palladium hydroxide on carbon, hydrogenated at 1 atm and room temperature for 3 hours, and filtered. . After methanol distillation, water 7r
Add nl, make alkaline with concentrated aqueous ammonia, and extract with chloroform. The chloroform layer was dried over magnesium sulfate and the solvent was distilled off to obtain 382 mg of a crude product. This was purified by PLC to obtain the target compound as a pale yellow oil 29.
8 mg was obtained. Leads to hydrochloride. Melting point 195-196°C (decomposed). Elemental analysis value C,, H, SNo.) Calculated value as ICI (%) C: 6g, 83H: 6.16 N: 5J5
Actual value (%) C: 68.60H: 6.07 N:
5J2HR-MS Calculated value as C,,H,,NO
225.1152 Actual value 225.1137 I R(KBr): 3062 cm-'(OHan
d N) l) (free base)') I-NMR (CDCI
s, 200M) Iz, δ) (free base): 6.9
4~? , 42(9)1. m). 3.97. 4.09 (each IH, d). 3.07. 3.18 (each IH, d). Example 1 N+C1z 508mg5Zn 256mg5PhsP
2054 mg was placed in a two-headed Kolben and the atmosphere was replaced with nitrogen. Add 17 ml of anhydrous, oxygen-free DMF and stir at 55° C. for 5 minutes. Anhydrous and oxygen-free 729 mg of the compound obtained in Reference Example 1
Add DMfl solution 3rn1 and stir at 55-60°C for 4.5 hours. The reaction mixture was adjusted to pH 2 with 2% hydrochloric acid and washed with ether. The aqueous layer is made alkaline with concentrated ammonia water and extracted with chloroform. The chloroform layer was dried over magnesium sulfate and the solvent was distilled off to obtain 423 mg of crude product. This was purified by PLC (A1.5.Benzene-chloroform 10:1) to obtain the target compound as colorless granular crystals.
41!1g was obtained. This leads to the hydrochloride salt in the form of colorless needles. Melting point 178-180°C (decomposed). Elemental analysis f C+tH+*N Calculated value as O・HCI (%) C Near 0.46H: 6.96 N: 4.
83 Actual value (%) C near 0.62H near, 00
N: 4.60I R(KBr): 3251 cm-
'(0)1) (free base)') I-NMR (CDCI
s, 400M) Iz, δ) (free base) = 6.9
4-7.47 (9H, m). 3.55. 4.03 (each 1) 1. d). 2.71. 3.05 (each 1)1. d). 2.62-2.74 (2H, m), 1.19 (3H
,t). Example 2 NiC12695mgSZn 358mg5Ph3P
2,878 mg was placed in a two-headed Kolben and the atmosphere was replaced with nitrogen. Anhydrous, oxygen-free DMF 30ml! and stir at 55°C for 5 minutes. 4 ml of an anhydrous, oxygen-free DMF solution containing 1057 mg of the compound obtained in Reference Example 2! and stirred at 55-60°C for 10 hours. The reaction mixture was adjusted to pH 2 with 2% hydrochloric acid and washed with ether. The water layer is made alkaline with concentrated ammonia water,
Extract with chloroform. The chloroform layer was dried over magnesium sulfate and the solvent was distilled off, yielding 639 mg of crude product.
was gotten. This was purified by PLC (Al2O2, benzene-chloroform 10:1) to obtain 431 mg of colorless needle-like crystals of the target compound. Melting point 63-64°C. Elemental analysis value Calculated value (%) as C1, H21NO・zH20 C Near 8.22H: 8.02 N: 5. O
? Actual value (%) C near 8.22H: 8.22N
:4.99I R(KBr): 3314 cm-'
(Otl)') I-NMR (CDCIs, 400Mt
lz, δ) 6.94-7.47 (9H, m). 3.57.4.05 (each IH, d). 2.75.3.05 (each IH, d). 2.52-2,64(2)1. m), 1.59~
1°68 (2)1. m). 0.96 (3H, t). This compound was converted into the hydrochloride salt of colorless needle-like crystals. Melting point 177-180°C (decomposition). Example 3 NiC 12366 mg, Zn 174 mg, P
1394 mg of h5P was placed in a two-headed Kolben and replaced with nitrogen. Add 25 ml of anhydrous, oxygen-free 0MF and stir at 55°C for 5 minutes. An anhydrous, oxygen-free DMF solution 3- containing 494 mg of the compound obtained in Reference Example 3 is added, and the mixture is stirred at 55 to 60°C for 8 hours. The reaction mixture was adjusted to pH 2 with 2% hydrochloric acid and washed with ether. The aqueous layer is made alkaline with concentrated ammonia water and extracted with chloroform. The chloroform layer was dried over magnesium sulfate and the solvent was distilled off to obtain 301 mg of crude product. This was purified by PLC (7:1 benzene-chloroform) to obtain 209 mg of the target compound as a pale yellow oil. This led to the hydrochloride salt in the form of colorless needle-like crystals. Melting point 184-189°C (decomposition). Elemental analysis value C1, H21N○・) Calculated value as ICI (%) C near 1.16H near, 30 N: 4.6
1 Actual value (%) C near 0.84H near, 56 N
:4.52IR(KBr) :3453 cm-'(
DH) (free base)'H-NMR (CDCl2.20
0MH2, δ) (free base): 6.9 (1-7.50
(9H, m). 3.83.3.93 (each IH, d). 2,88-3.08 (IH, m). 2.7? , 2.96 (each IH. 1.12(6)1.dd). Example 4 d). NiC12563mgSZn 291mg, PhaP
2334 tng was placed in 2 MM Kolben and replaced with nitrogen. Add 30− of anhydrous, oxygen-free DMF and stir at 55° C. for 5 minutes. 4 ml of an anhydrous, oxygen-free DMF solution containing 1177 mg of the compound obtained in Reference Example 4! and stirred at 55-60°C for 8 hours. The reaction mixture was adjusted to pH 2 with 2% hydrochloric acid and washed with ether. The water layer is made alkaline with concentrated ammonia water,
Extract with chloroform. The chloroform layer was dried with magnesium sulfate and the solvent was distilled off, yielding 629 mg of crude product.
was gotten. This was purified by PLC (130 g of A, benzene-chloroform 10:1) to obtain 379 mg of colorless granular crystals of the target compound. This led to the hydrochloride salt in the form of colorless needle-like crystals. Elemental analysis value C1゜H2,NO Calculated value as HCI (%) C near 1.80H near, 61 N: 4.4
1 Actual value (%) C near 1.46H near, 77 N
:4.28I R(KBr): 3351 cm-'
(0)1) (free base)'H-NL4R((:DCl
,, 200MHz, δ) (free base): 6, 9
1~? , 48 (9H, m). 3.51.3.98 (each IH, d). 2.69.2.99 (each 1)1. d). 2.52-2.64 (2) 1. m). 1.26-1.63 (4H, m). 0.93 (3N, t). Example 5 NiC12277mgSZn 140mg, Ph5P
1119 mg was placed in a two-head full pen and the atmosphere was replaced with nitrogen. Add 10 rnl of anhydrous, oxygen-free DIJF and stir at 57° C. for 5 minutes. Anhydrous and oxygen-free [IMF solution 2.5-] of compound 477H obtained in Reference Example 5 is added and stirred at 57-58°C for 7 hours. Reaction mixture m II I'l/L&a
1-11 Li L-1〒-#l+-)Lnh The eggplant aqueous layer is made alkaline with concentrated ammonia water and extracted with chloroform. The chloroform layer was dried over magnesium sulfate and the solvent was distilled off to obtain 398 mg of crude product. This was purified by PLC (A1.0., benzene-chloroform 1:1) to obtain an oily product of the target compound at 180%.
7 mg was obtained. This led to the hydrochloride salt in the form of colorless needles. Melting point: 194-198°C. Elemental analysis value C2゜H2SN0-・Calculated value as HCI (%') C: 66.02H near, 20 N: 3.
85 Actual value (%) C: 65.76H near, 37
N: 3.76IR (KBr): 3464 cm-
'(OH) (free base)') I-NMR (CDCI3
．． 200MH2, δ) (free base): 6.96-7.
26(5)1. m), 6.89 (IH, dd). 6.82 (IH, d). 4.00.3.53 (each 1)1. d). 3.88.3.87 (6H, s). 2.98.2.69 (each IH, d). 2.58.2.51 (each 1)1. dt). 2.48-1.52 (2H, m). 0.96(3)1. t). Example 6 810 mg of potassium carbonate was added to 5 ml of a dry benzene solution containing 88 mg of the compound obtained in Reference Example 6-(3), and 55 mg of potassium carbonate was added.
A dry benzene solution of 240 mg of allyl bromide under stirring at ℃ 1
Add Kura. The mixture is stirred at 55° C. for 6 hours and filtered. The filtrate was washed with water, dried over magnesium sulfate, and the solvent was distilled off to obtain 96 mg of a crude product. Purification was performed by PLC to obtain 85 mg of colorless plate-like crystals of the target compound. This led to the hydrochloride salt as a white powder. Melting point 179-181°C (decomposed). Elemental analysis value Calculated value as C1-H+sN○・HCI (
%) C near 1.63H: 6.68 N: 4.6
4 Actual value (%) C near 1.39H: 6.66 N
:4.56I R(KBr): 3402 cm-'
(0)1), 1644cm-'(C=C)'H-NM
R(CDCI3.200M)Iz, δ) (free base): 6,92-7.48 (9H, m). 5.9HIH, ddt). 5.23 (LH, dd, J=17.1.5Hz). 5.20(l)I, dd, J=10. 1.5Hz
). 3.53. 3.96 (each IH, d, J=
15Hz). 3.1? , 3.26 (each IH, dddd,
J=13.5. 6.5°1, 5. 1.5Hz)
. 2.67, 3.04 (each IH, d, J=
12Hz, CHa-C). Example 7 Compound obtained in Reference Example 6-(3) 380 mg of potassium carbonate was added to 42 mg of dry benzene solution 4-, and the mixture was heated at 55°C.
While stirring, 1 d of a dry benzene solution containing 111 mg of propargyl bromide was added. The mixture is stirred for 6 hours and filtered. The filtrate was washed with water, dried over magnesium sulfate, and the solvent was distilled off to obtain 45 mg of a crude product. Purification was performed by PLC to obtain 35 mg of colorless needle-like crystals of the target compound. This led to the hydrochloride salt in the form of white needles. Melting point 197-200°C (decomposition). Elemental analysis value C+aH, tN O” Calculated value as HCI (%) C near 2.11H: 6.05 N: 4
．． 67 Actual value (%') C near 1.89H: 6.10
N: 4.60I R (KBr): 3280
cm-'(OH), 2104cm-'(CC)'
H-NMR (CDCI 3+ 200MHz, δ)
(Free base): 6, 93-7.47 (9H, m)
. 3.7? , 3.87 (each 1) 1. d,
J=15Hz). 3.52(2)1. d, J=2.5flz)
. 2.91. 2.98 (each E, d, J
= 12Hz). 2.27 (LH, t, J=2.5Hz). [Pharmacological activity] In order to examine the pharmacological activity of the compound of the present invention, the effect on noradrenaline contraction in isolated rat anococcygeus muscle specimens was investigated. Male Wistar rats weighing 200 to 250 g were used in groups of 5 rats. Rat anococcygeus muscle was excised as a specimen according to the standard method of Gillespie (1972) and suspended in a 10-cm tissue bath filled with Tyrode's solution. The upper end of the specimen was connected to an isotonic transducer and an initial tension of ˜0.5 g OJ was applied. The specimen bath was aerated and kept at 37°C. After stabilization for 2 hours, noradrenaline 10-1 was added in the presence of propranolol 10-1M and cocaine 10-M.
3-3 X 10-'M were added cumulatively to the tissue bath and contraction of the specimen was recorded on a pen recorder. After thorough washing to restore the tension of the specimen to its original level, various concentrations of the test drug were treated for 30 minutes, and noradrenaline contractions in the presence of the test drug were similarly recorded to determine the effect of the test drug on noradrenaline contractions. Examined. From the concentration-response curve of contraction obtained, the concentration that causes a contraction of 50% of the maximum contraction in the absence and presence of the test drug (
50% reaction concentration: E Cs. ) to PO2 value (-1o
g(ECs.)) was determined. The results are shown in the table below. The pharmacological effects of the compounds of the invention are obvious. (See next page) Isopro 6.06 6.26 6J9 6.72
6.72 pills (1,0) (1,7)
(2,2) (4,8) (4,8) Hydrogen
------6,526,746,98 (1,6)
(2,6) (4,6) [Toxicity] The toxicity of the compound of the present invention is extremely low. [Stereoconfiguration] Among the compounds of the present invention, the compound obtained in Example 1 was analyzed by HPLC using an optical isomer separation column: [α], minus, and [α]. Divided into plus. The absolute configuration is CO
The spectral exciton chirality method estimated it to be an R-form and an 8-form, and X-ray analysis revealed it to be [α]. The plus was determined to be the R form. When the pharmacological effects of these substances were investigated, the R form had a pharmacological effect, but eight forms had no pharmacological effect at all. It is known that natural noradrenaline is in the R form, and among the compounds of the present invention, those that have pharmacological effects are:
It was found that it has the same absolute configuration as natural noradrenaline.

Claims (1)

[Claims] (1) Isoquinolinol derivatives represented by the following general formula [I] and pharmacologically acceptable salts thereof. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [I] Here, R^1 represents a saturated or unsaturated, linear or branched hydrocarbon having 2 to 4 carbon atoms. R^2,
R^3 are the same or different and represent hydrogen or lower alkoxy.