JPH037262A - Aromatic diamine derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R1 and R2 are H, substituted or unsubstituted alkyl or R1 and R2 link with ethylene to form a heterocyclic ring; R3 is H or carboxylic acid ester; Z is CH or N; Ar is chloro- substituted or unsubstituted phenyl or pyridyl). EXAMPLE:N-[2-(4-Chlorocinnamylamino)phenyl]-5-isoquinolinesulfonamide. USE:An ameliorant for cerebral circulation, remedy for angina pectoris, preventive and treating agent for thrombosis, etc. PREPARATION:A compound expressed by formula II is reacted with a compound expressed by formula III, reactive derivative or salt thereof in the presence of a base and, as desired, alkylated to afford the compound expressed by formula I. The above-mentioned reaction is carried out in the presence of pyridine serving also as the base and further DMF, chloroform, etc., as a solvent and triethylamine, NaOH, etc., are also used as the base.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention dilates blood vessels by relaxing the vascular smooth muscles of mammals, thereby improving cerebral circulation, treating angina pectoris, preventing thrombosis, etc. The present invention relates to a useful new aromatic diamine derivative and a method for producing the same.

[Conventional technology]

Compounds containing an isoquinoline ring as a part of their constituent molecules and having a vascular smooth muscle relaxing effect, such as the object compound of the present invention, include JP-A-57-156463;
200366, 58-121278, 58-121
279, 59-93054, 60-8+168, 61-126026, 61152658, 61-2
2758 6-271221, 61-293914
, 62-103066, 62-111981, 6
A number of publications have been published in publications such as No. 3-2980 and No. 63-211267.

[Invention or problem to be solved]

Some of these compounds have satisfactory effects as a smooth muscle relaxant, and some may be due to their rational production methods, but as pharmaceuticals, they have low toxicity, organ specificity, and safety, which are essential in addition to medicinal efficacy. There was room for improvement, and the compounds announced tended to be synthesized with this in mind. The present invention In order to obtain a compound that would be satisfactory as a pharmaceutical, Oton et al. filed Patent Application No. 325910 in 1985 as a compound with improved safety while retaining its medicinal efficacy. , improves the above,
The purpose of the present invention is to provide a new compound that is useful for improving circulation, treating angina pectoris, and preventing thrombosis without causing a drop in blood pressure or the like.

[Means to solve the problem]

In order to achieve the above object, the present invention uses the general formula (wherein R, , R are the same or different, hydrogen, substituted or unsubstituted alkyl, a group in which Ro and R1 are linked with ethylene to form a heterocycle). ; R1 is a carboxylic acid ester or hydrogen, 2 is the same or different and is CH or N; Ar is chloro-substituted or unsubstituted phenyl, pyridyl) and their production method. It is something.

Compound (1) according to the present invention is, for example, a compound having a condensate of aromatic noamine and isoquinoline sulfonic acid as a core, and both are novel compounds having a vascular smooth muscle relaxing effect.

The method for producing the compound (1) of the present invention is explained using the general formula:
- Substituted allyl halide represented by the formula %() (in the formula, Hat represents a halogen and Ar has the same meaning as above) and the general formula (in the formula, R1
The allylamine compound represented by the general formula obtained by reacting the aromatic ring diamine represented by The desired compound represented by the general formula is obtained by reacting a salt and a base in the presence of a base.

Further, the obtained compound (1-a) can be converted to compound (1) by a conventional alkylation reaction using diazomethane, methyl iodide, 1,2-dibromoethane, etc., and a phototransfer reaction in which the corresponding alkylation is carried out with alcohol. I was able to get it.

In the reaction to obtain compound (1-a), in addition to pyrinone, which also serves as a base, as a solvent, dimethylformamide, acetonitrile, dioxane, tetrahydrofuran, nochloromethane, chloroform, etc. are used.As an organic base, in addition to pyridine, dimethylaminopyridine, N- Tertiary amines such as methylpiperidine and triethylamine, and inorganic bases such as potassium carbonate, potassium bicarbonate, caustic potash, soda carbonate, sodium bicarbonate, and caustic soda can be used.

Also, although the alkylation reaction depends on the selection of the alkylating agent,
Tetrahydrofuran, trimethylformamide, dioxane, dimethoxyethane, methanol, ether, chloroform, ethyl acetate, etc. can be used as appropriate, and when an acid is generated during the reaction, sodium hydride, potassium carbonate, bicarbonate can be used as the acid acceptor. Potassium, soda carbonate, bicarbonate soda, etc. can be selected and used.

〔Example〕

The present invention will be specifically explained below with reference to examples, but the present invention is not limited to these examples.The melting points in the examples were measured using a melting point measuring device YaIIlat.

Measurement was performed using a capillary using MP-21 (manufactured by Yamato Kagaku Co., Ltd.), nuclear magnetic resonance spectrum ('H-NMR) was measured using JEOL, JNM-FX200 (manufactured by JEOL Ltd.), and molecular weight was determined by JMS-D300 model mass. The infrared absorption spectrum (!R) is rRA- using a leaf meter (manufactured by JEOL Ltd.).
1 (manufactured by JASCO Corporation).

Reference example 1 4-chlorocinnamyl alcohol p-chlorocinnamic acid 25.9g methanol 250a+
After adding 1.5a+1 of concentrated sulfuric acid and refluxing for 2 hours, the reaction solution was poured into water, made alkaline with sodium bicarbonate, and extracted twice with 10,100O of chloroform. The extract was washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was applied to a silica gel column and purified with hexane-ethyl acetate (lO:1). 26.5 g of p-chlorocinnamate methyl ester was dissolved in 250 ml of toluene, and while stirring while cooling with water, 200 ml of a 15 mol toluene solution of diisobutylaluminum hydride was added, followed by stirring for 2 hours. The reaction solution was poured into water, made acidic with concentrated hydrochloric acid, and extracted twice with 700 ml of benzene. The extract was washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. It was applied to a silica gel column and purified with hexane-ethyl acetate (4:1) to obtain the desired product in the form of colorless crystals. 21.0g was obtained.

'HNMR(CDCIs, δpp
m) 2 4.3 3 (2H.

brs), 6.33 (IH, dt, J=1'7.1.5
．． 7Hz), 6.59 (IH, dt, +7.1, 2,
0Hz), 7.29 (4H,s) Reference Example 2 \-(4-Chloronnamyl)-1,2-phenyleneamine 11.9g of the crystal of Reference Example 1 was dissolved in 120ml of chloroform.
After cooling with water and adding 1 g of thionyl chloride IO while stirring, the water bath was removed and the mixture was gradually warmed to room temperature while stirring was continued for 1 hour.

Chloroform and excess thionyl chloride were distilled off under reduced pressure, benzene was added to the residue, and the solvent was distilled off under reduced pressure. The resulting residue was applied to a silica gel column and diluted with hexane-ethyl acetate (15°1). After purification, 11.3 g of colorless crystalline p-chlorocinnal chloride was obtained.

'HN M R (CDC13, δppHl):
4.23 (2H.

dd, J = 6.3, I, OHZ), 6.29
(l H, dtJ = + 6.6, 6.9Hz), 6
．． 62 (I H, di.

J = l 6.6.1.0Hz), 7.30 (4H,
5) 196 g of 2-phenylenenoamine was dissolved in 300 volumes of trimethylformamide, 12.5 g of potassium carbonate and 11.3 g of the crystals obtained in the previous section were added to the solution under stirring at room temperature, and the mixture was stirred under the same conditions for 48 hours. After adding water and salt to the reaction solution, it was extracted twice with 00 ml of chloroform IO, the extract was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, the residue was applied to a silica gel column, and hexane-ethyl acetate (3: 1) to obtain colorless crystalline target product 12.85
I got g.

H-NMR (CDCI, δppm): 3.4
(3H.

brs), 3.93 (2H, dd, J=5.71 1.
0t (Z), 6.36 (lH, dt, J=16.0
5.7IHz), 6.59(IH, dl, J=+
6. OI.

0) [z), 6.68-6.9 (4H, m), 7.28
(4H, s) Example! N-(2-(4-Chloronnamylamino)phenylcou 5-isoquinoline sulnanic acid amide 12.85 g of the crystal obtained in Reference Example 2 was added to 200 m of bilin.
1, and added 15.1 g of 5-isoquinolinesulfonoyl chloride hydrochloride under water cooling and stirring, and then removed the water bath.
The reaction was allowed to proceed at room temperature for 18 hours. After pouring the reaction solution into water and making it alkaline with sodium bicarbonate, 100% of chloroform was added.
Extracted twice at 0g+1. Dry the extract over magnesium sulfate, distill off the solvent under reduced pressure, add chloroform to dissolve the slightly soluble crystals, heat and cool, collect the crystals by suction filtration, wash with chloroform and dry under reduced pressure. 17.23 g of the target product in the form of colorless crystals was obtained.

Melting point: 205-208°C (decomposition) [R(KBr)am-'+1600.1320,115
0.1135 'H-N Hey R(C1)C10+ CD20D
, δ pρlI+): 3.73 (2H, dd,
J = 5.62.1.46 Hz), 6.04 (IH
, dt, J=15.8.5.37Hz), 6.27~6
．． 35 (2H, m), 6.42 (IHdt, J=16.
l +, 1.46 Hz), 6.58 (IH, d, r =
7.8 I H2), 7.04 (l f(, ddd
J=8.30, 6.10, 2.93Hz), 7.25(
2H, d, J = 9.03 Hz), 7.31 (2H
, dJ=9.03Hz), 7. 6 3 (l
H, dd, J = 806.7.33Hz), 8
．． 1 7 (I Hldd, J = 73
2. 0. 98, Hz), 8. 3 0
(l H, dd, J = 7.57, 1.23) 1z
), 8. 4 7 (l H, dd, J='6
．． 35, l, 02 Hz), 8. 5
5 (lH, d, J=6.35Hz), 9
．． 2 5 (I H, d, J = 0.98
Hz) Example 2 N-(2-(4-chloronamylamino)phenyl)
N-Methyl-5-isoquinolinosulfonic acid amide 380 mg of the crystal of Example 1 was dissolved in 6 ml of methanol, and 10 ml of diazomethane ether solution was added under stirring at room temperature.
was added and stirred for 18 hours. The oil obtained by distilling off the solvent under reduced pressure was applied to a silica gel column and purified with hexane-ethyl acetate (l 1) to obtain crystals, which were further recrystallized from hexane-ethyl acetate. Colorless crystal object 2
1 g of 70II was obtained.

Melting point: 149-151°C IR (KBr) cm”: Ii5 9 3.1
3 2 5 1 1 25 830 745 H-NMR (CDCIl, δ ppm):
3.2 4 (3H8), 3.87 (2H, T11),
4. 8 1 (I H, t, J = 5.71
Hz), 6.1 3(I H, dt J =
+9.14. 5. 7 1 Hz), 6.
2 5 ~ 6.4 0 (2H, m) 6.53 (IH, d
t, J=I 9.1 4.1.0Hz)6. 6 7
(L H, d, J = 8.5 7 H
z), 705-7.18 (IH, m), 7. 2
8 (4H, s), 76 7 (l H, t
, J = 7. 4 2 Hz), 8.19 (
IH, d, J = 7. 4 2 Hz), 8
．． 2 8 (I H, d J = 6.28 Hz), 8.
3 2 (I H, dd, J = 7.42.1.0H
z), 8.5 1 (IH, d,, J=6.28Hz)
, 9.30 (IH, d, J = 1.0H2) Example 3 l-(4-Chloronnamyl)-4-(5isoquinolinesulfonyl)-1,2,3,4tetrahydroquinoxaline of crystalline form according to Example 1 5. Dissolve Og in 75 ml of dimethylformamide and add 4.0 mL of potassium carbonate while stirring at room temperature.
Add 6g11.2-nobromoethane 2.19g, 60
Stir for hours. The reaction solution was poured into water and saturated with sodium chloride, and then extracted twice with 400 ml of chloroform. The extract was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was applied to a silica gel column, followed by chloroform-methanol (400:1) and then hexane-ethyl acetate (21).
to obtain 3.32 g of yellow amorphous target product L0[R
(KBr)cm-1:I 600 1340 1150
．． 1130,660 H-NMR (CDC13, δppm): 2.6
8 (2Ht, J = 5.71 Hz), 3.49 (
2) (, dd, J = 6.28, 1°0Hz), 3 8
9 (2Ht J=5°71Hz), 5.43 (I H,
dt,, J = 15.426.28Hz), 6.10
(I H, dt, J = 15.42.1.0Hz),
6.48 (L H, dd, J = 7.99.1.0
Hz), 6.75 (I H, dt,, J = 7.9
9.1.0Hz), 7.09 (2H, d, J=7.99
Hz), 7.12 (I H, dt, J = 7.99
．． 1.0Hz), 7.3 1(2H, d, J=7.9
9Hz), 7.

5 = 1 (l [(, ad, J = 7
．． 9 9. 1. 0 Hz), 759(lH,L
, J=7.99) 12) , 7 , 7 7(
I H, d, J = 6. 28Hz),
7.94 (lH, dJ=7.99142), 8
．． 30(II-(dJ=6.28Hz), 8
．． 38 (IHdd J=7.99 10Hz),
9. 0 3 (l [(, d, J = I
, OHz) Example 4 tl-(3-(3pyridyl)allyl)- in place of N-(4-chloronnamyl)-12-phenylenediamine
A brown amorphous N-[2-(3-(3-pyridyl)allylamino]phenylco-5-isoquinolinesulfonic acid amide was obtained by the same procedure as in Example 1 except that 1,2-phenylene amine was used. Ta.

H-NMR (CDC1, δppm): 2.
2 (l H,br)3.78(2)(,dd,J=5
．． 14.1.0H2), 4.85 (l H, br),
6.14 (l H, dt, J = 15.99.5.
l4Hz), 6.33 (21i, d, J
=4.57Hz), 6.42 (I H, dt, J =
15.99.1.0Hz), 6. 5 8 (I
)(,d,,J = 7.4 2Hz),
6 98-7. 1 5 (l)(,m), 7
．． 26 (IH, dd, J = 7.4 2.4
．． 57 Hz), 7. 5 9 (IH, t
, J = 7. 4 2 Hz), 7
．． 6 5 (l H, dt J-7, 42
, 1,0H2), 8. 1 6 (I
H, d, J = 7.99 Hz), 8.30 (I
H, d, J=6.85Hz), 8.3 5 ~ 8.5
3 (3H, m), 8. 5 6 (1)(,d,
, J = 6. 2 8 Hz), 9.3 2
(I H,s) Example 5 The solid body obtained in Example 4 was treated with diazomethane as in Example 2 to obtain brown amorphous N-[2(3-(3-pyridyl)).
Alylamino]phenyl]-N-methyl-5-isoquinolinesulfonic acid amide was obtained.

'H-NMR (CDCl2.δppm): 3
．． 24 (3H3), 3.92 (2H, t, J = 4.57
Hz), 490 (lH, t, J=5.71Hz), 6.
26 (IH, dt, J = l 5.42.5.14
Hz), 632 (2H, d, J = 4.57 Hz
), 6. ．． 58 (I H, dt.

J=15.42, 1.0H2), 6.62-674
(2H, m), 7. 0 5-7. 2 0
(l Hlm), 726 (IH, dd, J=7.9
9,4.57Hz), 7.

6 to 7.75 (lH, m), 8. 2 1 (I
H, d, J ~7.99Hz), 8. 2
'8 (I H, d, J = 6.8 5Hz
), 8.3 2 (I H, d, J ~6.2 8
Hz), 84 7 (l H, dd, J =
5. 7 1, I, OHz), 85 1
(I H, d, J = 6', 2 8 Hz
), 8. 5 8 (IH, d, J = 1
．． 7 Hz), 9. 3 1 (I H,s)
Reference Example 3 2-Amino-3-(4-chlorocinnamyl amino)pyridine 7.71 g of p-chlorocinnamyl chloride and 13.5 g of 23-diaminopyridine were mixed with 220 g of dimethylformamide.
8.6 g of potassium carbonate was added and the mixture was stirred at room temperature for 50 hours. After adding 300+ al of water, the mixture was extracted twice with 200 IAl of chloroform. The residue obtained by drying with magnesium sulfate and concentrating under reduced pressure was applied to a silica gel column, and chloroform-methanol (100:I~
50:1) to obtain 4.52 g of the desired product in the form of yellow crystals.

H−N isI Rccoc+i, δppm): 3
．． 38 (l Hbr), 3.92 (2I-[1m),
4.20 (2H, br), 6.31 (IH, dt, J
=I6. l, 5.9 Hz), 6.59 (I H, dt,
J = l 6.1, 1.5Hz), 6.71 (IH,
dd, J=4.9, 7.8Hz), 6°86 (I H
, dd, J ~1.5.7.8) 1z), 7.29
(4H, s), 7.63 ([H, dd, J= 1.5.
49 Hz) Example 6 3-(4-chlorocinnamylamino)-2-(5-isoquinolinesulfonylamino)pyridine 452 g of the crystals obtained in Reference Example 3 were dissolved in 50 ml of pyridine, and 5-isoquinolinesulfonyl chloride hydrochloride 5 ．．
8 g and 3 g of dimethylaminopyridine were added, stirred at room temperature for 18 hours, added with 50 Ill of water, and extracted twice with 80 ml of chloroform. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was applied to a silica gel column and purified with chloroform-methanol (100:1). The resulting crystals were washed with ethyl acetate to give yellow crystals. 1.2 g of the desired product was obtained.

Melting point: 211-217°C (decomposition) rR(KBr)c+n-': 1595, 1550.1
345 1285.1250.1 05 H-N M R (CDCIl, δppm) + 3.8
9 (2H.

m), 5.45 (l H, t, J = 5.9 Hz)
, 6.12 (I H, dt, J = + 6.1.5
．． 4 Hz), 6,45 (I H, d, J = 16
, I Hz), 6.51-6°62 (2H, a+),
6.92 (I H, brs), 7,21 (2H, d,
J = 8.8 Hz), 7. ．． 29 (2H, d, J
=8.8Hz), 7.64 (I H, dd, J =
7.3.

8.3Hz), 8.12 (I H, d, J = 8.
3 Hz), 8.45 (lH, dd, J=1.o, 7.
3Hz), 864 (IH, d, J=5.9H2), 8.
69 (IH.

d, J = 5. 9 Hz), 9. 3
1 (I H, s) Reference Example 4 4-7mi/-3-(4-10ronononamylamino)an9
．． Methyl fragrant ester 3.4-Noaminoben C1 5.0 g of methyl fragrant acid was dissolved in 40 ml of dimethylformamide, 2.07 g of potassium carbonate, and 1.87 g of p-chlorocinnamyl chloride.
was added and reacted as in Reference Example 2 to obtain 2.0 g of the desired product as a light brown oil.

NMR(CDCl2.δ1)1)Ill) :
3.85 (3H, s), 3, 94 (2H, b, r
d), 6.35 (l H, dt, J ~5.86,1
5.8Hz), 6.59 (I H, d, J ~ 5.8H
z), 6.7 (L H, d, J -8,02Hz),
7.28 (4H, s), 7.4 (I H, d, J =
1.4Hz), 7.46 (I H, dd, J =
I, 4.8.0Hz) Example 7 4-(5-isoquinolinesulfonamide)-3-(4-
Chlorocinnamyl amino)-Anne B, methyl fragrant oil obtained in Reference Example 4! , 8゛g was dissolved in 18ml of pyridine, 1.29g of 5-inquinolinsulfonyl chloride hydrochloride was added under water cooling and stirring, and after the same procedure as in Example 1, it was applied to a silica gel column and chloroform:methanol ( 1.28 g of the target product in the form of pale yellow crystals was obtained from both fractions eluted at 100:l).

Melting point: 143-145℃ (sublimation above melting point) N M
R(CDCI3, δppm): 3.78 (
2H, brd), 3.82 (3H, S), 6.0 (
l H, dt, J = 5.86.15.87Hz),
6.4 (lH, d, J = 15° 8Hz), 6.45 (
I H, d, J = 8.3 Hz), 7°05 (I
H, dd, J = 1.8.8.3 Hz), 7.2
~7.3 (5H, brs), 7.60 (IH, t, J
=7゜6Hz), 8.15 (I H, d, J = 8
．． 3 Hz), 8°29 (l H, dd, J = 1
．． 2.7.3 Hz), 8,43 (I H, d, J
= 6.1 Hz), 8.61(1)(,d.

J = 6.1Hz), 9.3 (I H, d, J = 1
．． 2 Hz) Reference Example 5 N-nnnamyl 2-phenylenediamine 3.24 g of orthophenylenediamine was dissolved in 30 ml of dimethylformamide, 2.07 g of potassium carbonate and 1.32 g of cinnamyl chloride were added, and the mixture was stirred at room temperature overnight. After adding 100ml of water to the reaction solution, it was extracted with 100ml and 50ml of chloroform, the extract was washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was applied to a silica gel column. The target substance 24 was attached and eluted with chloroform as pale yellow crystals from both parts.
Obtained 0g.

Melting point: 59-66°C (decomposition) NMR (CDCl s, δppm): 3.3
(2H, brs), 3.93 (2H, brd), 6
．． 4 (I)l, dt, J = 5.

6.16.1Hz), 6.1-6.45 (4H.

complex), 5.2-5.7 (5H, comp
lex) Example 8 N-(2-nnnamylamino)phenyl-5-isoquinolinesulfonamide 1.8 g of the crystals obtained in Reference Example 5 was dissolved in pyridine I81, 1.83 g of isoquinolinesulfonyl chloride hydrochloride noble was added, and the mixture was heated to room temperature. Stirred for 18 hours. 50ml of water to the reaction solution
After addition of
2.40 g of the target product in the form of pale red crystals was obtained from the fraction eluted with form-methanol (100:1).

Melting point: 181-185°C NMR (CDC1, δppm>: 3.75
(2H,brd), 4.55 (IH,brs),6
．． 05 (I H, dt, J ~5.6, I 6 ,
I Hz), 6.35 (2H, brd), 6°45
(I H, d, J = 16, I Hz), 6.63
(l H, d, J = 8.3 Hz), 7.0-7.
13(IH, C0III1)leX), 7.25-7.
4 (5H, complex) 7.6 (I H, t,
J = 8.2 Hz), 8.15 (IH.

d, J = 8.3 Hz), 8.31 (1) (, d
d, J = 1.0.8.2Hz), 8.4 (l H
, d, J = 6.6 Hz), 8.65 (I H,
d, J = 6.6 Hz), 9.3 (IH.

d, J = 1.0 Hz) Reference Example 6 N-(4-chlorocinnamyl) I, 3-phenylenediamine 3.24g of metaphenylenediamine was dissolved in 40ml of dimethylformamide, and 2.07g of potassium carbonate 5p-
Added 1.87g of chlorocinnamyl chloride and prepared Reference Example 2.
After reacting as shown, it was applied to a silica gel column and n-
1.70 g of the target product as a pale brown oil was obtained from the fraction eluted with hexane-ethyl acetate (3:1 to 2:1).

NMR (CDC1, δppm): 3.65
(2H, brs), 3.90 (2H, dd, J =
1.4.5.6 Hz), 60-6, 2 (3H, c
complex), 6.3 (lH, ddJ=5.6,
15.9Hz), 6.56 (l H, dd.

J=1.4, 15.9H2), 6.97(IHt J=
8.1Hz), 7.3 (4H, s) Example 9 N-(3-(4-chlorocinnamylamino)phenyl]
-5-isoquinolinesulfonamide 1.7g of the oily substance obtained in Reference Example 6 was dissolved in 18ml of pyridine, and 1.99g of 5-isoquinolinesulfonyl chloride was added under stirring while cooling with water. 1.45 g of the oily target product was obtained.

NMR (CDCI, δppm): 3.8 (
2H,brd), 3.92 (lH,brs),6.
15 (I H, dt, J = 5.6 15.9H7)
, 6.25 (I H, brs), 635 (2H, b
rd), 6.49 (I H, d, J = 15°9Hz)
, 6.92 (lH, t, J = 8.1Hz), 7゜3 (
4H, s), 7.51 (l H, t, J = 8.3
Hz), 8, I (I Hld, J = 8.3
Hz), 8.35 (IH.

dd, J = 1.0.8.3 HZ), 8.45 (I
H, dJ = 6.1Hz), 8.65 (IH, d, J = 6
．． 4Hz), 9.3 (I H, d, J = I, O
Hz) Example 1O N-(2-(p-chlorocinnamylamino)phenyl)
-N-(2-Hydroxyethyl)5-isoquinolinesulfonic acid amide Example 1.5 g of the crystals obtained in
1.32 g of triphenylphosphine and 420 mg of ethylene glycol monoacetate were added thereto, and while stirring under water cooling, a solution of 1.01 g of neuisobrovir azonocarboxylate in 2 ml of tetrahydrofuran was added dropwise. After the dropwise addition, the water bath was removed, the temperature was returned to room temperature, and the mixture was stirred for 3 hours. The reaction solution was diluted with ethyl acetate and
Extracted twice with 70 ml of normal hydrochloric acid.

The aqueous layer was made alkaline with an aqueous bicarbonate solution and extracted twice with 150 ml of chloroform. After drying the extract over magnesium sulfate, the solvent was distilled off under reduced pressure. To the resulting oil, 20 g+l of methanol and 20 ml of tetrahydrofuran were added. After dissolution, 20 ml of 1N aqueous sodium hydroxide solution was added, and the mixture was allowed to react at room temperature. After 2 hours, the reaction solution was diluted with water and then diluted with 100+nl of chloroform and 11ml each of 50ml.
After multiple extractions and drying the extract over magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting oil was applied to a silica gel column and chloroform-methanol (100
: Yellow amorphous target product 1.5 was extracted from the fraction eluted in 1).
9g was obtained.

IR (KBr) cm-': I 603. I 516.
1491.1342゜+161.1 139 835.758.6 04 509 rXr M R (CDCIs, δ1)ri5m) +
3.09 (IH, m), 3.29 (IH, ddd,
J=13.43, 4.643.18Hz), 3.47
(L H, m), 3.75 (IH, m), 3.85
(2H, m), 4.33 (I H, ddd.

J=I3.43 8.30, 4.15Hz), 5I2(
I [(, m), 6.16 (I H, dt, J = 1
5.87.5.62 Hz), 6.23 (I H,d
d, J = 8.

06.1.47Hz), 6.40 (I H, td, J
= 733.1.47Hz), 6.55 (I H,
d, J = 16.1 lHz), 6.76 (IH, d,
J = 8.54Hz), 7.15 (I H,t, J =
8.30 Hz), 729 (4H, S), 7.63 (
IH, t, J=8.30Hz), 8.18 (IH,
d, J = 8.30 H2), 8°28 (IH9d,
J = 8.30Hz), 8.28 (1H, d, J =
6. 3 5 Hz), 8.5 2(l H,
dJ=6.3Hz), 9. 3 1 (L
H,s) Example! N-(2-(p-chlorocinnamylamino)phenyl)
-N-(2-dimethylaminoethyl)-5-isoquinolinesulfonic acid amide Crystals obtained in Example 1 2. Og to tetrahydrofuran lo
ml and add 1.75 triphenylphosphine to this.
g and 520 mg of N,N-dimethylethanolamine were added, and while stirring under water cooling, 1.3 g of noisoprobil azodicarpoquinlate and 3IIl of tetrahydrofuran were added.
l solution was added dropwise. The water bath was removed, the temperature was returned to room temperature, and after stirring for 3 hours, the reaction solution was diluted with ethyl acetate, extracted twice with 100 ml of 2N hydrochloric acid, the extract was made alkaline with an aqueous sodium bicarbonate solution, and 200 ml of chloroform was extracted.
Extracted twice with m1. The extract was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting oil was applied to a silica gel column, and chloroform-methanol (100:1
) 1.35g of yellow amorphous target substance eluted from both halves
I got it.

IR(KBr)am':1603 1521.1491
．． 1458,1329.1 +60 1137 834 749.601,507 N M R (CDCI, δppIll): 2.1
9 (6H, s), 2.15-2.55 (2H, m),
3.19 ([Hdt, J= I 2.69, 4.15H
z), 3.56' (2H, m), 4.35 (I H,
m), 5.78 (IH, m), 5.89 (IHldt,
J=15.87, 5.37Hz) 6.30-6.55
(3H, m), 6.64 (IH.

dd, J = 7.81.1.71 Hz), 7.09
(IH.

td, J = 7.81.1.71 Hz), 7.23
(2H.

d, J = 9.03 Hz), 7.30 (2H, d,
J=9°03Hz), 7.57(I H, dd, J=8
．． 30,7°57H2), 8.11 (I Hld, J
= 8.30 Hz), 8.24 (I H, d, J
= 7.57 H7), 8.40 (IH, d, J =
6.35 Hz), 8.53 (I H, d, J-=
6.35Hz), 9.26 (IH, S) [Effects of the Invention] The following are examples of test methods and results for determining the growth efficacy of the compounds according to the present invention.

Vascular smooth muscle relaxing effect (V, R,, ED 50) A rabbit was sacrificed by exsanguination, the abdomen was opened, and the extracted superior mesenteric artery was incised in a spiral shape according to a conventional method to prepare a strip specimen. Kre at 37±0.5℃ through oxygen gas containing carbon dioxide gas
It was suspended under tension in bs-Henseleit solution. The strip specimens were contracted with potassium chloride and a constant tension was maintained before cumulative administration of the target compound. The muscle relaxant effect is expressed as the concentration that causes 50% relaxation, taking the contraction tension caused by potassium chloride as 100%.

Suppression of platelet aggregation (P, A, IC5°) Preparation of washed platelets (centrifugal washing method) Blood collected from a healthy person and immediately mixed with 0°38% sodium citrate at I/10ft was centrifuged (700°C).
x G, I for 0 minutes) to prepare platelet-rich plasma (PRP), and add 1/6 volume of ACD solution (sodium citrate 2.2%, citric acid 0.8%, glucose 2.2%) to this PRP.
The platelet pellet obtained by centrifugation (1500xG, I 0 min) was added to modified HEPES.
Tyrode's solution (salt 135f1M).

Potassium chloride 2,71! M, magnesium chloride 1mM,
Glucose 0.1 mg/1 ml, HEPES20
(mM; pH 7,4). 1/6 to this
After adding 11 ACD solution, further centrifugation operation (+500XG
, 5 minutes) is suspended in a modified HEPES Tyrode's solution to obtain a washed platelet suspension of approximately 300,000 cells/μl.

Measurement of platelet aggregation reaction (turbidimetry) To 270 μl of the washed platelet suspension obtained in Moehang, add 3 μl of each concentration of test compound dissolved in an appropriate solvent and incubate at 37°C.
After prewarming for 2 minutes, 30 μl of a collagen 20 μg/ml solution is added, and the absorbance is measured using a 4-channel aggregation 51j constant 1i (HEM, Hetruizer 601; Niko Bioscience Co., Ltd. W).

As a control for determining the effect of the test compound, the absorbance at the time of maximum aggregation by collagen in the presence of the solvent used for the test compound is set as 100, and the absorbance before addition of collagen is set as 0.

Next, the percentage of inhibition was calculated from the absorbance at the time of maximum aggregation by collagen when the test compound was added, and 50%
IC, the concentration of test compound that gives inhibition. Display as .

(Ca” PDE T C5o) Calmodulin-dependent phosphonoesterase inhibitory effect 500mM Tris-HCl (pH 8.0)
20μm 50mM magnesium chloride 20
μm2mM Calcium chloride 20μ
l (or 1OII+M EGT^) 1mg/ml bovine serum albumin (manufactured by Sigma) 20
μl Phosphogesterase 20μm Calmodulin 200ng Test drug (IQ
The total volume is made up to 200 μl with appropriately concentrated nM-1mM 201 distilled water.

Prepare the above solution in a test tube and add 4 μM (3H)
- cyclic guanosine monophosphate (2,5μ
After adding 20 μl of Ci/Il+1) and treating at 30° C. for 15 minutes, the mixture was heated in a boiling water bath for 3 to 5 minutes. After cooling this reaction mixture in ice water, 20 μg of 5'-nucleotidase (manufactured by Sigma, Snake Venom) was added, and after treatment at 30°C for 10 minutes, approximately 2 ml of water was added, and a cation exchange resin (
AG50W-X4. (manufactured by Bio-Rad) column,
After adding the wash solution used to wash the test tube, the column was washed with about 20 liters of water. Add 3 to 1 part of 3N ammonia water to this column.
Pour the eluted solution into a vial, and add emulsified scintillation solution (ACS-II) to the vial.

After adding fO+al (manufactured by Amajam), the radioactivity due to C'H) -guanosine in the eluate was measured using a liquid scintillation counter LS 7500 (manufactured by Beckman), and the enzyme activity in the presence of calmodyulin was reduced to 0.
The μMa degree of the test drug that gives 50% inhibition is [C
i.

Calculated as a value.

The calmodyulin-dependent phosphogesterase used in this experiment was partially purified from rat brain using a DEAE-cellulose column, and the calmodyulin was prepared from bovine brain by the TCA method using a calmodulin and phosphorus inhibitor W-7 affinity column. The purified product was used.

EGTA is [ethylene bis (oxyethylene nitrilo)]
] Tetraacetic and.

Example number V, R, EDs. P, A, IC5o Ca”
PDEICs.

(μM) (μM) (μM) 1 6
．． 8' 1,12 0.82
1.53 1.8
1.04 12 8 28 61・2 42 7 1.8 76 8.
183, 1 609
0.57 10 0.25 3.
411 4゜4 62 1
7 The compound according to the shrub invention is protein kinase A
, had an inhibitory effect on enzymes such as myosin light chain kinase, protein kinase C, and cyclic AMP-dependent phosphogesterase, but had little effect on cardiac function.

In view of these results, the compound according to the present invention has a smooth muscle relaxing effect, can be used as a vasodilator, a cerebral circulation improving agent, and has an inhibitory effect on platelet aggregation, so it can be used as a prophylactic and therapeutic agent for thrombosis. It is a low-toxic compound that is useful as an antitumor agent because it inhibits the activity of various phosphorylating enzymes, and is suitable as a medicine.

Claims (1)

[Claims] 1) General formula ▲ Numerical formula, chemical formula, table, etc. An aromatic diamine derivative represented by a ring-forming group; R_3 is hydrogen or a carboxylic acid ester; Z is the same or different and represents CH or N; A represents chloro-substituted or unsubstituted phenyl or pyridyl. 2) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_3 is carboxylic acid ester or hydrogen; Z is CH or N; Ar is chloro-substituted or unsubstituted phenyl,
The allylamine compound represented by the general formula ▲ has mathematical formulas, chemical formulas, tables, etc. ▼ is a general allylamine compound characterized by reacting a sulfonic acid represented by the formula ▼, its reactive derivatives, and its salts, and optionally alkylating it. Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_1 and R_2 are the same or different and are hydrogen, substituted or unsubstituted alkyl, R_1 and R_2 are connected with ethylene to form a heterocycle; others are A method for producing an aromatic diamine derivative represented by (having the same meaning as above).