JP3159995B2 - Toluidine derivative and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention inhibits the activities of protein kinases and various phosphodiesterases and 5-.alpha.-reductase, thereby improving cerebral circulation, treating angina, preventing and treating thrombosis, and the like. The present invention relates to a novel toluidine derivative useful for suppressing tumor and prostatic hypertrophy and lowering blood sugar, and a method for producing the same.

[0002]

2. Description of the Related Art As a compound containing an isoquinoline ring and / or a sulfonamide as a part of its constituent molecules and inhibiting protein kinases to exhibit a vascular muscle relaxation or platelet aggregation-inhibiting action, Japanese Patent Application Laid-Open (JP-A) no. 57-156
463, 57-200366, 58-12127
8, 58-112279, 59-93054, 6
0-81168, 61-1226026, 61-15
2658, 612-27581, 61-27122
1, 61-293914, 62-103066, 62-111981, 63-2980, 63-21
Many publications have been published in each of the publications 1167 and 1167.

[0003]

Some of these compounds have a satisfactory effect of relaxing smooth muscle, but have low toxicity which is essential as a medicinal product as well as a medicinal effect.
And have your organ specificity and safety, room for improvement exists,
The compounds to be published also tended to be synthesized with awareness of them.

[0004]

Means for Solving the Problems In order to obtain a compound which is satisfactory as a drug, the present inventors have proposed a compound which has further improved safety while preserving its medicinal effects, as disclosed in Japanese Patent Application Nos. Filed Japanese Patent Application No. 11719. The present invention is a compound as a part thereof,
The novel toluidine derivative according to the present invention further enhances the conventional vasorelaxant action and significantly improves the undesired blood pressure lowering action of existing compounds.

The toluidine derivative for achieving the above object has a general formula (1): (Wherein iQ is 5-isoquinoline sulfonyl, 1-3
Lower alkoxy- substituted benzenesulfonyl, methanesulfonyl, lower alkyl group, lower alkoxy group, or
Mino lower alkyl group (amino group is substituted with lower alkyl group
Benzoyl substituted with a may be), the full acryloyl or nicotinate Noi Le, Ph is a phenylene which may be substituted with methoxy, X is nitrogen or sulfur, A is a vinylene or methyleneoxy, Ar 1 is halogen, methyl, cyano and have the methoxycarbonyl, lower alkoxycarbonyl <br/> alkoxy other than methoxy, phenyl substituted with 1-3 methoxy selected from the group, R ₁ is located represents hydrogen ~ 2 hydroxy, amino, ethoxycarbonyl, amino lower alkoxy, acetoxy, hydroxy lower alkoxy,
Methoxy, been the or unsubstituted lower alkyl substituted with a group selected from pyrrolidine, R ₂ is X is represented when only shows the <br/> hydrogen or lower alkyl) nitrogen.

The compound ( Chemical Formula 1 ) according to the present invention has a substituted toluidine as a mother nucleus, and all of them strongly inhibit the activities of various protein kinases, phosphodiesterases and 5-α-reductase, and have side effects. Is a novel compound that has significantly improved blood pressure lowering action.

The second invention of the present invention relates to a method for producing the compound represented by the above formula (1), and comprises a general formula (2): Wherein Ph, X, R ₂ , A and Ar have the same meanings as in Chemical Formula 1. [Wherein iQ has the same meaning as in Chemical Formula 1], or amidated with an acid or a reactive derivative thereof, or further represented by General Formula (Formula 4): [Wherein R ₃ is substituted by 1 to 2 hydroxy, amino, ethoxycarbonyl, amino lower alkoxy, acetoxy, hydroxy lower alkoxy, methoxy, pyrrolidine (provided that the hydroxy and amino in the group may be protected)] Or an unsubstituted lower alkyl, and Y represents hydroxy or halogen], and then, if necessary, removing the protecting group.

[0008] The method for producing a compound according to the present invention will be briefly described with reference to actual compounds. 1), General formula (Formula 5):

Embedded image And a toluidine compound of the general formula (Formula 6):

A compound obtained from a halogenated form of Ar-A-CH ₂ -Cl is reduced to obtain a compound represented by the following general formula (Formula 7):

Embedded image A toluidine compound of the general formula (Formula 8):

## STR8 ## After amidation by reacting iQ-Cl.sub.2, the compound of formula (9) is obtained by Mitsunobu reaction.

HOCH₂CH₂OCOCH₃  To alkylate the amide and, if necessary, alkali
Deacetylation by hydrolysis yields the general formula (Formula 10):

Embedded image It is possible to obtain an example of the present invention compounds. Chi words,
A method in which cinnamyl halide is reacted with 2-nitro-N-methylbenzylamine, reduced, sulfonamidated, alkylated by Mitsunobu reaction, and if necessary, the protecting group is eliminated.

The compound of the present invention can be produced by the following method in addition to this method. 2) Reaction of cinnamaldehyde with 2-nitrobenzylamine and treatment with sodium borohydride 2
N-methylation of -nitro-N-cinnamylbenzylamine, followed by reduction with tin to sulfonate the resulting amino acid and, if necessary, removing the protecting group

3) A method of reducing with tin in 2), alkylating with a halide, and then amidating

4) 2-nitro-N-methyl-N-Bo
C-benzylamine is catalytically reduced with palladium / carbon, and the amine is sulfonated to obtain N- [2-
(N'-Boc-N'-amino) methyl] phenyl-sulfonamide is alkylated with a halide in the presence of Mitsunobu reaction or sodium hydride, Boc is eliminated, and treated with cinnamyl halide or cinnamaldehyde and a reducing agent. And, if necessary, removing the protecting group

5) After the reaction of cinnamyl halide with 2-nitrobenzylmercaptan, the same treatment as in 2) is performed to obtain a sulfonamide, which is further alkylated with a halide, and if necessary, the protecting group is eliminated. Method

6) A method of reacting 2-nitro-N-methylbenzylamine with cinnamaldehyde and a reducing agent or cinnamyl halide, reducing with tin, and further sulfonamidating.

In this context, "reduction" and "catalytic reduction" refer to the reduction of a nitro group to an amino group, "sulfonamidation" and "amidation" refer to the amidation of the amino group, and "alkylation" refers to the same. In the alkylation of the amino group, "elimination of the protecting group" mainly indicates elimination of the protecting group for the substituent of the alkyl.

[0015] The present invention Methods Contact Keru amidation reaction in the addition using a solvent which also serves as a such as pyridine base, tetrahydrofuran, methylene chloride, dimethylformamide, dioxane, chloroform (containing no alcohol) aprotic solvent such as When carried out in, it is preferably carried out in the presence of a base such as triethylamine, the alkylation by Mitsunobu reaction is tetrahydrofuran, dioxane,
It is carried out in an aprotic solvent such as methylene chloride.

[0016] For protecting groups used in the manufacturing method of the present compound, but both are intended to be used have _your normal chemical reactions, for example as an ester type of hydroxy protecting groups are acetyl, phenylacetyl , each Ki acid residue benzoyl, tetrahydropyranyl as ether type, p- methoxybenzyl, methoxyethoxymethyl and the like, acetyl amino protecting group, benzoyl, t-butoxycarbonyl, benzyloxycarbonyl, phthaloyl and the like And hydroxycarbonyl protecting groups such as methyl, ethyl and benzyl .
Doo-out various alcohols are used.

The Mitsunobu reaction was performed based on the following literature.
Synthesis, pages 1-28 (19 )
81)

[0018]

EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples. The melting point in the examples the melting point measuring YamatoM
It was measured with a capillary using P-21 (manufactured by Yamato Scientific Co., Ltd.), and the nuclear magnetic resonance spectrum ( ¹ H-NMR) was JEO.
L, JNM-FX200 (manufactured by JEOL Ltd.), the molecular weight was measured using a JMS-D300 mass spectrometer (manufactured by JEOL Ltd.), and the infrared absorption spectrum (IR) was measured by IRA-
1 (manufactured by JASCO Corporation).

Reference Example 1 2-nitrobenzylamine 11 g of 2-nitrobenzyl chloride was dissolved in 100 ml of dimethylformamide, and 9.62 g of sodium iodide was dissolved.
及 beauty phthalimide potassium 13.0g was added, 2 at 100 ° C.
It was time stirring . After cooling, water 200ml added and after the precipitated crystals suction filtration, washed with water, and heated to reflux for 1 hour by adding ethanol 150ml and hydrazine hydrate 15ml crystal obtained air dried (about 15 g). After cooling, concentrate the ethanol layer to about 1/3 volume, then 1N
Adding caustic soda 300 ml, chloroform 150m
and the aqueous layer was further extracted with 150 ml of chloroform. The extract is dried over magnesium sulfate, and the solvent is removed under reduced pressure.
The residue obtained by distilling off subjected to silica gel column, chloroform and chloroform - methanol: to obtain the desired compound 9.65g of colorless MuAkirajo from fractions eluted with (100 1). NMR (CDClc) δ ppm: 1.67 (> 2H,
s), 4.11 (2H, s), 7.43 (1H, m),
7.56 to 7.63 (2H, m), 7.99 (1H,
d, J = 7.81 Hz)

Reference Example 2 t-butyl 2-nitrobenzyl carbamate 9.65 g of the amorphous substance obtained in Reference Example 1 was dissolved in 90 ml of dimethylformamide, and 9 ml of water, 12.31 g of diisopropylethylamine and di-t-butyl dicarbonate 1
6.63 g was added, and the mixture was stirred at room temperature for 14 hours. Saturated saline was added to the reaction solution, and then 400 ml of chloroform was added.
In extracted twice, dried over magnesium sulfate, the residue was subjected obtained by distilling off the solvent under reduced pressure to a silica gel column, hexane - ethyl acetate (4: 1) Colorless than fractions eluted with MuAkirajo 12.54 g of the desired product was obtained. NMR (CDClc) δ ppm: 1.44 (9H,
s), 4.57 (2H, d, J = 6.30 Hz);
32 (1H, br), 7.37 to 7.52 (1H,
m), 7.55 to 7.68 (2H, m), 8.06 (1
H, d, J = 7.43 Hz)

Reference Example 3 t-butyl 2-aminobenzylcarbamate 12.54 g of the amorphous substance obtained in Reference Example 2 was treated with methanol 300
dissolved in ice-cold water and 3 g of 5% palladium / carbon under ice-cooling
And stirred in a hydrogen atmosphere. Washed palladium / carbon aspiration collected by filtration to methanol, combined filtrate and washings, and the residue obtained by distilling off the solvent under reduced pressure and subjected to silica gel column, the product from the fraction eluted with chloroform Was recrystallized from ether-hexane to obtain 7.56 g of the target compound as colorless crystals. NMR (CDClc) δ ppm: 1.45 (9H,
s), around 4.2 (2H, br), 4.24 (2H,
d, J = 6.10 Hz), 4.75 (1H, br),
6.60 to 6.73 (2H, m), 6.97 to 7.15
(2H, m)

Reference Example 4 N- [2- (t-butoxycarbonylamino) methyl]
Phenyl-5-isoquinoline sulfonamide 5.56 g of the product of Reference Example 3 was dissolved in 80 ml of pyridine, and 7.87 g of isoquinoline sulfonyl chloride hydrochloride was added thereto while stirring at room temperature, followed by stirring for 15 hours. After adding 600 ml of ethyl acetate to the reaction solution,
After drying with washing, magnesium sulfate in each 300ml of saturated brine, the residue was subjected obtained by distilling off the solvent under reduced pressure to a silica gel column, chloroform - methanol (10
0: 1) then hexane-ethyl acetate (2: 1 to 1:
10.0 g of the target compound as colorless crystals from the fraction eluted in 1)
I got IR (KBr) cm ^-1 : 3426, 1670, 152
0,1337,1290,1162,1140,76
1,604,571,509, NMR (CDClc) δ
ppm: 1.47 (9H, s), 3.80 (2H, d,
J = 6.59 Hz), 5.07 (1H, brt, J =
6.59 Hz), 6.93 to 7.10 (2H, m),
7.12 to 7.26 (1H, m), 7.39 (1H,
d, J = 8.30 Hz), 7.63 (1H, dd, J =
8.05, 7.57 Hz), 8.15 (1H, br)
d), 8.42 (1H, dd, J = 7.57, 1.22)
Hz), 8.59 (1H, d, J = 6.1 Hz), 8.
65 (1H, brs), 9.31 (1H, brs), 1
0.08 (1H, brs)

Reference Example 5 N- [2- (t-butoxycarbonylamino) methyl]
Phenyl-N-methyl-5-isoquinolinesulfonic acid amide 3.0 g of the crystal obtained in Reference Example 4 was treated with dimethylformamide-
Dissolve in 30 ml of tetrahydrofuran (1: 1), add 1.24 g of methyl iodide, and add 305 ml of 60% sodium hydride while stirring under ice-cooling.
The ice bath was removed, the temperature was returned to room temperature, and the mixture was stirred for 3 hours. Subjected after adding ethyl acetate 400ml to the reaction solution, twice with water, each washed once with saturated brine, dried over magnesium sulfate, the residue obtained by distilling off the solvent under reduced pressure to a silica gel column, From the fraction eluted with hexane-ethyl acetate (2: 1 to 1: 1), 2.26 g of a colorless crystalline target compound was obtained. NMR (CDClc) δ ppm: 1.48 (9H,
s), 3.23 (3H, s), 4.39 (1H, dd,
J = 14.30, 7.08 Hz), 4.68 (1H, d
d, J = 14.30, 7.81 Hz), 5.38 (1
H, br), 6.25 (1H, dd, J = 8.06,
0.98 Hz), 6.90 (1H, brt), 7.29
(1H, brt), 7.56 (1H, brd), 7.7
0 (1H, dd, J = 8.05, 7.57 Hz), 8.
11 (1H, brd), 8.25 (1H, brd),
8.29 (1H, dd, J = 7.57, 1.22H
z), 8.48 (1H, d, J = 6.10 Hz), 9.
34 (1H, brd)

Example 1 N- [2- (4-chlorocinnamylamino) methyl] phenyl-N-methyl-5-isoquinolinesulfonic acid 2.26 g of the crystal obtained in Reference Example 5 was dissolved in 10 ml of methanol. Under stirring at room temperature, 35 ml of a 4N hydrogen chloride / ethyl acetate solution was added, and the mixture was stirred for 30 minutes. The solvent distilled Sanochi under reduced pressure, after alkaline with sodium bicarbonate, chloroform - extracted twice with methanol 100 ml. The extract was dried over magnesium sulfate, then the residue obtained by distilling off the solvent under reduced pressure dissolved in methanol 20 ml, p-Kuroroshin cinnamaldehyde 1.06g was added, at room temperature for one hour
Stirred . Sodium borohydride 240 under ice cooling
Add 15 mg at 0 ° C for 15 minutes and return to room temperature for 15 minutes .
After stirring , the reaction solution was poured into a saturated aqueous solution of sodium bicarbonate and extracted twice with 100 ml of chloroform. Dried over magnesium sulfate, the residue obtained by distilling off the solvent under reduced pressure chloroform - methanol (100: 1 to 50: 1) silica gel column with eluting solvent, the desired product 1 as a pale yellow MuAkirajo. 80 g were obtained. IR (KBr) cm ^-1 : 1490, 1346, 113
5,835,762,708,601,578,53
5, NMR (CDClc) δ ppm: 3.24 (3H,
s), 3.44 (2H, dd, J = 6.10, 0.97)
Hz), 3.94 (2H, s), 6.30 (1H, d
t, J = 15.87, 6.10 Hz), 6.38 (1
H, brd), 6.52 (1H, brd), 6.93
(1H, brt), 7.26 (2H, d, J = 8.30)
Hz), 7.32 (2H, d, J = 8.30 Hz),
7.24 to 7.34 (1H, m), 7.60 (1H, b
rd), 7.68 (1H, dd, J = 8.06, 7.5)
7 Hz), 8.12 (1H, brd), 8.22 (1
H, b, d), 8.30 (1H, dd, J = 7.57,
1.22 Hz), 8.46 (1H, d, J = 6.10H)
z), 9.32 (1H, brd)

Example 2 The crystals obtained in Reference Example 4 were treated in the same manner as in Example 1 to give pale yellow amorphous N- [2- (4-chlorocinnamylamino) methyl] phenyl-5-isoquinoline sulfone. The acid amide was obtained. IR (KBr) cm ^-1 : 1491,1336,128
6,1161,1139,1109,833,760,
598, 571, 530, 510, NMR (CDCl
c) δ ppm: around 1.7 (2H, br), 3.34
(2H, dd, J = 6.35, 0.98 Hz), 3.5
0 (2H, s), 6.27 (1H, dt, J = 16.1)
1.6.35Hz), 6.50 (1H, brd), 6.
85 to 7.0 (2H, m), 7.1 to 7.25 (1H,
m), 7.32 (4H, s), 7.42 (1H, br)
d), 7.60 (1H, dd, J = 8.05, 7.57)
Hz), 8.14 (1H, brd), 8.4-8.53
(2H, m), 8.55 (1H, d, J = 6.35H)
z), 9.31 (1H, brd)

Example 3 N- {2- (4-chloro-N-methylcinnamylamino) methyl} phenyl-N-methyl-5-isoquinolinesulfonic acid amide 523 mg of the amorphous substance obtained in Example 1 was added to 5 ml of methanol. After dissolving, 0.1 ml of 37% formalin was added and stirred at room temperature for 1 hour. The reaction solution was ice-cooled, 46 mg of sodium borohydride was added, and the mixture was stirred at 0 ° C for 5 minutes, and then returned to room temperature and stirred for 30 minutes. After the reaction solution was poured into saturated sodium bicarbonate solution, extracted twice with chloroform 50 ml, dried over magnesium sulfate, the residue was subjected obtained by distilling off the solvent under reduced pressure to a silica gel column, chloroform - methanol (100: 1 ) Was eluted to obtain 350 mg of a pale yellow amorphous target product. NMR (CDClc) δ ppm: 2.18 (3H,
s), 3.13 (2H, d, J = 5.37 Hz);
25 (3H, s), 3.35 to 3.67 (1H, m),
3.67 to 3.95 (1H, m), 6.23 (1H, d
t, J = 15.87, 5.37 Hz), 6.35-6.
55 (2H, m), 6.93 (1H, brt), 7.1
5-7.45 (5H, m), 7.6-7.75 (2H,
m), 8.14 (1H, brd), 8.20 (1H, b
rd), 8.28 (1H, dd, J = 7.32, 1.2)
2.47), 8.47 (1H, d, J = 6.11 Hz),
9.31 (1H, brs)

Reference Example 6 2-nitro-N-methyl-benzylamine hydrochloride 45.3 g of 2-nitrobenzaldehyde in methanol 9
07.9 ml of a 40% aqueous methylamine solution at room temperature
After stirring 1 hour added ml, and added One not a sodium borohydride 10g under ice-cooling. Ethyl acetate and water were added to the solution, and the mixture was saturated with sodium chloride, extracted three times with 150 ml of ethyl acetate, dried over magnesium sulfate,
The residue obtained by concentration under reduced pressure was applied to a silica gel column,
From the fraction eluted with ethyl acetate-methanol (9: 1), 42.15 g of an orange oil was obtained, dissolved in 300 ml of ethyl acetate, and 70 ml of 4N hydrogen chloride / ethyl acetate was added dropwise under ice cooling. After stirring for 1 hour, the precipitated crystals were collected by filtration , washed with ethyl acetate and n-hexane,
Drying under reduced pressure gave 48.39 g of the target compound as a colorless crystal.

Reference Example 7 2-Nitro-N-methyl-benzylamine hydrochloride 2-nitrobenzyl chloride 50 g of methanol 250
225 ml of a 40% aqueous solution of methylamine was added to the ml solution under ice cooling under a nitrogen atmosphere, and the mixture was stirred at room temperature for 17 hours. This was concentrated under reduced pressure to about 300 ml, saturated sodium bicarbonate (50 ml) and sodium chloride were added, and chloroform (150 ml) was added.
The residue obtained by extracting with magnesium sulfate three times, drying with magnesium sulfate and concentrating under reduced pressure was applied to a silica gel column, and chloroform-
From the fraction eluted with methanol (49: 1), a red oily substance was obtained, which was treated in the same manner as in Reference Example 6 to obtain 48.17 g of a light brown target substance.

REFERENCE EXAMPLE 8 Methyl 4-chlorocinnamic acid ester To a suspension of 50 g of 4-chlorocinnamic acid in 250 ml of methanol was added 5 ml of concentrated sulfuric acid, and the mixture was refluxed for 2.5 hours and concentrated under reduced pressure to about 100 ml. After adding 100 ml of saturated sodium bicarbonate, the mixture was extracted with 300 ml of ethyl acetate. The extract was washed successively with an aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, concentrated under reduced pressure, and dried under reduced pressure to obtain 53.78 g of the target compound as colorless crystals.

Reference Example 9 4-chlorocinnamyl alcohol 44.2 g of the crystal obtained in Reference Example 8 was dried in tetrahydrofuran.
Cool the 300 ml solution to −20 ° C.
300ml of aluminum hydride is dropped over 1 hour
did. Transfer to water bath, water 67ml, 1NOrWater soluble soda
Be careful with 67ml of liquidDeep1.5 hoursStirring
rear,RoThe mixture was washed with tetrahydrofuran.RoLiquid and washing
Combine the purified solutions, concentrate under reduced pressure, add about 200 ml of toluene
After further concentration under reduced pressure, 37.3% of colorless crystals obtained by drying under reduced pressure.
22.93 g of g was dropped into a calcium chloride tube.funnelTo
And put 150 ml of chloroform
Add 15 ml of thionyl chloride dropwise over 30 minutes while adding water
And then 20 minutesStirringdid. N-Hexane 2
The concentration under reduced pressure after the addition of 00 ml was repeated three times.
Azeotropic removal of thionyl chloride from
6.57 g were obtained.

Reference Example 10 2-nitro-N- (4-chlorocinnamyl) -N-methyl-benzylamine 26.33 g of the crystal of Reference Example 6 and the crystal of Reference Example 29.
To a suspension of 17 g of methylene chloride (200 ml) was added dropwise 32.83 g of triethylamine over 40 minutes under ice-cooling, and the mixture was stirred at room temperature for 17 hours. Saturated saline was added thereto, and the mixture was separated. The aqueous layer was extracted three times with 150 ml of chloroform.
After drying over magnesium sulfate, the residue obtained by concentrating under reduced pressure was applied to a silica gel column, and 27.43 g of the yellow crystalline target product was obtained from the fraction eluted with n-hexane-ethyl acetate (4: 1). Obtained. NMR (CDClc) δ ppm: 2.12 (3H,
s), 3.08 (2H, d, J = 6.4 Hz), 3.7
4 (2H, s), 6.12 (1H, dt, J = 6.4,
15.9 Hz), 6.38 (1H, d, J = 15.9H)
z), 7.19 (4H, s), 7.31 (1H, d, J
= 7.3 Hz), 7.45 (1H, t, J = 7.3H)
z), 7.53 (1H, t, J = 7.3 Hz), 7.7
3 (1H, d, J = 7.3 Hz)

Reference Example 11 2-amino-N- (4-chlorocinnamyl) -N-methyl-benzylamine 27.0 g of the crystal obtained in Reference Example 10 was added to 260 ml of acetic acid,
Dissolve it in 260 ml of normal hydrochloric acid, carefully add 27.0 g of tin at room temperature, stir for 40 minutes, and remove the solvent under reduced pressure.
It was distilled off. After alkalified by adding 10% caustic potash solution to this, by adding ethyl acetate 300ml was stirred for 30 minutes, vacuum insolubles in funnel topped with silica gel
I filtered . After separating the organic layer from the filtrate , the aqueous layer was extracted twice with 200 ml of ethyl acetate, and the combined organic layers were dried over magnesium sulfate, concentrated under reduced pressure, and dried under reduced pressure to obtain a light yellow crystalline target compound. 23.17 g were obtained. NMR (CDClc) δ ppm: 2.19 (3H,
s), 3.13 (2H, d, J = 6.8 Hz), 3.5
3 (2H, s), 4.50 (2H, brs), 6.20
(1H, dt, J = 6.8, 15.9 Hz), 6.45
(1H, d, J = 15.9 Hz), 6.6 to 6.8 (2
H, m), 6.9 to 7.2 (2H, m), 7.27 (4
H, s)

Example 4 2- (4-methoxybenzenesulfonyl) amino-N-
(4-chlorocinnamyl) -N-methyl-benzylamine In a solution of 5.16 g of the crystals obtained in Reference Example 11 in 10 ml of pyridine, p-methoxybenzenesulfonyl chloride 4.46 was added.
g of methylene chloride solution (10 ml) was added dropwise over 30 minutes under ice cooling, and the mixture was stirred at room temperature for 25 hours. This ethyl acetate 50 ml, saturated sodium bicarbonate 20m and l and after stirring separation adding a saturated aqueous sodium chloride solution 20 ml, and the aqueous layer was combined organic layer was extracted twice with ethyl acetate 50 ml. After drying over magnesium sulfate, the residue obtained by concentrating under reduced pressure was applied to a silica gel column, and n-hexane-ethyl acetate (4: 1 to 1) was used.
7. From the fraction eluted in 1: 1), the target compound is a pale yellow oil.
00 g were obtained. NMR (CDClc) δ ppm: 2.16 (3H,
s), 3.15 (2H, d, J = 6.3 Hz), 3.2
7 (2H, s), 3.75 (3H, s), 6.29 (1
H, dt, J = 15.9, 6.3 Hz), 6.51 (1
H, d, J = 15.9 Hz), 6.67 (2H, d, J)
= 9.0 Hz), 6.9 to 7.0 (2H, m), 7.2
７7.3 (1H, m), 7.32 (2H, d, J = 9.
1 Hz), 7.37 (2H, d, J = 9.1 Hz),
7.54 (1H, d, J = 8.8 Hz), 7.62 (2
(H, d, J = 9.0 Hz)

The following compound was obtained in the same manner as in Example 4.

Example 5 2- [N- (5-isoquinolinesulfonyl)] amino-
N- (4-chlorocinnamyl) -N-methyl-benzylamine colorless amorphous NMR (CDClc) δ ppm: 2.17 (3H,
s), 3.18 (2H, d, J = 6.6 Hz), 3.3
4 (2H, s), 6.38 (1H, dt, J = 15.
9, 6.6 Hz), 6.55 (1H, d, J = 15.9)
Hz), 6.91 (2H, d, J = 4.5 Hz), 7.
1 to 7.2 (1H, m), 7.25 to 7.4 (5H,
m), 7.62 (1H, t, J = 7.3 Hz), 8.1
4 (1H, d, J = 7.3 Hz), 8.4 to 8.6 (3
H, m), 9.30 (1H, s)

Example 6 2- [2- (4-chlorophenoxy) ethylthio] methyl-N- (5-isoquinolinesulfonyl) -aniline pale yellow oil NMR (CDClc) δ ppm: 2.6 (2H, t, J
= 6.3 Hz), 3.35 (2H, s), 3.95 (2
H, d, J = 6.3 Hz), 6.75 (2H, d, J =
9.1Hz), 7.0~7.15 (2H, Comp Lek
S ), 7.15 to 7.4 (4H, complex ),
7.65 (1H, dd, J = 8.3, 6.3 Hz),
8.03 (1H, brs), 8.2 (1H, d, J =
8.3 Hz), 8.38 (1H, d, J = 8.3H)
z), 8.43 (1H, d, J = 6.3 Hz), 8.6
2 (1H, d, J: 6.3 Hz), 9.35 (1H,
s)

2- [2- (4
The analytical data of -chlorophenoxy) ethylthio] methyl-nitrobenzene are as follows. Pale yellow oil NMR (CDClc) δ ppm: 2.85 (2H, t,
J = 7.3 Hz), 4.1 (2H, t, J = 7.3H)
z), 4.2 (2H, s), 6.8 (2H, d, J =
9.9 Hz), 7.23 (2H, d, J = 9.9H)
z), 7.4-7.7 (3H, complex ), 8.
0 (1H, d, J = 9.7 Hz)

Example 7 2- (4-chlorocinnamylthiomethyl) -N- (5-
Isoquinoline sulfonyl) -aniline pale yellow oil NMR (CDClc) δ ppm: 3.1 (2H, d, J
= 7.0 Hz), 3.25 (2H, s), 6.05 (1
H, dd, J = 15.8, 7.0 Hz), 6.25 (1
H, d, J = 15.8 Hz), 6.95 to 7.4 ( toe
Tal 8H, complex ), 7.6 (1H, dd, J
= 8.3, 6.3 Hz), 8.15 (1H, d, J =
8.3 Hz), 8.2 (1H, d, J = 6.3 Hz),
8.4 (1H, d, J = 6.3 Hz), 8.43 (1
H, d, J = 6.3 Hz), 8.65 (1H, d, J =
6.3 Hz), 9.35 (1H, s)

The analytical data of 2- (4-chlorocinnamylthio) methyl-nitrobenzene which is an intermediate of this compound is as follows. Pale yellow oil NMR (CDClc) δ ppm: 3.25 (2H, d,
J = 7.1 Hz), 4.05 (2H, s), 6.1 (1
H, dt, J = 15.5, 7.1 Hz), 6.37 (1
H, d, J = 15.5 Hz), 7.28 (4H, s),
7.1 to 7.6 (3H, complex ), 7.96
(1H, d, J = 6.8Hz)

Example 8 2- [N- (5-isoquinolinesulfonyl)] amino-
N-methyl-N- (4-methylcinnamyl) benzylamine pale yellow amorphous NMR (CDClc) δ ppm: 2.14 (3H,
s), 2.33 (3H, s), 3.17 (2H, d, J
= 6.6 Hz), 3.33 (2H, s), 6.32 (1
H, dt, J = 15.8, 5.6 Hz), 6.54 (1
H, d, J = 15.8 Hz), 6.89 (2H, d, J)
= 4.2 Hz), 7.12 to 7.16 (3H, m),
7.31 to 7.42 (4H, m), 7.58 (1H,
t, J = 7.6 Hz), 8.11 (1H, d, J = 8.
2Hz), 8.42 to 8.50 (3H, m), 9.26
(1H, s)

Example 9 2- [N- (5-isoquinoline sulfonyl)] amino-
N-(4-methoxy cinnamyl) -N- methyl - base emissions di <br/> triethanolamine pale yellow oil NMR (CDClc) δppm: 2.14 ( 3H,
s), 3.17 (2H, d, J = 6. Hz), 3.34
(2H, s), 3.81 (3H, s), 6.16-6.
32 (1H, m), 6.53 (1H, d, J = 16.0)
Hz), 6.83-6.94 (5H, m), 7.08-
7.20 (1H, m), 7.35 to 7.42 (3H,
m), 7.60 (1H, t, J = 7.4 Hz), 8.1
3 (1H, d, J = 6.2 Hz), 8.47 to 8.51
(3H, m), 9.28 (1H, s)

Example 10 2- [N- (5-isoquinolinesulfonyl)] amino-
N- (4-fluorocinnamyl) -N-methyl-benzylamine yellow amorphous NMR (CDClc) δ ppm: 2.20 (3H,
s), 3.18 (2H, d, J = 5.4 Hz), 3.3
4 (2H, s), 6.32 (1H, dt, J = 15.
6, 5.4 Hz), 6.62 (1H, d, J = 15.6)
Hz), 6.90 (2H, d, J = 4.2 Hz), 7.
04 (2H, t, J = 8.0 Hz), 7.12 to 7.2
0 (1H, m), 7.38 to 7.47 (3H, m),
7.62 (1H, t, J = 7.4 Hz), 8.14 (1
H, d, J = 8.0 Hz), 8.44 to 8.52 (4
H, m), 9.30 (1H, s)

Example 11 2- [N- (5-isoquinolinesulfonyl)] amino-
N- (4-cyanocinnamyl) -N-methyl-benzylamine pale yellow amorphous NMR (CDCl ₃ ) δ ppm: 2.20 (3H,
s), 3.22 (2H, d, J = 5.6 Hz), 3.3
5 (2H, s), 6.51 (1H, dt, J = 15.
9, 5.6 Hz), 6.64 (1H, d, J = 15.9)
Hz), 6.92 (2H, Brd), 7.1-7.2
(1H, m), 7.38 (1H, d, J = 8.1H)
z), 7.51 (2H, d, J = 8.5 Hz), 7.6
７7.7 (3H, m), 8.16 (1H, d, j = 8.
3 Hz), 8.4 to 8.6 (3H, m), 9.32 (1
H, s)

Example 12 2- [N- (5-isoquinolinesulfonyl)] amino-
N- (4-methoxycarbonylcinnamyl) -N-methyl-benzylamine pale yellow amorphous NMR (CDCl ₃ ) δ ppm: 2.19 (3H,
s), 3.21 (2H, d, J = 6.1 Hz), 3.3
4 (2H, s), 3.92 (3H, s), 6.48 (1
H, dt, J = 15.9, 6.1 Hz), 6.62 (1
H, d, J = 15.9 Hz), 6.92 (2H, d, J)
= 4.2 Hz), 7.1 to 7.2 (1H, m), 7.4
0 (1H, d, J = 8.0 Hz), 7.48 (2H,
d, J = 8.3 Hz), 7.62 (1H, t, J = 7.
8 Hz), 8.01 (2H, d, J = 8.3 Hz),
8.14 (1H, d, J = 8.0 Hz), 8.4-8.
6 (3H, m), 9.30 (1H, s)

Example 13 2- (5-isoquinoline sulfonyl) amino-N- [2
-(4-Chlorophenoxy) ethyl] -N-methyl-benzylamine colorless oil NMR (CDCl ₃ ) δ ppm: 2.14 (3H,
s), 2.8 (2H, brt), 3.29 (2H,
s), 4.11 (2H, complex ), 6.85-
7.0 (2H, complex ), 6.95 (2H,
d, J = 9.0Hz), 7.1~7.3 ((1H, con
Plex ), 7.25 (2H, d, J = 9.0H)
z), 7.45 (1H, brd), 7.61 (1H, d
d, J = 6.3, 8.3 Hz), 8.15 (1H, d,
J = 8.3Hz), 8.4~8.6 (3H , compressors
C ), 9.3 (1H, s)

The analytical data of the intermediate of this compound was as follows. N- [2- (4-chlorophenoxy) ethyl] -2-nitrobenzylamine pale yellow oil NMR (CDCl ₃ ) δ ppm: 3.0 to 3.2 (2
H, br), 4.0-4.2 (2H, br), 4.18
(2H, s), 6.83 (2H, d, J = 9.0H)
z), 7.24 (2H, d, J = 9.0 Hz), 7.4
5 (1H, brt), 7.61 (1H, brt), 7.
68 (1H, complex ), 8.0 (1H, d, J
= 8.0Hz)

N- [2- (4-chlorophenoxy) ethyl] -N-methyl-2-nitrobenzylamine NMR (CDCl ₃ ) δ ppm: 2.31 (3H, br)
s), 2.83 (2H, brt), 3.92 (2H, b
rs), 4.02 (2H, brt), 6.82 (2H,
d, J = 9.0 Hz), 7.24 (2H, d, J = 9.
0 Hz), 7.3 to 7.45 (1H, br), 7.45
To 7.7 (2H, br), 7.75 to 7.9 (1H, b
r)

Example 14 4- [N- (5-isoquinoline sulfonyl)]-amino-N- (4-chlorocinnamyl) -N-methyl-benzylamine colorless amorphous NMR (CDCl ₃ ) δ ppm: 2.15 (3H,
s), 3.1 (2H, d, J = 6.6 Hz), 3.4
(2H, s), 6.2 (1H, dd, J = 16.6,
6.6 Hz), 6.45 (1H, d, J = 16.6H)
z), 6.9 (2H, d, J = 8.1 Hz), 7.15
(2H, d, J = 8.1 Hz), 7.3 (4H, s),
7.6 (1H, dd, J = 8.0, 6.1 Hz), 8.
18 (1H, d, J = 8.0 Hz), 8.35 (1H,
d, J = 6.1 Hz), 8.4 (1H, d, J = 6.1)
Hz), 8.68 (1H, d, J = 6.1 Hz), 9.
34 (1H, s)

Example 15 2- [N- (2-acetoxyethyl) -N- (4-methoxybenzenesulfonyl)] amino-N- (4-chlorocinnamyl) -N-methyl-benzylamine 671 mg of the obtained liquid, 216 mg of 2-hydroxyethyl acetate and 578 mg of triphenylphosphine
Was added dropwise over 5 minutes to a 7 ml solution of tetrahydrofuran under ice-cooling over 1 minute, and a solution of 446 mg of diisopropylazodicarboxylate was added dropwise over 5 minutes.
Stirred . The residue obtained by concentrating the reaction solution under reduced pressure was applied to a silica gel column, and the desired product as a pale yellow oil was obtained as a crude product from the fraction eluted with n-hexane-ethyl acetate (1: 1). Rf value 0.41 (hexane: ethyl acetate-1: 1)

Example 16 2- [N- (2-hydroxyethyl) -N- (4-methoxybenzenesulfonyl)] amino-N- (4-chlorocinnamyl) -N-methyl-benzylamine the resulting crude material in methanol 4.5ml, 1 defines caustic soda 4.5ml and tetrahydrofuran 4.5
Then, the mixture was stirred at room temperature for 2 hours. After adding 10 ml of saturated saline to the reaction solution, 3 ml of ethyl acetate was added.
It was extracted once, dried over magnesium sulfate, and concentrated under reduced pressure. The residue obtained was applied to a silica gel column, and 643 mg of the target compound was obtained as a colorless amorphous substance from the fraction eluted with ethyl acetate. NMR (CDCl ₃ ) δ ppm: 2.22 (3H,
s), 2.88 (1H, d, J = 12.0 Hz), 3.
0 to 3.5 (4H, m), 3.6 to 3.8 (1H,
m), 3.88 (3H, s), 4.0-4.2 (1H,
m), 4.99 (1H, d, J = 12.0 Hz), 6.
4-6.5 (2H, m), 6.55 (1H, d, J = 1
6.1 Hz), 6.95 (2H, d, J = 8.8H)
z), 7.1-7.4 (7H, m), 7.55 (2H,
d, J = 8.8 Hz)

The following compounds were obtained in the same manner as in Examples 15 and 16.

Example 17 2- [N- (2-hydroxyethyl) -N- (5-isoquinolinsulfonyl)] amino-N- (4-chlorocinnamyl) -benzylamine colorless amorphous NMR (CDCl ₃ ) dppm : 2.9 to 3.1 (2
H, m), 3.29 (1H, brt), 3.5-3.8
(2H, m), 4.06 (1H, brt) , 4.26
(1H, brt), 5.21 (1H, d, J = 12.7)
Hz), 6.10 (1H, d, J = 7.8 Hz), 6.
3-6.5 (1H, m), 6.58 (1H, d, J = 1)
6.1 Hz), 6.88 (1H, t, J = 7.8H)
z), 7.2-7.5 (6H, m), 7.72 (1H,
t, J = 7.8 Hz), 7.86 (1H, d, J = 6.
1 Hz), 8.2 to 8.4 (3H, m), 9.31 (1
H, s)

Example 18 2- [N- (2-hydroxyethyl) -N- (5-isoquinolinsulfonyl)] amino-N- (4-chlorocinnamyl) -N-methyl-benzylamine colorless amorphous NMR ( CDCl ₃ ) δ ppm: 2.21 (3H,
s), 2.94 (1H, d, J = 12.2 Hz), 3.
07 (1H, brd), 3.15 to 3.35 (2H,
m), 3.45 (1H, brd), 3.68 (1H, b
rd), 4.22 (1H, brt), 5.10 (1H,
d, J = 12.2 Hz), 6.14 (1H, d, J =
8.0 Hz), 6.3 to 6.5 (1H, m), 6.55
(1H, d, J = 16.1 Hz), 6.88 (1H,
t, J = 7.8 Hz), 7.2 to 7.5 (6H, m),
7.72 (1H, t, J = 7.6 Hz), 7.89 (1
H, d, J = 6.4 Hz), 8.2 to 8.4 (3H,
m), 9.31 (1H, s)

Example 19 2- (4-chlorocinnamylthiomethyl) -N- (2-
Hydroxyethyl) -N- (5-isoquinolinesulfonyl) -aniline pale yellow oil NMR (CDCl ₃ ) δ ppm: 3.3 (1H, comp
Rex ), 3.35 (2H, d, J = 7.3 Hz),
3.45 to 3.7 (2H, complex ), 3.7
(1H, d, J = 12.5 Hz), 4.0 to 4.2 (1
H, complex ), 4.42 (1H, d, J = 1)
2.5 Hz), 6.3 (1H, dd, J = 15.3,
7.3 Hz), 6.47 (1H, d, J = 15.3H)
z), 6.9 (1H, brt), 7.2-7.4 (2
H, complex), 7.4~7.6 (4H, Comp
Rex), 7.6~7.8 (2H, Comp Lek
Scan), 7.9 (1H, d, J = 6.3Hz), 8.21
(1H, d, J = 8.0 Hz), 8.3 (1H, d, J)
= 7.3 Hz), 8.36 (1H, d, J = 5.9H)
z), 9.3 (1H, s)

Example 20 2- [N-2- (hydroxyethyl) -N- (5-isoquinolinesulfonyl)] amino-N- [2- (4-chlorophenoxy) ethyl] -N-methyl-benzylamine colorless Amorphous NMR (CDCl ₃ ) δ ppm: 2.32 (3H,
s) 2.8-3.15 (4H, complex );
3.15 to 3.35 (1H, complex ), 3.6
-3.75 (1H, brd), 4.1-4.4 (3H,
Complex ) , 5.11 (1H, d, J = 12.4)
Hz), 6.18 (1H, brd), 6.85-7.0
(1H, complex ), 6.95 (2H, d, J =
6.9Hz), 7.2~7.35 (1H, Comp Lek
S ), 7.25 (2H, d, J = 6.9 Hz), 7.4
(1H, brd), 7.4 (1H, d, J = 6.4H)
z), 7.75 (1H, t, J = 7.5 Hz), 8.2
5 (1H, d, J = 8.0 Hz), 8.30 (1H,
d, J = 7.5 Hz), 8.35 (1H, d, J = 6.
4Hz), 9.32 (1H, s)

Example 21 2- [N- (2-hydroxyethyl) -N- (5-isoquinolinesulfonyl)] amino-N- [2- (4-chlorophenoxy) ethyl] -N-methyl-penzylamine Crystalline NMR (CDCl ₃ ) δ ppm: 2.3 (3H, s),
2.8-3.15 (4H, complex ), 3.25
(1H, brd), 3.65 (3H, brd) , 4.3
(1H, d, J = 12.4 Hz), 4.1 to 4.4 (2
H, complex ) , 5.11 (1H, d, J = 1)
2.4 Hz), 6.15 (1H, d, J = 7.8H)
z), 6.93 (2H, d, J = 9.0 Hz), 6.8
5-6.95 (1H, complex ), 7.25 (2
H, d, J = 9.0Hz) , 7.2~7.3 (1H, co
Simplex), 7.4 (1H, brd) , 7.71
(1H, dd, J = 6.3 , 8.3 Hz) , 7.9 (1
H, d, J = 7.3 Hz), 8.25 (1H, d, J =
8.3 Hz), 8.3 (1H, d, J = 7.3 Hz),
8.35 (1H, d, J = 6.3 Hz), 9.3 (1
H, s)

Example 22 2- [N- (2-aminoethyl) -N- (5-isoquinolinesulfonyl)] amino-N- [2- (4-chlorophenoxy) ethyl] -N-methyl-benzylamine pale Yellow amorphous NMR (CDCl ₃ ) δ ppm: 2.26 (3H,
s), 2.4 to 2.7 (1H, complex );
8-3.4 (5H, complex ), 4.1-4.4
(3H, complex ), 5.2 (1H, d, J = 1
0.4 Hz), 6.1 (1H, d, J = 7.8 Hz),
6.9 (1H, brt), 7.1 (2H, d, J = 9.
0 Hz), 7.2 (2H, d, J = 9.0 Hz), 7.
15-7.25 (1H, Complex ), 7.25-
7.4 (1H, complex ), 7.7 (1H, br)
d), 7.75 (1H, d, J = 7.8 Hz), 8.2
5 (1H, d, J = 8.1 Hz), 8.3 (1H, d,
J = 6.1 Hz), 8.33 (1H, d, J = 6.1H)
z), 9.3 (1H, s)

Example 23 2- [N- (2-aminoethyl) -N- (5-isoquinolinesulfonyl)] amino-N- [2- (4-chlorophenoxy) ethyl] -N-methyl-benzylamine pale Yellow oil NMR (CDCl ₃ ) δ ppm: 2.3 (3H, s),
2.7 to 2.85 (4H, complex ), 3.3 to
3.55 (2H, complex ), 3.8-4.0
(1H, multiplet ) 4.0-4.2 (3H, core
Simplex), 6.4 (1H, d, J = 7.8H
z), 6.85-7.0 (1H, complex ),
7.27.35 (1H, complex ), 7.25
(1H, d, J = 9.0 Hz), 7.63 (1H, br)
d), 7.65 (1H, dd, J = 8.3, 6.3H
z), 7.84 (2H, d, J = 9.0 Hz), 7.9
5 (1H, d, J = 7.3 Hz), 8.2 (1H, d,
J = 8.3 Hz), 8.3 (1H, d, J = 7.3H)
z), 8.4 (1H, d, J = 6.3 Hz), 9.3
(1H, s)

Example 24 2- [2- (4-chlorophenoxy) ethylthio] methyl-N- (2-hydroxyethyl) -N- (5-isoquinolinsulfonyl) aniline colorless oil NMR (CDCl ₃ ) δ ppm: 2 .95 (2H, br
t), 3.32 (1H, brd), 3.5-3.7 (1
H, complex ), 3.9 (1H, d, J = 12.
7Hz), 4.1-4.3 (2H, complex ),
4.15 (2H, t, J = 6.4 Hz), 4.6 (1
H, d, J = 12.7), 6.35 (1H, dd, J =
1.2, 8.1 Hz), 6.88 (2H, d, J = 9.
1 Hz), 6.9 (1H, brt), 7.25 (2H,
d, J = 9.1 Hz), 7.3 (1H, brt), 7.
57 (1H, dd, J = 1.4, 7.8 Hz), 7.7
(1H, t, J = 8.1 Hz), 7.95 (1H, d,
J = 6.3 Hz), 8.25 (1H, d, J = 8.1H)
z), 8.35 (1H, d, J = 7.3 Hz), 8.4
(1H, d, J = 6.3 Hz), 9.32 (1H, s)

Example 25 2- [N- (2-hydroxyethyl) -N- (5-isoquinoline sulfonyl)] amino-N-methyl- (4-methylcinnamyl) -benzylamine pale yellow amorphous NMR (CDCl ₃ ) δ ppm: 2.22 (3H,
s), 2.32 (3H, s), 2.99 (1H, d, J
= 12.4 Hz), 3.02 to 3.73 (5H, m),
4.14 to 4.20 (1H, m), 5.04 (1H,
d, J = 12.4 Hz), 6.16 (1H, d, J =
8.0 Hz), 6.24 to 6.48 (2H, m), 6.
53 to 6.62 (2H, m), 6.84 to 6.96 (1
H, brt), 7.12 (2H, d, J = 8.2H)
z), 7.68 (2H, d, J = 8.2 Hz), 7.7
0 (1H, t, J = 8.0 Hz), 7.91 (1H,
d, J = 8.0 Hz), 8.20 to 8.35 (3H,
m), 9.30 (1H, s)

Example 26 2- [N- (2-hydroxyethyl) -N- (5-isoquinoline sulfonyl)] amino-N- (4-methoxycinnamyl) -N-methyl-benzylamine Yellow amorphous NMR ( CDCl ₃ ) δ ppm: 2.22 (3H,
s), 2.97 (1H, d, J = 12.2 Hz);
07 to 3.49 (5H, m), 3.27 (3H, s),
4.13 to 4.26 (1H, m), 5.06 (1H,
d, J = 12.2 Hz), 6.14 (1H, d, J =
7.8 Hz), 6.18 to 6.35 (1H, m), 6.
53 (1H, d, J = 14.8 Hz), 6.82-6.
93 (3H, m), 7.23 to 7.44 (6H, m),
7.68 (1H, t, J = 7.8 Hz), 7.92 (1
H, d, J = 6.4 Hz), 8.19 to 8.34 (1
H, m), 9.26 (1H, s)

Example 27 2- [N- (2-hydroxyethyl) -N- (5-isoquinoline sulfonyl)] amino-N- (4-fluorocinnamyl) -N-methyl-benzylamine pale yellow amorphous NMR (CDCl ₃ ) δ ppm: 2.22 (3H,
s), 2.95 (1H, d, J = 12.2 Hz), 3.
02 to 3.82 (5H, m), 4.14 to 4.30 (1
H, m), 5.10 (1H, d, J = 12.2 Hz),
6.14 (1H, d, J = 8.0 Hz), 6.28-
6.46 (1H, m), 6.58 (1H, d, J = 1)
6.2 Hz), 6.84 to 7.04 (3H, m), 7.
24 to 7.48 (4H, m), 7.74 (1H, t, J
= 7.8 Hz), 7.89 (1H, d, J = 7.0H)
z), 8.21 to 8.35 (3H, m), 9.30 (1
H, s)

Example 28 2- [N- (2-hydroxyethyl) -N- (5-isoquinolinsulfonyl)] amino-N- (4-cyanocinnamyl) -N-methyl-benzylamine pale yellow amorphous NMR (CDCl ₃ ) δ ppm: 2.23 (3H,
s), 2.92 (1H, d, J = 12.2 Hz), 3.
0 to 3.7 (5H, m), 4.1 to 4.3 (1H,
m), 5.13 (1H, d, J = 12.2 Hz), 6.
13 (1H, d, J = 8.1 Hz), 6.6 to 6.7
(2H, m), 6.88 (1H, t, J = 7.8H)
z), 7.2-7.4 (2H, m), 7.60 (4H,
s) , 7.72 (1H, t, J = 7.8 Hz), 7.8
6 (1H, d, J = 6.1 Hz), 8.2 to 8.4 (3
H, m), 9.31 (1H, s)

Example 29 2- [N- (2-hydroxyethyl) -N- (5-isoquinolinesulfonyl)] amino-N- (4-methoxycarbonylcinnamyl) -N-methyl-benzylamine colorless amorphous NMR (CDCl ₃ ) δ ppm: 2.24 (3H,
s), 2.97 (1H, d, J = 12.5 Hz), 3.
0-3.7 (5H, m), 3.90 (3H, s), 4.
1 to 4.3 (1H, m), 5.10 (1H, d, J = 1)
2.5 Hz), 6.15 (1H, d, J = 7.8H)
z), 6.5-6.7 (2H, m), 6.89 (1H,
t, J = 7.8 Hz), 7.2 to 7.4 (2H, m),
7.54 (2H, d, J = 8.6 Hz), 7.71 (1
H, t, J = 7.8 Hz), 7.90 (1H, d, J =
6.1H, 7.99 (2H, d, J = 8.6 Hz),
8.2 to 8.4 (3H, m), 9.30 (1H, s)

Example 30 2- [N- (3-hydroxypropyl) -N- (5-isoquinolinsulfonyl)] amino-N- (4-chlorocinnamyl) -N-methyl-benzylamine colorless amorphous NMR ( CDCl ₃ ) δ ppm: 1.77 (2H, br)
q), 2.15 (3H, s), 3.10 (2H, d, J
= 6.3 Hz), 3.39 (2H, d, J = 14.4H)
z) 3.4-3.6 (1H, m), 3.7-4.0
(4H, m), 6.21 (1H, dt, J = 15.9,
6.3 Hz), 6.46 (1H, d, J = 15.9H)
z), 6.47 (1H, d, J = 8.3 Hz), 6.9
2 (1H, t, J = 7.9 Hz), 7.2 to 7.3 (5
H, m), 7.6 to 7.7 (2H, m), 7.94 (1
H, d, J = 6.3 Hz), 8.18 (1H, d, J =
7.9 Hz), 8.29 (1H, d, J = 8.3H)
z), 8.39 (1H, d, J = 6.3 Hz), 9.2
8 (1H, s)

Example 31 4,5-Dimethoxy-2- [N- (2-hydroxyethyl) -N- (5-isoquinolinesulfonyl)] amino-
N- (4-chlorocinnamyl) -N-methyl-benzylamine pale yellow amorphous NMR (CDCl ₃ ) δ ppm: 2.24 (3H,
s), 2.85 (1H, d, J = 12.4 Hz), 3.
05 (3H, s), 3.1~3.5 (5H, compressors
Hex), 3.75 (1H, brd) , 3.9 (3H,
s), 4.1-4.3 (1H, complex );
95 (1H, d, J = 12.4 Hz), 5.55 (1
H, s), 6.4 (1H, dt, J = 15.9, 5.9)
Hz), 6.8 (1H, s), 7.3 (2H, d, J =
8.8 Hz), 7.4 (2H, d, J = 8.8 Hz),
7.7 (1H, dt, J = 8.3, 7.6 Hz), 8.
05 (1H, d, J = 6.4 Hz), 8.25 (1H, d, J = 6.4 Hz)
d, J = 8.3 Hz), 8.3 (1H, d, J = 7.6)
Hz), 8.43 (1H, d, J = 6.4 Hz), 9.
31 (1H, s)

The analytical data of the intermediate used in the production of this compound were as follows. a) 2- (acetoxymethyl) -4,5 (dimethoxy)
-Nitrobenzene yellow crystal MP: 160 to 161 ° C. NMR (CDCl ₃ ) δ ppm: 2.2 (3H, s),
3.98 (3H, s), 4.0 (3H, s), 5.5
(2H, s), 7.0 (1H, s), 7.72 (1H,
s)

B) 4,5-dimethoxy-2-nitro-N
-Methylbenzylamine yellow crystal MP: decomposed at 205 ° C. or higher NMR (d ₆ DMSO) δ ppm: 2.36 (3H,
s), 3.90 (3H, s), 3.95 (3H, s),
4.38 (2H, s), 7.5 (1H, s), 7.74
(1H, s)

Example 32 2- [N- (2-hydroxyethyl) -N- (5-isoquinolinesulfonyl)] amino-N- (3,4,5-trimethoxycinnamyl) -N-methyl-benzylamine Colorless amorphous NMR (CDCl ₃ ) δ ppm: 2.22 (3H,
s), 2.93 (1H, d, J = 12.2 Hz), 3.
0-3.7 (5H, m), 3.84 (3H, s), 3.
4. 91 (6H, s), 4.1 to 4.3 (1H, m);
14 (1H, d, J = 12.2 Hz), 6.15 (1
H, d, J = 7.9 Hz), 6.3 to 6.7 (2H,
m), 6.74 (2H, s), 6.8 (1H, br)
t), 7.2-7.4 (2H, m), 7.72 (1H,
t, J = 7.9 Hz), 7.89 (1H, d, J = 6.
3 Hz), 8.2 to 8.4 (3H, m), 9.31 (1
H, s)

Example 33 2- [N- (2-hydroxyethyl) -N- (2,3,
4-trimethoxybenzenesulfonyl)] amino-N-
(4 Kuroroshi down Namiru) -N- methyl - benzylamine pale yellow liquid _{NMR (CDCl 3) δppm: 2.22} (3H,
s), 2.88 (1H, d, J = 12.2 Hz), 3.
2-3.5 (3H, m), 3.6-3.8 (2H,
m), 3.90 (3H, s), 3.94 (3H, s),
3.97 (3H, s), 4.25 to 4.4 (1H,
m), 5.03 (1H, d, J = 12.2 Hz), 6.
3-6.6 (3H, m), 6.73 (1H, d, J =
8.0 Hz), 7.05 to 7.3 (6H, m), 7.3
8 (2H, d, J = 6.6 Hz)

Example 34 2- [N- (2-aminoethyl) -N- (4-methoxybenzenesulfonyl)] amino-N- (4-chlorocinnamyl) -N-methyl-benzylamine colorless liquid NMR ( CDCl ₃ ) δ ppm: 1.59 (2H, br)
s), 2.24 (3H, s), 2.70 (2H, t, J
= 6.8 Hz), 3.21 (2H, d, J = 6.3H)
z), 3.25 (1H, t, J = 6.8 Hz), 3.5
7 (1H, d, J = 14.4 Hz), 3.81 (1H, d, J = 14.4 Hz)
t, J = 6.8 Hz), 3.87 (3H, s), 4.0
6 (1H, d, J = 14.1 Hz), 6.30 (1H,
dt, J = 15.8, 6.3 Hz), 6.52 (1H,
d, J = 15.8 Hz), 6.54 (1H, d, J =
6.8 Hz), 6.94 (2H, d, J = 8.6H)
z), 7.12 (1H, t, J = 7.8 Hz), 7.2
７7.4 (5H, m), 7.55 (2H, d, J = 8.
6Hz), 7.67 (1H, d, J = 7.8Hz)

Example 35 2- [N- (2-aminoethyl) -N- (5-isoquinolinsulfonyl)] amino-N- (4-chlorocinnamyl) -N-methyl-benzylamine colorless liquid NMR (CDCl ₃ ) δ ppm: 2.25 (3H,
s), 2.52 to 2.70 (1H, m), 2.98 (1
H, d, J = 12.8 Hz), 3.08 to 3.30 (3
H, m), 3.51-3.62 (1H, m), 4.24
４4.40 (1H, m), 5.13 (1H, d, J = 1
2.6 Hz), 6.09 (1H, d, J = 8.0H)
z), 6.43-6.60 (2H, m), 6.89 (1
H, t, J = 7.0 Hz), 7.19 to 7.36 (4
H, m), 7.49 (2H, d, J = 8.6 Hz),
7.67 to 7.76 (2H, m), 8.23 to 8.36
(3H, m), 9.29 (1H, s)

Example 36 2- [N- (2-hydroxyethyl) -N- (5-isoquinolinesulfonyl)] amino-N- [4- (n-butyloxy) cinnamyl] -N-methyl-benzylamine pale yellow Oil NMR (CDCl ₃ ) δ ppm: 0.96 (3H, t,
J = 7.3 Hz), 1.43 (2H, br, sex)
G ), 1.78 (2H, br, quintet , J = 7.
3Hz), 2.22 (3H, s), 2.96 (1H,
d, J = 12.5Hz), 3.0~3.5 (3H, con
Plex ), 3.7 (2H, brd), 3.95 (2
H, t, J = 6.6Hz) , 4.1~4.3 (2H, co
Simplex), 5.05 (1H, d, J = 12.5H
z), 6.16 (1H, d, J = 8.1 Hz), 6.3
(1H, dt, J = 16.3, 7.5 Hz), 6.55
(1H, d, J = 16.3 Hz), 6.8 to 7.0 (2
H, complex ), 6.85 (2H, d, J = 8.
8 Hz), 7.4 (2H, d, J = 8.8 Hz), 7.
2 to 7.45 (2H, complex ), 7.7 (1
H, dd, J = 5.8, 8.3 Hz), 7.92 (1
H, d, J = 5.8 Hz), 8.25 (1H, d, J =
8.3 Hz), 8.31 (1H, d, J = 6.3H)
z), 8.33 (1H, d, J = 6.3 Hz), 9.3
(1H, s)

Example 37 2- {N- [2- (2-hydroxyethoxy) ethyl]
-N- (5-isoquinolinesulfonyl)} amino-N-
(4-chlorocinnamyl) -N-methyl-benzylamine pale yellow liquid NMR (CDCl ₃ ) δ ppm: 2.05 (3H,
s), 2.97 (2H, d, J = 5.9 Hz), 3.1.
8 (1H, d, J = 6.7 Hz), 3.4 to 3.7 (7
H, m), 3.7 to 3.8 (1H, m), 3.8 to 4.
0 (2H, m), 6.15 (1H, dt, J = 15.
9, 5.9 Hz), 6.41 (1H, d, J = 15.9)
Hz), 6.82 (1H, d, J = 7.8 Hz), 7.
05 (1H, t, J = 7.8 Hz), 7.2 to 7.4
(5H, m), 7.5-7.7 (2H, m), 8.1-
8.2 (2H, m), 8.25 (1H, d, J = 7.8)
Hz), 8.48 (1H, d, J = 6.3 Hz), 9.
28 (1H, s)

Example 38 2- {N- [2- (2-aminoethoxy) ethyl] -N
-(5-isoquinolinesulfonyl)} amino-N- (4
-Chlorocinnamyl) -N-methyl-benzylamine pale yellow amorphous NMR (CDCl ₃ ) δ ppm: 2.09 (3H,
m), 3.05 (2H, d, J = 6.1 Hz), 3.1
To 3.3 (3H, m), 3.4 to 3.6 (3H, m),
3.6 to 3.8 (2H, m), 3.8 to 4.0 (2H,
m), 5.4 (2H, brs), 6.16 (1H, d
t, J = 15.9, 6.1 Hz), 6.43 (1H,
d, J = 15.9 Hz), 6.84 (1H, d, J =
7.3 Hz), 7.11 (1H, t, J = 7.3H)
z), 7.2-7.4 (5H, m), 7.56 (1H,
t, J = 8.0 Hz), 7.66 (1H, d, J = 6.
3 Hz), 8.0 to 8.2 (2H, m), 8.22 (1
H, d, J = 7.6 Hz), 8.49 (1H, d, J =
6.3 Hz), 9.26 (1H, s)

Example 39 3- [N- (2-hydroxyethyl) -N- (5-isoquinolinesulfonyl)] amino-N- (4-chlorocinnamyl) -N-ethyl-benzylamine colorless liquid NMR (CDCl ₃ ) δ ppm: 1.0 (3H, t, J
= 7.4 Hz), 2.43 (2H, q, J = 7.4H
z), 3.06 (2H, d, J = 5.37 Hz);
45 (2H, s), 3.68 (2H, t, J = 4.64)
Hz), 3.81 (2H, t, J = 4.64 Hz),
6.1 (1H, dt, J = 15.95, 5.37H
z), 6.42 (1H, d, J = 15.95 Hz),
6.9-7.05 (2H, complex ), 7.1-
7.35 (2H, complex ), 7.27 (4H,
s), 7.62 (1H, dd, J = 6.3, 8.3H)
z), 8.0 (1H, d, J = 7.3 Hz), 8.12
(1H, d, J = 8.3 Hz), 8.32 (1H, d,
J = 7.3 Hz), 8.42 (1H, d, J = 6.3H)
z), 9.25 (1H, s)

Example 40 2- [N- (2-hydroxyethyl) -N- (methanesulfonyl)] amino-N-methyl-benzylamine colorless amorphous NMR (CDCl ₃ ) δ ppm: 2.22 (3H,
s), 2.84 (1H, d, J = 12.6 Hz), 2.
92 (3H, s), 3.12 to 3.22 (1H, m),
3.30 to 3.53 (3H, m), 3.64 to 3.78
(1H, m), 3.98 to 4.11 (1H, m);
78 (1H, d, J = 12.2 Hz), 6.34 (2
H, dt, J = 15.9, 5.8 Hz), 7.24-
7.40 (9H, m)

Example 41 2- [N- (2,3-dihydroxypropyl) -N-
(4-methoxybenzenesulfonyl)] amino-N-
(4-chlorocinnamyl) -N-methyl-benzylamine colorless amorphous NMR (CDCl ₃ ) δ ppm: 2.22 (1,5H,
s), 2.24 (1, 5H, s), 2.8 to 3.7 (7
H, m), 3.88 (3H, s), 3.8 to 4.0 (1
H, m), 4.99 (0, 5H, d, J = 13.2H
z), 5.04 (0, 5H, d, J = 13.2 Hz),
6.4-6.6 (3H, m), 6.94 (2H, d, J
= 7.8 Hz), 7.1 to 7.6 (9H, m)

Example 42 2- [N- (2-aminoethyl) -N- (4-methoxybenzenesulfonyl)] amino-N- (3,4,5-trimethoxycinnamyl) -N-methyl-benzyl Amine pale yellow amorphous NMR (CDCl ₃ ) δ ppm: 2.25 (3H,
s), 2.70 (2H, t, J = 6.1 Hz), 3.1
~ 3.3 (3H, m), 3.58 (1H, d, J = 1
4.4 Hz), 3.7 to 3.9 (1H, m), 3.84
(3H, s), 3.87 (3H, s), 3.88 (6
H, s), 4.07 (1H, d, J = 14.4 Hz),
6.26 (1H, dt, J = 15.4, 6.3 Hz),
6.49 (1H, d, J = 15.4 Hz), 6.55
(1H, d, J = 7.8 Hz), 6.65 (2H,
s), 6.94 (2H, d, J = 9.0 Hz), 7.1
0 (1H, t, J = 7.8 Hz), 7.31 (1H,
t, J = 7.8 Hz), 7.55 (2H, d, J = 9.
0 Hz), 7.68 (1H, d, J = 7.8 Hz)

Example 43 2- [N- (2-hydroxyethyl) -N- (4-methoxybenzenesulfonyl)] amino-N- (3,4,5
-Trimethoxycinnamyl) -N-methyl-benzylamine colorless amorphous NMR (CDCl ₃ ) δ ppm: 2.21 (3H,
s), 2.86 (1H, d, J = 12.2 Hz), 3.
0 to 3.3 (3H, m), 3.4 to 3.55 (1H,
m), 3.6 to 3.75 (1H, m), 3.83 (3
H, s), 3.88 (3H, s), 3.89 (6H,
s), 4.0 to 4.15 (1H, m), 5.02 (1
H, d, J = 12.2 Hz), 6.3 to 6.6 (3H,
m), 6.72 (2H, s), 6.95 (2H, d, J
= 8.5 Hz), 7.15 to 7.35 (3H, m),
7.54 (2H, d, J = 8.5 Hz)

Example 44 2- [N- (4-methoxybenzenesulfonyl) -N-
(2-methoxyethyl)] amino-N- (4-chlorocinnamyl) -N-methyl-benzylamine pale yellow liquid NMR (CDCl ₃ ) δ ppm: 2.26 (3H,
s), 3.18 (2H, brs), 3.21 (3H,
s) 3.3-3.5 (3H, m), 3.79 (2H,
d, J = 5.6 Hz), 3.86 (3H, s), 3.8
４4.0 (1H, m), 6.29 (1H, dt, J = 1)
5.9, 5.6 Hz), 6.52 (1H, d, J = 1)
5.9 Hz), 6.57 (1H, d, J = 7.5H)
z) , 6.92 (2H, d, J = 8.9 Hz), 7.0
9 (1H, t, J = 7.5 Hz), 7.2 to 7.4 (5
H, m), 7.59 (2H, d, J = 8.9 Hz),
7.75 (1H, d, J = 6.6Hz)

Example 45 2- {N- (4-methoxybenzenesulfonyl) -N-
[2- (1-pyrrolidinyl) ethyl] {amino-N-
(4-chlorocinnamyl) -N-methyl-benzylamine yellow liquid NMR (CDCl ₃ ) δ ppm: 1.6 to 1.8 (4
H, m), 2.26 (3H, s), 2.3 to 2.5 (5
H, m), 2.5 to 2.7 (1H, m) , 3.19 (2
H, d, J = 5.6 Hz), 3.2 to 3.4 (1H,
m) 3.8-4.0 (3H, m), 3.87 (3H,
s), 6.29 (1H, dt, J = 16.1, 5.6H)
z), 6.51 (1H, d, J = 16.1 Hz), 6.
57 (1H, d, J = 7.7 Hz), 6.93 (2H,
d, J = 6.9 Hz), 7.09 (1H, t, J = 7.
4 Hz), 7.2 to 7.4 (5H, m), 7.59 (2
H, d, J = 6.9 Hz), 7.75 (1H, d, J =
7.4 Hz)

Example 46 2- [N- (2-hydroxyethyl) -N- (5-isoquinolinsulfonyl)] amino-N- (2,4,5-trimethoxycinnamyl) -N-methyl-benzylamine Yellow amorphous NMR (CDCl ₃ ) δ ppm: 2.22 (3H,
s), 2.94 (1H, d, J = 12.4 Hz), 3.
0-3.7 (5H, m), 3.84 (3H, s), 3.
89 (3H, s), 3.92 (3H, s), 4.1 to
4.3 (1H, m), 5.10 (1H, d, J = 12.
4 Hz), 6.15 (1H, d, J = 8.1 Hz),
6.2 to 6.4 (1H, m), 6.50 (1H, s),
6.8-7.0 (2H, m), 7.21 (1H, s),
7.2 to 7.3 (1H, m), 7.38 (1H, br)
d), 7.71 (1H, t, J = 8.1 Hz), 7.9
0 (1H, d, J = 6.3 Hz), 8.2 to 8.4 (3
H, m), 9.30 (1H, s)

Example 47 2- [N- (2-hydroxyethyl) -N- (5-isoquinolinsulfonyl)] amino-N, (2,3,4-trimethoxycinnamyl) -N-methyl-benzylamine Pale yellow amorphous NMR (CDCl ₃ ) δ ppm: 2.22 (3H,
s), 2.94 (1H, d, J = 12.0 Hz), 3.
02 to 3.34 (3H, m), 3.43 to 3.52 (1
H, m), 3.67-3.79 (1H, m), 3.87
(6H, s), 3.94 (3H, s), 4.18-4.
31 (1H, m), 5.12 (1H, d, J = 12.0
Hz), 6.27 to 6.41 (1H, m), 6.56
(1H, d, J = 16 Hz), 6.81 (2H, d, J)
= 8.4 Hz), 6.88 to 7.02 (1H, m),
7.11 (1H, s), 7.24-7.39 (2H,
m), 7.70 (1H, t, J = 7.6 Hz), 7.9
0 (1H, d, J = 6.4 Hz), 8.21 to 8.37
(3H, m) , 9.30 (1H, s)

Example 48 2- [N- (2-hydroxyethyl) -N- (5-isoquinolinsulfonyl)] amino-N- (2,4,6-trimethoxycinnamyl) -N-methyl-benzylamine Pale yellow oil NMR (CDCl ₃ ) δ ppm: 2.21 (3H,
s), 2.92 (1H, d, J = 12.4 Hz), 3.
02 to 3.32 (3H, m), 3.44 to 3.57 (1
H, m), 3.65 to 3.72 (1H, m), 3.83
(3H, s), 3.87 (3H, s), 3.90 (3
H, s), 4.16 to 4.30 (1H, m), 5.13
(1H, d, J = 12.4 Hz), 6.14 (1H,
d, J = 7.8 Hz), 6.42 to 6.52 (1H,
m), 6.60 to 6.67 (1H, m), 6.74 (1
H, s), 6.88 (1H, brt), 7.21-7.
38 (2H, m), 7.70 (2H, t, J = 8.0H)
z), 7.89 (1H, d, J = 6.4 Hz), 8.2
1 to 8.36 (3H, m), 9.30 (1H, s)

Example 49 2- [N- (2-hydroxyethyl) -N- (5-isoquinolinsulfonyl)] amino-N- (3,4-dimethoxycinnamyl) -N-methyl-benzylamine colorless amorphous NMR (CDCl ₃ ) δ ppm: 2.22 (3H,
s), 2.96 (1H, d, J = 12.4 Hz), 3.
18 to 3.52 (4H, m), 3.62 to 3.74 (1
H, m), 3.84 (3H, s), 3.86 (3H,
s), 4.16 to 4.33 (1H, m), 5.06 (1
H, d, J = 12.4 Hz), 6.17 (1H, d, J)
= 8.2 Hz), 6.20 to 6.41 (1H, m),
6.67 (1H, d, J = 8.4 Hz), 6.74-
6.92 (2H, m), 7.22 to 7.41 (4H,
m), 7.69 (1H, t, J = 7.4 Hz), 7.9
2 (1H, d, J = 6.8 Hz), 8.21 to 8.36
(3H, m), 9.30 (1H, s)

Example 50 4- [N- (2-hydroxyethyl) -N- (5-isoquinolinsulfonyl)] amino-N- (4-chlorocinnamyl) -N-methyl-benzylamine colorless amorphous NMR ( CDCl ₃ ) δ ppm: 2.22 (3H,
s), 3.15 (2H, d, J = 5.8 Hz), 3.5
(2H, s), 3.65, 3.8 (2H, br respectively )
t), 6.25 (1H, dt, J = 15.6, 5.8H)
z), 6.5 (2H, d, J = 15.6 Hz), 7.
0, 7.23 (2H, d, J = 8.1 Hz respectively ),
7.3 (4H, s), 7.64 (1H, dd, J = 8.
3, 6.1 Hz), 8.05 (1H, d, J = 6.1H)
z), 8.18 (1H, d, J = 8.3 Hz), 8.3
(1H, d, J = 7.5 Hz), 8.41 (1H, d,
J = 6.1 Hz), 9.3 (1H, s)

Example 51 2- [N- (2-methoxyethyl) -N- (5-isoquinolinsulfonyl)] amino-N- (3,4,5-trimethoxycinnamyl) -N-methyl-benzylamine Light yellow amorphous NMR (CDCl ₃ ) δ ppm: 2.16 (3H,
s), 3.09 (1H, d, J = 62 Hz), 3.17
(3H, s), 3.32 to 3.55 (4H, m);
68 to 3.74 (1H, m), 3.84 (3H, s),
3.88 (6H, s), 6.11 to 6.21 (1H,
m), 6.41 to 6.54 (2H, m), 6.62 (1
H, s), 6.94 (1H, t, J = 7.4 Hz),
7.26 to 7.48 (2H, m), 7.42 to 7.54
(1H, m), 7.60 to 7.73 (3H, m), 8.
08 (1H, d, J = 6.4 Hz), 8.17 (1H,
d, J = 8.2 Hz), 8.30 (1H, d, J = 7.
2Hz), 8.44 (1H, d, J = 6.2Hz),
9.29 (1H, s)

Example 52 2- [N- (3-amino-2-hydroxy) propyl-
N- (4-methoxybenzenesulfonyl)] amino-N
-(4-chlorocinnamyl) -N-methyl-benzylamine colorless amorphous NMR (CDCl ₃ ) δ ppm: 2.24 (3H,
s), 2.5-3.5 (8H, m), 3.88 (3H,
s), 4.97 (0.5 H, d, J = 12.2 Hz),
5.04 (0,5H, d, J = 16.1 Hz), 6.3
5-6.6 (3H, m), 6.95 (2H, brd),
7.1 to 7.3 (5H, m), 7.39 (2H, d, J
= 8.1 Hz), 7.64 (2H, brd)

Example 53 2- [N-ethoxycarbonylmethyl-N- (4-methoxybenzenesulfonyl)]-amino-N- (4-chlorocinnamyl) -N-methyl-benzylamine pale yellow oil NMR ( CDCl ₃ ) δ ppm: 1.25 (3H, br
t), 2.2 (3H, s), 3.2 (2H, br),
3.87 (3H, s), 4.05~4.2 (4H, con
Plex ), 4.5 (2H, br), 6.25 (1
H, dt, J = 15.9, 6.3 Hz), 6.5 (1
H, d, J = 15.9 Hz), 6.92 (2H, d, J)
= 8.7 Hz), 7.0 (1H, brd), 7.1 (1
H, brt), 7.3 (4H, brs), 7.3-7.
4 (1H, complex ), 7.6 (1H, br
d), 7.65 (2H, d, J = 8.7)

Reference Example 12 2- (N-ethoxyoxalyl) amino-N- (4-n
-Butyloxy) cinnamyl-N-methyl-benzylamine 2-amino-N- (4-n-butyloxycinnamyl)
1.1 g of -N-methylbenzylamine in 11 m of pyridine
The resulting mixture was dissolved in 1 l of the solution, and a solution prepared by diluting 557 mg of ethyl oxalyl chloride in 1 ml of chloroform was added dropwise under stirring with an ice bath. After stirring at room temperature overnight, add 20 ml of water, extract twice with 50 ml of ethyl acetate, wash with saturated saline, dry over magnesium sulfate, and remove the solvent under reduced pressure.
The residue was subjected obtained by distilling off the silica gel column, n- hexane - ethyl acetate (8: 2) to obtain the desired compound 0.80g exhibiting a pale brown oil from the fraction eluted with. NMR (CDCl ₃ ) δ ppm: 0.98 (3H, t,
J = 7.3 Hz), 1.46 (3H, t, J = 7.5H)
z), 1.5 (2H, br, sext ), 1.77 (2
H, br, quintet), 2.3 (3H, s), 3.
25 (2H, d, J = 7.1 Hz), 3.65 (2H, d, J = 7.1 Hz)
s), 3.96 (2H, t, J = 6.5 Hz), 4.4
3 (2H, q, J = 7.5 Hz), 6.3 (1H, d
t, J = 16.3, 7.1 Hz), 6.5 (1H, d,
J = 16.3 Hz), 6.85 (2H, d, J = 9.9)
Hz), 7.0-7.2 (2H, complex ),
7.2-7.4 (3H, complex ), 8.35
(1H, J = 9.7Hz)

Reference Example 13 2- [N- (2-hydroxy) ethyl] amino-N-
(4-n-butyloxycinnamyl) -N-methyl-benzylamine 665 mg of the oil obtained in Reference Example 12 was dissolved in 6 ml of anhydrous tetrahydrofuran, and diisobutylaluminum hydride (1 .5 molar solution)
4.2 ml were added dropwise. Later was stirred 10 minutes <br/> at the same temperature, water was added carefully filtered insolubles from, The filtrate was washed with saturated brine, dried over magnesium sulfate, Shi distilled off the solvent under reduced pressure The resulting residue was applied to a silica gel column,
From the fraction eluted with n-hexane-ethyl acetate (4: 1), 340 mg of the target compound as a colorless oil was obtained. NMR (CDCl ₃ ) δ ppm: 0.98 (3H, t,
J = 7.3 Hz), 1.5 (2H, br, sext ),
2.2 (3H, s), 1.75 (2H, br, quinte
2. ), 3.12 (2H, d, J = 7.1 Hz);
35 (2H, brt), 3.52 (2H, s), 3.7
5 (2H, t, J = 5.4 Hz), 3.95 (2H, t, J = 5.4 Hz)
t, J = 6.3 Hz), 6.5 (1H, d, J = 16.
1 Hz), 6.1 (1H, dt, J = 16.1, 7.1)
Hz), 6.65~6.75 (2H, Comp Lek
Scan), 6.83 ((2H, d , J = 8.8Hz), 7.
02 (1H, brd), 7.1~7.25 (1H, con
Plex ), 7.3 (2H, d, J = 8.8 Hz)

Example 54 2- {N- (2-hydroxyethyl) -N- [3-
(N, N-dimethylaminomethyl) -benzoyl] {amino-N- [4-n-butyloxy) cinnamyl] -N
-Methyl-benzylamine 1.7 g of the oil obtained by performing Reference Example 13 was dissolved in 30 ml of anhydrous dichloromethane, and
26 g and 3- (N, N-dimethylamino) -methyl-benzoyl chloride HCl salt 2.62 under ice-bath stirring.
g was added. Thereafter, the ice bath was removed and the reaction was carried out at room temperature for 3 hours. The reaction mixture was washed with water, the organic layer was dried over magnesium sulfate, the residue was subjected obtained by distilling off the solvent under reduced pressure to a silica gel column, chloroform - methanol (100: 1) colorless oil bodies from the fraction eluted with 740 mg of the desired product were obtained. NMR (CDCl ₃ ) δ ppm: 0.98 (3H, t,
J = 7.0 Hz), 1.5 (2H, sext , J = 7.
0 Hz), 1.75 (2H, quintet , J = 7.0)
Hz), 2.0 (3H, brs), 2.12 (3H, b
rs), 2.25 (3H, brs), 2.4 (1H, b
rd), 2.8-3.2 (2H, complex ),
3.2 to 3.5 (2H, complex ), 3.6 to
3.9 (2H, complex ), 3.97 (2H,
t, J = 7.0 Hz), 4.0 to 4.4 (2H, comp
Rex ), 4.7 (1H, brd), 6.1-6.3
(1H, complex ), 6.5 (1H, d, J = 1)
6.1Hz), 6.7~7.1 (4H, Comp Lek
Scan), 7.1~7.2 (1H, complex), 7.
2-7.6 (1H, complex ), 7.7 (1H,
brs)

The following compound was obtained in the same manner as in Example 54.

Example 55 2- [N- (4-methoxybenzoyl)] amino-N-
(4-chlorocinnamyl) -N-methyl-benzylamine pale yellow crystal NMR (CDCl ₃ ) δ ppm: 2.32 (3H,
s), 3.24 (2H, d, J = 6.7 Hz), 3.6
6 (2H, s), 3.83 (3H, s), 6.16 (1
H, dt, J = 15.9, 6.7 Hz), 6.46 (1
H, d, J = 15.9 Hz), 6.94 (2H, d, J)
= 7.8 Hz), 7.0 to 7.3 (6H, m), 7.3
4 (1H, t, J = 7.4 Hz), 7.91 (2H,
d, J = 7.8 Hz), 8.42 (1H, d, J = 7.
4Hz)

Example 56 2- {N- [3- (N, N-dimethylaminomethyl)]
Benzoyl @ amino-N- (4-chlorocinnamyl)-
N-methyl-benzylamine pale yellow crystal NMR (CDCl ₃ ) δ ppm: 2.21 (6H,
s), 2.37 (3H, s), 3.24 (2H, d, J
= 6.7 Hz), 3.45 (2H, s), 3.70 (2
H, s), 6.12 (1H, dt, J = 15.9, 6.
7 Hz), 6.44 (1H, d, J = 15.9 Hz),
7.0 to 7.5 (9H, m), 7.88 (1H, d, J
= 8.8 Hz), 7.91 (1H, s), 8.47 (1
H, d, J = 7.9 Hz), 11.63 (1H, br)
s)

Example 57 2- [N- (2-furoyl) -N- (2-hydroxyethyl)] amino-N- (4-chlorocinnamyl) -N-
Methyl-benzylamine colorless amorphous NMR (CDCl ₃ ) δ ppm: 2.17 (3H,
s), 2.84 (1H, d, J = 13.0 Hz), 3.
04 (1H, dd, J = 7.4 Hz), 3.27-3.
48 (1H, m), 3.58 to 3.79 (3H, m),
3.97 to 4.12 (1H, m), 4.40 to 4.56
(1H, m), 5.54 (1H, brs), 6.13-
6.27 (2H, m), 6.44 (1H, d, J = 1)
6.0Hz), 7.17 to 7.50 (9H, m)

Example 58 2- {N- (2-hydroxyethyl) -N- [3-
((N, N-dimethylaminomethyl) -benzoyl]} amino-N- (4-chlorocinnamyl) -N-methyl-benzylamine pale yellow oil NMR (CDCl ₃ ) δ ppm: 2.0 (3H, br)
s), 2.13 (3H, brs), 2.27 (3H, b
rs), 2.4 (2H, brd), 2.9-3.2 (2
H, complex), 3.3~3.6 (2H, Comp
Rex ) 3.6-3.9 (2H, Complex
S ), 4.0 to 4.1 (1H, brd), 4.7 (1
H, brd), 6.3 (1H, dt, J = 16.3,
7.5 Hz), 6.5 (1H, d, J = 16.3H)
z), 6.4-7.1 (2H, brs), 7.1-7.
5 (10H, complex )

Example 59 2- [N- (2-hydroxyethyl) -N-nicotinoyl] amino-N- (4-chlorocinnamyl) -N-methyl-benzylamine yellow liquid NMR (CDCl ₃ ) δ ppm: 2 .12 (1 , 5H ,
s), 2.17 (1 , 5H , s), 2.49 (0 , 5)
H , d, J = 12.9 Hz), 2.9 to 3.2 (1 , 5)
H , m), 3.3-3.5 (2H, m), 3.55-55
3.85 (2H, m), 3.9 to 4.35 (1 , 5H ,
m), 4.6~4.75 (0, 5H , brd), 6.2
６6.4 (1H, m), 6.51 (1H, d, J = 1)
6.9 Hz), 6.85 to 7.1 (2H, m), 7.1
5 to 7.55 (8H, m), 8.15 to 8.4 (2H,
m)

Example 60 2- [N- (2-aminoethyl) -N- (4-methoxybenzoyl)] amino-N- (4-chlorocinnamyl)
-N-methyl-benzylamine pale yellow liquid NMR (CDCl ₃ ) δ ppm: 2.12 (3H,
s), 2.9-3.2 (5H, s), 3.35 (1H,
d, J = 14.1 Hz), 3.5 to 3.7 (1H,
m), 3.63 (3H, s), 4.22 (1H, m),
6.18 (1H, dt, J = 15.8, 6.3 Hz),
6.4 to 6.6 (3H, m), 7.2 to 7.6 (10
H, m)

[0101]

Test method and results for efficacy of the determination in accordance with the present invention the compounds according to the present invention were rather each follows.

Vascular smooth muscle relaxing action (VR, E
D ₅₀ ) A domestic rabbit was exsanguinated and exsanguinated, and the abdomen was opened .
37 ± 0.5 ° C. through oxygen gas containing
Krebs -Hensele
it ) Suspended by applying tension to the solution. 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 by potassium chloride is reduced by 50% is shown, with the contraction tension by potassium chloride being 100%.

Platelet aggregation inhibitory action (PA, I
C ₅₀ ) Preparation of Washed Platelets (Centrifugal Washing Method) Blood collected from a healthy person and immediately mixed with 1/10 volume of 0.38% sodium citrate was centrifuged (700 ×
G, 10 minutes) to obtain platelet-rich plasma (PRP), and add 1/6 volume of ACD solution (2.2% sodium citrate, 0.8% citric acid, 2.2% glucose—adjusted for use) to this PRP. And centrifugation (1500 × G, 10 minutes)
Of the platelet pellet obtained by the above method with a modified HEPES Tyrode solution (135 mM salt, 2.7 m potassium chloride).
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 thereto, the platelet pellet obtained by further centrifugation (1500 × G, 5 minutes) is suspended in a modified HEPES Tyrode solution, and about 300,000 cells /
Make μl of washed platelet suspension.

Measurement of Platelet Aggregation Reaction (Nephelometry) 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 was added, and after preheating at 37 ° C. for 2 minutes, After adding 30 μl of a 20 μg / ml collagen solution, a 4-channel aggregometer (H
The absorbance is measured with EMA Tracer 601 (manufactured by Nikko Bioscience).

Determination of Effect of Test Compound As a control, the absorbance at the time of maximum aggregation with collagen in the presence of the solvent used for the test compound is set to 100, and the absorbance at the time of 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.

Calcium-dependent phosphodiesterase inhibitory action (CaPDE, IC ₅₀ )

[0107]

Table 1 500 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 20 μl (manufactured by Sigma) phosphodiesterase 20 μl calmodulin 200 μg test compound 20 μl (Appropriate concentration of 1 mM) ────────────────────────────── Adjust the total volume to 200 μl with distilled water.

The above solution was prepared in a test tube, and 4 μl was added thereto.
M ^[3 H] - with the addition of cyclic guanosine monophosphate Fe over DOO (2.5μCi / ml) 20μl, after 15 minutes treatment at 30 ° C., and heated for 3-5 minutes in a boiling water bath. After cooling the reaction mixture in ice water, 20 μg of 5′-nucleotidase (snake venom manufactured by Sigma) was added, and the mixture was again heated at 30 ° C.
After treatment for 10 minutes, about 2 ml of water is added, and then a cation exchange resin (AG50W-X4, manufactured by Bio-Rad)
After pouring into the column and adding a washing solution for washing the test tube, the column was washed with about 20 ml of water. 3 ml of 3N aqueous ammonia was poured into this column, and the eluted solution was received in a vial bottle, and the emulsified scintillation solution (ACS-II, ACS-II,
After addition of Amersham production) 10 ml, a liquid scintillation counter LS7500 ^{([3 H]} in the eluate by Beckman production) - The radioactivity is measured by guanosine, the enzyme activity in the presence of calmodulin 0
The μM concentration of the test compound giving 50% inhibition
It was calculated as C _50. Calmodulin-dependent phosphodiesterase used in this experiment was derived from rat brain by DEAE.
-Calmodulin was partially purified using a cellulose column, calmodulin was prepared from bovine brain by the TCA method, and purified using a calmodulin inhibitor W-7 affinity column. EGTA is a [ethylenebis (oxyethylenenitrilo)] tetraacetic reed head.

[0109]

[Table 2]

[0110]

[Table 3]

Efficacy test on cerebral blood flow (in vivo)
vo) Experimental animals Three dogs weighing 9 to 15 kg were used regardless of gender. Test method Dogs were treated with sodium pentobarbital (30 mg / kg
iv) 0.3 and 1 mg / kg of the compound of the example dissolved in physiological saline was administered through a polyethylene cannula which was fixed under anesthesia and inserted into the jugular vein, respectively. Vertebral artery blood flow was measured using a non-invasive probe (1.5-4.0 m diameter).
m Nihon Kohden) and an electromagnetic blood flow meter (MF26, Nihon Kohden) measured the blood pressure from a polyethylene cannula inserted into the femoral artery using a pressure transducer (TP-200T,
Recorder (RECTI-HO) via Nihon Kohden and pressure strain amplifier (AP-601G, Nihon Kohden)
RIZ-8K, manufactured by NEC Sanei). The following blood pressure drop rate in the table is the "BP", also vertebral arterial blood flow increase rate was abbreviated as "VBF".

[0112]

[Table 4]

In addition, the compounds according to the present invention have an inhibitory effect on enzymes such as A-kinase, myosin light chain kinase, C-kinase, cyclic AMP-specific phosphodiesterase, calmodulin kinase and 5-α-reductase. it had never photo command influence for the function.

[0114] as seen from these results, the compounds according to the invention have smooth muscle relaxant activity, vasodilating agents, as cerebral circulation improving agents, also thrombosis from where having a platelet aggregation inhibitory action prophylactic and therapeutic agent In addition, it is a low-toxic compound useful as a prostatic hypertrophy inhibitor, a hypoglycemic agent and an antitumor agent, and is suitable as a medicament.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61K 31/44 A61K 31/44 31/47 31/47 A61P 3/10 A61P 3/10 7/02 7/02 9/08 9 / 08 9/10 9/10 13/08 13/08 25/28 25/28 35/00 35/00 C07C 233/69 C07C 233/69 233/80 233/80 235/56 235/56 237/40 237 / 40 311/03 311/03 311/08 311/08 311/28 311/28 311/29 311/29 C07D 213/82 C07D 213/82 217/02 217/02 295/12 295/12 307/68 307 / 68 (72) Inventor Tsutomu Inoue 1-2-2-1201 Niwanishi, Funabashi-shi, Chiba (72) Inventor Tadashi Morita 2-9-10, Minamikashiwa, Kashiwa-shi, Chiba 4-20-13-901, Kichijoji-minami-cho, Ichi-ichi (72) Inventor Masayuki Yuasa 3-25-5, Showa-cho, Akishima-shi, Tokyo Corp. 103 Harajima 103 (72) Kenji Naito 5-7-6, Matsubara-cho, Akishima-shi, Tokyo Reebenhaus 106 (72) Inventor Osamu Sakuma 2-40-3 Sekido, Tama-shi, Tokyo 1105 The 4th Seiseki Sakuragaoka, Hito 1105 (72) Inventor Shinpei Shirosho 6-27-16, Daida, Setagaya-ku, Tokyo 4-11-6 Sakaemachi, Tachikawa-shi, Tokyo Examiner Norihiko Maeda (56) References JP-A-2-256666 (JP, A) JP-A-58-15941 (JP, A) (58) Fields investigated (Int. Cl. ^7, DB name) C07C 311/00 A61K 31/00 C07C 233/00 C07C 235/00 C07C 237/00 C07D 213/00 C07D 217/00 C07D 295/00 C07D 307/00 CA (STN) REGISTRY (STN )

Claims (2)

(57) [Claims] 1. A compound of the general formula (1): [ Wherein iQ is 5-isoquinoline sulfonyl, 1-3
Lower alkoxy- substituted benzenesulfonyl, methanesulfonyl, lower alkyl group, lower alkoxy group, or
Mino lower alkyl group (amino group is substituted with lower alkyl group
Is substituted with may also be) benzoyl, a full acryloyl or <br/> nicotinate Noi Le, Ph is a phenylene which may be substituted with methoxy, X is nitrogen or sulfur, A is vinylene or methyleneoxy Ar represents phenyl substituted with a group selected from halogen, methyl, cyano, methoxycarbonyl, lower alkoxy other than methoxy , 1 to 3 methoxy, and R ₁ represents hydrogen , there have 1-2 hydroxy, amino, ethoxycarbonylamino, amino lower <br/> alkoxy, acetoxy, hydroxy lower alkoxy,
Methoxy, been a have or unsubstituted lower alkyl substituted with a group selected from pyrrolidine, R ₂ TMG X is nitrogen
Only hydrogen or lower alkyl ] . 2. A compound represented by the general formula (2): (Wherein Ph is phenylene optionally substituted by methoxy, X is nitrogen or sulfur, A is vinylene or methyleneoxy, Ar is halogen, methyl, cyano, methoxycarbonyl, lower alkoxy other than methoxy , 1 to Phenyl substituted with a group selected from three methoxy,
R ₂ represents hydrogen or lower alkyl only when X is nitrogen ) to form a toluidine compound represented by the general formula (Chemical Formula 3): [ Wherein iQ is 5-isoquinoline sulfonyl, 1-3
Lower alkoxy- substituted benzenesulfonyl, methanesulfonyl, lower alkyl group, lower alkoxy group, or
Mino lower alkyl group (amino group is substituted with lower alkyl group
Or amidated with an acid or a reactive derivative thereof represented by the substituted benzoyl, showing the full acryloyl or nicotinyl Noi le] In may also) have been, or even general formula (4): ## STR4 ## [Wherein R ₃ is 1-2 hydroxy, substituted amino, ethoxy alkoxycarbonyl, amino-lower alkoxy, acetoxy, hydroxy lower alkoxy, methoxy, by pyrrolidine (wherein hydroxy in groups, amino may be protected) Or an unsubstituted lower alkyl, and Y represents hydroxy or halogen ) , followed by removing a protecting group if necessary. (Wherein R ₁ represents hydrogen or 1-2 hydroxy,
Amino, ethoxycarbonyl, amino lower alkoxy,
A substituted or unsubstituted lower alkyl with a group selected from acetoxy, hydroxy- lower alkoxy, methoxy and pyrrolidine, and the others have the same meanings as described above).