JP2886225B2 - Alkylenediamine derivative and method for producing the same - Google Patents

Description

The present invention affects the vascular smooth muscle of mammals, and is useful as a vasodilator, a cerebral circulation improving agent, a therapeutic agent for angina pectoris, and a preventive therapeutic agent for thrombosis. And a method for producing the same.

[Conventional technology]

The relaxing action of the compound having an isoquinoline ring contained in the compound of the present invention on vascular smooth muscle is currently disclosed in JP-A-57-15646.
3, 57-200366, 58-121278, 58-121279, 59
-93054, 60-81168, 61-226026, 61-152658,
61-227581, 61-271221, 61-293914, 62-10
3066, 62-111981, 63-2980, 63-211267, etc., many useful compounds have been synthesized and are known.

[Problems to be solved by the invention]

All of these compounds have satisfactory smooth muscle relaxing effects, and their production methods are rational. There is room for improvement, and it is desired to maintain the effectiveness and improve the above factors. Therefore, an object of the present invention is to provide a novel compound which is improved in low toxicity, organ specificity and safety while maintaining the efficacy as a pharmaceutical.

[Means for solving the problem]

The present invention relates to a compound of the formula (I) Wherein R ¹ and R ² are the same or different and are hydrogen, substituted or unsubstituted lower alkyl, formyl, dimethoxyphenyl or chlorophenylpropargyl; R ³ is hydrogen or lower alkyl; R ⁴ , R ⁵ , R ⁶ is the same or different and hydrogen, halogen atom, nitro group, lower alkyl group, di-lower alkylamino group, lower alkoxy group, polyfluoro lower alkyl group, hydroxy group, carboxy group, carbamoyl group, cyano group, methoxycarbonyl group , Hydroxymethyl group,
Methylthio group, methylsulfinyl group, methylsulfonyl group, acetamido group, methoxyethoxymethoxy group or a lower alkylenedioxy group in which two groups are combined; X is a vinylene group or ethynylene group; Ar is a phenyl group,
A naphthyl group or a heterocyclic group; m and n each represent an integer of 1 to 3); a quaternary ammonium salt thereof; a non-toxic salt thereof;

The compound according to the present invention is designed and synthesized so that an aromatic ring is bonded to a sulfonamide compound of an alkylenediamine and isoquinolinesulfonic acid through an unsaturated carbon chain, and the above-mentioned object is sufficiently achieved. All are new compounds.

In the definitions of the symbols in the above formula, the lower alkyl is a methyl group, an ethyl group, a propyl group, an isopropyl group and the like, the lower alkylene is a methylene group, an ethylene group, a propylene group and the like, and the lower alkoxy is a methoxy group And ethoxy groups. Examples of the substituent in the substituted lower alkyl group include an amino group, an alkylamino group, a phenyl group or a phenyl group substituted with a hydroxyl group, a halogen atom, and the like. Further, as the heterocyclic group, specifically, 2-pyridyl Group, 4-pyridyl group, 2-
Examples thereof include a pyrrolyl group, a 2-thienyl group and a 2-furyl group.

Next, the method for producing the compound (I) of the present invention will be described. A known compound, an isoquinolinesulfonic acid amide compound (II) To the general formula (III) (Wherein A is -CH ₂ Cl or -CO-R ^3; and the other symbols represents the same group as above) is reduced if necessary by reacting the compound of, R ¹ further amino group
And alkyl groups with R ¹ Ha and R ² Ha (Ha is halogen), or formylation, and then salting to introduce R ² groups. In the reaction, methanol and dimethylformamide can be used as a solvent, and sodium borohydride, lithium aluminum hydride and the like can be used as a reducing agent.

Reaction above compound (II) with the compound (III), from compounds of R ¹ and R ² are hydrogen are obtained in the compound (I), if R ^1, R ² is manufacturing the substituents Is
Further alkylation or formylation is required. For alkylation, various substituents can be introduced into R ¹ and R ² by subjecting the above compound (I) and alkyl halide to dehydrohalogenation and alkylation. Further, a formyl group can be introduced into R ¹ and R ² by reacting in the presence of formic acid and acetic anhydride.

Methyl iodide is usually used as a quaternary ammonium salt according to the compound of the present invention, and inorganic acids (hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, etc.) which are usually used as non-toxic salts ) And organic acids (citric acid, acetic acid,
Oxalic acid, tartaric acid, sulfonic acids, fumaric acid, propionic acid, maleic acid, malic acid, etc.) can be used.

〔Example〕

Hereinafter, the present invention will be described specifically with reference to Examples.
The present invention is not limited to these examples.

The melting points in the examples were measured (uncorrected) using a capillary with a melting point measuring apparatus Yamato MP-21 (manufactured by Yamato Scientific Co., Ltd.). (Manufactured by JEOL Ltd.).

Manufacturing method (a) General formula Example 1 (n = 2, Ary1 = 4-chlorophenyl) N- [2- (4-chloro-α-methylcinnamylamino) ethyl] -5-isoquinolinesulfonic acid amide N- (2-aminoethyl) -5 Dissolve 7.30 g of isoquinolinesulfonic acid amide in 150 ml of methanol, add 6.30 g of parachlorobenzalacetone, stir at room temperature for 36 hours, then add 1.32 g of sodium tetrahydrideborate under ice water cooling, and stir for 30 minutes did. The reaction solution was reduced to about ¹ under reduced pressure.
After concentrating to _1/2 volume, 300 ml of ethyl acetate was added, and the mixture was washed three times with water. The aqueous layer was extracted with 100 ml of ethyl acetate, washed similarly with water, combined with the ethyl acetate layer, washed twice with a saturated saline solution, and dried over anhydrous magnesium sulfate. After the mixture was filtered, the solvent was distilled off under reduced pressure, and the residue was separated and purified with a silica gel column (silica gel 200 g, eluent: 5% methanol / chloroform). 6.78 g of the product were obtained. ¹ H-NMR (CDCl ₃ , δ ppm): 1.06 (3H, d, J = 6.6 Hz), 1.8
~ 2.8 (2H, br), 2.57 ~ 2.64 (2H, m), 2.96 (2H, t, J =
5.7Hz), 3.06 (1H, dq, J = 7.8,6.6Hz), 5.79 (1H, dd, J
= 15.8,7.8Hz), 6.24 (1H, d, J = 15.8Hz), 7.19 (2H, d
m, J = 8.8Hz), 7.25 (2H, dm, J = 8.8Hz), 7.67 (1H, dd,
J = 8.0,7.6Hz), 8.28 (1H, dt, J = 8.0,1.0Hz), 8.42 ~
8.46 (2H, m), 8.69 (1H, d, J = 6.1Hz), 9.35 (1H, d, J
= 1.0 Hz) The following compound was obtained by the same method (Production method A).

Example 2 (n = 2, Ary1 = phenyl) N- [2- (α-methylcinnamylamino) ethyl]-
5-isoquinolinesulfonic acid amide colorless amorphous ¹ H-NMR (CDCl ₃ , δ ppm): 2.0 to 3.0 (2H, br), 2.59 to
2.66 (2H, m), 2.98 (2H, t, J = 5.5Hz), 3.09 (1H, dq, J
= 8.0,6.6Hz), 5.80 (1H, dd, J = 15.9,8.0Hz), 6.28
(1H, d, J = 15.9Hz), 7.28 (5H, brs), 7.66 (1H, dd, J
= 8.3,7.3Hz), 8.17 (1H, brd, J = 8.3Hz), 8.43 (1H, d
d, J = 7.3,1.2Hz), 8.44 (1H, d, J = 6.1Hz), 8.64 (1H,
d, J = 6.1 Hz), 9.34 (1H, d, J = 1.0 Hz) Example 3 (n = 2, Ary1 = 2,4-difluorophenyl) N- [2- (2,4-difluoro-α- Methylcinnamylamino) ethyl] -5-isoquinolinesulfonic acid amide colorless amorphous ¹ H-NMR (CDCl ₃ , δ ppm): 1.06 (3H, d, J = 6.4 Hz), 1.3
~ 2.2 (2H, br), 2.57 ~ 2.67 (2H, m), 2.96 (2H, t, J =
5.6Hz), 3.04 (1H, dq, J = 8.0,6.4Hz), 5.81 (1H, dd, J
= 16.1, 8.0Hz), 6.35 (1H, d, J = 16.1Hz), 6.79 (1H,
d, J = 8.3Hz and 1H, ddd, J = 17.6,8.8,2.0Hz), 7.30 (1
H, ddd, J = 14.9,8.3,2.0Hz), 7.69 (1H, dd, J = 8.3,7.3H)
z), 8.29 (1H, dt, J = 8.3,1.0Hz), 8.42-8.47 (2H,
m), 8.70 (1H, d, J = 6.1 Hz), 9.35 (1H, d, J = 1.0 Hz) Example 4 (n = 2, Ary1 = 2,4-dichlorophenyl) N- [2- (2, 4-Dichloro-α-methylcinnamylamino) ethyl] -5-isoquinolinesulfonic acid amide colorless amorphous ¹ H-NMR (CDCl ₃ , δ ppm): 1.07 (3H, d, J = 6.6 Hz), 1.5
2.5 (2H, br), 2.58-2.65 (2H, m), 2.97 (2H, t, J =
5.5Hz), 3.09 (1H, dq, J = 8.0,6.6Hz), 5.75 (1H, dd, J
= 15.8,8.0Hz), 6.58 (1H, d, J = 15.8Hz), 7.18 (1H, d
d, J = 8.5,2.0Hz), 7.28 (1H, d, J = 8.5Hz), 7.35 (1H,
d, J = 2.0Hz), 7.68 (1H, dd, J = 8.0,7.3Hz), 8.18 (1
H, td, J = 8.0,1.0Hz), 8.42-8.47 (2H, m), 8.70 (1H,
d, J = 6.1 Hz), 9.34 (1 H, d, J = 1.0 Hz) Example 5 (n = 2, Ary1 = 3-chlorophenyl) N- [2- (3-chloro-α-methylcinnamylamino) Ethyl] -5-isoquinolinesulfonic acid amide colorless amorphous ¹ H-NMR (CDCl ₃ , δ ppm): 1.06 (3H, d, J = 6.6 Hz), 1.3
~ 2.4 (2H, br), 2.56-2.63 (2H, m), 2.97 (2H, t, J =
5.6Hz), 3.06 (1H, dq, J = 7.8,6.6Hz), 5.80 (1H, dd, J
= 15.9, 7.8Hz), 6.22 (1H, d, J = 15.9Hz), 7.10 to 7.26
(4H, m), 7.68 (1H, dd, J = 8.1,7.5Hz), 8.18 (1H, dt,
J = 8.1,1.0Hz), 8.42 ~ 8.47 (2H, m), 8.70 (1H, d, J =
6.1 Hz), 9.35 (1H, d, J = 1.0 Hz) Example 6 (n = 2, Ary1 = 2-nitrophenyl) N- [2- (α-methyl-2-nitrocinnamylamino) ethyl]- 5-Isoquinolinesulfonic acid amide pale yellow amorphous ¹ H-NMR (CDCl ₃ , δ ppm): 1.08 (3H, d, J = 6.4 Hz), 1.3
~ 2.6 (2H, br), 2.61 ~ 2.77 (2H, m), 2.99 (2H, t, J =
5.6Hz), 3.09 (1H, dq, J = 7.8,6.4Hz), 5.73 (1H, dd, J
= 15.6,7.8Hz), 6.73 (1H, d, J = 15.6Hz), 7.36 to 7.56
(3H, m), 7.68 (1H, dd, J = 8.3,7.3Hz), 7.92 (1H, dd,
J = 7.9,1.2Hz), 8.42-8.47 (2H, m), 8.67 (1H, d, J =
6.1 Hz), 9.31 (1H, d, J = 1.0 Hz) Example 7 (n = 2, Ary1 = 4-nitrophenyl) N- [2- (α-methyl-4-nitrocinnamylamino) ethyl]- 5-isoquinolinesulfonic acid amide pale yellow amorphous ¹ H-NMR (CDCl ₃ , δ ppm): 1.10 (3H, d, J = 6.6 Hz), 1.4
~ 2.6 (2H, br), 2.60 ~ 2.77 (2H, m), 2.99 (2H, t, J =
5.5Hz), 3.14 (1H, dq, J = 7.6,6.6Hz), 6.05 (1H, dd, J
= 15.9,7.6Hz), 6.38 (1H, d, J = 15.9Hz), 7.40 (2H, d
m, J = 8.8Hz), 7.69 (1H, dd, J = 8.3,7.5Hz), 8.14 (2
H, dm, J = 8.8Hz), 8.23 (1H, brd, J = 8.3Hz), 8.43-8.
48 (2H, m), 8.68 (1H, d, J = 6.1Hz), 9.36 (1H, d, J =
1.0 Hz) Example 8 (n = 2, Ary1 = 4-methylphenyl) N- [2- (α, 4-dimethylcinnamylamino) ethyl] -5-isoquinolinesulfonic acid amide colorless amorphous ¹ H-NMR ( CDCl ₃ , δ ppm): 1.05 (3H, d, J = 6.6 Hz), 2.0
~ 2.5 (2H, br), 2.33 (3H, s), 2.56-2.64 (2H, m),
2.96 (2H, t, J = 5.9Hz), 3.05 (1H, m), 5.73 (1H, dd, J
= 15.9,7.8Hz), 6.24 (1H, d, J = 15.9Hz), 7.09 (2H, b
rd, J = 8.3Hz), 7.16 (2H, brd, J = 8.3Hz), 7.67 (1H,
t, J = 8.0Hz), 8.17 (1H, brd, J = 8.0Hz), 8.43 (1H, d,
J = 8.0Hz), 8.44 (1H, d, J = 6.1Hz), 8.68 (1H, d, J =
6.1 Hz), 9.34 (1H, d, J = 1.0 Hz) Example 9 (n = 2, Ary1 = 3,4-methylenedioxyphenyl) N- [2- (α-methyl-3,4-methylenedi) Oxycinnamylamino) ethyl] -5-isoquinolinesulfonic acid amide colorless amorphous ¹ H-NMR (CDCl ₃ , δ ppm): 1.04 (3H, d, J = 6.3 Hz), 2.5
6 to 2.63 (2H, m), 2.95 (2H, t, J = 5.6Hz), 3.05 (1H, d
q, J = 8.0,6.3Hz), 5.60 (1H, dd, J = 15.9,8.0Hz), 5.9
5 (2H, s), 6.18 (1H, d, J = 15.9Hz), 6.70 (1H, dd, J =
7.5, 1.5Hz), 6.73 (1H, d, J = 7.5Hz), 6.79 (1H, d, J =
1.5Hz), 7.68 (1H, dd, J = 8.1,7.5Hz), 8.19 (1H, brd,
J = 8.1Hz), 8.42 ~ 8.46 (2H, m), 8.69 (1H, d, J = 6.1H
z), 9.35 (1H, d, J = 1.0 Hz) Example 10 (n = 2, Ary1 = 2-pyridyl) N- [2- [1-methyl-3- (2-pyridyl) -2-]
[Propenylamino] ethyl] -5-isoquinolinesulfonic acid amide ¹ H-NMR (CDCl ₃ , δ ppm): 1.07 (3H, d, J = 6.6 Hz), 1.5
~ 4.0 (2H, br), 2.62 (2H, dt, J = 5.7,5.7Hz), 2.97
(2H, t, J = 6.4Hz), 3.06 (1H, dq, J = 5.6,6.6Hz), 6.3
5 (1H, d, J = 5.6Hz), 6.37 (1H, s), 7.12 (1H, dddd, J
= 7.8,5.0,2.0,1.0Hz), 7.21 (1H, d, J = 7.8Hz), 7.62
(1H, td, J = 7.8,2.0Hz), 7.68 (1H, dd, J = 8.0,7.3H
z), 8.18 (1H, brd, J = 8.0Hz), 8.44 (1H, d, J = 7.3H)
z), 8.45 (1H, d, J = 7.3Hz), 8.52 (1H, ddd, J = 5.0,2.
0,1.0Hz), 8.67 (1H, d, J = 6.1Hz), 9.34 (1H, d, J = 1.
0 Hz) Example 11 (n = 2, Ary1 = 4-pyridyl) N- [2- [1-methyl-3- (4-pyridyl) -2-
Propenylamino] ethyl] -5-isoquinolinesulfonic acid amide colorless amorphous ¹ H-NMR (CDCl ₃ , δ ppm): 1.09 (3H, d, J = 6.3 Hz), 1.2
~ 1.9 (2H, br), 2.59 ~ 2.65 (2H, m), 2.98 (2H, t, J =
6.0Hz), 3.12 (1H, dq, J = 7.3,6.3Hz), 6.06 (1H, dd, J
= 15.9,7.3Hz), 6.26 (1H, d, J = 15.9Hz), 7.14 (2H, d
d, J = 6.1,1.5Hz), 7.69 (1H, dd, J = 8.1,7.5Hz), 8.19
(1H, brd, J = 8.1Hz), 8.42-8.47 (2H, m), 8.51 (2H,
dd, J = 6.1,1.5Hz), 8.68 (1H, d, J = 6.3Hz), 9.35 (1
H, d, J = 1.0 Hz) Example 12 (n = 2, Ary1 = 2-thienyl) N- [2- [1-methyl-3- (2-thienyl) -2-
Propenylamino] ethyl] -5-isoquinolinesulfonic acid amide colorless amorphous ¹ H-NMR (CDCl ₃ , δ ppm): 1.05 (3H, d, J = 6.6 Hz), 1.2
~ 2.5 (2H, br), 2.56-2.64 (2H, m), 2.93-3.05 (3
H, m), 5.65 (1H, dd, J = 15.6,8.0Hz), 6.41 (1H, d, J =
15.6Hz), 6.85 (1H, dd, J = 3.7,2.4Hz), 6.94 (1H, dd,
J = 4.9,3.7Hz), 7.13 (1H, dd, J = 4.9,2.4Hz), 7.68
(1H, dd, J = 8.3,7.5Hz), 8.19 (1H, brd, J = 8.3Hz),
8.42 to 8.46 (2H, m), 8.69 (1H, d, J = 6.1Hz), 9.35 (1
H, d, J = 1.0 Hz) Example 13 (n = 2, Ary1 = 2-furyl) N- [2- [3- (2-furyl) -1-methyl-2-propenylamino] ethyl] -5 - isoquinoline sulfonic acid amide colorless MuAkirakarada _{^{1 H-NMR (CDCl 3,}} δppm): 1.04 (3H, d, J = 6.4Hz), 1.3
~ 1.5 (2H, br), 2.59 (2H, td, J = 6.0,4.9Hz), 2.95
(2H, t, J = 6.0Hz), 2.98 (1H, dq, J = 7.8,6.4Hz), 5.7
5 (1H, dd, J = 15.9,7.8Hz), 6.10 (1H, d, J = 15.9Hz),
6.16 (1H.d, J = 3.2Hz), 6.35 (1H, dd, J = 3.2,1.9H
z), 7.32 (1H, d, J = 1.9Hz), 7.68 (1H, dd, J = 8.3,7.5
Hz), 8.19 (1H, brd, J = 8.3Hz), 8.42-8.47 (2H,
m), 8.69 (1H, d, J = 6.1 Hz), 9.35 (1H, d, J = 1.0 Hz) Example 14 (n = 2, Ary1 = 4-fluorophenyl) N- [2- (4-fluoro -Α-methylcinnamylamino) ethyl] -5-isoquinolinesulfonic acid amide colorless amorphous ¹ H-NMR (CDCl ₃ , δ ppm): 1.06 (3H, d, J = 6.4 Hz), 1.3
~ 2.0 (2H, br), 2.57 ~ 2.63 (2H, m), 2.95 (2H, t, J =
5.5Hz), 3.05 (1H, dq, J = 8.0,6.4Hz), 5.72 (1H, dd, J
= 15.9,8.0Hz), 6.25 (1H, d, J = 15.9Hz), 6.98 (2H, t
m, J = 8.7Hz), 7.20-7.27 (2H, m), 7.68 (1H, dd, J =
8.1,7.3Hz), 8.18 (1H, brd, J = 8.1Hz), 8.42-8.47
(2H, m), 8.69 (1H, d, J = 6.1Hz), 9.35 (1H, d, J = 1.0
Hz) Example 15 (n = 2, Ary1 = 4-bromophenyl) N- [2- (4-bromo-α-methylcinnamylamino) ethyl] -5-isoquinolinesulfonic acid amide colorless amorphous ¹ H-NMR (CDCl ₃ , δppm): 1.06 (3H, d, J = 6.4Hz), 1.3
~ 2.2 (2H, br), 2.56-2.63 (2H, m), 2.95 (2H, t, J =
5.7Hz), 3.05 (1H, dq, J = 8.0,6.4Hz), 5.79 (1H, dd, J
= 15.9, 8.0Hz), 6.22 (1H, d, J = 15.9Hz), 7.13 (2H, d
m, J = 8.5Hz), 7.41 (2H, dm, J = 8.5Hz), 7.68 (1H, dd,
J = 8.3,7.4Hz), 8.19 (1H, brd, J = 8.3Hz), 8.42-8.4
6 (2H, m), 8.69 (1H, d, J = 6.1Hz), 9.34 (1H, d, J = 1.
0 Hz) Example 16 (n = 2, Ary1 = 4-isopropylphenyl) N- [2- (4-isopropyl-α-methylcinnamylamino) ethyl] -5-isoquinolinesulfonic acid amide colorless amorphous ¹ H-NMR (CDCl ₃ , δppm): 1.05 (3H, d, J = 6.6Hz), 1.2
4 (6H, d, J = 6.8 Hz), 1.5 to 2.5 (2H, br), 2.56 to 2.63
(2H, m), 2.80 to 3.05 (3H, m), 5.74 (1H, dd, J = 15.9,
8.0Hz), 6.24 (1H, d, J = 15.9Hz), 7.16 (2H, d, J = 8.6
Hz), 7.20 (2H, d, J = 8.6Hz), 7.66 (1H, dd, J = 8.3,7.
3Hz), 8.17 (1H, brd, J = 8.3Hz), 8.43 (1H, dd, J = 7.
3,1.0Hz), 8.44 (1H, d, J = 6.1Hz), 8.69 (1H, d, J = 6.
Example 17 (n = 2, Ary1 = 4-methoxyphenyl) N- [2- (4-methoxy-α-methylcinnamylamino) ethyl] -5 (1 Hz), 9.34 (1H, d, J = 1.0 Hz) - isoquinoline sulfonic acid amide colorless MuAkirakarada _{^{1 H-NMR (CDCl 3,}} δppm): 1.05 (3H, d, J = 6.4Hz), 1.5
~ 2.5 (2H, br), 2.56-2.63 (2H, m), 2.96 (2H, t, J =
5.6Hz), 3.02 (1H, dq, J = 8.0,6.4Hz), 3.81 (3H,
s), 5.64 (1H, dd, J = 15.9,8.0Hz), 6.21 (1H, d, J = 1
5.9Hz), 6.83 (2H, dm, J = 8.8Hz), 7.20 (2H, dm, J = 8.
8Hz), 7.67 (1H, dd, J = 8.3,7.3Hz), 8.19 (1H, brd, J
= 8.3Hz), 8.44 (1H, dd, J = 7.3,1.2Hz), 8.44 (1H, d,
J = 6.1Hz), 8.69 (1H, d, J = 6.1Hz), 9.34 (1H, d, J =
1.0 Hz) Example 18 (n = 2, Ary1 = 4-hydroxyphenyl) N- [2- (4-hydroxy-α-methylcinnamylamino) ethyl] -5-isoquinolinesulfonic acid amide Colorless crystal Melting point: 70- 73 ° C. ¹ H-NMR (CDCl ₃ , δ ppm): 1.06 (3H, d, J = 6.4 Hz), 2.6
1 (2H, brt, J = 5.7Hz), 3.00 (2H, brt, J = 5.7Hz), 3.0
5 (1H, dq, J = 8.0, 6.4Hz), 3.3 to 3.5 (3H, br), 5.61
(1H, dd, J = 15.9,8.0Hz), 6.19 (1H, d, J = 15.9Hz),
6.75 (2H, brd, J = 8.5Hz), 7.10 (2H, brd, J = 8.5Hz),
7.65 (1H, dt, J = 8.3,7.3Hz), 8.16 (1H, brd, J = 8.3H
z), 8.40-8.46 (2H, m), 8.59 (1H, d, J = 6.1Hz), 9.
Example 19 (n = 3, Ary1 = phenyl) N- [3- (α-methylcinnamylamino) propyl] 32 (1H, d, J = 1.0 Hz)
-5-isoquinolinesulfonic acid amide colorless amorphous ¹ H-NMR (CDCl ₃ , δ ppm): 1.27 (3H, d, J = 6.6 Hz), 1.5
0 to 1.60 (2H, m), 1.6 to 2.5 (2H, br), 2.60 to 2.67 (2
H, m), 3.01 ~ 3.09 (2H, m), 3.24 (1H, dq, J = 7.8,6.6H
z), 5.91 (1H, dd, J = 15.9,7.8Hz), 6.40 (1H, d, J = 1
5.9Hz), 7.30 (5H, m), 7.68 (1H, dd, J = 8.0,7.3H)
z), 8.18 (1H, brd, J = 8.0Hz), 8.43 (1H, dd, J = 7.3,
1.2Hz), 8.47 (1H, d, J = 6.1Hz), 8.67 (1H, d, J = 6.1H)
z), 9.36 (1H, d, J = 1.0Hz) Manufacturing method (b) General formula Example 20 (n = 2, m = 1, Ary1 = 4-chlorophenyl) N- [2- (4-chlorocinnamylamino) ethyl]-
5-Isoquinolinesulfonic acid amide N- (2-aminoethyl) -5-isoquinolinesulfonic acid amide (2.01 g) was dissolved in methanol (30 ml), parachlorocinnamaldehyde (1.60 g) was added, the mixture was stirred at room temperature for 1 hour, and then cooled with ice water. Underneath, 350 mg of sodium tetrahydrideborate was added in several portions and stirred for 30 minutes. Ethyl acetate was added to the reaction solution, and the mixture was washed three times with water and twice with a saturated saline solution and dried over anhydrous magnesium sulfate. After the mixture was filtered, the solvent was distilled off under reduced pressure. The residue was separated and purified on a silica gel column (silica gel 80 g, developing solvent: 5% methanol / chloroform), and washed with benzene-hexane (1: 1). This gave 2.30 g of the desired product as colorless crystals.

Melting point: 120-123 ° C ¹ H-NMR (CDCl ₃ , δ ppm): 1.8-3.5 (2H, br), 2.64-
2.70 (2H, m), 2.97-3.03 (2H, m), 3.14 (2H, dd, J =
6.1, 1.2Hz), 6.00 (1H, dt, J = 15.9, 6.1Hz), 6.32 (1
H, d, J = 15.9Hz), 7.21 (2H, dd, J = 8.8,2.4Hz), 7.28
(2H, dd, J = 8.8,2.4Hz), 7.69 (1H, dd, J = 8.3,7.4H)
z), 8.19 (1H, dd, J = 8.3,1.0Hz), 8.42-8.47 (2H,
m), 8.69 (1H, d, J = 6.1 Hz), 9.34 (1H, d, J = 1.0 Hz) The following compound was obtained by the same method (production method b).

Example 21 (n = 2, m = 1, Ary1 = phenyl) N- (2-cinnamylaminoethyl) -5-isoquinolinesulfonic acid amide colorless amorphous ¹ H-NMR (CDCl ₃ , δ ppm): 1.8 to 2.8 (2H, br), 2.64 ~
2.69 (2H, m), 2.97-3.03 (2H, m), 3.14 (1H, dd, J =
6.3,1.2Hz), 6.02 (1H, dt, J = 15.9,6.3Hz), 6.46 (1
H, dt, J = 15.9,1.2Hz), 7.30 (5H, s), 7.68 (1H, dd, J
= 8.1,7.3Hz), 8.18 (1H, dt, J = 8.1,1.0Hz), 8.42 ~
8.48 (2H, m), 8.70 (1H, d, J = 6.1Hz), 9.34 (1H, d, J
= 1.0 Hz) Example 22 (n = 2, m = 1, Ary1 = 4-dimethylaminophenyl) N- [2- (4-dimethylaminocinnamylamino) ethyl] -5-isoquinolinesulfonic acid amide colorless amorphous ¹ H-NMR (CDCl ₃ , δ ppm): 2.65 (2H, brs), 2.70 (2H, d
d, J = 6.1,4.9Hz), 2.96 (6H, s), 3.02 (2H, dd, J = 6.
1,4.9Hz), 3.14 (2H, dd, J = 6.6,1.0Hz), 5.81 (1H, d
t, J = 15.9,6.5Hz), 6.27 (1H, brd, J = 15.9Hz), 6.66
(2H, brd, J = 8.8Hz), 7.20 (2H, brd, J = 8.8Hz), 7.68
(1H, dd, J = 8.0,7.5Hz), 8.18 (1H, dt, J = 8.0,1.0H
z), 8.44 (1H, d, J = 6.0Hz and 1H, d, J = 7.5Hz), 8.71
(1H, d, J = 6.0 Hz), 9.34 (1H, d, J = 1.0 Hz) Example 23 (n = 2, m = 1, Ary1 = 4-fluorophenyl) N- [2- (4-fluoro Cinnamylamino) ethyl
-5-isoquinolinesulfonic acid amide colorless amorphous ¹ H-NMR (CDCl ₃ , δ ppm): 1.5 to 2.5 (2H, br), 2.63 to
2.69 (2H, m), 2.97 to 3.02 (2H, m), 3.12 (2H, dd, J =
6.1, 1.2Hz), 5.94 (1H, dt, J = 15.9, 6.1Hz), 6.33 (1
H, d, J = 15.9Hz), 7.00 (2H, ddd, J = 8.6,8.6,2.2Hz),
7.27 (2H, dd, J = 8.6,5.3,2.2Hz), 7.69 (1H, dd, J = 8.
2,7.6Hz), 8.19 (1H, brd, J = 8.2Hz), 8.42 to 8.48 (2
H, m), 8.70 (1H, d, J = 6.1Hz), 9.35 (1H, d, J = 1.0H)
z) Example 24 (n = 2, m = 1, Ary1 = 4-bromophenyl) N- [2- (4-bromocinnamylamino) ethyl]-
5-isoquinolinesulfonic acid amide colorless crystal Melting point: 124-127 ° C ¹ H-NMR (CDCl ₃ , δ ppm): 2.0-3.5 (2H, br), 2.64-
2.69 (2H, m), 2.97-3.03 (2H, m), 3.13 (2H, dd, J =
6.1,1.0Hz), 6.01 (1H, dt, J = 15.9,6.3Hz), 6.30 (1
H, d, J = 15.9Hz), 7.14 (2H, dm, J = 8.6Hz), 7.41 (2H,
dm, J = 8.6Hz), 7.68 (1H, dd, J = 8.3,7.5Hz), 8.18 (1
H, brd, J = 8.3Hz), 8.43-8.47 (2H, m), 8.68 (1H, d, J
= 6.1 Hz), 9.34 (1H, d, J = 1.0 Hz) Example 25 (n = 2, m = 1, Ary1 = 4-isopropylphenyl) N- [2- (4-isopropylcinnamylamino) ethyl] -5-isoquinolinesulfonic acid amide colorless amorphous ¹ H-NMR (CDCl ₃ , δ ppm): 1.24 (6H, d, J = 7.1 Hz), 2.0
-2.3 (2H, br), 2.63-2.69 (1H, m), 2.87 (1H, q, J =
7.1Hz), 2.97 ~ 3.03 (2H, m), 3.13 (1H, dd, J = 6.3,1.
2Hz), 5.97 (1H, dt, J = 15.9,6.3Hz), 6.33 (1H, brd, J
= 15.9Hz), 7.16 (2H, dm, J = 8.3Hz), 7.23 (2H, dm, J
= 8.3Hz), 7.67 (1H, dd, J = 8.3,7.3Hz), 8.17 (1H, d,
J = 8.3Hz), 8.43-8.47 (2H, m), 8.69 (1H, d, J = 6.1H)
z), 9.34 (1H, d, J = 1.0 Hz) Example 26 (n = 2, m = 1, Ary1 = 4-methoxyphenyl) N- [2- (4-methoxycinnamylamino) ethyl]
-5-isoquinolinesulfonic acid amide colorless crystal Melting point: 92-95 ° C ¹ H-NMR (CDCl ₃ , δ ppm): 2.0-3.0 (2H, br), 2.63-
2.69 (2H, m), 2.97-3.06 (2H, m), 3.11 (2H, dd, J =
6.3,1.2Hz), 3.81 (3H, s), 5.88 (1H, dt, J = 15.9,6.3
Hz), 6.30 (1H, d, J = 15.9Hz), 6.84 (2H, dm, J = 8.8H)
z), 7.23 (2H, dm, J = 8.8Hz), 7.68 (1H, dd, J = 8.3,7.
5Hz), 8.19 (1H, brd, J = 8.3Hz), 8.42-8.47 (2H,
m), 8.69 (1H, d, J = 6.1 Hz), 9.34 (1H, d, J = 1.0 Hz) Example 27 (n = 2, m = 1, Ary1 = 4-trifluoromethylphenyl) N- [ 2- (4-trifluoromethylcinnamylamino) ethyl] -5-isoquinolinesulfonic acid amide colorless amorphous ¹ H-NMR (CDCl ₃ , δ ppm): 1.5 to 2.5 (2H, br), 2.66 to
2.72 (2H, m), 2.98 to 3.04 (2H, m), 3.19 (2H, dd, J =
6.1,1.2Hz), 6.14 (1H, dt, J = 15.9,6.1Hz), 6.41 (1
H, d, J = 15.9Hz), 7.39 (2H, brd, J = 8.3Hz), 7.56 (2
H, brd, J = 8.3Hz), 7.69 (1H, dd, J = 8.3,7.3Hz), 8.20
(1H, brd, J = 8.3Hz), 8.42-8.48 (2H, m), 8.70 (1H,
d, J = 6.1 Hz), 9.35 (1H, d, J = 1.0 Hz) Example 28 (n = 2, m = 2, Ary1 = 4-trifluoromethylphenyl) N- [2- [5- (4 -Trifluoromethylphenyl)
−2,4-pentadienylamino] ethyl] -5-isoquinolinesulfonic acid amide pale yellow amorphous ¹ H-NMR (CDCl ₃ , δ ppm): 1.0 to 2.5 (2H, br), 2.61 to
2.67 (2H, m), 2.96 to 3.05 (2H, m), 3.08 (2H, dd, J =
6.3,1.0Hz), 5.69 (1H, dt, J = 15.0,6.3Hz), 6.19 (1
H, dd, J = 15.0,10.0Hz), 6.48 (1H, d, J = 15.7Hz), 6.7
5 (1H, dd, J = 15.7,10.0Hz), 7.47 (2H, brd, J = 8.3H
z), 7.57 (2H, brd, J = 8.3Hz), 7.72 (1H, dd, J = 8.3,
7.3Hz), 8.20 (1H, dt, J = 8.3,1.0Hz), 8.43 to 8.48 (2
H, m), 8.72 (1H, d, J = 6.1Hz), 9.36 (1H, d, J = 1.0H)
z) Example 29 (n = 2, m = 3, Ary1 = 4-trifluoromethylphenyl) N- [2- [7- (4-trifluoromethylphenyl)
2,4,6 hept trienyl amino] ethyl] -5-isoquinoline sulfonamide pale yellow MuAkirakarada _{^{1 H-NMR (CDCl 3,}} δppm): 2.0~3.5 (2H, br), 2.61~
2.67 (2H, m), 2.95 to 3.01 (2H, m), 3.07 (2H, dd, J =
6.3,1.0Hz), 5.59 (1H, dt, J = 14.6,6.3Hz), 6.05-6.
22 (1H, m), 6.29-6.34 (2H, m), 6.55 (1H, d, J = 15.6
Hz), 6.81-6.93 (1H, m), 7.47 (2H, brd, J = 8.3H
z), 7.55 (2H, brd, J = 8.3Hz), 7.71 (1H, dd, J = 8.3,
7.3Hz), 8.21 (1H, brd, J = 8.3Hz), 8.43-8.48 (2H,
m), 8.72 (1H, d, J = 6.1 Hz), 9.37 (1H, d, J = 1.0 Hz) Example 30 [n = 2, m = 1, Ary1 = 4- (2-methoxyethoxy) methoxyphenyl of N- [2- [4- (2-methoxyethoxy) methoxy cinnamyl amino] ethyl] -5-isoquinoline sulfonamide colorless MuAkirakarada _{^{1 H-NMR (CDCl 3,}} δppm): 1.8~2.7 (2H, br ), 2.63-
2.69 (2H, m), 2.96 to 3.02 (2H, m), 3.11 (2H, dd, J =
6.4, 1.2Hz), 3.37 (3H, s), 3.53-3.58 (2H, m), 3.8
0 to 3.85 (2H, m), 5.27 (2H, s), 5.90 (1H, dt, J = 15.
9,6.4Hz), 6.30 (1H, d, J = 15.9Hz), 6.99 (2H, dm, J =
8.8Hz), 7.23 (2H, dm, J = 8.8Hz), 7.68 (1H, dd, J = 8.
3,7.3Hz), 8.19 (1H, dt, J = 8.3,1.0Hz), 8.42 to 8.47
(2H, m), 8.70 (1H, d, J = 6.1Hz), 9.34 (1H, d, J = 1.0
Hz) Example 31 [n = 2, m = 1, Ary1 = 4-hydroxyphenyl) N- [2- (4-hydroxycinnamylamino) ethyl] -5-isoquinolinesulfonic acid colorless crystal Melting point: 156-159 ^{℃ 1 H-NMR (DMSO-} d 6, δppm): 2.44 (2H, brt, J = 6.3H
z), 2.88 (2H, brt, J = 6.3Hz), 3.01 (2H, brt, J = 6.1H)
z), 3.39 (3H, br), 5.83 (1H, dt, J = 15.9,6.1Hz),
6.20 (1H, d, J = 15.9Hz), 6.70 (2H, brt, J = 8.3Hz),
7.14 (2H, brt, J = 8.3Hz), 7.81 (1H, t, J = 7.8Hz), 8.
34-8.46 (3H, m), 8.68 (1H, d, J = 6.1Hz), 9.46 (1H,
d, J = 1.0 Hz) Example 32 (n = 2, m = 1, Ary1 = 1-naphthyl) N- [2- [3- (1-naphthyl) -2-propenylamino] ethyl] -5-isoquinoline Sulfonamide colorless crystals Melting point: 135-138 ° C ¹ H-NMR (CDCl ₃ , δ ppm): 1.5-4.0 (2H, br), 2.68-
2.73 (2H, m), 3.01 to 3.06 (2H, m), 3.26 (1H, dd, J =
6.3,1.5Hz), 6.00 (1H, dt, J = 15.6,6.3Hz), 7.10 (1
H, d, J = 15.6Hz), 7.43-7.51 (4H, m), 7.61 (1H, dt, J
= 8.3,7.3Hz), 7.78 (1H, dd, J = 7.1,2.7Hz), 7.83 ~
7.89 (1H, m), 7.97 to 8.02 (1H, m), 8.07 (1H, brd, J =
8.3Hz), 8.44 (1H, dd, J = 7.3,1.0Hz), 8.44 (1H, d, J
= 6.1Hz), 8.68 (1H, d, J = 6.1Hz), 9.27 (1H, d, J = 1.
Example 33 (n = 2, m = 1, Ary1 = 3,4,5-trimethoxyphenyl) N- [2- (3,4,5-trimethoxycinnamylamino)
Ethyl] -5-isoquinolinesulfonic acid amide colorless amorphous ¹ H-NMR (CDCl ₃ , δ ppm): 1.5 to 2.6 (2H, br), 2.65 to
2.71 (2H, m), 2.97 to 3.03 (2H, m), 3.15 (2H, dd, J =
6.3,1.2Hz), 3.85 (3H, s), 3.88 (6H, s), 5.97 (1H,
dt, J = 15.6,6.3Hz), 6.31 (1H, d, J = 15.9Hz), 6.55
(2H, s), 7.69 (1H, dd, J = 8.3,7.5Hz), 8.20 (1H, br
d, J = 8.3Hz), 8.43 (1H, brd, J = 6.1Hz), 8.46 (1H, d
d, J = 7.5,1.2Hz), 8.70 (1H, d, J = 6.1Hz), 9.35 (1H,
d, J = 1.0 Hz) Example 34 (n = 2, m = 1, Ary1 = 4-methoxycarbonylphenyl) N- [2- (4-carbomethoxycinnamylamino) ethyl] -5-isoquinolinesulfonic acid amide Colorless crystals Melting point: 110-113 ° C ¹ H-NMR (CDCl ₃ , δ ppm): 1.2-2.0 (2H, br), 2.65-
2.70 (2H, m), 2.97 to 3.02 (2H, m), 3.17 (2H, dd, J =
5.9,1.2Hz), 3.92 (3H, s), 6.15 (1H, dt, J = 15.9,5.9
Hz), 6.41 (1H, d, J = 15.9Hz), 7.36 (2H, dm, J = 8.3H)
z), 7.69 (1H, dd, J = 8.3,7.3Hz), 7.98 (2H, dm, J = 8.
3Hz), 8.19 (1H, brd, J = 8.3Hz), 8.43 (1H, brd, J = 6.
1Hz), 8.46 (1H, dd, J = 7.3,1.5Hz), 8.71 (1H, d, J =
6.1 Hz), 9.35 (1H, d, J = 1.0 Hz) Example 35 (n = 2, m = 1, Ary1 = 4-carboxyphenyl) N- [2- (4-carboxycinnamylamino) ethyl]- 5-isoquinolinesulfonic acid amide colorless crystal Melting point: 239 to 240 ° C (decomposition) ¹ H-NMR (DMSO-d ₆ , δ ppm): 2.49 (2H, brt, J = 6.3H)
z), 2.91 (2H, brt, J = 6.3Hz), 3.13 (2H, brd, J = 5.7H)
z), 3.0-4.0 (3H, br), 6.24 (1H, dt, J = 16.1,5.7H
z), 6.44 (1H, d, J = 16.1Hz), 7.44 (2H, brd, J = 8.3H)
z), 7.82 (1H, dd, J = 8.3,7.3Hz), 7.88 (2H, brd, J =
8.3Hz), 8.36 (1H, dd, J = 7.3,1.2Hz), 8.42 (1H, brd,
J = 8.3Hz), 8.44 (1H, brd, J = 6.1Hz), 8.69 (1H, d, J
Example 36 (n = 3, m = 1, Ary1 = phenyl) N- (3-cinnamylaminopropyl) -5-isoquinolinesulfonic acid amide colorless = 6.1 Hz), 9.46 (1H, d, J = 1.0 Hz) Amorphous ¹ H-NMR (CDCl ₃ , δ ppm): 1.5 to 2.2 (2H, br), 1.59 (2
H, tt, J = 5.6,5.6Hz), 2.66 (2H, t, J = 5.6Hz), 3.06
(2H, t, J = 5.6Hz), 3.30 (2H, dd, J = 6.1,1.5Hz), 6.2
1 (1H, dt, J = 15.9,6.1Hz), 6.52 (1H, d, J = 15.9Hz),
7.21 to 7.40 (5H, m), 7.67 (1H, dd, J = 8.3,7.5Hz), 8.
18 (1H, d, J = 8.3Hz), 8.43 (1H, dd, J = 7.5,1.2Hz),
8.44 (1H, d, J = 6.1Hz), 8.63 (1H, d, J = 6.1Hz), 9.35
(1H, d, J = 1.0 Hz) Example 37 N- [2- [3- (4-chlorophenyl) -2-propynylamino] ethyl] -5-isoquinolinesulfonic acid amide (Compound 37-I) N- [ 2- [bis- (3- (4-chlorophenyl) -2
-Propynyl) amino] ethyl] -5-isoquinolinesulfonic acid amide (compound 37-II) N- [3- (4-chlorophenyl) -2-propynyl]
-N- [2- (p-chlorophenyl) -2-propynylamino] ethyl] -5-isoquinolinesulfonic acid amide (compound 37-III) 1.90 g of N- (2-aminoethyl) -5-isoquinolinesulfonic acid amide and 1.39 g of 3-parachlorophenyl-2-propynyl chloride were dissolved in 10 ml of dimethylformamide, and 1.38 g of anhydrous potassium carbonate was added. Stirred for hours. Pour the reaction mixture into 100 ml of ethyl acetate and add 3
The extract was washed twice with saturated saline twice, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was separated and purified on a silica gel column (silica gel 100 g, developing solvent: 5% methanol / chloroform), and each was crystallized from a mixture of ether and hexane to give 855 mg of compound 37-I as colorless crystals, each of which was colorless. Amorphous
220 mg of compound 37-II and 214 mg of compound 37-III were obtained.
(Compound 37-I) Colorless crystals Melting point: 120-123 ° C. ¹ H-NMR (CDCl ₃ , δ ppm): 1.30-1.80 (2H, br), 2.74
~ 2.80 (2H, m), 3.00 ~ 3.05 (2H, m), 3.39 (1H, s),
7.26 (4H, s), 7.69 (1H, dd, J = 8.3,7.3Hz), 8.20 (1
H, dt, J = 8.3,1.0Hz), 8.42 (1H, dt, J = 6.1,1.0Hz),
8.46 (1H, dd, J = 7.3,1.2Hz), 8.70 (1H, d, J = 6.1H)
z), 9.36 (1H, d, J = 1.0 Hz) (Compound 37-II) colorless amorphous ¹ H-NMR (CDCl ₃ , δ ppm): 2.69 to 2.74 (2H, m), 3.01 to
3.09 (2H, m), 3.43 (4H, s), 5.48 (1H, t, J = 5.0H
z), 7.27 (4H, dm, J = 9.0Hz), 7.30 (4H, dm, J = 9.0H)
z), 7.68 (1H, dd, J = 8.3,7.3Hz), 8.20 (1H, brd, J =
8.3Hz), 8.42 (1H, brd, J = 6.1Hz), 8.47 (1H, dd, J =
7.3, 1.2Hz), 8.66 (1H, d, J = 6.1Hz), 9.35 (1H, d, J =
1.0 Hz) (Compound 37-III) colorless amorphous ¹ H-NMR (CDCl ₃ , δ ppm): 1.58 (1 H, br), 3.02 (2 H, t,
J = 6.0Hz), 3.55 (2H, t, J = 6.0Hz), 3.64 (2H, s),
4.50 (2H, s), 6.81 (2H, dm, J = 8.8Hz), 7.15 (2H, dm,
J = 8.8Hz), 7.27 (2H, dm, J = 9.0Hz), 7.31 (2H, dm, J
= 9.0Hz), 7.66 (1H, dd, J = 8.3,7.3Hz), 8.13 (1H, br
d, J = 8.3Hz), 8.48 (1H, dd, J = 7.3,1.2Hz), 8.57 (1
H, brd, J = 6.1Hz), 8.69 (1H, d, J = 6.1Hz), 9.26 (1H,
d, J = 1.0 Hz) Example 38 N- [2- (4-Chloro-N-methylcinnamylamino) ethyl] -5-isoquinolinesulfonic acid amide 1.50 g of the product of Example 20 was dissolved in 10 ml of chloroform, 3 ml of methyl iodide was added at room temperature, and the mixture was stirred for 40 minutes.
Immediately, excess methyl iodide is distilled off under reduced pressure, and the residue is separated and purified on a silica gel column (silica gel 50 g, developing solvent: 5% methanol / chloroform) to give a colorless amorphous target substance.
0 mg was obtained. ¹ H-NMR (CDCl ₃ , δ ppm): 1.4 to 2.1 (1 H, br), 1.95 (3
H, s), 2.37 (2H, t, J = 5.5Hz), 2.92 to 3.00 (3H, m),
5.97 (1H, dt, J = 15.9,6.6Hz), 6.34 (1H, d, J = 15.9H
z), 7.25 (2H, dm, J = 8.8Hz), 7.28 (2H, dm, J = 8.8H)
z), 7.68 (1H, dd, J = 8.3,7.8Hz), 8.19 (1H, brd, J =
8.3Hz), 8.44 (1H, brd, J = 6.1Hz), 8.45 (1H, dd, J =
7.8,1.5Hz), 8.69 (1H, d, J = 6.1Hz), 9.34 (1H, d, J =
1.0 Hz) Example 39 (Reference Example) 1- (4-chlorocinnamyl) -4- (5-isoquinoline sulfonyl) piperazine 1.31 g of the product of Example 20 was dissolved in 3 ml of dimethylformamide, 644 mg of 1,2-dibromoethane and 1.13 g of anhydrous potassium carbonate were added at room temperature, and the mixture was stirred for 24 hours. Ethyl acetate 1
After adding 00 ml, the ethyl acetate layer was successively washed twice with water and saturated saline, and dried over anhydrous magnesium sulfate.
After the mixture was filtered, the solvent was distilled off under reduced pressure, and the residue was separated and purified using a silica gel column (silica gel 50 g, eluent: 5% methanol / chloroform) to recover the residual raw material and at the same time to recover the colorless amorphous substance. 356 mg were obtained. ¹ H-NMR (CDCl ₃ , δ ppm): 2.53 (4H, brt, J = 4.9 Hz),
3.10 (2H, dd, J = 6.6,1.2Hz), 3.20 (4H, brt, J = 4.9H
z), 6.07 (1H, dt, J = 15.9,6.6Hz), 6.43 (1H, d, J = 1
5.9Hz), 7.24 (4H, s), 7.72 (1H, dd, J = 8.1,7.3H)
z), 8.22 (1H, brd, J = 8.1Hz), 8.37 (1H, dd, J = 7.3,
1.2Hz), 8.55 (1H, brd, J = 6.1Hz), 8.68 (1H, d, J = 6.
Example 1 N-ethyl-N- [2- (4-chloro-N-ethylcinnamylamino) ethyl] -5-isoquinolinesulfonic acid amide (1 Hz), 9.34 (1H, d, J = 1.0 Hz) The same procedure as in Example 39 was repeated, except that 1.34 g of the product of Example 20 was replaced with 2.14 g of ethyl iodide as the N-alkylating agent, to give 720 mg of the target compound as a colorless amorphous substance. ¹ H-NMR (CDCl ₃ , δ ppm): 0.99 (3H, t, J = 7.1 Hz), 1.0
5 (3H, t, J = 7.1 Hz), 2.53 (2H, q, J = 7.1 Hz), 2.61 (2
H, t, J = 7.8Hz), 3.19 (2H, dd, J = 6.5,1.2Hz), 3.33 ~
3.43 (4H, m), 6.12 (1H, dt, J = 15.9,6.5Hz), 6.32 (1
H, d, J = 15.9Hz), 7.26 (4H, s), 7.62 (1H, dd, J = 8.1,
7.3Hz), 8.14 (1H, dd, J = 8.1Hz), 8.35 (1H, dd, J = 7.
3,1.2Hz), 8.42 (1H, brd, J = 6.1Hz), 8.66 (1H, d, J =
6.11), 9.31 (1H, d, J = 1.0 Hz) Example 41 N- [2- (4-Chloro-N-formylcinnamylamino) ethyl] -5-isoquinolinesulfonic acid amide 3 ml of acetic anhydride was added to 3 ml of formic acid, and the mixture was stirred at room temperature, and 1.41 g of the product of Example 20 was added thereto and stirred for 1 hour. The reaction solution was added to 50 ml of ethyl acetate to which ice was added and 30 ml of saturated sodium carbonate water and stirred. After the foaming was stopped, the ethyl acetate layer was washed twice with water and once with saturated saline, and then dried. It was dried over magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to a silica gel column (silica gel 60).
g, developing solvent: 2% methanol / chloroform) to obtain a mixture of two types of isomers (3: 2) as a colorless amorphous target of 1.49 g. ¹ H-NMR (CDCl ₃ , δ ppm): 3.07 to 3.16 (2H, m), 3.39 to
3.47 (2H, m), 3.90 (0.6 × 2H, dd, J = 6.3,1.0Hz), 4.0
3 (0.4 × 2H, dd, J = 6.3,1.0Hz), 5.93 (0.6H, dt, J = 15.
9,6.3Hz), 6.01 (0.4H, dt, J = 15.9,6.3Hz), 6.04 (0.
4H, d, J = 15.9Hz), 6.44 (0.6H, d, J = 15.9Hz), 7.20
(0.6 × 2H, d, J = 8.8Hz), 7.21 (0.4 × 2H, d, J = 8.8H)
z), 7.26 (0.6 × 2H, d, J = 8.8Hz), 7.27 (0.4 × 2H, d, J
= 8.8Hz), 7.61 (0.6H, dd, J = 8.0,7.6Hz), 7.64 (0.4
H, dd, J = 8.0,7.6Hz), 8.05 (0.6H, s), 8.09 (0.4H,
s), 8.16 (0.6H, brd, J = 8.0Hz), 8.17 (0.4H, brd, J =
8.0Hz), 8.33-8.42 (2H, m), 8.60 (0.4H, d, J = 6.1H)
z), 8.65 (0.6H, d, J = 6.1Hz), 9.33 (1H, d, J = 1.0H)
z) Example 42 N- {2- [4-Chloro-N- (4-hydroxybenzyl) cinnamylamino] ethyl} -5-isoquinolinesulfonic acid amide 0.2 g of the product of Example 20, p-hydroxybenzaldehyde 0.13 g was dissolved in 10 ml of methanol, and while stirring, 60 mg of sodium cyanoborohydride and 2 drops of acetic acid were added, followed by stirring at room temperature for 2 days. The reaction solution was concentrated under reduced pressure, and saturated saline was added. The mixture was extracted three times with 20 ml of ethyl acetate. The combined extracts were washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to a silica gel column (silica gel 10 g, elution solvent: 2% methanol /
Separation and purification with chloroform) to give the target compound as a colorless amorphous 15
0 mg was obtained. ¹ H-NMR (CDCl ₃ , δ ppm): 2.50 (2H, brt), 2.90 (2H, b
rt), 3.10 (2H, d, J = 6.6Hz), 3.35 (2H, s), 6.06 (1
H, dt, J = 15.6,6.6Hz), 6.35 (1H, d, J = 15.9Hz), 6.75
(2H, d, J = 8.5Hz), 6.97 (2H, d, J = 8.5Hz), 7.30 (4
H, s), 7.65 (1H, t, J = 8.0Hz), 8.15 (1H, d, J = 8.0H)
z), 8.37-8.41 (2H, m), 8.63 (1H, d, J = 6.0Hz), 9.
32 (1H, s) Example 43 2-methyl-5-{[2- (4-chloro-N, N-dimethylcinnamylammonio) ethyl] aminosulfonyl}
Isoquinolium diiodide 83 mg of the product of Example 20 in dimethylformamide 2.0 ml
And 1.0 ml of methyl iodide was added thereto, followed by stirring at room temperature for 4 hours. After distilling off excess methyl iodide and dimethylformamide under reduced pressure, methanol: chloroform (1: 1) is used.
Crystallization was carried out using 5 ml of the mixture of 5). The obtained crude crystals were recrystallized from 10 ml of a mixture of methanol and chloroform (1: 5) to obtain 78 mg of the desired product as pale yellow crystals. Melting point: 199-200 ° C. ¹ H-NMR (DMSO-d ₆ , δ ppm) : 3.09 (6H, s), 3.43 (4H,
brs), 4.16 (2H, d, J = 7.0Hz), 4.53 (3H, s), 6.48
(1H, dt, J = 15.9,7.0Hz), 6.89 (1H, d, J = 15.9Hz),
7.58 (2H, dm, J = 9.4Hz), 7.61 (2H, dm, J = 9.4Hz), 8.
21 (1H, t, J = 7.9Hz), 8.72 to 8.78 (2H, m), 8.90 to 8.9
9 (3H, m), 10.22 (1H, brs) Example 44 2-Methyl-5- {N-methyl-N- [2- (4-chloro-N, N-dimethylcinnamylammonio) ethyl] amino 83 mg of the product of Sulfonyl diisoquinolium diiodide Example 20 in 2.0 ml of dimethylformamide
Dissolved in methyl iodide 1.0 ml and anhydrous sodium carbonate 8
3 mg was added and the mixture was stirred at room temperature for 4 hours. After distilling off excess methyl iodide and dimethylformamide under reduced pressure, 10 ml of a mixed solution of methanol: chloroform (1: 5) was added and the mixture was stirred, and the resulting insolubles were collected by filtration. After concentrating the filtrate under reduced pressure, methanol: chloroform: further performed two times operation of collected by filtration to stirring caused insolubles with mixture 10ml of (1 5), the desired product was obtained 145mg of yellow MuAkirakarada ¹ H-NMR (DMSO-d ₆ , δ ppm): 2.97 (3H, s), 3.15 (6H,
s), 3.60-3.70 (2H, m), 3.70-3.80 (2H, m), 4.21
(2H, d, J = 7.3Hz), 4.54 (3H, s), 6.54 (1H, dt, J = 1
5.6,7.3Hz), 6.93 (1H, d, J = 15.6Hz), 7.48 (2H, brd,
J = 8.5Hz), 7.63 (2H, brd, J = 8.5Hz), 8.23 (1H, t, J
= 7.9Hz), 8.75 to 8.85 (3H, m), 8.99 (1H, d, J = 7.1H)
z), 10.22 (1H, brs) Other isoquinoline compounds other than Example 20 were reacted with an excess amount of methyl iodide in dimethylformamide, which is the same operation as in this example, to thereby reduce the nitrogen atom in the isoquinoline ring. As a result, a quaternary methylated compound was obtained.

Example 45 N- [2- (4-chlorocinnamylamino) ethyl]-
5-Isoquinolinesulfonic acid amide dihydrochloride 2.00 g of the product of Example 20 was suspended in 20 ml of methanol, and 1 ml of concentrated hydrochloric acid was added to obtain a clear solution. The crystals are collected by filtration, and methanol
Recrystallized from a mixture of 20ml and 30ml of water to give colorless crystalline dihydrochloride
1.65 g was obtained.

Melting point: 205-208 ° C ¹ H-NMR (DMSO-d ₆ , δ ppm): 2.90 to 3.05 (2H, m), 3.1
0 to 3.20 (2H, m), 3.65 to 3.75 (2H, m), 4.3 to 4.9 (b
r), 6.33 (1H, dt, J = 16.1, 7.1 Hz), 6.76 (1H, d, J = 1
6.1Hz), 7.45 (4H, s), 8.00 (1H, dd, J = 8.3,7.5H)
z), 8.54 (1H, dd, J = 7.5,1.2Hz), 8.64 (1H, brd, J =
8.3Hz), 8.71 (1H, brd, J = 6.4Hz), 8.80 (1H, br),
8.82 (1H, d, J = 6.4Hz), 9.39 (1H, br), 9.79 (1H, br
s) Example 46 N- [2- (α-methylcinnamylamino) ethyl]-
5-Isoquinolinesulfonic acid amide dihydrochloride The same procedure as in Example 42 was carried out except using the product of Example 2, to obtain a dihydrochloride of colorless crystals.

Melting point: 80-85 ° C. ¹ H-NMR (DMSO-d ₆ , δ ppm): 1.40 (2H, d, J = 6.5 Hz),
2.89 (2H, m), 3.16 (2H, brt, J = 6.5Hz), 3.19 (1H,
m), 5.0-6.0 (br), 6.19 (1H, dd, J = 16.1,7.5Hz),
6.71 (1H, d, J = 16.1Hz), 7.39 (5H, m), 7.97 (1H, dd,
J = 8.0,7.6Hz), 8.51-8.82 (5H, m), 9.44 (2H, b
r), 9.76 (1H, d, J = 1.0 Hz) Example 47 N- [2- (4-chloro-α-methylcinnamylamino) ethyl] -5-isoquinolinesulfonic acid amide dihydrochloride Example 1 The same procedure as in Example 42 was carried out, except that the product of the above formula was used to obtain a dihydrochloride as a colorless and hygroscopic powder. ¹ H-NMR (DMSO-d ₆ , δ ppm): 1.40 (3H, d, J = 6.5 Hz),
2.85 to 3.96 (2H, m), 3.10 to 3.20 (2H, m), 3.80 to 4.00
(1H, m), 5.1-6.1 (br), 6.23 (1H, dd, J = 15.9,8.5H
z), 6.72 (1H, d, J = 15.9 Hz), 7.44 (4H, s), 7.99 (1
H, dd, J = 8.2,7.4Hz), 8.54 (1H, dd, J = 7.4,1.2Hz),
8.64 (1H, brd, J = 8.2Hz), 8.72 (1H, brd, J = 6.4Hz),
8.80 (1H, br), 8.82 (1H, d, J = 6.4Hz), 9.48 (2H, br
s), 9.80 (1H, brs) Example 48 N- [2- (4-bromocinnamylamino) ethyl]-
5-Isoquinolinesulfonic acid amide dihydrochloride The same procedure as in Example 42 was carried out except using the product of Example 24, to obtain colorless crystals of the dihydrochloride.

Melting point: 195-200 ° C ¹ H-NMR (DMSO-d ₆ , δ ppm): 2.90-3.10 (2H, brs),
3.2-3.3 (2H, m), 3.65-3.75 (2H, brs), 6.35 (1H, d
t, J = 16.0,7.1Hz), 6.76 (1H, dd, J = 16.0Hz), 7.38
(2H, d, J = 8.5Hz), 7.57 (2H, d, J = 8.5Hz), 8.10 (1
H, t, J = 7.6Hz), 8.67 (1H, d, J = 7.6Hz), 8.78 (1H, d,
J = 7.6Hz), 8.90 (1H, brs), 9.05 (1H, brs), 10.0
(1H, s) Example 49 N- [2-Cinnamylaminoethyl] -5-isoquinolinesulfonic acid amide 1/2 fumarate 303 mg of the product of Example 21 was dissolved in 5 ml of ethyl acetate, and the solution was dissolved at room temperature in fumaric acid. A solution of 89 mg of acid in 2 ml of methanol was added, and the mixture was stirred for 30 minutes.The precipitated crystals were collected by filtration and washed with ethyl acetate to give 1/2 fumarate of the product of Example 21 as colorless crystals.
12 mg were obtained.

Melting point: 153 to 156 ° C. ¹ H-NMR (DMSO-d ₆ , δ ppm): 2.69 (2H, brt, J = 6.3 H)
z), 3.00 (2H, brt, J = 6.3Hz), 3.34 (2H, brd, J = 6.1H)
z), 5.0-8.0 (3H, br), 6.16 (1H, dt, J = 16.0,6.1H
z), 6.51 (1H, d, J = 16.0Hz), 6.54 (1H, s), 7.23-
7.30 (2H, m), 7.34-7.40 (3H, m), 7.82 (1H, dd, J =
8.1,7.5Hz), 8.36 (1H, dd, J = 7.5,1.0Hz), 8.42 (1H,
brd, J = 8.1Hz), 8.44 (1H, brd, J = 6.1Hz), 8.69 (1H,
d, J = 6.1 Hz), 9.47 (1 H, d, J = 1.0 Hz) Example 50 N- [2- (α-methylcinnamylamino) ethyl]-
5-Isoquinolinesulfonic acid amide 1/2 fumarate Except for using the product of Example 2, the same procedure as in Example 46 was carried out to obtain a colorless crystalline 1/2 fumarate.

Melting point: 162-167 ° C ¹ H-NMR (DMSO-d ₆ , δ ppm): 1.02 (3H, d, J = 6.4 Hz),
2.49 (2H, brt, J = 6.6Hz), 2.5-5.7 (3H, br), 2.93
(2H, brt, J = 6.6Hz), 3.17 (1H, dd, J = 7.9,6.4Hz),
5.91 (1H, dd, J = 16.1,7.9Hz), 6.35 (1H, d, J = 16.1H
z), 6.55 (1H, s), 7.32 (5H, m), 7.79 (1H, dd, J = 8.
0,7.3Hz), 8.34 (1H, dd, J = 7.3,1.2Hz), 8.39 (1H, br
d, J = 8.0Hz), 8.43 (1H, brd, J = 6.1Hz), 8.69 (1H, d,
Example 51: N- [2- (4-chloro-α-methylcinnamylamino) ethyl] -5-isoquinolinesulfonic acid amide L
-(+)-Tartrate salt 6.60 g of the product of Example 1 are dissolved in 50 ml of ethyl acetate,
A methanol solution of 2.38 g of L-(+)-tartaric acid was added, and the precipitated crystals were collected by filtration and washed with ethyl acetate. Obtained.

Melting point: 125-130 ° C. ¹ H-NMR (DMSO-d ₆ , δ ppm): 1.14 (3 H, d, J = 6.3 Hz),
2.64 (2H, brt, J = 6.5Hz), 2.98 (2H, brt, J = 6.5Hz),
3.45 (1H, dd, J = 8.0,6.3Hz), 3.5-4.7 (6H, br), 4.1
3 (2H, s), 6.03 (1H, dd, J = 15.9,8.0Hz), 6.49 (1H,
d, J = 15.9Hz), 7.41 (4H, s), 7.81 (1H, dd, J = 8.0,7.
3Hz), 8.36 (1H, brd, J = 8.0Hz), 8.41 (1H, d, J = 6.1H)
z), 8.42 (1H, brd, J = 7.3Hz), 8.69 (1H, d, J = 6.1H)
z), 9.46 (1H, d, J = 1.0 Hz) Example 52 N- (2-aminoethyl) -N- (2-cinnamylaminoethyl) -5-isoquinolinesulfonic acid amide trihydrochloride Example 21 To a solution of 1.10 g of the amorphous substance obtained in 1 above, 1.18 g of triphenylphosphine and 0.73 g of 2- (t-butoxycarbonylamino) ethanol in 15 ml of tetrahydrofuran, 0.78 g of diethylazodicarboxylate and 5% of tetrahydrofuran 5
After the ml solution was added dropwise over 15 minutes under ice-cooling, the mixture was stirred at room temperature for 4 hours. After returning to ice, 0.39 g of triphenylphosphine
After adding 0.20 g of diethyl azodicarboxylate
Was added dropwise and stirred at room temperature for 1 hour. The residue obtained by concentrating the reaction solution under reduced pressure was applied to a silica gel column with chloroform-methanol (19:
From the fraction obtained in 1), 0.99 g of a light orange amorphous substance was obtained. 20 ml of methanol was added and dissolved, 7.7 ml of a 4N hydrochloric acid / ethyl acetate solution was added, and the mixture was stirred at room temperature for 3 hours. Then, methanol was distilled off under reduced pressure, and ethyl acetate was added to solidify, and the solid was collected by filtration. After washing with ethyl acetate and n-hexane, the residue was dried under reduced pressure to obtain 0.97 g of the target product as a colorless hygroscopic powder.

NMR (D ₂ O) δ ppm: 3.2-3.5 (4H, m), 3.7-4.0 (6H,
m), 6.1-6.3 (1H, m), 6.82 (1H, d, J = 15.9Hz), 7.4
4 (5H, s), 8.15 (1H, t, J = 7.6Hz), 8.1 ~ 8.3 (3H,
m), 9.09 (1H, d, J = 7.0 Hz), 9.71 (1H, s) Example 53 N- (4-aminobutyl) -N- [2- (4-chlorocinnamylamino) ethyl] -5 -Isoquinolinesulfonic acid amide trihydrochloride A solution of 0.4 g of the amorphous obtained in Example 20, 0.226 g of 4- (t-butoxycarbonylamino) butanol and 0.445 g of triphenylphosphine in 5 ml of tetrahydrofuran was stirred under ice-cooling with stirring.
A solution of 0.295 g of diethyl azodicarboxylate in 2 ml of tetrahydrofuran was added, and the mixture was allowed to stand at room temperature. The solvent was distilled off under reduced pressure. The residue was applied to a silica gel column and eluted with methanol-chloroform (2:98). 0.28 g of oil
I got This oily substance was dissolved in methanol (1 ml) and 4N hydrochloric acid / ethyl acetate was added. The resulting precipitate was collected by filtration, washed with ethyl acetate, and dried to obtain 0.2 g of the target compound as a colorless powder.

NMR (D ₂ O) δ ppm: 1.70 (4H, brs), 2.95 (2H, m), 3.30
(2H, m), 3.55 (2H, m), 3.77 (2H, m), 3.89 (2H, dd,
J = 7.3Hz), 6.15 (2H, dt, J = 15.8,7.3Hz), 6.76 (1H,
d, J = 15.8Hz), 7.35 (4H, s), 8.11 (1H, t, J = 8.0H)
z), 8.6-8.8 (2H, m), 8.98 (1H, d, J = 7.0Hz), 9.75
(1H, s) Example 54 N- [2- (4-Chloro-N-methylcinnamylamino) ethyl] -N- [2- (4-piperidyl) ethyl]
-5-isoquinolinesulfonic acid amide 0.39 g of the amorphous substance obtained in Example 38, 0.145 g of 4-piperidineethanol and 0.265 g of triphenylphosphine in 5 ml of tetrahydrofuran, a solution of 0.245 g of diethyl azodicarboxylate in tetrahydrofuran under ice-cooling in 2 ml of tetrahydrofuran And add
After stirring at room temperature for 1 hour, tetrahydrofuran was distilled off under reduced pressure, and then 30 ml of ethyl acetate was added.
Extracted three times with l. The extract was made alkaline with sodium bicarbonate, extracted three times with 10 ml of ethyl acetate, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was subjected to alumina chromatography, and the fraction eluted with chloroform containing 1% methanol. 180 mg of the desired product was obtained as a more colorless oil.

NMR (CDCl ₃ ) δ ppm: 0.87 to 1.05 (2H, m), 1.30 to 1.45
(5H, m), 1.85 (1H, brs), 2.21 (3H, s), 2.33 (2H,
m), 2.51 (2H, t, J = 7.6Hz), 2.89 (2H, m), 3.08 (2
H, d, J = 6.6Hz), 3.30 (2H, t, J = 7.8Hz), 3.42 (2H, t,
J = 7.3Hz), 6.09 (1H, dt, J = 15.8,6.6Hz), 6.41 (1H,
d, J = 15.8Hz), 7.26 (4H, s), 7.65 (1H, dd, J = 8.0,8.
6Hz), 8.15 (1H, d, J = 8.0Hz), 8.4 (1H, d, J = 8.6H)
z), 8.40 (1H, d, J = 6.1Hz), 8.67 (1H, d, J = 6.1H)
z), 9.31 (1H, s) The obtained oil was dissolved in methanol (1 ml), 4N hydrochloric acid / ethyl acetate (0.3 ml) was added, and ether (30 ml) was further added to obtain a colorless powdery trihydrochloride.

Example 55 N- [2- (4-Chloro-N-methylcinnamylamino) ethyl] -N- (2-morpholinoethyl) -5-isoquinolinesulfonic acid amide / 3 hydrochloride Amorphous substance obtained in Example 38 To a solution of 1 g, 0.377 g of 2-N-morpholinoethanol and 1.25 g of triphenylphosphine in 5 ml of tetrahydrofuran was added dropwise a solution of 0.835 g of diethylazodicarboxylate in 2 ml of tetrahydrofuran under ice-cooling and stirring, and after stirring for 2 hours, the solvent was evaporated under reduced pressure. The residue obtained by distilling off the residue was added with 20 ml of ethyl acetate and extracted three times with 10 ml of 1N hydrochloric acid. The extract was made alkaline with sodium bicarbonate, extracted three times with 10 ml of ethyl acetate, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. : 9
An oil was obtained from the fraction eluted in 0).

NMR (CDCl ₃ ) δ ppm: 2.18 (3H, s), 2.28 to 2.33 (4H,
m), 2.4-2.6 (4H, m), 3.07 (2H, d, J = 6.6Hz), 3.4
~ 3.6 (8H, m), 6.07 (1H, dt, J = 15.9,6.6Hz), 6.40
(1H, d, J = 15.9Hz), 7.26 (4H, s), 7.63 (1H, dd, J =
8.0, 7.1Hz), 8.14 (1H, d, J = 8.0Hz), 8.42 (1H, d, J =
7.1Hz), 8.42 (1H, d, J = 7.1Hz), 8.42 (1H, d, J = 6.1H)
z), 8.67 (1H, d, J = 6.1 Hz), 9.31 (1H, s) The obtained oil was dissolved in methanol (4 ml), 4N hydrochloric acid / ethyl acetate (2 ml) was added, and the solvent was distilled off under reduced pressure. After removal, the crystals were recrystallized from ethanol to obtain 0.67 g of the target compound as colorless crystals.

MP: 172-6 ° C. NMR (D ₂ O) δ ppm: 3.04 (3H, s), 3.2-3.6 (8H, m), 3.
8-4.1 (10H, m), 6.18 (1H, dt, J = 15.9,7.0Hz), 6.76
(1H, d, J = 15.9Hz), 7.22 (4H, s), 8.09 (1H, dd, J =
7.6,8.2Hz), 8.52 (1H, d, J = 7.6Hz), 8.65 to 8.75 (2
H, m), 8.87 (1H, d, J = 7.0 Hz), 9.74 (1H, s) Example 56 N- [2- (4-Chloro-N-methylcinnamylamino) ethyl] -N- (2 -Piperidinoethyl) -5-isoquinolinesulfonic acid amide 0.29 g of diethyl azodicarboxylate was added to a solution of 0.39 g of the amorphous substance obtained in Example 38, 0.145 g of 1-piperidineethanol and 0.369 g of triphenylphosphine in 5 ml of tetrahydrofuran under ice-cooling and stirring. After 2 ml of tetrahydrofuran solution was added dropwise and stirred for 2 hours, the solvent was distilled off under reduced pressure. This was dissolved in 30 ml of ethyl acetate and extracted three times with 10 ml of 1N hydrochloric acid.
The extract was made alkaline with sodium bicarbonate, extracted three times with 10 ml of ethyl acetate, dried over magnesium sulfate, and the residue obtained by evaporating the solvent under reduced pressure was applied to a silica gel column.
From the fraction eluted with chloroform containing 2% methanol, 0.37 g of the target product was obtained as a colorless oil.

NMR (CDCl ₃ ) δ ppm: 1.3-1.5 (6H, m), 2.20 (3H, s),
2.20 to 2.30 (4H, m), 2.39 (2H, t, J = 7.1Hz), 2.55 (2
H, t, J = 7.1Hz), 3.08 (2H, d, J = 6.8Hz), 3.46 (4H, q,
J = 7.1Hz), 6.09 (1H, dt, J = 15.9,6.8Hz), 6.40 (1H,
d, J = 15.9Hz), 7.25 (4H, s), 7.63 (1H, dd, J = 7.3,8.
1Hz), 8.14 (1H, d, J = 8.1Hz), 8.43 (1H, d, J = 7.3H)
z), 8.43 (1H, d, J = 6.1Hz), 8.67 (1H, d, J = 6.1H)
z), 9.31 (1H, s) The obtained oil was dissolved in methanol (3 ml), 4N hydrochloric acid / ethyl acetate (0.5 ml) was added, the solvent was distilled off under reduced pressure, and ether was added to obtain a powder. After that, the crystals were collected by filtration to obtain 0.35 g of a colorless powdery trihydrochloride NMR (D ₂ O) δ ppm: 1.3 to 2.0 (6H, m), 2.8 to 3.0 (2H,
m), 3.05 (3H, s), 3.3-3.6 (6H, m), 3.8-4.1 (6H,
m), 6.25 (1H, dt, J = 15.8,8.0Hz), 6.80 (1H, d, J = 1
5.8Hz), 7.25 (4H, s), 8.13 (1H, t, J = 8.0Hz), 8.60
(1H, d, J = 8.0Hz), 8.68 ~ 8.78 (2H, m), 8.95 (1H, d,
J = 7.0 Hz), 9.70 (1H, s) Example 57 N- [2- (4-Chloro-N-methylcinnamylamino) ethyl] -N- (2-dimethylaminoethyl) -5
-Isoquinoline sulfonic acid amide 1.0 g of the amorphous substance obtained in Example 38, 0.267 g of 2-dimethylaminoethanol, and 0.982 g of triphenylphosphine in a 5 ml solution of tetrahydrofuran 5 ml of a tetrahydrofuran solution of 0.652 g of diethylazodicarboxylate under ice-cooling and stirring. The solution was added dropwise, and after 2 hours, tetrahydrofuran was distilled off under reduced pressure and dissolved in 10 ml of ethyl acetate.
Extracted three times. The extract was made alkaline with sodium bicarbonate, extracted three times with 10 ml of ethyl acetate, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was applied to a silica gel column, and the fraction eluted with chloroform containing 3% methanol. 0.77 g of the target compound was obtained as a more colorless oil.

NMR (CDCl ₃ ) δ ppm: 2.11 (6H, s), 2.20 (3H, s), 2.38
(2H, t, J = 7.3Hz), 2.54 (2H, t, J = 7.3Hz), 3.08 (2
H, d, J = 6.6Hz), 3.38-3.50 (4H, m), 6.08 (1H, dt, J
= 15.8,6.6Hz), 6.40 (1H, d, J = 15.8Hz), 7.26 (4H,
s), 7.63 (1H, dd, J = 8.1,7.5Hz), 8.14 (1H, d, J = 8.1
Hz), 8.40-8.45 (2H, m), 8.68 (1H, d, J = 6.1Hz),
9.31 (1H, s) The obtained oil was dissolved in methanol (5 ml), 4N hydrochloric acid / ethyl acetate (1.4 ml) was added, the solvent was distilled off under reduced pressure, ether was added, the mixture was powdered, and then filtered. Dried to obtain 0.7 g of a powdery trihydrochloride NMR (D ₂ O) δ ppm: 2.96 (6H, s), 3.03 (3H, s), 3.4 to
3.6 (4H, m), 3.9-4.1 (6H, m), 6.17 (1H, dt, J = 15.
9,7.0Hz), 6.73 (1H, d, J = 15.9Hz), 7.19 (4H, s),
8.01 (1H, t, J = 8.0Hz), 8.54 (1H, d, J = 8.0Hz), 8.70
(2H, m), 8.91 (1H, d, J = 8.0 Hz), 9.78 (1H, s) Example 58 N- (2-piperidinoethyl) -N- [2- (N-methylcinnamylamino) ethyl] -5-Isoquinolinesulfonic acid amide A colorless oily N- [2- (N-methylcinnamylamino) ethyl] -5-isoquinoline sulfone obtained by operating the amorphous substance obtained in Example 21 in the same manner as in Example 38 Acid amide 0.47
To a solution of 6 g, 0.193 g of 1-piperidineethanol and 0.524 g of triphenylphosphine in 5 ml of tetrahydrofuran was added a solution of 2 ml of tetrahydrofuran in 0.348 g of diethylazodicarboxylate under ice-cooling and stirring, and the mixture was left for 3 hours. , 30 ml of ethyl acetate and 1N hydrochloric acid
Extracted three times with 10 ml. The extract was made alkaline with sodium bicarbonate, extracted three times with 10 ml of ethyl acetate, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was applied to a silica gel column, and chloroform containing 5% methanol was added. 0.44 g of the target compound as a colorless oil was obtained from the fraction eluted with.

NMR (CDCl ₃ ) δ ppm: 1.3-1.5 (6H, m), 2.20 (3H, s),
2.20 to 2.30 (4H, m), 2.41 (2H, t, J = 6.8Hz), 2.53 (2
H, t, J = 6.3Hz), 3.09 (2H, d, J = 6.6Hz), 3.4 ~ 3.55
(4H, m), 6.10 (1H, dt, J = 15.8,6.6Hz), 6.45 (1H, d,
J = 15.8Hz), 7.2-7.4 (5H, m), 7.61 (1H, dd, J = 8.0,
7.5Hz), 8.11 (1H, d, J = 8.0Hz), 8.4-8.5 (2H, m),
8.66 (1H, d, J = 6.1 Hz), 9.29 (1H, s) The obtained oil was dissolved in 5 ml of methanol, and 4N hydrochloric acid /
0.8 ml of ethyl acetate was added, the solvent was distilled off under reduced pressure, and then 50 ml of ether was added to make a powder, which was collected by filtration and dried.
NMR (D ₂ O) δ ppm to obtain 0.4 g of trihydrochloride as a colorless powder: 1.6 to 2.0 (6H, m), 2.7 to 2.9 (2H,
m), 3.04 (3H, s), 3.4-3.6 (6H, m), 3.9-4.1 (6H,
m), 6.25 (1H, dt, J = 15.8,8.0Hz), 6.86 (1H, d, J = 1
5.8Hz), 7.40 (5H, s), 8.14 (1H, t, J = 8.0Hz), 8.6
~8.7 (3H, m), 9.0 (1H, d, J = 7.0Hz), 9.72 (1H, s) * NMR (CDCl 3) δppm: 1.95 (3H, s), 2.37 (2H, t, J = 5 .
7Hz), 2.93 ~ 3.00 (4H, m), 6.00 (1H, dt, J = 15.8,6.6
Hz), 6.38 (1H, d, J = 15.8Hz), 7.31 (5H, s), 7.68
(1H, dd, J = 8.3,7.3Hz), 8.18 (1H, d, J = 8.3Hz), 8.4
3-847 (2H, m), 8.69 (1H, d, J = 6.1Hz), 9.34 (1H,
s) Example 59 N-anisyl-N- [2- (4-chlorocinnamylamino) ethyl] -5-isoquinolinesulfonic acid amide 0.4 g of the amorphous obtained in Example 20, 0.276 of anisyl alcohol
g, dissolved in 10 ml of tetrahydrofuran in 0.524 g of triphenylphosphine, and a solution of 2 ml of tetrahydrofuran in 0.404 g of diisopropylazodicarboxylate was added dropwise with stirring under ice-cooling, and then left overnight at room temperature.The solvent was distilled off under reduced pressure. Dissolve by adding 30 ml of ethyl acetate, and add 2 ml with 30 ml of 1N hydrochloric acid.
Extracted times. The extract was made alkaline with sodium bicarbonate, extracted twice with 30 ml of ethyl acetate, washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Colorless oily target from the fraction eluted with chloroform containing 0.22
g was obtained.

NMR (CDCl ₃ ) δ ppm: 2.61 (2H, t, J = 6.6 Hz), 3.14 (2H,
d, J = 6.1Hz), 3.34 (2H, t, J = 6.6Hz), 3.74 (3H,
s), 4.43 (2H, s), 6.0 (1H, dt, J = 15.9, 6.1Hz), 6.3
0 (1H, d, J = 15.9Hz), 6.75 (2H, d, J = 8.8Hz), 7.08
(2H, d, J = 8.8Hz), 7.26 (4H, s), 7.66 (1H, dd, J = 8.
3,7.3Hz), 8.17 (1H, brd, J = 8.3Hz), 8.39 to 8.49 (2
H, m), 8.69 (1H, d, J = 6.1 Hz), 9.3 (1H, s) Example 60 N- [2- (4-chlorocinnamylamino) ethyl]-
N-Phenethyl-5-isoquinolinesulfonic acid amide The same operation as in Example 59 was carried out, except that 0.146 g of phenethyl alcohol was used instead of anisyl alcohol to obtain 0.37 g of the target compound as a colorless oil.

NMR (CDCl ₃ ) δ ppm: 1.4 (1H, brs), 2.75 to 2.90 (4H,
m), 3.27 (2H, d, J = 6.1 Hz), 3.4 to 3.6 (4H, m), 6.10
(1H, dt, J = 15.9,6.1Hz), 6.39 (1H, d, J = 15.9Hz),
6.59-7.05 (2H, m), 7.1-7.2 (3H, m), 7.26 (4H, m
s), 7.65 (1H, dd, J = 8.3,7.6Hz), 8.15 (1H, d, J = 8.3
Hz), 8.38 (2H, t, J = 6.1Hz), 8.63 (1H, d, J = 6.1H)
z), 9.28 (1H, s) Example 61 N-benzyl-N- [2- (4-chlorocinnamylamino) ethyl] -5-isoquinolinesulfonic acid amide Using 0.162 g of benzyl alcohol instead of silalcohol, 0.3 g of the desired product was obtained as a colorless oil.

NMR (CDCl ₃ ) δ ppm: 2.0 (1H, brs), 2.6 (2H, t, J = 6.6H
z), 3.15 (2H, d, J = 6.1Hz), 3.40 (2H, t, J = 6.6H)
z), 4.50 (2H, s), 6.0 (1H, dt, J = 15.8, 6.1Hz), 6.3
0 (1H, d, J = 15.8Hz), 7.15 to 7.25 (9H, m), 7.66 (1H,
dd, J = 8.0,7.6Hz), 8.16 (1H, d, J = 8.0Hz), 8.4-8.5
(2H, m), 8.70 (1H, d, J = 6.1 Hz), 9.31 (1H, s) Example 62 N- [2- (4-chlorocinnamylamino) ethyl]-
N-methyl-5-isoquinolinesulfonic acid amide The same procedure as in Example 59 was carried out, except that 48 mg of methanol was used instead of anisyl alcohol to obtain 0.3 g of the desired product as a colorless oil.

NMR (CDCl ₃ ) δ ppm: 1.5 (1H, brs), 2.86 (2H, t, J = 6.2
Hz), 2.88 (3H, s), 3.3-3.4 (4H, m), 6.15 (1H, dt,
J = 15.8,6.1Hz), 6.43 (1H, d, J = 15.8Hz), 7.27 (4H,
s), 7.69 (1H, dd, J = 8.3,7.3Hz), 8.18 (1H, d, J = 8.3
Hz), 8.38 (1H, d, J = 7.3Hz), 8.50 (1H, d, J = 6.3H)
z), 8.67 (1H, d, J = 6.3 Hz), 9.31 (1H, s) Reference Example 1 3.06 g of N- (3,4-dimethoxyphenyl) -5-isoquinolinesulfonic acid amide 3,4-dimethoxyaniline After dissolving in 30 ml of pyridine, 5.28 g of 5-isoquinoline sulfonyl chloride hydrochloride was added little by little under ice-cooling and stirring, and the mixture was stirred for 30 minutes and then at room temperature overnight. After distilling off pyridine under reduced pressure, 20 ml of water was added, and then chloroform-isopropanol (10: 1) 50
The mixture was extracted twice with ml, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure.
1) 20 ml was added, and the mixture was slightly heated and collected by filtration to obtain 5.64 g of the target compound as colorless crystals.

_{MP: 195~197 ℃ NMR (CDCl 3} ) δppm: 3.67 (3H, s), 3.77 (3H, s), 6.3
(1H, dd, J = 8.5,2.7Hz), 6.5-6.6 (3H, complex), 7.
61 (1H, t, J = 8.3Hz), 8.2 (1H, d, J = 8.3Hz), 8.3 (1
H, dd, J = 1.3,7.3Hz), 8.4 (1H, d, J = 6.1Hz), 8.7 (1
H, d, J = 6.4 Hz), 9.36 (1H, d, J = 1.3 Hz) Reference Example 2 N- (3,4-dimethoxyphenyl) -N- (2-phthalimidoethyl) -5-isoquinolinesulfonic acid amide 500 mg of the crystals obtained in Reference Example 1 were treated with dimethylformamide 7m
l, dissolved in tetrahydrofuran (4 ml)
After adding 70 mg of sodium hydride and stirring for 20 minutes, 406 mg of bromoethylphthalimide was added and the mixture was stirred under reflux for 6 hours.
After adding 10 ml of ice water to the reaction solution, the mixture was extracted twice with 30 ml of ethyl acetate, washed with saturated saline, dried over magnesium sulfate, and the residue obtained by evaporating the solvent under reduced pressure was applied to a silica gel column. From the fraction eluted with chloroform-methanol (100: 1), 320 mg of the target compound was obtained as colorless crystals.

_{MP: 197~201 ℃ NMR (CDCl 3} ) δppm: 3.80 (3H, s), 3.88 (3H, s), 3.7
~ 3.78 (2H, complex) 、 3.75-4.0 (2H, complex) 、 6.6
7 (1H, s), 6.68 (1H, s), 6.73 (1H, s), 7.57 (1H, t,
J = 7.57Hz), 7.73 (4H, s), 8.0 (1H, dd, J = 1.0,8.3H)
z), 8.05 (1H, d, J = 7.3 Hz), 8.24 (1H, dd, J = 1.0, 7.5)
7 Hz), 8.44 (1H, brd), 9.1 (1H, brs) Reference Example 3 N- (3,4-dimethoxyphenyl) -N- (2-aminoethyl) -5-isoquinolinesulfonic acid amide 517 mg of methanol 5m
l, dissolved in chloroform 5 ml, hydrazine hydrate 60
mg was added and the mixture was heated under reflux for 3 hours. After the precipitated insoluble matter was removed by filtration, the solvent was distilled off under reduced pressure to obtain a residue, to which ethyl acetate 10 was added.
After adding ml, the insolubles were removed by filtration again, and the solvent was distilled off under reduced pressure to obtain 420 mg of the desired product as a slightly yellow oil.

NMR (CDCl ₃ ) δ ppm: 2.76 (2H, t, J = 6.1 Hz), 3.60 (3H,
s), 3.75 (2H, t, J = 6.1Hz), 3.83 (3H, s), 6.48 (1
H, s), 6.46 (1H, d, J = 9.2Hz), 6.63 (1H, d, J = 9.2H)
z), 7.61 (1H, t, J = 7.5Hz), 8.18 (1H, d, J = 8.0H)
z), 8.25 (1H, dd, J = 1.3,8.3Hz), 8.5 (1H, d, J = 6.1H)
z), 9.3 (1H, d, J = 1.3 Hz) Example 63 N- (3,4-dimethoxyphenyl) -N- [2- (4-
Chlorocinnamylamino) ethyl] -5-isoquinolinesulfonic acid amide 320 mg of the oil obtained in Reference Example 3 was treated with dimethylformamide 6
The mixture was dissolved in 200 ml of potassium carbonate, and 200 mg of potassium carbonate and 150 mg of p-chlorocinnamyl chloride were added, followed by stirring at room temperature overnight. After adding 20 ml of water to the reaction solution, the mixture was extracted twice with 30 ml of chloronerm, washed with saturated saline, dried over magnesium sulfate, and the residue obtained by evaporating the solvent under reduced pressure was applied to a silica gel column. 90 mg of the target compound was obtained as colorless crystals from the fraction eluted with methanol (100: 1).

NMR (CDCl ₃ ) δ ppm: 2.75 (2H, t, J = 6.1 Hz), 3.36 (1H,
d, J = 6.1Hz), 3.6 (3H, s), 3.74 (2H, d, J = 6.1Hz),
3.82 (3H, s), 6.15 (1H, d and dt, J = 15.6,6.1Hz), 6.
42 (1H, d, J = 15.6Hz), 6.5 (1H, s), 6.61 (1H, d, J =
8.1Hz), 6.48 (1H, d, J = 6.1Hz), 7.3 (4H, brs), 7.6
3 (1H, t, J = 8.1Hz), 8.16 (1H, d, J = 6.1Hz), 8.17 (1
H, d, J = 8.1Hz), 8.3 (1H, dd, J = 1.0,6.1Hz), 8.5 (1
(H, d, J = 6.1 Hz), 9.3 (1H, d, J = 1.0 Hz) Example 64 N- {2- [bis (4-chlorocinnamyl) amino] ethyl} -5-isoquinolinesulfonic acid amide The silica gel column in Example 63 was replaced with chloroform-
Prior to elution with methanol, 100 mg of the target compound was obtained as a colorless crystal from the fraction eluted with chloroform.

NMR (CDCl ₃ ) δ ppm: 2.66 (2H, t, J = 6.2 Hz), 3.25 (4H,
d, J = 6.2Hz), 3.52 (3H, s), 3.75 (2H, t, J = 6.2H)
z), 3.71 (3H, s), 6.1 (2H, d and t, J = 15.6, 6.2H
z), 6.3 (1H, d, J = 5.6Hz), 6.4 (1H, s), 6.4 (2H, d,
J = 15.6Hz), 6.45 (1H, d, J = 5.6Hz), 7.3 (8H, s),
7.51 (1H, t, J = 8.1Hz), 8.14 (1H, d, J = 6.1Hz), 8.16
(1H, d, J = 8.1Hz), 8.2 (1H, dd, J = 1.0,6.1Hz), 8.45
(1H, d, J = 6.1 Hz), 9.3 (1H, d, J = 1.0 Hz) The following compounds were produced in the same manner.

Example 65 N- [2- (4-methoxy-α-methylcinnamylamino] ethyl] -5-isoquinolinesulfonic acid amide · 2
Hydrochloride colorless amorphous IR (KBr) cm ^-1 : 3420,3200-2300,1720,1605,1345,1280 NMR (D ₂ O) δ ppm: 1.59 (3H, d, J = 6.7 Hz), 3.19 (2H, br
t), 3.38 (2H, brt), 4.01 (3H, s), 4.16 (1H, m),
6.28 (1H, dd, J = 15.9,8.9Hz), 6.83 (1H, d, J = 15.9H
z), 7.51 (2H, d, J = 8.4Hz), 7.94 (2H, d, J = 8.4H)
z), 8.10 (1H, brt), 8.64 (1H, d, J = 8.6Hz), 8.76
(2H, brt), 8.98 (1H, d, J = 7.0 Hz), 9.72 (1H, s) Example 66 N- [2- (4-methoxycarbonyl-N, α-dimethylcinnamylamino) ethyl]- 5- isoquinoline sulfonamide dihydrochloride colorless MuAkirakarada ^{IR (KBr) cm -1: 3420,3150~2300,1715,1605,1345,1285} NMR (D 2 O) δppm: 1.59 (3H, d, J = 6.4Hz), 2.94 (3H,
s), 3.44 (4H, brs), 3.99 (3H, s), 4.31 (1H, m),
6.37 (1H, dd, J = 16.2,8.7Hz), 6.89 (1H, d, J = 16.2H
z), 7.54 (2H, d, J = 8.1Hz), 8.08 (2H, d, J = 8.1H)
z), 8.10 (1H, brt), 8.67 (1H, d, J = 8.5Hz), 8.75
(2H, brt), 8.96 (1H, d, J = 7.0 Hz), 9.74 (1H, s) Example 67 N- [2- (4-methoxy-N, α-dimethylcinnamylamino) ethyl] -5 - isoquinoline sulfonamide colorless oil which _{NMR (CDCl 3) δppm: 1.07} (3H, d, J = 6.6Hz), 1.85 (3H,
s), 2.3-2.5 (2H, m), 2.91 (2H, t, J = 6.0Hz), 2.95
~ 3.10 (1H, m), 3.80 (3H, s), 5.86 (1H, dd, J = 16.1,
7.3Hz), 6.24 (1H, d, J = 16.1Hz), 6.84 (2H, d, J = 8.8
Hz), 7.24 (2H, d, J = 8.8Hz), 7.68 (1H, dd, J = 7.3,8.
0Hz), 8.20 (1H, d, J = 8.0Hz), 8.4 to 8.5 (2H, m), 8.
66 (1H, d, J = 6.1 Hz), 9.34 (1H, s) Example 68 N- (2-methylaminoethyl) -N- [2- (4-chloro-N-methylcinnamylamino) ethyl] 5-isoquinoline sulfonic acid amide colorless oil which _{NMR (CDCl 3) δppm: 1.9~2.2} (1H, br), 2.23 (3H,
s), 2.35 (3H, s), 2.59 (2H, t, J = 6.6 Hz), 2.80 (2
H, t, J = 6.1Hz), 3.12 (2H, d, J = 6.6Hz), 3.4-3.5 (4
H, m), 6.10 (1H, dt, J = 15.9,6.6Hz), 6.44 (1H, d, J =
15.9Hz), 7.26 (4H, s), 7.66 (1H, t, J = 7.8Hz), 8.1
7 (1H, d, J = 7.8Hz), 8.40 (1H, d, J = 7.8Hz), 8.46 (1
H, d, J = 6.1Hz), 8.67 (1H, d, J = 6.1Hz), 9.32 (1H,
s) Example 69 N- (2-methylaminoethyl) -N- [2- (4-chloro-N-methylcinnamylamino) ethyl] -5-isoquinolinesulfonic acid amide trihydrochloride colorless amorphous NMR ( D ₂ O) δppm: 2.80 (3H, s), 3.05 (3H, s), 3.4 ~
3.6 (4H, m), 3.9-4.1 (6H, m), 6.17 (1H, dt, J = 15.
9,7.2Hz), 6.74 (1H, d, J = 15.9Hz), 7.18 (4H, s),
8.10 (1H, t, J = 7.9Hz), 8.53 (1H, d, J = 7.9Hz), 8.6
8.88.8 (2H, m), 8.93 (1H, d, J = 7.0 Hz), 9.77 (1H, s) Example 70 N- (2-hydroxyethyl) -N- [2- (4-methoxy-N, α-Dimethylcinnamylamino) ethyl] -5
- isoquinoline sulfonamide colorless oil which _{NMR (CDCl 3) δppm: 1.29} (3H, d, J = 6.6Hz), 2.30 (3H,
s), 2.7-3.0 (2H, m), 3.2-3.4 (5H, m), 3.80 (3H,
s), 3.8-3.9 (2H, m), 6.04 (1H, dd, J = 16.1,7.8H
z), 6.40 (1H, d, J = 16.1Hz), 6.86 (2H, d, J = 8.7H)
z), 7.32 (2H, d, J = 8.7Hz), 7.68 (1H, dd, J = 8.0,7.3)
Hz), 8.19 (1H, d, J = 8.0Hz), 8.26 (1H, d, J = 7.3H)
z), 8.58 (1H, d, J = 6.1Hz), 8.68 (1H, d, J = 6.1H)
z), 9.33 (1H, s) Example 71 N- [2- (methoxy) ethyl] -N- [2- (N-methyl-4-methoxy-α-methylcinnamylamino) ethyl] -5-isoquinoline Sulfonamide colorless oil NMR (CDCl ₃ ) δ ppm: 1.12 (3H, d, J = 6.6 Hz), 2.18 (3H,
s), 2.4 to 2.65 (2H, m), 3.1 (3H, s), 3.10 to 3.20 (1
H, m), 3.35-3.60 (6H, m), 3.81 (3H, s), 5.93 (1H,
dd, J = 16.1,7.3Hz), 6.31 (1H, d, J = 16.1Hz), 6.85
(2H, d, J = 8.7Hz), 7.26 (2H, d, J = 8.7Hz), 7.62 (1
H, dd, J = 7.6,8.1Hz), 8.13 (1H, d, J = 8.1Hz), 8.35 ~
8.45 (2H, m), 8.67 (1H, d, J = 6.1 Hz), 9.30 (1H, s) Example 72 N- [2- (4-chlorocinnamylamino) ethyl]-
N- (2-dimethylaminoethyl) -5-isoquinolinesulfonic acid amide trihydrochloride colorless amorphous IR (KBr) cm ^-1 : 3420,2700,1340,1150,840,590 NMR (D ₂ O) δ ppm: 2.99 ( 6H, s), 3.33 (2H, t, J = 6.8H
z), 3.55 (2H, t, J = 6.8Hz), 3.8-4.0 (6H, m), 6.18
(1H, dt, J = 16.2,6.7Hz), 6.76 (1H, d, J = 16.2Hz),
7.32 (4H, s), 8.12 (1H, t, J = 8.0Hz), 8.6-8.8 (3H,
m), 8.97 (1H, d, J = 7.0 Hz), 9.74 (1H, s) Example 73 N- [2- (4-chlorocinnamylamino) ethyl]-
N- (2-methylaminoethyl) -5-isoquinolinesulfonic acid amide · 3 hydrochloride colorless amorphous NMR (D ₂ O) δ ppm: 2.81 (3H, s), 3.4 to 3.6 (4H, m), 3.
7-4.0 (6H, m), 6.17 (1H, dt, J = 16.1,7.3Hz), 6.78
(1H, d, J = 16.1Hz), 7.33 (4H, s), 8.14 (1H, t, J = 8.
0Hz), 8.6-8.8 (3H, m), 9.06 (1H, d, J = 7.0Hz), 9.
80 (1H, s) IR (KBr) cm ^-1 : 3420,2790,1340,1140,590 Example 74 N- [2- (4-chlorocinnamylamino) ethyl]-
N- (2-pyridylmethyl) -5-isoquinolinesulfonic acid amide trihydrochloride pale yellow amorphous IR (KBr) cm ^-1 : 3420, 2790, 1360, 1160, 590 NMR (D ₂ O) δ ppm: 3.16 ( 2H, brt), 3.92 (4H, brt), 5.
04 (2H, s), 6.1 to 6.3 (1H, m), 6.77 (1H, d, J = 15.6H
z), 7.38 (4H, s), 7.68 (1H, t, J = 6.7Hz), 7.82 (1
H, d, J = 7.6Hz), 8.0-8.3 (2H, m), 8.57 (1H, d, J = 5.
8Hz), 8.7-8.9 (3H, m), 9.02 (1H, d, J = 7.3Hz), 9.
80 (1H, s) Example 75 N- [2- (4-Chlorocinnamylamino) ethyl]-
N- (3- pyridylmethyl) -5-isoquinoline sulfonamide trihydrochloride pale yellow MuAkirakarada ^{IR (KBr) cm -1: 3420,2800,1350,1150,590} NMR (D 2 O) δppm: 3.12 ( 2H, brt), 3.8-4.0 (4H, m),
4.96 (2H, s), 6.0-6.2 (1H, m), 6.70 (1H, d, J = 15.7
Hz), 7.37 (4H, brq), 7.39 (1H, t, J = 6.3Hz), 8.16
(2H, brt), 8.54 (1H, d, J = 5.8Hz), 8.61 (1H, d, J =
8.5Hz), 8.7-8.8 (2H, m), 8.83 (1H, s), 9.01 (1H,
d, J = 6.7 Hz), 9.76 (1H, s) Example 76 N- [2- (3,4-Dimethoxy-α-methylcinnamylamino) ethyl] -5-isoquinolinesulfonic acid amide dihydrochloride Yellow Amorphous NMR (D ₂ O) δ ppm: 1.56 (3H, d, J = 6.7 Hz), 3.1-3.2 (2
H, m), 3.35-3.45 (2H, m), 3.84 (3H, s), 3.91 (3H,
s), 4.0 to 4.15 (1H, m), 6.0 (1H, dd, J = 15.6,9.0H
z), 6.64 (1H, d, J = 15.6Hz), 6.92 (3H, s), 8.07 (1
H, t, J = 8.0Hz), 8.60 (1H, d, J = 8.0Hz), 8.73 (1H, d,
J = 8.0Hz), 8.73 (1H, d, J = 6.7Hz), 8.95 (1H, d, J =
6.7 Hz), 9.68 (1 H, s) Example 77 N- [2- (α-methyl-3,4,5-trimethoxycinnamylamino) ethyl] -5-isoquinolinesulfonic acid amide dihydrochloride NMR ( D ₂ O) δ ppm: 1.65 (3H, d, J = 6.4 Hz), 3.2 to 3.5 (4
H, m), 3.84 (3H, s), 3.91 (6H, s), 4.1-4.3 (1H,
m), 6.13 (1H, dd, J = 14.1,8.8Hz), 6.70 (1H, d, J = 1
4.1Hz), 6.67 (2H, s), 8.16 (1H, t, J = 8.0Hz), 8.17
(1H, d, J = 8.0Hz), 8.75-8.85 (2H, m), 9.02 (1H, d,
J = 7.0 Hz), 9.80 (1H, s) Example 78 N- (2-dimethylaminoethyl) -N- [2- (N-
Methyl-3,4,5-trimethoxycinnamylamino) ethyl] -5-isoquinolinesulfonic acid amide colorless oil NMR (CDCl ₃ ) δ ppm: 2.12 (6H, s), 2.22 (3H, s), 2.39
(2H, t, J = 6.8Hz), 2.57 (2H, t, J = 6.8Hz), 3.10 (2
H, d, J = 6.6Hz), 3.4-3.5 (4H, m), 3.84 (3H, s), 3.
87 (6H, s), 6.06 (1H, dt, J = 16,6.6Hz), 6.40 (1H, d,
J = 16Hz), 6.61 (2H, s), 7.64 (1H, t, J = 7.4Hz), 8.
15 (1H, d, J = 7.4Hz), 8.44 (2H, m), 8.68 (1H, d, J =
6.1 Hz), 9.32 (1H, s) Example 79 N- (2-dimethylaminoethyl) -N- [2- (N-
Methyl-3,4,5-trimethoxycinnamylamino) ethyl] -5-isoquinolinesulfonic acid amide trihydrochloride Yellow amorphous NMR (D ₂ O) δ ppm: 3.00 (6H, s), 3.08 (3H, s ), 3.80
(3H, s), 3.82 (6H, s), 3.5-4.1 (10H, m), 6.1 (1
H, m), 6.51 (2H, s), 6.68 (1H, d, J = 16Hz), 8.0 (1
H, t, J = 8.1Hz), 8.5 (2H, m), 8.7 (2H, m), 9.55 (1
H, s) Example 80 N- [2- (4-chlorocinnamylamino) ethyl]-
N- (3,4,5-trimethoxybenzyl) -5-isoquinolinesulfonic acid amide dihydrochloride colorless amorphous IR (KBr) cm ^-1 : 3420,2920,1330,1130,590 NMR (DMSO-d ₆ ) Δppm: 2.99 (2H, brs), 3.55 (6H,
s), 3.56 (3H, s), 3.68 (4H, brs), 4.47 (2H, s),
6.2 to 6.4 (1H, m), 6.76 (1H, d, J = 15.9Hz), 7.45 (4
H, s), 7.95 (1H, t, J = 7.9Hz), 8.54 (1H, t, J = 7.6H)
z), 8.6-8.7 (2H, m), 8.78 (1H, d, J = 6.3Hz), 9.48
Example 81 N-cyanomethyl-N- [2- (4-methoxycarbonyl-N, α-dimethylcinnamylamino) ethyl] -5- (2H, brs), 9.73 (1H, s)
Isoquinolinesulfonic acid amide colorless oil IR (KBr) cm ^-1 : 2250,1718,1280 NMR (CDCl ₃ ) δ ppm: 1.16 (3H, d, J = 6.6 Hz), 2.23 (3H,
s), 2.65 to 2.8 (2H, m), 3.35 (1H, m), 3.43 (2H, t, J
= 5.6Hz), 3.91 (3H, s), 4.63 (2H, s), 6.23 (1H, d
d, J = 15, 9, 7.1 Hz), 6.46 (1H, d, J = 15.9 Hz), 7.39 (2
H, d, J = 8.3Hz), 7.73 (1H, t, J = 8.3Hz), 7.98 (2H, d,
J = 8.3Hz), 8.25 (1H, d, J = 8.3Hz), 8.4 ~ 8.5 (2H,
m), 8.70 (1 H, d, J = 6.1 Hz), 9.36 (1 H, s) Example 82 N-cyanomethyl-N- [2- (4-methoxycarbonyl-N, α-dimethylcinnamylamino) ethyl -5
- isoquinoline sulfonamide dihydrochloride Colorless MuAkirakarada _{NMR (D 2 O) δppm:} 1.62 (3H, d, J = 6.7Hz), 3.02 (3H,
s), 3.55 (2H, m), 3.90 (2H, m), 4.0 (3H, s), 4.35
(1H, s), 4.70 (2H, s), 6.40 (1H, dd, J = 15.9,7.0H
z), 6.95 (1H, d, J = 15.9 Hz), 7.53 (2H, d, J = 8.2H)
z), 7.89 (2H, d, J = 8.2Hz), 8.15 (1H, t, J = 7.7H)
z), 8.7-8.85 (3H, m), 8.99 (1H, d, J = 7.0Hz), 9.7
6 (1H, s) Example 83 N- (2-dimethylaminoethyl) -N- [2- (4-
Methoxycarbonyl-N, α-dimethylcinnamylamino) ethyl] -5-isoquinolinesulfonic acid amide colorless oil IR (KBr) cm ⁻¹ : 1780,1280 NMR (CDCl ₃ ) δ ppm: 1.14 (3H, d, J = 6.6Hz), 2.10 (6H,
s), 2.21 (3H, s), 2.37 (2H, t, J = 7.3 Hz), 2.45 to 2.
65 (2H, m), 3.22 (1H, m), 3.35-3.50 (4H, m), 3.91
(3H, s), 6.21 (1H, dd, J = 15.9,6.8Hz), 6.42 (1H, d,
J = 15.99Hz), 7.38 (2H, d, J = 8.3Hz), 7.63 (1H, t, J =
7.9Hz), 7.98 (2H, d, J = 8.3Hz), 8.14 (1H, d, J = 7.9H)
z), 8.4-8.5 (2H, m), 8.67 (1H, d, J = 6.4Hz), 9.31
(1H, s) Example 84 N- (2-dimethylaminoethyl) -N- [2- (4-
Methoxycarbonyl-N, α-dimethylcinnamylamino) ethyl] -5-isoquinolinesulfonic acid amide.3
Hydrochloride colorless amorphous NMR (D ₂ O) δ ppm: 1.53 (3H, d, J = 6.7 Hz), 2.95 (9H,
s), 3.3-3.6 (4H, m), 3.9-4.0 (4H, m), 4.0 (3H,
s), 4.25 (1H, m), 6.30 (1H, m), 6.75 (1H, d, J = 16.
0Hz), 7.37 (2H, brs), 7.81 (2H, brs), 8.04 (1H, t,
J = 8.1Hz), 8.55 (2H, m), 8.65 (1H, d, J = 7,0Hz),
8.84 (1H, d, J = 7.0 Hz), 9.60 (1 H, s) Example 85 N- (2-morpholinoethyl) -N- [2- (4-methoxycarbonyl-N, α-dimethylcinnamylamino) Ethyl] -5-isoquinolinesulfonic acid amide colorless oil IR (KBr) cm ^-1 : 1720,1280 NMR (CDCl ₃ ) δ ppm: 1.15 (3H, d, J = 6.4 Hz), 2.21 (3H,
s), 2.25 to 2.7 (2H, m), 3.1 to 3.3 (1H, m), 3.4 to 3.6
(8H, m), 3.91 (3H, s), 6.20 (1H, dd, J = 16.1,7.3H
z), 6.42 (1H, d, J = 16.1 Hz), 7.38 (2H, d, J = 8.3H)
z), 7.63 (1H, t, J = 7.8Hz), 7.98 (2H, d, J = 8.3H)
z), 8.15 (1H, d, J = 7.8 Hz), 8.42 (1H, d, J = 7,8H)
z), 8.42 (1H, d, J = 7.1 Hz), 8.67 (1H, d, J = 7.1H)
z), 9.32 (1H, s) Example 86 N- (2-morpholinoethyl) -N- [2- (4-methoxycarbonyl-N, α-dimethylcinnamylamino) ethyl] -5-isoquinolinesulfonic acid amide・ Trihydrochloride colorless amorphous NMR (D ₂ O) δ ppm: 1.55 (3H, d, J = 6.8 Hz), 3.00 (3H,
s), 3.2-3.7 (8H, m), 3.8-4.1 (8H, m), 4.0 (3H,
s), 4.24 (1H, m), 6.35 (1H, m), 6.76 (1H, d, J = 16H)
z), 7.40 (2H, brs), 7.82 (2H, brs), 8.06 (1H, t, J
= 7.5Hz), 8.5 ~ 8.75 (3H, m), 8.80 (1H, d, J = 7.0H)
z), 9.63 (1H, s) Example 87 N- [2-Aminoethyl] -N- [2- (4-methoxycarbonyl-N, α-dimethylcinnamylamino) ethyl] -5-isoquinolinesulfonic acid amide Colorless oil IR (KBr) cm ^-1 : 1718,1280 NMR (CDCl ₃ ) δ ppm: 1.13 (3H, d, J = 6.6 Hz), 2.19 (3H,
s), 2.6 (2H, m), 2.86 (2H, brs), 3.22 (1H, m), 3.
37 (4H, t, J = 6.9Hz), 3.91 (3H, s), 6.20 (1H, dd, J =
16.0,6.9Hz), 6.42 (1H, d, J = 16.0Hz), 7.39 (2H, d, J
= 8.3Hz), 7.64 (1H, t, J = 8.1Hz), 7.98 (2H, d, J = 8.
3Hz), 8.14 (1H, d, J = 8.1Hz), 8.38 (1H, d, J = 8.1H)
z), 8.45 (1H, d, J = 6.1Hz), 8.68 (1H, d, J = 6.1H)
z), 9.31 (1H, s) Example 88 N- [2-aminoethyl] -N- [2- (4-methoxycarbonyl-N, α-dimethylcinnamylamino) ethyl] -5-isoquinolinesulfonic acid amide・ Trihydrochloride colorless amorphous NMR (D ₂ O) δ ppm: 1.53 (3H, d, J = 6.4 Hz), 2.96 (3H,
s), 3.3-3.5 (4H, m), 3.8-4.0 (4H, m), 4.0 (3H,
s), 4.2 (1H, m), 6.3 (1H, m), 6.76 (1H, d, J = 15.9H)
z), 7.35 (2H, d, J = 8.0Hz), 7.78 (2H, brs), 8.03
(1H, t, J = 7.9Hz), 8.6 (2H, m), 8.66 (1H, d, J = 6.7H)
z), 8.85 (1H, d, J = 6.7 Hz), 9.58 (1H, s) Example 89 N- [2- (4-Chloro-N-methylcinnamylamino) ethyl] -N-methoxycarbonylmethyl- amide dihydrochloride 5- isoquinoline sulfonic acid yellow MuAkirakarada ^{IR (KBr) cm -1: 3420,2650,1750,1350,1150,840,590} NMR (D 2 O) δppm: 3.05 (3H, s), 3.51 (2H , brt), 3.61
(3H, s), 3.89 (2H, brs), 4.06 (2H, d, J = 7.3Hz),
4.45 (2H, s), 6.2 to 6.4 (1H, m), 6.85 (1H, d, J = 15.6
Hz), 7.34 (4H, brq), 8.12 (1H, t, J = 8.0Hz), 8.6 ~
8.8 (3H, m), 8.95 (1H, d, J = 7.0 Hz), 9.79 (1H, s) Example 90 N-carboxymethyl-N- [2- (4-chloro-N-
Methylcinnamylamino) ethyl] -5-isoquinolinesulfonic acid amide light brown amorphous IR (KBr) cm ^-1 : 3420,1620,1330,1140,590 NMR (DMSO-d ₆ ) δppm: 2.43 (3H, s) , 2.89 (2H, br
t), 3.3-3.6 (4H, m), 3.91 (2H, s), 6.2-6.4 (1H,
m), 6.67 (1H, d, J = 15.8 Hz), 7.45 (4H, brq), 7.85
(1H, t, J = 8.0Hz), 8.3-8.5 (3H, m), 8.71 (1H, d, J
= 6.2 Hz), 9.49 (1H, s) Example 91 N- [2- (N-carboxymethyl-4-chloro-cinnamylamino) ethyl] -N-methyl-5-isoquinolinesulfonic acid amide pale yellow amorphous IR (KBr) cm ^-1 : 3400, 1630, 1320, 1140, 590 NMR (DMSO-d ₆ ) δ ppm: 2.75 (2H, brt), 2.79 (3H,
s), 3.2-3.4 (6H, m), 6.1-6.3 (1H, m), 6.50 (1H,
d, J = 16.2Hz), 7.39 (4H, brq), 7.83 (1H, t, J = 7.8H)
z), 8.3-8.5 (3H, m), 8.68 (1H, d, J = 6.1Hz), 9.48
(1H, s) Example 92 N- [2- (4-Chloro-N-methylcinnamylamino) ethyl] -N-methyl-5-isoquinolinesulfonic acid amide dihydrochloride Light brown amorphous IR (KBr) cm ^-1 : 3420,2670,1350,1140,830,590 NMR (D ₂ O) δ ppm: 3.00 (3H, s), 3.04 (3H, s), 3.51
(2H, brs), 3.66 (2H, brs), 4.10 (2H, brd), 6.2
~ 6.4 (1H, m), 6.90 (1H, d, J = 15.9Hz), 7.39 (4H, br
q), 8.15 (1H, t, J = 8.0Hz), 8.6-8.8 (3H, m), 9.08
(1H, d, J = 6.3 Hz), 9.80 (1H, s) Example 93 N-carbamoylmethyl-N- [2- (4-chloro-N
- methyl cinnamyl amino) ethyl] -5-isoquinoline sulfonamide dihydrochloride Colorless MuAkirakarada ^{IR (KBr) cm -1: 3420,2670,1680,1350,1150,840,590} NMR (D 2 O) δppm: 3.04 (3H, s), 3.4-3.7 (2H, m), 3.
89 (2H, brt), 4.06 (2H, brt), 4.29 (2H, s), 6.2 ~
6.4 (1H, m), 6.86 (1H, d, J = 16.1Hz), 7.35 (4H, br
q), 8.14 (1H, t, J = 8.0Hz), 8.6 ~ 8.8 (3H, m), 8.99
(1H, d, J = 7.0 Hz), 9.80 (1H, s) Example 94 N- [2- (4-chlorocinnamylamino) ethyl]-
N-[(5-methyl-4-imidazolyl) methyl] -5
- isoquinoline sulfonic acid amide trihydrochloride pale yellow MuAkirakarada ^{IR (KBr) cm -1: 3420,3020,1350,1150,830,590} NMR (D 2 O) δppm: 2.49 (3H, s), 3.52 (4H, brs ), 4.10
(2H, brd), 4.70 (2H, s), 6.1-6.3 (1H, m), 6.83
(1H, d, J = 15.8Hz), 7.34 (4H, s), 8.10 (1H, t, J = 8.
0Hz), 8.6-8.8 (3H, m), 8.83 (1H, s), 8.95 (1H, d,
J = 7.0 Hz), 9.81 (1H, s) Example 95 N- [2- (4-Chloro-N-methoxycarbonylmethylcinnamylamino) ethyl] -N-methyl-5-isoquinolinesulfonic acid amide · 2HCl Salt Yellow amorphous IR (KBr) cm ^-1 : 3420, 2620, 1750, 1350, 1140, 840, 590 NMR (D ₂ O) δ ppm: 3.07 (3H, s), 3.73 (4H, brt), 3.89
(3H, s), 4.21 (2H, brd), 4.37 (2H, s), 6.2-6.4
(1H, m), 6.89 (1H, d, J = 16.0Hz), 7.32 (4H, brq),
8.14 (1H, t, J = 7.9Hz), 8.6-8.8 (3H, m), 9.04 (1H,
d, J = 7.0 Hz), 9.83 (1H, s) Example 96 N- [2- (N-carbamoylmethyl-4-chlorocinnamylamino) ethyl] -N-methyl-5-isoquinolinesulfonic acid amide · 2 hydrochloride pale yellow MuAkirakarada ^{IR (KBr) cm -1: 3400,1690,1350,1140,830,590} NMR (D 2 O) δppm: 3.05 (3H, s), 3.5~3.8 (4H, m), 4.
1 to 4.2 (2H, m), 4.23 (2H, s), 6.2 to 6.4 (1H, m), 6.
91 (1H, d, J = 15.9 Hz), 7.34 (4H, brq), 8.11 (1H, t, J
7.9Hz), 8.6-8.8 (3H, m), 9.00 (1H, d, J = 7.0H)
z), 9.80 (1H, s) Example 97 N- [2- (4-Chloro-N-cyanomethylcinnamylamino) ethyl] -N-methyl-5-isoquinolinesulfonic acid amide dihydrochloride Akirakarada ^{IR (KBr) cm -1: 3420,2570,1350,1140,830,590} NMR (DMSO-d 6) δppm: 2.80 (2H, brt), 2.89 (3H,
s), 3.3-3.5 (4H, m), 3.89 (2H, s), 6.1-6.3 (1H,
m), 6.64 (1H, d, J = 15.8 Hz), 7.43 (4H, brq), 8.09
(1H, t, J = 8.0Hz), 8.63 (1H, d, J = 7.6Hz), 8.7-8.9
(3H, m), 9.98 (1H, s) Example 98 N- [2- (4-Chloro-N-methylcinnamylamino) ethyl] -N-morpholinocarbonylmethyl-5-
Isoquinoline sulfonic acid amide colorless oil IR (KBr) cm ^-1 : 1660,1330,1130 NMR (D ₂ O) δ ppm: 2.17 (3H, s), 2.57 (2H, t, J = 6.3H)
z), 3.06 (2H, d, J = 6.3Hz), 3.39 (4H, brs), 3.5 ~
3.7 (6H, m), 4.41 (2H, s), 6.06 (1H, dt, J = 15.9,6.3
Hz), 6.40 (1H, d, J = 15.9Hz), 7.27 (4H, s), 7.66
(1H, t, J = 8.0Hz), 8.15 (1H, d, J = 8.3Hz), 8.43 (1
H, d, J = 6.4Hz), 8.54 (1H, d, J = 8.0Hz), 8.66 (1H, d,
J = 6.4 Hz), 9.30 (1H, s) Example 99 N- {2- [N- (2-aminoethyl) -4-chlorocinnamylamino] ethyl} -N-methyl-5-isoquinolinesulfonic acid amide trihydrochloride colorless MuAkirakarada ^{IR (KBr) cm -1: 3420,2950,1490,1350,1140,590} NMR (D 2 O) δppm: 3.05 (3H, s), 3.5~3.8 (8H, m), Four.
20 (2H, brd), 6.2 to 6.4 (1H, m), 6.95 (1H, d, J = 15.9
Hz), 7.37 (4H, brq), 8.16 (1H, t, J = 7.9Hz), 8.6 ~
8.8 (3H, m), 9.07 (1H, d, J = 7.0 Hz), 9.84 (1H, s) Example 100 N- [2- [4-Chloro-N-methylcinnamylamino] ethyl] -N- [2- (1-Piperazinyl) ethyl] -5-isoquinolinesulfonic acid amide tetrahydrochloride colorless amorphous IR (KBr) cm ^-1 : 3420, 2660, 1460, 1350, 1150, 590 NMR (D ₂ O) δ ppm : 3.04 (3H, s), 3.3-3.7 (12H, m),
3.8-4.1 (6H, m), 6.0-6.2 (1H, m), 6.73 (1H, d, J =
15.9Hz), 7.18 (4H, s), 8.11 (1H, t, J = 7.9Hz), 8.5
3 (1H, d, J = 7.3Hz), 8.6 to 8.8 (2H, m), 8.89 (1H, d, J
= 6.9 Hz), 9.78 (1H, s) Example 101 N- [2- (4-Chloro-N-methylcinnamylamino) ethyl] -N- [2- (4-methyl-1-piperazinyl) ethyl] -5-isoquinolinesulfonic acid amide
Tetrahydrochloride colorless amorphous IR (KBr) cm ^-1 : 3420,2660,1460,1140,590 NMR (D ₂ O) δ ppm: 3.02 (3H, s), 3.02 (3H, s), 3.3 to
3.7 (12H, m), 3.8-4.1 (6H, m), 6.1-6.3 (1H, m),
6.74 (1H, d, J = 16.9Hz), 7.19 (4H, s), 8.11 (1H, t, J
= 7.9Hz), 8.55 (1H, d, J = 7.0Hz), 8.6-8.8 (2H,
m), 8.90 (1 H, d, J = 7.0 Hz), 9.79 (1 H, s) Example 102 N- [2- (3-methoxy-α-methylcinnamylamino) ethyl] -5-isoquinolinesulfonic acid amide・ 2
Hydrochloride pale yellow crystal MP: 115-118 ° C IR (KBr) cm ^-1 : 3420, 3200-2660, 1605, 1350, 1162, 1150 NMR (DMSO-d ₆ ) δ ppm: 1.40 (3H, d, J = 6.4) Hz), 2.90-
3.0 (2H, m), 3.15-3.25 (2H, m), 3.78 (3H, s), 3.8
0 to 4.0 (1H, m), 6.22 (1H, dd, J = 15.9,8.8Hz), 6.70
(1H, d, J = 15.9Hz), 6.85-7.05 (3H, m), 7.30 (1H,
t, J = 7.9Hz), 7.30 (1H, br, D 2 O in loss), 8.0 (1H,
d, J = 7.9Hz), 8.04 (1H, d, J = 7.3Hz), 8.59 (1H, d, J
= 7.3Hz), 8.68 (1H, d, J = 7.9Hz), 8.82 (2H, s), 8.
_{91 (1H, m, D 2} O in loss), 9.60 (2H, br, D 2 O in loss), 9.88 (1H, s) Example 103 N-[2- (4-hydroxymethyl -α- Mechirushin'na Milamino) ethyl] -5-isoquinolinesulfonic acid amide colorless amorphous IR (KBr) cm ^-1 : 1620,1326,1160,1139,831,761,598 NMR (CDCl ₃ ) δ ppm: 1.07 (3H, d, J = 6.35 Hz) , Around 1.95 (3H, br), 2.60 (2H, t, J = 6.0Hz), 2.96 (2H, m), 3.
05 (1H, m), 4.68 (2H, s), 5.78 (1H, dd, J = 15.87,7.8
2Hz), 6.27 (1H, d, J = 15.87Hz), 7.24 (2H, d, J = 8.30)
Hz), 7.31 (2H, d, J = 8.30Hz), 7.67 (1H, dd, J = 8.30,
7.32Hz), 8.18 (1H, d, J = 8.30Hz), 8.40 (1H, d, J = 6.
11Hz), 8.44 (1H, d, J = 7.32Hz), 8.61 (1H, d, J = 6.11
Hz), 9.32 (1H, s) Example 104 N- [2- (α-methyl-4-methylthiocinnamylamino) ethyl] -5-isoquinolinesulfonic acid amide Colorless amorphous IR (KBr) cm ⁻¹ : 1618 , 1493,1324,1160,1138,1094,830,80
7,760,598 NMR (CDCl ₃ ) δ ppm: 1.05 (3H, d, J = 6.35 Hz), 2.48 (3
H, s), 2.60 (2H, m), 2.96 (2H, t, J = 6.10Hz), 3.03
(1H, m), 5.75 (1H, dd, J = 15.87,7.81Hz), 6.22 (1H,
d, J = 15.87 Hz), 7.18 (4H, s), 7.67 (1H, dd, J = 8.30,
7.32Hz), 8.17 (1H, d, J = 8.30Hz), 8.43 (1H, d, J = 6.
10Hz), 8.44 (1H, d, J = 7.32Hz), 8.68 (1H, d, J = 6.10
Hz), 9.34 (1H, s) Example 105 N- [2- (α-methyl-4-methylsulfinylcinnamylamino) ethyl] -5-isoquinolinesulfonic acid amide Colorless amorphous IR (KBr) cm ⁻¹ : 1618,1326,1160,1138,1089,1041,831,76
2,599 NMR (CDCl ₃ ) δ ppm: 1.11 (3H, d, J = 6.59 Hz), 2.0 to 4.0
(2H, br), 2.65 (2H, m), 2.73 (3H, s), 3.00 (2H, t,
J = 5.62Hz), 3.15 (1H, m), 5.96 (1H, dd, J = 16.11,7.
81Hz), 6.36 (1H, d, J = 16.11Hz), 7.42 (2H, d, J = 8.3
0Hz), 7.58 (2H, d, J = 8.30Hz), 7.68 (1H, dd, J = 8.3
1,7.32Hz), 8.19 (1H, d, J = 8.31Hz), 8.44 (1H, d, J =
6.1Hz), 8.44 (1H, d, J = 7.32Hz), 8.67 (1H, d, J = 6.1
0 Hz), 9.35 (1H, s) Example 106 N- [2- (α-methyl-4-methylsulfonylcinnamylamino) ethyl] -5-isoquinolinesulfonic acid amide colorless amorphous IR (KBr) cm ⁻¹ : 1310,1149,1090,960,832,765,599,542 NMR (CDCl ₃ ) δ ppm: 1.09 (3H, d, J = 6.35 Hz), 2.62 (2
H, m), 2.98 (2H, t, J = 5.62Hz), 3.05 (3H, s), 3.10
(1H, m), 6.02 (1H, dd, J = 15.87,7.571Hz), 6.37 (1
H, d, J = 15.87Hz), 7.44 (2H, d, J = 8.30Hz), 7.69 (1
H, dd, J = 8.06,7.57Hz), 7.85 (2H, d, J = 8.30Hz), 8.2
0 (1H, d, J = 8.06Hz), 8.44 (1H, d, J = 6.35Hz), 8.45
(1H, d, J = 7.57Hz), 8.67 (1H, d, J = 6.35Hz), 9.36
(1H, s) Example 107 N- [2- (4-Cyano-α-methylcinnamylamino) ethyl] -5-isoquinolinesulfonic acid amide Colorless needles MP: 62 to 65 ° C IR (KBr) cm ^{− 1} : 2230,1620,1322,1140,600 NMR (CDCl ₃ ) δ ppm: 1.08 (3H, d, J = 6.3 Hz), 2.57 to 2.6
5 (2H, m), 2.9-3.0 (2H, m), 3.0-3.2 (1H, m), 5.9
8 (1H, dd, J = 15.9,7.8Hz), 6.33 (1H, d, J = 15.9Hz),
7.36 (2H, d, J = 8.3Hz), 7.58 (2H, d, J = 8.3Hz), 7.69
(1H, t, J = 8.0Hz), 8.20 (1H, d, J = 8.0Hz), 8.40-8.
50 (2H, m), 8.69 (1H, d, J = 6.1 Hz), 9.36 (1H, s) Example 108 N- [2- (4-carbamoyl-α-methylcinnamylamino) ethyl] -5- isoquinoline sulfonamide colorless needles MP: 66~70 ℃ IR (KBr) cm -1: 3450,1662,1610,1320,1160,1140 NMR (CDCl 3) δppm: 1.08 (3H, d, J = 6.4Hz ), 2.61 (2H,
m), 2.90-3.20 (3H, m), 5.93 (1H, dd, J = 16.1,7.8H
z), 6.32 (1H, d, J = 16.1Hz), 7.32 (2H, d, J = 8.3H)
z), 7.66 (1H, t, J = 8.3Hz), 7.74 (2H, d, J = 8.3H)
z), 8.18 (1H, d, J = 8.3Hz), 8.40-8.50 (2H, m), 8.
67 (1H, d, J = 6.1 Hz), 9.34 (1H, s) Example 109 N- [2- (4-acetamido-α-methylcinnamylamino) ethyl] -5-isoquinolinesulfonic acid amide colorless amorphous IR (KBr) cm ^-1 : 3300 ~ 2800,1670,1600,1538,1320,1160,
1140 NMR (CDCl ₃ ) δ ppm: 1.03 (3H, d, J = 6.6 Hz), 2.16 (3H,
s), 2.55-2.65 (2H, m), 2.90-3.10 (3H, m), 5.68
(1H, dd, J = 15.9,8.1Hz), 6.20 (1H, d, J = 15.9Hz),
7.17 (2H, d, J = 8.5Hz), 7.44 (2H, d, J = 8.5Hz), 7.66
(1H, dd, J = 8.3,7.3Hz ), 7.66 (1H, s, D 2 O in loss),
8.16 (1H, d, J = 8.3Hz), 8.44 (1H, d, J = 7.3Hz), 8.44
(1H, d, J = 6.1Hz), 8.61 (1H, d, J = 6.1Hz), 9.31 (1
H, s) Example 110 N- [2- (2-Nitro-3-methoxy-α-methylcinnamylamino) ethyl] -5-isoquinolinesulfonic acid amide monohydrochloride Colorless crystal MP: 159 to 163 ° C IR (KBr) cm ^-1 : 3450,3150-2600,1530,1330,1160,1140 NMR (DMSO-d ₆ ) δ ppm: 1.34 (3H, d, J = 6.6 Hz), 2.75-
3.0 (2H, m), 3.02 to 3.20 (2H, m), 3.90 (3H, s), 3.9
0 to 4.10 (1H, m), 6.30 (1H, dd, J = 15.9,8.6Hz), 6.57
(1H, d, J = 15.6Hz), 7.26 (1H, d, J = 7.8Hz), 7.32 (1
H, d, J = 7.8Hz), 7.83 (1H, t, J = 7.8Hz), 8.35 to 8.45
(3H, m), 8.52 (disappears in 1H, brs, D ₂ O), 8.70 (1H, d, J
= 6.1Hz), 9.25 (2H, brs, D 2 O in loss), 9.47 (1H,
s) Example 111 N- [2- (2-Methoxy-α-methylcinnamylamino) ethyl] -5-isoquinolinesulfonic acid amide colorless amorphous IR (KBr) cm ^-1 : 1490,1463,1326,1244, 1160,1138,755,59
9 NMR (CDCl ₃ ) δ ppm: 1.05 (3H, d, J = 6.35 Hz), 2.6 (2H,
m), 2.96 (2H, t, J = 5.62Hz), 3.04 (1H, m), 3.82 (3
H, s), 5.79 (1H, dd, J = 16.12,7.94Hz), 6.85 (1H, br
d, J = 8.06 Hz), 6.90 (1H, brt, J = 7.57 Hz), 7.21 (1H,
m), 7.31 (1H, dd, J = 7.57,1.71Hz), 7.66 (1H, dd, J =
8.06, 7.57Hz), 8.16 (1H, t, J = 8.06Hz), 8.44 (2H,
m), 8.67 (1H, d, J = 6.35 Hz), 9.33 (1H, s) [Effect of the Invention] The test method for determining the effectiveness of the compound according to the present invention and the results thereof are as follows. Was.

Relaxing action of vascular smooth muscle (VR, ED ₅₀ ) Rabbits were exsanguinated to death, laparotomy was performed, and the excised superior mesenteric artery was spirally incised according to a conventional method to prepare a strip specimen.
Krebs at 37 ± 0.5 ° C passed through oxygen gas containing carbon dioxide
The Henseleit solution was suspended under tension. The strip specimen was contracted with potassium chloride to maintain a constant tension, and then the target compound was cumulatively administered. As for the relaxation action, the concentration at which the contraction tension due to potassium chloride is relaxed by 50% is indicated, with the contraction tension caused by potassium chloride being 100%.

Platelet aggregation inhibition (PAIC ₅₀ ) Preparation of washed platelets (centrifugal washing method) Blood collected from healthy humans and immediately mixed with 1/10 volume of 0.38% sodium citrate is centrifuged (700 × G, 10 minutes). Platelet-rich plasma (PRP) was used, and this PRP was added to 1/6 volume of ACD solution (2.2% sodium citrate, 0.8% citric acid,
Glucose 2.2%-freshly prepared) and centrifugation (1500
× G, 10 minutes) to correct the platelet pellet obtained
HEPES Tyrode solution (salt 135mM, potassium chloride 2.7m
M, magnesium chloride 1 mM, glucose 0.1 mg / 1 ml, HEPES
20 mM; pH 7.4). After adding 1/6 volume of the ACD solution, the platelet pellet obtained by further centrifugation (1500 × G, 5 minutes) is suspended in the modified HEPES Tyrode solution, and
Use the washed platelet suspension of 100,000 cells / μl.

Measurement of platelet agglutination (turbidimetric method) To 270 µl of the washed platelet suspension obtained in the preceding section, 3 µl of each concentration of the test compound dissolved in an appropriate solvent is added.
After preheating for 30 minutes, 30μl of collagen 20μg / ml solution
, And the absorbance is measured using a 4-channel aggregometer (HEMA Tracer 601; manufactured by Nikko Bioscience).

Determination of Effect of Test Compound As a control, the absorbance at the time of maximum aggregation by collagen in the presence of the solvent used for the test compound is set to 100, and the absorbance before addition of collagen is set to 0. Then, from the absorbance at the time of maximum aggregation by collagen when the test compound was added,
Calculating the percentage of inhibition, and displays the concentration of the test compound giving 50% inhibition as IC _50.

Calmodulin-dependent phosphodiesterase inhibitory activity (CaMKII, IC ₅₀ ) 500 mM Tris-HCl (pH 8.0) 20 μl 50 mM magnesium chloride 20 μl 2 mM calcium chloride 20 μl (or 10 mM EGTA) 1 mg / ml bovine serum albumin (manufactured by Sigma) 20 μl phosphodiesterase 20 μl calmodulin 200 μg Test chemical (appropriate concentration of 10 μM to 1 mM) Make up to 200 μl with 20 μl distilled water.

The above solution was prepared in a test tube, and 4 μM [ ³ H]-
Cyclic guanosine monophosphate (2.5μCi / m
l) 20 μl was added, and the mixture was treated at 30 ° C. for 15 minutes, and then heated in a boiling water bath for 3 to 5 minutes. After cooling this reaction solution in ice water,
5 μ-nucleotidase (Sigma snake venom) 20 μg
And treated again at 30 ° C. for 10 minutes. After adding about 2 ml of water, the mixture was poured into a cation exchange resin (AG50W-X4, manufactured by Bio-Rad) column, and a washing solution for washing the test tube was also added. The column was washed with about 20 ml of water. Pour 3 ml of 3N ammonia water into this column, receive the eluted solution in a vial, add 10 ml of emulsified scintillation liquid (ACS-II, manufactured by Amersham), and elute with a liquid scintillation counter LS7500 (manufactured by Beckman). The radioactivity due to [ ³ H] -guanosine in the solution was measured, and the enzyme activity in the presence of calmodulin was defined as 0, and the μM concentration of the test drug that gave 50% inhibition was calculated as the IC ₅₀ value.

Calmodulin-dependent phosphodiesterase used in this experiment was partially purified from rat brain on a DEAE-cellulose column, and calmodulin was prepared from bovine brain by the TCA method and purified on a calmodulin inhibitor W-7 affinity column. Was.

EGTA is [ethylene bis (oxyethylene nitrilo)]
Tetraacetylic acid.

Other compounds according to the present invention are protein kinase A,
It had an inhibitory effect on enzymes such as myosin light chain kinase, protein kinase C and cyclic AMP-dependent phosphodiesterase, but had little effect on cardiac function.

In view of these results, the compound according to the present invention has a smooth muscle relaxing action, as a vasodilator, a cerebral circulation improving agent,
It is a low-toxic compound which is useful as a prophylactic and therapeutic agent for thrombosis because it has a platelet aggregation inhibitory action and as an antitumor agent because it inhibits the activity of various phosphorylases, and is suitable as a drug .

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI C07D 401/12 C07D 401/12 405/12 405/12 409/12 409/12 (72) Inventor Masatoshi Hagiwara Higashi-ku, Nagoya-shi, Aichi 2-66 Yadacho Nagoya University Yada Dormitory 232 (72) Inventor Isao Umezawa 2-21-16 Akabane Nishi, Kita-ku, Tokyo (72) Inventor Kenji Naito 5-7-6-106 (72) ) Inventor Inoue ▲ Tsumu ▼ 1-2-201, Futawa-nishi, Funabashi-shi, Chiba (72) Inventor Gihi Tomioka 5-11-806, Mihama, Urayasu-shi, Chiba (72) Inventor Osamu Sakuma Sekido, Tama-shi, Tokyo 2-40-3-1105 (72) Inventor Tadashi Morita 2-9-10 Minamikashiwa, Kashiwa City, Chiba Prefecture (72) Inventor Masayuki Yuasa 3-25-5-103 Showa-cho, Akishima City, Tokyo (72) Inventor Inaba Takayuki 3-3-11-403 Sakaecho, Higashimurayama-shi, Tokyo (56) References Open Akira 57-156463 (JP, A) JP Akira 58-121278 (JP, A) JP Akira 62-103066 (JP, A) (58 ) investigated the field (Int.Cl. ^6, DB name) C07D 217 / 02

Claims (2)

(57) [Claims] 1. The compound of the general formula (I) (Wherein R ¹ and R ² are the same or different and are hydrogen, substituted or unsubstituted lower alkyl, formyl, dimethoxyphenyl or chlorophenylpropargyl; R ³ is hydrogen or lower alkyl; R ⁴ , R ⁵ And R ⁶ are the same or different and are hydrogen, a halogen atom, a nitro group, a lower alkyl group, a di-lower alkylamino group, a lower alkoxy group, a polyfluoro lower alkyl group, a hydroxy group, a carboxy group, a carbamoyl group, a cyano group, and methoxycarbonyl. Group, hydroxymethyl group,
Methylthio group, methylsulfinyl group, methylsulfonyl group, acetamido group, methoxyethoxymethoxy group or a lower alkylenedioxy group in which two groups are combined; X is a vinylene group or ethynylene group; Ar is a phenyl group,
A naphthyl group or a heterocyclic group; m and n each represent an integer of 1 to 3); a quaternary ammonium salt thereof; and a nontoxic salt thereof. 2. A compound of the general formula (II) (Wherein n represents an integer of 1 to 3) to an isoquinolinesulfonic acid amide compound represented by the general formula (III): Wherein A is —CH ₂ Cl or —CO—R ³ ; R ⁴ , R ⁵ , and R ⁶ are the same or different and are hydrogen, halogen, nitro, lower alkyl, di-lower alkylamino, lower alkoxy Group,
Polyfluoro lower alkyl group, hydroxy group, carboxy group, carbamoyl group, cyano group, methoxycarbonyl group, hydroxymethyl group, methylthio group, methylsulfinyl group, methylsulfonyl group, acetamido group, methoxyethoxymethoxy group or two groups together X is a vinylene group or an ethynylene group; R ³ is hydrogen or a lower alkyl group; Ar is a phenyl group;
A naphthyl group or a heterocyclic group, m represents an integer of 1 to 3)
To the compound, if necessary, reduce
General formula (I) characterized by alkylating or formylating with R ¹ Ha and R ² Ha (Ha is a halogen) for introducing R ¹ and R ² groups and then forming a salt. (Wherein R ¹ and R ² are the same or different and are hydrogen, substituted or unsubstituted lower alkyl group, formyl group, dimethoxydiphenyl group or chlorophenylpropargyl group, R ³ , R ⁴ , R ⁵ , R ⁶ , X,
Ar, n and m represent the same groups as described above), or a quaternary ammonium salt thereof and a non-toxic salt thereof.