JPH0347170A - Aromatic amino acid derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R1 and R2 are H, nitro, amine which may be replaced, OH which may be replaced or alkyl; R3 is H, alkyl which may be replaced, aralkyl which may be replaced or alkylene coupled to Ar ring; R4 and R5 are H or form oxo together; Ar is benzene ring or imidazole ring; Y is CH or N; A is CR6R7 or NR6 (R6 is H, OH, phenyl, acyl, etc.; R4 is H or alkoxy); n is 2 or 3). EXAMPLE:N-[1-(Imidazol-4(5)-yl-methyl)-2-(4-phenylpiperazinyl)ethyl]-5 -isoquinoline sulfonic acid amide. USE:Useful as a medicine for preventing and treating vasodilator, nerve circulation improving agent or thrombosis and antitumor agent. PREPARATION:For example, an amino acid derivative expressed by formula II is reacted with a sulfonic acid expressed by formula III or reactive derivative thereof to provide the compound expressed by formula I.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention dilates blood vessels by relaxing the vascular smooth muscles of mammals, improves cerebral circulation, treats angina pectoris, prevents thrombosis, etc. The present invention relates to a novel aromatic amino acid derivative useful for and a method for producing Rρ thereof.

[Conventional technology]

Currently, as a compound having a vascular smooth muscle relaxing effect, which contains an isoquinoline ring as a part of its FM structure, such as the object compound of the present invention, Japanese Patent Application Laid-Open No. 57-156463
, 57-200366, 5B-121278, 5
B-121279, 59-93054, 60-81
168, 61-126026, 61-152658
, 61-227581, 61-271221, 6
1-293914, 62-103066, 62-1
11981, 63-2980, 63-211267
A large number of them have been published in various publications.

Some of these compounds have satisfactory smooth muscle relaxing effects, and some have rational production methods, but as pharmaceuticals, they have no medicinal efficacy. There is room for improvement in the essential aspects of low toxicity, organ specificity, safety, etc., and the compound represented by 1 also improves them by α+1iil! There was a tendency to synthesize L/. In order to obtain a compound that would be effective as a medicine, Moo Mei and others developed a compound with improved safety while retaining its medicinal efficacy.
It was published as No. 5910, but Kivu and Akira, as a link to it, ``improve the second layer and do not lower blood pressure (improve cerebral circulation, treat angina pectoris, preventive treatment of thrombosis, etc. The purpose is to provide new compounds useful for.

[Means to solve the problem]

The present invention relates to the general formula (wherein R1+R2 are the same or different, hydrogen, nitro, substituted or unsubstituted amino, substituted or unsubstituted hydroxyl group,
A group such as lower alkyl; R8 is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted aralkyl, or a group such as alkylene connected to the Ar ring; R,,R
, are each hydrogen or together are oxo;A
r is a ring such as benzene or imidazole; Y is CH
or N; A is ORa Rt or NR6; n is 2 or 3; R6 is hydrogen, substituted or unsubstituted hydroxyl group, substituted or unsubstituted phenyl, acyl, IRBM alkoxycarbony~, substituted carbamoyl, substituted amino , arylsulfonyl, aralkylsulfonyl, aralkyl, compound ring, etc.; R7 is hydrogen, alkoxy, or R6, and aromatic amino acid derivatives represented by 7yylenedioquine or oxo) and their glues (ν This is related to the method of delivery.

The compound according to the present invention has a condensate of an aromatic amino acid and an aromatic nulphonic acid as its core, and both are novel compounds having a vascular smooth muscle relaxing effect.

To give an example of the definition of the symbols in compound (1), u,...
Substituted aminos for R2 include isoquinolinesulfonamide, N-methylisoquinolinesulfonamide, naphthalenesulfonamide, N-methylnaphthalenesulfonamide, methanesulfonamide, N-methylmethanesulfonamide, toluenesulfonamide, etc. It is an acid imide or an ester of isoquinolinesulfonyloxy, toluenesulfonyloxy, naphthalenesulfonyloxy, acetoxy, etc., and esters such as methoxy, benzyloxy,
It is a protecting group for ethers such as acetoxymethyloxy and other hydroxyl groups. The substituted aralkyl in R5 is an aralkyl substituted with a mono- or di-lower alkyl p1 halogen. The substituted hydroxyl in Ro is a mono- or di-lower alkyl, or an ether such as aralkyloxy substituted with a halogen, and an ester such as hyacetoxy, and the substituted phenyl is a lower alkyl,
halog/, alkoxy), I, acyl, benzylcarbonyl, phenylglobionyl, benzoyl, Iti1% alkoxycarbonyl, benzyloxycarbonyl, I, t-butoxy carbonyl, and the substituent power p is phenylcarbamoyl-substituted amino, such as N,N-methylbenzylamine, benzylamine, arylsulfonylsulfony, etc., and aralkylsulfonyl, benzylsulfonyl, etc.;, (1 Examples of the heterocycle include pyridine and pyrimidine.

Next, the method for producing the compound C of the present invention (1) will be explained in terms of the general formula (where R1I is hydrogen or lower alkyl, and the others have the same meanings as above) derived from a known aromatic amino acid. ) to the compound of formula C, where Ar is ' RO + R + O or NR; R
, is hydrogen, 1d-substituted or unsubstituted phenyl, 1d-substituted or unsubstituted phenyl, RIG represents a group that forms an acetal together with hydrogen, alkoxy or R; n represents 2 or 3) obtained by reacting the heterocycle of, or its carbonyl with 1
of the general formula obtained by alkylating or/and an amino group (in the formula, horse is hydrogen, a lower anorex, or a group such as an alkyne linked to an Ar ring; the others have the same meanings as above). A sulfonic acid amide compound is obtained by condensing an amino acid derivative with a sulfonic acid derivative represented by the general formula (the symbols in the formula have the same meanings as above), or a reactive derivative of acid such as an acid anhydride or a halide, and its salt. This is what you get. The obtained condensed compound may be further subjected to a step of (1) hydrolyzing to liberate a water rtx group or an amino group, 12) a step of removing a protecting group for a hydroxyl group or an amino group, and (3) a step of removing a hydroxyl group or an amino group. A step of acylating or substituted alkoxycarbonylation of a group, (4) a step of alkylating a hydroxyl group or an amino group,
(5) Carbonyl conversion, (6) Amination step by reducing the nitro group, (7
) Compound (1) fj can be obtained by sequentially reacting one or more of the steps of converting an acetal into calrebo-difluorinated acetal and the above-mentioned steps in combination or overlappingly.

Next, the method for producing the compound of the present invention will be described in more detail by giving an example, and the amino-protected compound obtained by reacting a known compound, tyrosine H with a protected amino group, with piperazine with one nitrogen protected. The free 4-amino compound obtained by removing the group was condensed with inquinoline 7,) lefonic acid chloride to obtain it. In addition, if desired, this compound (IV) may be added with (1
a) Step of liberating the hydroxyl group by hydrolysis, (2a)
Piperazine protection 11! 1 or 2 of operations such as eliminating &, (3a) acylating or alkylating free hydroxyl groups, (3a) acylating piperazine, (4a) alkylating sulfonic acid amide, etc.
By performing the above steps, some of the compounds of the present invention can be produced.

For the tyrosine used in this example, an aromatic amino acid such as hinuzendine or ring-substituted phenylalanine can be used, and for the piperazine, piperidine can also be used.

In the compound (Ila), the protected amino group may be substituted with alkyl μ, or the hydroxyl group may be protected.

In the compound (IVa), the carbonyl may be reduced to a methylene chain at this stage, or the ortho position of the benzene ring and the amino group may be cyclized by bonding with alkylene:11.

In addition, in the case of a compound in which piperidine is used instead of piperazine and an acetal is formed at the 4-position, after condensation with a sulfonic acid derivative, (7a) a step of carbonylating acecool, (5a) carbonyl By performing steps such as hydroxylation or amination of a group, (3b) acyN-formation of a hydroxyl group or amino group, or (4b) alkylation, a desired compound of the present invention can be produced! A
can be built.

The condensation reaction of compounds (IV) and (V) is carried out in an aprotic solvent such as tetrahydrofuran, methylene chloride, chloroform, or dimethylformamide in the presence of a base such as triethylamine, and the hydrolysis step of (1) is carried out in methanol or tetrahydrofuran. or a mixed solvent thereof, a solvent such as dimethyl sulfoxide, and the presence of a base such as caustic soda or caustic potassium.
The acylation step (3) is carried out in a solvent such as methanol, ethanol, chloroform, or dithyl acetate, and the acylation step (3) is carried out in a solvent such as chloroform, tetrahydrofuran, or pyridine in the presence of a base such as triethylamine. The reaction step is carried out in dimethylformamide, tetrahydrofuran, ethyl acetate, methanol, methylene chloride, or a mixed solvent thereof.

The hydroxylation step (5) is carried out in a protic solvent such as methanol or ethanol in the presence of sodium borohydride or sodium cyanoborohydride, and the amination is carried out in the same solvent after imine formation, followed by reduction in the same manner. (G) In the nitro group reduction step, it was effective to use a noble metal catalyst of alcohol carbon such as methanol or ethanol.

The acetal oxation step (7) proceeded satisfactorily by performing hydrolysis in water in the presence of an acid.

〔Example〕

EXAMPLES The present invention will be specifically explained below using Examples, but the present invention is not limited to these Examples.

The melting points in the examples were measured using a melting point measuring machine Yamato MP-
21 (measured using a capillary using a Yamato Scientific Co., Ltd. nuclear magnetic resonance spectrum ('H-NMR)
Using L-JNM-FX200 (manufactured by Shiraki Denshi), the molecular weight was . TMS-D 300 type 'J! An infrared absorption spectrum (IR
) was measured using IRA-1 (manufactured by JASCO Corporation).

Reference Example 1 1-[N-(benzyloxykalbonyl)histidyl-4-phenylpiperazine N,N'-dibenzyloxycarbonyl histidyl/
7.13f,4-phenylpiperaziy5002 and N-
Hydroxybenzotriacy/I/1 & 1 was dissolved in 100 ml of tetrahydrofuran, and DCC synchhexylcarbodiimide 3 was added thereto.

842 was added and stirred at room temperature for 3 hours. After removing insoluble materials and concentrating the p solution under reduced pressure, ethyl acetate A/20
0 ml was added, and the precipitated crystals were separated from each other. Solution F was washed successively with a 20% aqueous potassium carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in 60 ml of methanol/V, added with 10% ammonia/methanol solution VIE, stirred at room temperature for 30 minutes, concentrated under reduced pressure, and the resulting residue was chromatographed on silica gel and chromatographed with chloroform/methanol. -)V (5 0
:1 to 10:1) to obtain the desired product 6.619 as a color amorphous substance.

]H-NMR (CDCt,, δ
ppm): 2. 8 1 ml
2 0 (6H, m), x4o ~xa2 (4H, m)
4,95(IT(,rrL),5.09(2H,s)
5.

7 8 (IT(1d, J=a3Hz), 6.
80 ~&97 (4H, m'), 7.20 ~7.30
(2HXm)7, 34(5T(,s), 7.55(IH
,s) Reference Example 2 1-CN-(t-butylcarbony/l/)histidyl]-4-phenylpiperazine 1-(N-(penzyloxycarbony)V)histidyl]-4-phenylpiperazine 6,619 Methanol/L
/80 nt dissolved in 5% palladium/carbon 4.2
was added under water cooling, stirred at room temperature in a hydrogen atmosphere for 20 hours, filtered, and concentrated under reduced pressure to obtain a residue 4.2.
69 was dissolved in dimethylformamide B (:Jml,
t-Butoxycarboxylic anhydride 1. , B9 and 10 ml of triethylamine were sequentially added thereto, and the mixture was stirred at room temperature for 1 hour and 30 minutes. Add 200 ml of ethyl acetate to the reaction solution, wash twice with saturated brine, dry over magnesium sulfate, filter, and concentrate under reduced pressure. The resulting residue was dissolved in 100 ml of methanol, followed by 20 ml of 10% aqueous sodium hydroxide solution. was added and stirred at room temperature for 30 minutes. After concentrating under reduced pressure until the total volume is %, add 150ml of water. 7X+, extracted twice with 80-chloroform, dried over magnesium sulfate, filtered, and concentrated under reduced pressure.
:1) to obtain :su(zeta-colored amorphous target substance 4.53)
I got r.

'H-NMR (CDC1, δpprn):
1.43 (9T(,s), 2.80~122
('Otsu I-I, m), 3.4θ ~ 3.83 (4H, m
), 4.87 (IH%m), 5°46 (IH, br)
, 6.86~&93 (4H, m).

7.23-7.31 (2H, rn), 7.57 (IH
%s) Reference Example 3 1-[:2-(t-butoxycarbonylamino)-3
-Imida Sole-4 (5) -Imida Sole-4-PhenylpiperazineHydrogen ratio: Add aluminum chloride to a solution of 1.37 lithium aluminum dissolved in 38 ml of tetrahydrofuran.
67 to ethyl ether 58mgK! 8 Add the dissolved solution under water cooling and stir for 20 minutes under water cooling. &, 1 − (N
- (t-butoxycarbonylhistidyl]-4-phenylpiperazine 4.531 of tetrahydrofuran 5
1m+! ! The solution was added dropwise over 30 minutes under water cooling, and after stirring for 1 hour under water cooling, 20 m of 25% potassium carbonate aqueous solution was added.
Added l.

100 ml of chloroform was added to the reaction mixture, which became suspended, and silica was added as a filter aid and filtered. After washing the silica with a 20% methanol-chloroform solution, the furnace solution was drained under reduced pressure. The obtained residue was applied to a silica gel column and chloroform-methanol)v (4
0:1 to 10:1) to obtain 2j1 (color: 10:1 to 10:1).

'H-NMR (CDCt,, δppm)
: 1.4 4 (9H.

s), 2. 3 3 (I H, dd,
J = 7. 3 12. 2Hz), 2.
4 7 (IH, dd, J −= 7.8
, 1 2. 2T. IZ), 2.6 4
(4T-1, m), 2.9
3 (2H, m).

i20(4T(,m), 3.97(IH,m), 5.

10 (IH, br), 6.81 to 6.97 (4H, m
).

7, 2M ~ 7.30 (2H% m), 7.58 (IH
,S) Example 1 N-(1-(1-(5-isoquinolinenulphoni/L/)
imidazol-4(5)-yl-methyl]-2-(4-
Phenylpiperazinyl-5-isoquinolinesulfonamide 51,9 obtained in Reference Example 3 was dissolved in 10 ml of acetic acid, and a 4N salt was added to the solution. After adding 16 ml of Shun's ethyl acetate solution and stirring at room temperature for 30 hours, evaporate to dryness under reduced pressure, and add 7 ml of tetrahydrofuran.
0 mt and 30 ml of chloroform were added to make a 1-ura ceramic solution, and while cooling with water, isoquinoline sulfone chloride 69 and triethylamine 30+++t'i were sequentially added. After stirring at room temperature for 18 hours, 70 mε of chloroform was added while adding 50 ml of water. I took out hb twice. Extraction Q. l
After drying the Xe with magnesium, the resulting residue was subjected to silica gel chromatography and purified with chloroform-methanol (80:1 to 60:1); iH
HE color amorphous object 1.

I got 862.

I R (KBr)cPR-': 1 6 1 B
, 1 6 0 0, 1 4 9 0.

1580 1325 1210 1
170 1132 1073 NOH-NMR (CDCt,, δ
ppm): 2. O O ~2.
3 4 (61, m), 2.59 ~ 2.81 (
6H, m) 3, 39 (1H, m), &74 ~ &89 (
3H.

m), 7. 0 4 (I H, d, J =
1. 5 Hz), 7.19~7.29 (3
H, m), 7.69 (IT-(,t,
J = 7.3 Hz), 7.80 (I
H, t,, J = 7.8 Hz).

7.9 3 (IH, d, J=15)Tz), a2
1 (IH, d, J==a3 Hz), a3 4
(I H, d, J=a3Hz), a3B ~a46
(3H, m), 13°52 (IH, dd, J=t0,
7.3H2), a69(j H, d, J=6.3H
z), a77 (I Hld.

J=&3Hz), 9.3 6 (IH, S), 9.39
(1H,s) Example 2 N-(1-(imidazol-4(5)-yl-methyl)
-2-(4-phenylpiperazinyl)ethyl]-5-isoquinolinesulfonic acid amide 250 rrPg of Tsubame polymer obtained in Example 1 was mixed with 1 mg of tetrahydrofuran and 5 ml of methano-JV.
Add 1 ml of 4N soda and stir at room temperature.
After stirring for 0 minutes, 20 ml of water was added, and the mixture was extracted twice with a mixed solvent of 10 ml of chloroform and 2 ml of isopropano/l'. The extract was dried over sulfuric acid and danenium, concentrated under reduced pressure, and the resulting residue was subjected to silica gel chromatography, chloroform-methanol/l/(20:1).
and chloroform-methano-! Shi - Tori
Echi! Shi Amin (20: 1:
0. 2) to construct 21((G of rapidly heated heavy body)
About 163η and m.

IR(KBr)m-”: 1615, 1600 14
90144B, 1320 1225.1153 130 7H-NMR (CDC1,, δppm): 2
．． 06-2.44 (6H%m), 2.67-2.90
(5H, m) 3.02 (18, dd, J==5.4
1Q, 0Hz), 3°25 (1H, m), &74~6.
90 (4H, m).

719-7.33 (2H, m), 7.54 (IH.

s), 7.74 (IH, t, J=7.8Hz), a2
4 (IH, d, J=Zar-xz), a, 47 (1H
,d.

J:==&4Hz), a52(fH, dd, J-~1.
07, 32) Tz ), a70 (I H, d, J=
5.9 Hz).

9.58 (IH,s) Example 5 N-(1-C1-C5-isoquinolinesulfonyl)imitasol-4(s)-yl-methyl]-2-(phenylpiperazi;yl)ethyl/I/)- N-Methyl IV-5-isoquinoline sulfonic acid amide 1.452 of the heavy substance obtained in Example 1 was dissolved in 20 mejC of dimethylformamide and diluted to 60% under water cooling.
Sodium hydride 120η, methioiodide/L'0.2m
After stirring for 30 minutes while cooling with water, 30 ml of water was added, and the mixture was extracted with 30 ml of ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was applied to a silica gel column and purified with chloroform-methanol (80:1) to give a colorless product. tr: A crystalline mass of 616 cm was obtained.

IR(KBr)z-' : 1618 1600 j
4901380 1320 1210
1170 1140 1080'H-NMR (CDC1,, δppm):
2.35-2.47<6H, m), 2.64 (IH, d
d, J=7.8°14, 6 Hz), 2.80
(3Hls),,,2.85~2.97(5T(
, m), 4.36 (1H, m), 6.82~&89(
3H,m), 7.06(IT(,dS J=1.5Hz
), 7.2 1-7.29 (28,m)
7.61 (IH, t, J=73Hz), 775 (1H,
t.

J = 78 Hz), 7.87 (IH
, d, J = 1.5Hz), al4 (
IT-1, d, J=7.8Hz), a25~a
29 (2H% m), a37-B, 45 (5H.

m), a64 (IH, d, J=5.9 Hz)
, 8.76 (11■, a, J=6.31 (Z )
, 9.31 (I H,S).

93 s(1H,s) Real #iri14 N-(1-(imidazol-4(5)-yl-methy/L
')-2-(4-phenylpiperazigo/L/)ethyl]
-N-Methyl-5-isoquinoline 71 Lefonic acid amide obtained in Example 3: 0 ml of the +! After adding 1 ml of chlorine and stirring at room temperature for 10 minutes, the mixture was treated in the same manner as in Example 2 to obtain a colorless, weightless substance with the objective of #299■.

IR(KBr)m-': 1 59 5, 1
490 1 4 4 B.

1320　1225.1150　112B.

Engineering H-NMR (C!DC4, δppm): 2
．． 45-2.65 (6■1, m), 2.89
(3T(,S), 2.90~x08(6H
, m), 4.37 (IH, m), 6°68 (IH, s
), & 82 to & 90 (3H, m).

7.20-7.32 (3H,'m), 7.64 (IH
.

t, J = 18Hz), al4 (I
H, d, J = 7.8Hz), 8.3 1
(I H, d, J=6.3Hz), a46
(1H, dd, J = 1.0, 7.3 Hz
), Mr62 (11(,d, J=5.9 Hz
), 9.29 (I H, S') Reference Example 4 N-(t-butoxycarbonyl)-14-dibenzyloxyphenylalanine pendyl ester N-(t,-butoxycarbonyl)dopa 21°122
was dissolved in 200 g of dimethylformamide, 50 g of benzyl bromide and 40 g of potassium carbonate were added thereto, and the mixture was stirred at room temperature for 40 hours.

After adding 400 ml of brine to the reaction solution, extract with 500 ml of ethyl acetate, and read the extract twice with saturated brine.
(After drying with magnesium acid and filtration, hexane was added to the residue obtained by concentrating under reduced pressure, washing the precipitated crystals, and drying the collected crystals to obtain the desired product as colorless crystals 30.09
I got it.

'FI-NMR (cDcz,, δppm):
1.42 (9H.

q), 2.99 (2H%d, J=14.14Hz).

4.59 (IH, m), 4.98 (1) 1% bra) 5
．． 05(2I(,S) 5.07(2H,s), 5゜11(2H,s) &56(IH,dd, J=2.0
゜7,8Hz), 6.71 (1H1d, J=2.0
Hz).

6.79 (I H, d, J = 7.8 Hz),
7.20 to 7.50 (15H, m) Reference Example 5 N-(t,-ptoxycarponi/l/) -> 4-
Dibenzyloxyphenyl 7- Crystals obtained in Reference Example 4 0. 0 9 as methano-/I/
Dissolve IR in 600ml, 10% caustic soda aqueous solution 65
In addition to rnε, 1000 m of water was added after stirring at room temperature for 20 hours.
After adding 1 liter of water, adjust the pH to 4 with concentrated hydrochloric acid, and add 8 ml of chloroform.
Extracted twice with 0.0 ml. Dry the extract with magnesylanosulfate, concentrate under reduced pressure, collect the precipitated crystals, wash with hexane, and obtain colorless crystals! : Of course 2, 5.
I got 29.

'H-NMR (CDCt,, δppm)
: 1.4 0 (9H.

S), 3.02 (2H, m), 4.49 (IH.

brs), 4.88(1H, brs), 5
．． 1 1 (4H.

s), 6. 6 8 (I H, dd, J
= 2. o, 7. 8 Hz).

6, 7 6 (I H, d, J==2.0Hz),
6.74 (1H, d, J = 7.8Hz), 7.
2 3 ~ 7.4 5 (1 0H, m) Reference example 6 1-CN-(t-butoxycarponi/L/) - z
4-dibenzyloxyfe=7realanyl]-4-phenylpiperazine 5.679, N-phenylpiperazine 1.9f of the crystals obtained in Reference Example 5, N-hydroxype/citriazo-IV
1. 539 was dissolved in 80-methylene chloride, 2.41 DCC was added thereto, and the mixture was stirred at room temperature for 18 hours. The generated insoluble materials were separated from each other, washed with ethyl acetate, and the mixture was combined and concentrated under reduced pressure. The resulting residue was applied to a silica gel column, and hexane-ethyl acetate/l,' (2:1
) to make it colorless and V! + Body purpose 'proboscis & 399 obtained.

'H-NMR (CDCt,, δppm)
: 1. 4 4 (9 H, s), 2.39 (1
H,, m), 2.76-310 (6H, m) 3.3
0(11(,m), 3.61(2H,m), 4.78(
IH, m) 5.03 (2H.

s), 5.14 (2H, s) 5.42 (IH.

brd, J=a3Hz), &69(II-1, dd,
J~2,0,a3Hz), &79~&91(
5H, m).

7, 2 0 ~7. 4 8 ( 1 2 H %m
) Reference Example 7 1-(2-[N-(t-butoxycarbonylreamino)
]-3-(&4-Dibenzyloxyphenyldine) The anionic 5662 obtained in Reference Example 6 was dissolved in 50 ml of tetrahydrofuran, and lithium hydride 7 was added under water cooling.
After adding 700 rFIg of aluminum and stirring for 1 hour and 30 minutes under water cooling, water was added at a point where foaming had stopped. Add chloroform to the reaction mixture to suspend it, and add silica gel to the reaction mixture.
The insoluble matter was separated as rlI, the F solution was concentrated under reduced pressure, and the obtained residue was applied to a silica gel column and purified with hexane-ethyl acetate/L/(3:1) to give a colorless: j+1'; heavy substance. The target object 2°67f was obtained.

'r1-NMR(CDC1,, δppm)
: 1.43 (9HlS), 2.24 (
2Hlm), 2.53 (4)I, m)1
2.79 (21 (, m), 116 (4I (, m) 590 (IH, m), 4.58 (IH, brs) 5
゜13 (2H, S), 5.16 (2H1s),
6.70 (I H%dd, J = 2.0, a3Hz
), &80-6.93 (5H, m), 7.20-7.
46 (12H% m) Reference Example 8 1-[2-amino-3-(to-4-dibenzyloxyphenylpiperazine) Obtained by carrying out Reference Example 7; i!!'; Heavy 4.3
59 was dissolved in ethyl acetate (tL/20 ml), 30 ml of a 4N hydrochloric acid solution in ethyl acetate was added thereto, and the mixture was stirred at room temperature for 1 hour. After concentrating the reaction solution under reduced pressure, it was made alkaline with an aqueous solution of sodium bicarbonate, and then added with 80% 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 to 30:1) to obtain a colorless and sterile state. Objective of 1. I got 6 4 9.

'H-NMR (CDCt,, δppm)
: 2. 2 7 ~2. 6 8 (8H, m), 5 10 to 12 0 (58, m) 5, 10 (2H
%brs) 5.14(2)(,S)5,17(2
H, S), &73 (IH, aa, J=2, 0, a3
I-1z), 6.8 1 ~&9 4 (5H%m
).

7,22-7.46 (12IT,m) Example 5 N-(1-C(3.4-dibenzyloxyphenyldini/l/)ethyl)-5-isoquinoline Nhonm
The 64-polymer η obtained in Amide Reference Example 8: i+1': was dissolved in 15 mt of methylene chloride, and 1 m of triethylamine was added thereto.
l,5-isoquinoline sulfotonic acid chloride 350■
was added under water cooling, stirred under water cooling for 1r+7, and then added 50 ml of water.
ml and extracted twice with 50 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 hexane-ethyl acetate/L/(1:1) to obtain the colorless and heavy target product 470.
I got TNJ.

1H-NMR (CDCt, δppm)
: 2.0 8 ~ 2.2 4 ( 6) (, m), 2
．． 64 ~ 2.9 1 (6H, m) s. 30 (IH
, m) 5.08 (2H, s), 5.

10(2)1%s), &51(IH,
dd, J=2.0.

a3Hz), 6.63 (IH, d, J=2.0Hz).

6, 7 1 (I H, d, J = a 3
Hz), 6.76 ~&89 (3H%m),
7.2 1 to 7.4 3 (1 2H, m).

7, 67 (IH, t, J = 7.8 Hz), &18 (1)
(,d,J=a3Hz),a44(2I(,m)a6
7 (I H s d - J = 5 - 9 Hz
) - 'i. 3 4 (IH,s) Example 6 N-(1-((3.4-dibenzyloxyphenyl)methyl)-2-(4-phenylpiverazini/L/)ethyl)-N-methy/l /-5-Isoquinoline Nhonmamide 470 μg of the polymer obtained in Example 5 was dissolved in 8 ml of dimethylformamide, and 30 WIg of 6ON sodium hydride and 0.1 ml of methyl iodide JV were sequentially added to this under water cooling. After stirring for 2 hours while cooling with water, saturated brine was added, followed by extraction with 50 ml of ethyl acetate/L'.

Wash the extract with saturated saline, dry with magnesium sulfate,
The residue obtained by layer separation under reduced pressure was applied to a silica gel column and purified with hexane-ethyl acetate (1:1).
l (color; i!tl; heavy target product 413η was obtained.

7H-NMR (CDCt, δppm):
2.34 (IH.

dd, J = &3 5, 1 &2Hz), 2.
4 2 ~ 2.6 0 (5H, m), 2.65 (IH%
ad, J=y. 31 4, 2Hz), 2.8 1
(IH, dd, J=6.4, 14, 2Hz)
, 2.86 (3H, s), 2.99 (4H.

m), 4.22(1)1,m), 5.03(2F(,1
3).

5.10 (2H, s ), 6.54 (IH, dd, J=
2.0, a3)Tz), 6.6 1 (IH
, d, J = 2.0Hz), &6 3 (I
H, d, J = a3Hz), 6.82~&
90(3)I, m), 7.19-7.53(13H
, m), a05 (1H, d, J=a3Hz).

a2 4 (1H%dd%J = 1.0, 7.
3Hz), a30(IH, d% J = 5.9H
z), a 60 (II(, d.

J = 5.9 Hz), 9.2 4 (I H
, d, J=1.0 Example 7 N (1-[(3,4-dihydroxyphenyl)mer)-2-(4-phenylbiperazini)V)ethyl7L/) N-methyl- Isoquinoline sulfonic acid amide 310η of the anhydrous substance obtained in Example 6 was dissolved in 2 ml of 1,2-ethaneshinol, 1 ml of boron trifluoride, ethyl ether) was added thereto, and the mixture was stirred at air temperature for 18 hours. Afterwards, a saturated aqueous sodium bicarbonate solution was processed and extracted twice with a mixed solution of chloroform and methanol (10:1). extraction? Dry the t't with magnesium sulfate and under reduced pressure.
The resulting residue was applied to a silica gel column and chloroform-methanol/l/(80:1-20
The product was purified by step 1) to obtain colorless and heavy target product 148.

Engineering R (KBr) cln-': 16CJO1149
5,1448,1328,1230,1155,115
0'H-NMR (CDC13, δppm): 2.41
(1) T-1(1(1,, T=10.25.14.6
5Hz), 2.50-2.98 (7T(,m), 3
．． 01 (3H, s), 3.17 (4H, m), 4. o
6 (1H, m), 6.12 (I H, aa, :r=
2. a, a3Hz), 6.2o (1H, a.

, T=a3Hz), 6.28 (I H,d, J=2
．． OHZ), 6.82-6.95 (3H, m), 7.
26 (2H, m), Z62 (1u, t.

J=7.8Hz), afl 9 (I H,d, J=
6.8Hz), a13(1)T, d,, r=9.3H
2), a30 (IHSd%J:6.8Hz), 8
．． 4j (IH, dSJ=4.9Hz), 9.25(I
H,s) Example 8 N-(1-C(3,4-dihydroxypheni)v)
Methyl)-2-(4-phenylbiverazini)V) Ethyl)-5-isoquinolinesulfonic acid amide The colorless weightless substance obtained by carrying out Example 5 was treated in the same manner as in Example 7 to obtain the colorless weightless substance. I got something.

Engineering R (KBr) crn-': 1610.1600
．． 1490.1445.1320.1220.1150
．． 1128'H-NMR (CDC13, δppm)
: 2.30-2.60 (6HSm), 2.7
4-502 (6H, m), 3.36 (1H1m), 6.
15 (IH, cl, J = a5Hz), 6.33 (I
H%d, J=9.5Hz), 6,! JIS (IH)
, 8), 6.76-6.90 (5H,'m), 7.
19-7.29 (2H, m), 7.6 s (1) (,
t, , T=7.8Hz), 8.16(I H,d,
, r=a3Hz), 8.33 (I H,d, ,
T=&5Hz), a39 (IH, dSJ=7.3
Hz), as 1 (IH, a, J=5.5Hz)
, 9.28(IH,s) Reference Example 9 6.7-Dipenzyloxy-3-((4-phenylpiperazine)v)methyl)-1,2,3,4-tetrahydroisoquinoline Obtained in Reference Example 8 1.001 of the obtained non-gray substance was dissolved in 2-tetrahydrofuran, 0.25 rnt of formalin (37 g) was added thereto, and after stirring at room temperature for 30 minutes, 600 μm of 12N hydrochloric acid was added, and the solution was heated to room temperature. The mixture was stirred for 2 hours.

After adding a saturated aqueous sodium bicarbonate solution to the reaction solution, the mixture was extracted twice with 20 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 chloroform-methanol (100:1
) to obtain the colorless, non-heavy target product 585η.

'H-NMR (CDC13, δppm): 2.2
8-2.38 (8H.

m), 10102 (IHX, x21 (4H, m), 3.
95 (2H.

8), 5.11 (4H, θ), 6.63 (IH, day),
6.68 (IH.

S), 6.80-6.95 (3H, m), 7.20
~7.46 (12H.

m) Examples? 6.7-Dipenzyloxy-2-(5-isoquinolinesulfony/V)-3-((4-phenylpiperazinyl)methyl)-1,2,3,4-tetrahydroisoquinoline Reference example? The anionic 580η obtained in
Melt to 0-! ! y(, L/, triethylamine, -55-isoquinoline sulfonic acid chloride, 戊if
Add I*tL 400 rrq under ice cooling, stir at room temperature for 2 hours, add 20rnt of water, and then add 10ml of chloroform.
Extracted twice at +nt. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography and purified with hexane-ethyl acetate/L/(1:1) to obtain 610η of the target product as a colorless and heavy substance. Ta.

! (-NMR(C, Dot3, δppm): 2.
31 (IH, dal, r=78.1t6az), 2.
43 (IT(, da, J=6.a, 11.6Hz
), 2.53 (4HSm), 2.70 (I H, dd
%, T=2.0.16.2Hz), 2.87 (I H
,aa, J=4.2.16.2Hz),3,os(+
aSm), 4.26 (I HS(1,, T=15.61
(z), 4.48 (I H, d, J=15.6J
(z), 4.49 (I H, m), 5.06 (2H
, e), 5.07 (2H,s), 6.56 (IH%
s), 6.60 (IH, s), 6.80-6.90 (
3H,m), 7.20-7.95 (12H1m),
;+, 64 (1H, t, J=7.8Hz), als(1
H,aSJ=7.81H2),a37(IH,d,,T
=5.9Hz), a48 (I H, dd, , T=1
．． 0.7.3HZ), a64 (IH, d, J=6.
4Hz), 9.30(11(,a,J=i,0H2)Example 10 6,7-dihydroxy-2-(5-isoquinolinesulfonyl)-3-C(4-phenylpiperazine)methy/ ) -1,2,5,4-tetrahydroisoquinoline obtained in Example 9; 2 ml of 1,2-ethanedithiol and boron trifluoride/ethyl ether/L/1- were added to the heavy 4η of the IHIE crystal, and the mixture was heated at room temperature. Stirred for 18 hours.

After adding a saturated aqueous sodium bicarbonate solution to the reaction solution, it was extracted twice with 20 d of chloroform-methanol ff4 combined M (1:1), and the extract was dried over magnesium 14ate and concentrated under reduced pressure, and the resulting residue was purified with silica gel. attached to the column,
Chloroform-methano-/I/(50:1-20:1)
Purification was performed to obtain the target product 213η as a colorless and non-heavy substance.

Engineering R (KBr) cTn-': 1610.1600
．． 1490.1445.1320.1225.1150
．． 1130'H-NMR (cDct3, δppm):
2.35-2.80 (8H, m), 3.11 (4H,
m), 4.24 (1)(, d1J=j 6.I H2
), 4.40 (I H,a, :r=16.I H2
), 4.55 (IH, m), 6.45 (2H, s), 6
．． 80-6.90 (3H, m), 7.20-7.2
8 (2HSm), 7.67 (rHlt, J=7.8
7(Z), a14(IH, d, , T=a5Hz), a
40 (IT(, d, J=6.31(z), as
o (I H, aa, J=to, 7.3H2), a
59(1)(, d.

, T-6,4Hz), 9.25(IHla, J=t,
oHz) Reference Example 10 1-(N-(t-ptoxycarbony)v) -p-nitrophenylalanyl]-4-phenylhyberazine p-nitrophenylalanine 7.039 1.4-dioxane 70-) 1 Ura cloudy, 10 width caustic soda water soluble F
[Add 28 ml of T-butyl dicarbonate 7,59 and stir at room temperature for 30 minutes, then add 200 ml of water.
- After adding 112N hydrochloric acid 7-, ethyl acetate) V 1
It was extracted with 50 ml, and the extract was washed with saturated saline.

After washing, the extract was dried over magnesium sulfate, concentrated under reduced pressure, and the resulting residue was dissolved in 150% of tetrahydrone, and 6.0% of N-phenylpiperazine was added. , N-hydroxybenzotriacy/V 5.59 and D while stirring.
CC7 and 69 were further added, and after stirring in one chamber for 3 hours, the insoluble matter was separated in a furnace, the obtained P solution was heated to oA under reduced pressure, and the residue was dissolved in ethyl acetate (V2O3-). This was washed successively with a 10-ml potassium carbonate aqueous solution and saturated brine, dried over magnesium chloride, concentrated under reduced pressure, and the resulting residue was applied to a silica gel column using a mixture of hexane and ethyl acetate (2:1).
Inhale and get a pale yellow crystal object 1t t? I got it.

'H-NMR (aDcz3, δppm): 1.40
(9H, s), 2.83-3.20 (6H, m), x
37 (1u, m), 3.57-170 (3H, m), 3
．． 84 (IH, m), 4.92 (1u, m), 5.40
(IH, a%J=a3Hz), 6.85-6.95
(5H, m), 7.24-7.32 (2H, m)
, 7.38 (2 guns (,a, J=a8Hz),
al 6(2)1. d, J-48Hz) Example 11 1-(N-(5-isoquinolinesulfony)v)-p-=
) lophenylalani/l/ ) -4-phenylpiperazine 11. of the crystals obtained in Reference Example 10. Of 100 trt
of 4 N hydrochloric acid in ethyl acetate and 1
After adding 00- and stirring at room temperature for 1 hour, the reaction mixture was dried under reduced pressure, 200- was added with a saturated aqueous solution of sodium bicarbonate, and the mixture was extracted twice with 100 tRt 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 (80:1 to 10:1) to obtain an amine free form. The obtained educt was dissolved in 100-methylene chloride, 5-7-itsquinolinesulfonic acid chloride titiate &5F and 20-triethylamine were sequentially added under water cooling, and after stirring at room temperature for 18 hours, water was added. The mixture was extracted twice with 100 ml of chloroform. The extract was dried over sulfuric acid and magnesium, concentrated under reduced pressure, the resulting residue was applied to a silica gel column, and chloroform-methanol/l/
(100:1 to 50:1) to obtain the desired product 9.669 as colorless crystals.

Melting point: 184-188°C (decomposition) Engineering R (KBr) m-': 1660.1600.1
520.1420.1345.1625.1230.1
150.1135'H-NMR (CDC13, δppm
): 2.72-3.06 (6H, m), 3.2
0-461 (4H, m), t46 (1HSm), 6.
o6 (1H, br), 6.85 (2H, d, , T=7
．． 8H2), 6.94 (IHlt, J=7.3Hz)
, 7.10 (2)1. t, ,T:&8H2),7
．． 29 (2H, m), 7s6 (1H, t, J=7.8
H2), 7.82 (2H, d, J=a8Hz), a0
9 (IH, a, , T=7, 811 Z), a22~
a29 (2H, m), a71 (1H%a.

, T = 6.3H2), 9.26 (IH, s) Example 12 1-'(N-(5-isoquinolinesulfony/L/) -
Kenichi Methyl-p-nitrophenylalanyl]-4-phenylpiperazine 5.78 SF of the crystals obtained in Example 11 was dissolved in 60 W It of dimethylformamide, and under water cooling, 60 W of sodium hydride, 1 of methyl iodide were dissolved. .54 was sequentially added, and after stirring for 2 hours under water cooling, water was added and then ethyl acetate/L'
Extracted at 150-. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure.
100:1) to obtain a yellow non-baric target product 5,93
I got an F.

IR (KBr) cm': 1640.1600
．． 1535.1445.1340.1225.1150
．． 1125'H-NMR (CDC1, δppm):
2.60 (11 (Sda, J=4.9.12.7
Hz), 2.83 (IH, m), 2.92-106 (3
H, m), 506 (3H, E+), 140 (IH, cu
d, , T=7.8.112Hz), A46~51.6
3 (2H, m), 570-58B (2H, m), 5.
23 (I H, dd, , T=4.9.9.8 Hz
), 6.82 (21, d, J = 7.8H2), 6.
91 (IHStS: r=7.3H2), 7.22-7.
30 (4H, m), 7.73 (IH, t.

J=near, 8H2), an7(2I(Sd, J=a8
Hz), a25 (IHSd, J=a3Hz), 8.3
6 (I H, da, J=1.0.7.3H2), a4
s (1HSa, , T: 6.4H2), 8.71 (IH.

a1J=6.4H2), 9.37 (I H, d, ,
T = 1.0 Hz) Actually, case 13 1-[p-amino-N-(5-isoquinolinesulfonyl)-N-methylalani~]-4-phenylpiperazine Methanol)
Dissolve in V70-, add 12N hydrochloric acid 5-1 water 30-
wt was added, 5 oz of palladium/carbon 51 was added thereto, and the mixture was stirred for 2 hours and 30 minutes at room temperature under a hydrogen atmosphere to remove insoluble matter.
After breaking up, Pg! ;t was concentrated under reduced pressure, 150 ml of a saturated aqueous sodium bicarbonate solution was added thereto, and the mixture was extracted twice with 200 tnl of chloroform. 1v of sulfur extract! The residue obtained by drying with magnesium and concentrating under reduced pressure was applied to a silica gel column, and chloroform-methanol (50:
1) to obtain yellow anonymous substance 1322.

ER(KBr)m': 1635.16[]Q,
1495.1445.1325.1220.1150.
1125'H-NMR (0DC13, δppm):
2.47-2.56 (2H.

m), 2.87-3.22 (4H, m), x14 (3H
, s), 3.33-3.7s (4H, m), 5.14
(I H, dd, J=4.9.9.8Hz), 6.5
0 (2H, dl, T=a3Hz), 6. BO~6.92
(5H, m), 7.22-7.34 (2H, m), z6
9 (1a, t.

J==Z8Hz), a2o(IH,a, J=asHz
), a36(I H, aa, , T=1.5.7.3H
2), a4o (1u, a,:r=5.9H2), a68
(1H,a,,T=6.4Hz), 9.34(11(.

8) Example 14 Using the crystal 3.759 produced in Example 11, the same procedure as in Example 13 was carried out to obtain yellow crystals of 1-(p-amino-N
-(5-isoquinolinesulfonyl)phenylalani/V
) 2.179 of -4-phenylhyverazine was obtained.

Engineering R (KBr) crn-': 1655.1600
．． 1495.171, 1LI.

1320.1225.1155.11351 )! -N
MR (aDeOtsu3, δppm): 2.4
1 (jHS m), 2,59-3. T] 7 (6H
, m), x17 (1aSm), 3.33 (IHSm)
, 3.51 (1H, m), 4.55 (IH, m), 5.
95 (IH, d.

, T=9.3Hz), 6.38 (2H,d, J=8
．． 3Hz), 6.75 (2H, d1J=a3Hz),
6.7B(2H,d,,T=lH2),6,. 91 (I
HSt, Julnia, 3Hz), 7.22-7.30
(2I(Sm), 7.60(IH, t, J==a3H
z), 8.12 (IHSa, :r=a3Hz), a30
~a35 (2H, m), a71 (IHla.

J = 5.9Hz), 9.30 (IH, s) Example 15 1-(N-(5-isoquinolinesulfony/L/) -p
-(p-toluenesulfonirami) ) phenylawoni)V ) -4
-Phenylpiperazine Crystalline obtained in Example 14 200■
Pyridine 5w < (6 solution, under water cooling, p-) Luens J
90 μg of Vφ2p crophyte was added, and the mixture was stirred for 1 hour while cooling with water. The reaction mixture was diluted with 3 ml of saturated aqueous sodium bicarbonate solution.
The mixture was extracted twice with chloroform (15%). The extract was dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was applied to a silica gel column and subjected to Piif with chloroform-methanol (80:1 to 50:1) to obtain the target product 128. is.

Engineering R (KBr) m-': 1b3s, 1600,
1335.1225.1155.1090' H-NMR (CD013, δppm): 2.3
0 (3L s), 2.65-2.80 (4H, m)
, 2.85-5.04 (2H, m), 3.17-3
．． 50 (4H1m), 4.33 (I HSm), 6.
14 (IH, a, J=9snz), in ~6.83
(6I(,m), 6.93(IH,t, J=7.31
(z), 6.77(1)! , 8), 7.17 (2HS
d%J=a3Hz), 7.26-7.36 (2H, m)
, 7.59 (I H, tXJ=near, 3Hz), 7.
59(2H,a, J=a3H2), als(1)(1
a,, T=7.8H2), 8.30(2H,m), a6
4 (IH, br), 93t (1H, b) Example 16 5-isoquinolinesulfonyl chloride hydrochloride at 20
1-(N-, (5
-isoquinolinesulfonyl)-p-(5-inquinoline7,/L/honylamino)phenylalanyl]-4-phenylpiperazine 372r! Obtained Pg.

IR(KBr)m-1: 16301L600.134
0.1225.1155.1135'n-NMR (cDcz3, δppm): 2.
35-3.07 (9H1m), 3.30 (11(, m
), 4.26 (IH, m), 6.67-6.84 (6)
(, m), 6.89-6.96 (2H, m), 7.23
(2H, t.

y=aanz), 7.52(1H,t, , r=7.8
Hz), 7.54 (IH%t, J=7.8Hz)
, 7.98 (I H, dSJ-7,8Hz).

an 7 (I H, d, , T=a3Hz), a2
s (1n, a, y=6.8Hz), a31 to a36
(2H, m), as4 (1n, a.

J==6.3Hz), a65(21(,d,, J=6
．． 4H2), 917(1H,8), 9.26(fH,s
), 1o, o6 (1H, s) Example 17 Purification is carried out with chloroform-methano-Jv (80:1 to 5°:1) using 200 η of 1-naphthalenesulfonyl chloride and 360 η of the crystal of Example 14. Others are Example 1
5 to prepare 1-(N-(5-isoquinolinesulfony/L/)-p-(1-naphthalenesulfonylamino)phenylalanyl]-4-phenylpiperazine 38
5η was obtained.

lH-NMR (CDC43, δppm): 2.
40-2.74 (6H.

m), 2.80-104 (3H, m), 3.33 (
IHSm), 4.24 (IHSm), 6.68-6.8
2 (6H, m), 6.92 (1H, t.

J=7.3Hz), 7.12 (I Hla, , T=
9.3H2), 7.26-7.57 (5H, m), 7.
65 (IHlm), 7.78 (IH, d.

J=a3Hz), 7.88(IH,d, , T=7.8
Hz), 7.99(1)1. d, ,T=&3Hz
), al 6 (I H, dd, , r=1.0.7.3
Hz), a21 (I H, dd, , T=1.0.7
．． 3 Hz), a36(IH, dSJ=5.9H
Z), a6s (1HSa, J=6.4H2), a7
7 (I Hld, J=a8Hz),? , 22 (I
H, s), 9.88 (IH, e) Actual 1 Strong Example 18 Methanesulfonic acid chloride o, o y tnt,
1-(N-( 5-isoquinolinesulfony)v)-p-(methanesulfonylamino)phenylawonyl]4-phenylpiperazine 356
IIIgwo get'c.

Engineering R (KBr) cln-': 1635.160
0.1330.1225, 150 IH-NMR (aDat3, δppm): 2.3B
(IH, m), 2.72 (5H, s), 2.70-2.
90 (6H, m), 3.04-3.21 (3H,
m), 3b42 (IH, m), 4.39 (IHlm),
6.78 (2HSd, J=7.8Hz), 6.8
8 (IHStSJ: ~7, 5 HZ), 6.92 (
2H, d, , T=a3H2), 7.00 (2H.

aSJ=8.3Hz), 7.20-7. +o(sH, m
), 7.62 (IH, tS, T=7.8H2), a1
6 (IHSa,, r=a3Hz), as 2 (I H
, aa, J=to, 7.3 Hz), a42 (1H
,a.

J''-5,9HZ), a69(IH,d,'J=6.
4H2), 9,15(IH,s), 9.31(IH,s
) Example 19 1-(N-(5-isoquinolinesulfony/L/) -p
-methane I lephonylamino-N-methylphenylated ~7-
72/L/ ) -4-phenylpiperazine Example 13
Anonymous 700#9 obtained in step 1 was dissolved in 7η of pyridine, and 0.13% of methanesulfonyl glycol was added under cooling with water. After stirring for 1 hour under cooling with water, 5% of a saturated aqueous sodium bicarbonate solution was added.
The reaction mixture was poured into 30-ml of chloroform and extracted twice with 30-chloroform. The residue obtained by drying over magnesium sulfate and condensation under reduced pressure was applied to a silica gel column and purified with chloroform-methanol (100:1 to 50:1) to obtain the desired product 79Of9.

Engineering R (KBr) cm”: 1635.1595.
1625.1220, 145! H-NMR (ODCt3, δppm): 2.4
8-2.59 (2H.

m), 2.8! +(3H,+3), 2.8 s ~3.
10 (3H, m), 3.12 (3H, s), 3.22
(I H, aal: r=q, s, i3.2uz),
3.44-5.80 (4H, m), 5.16 (I H
, dd, , T=5.4.9.8Hz), 6. BO~
6.93 (4T(,m), 7.04(4H,s),
7.26 (2H, t, J=8.3H2), 7.72
(11(,t, J=7,8Hz), a23 (I H
,a, ,T=a5Hz),a,55(j)I,da
, J=1.0.7.3 HZ), a42 (I H
, d, , r=5.9Hz ), a68 (I H, d
, J = 5.9 Hz), 9.36 (IH, s) Example 20 1-1-7 talenesulfonyl chloride 360 cape, using the anhydrous 700 η of Example 13, chloroform-mechnose) v (100 :1) except that 1(N-(5-isoquinolinesulfony/V)-N-methy/l/-1)-(1-naphthalenesulfonylamine)phenylalani/ V) 770η of -4-phenylpiperazine was obtained.

Engineering R (KBr) crn-”: 1635.1595.
1440.1330.1220.1150.1120 "H-NMR (CDC63, δppm): 2.42
(IHScod, J=4.9.12.7H2), 2.
63 (IH, m), 2.85-5.17 (4H, m)
, 3.07 (3H, s), 5.32-5.73 (4H
, m ), 5.04 (I H,aa, , T=5.4
．． 10.3Hz), 6.73-6.96 (7HSm),
7.05 (IH, br), 7.30-7.41 (3H
.

m), 7.54-7.70 (3H, m), 7.88 (I
H, aSJ=7.8H2), 7.95 (I H, d,
J=EL31Hz), a12 (1u.

dd, J=1.0.7.3H2), al6 (I
H, d, J=a3Hz), a27 (I H, dd,
, T=1.5.7.5 HZ ), as7(1H, a
.

J=6.3Hz), a62~&6B (2H,m)
, 9.32 (IH.

Example 21 5-isoquinolinesulfonyl chloride-jWL salt was prepared by adding sulfone and other agents to 620~, and the non-heavy substance of Example 15 was added to 5
Example 1 except that 00■, pyridine was used as 5-1 purified nichloroform-methanol/L/(80:1~SO:1)
In the same manner as in 9, 1-CN-(s-isoquinolinesulfony/l/)-p-(5-isoquinolinesulfonylaminophenylpiperazine 498I!lI) was obtained.

Engineering R (KBr) cIn-': 1640, 159
5, 1550, 1225, 1155, 1135 IH-NMR (cnct3, δppm): 2.4
4 (I H, da, J=4, 9, 1&2Hz
), 2.61 (IH, m), 2.8 5 ~ 3.2 6
(5HSm), s. os(sH,s), 3.4 0
~3.70 (3H, m), 5,06 (
IH, da1J=4.9, 9.8Hz), 6.7
7 (2H, d.

J=a8Hz), b. 7 9 ~ 6.9 7 ( 5
)1, m), 7.31 (2H.

t, , T=7.3Hz), 7.53(IH, t,
, T=a3Hz), 7, 63(IH, t, J=a8
Hz), a08 (IH, d, , T=a3Hz), a
2 0 (I H, d, , T=a3Hz), a
27~IIL32 (2H, m), &3 7 (2H,
(1, , T=6.4Hz), ais4 (IH,
d, , T=6,4Hz), a67(1)(, d,
, T: 6.4Hz), 9, 29 (IH, s), 9.34
(IH, El) Example 22 S) Toluenesulfonyl chloride pyridine 10WLt was used as a V-honation agent, and the purification was carried out with chloroform-meknol (100:1). was operated in the same manner as in Example 19 to prepare 1-(N-(5-isoquinoline sulfonyl)-N-methyl-p-(
p- ) L-enesulfonylamino)phenylawanyl]-4-phenylpiperazine 81 2 mgt
Obtained rc.

Engineering R (KBr) cm-': 1635, 1595
, 1440, 1325, 1220, 1150 IH-NMR (cpaz3, δppm): 2.3
2 (5H, s), 2.50 (I H, aa, ,
T=4.9, 12.7Hz), 2.68 (IH, m),
2,90~5.03(4H,m),5
．． 10 (5H, s), x29 (1H, m), 542-573 (3HSm), 5.1 2 (I H, dd.

, T = 5.4, 9. 8 Hz), 6.7 9
~6.9 7 (7H, m), 717 (2H
, eL. , J = 8.3Hz), 7.28(2H,
t, J=7.3Hz), 7, 61(2H, d,
J=a3Hz), 7.69(IH, t, J=7,
a H Z ), a21 ( I H, a, J=a3H
z ), a31(1H1dd, , T=1.5, 7.3
Hz), aa 0 (I H, dS.T=5.9H
z), F3-6 5 (I H, (ISJ=6.4
Hz), 9.35 (IH, s) Example 23 1-(N-(5-isoquinolinesulfony/I/) -p
-(N'-(5-isoquinolinesulfony)v)-N'-
methylamino)-N-methylphenylrealanyl)-4
- Phenylpibefudine The product 306j9 of Example 21 was dissolved in dimethylformamide 5- and 60% sodium hydride 251 was added under water cooling.
After adding 19 and hydrogen iodide α1- and stirring for 1 hour under ice cooling, 30 d of saturated brine was added, and then methyl acetate l
The mixture was extracted with 30 ml, and the 111+ eluate was washed with saturated saline. The washed extract was dried with magnesium carbonate,
The residue obtained by concentrating in a vacuum column was applied to a silica gel column,
A chloroform-methanol product of 266η was obtained.

Engineering R (KBr)or+-': 1640, 1600
, 1445, 1540, 1225, 1150, 1130 IH-NMR (ODOt3, δppm): 2.4
1-2.61 (2H, m), 2,83-3.0
7 (3H, m), 3.07 (6H, s), 3.27 (i
H, dd, J=1 0.7, 1 3.2Hz),
x43 (1H, m), 3, 5 6 ~S. 7 1 (
3H, m), s. 1a (I H, aa, J
=4.4, IQ. 7Hz), 6. BO ~6.9
1 (3) ISm), 6.9 4 (2H, a.

J=a8Hz), 7.00 (2H, a, J=
a8Hz), 7.21-7, 30 (2H1m), 7.
60 (IH, t, J=7.8Hz), 7, 7 3 (
IHStSJ:=7.8Hz), 7. q a (
IH, d, , T=5, 9Hz), a14-a25
(3H1m), a36 (1HSa.

J-EL4T (Z), aa 0 (I H. d,
, T=5.9Hz), a46(IHSd, J=
&4Hz), a69 (IT(1d, , r=6
．． 4 Hz), 9, 29 (IH, s), 9.37 (IH
, 8) Example 24 The product 594 of Example 19 was dissolved in dimethylformamide 6
- dissolved in 60% sodium hydride and methyl iodide) V0. 1-[N-(5-isoquinolinesulfonyl)-p-(N'-methanesulfonyl/
V-N'-1 Nalamino) N-methylphenylawoni/
L/)-4-phenylpiperazine 45011q was obtained.

ER(KBr)crn-': 1635.1595
．． 1445.1335.1225.1150.1140 1H-NMR (CDOL3, δppm): 2.36 (
IH,m), 2.50 (IH%dd, , T=3.
9.12.2Hz), 2.64 (3H.

S), 2.51 (1H, m), 2.96-3.16 (2
H, m), 111 (3H, s), 3.16 (5H, s)
, 3.31 (IH, dd.

, T=10.7; 12.7Hz), 3.37-3.
62 (3H, m), S, 78 (IH, m), 5.20
(I H, aa, , T=4.4.1α7H2), 6
．． 80 (2HSdS, T = 7.8Hz), 6.88 (I
H,t.

J=7.3Hz), 7.12 (2H, dS, r=a8
Hz), 721-7.31 (4H, m), 7.74 (
IHSt,, T=7.8Hz), a24 (I H,a
1J=7.8I(Z), a3s(1a, aa, :r=
1.0.7.3 Hz), &47(IH,d,,r=
6.4Hz), a71(IH,dSJ=6.4Hz
), 9.37 (1H, 8) Example 25 The product 5871q of Example 20 was dissolved in dimethylformamide 6-, and 604 sodium hydride 50 μ and methioiodide/L'! 1. Add 1- and chloroform-
Example 23 except for purification with methanol-1v (100:1)
1-[N-(5-isoquinolinesulfonyl)-N-methyl-p-[N'-methyl-N'-(1
-naphthalenesulfonyl)amine]phenylalanyl)
-4-phenylpiperazine 4901IPLI was obtained.

Engineering R (KBr) m-': 1640.1600.14
40.1330.1220.1150.1125”H-NMR (CDOL, δppm): 2.
47 (IHSdd, , T=4.4.12.7H2),
2.53 (IH, m), 2.8 (1 to 3.07 (+a,
m), xo7(sH,s), 3. oa (3H, s), 527 (I H, aa, J=10.3.12.7Hz)
, 348 (IH, m), 3.51-3.6s (saSm
), 5.17 (I H, dd%J=4.4.10.3
H2), 6.81 (2H, d1J=a8Hz), 6
．． 88 (IH, tS, r=7.3Hz), 6.98 (4
H,s), 7.24(2T(.

dd, J=7.5, a8Hz), 7.38-7.57 (
3H, m), 7.72 (IH, d, J=7.3Hz)
, 7.88 (IH, a, J=7, a HZ ), a
n 1 (I H, d, J=a3Hz), aa4(
1H.

a, J=7.3H2), a23 (I H%d, J
= a3Hz ), a32 to a37 (2H, m), a4b
(I H, (1, J=5.9Hz), a68 (I
H, d, J=6.3Hz), 9.36(jH,s
) Example 26 650 η of the product of Example 22 was dissolved in dimethylformamide 1
Dissolve in 0 wIt and add 60% sodium hydride to this.
#v and 0.1 d of methyl iodide were added, and chloroform-
Example 2 except for purification with methanol/I/(100:1)
1-(N-(5-isoquinolinesulfonyl)-N-methyl-p-[N'-methyl-N'-(p-to A/enesulfony)V
) Aminocophenylalanyl)-4-phenylpiperazine 605η was obtained.

Engineering R (KBr) crn': 1640.1600.
1440.1335.1220.1145'H-NMR (C!Dot3, δppm): 2.3
7 (3H, s), 2.52 (I H, dd, , T=
4.9.12.7H2), 2.55 (IH.

m), 2.80-i10 (3H1m), 2.99 (3
H, s), 3.11 (3H, s), 3.2 a (I
H, aa, , T=10.3.12.7H2), 3.4
0 (IH, m), 3.50-3.68 (3HSm)
, 5.20(IH, d4S, T=4.9.1α31(z
), b, s 1 (2H, a%, r=a3Hz), 6
．． 88 (IHlt, , J = 7.3Hz), 6.98 (2
H.

a, , r=aaHz), 7, o s (2H, a,
, T=8.8H2), 7.18(2H,d, J=a3
Hz), 7.24 (2H, d, a, , T=7.5
, a3Hz), 7.37 (2Hla,, T=&3Hz
), 7.73 (IH.

t%J=7+3Hz), a23 (I H, d, J=
a3Hz), a56 (I H, dd, , T=1.
0.7. a HZ ), a46 (1H, a.

J=lS, 4Hz), &7 [1(1)ISd, :J
=6.4Hz), 9.36 (IH, 8) Reference Example 11 1-(N-pencyloxylponyltyrosy)V)-4
-(t-butoxycarbony)v) Piperazine N-benzyloxycarbonyltyrosine r and N-(t-butoxycarbony)V) Piperazine 1 1. 79 F was dissolved in a mixed solvent of 200-methylene chloride and acetic acid F-/L/100 dv, 14 t of DCC was added, and after stirring at room temperature for 40 hours, the precipitated insoluble matter was removed, and the p solution was concentrated under reduced pressure. The residue obtained was applied to a silica gel column and purified with hexane-ethyl acetate Az (1:1) to obtain the colorless and heavy target product 2.
I got 59f.

'H-NMR (CDOL3, δppm): 1.
45 (9H, s), 2, 8 0 ~ 3.0 2 (
4 H, m), 5.14-539 (4H1m), 3
, 49 (2HSm), 4.83 (IHSm), 5.08
(IHSd.

, T=12Hz), 5.10 (I H,d, J=1
2H2), 5.69 (I H, d, J=a8Hz)
, 6.17 (IH, br), 6.72 (2H, al, 7
;a8Hz), 7.01 (2HS(Ll, T=a3H
z), 7.34 (5H 1 day) Ichidai Snoill (column 27 l-(N,O-bis(5-isoquinolinesulfony)V)
Tyrosyl)-4-(t-butoxycarbonyl)pibeodine 1.00 S' of the non-polymer in Reference Example 11 was converted into methano-/I
/20ml dissolved in 50ml palladium/carbon 500
q was added thereto, and the mixture was stirred at room temperature under a hydrogen atmosphere for 5 hours. Insoluble matter was removed in an oven, and the p liquid was concentrated under reduced pressure. Tetofhydrofuran 50- was processed into the resulting residue, and 5-isoquinoline sulfonic acid crophyte/'A'A acid Jibso was added.
η TODORU E CHILUAMIN 1. 4
ml! were added sequentially, and after stirring at room temperature for 50 hours, 10
After adding 〇-, the residue was extracted twice with chloroform 50-, dried over magnesium sulfate, and concentrated under reduced pressure. ) to obtain the target product 1 as a yellow non-weight substance.
．． I got 389.

"H-NMR (cvct3, δppm): 1.4
5 (9H, e), 2.53-3.18 (10HSm)
,4.29(IH,m),/,,05(1H.

dSJ=9.3Hz), 6.61 (2H,a, ,T
=a8Hz), 6.85(2H,d, J=aaHz
), 7.62 (IH, tSJ=7.8Hz), 7.66
(I H, t1J=7.8Hz), a19 (2H
, aSJ=7. aHz), a26 to a31 (3HSm)
, as2 (1u, a, :r=5.9Hz), a69
(IH, dSJ=5.9Hz), aa4 (1H.

d, , r=6.4H2), 9.33(IH,s), 9
．． 43(IH,s) Example 28 1-(N,Q-bis(5-isoquinolinesulfonyl)
Dissolve in 3 N hydrochloric acid and ethyl acetate/I/5-
was added, stirred at room temperature for 1 hour, and concentrated under reduced pressure.
- twice, dried over magnesium sulfate, and concentrated under reduced pressure to obtain crude product 501 in rapidly heated crystalline form.

1H-NMR (aDct3, δppm): 2.1
1 (IH, m), 2, 35 (IH, m), 2.43 (
2u, m), 2.7 0 ~ 2.8 3 (4H, m
), 2.90 (IH, m), 3.09 (IH, m), 4
．． 30 (IH, t, J=7.4Hz), 6.
6 5 (2H, dS, T-a3Hz), 6, 8
a (2H, a, , T=a3Hz), 7.62
(IH, dd,, T=z5, asaz), 7.64 (I
H,t,J=7.8)1z), ai7(IHldS,T
=a3Hz), EL2 4 ~a3 1 (4H,
m), a5 2 (I H, dS:J=5.9Hz
), a6B (IHSdS, T=6, 3Hz), a8
5 (IH, d, J: 6.4Hz), 9.3
2 (IH.

8), 9.43 (IH, Japan) Example 29 1-bendi/l/oxycarbonylation IV-4-(N-(5
-Isoquinoline sulfony) V) Tyrosylcopiperazine The crude product 620 ~ obtained by carrying out Example 2B was dissolved in methylene chloride (10), and under water cooling, 0.29 td of benzyloxycarbonyl chloride and 3.04 d of) ethylamine were sequentially added. After stirring for 2 hours under water cooling, 40% saturated saline solution was added.
- and then extracted twice with chloroform 20tRt,
The mixture was dried over magnesium sulfate and concentrated under reduced pressure to obtain a residue.

This was dissolved in 6 ml of methanol, added with 1N aqueous sodium hydroxide solution, heated under reflux for 2 hours, dried over magnesium sulfate, and concentrated under reduced pressure. , chloroform-methanol/
Purification was performed using L/(80:1 to 50:1) to obtain the desired product 356Ifq as colorless crystals.

Melting point: 137-141°C IR (KBr)cyr+-': 1700, 16
30, 1510, 1417, 1318, 1218,
1148, 1128 Violet H-NMR (c Dat
3-CD30D, δppm):
2.60 - 2,77 (2H, m), 2.8 0
~3.55 (8H, m), 4.25 (IH,
t, J=7.8Hz), 5.10(II(,s), 5.
12 (1H1e), 6.29, 6.74 (Totl.a
l 2H, each d1 each J=a3Hz), 6.60
,7. 0 1( To. b12 H, each d1 each J
=a3Hz), 7.35(5H,e), 7.60(I
H, t%. T7, 8 H Z ), al 5 (
I Hld, J:&! IHz), a26 (1H.

al, T=7.8Hz), &2 9 (I H, (
1, J=5.9Hz), a57 (I HSd
.
s-isoquinoline sulfony/L/)tyrosyl]-4-
Phenylacetylpiverazine was obtained.

Engineering R(KBr)z': 1620.1510.
1435.1320.1228.1152.1130 1H-NMR (DMSO-d6, δppm)
: 2.20~A45 (10H1m), 5,67.3
．． 70 (Total 2H, 4 days each), 4.32.4.
82 (Total I H, each m), 6.45.6
．． 65 (Total.

2H, 4d each, T=&3H2), 6.82.7.
OO(Tota12H, each d1 each, T=a3Hz
), 7. i 5-7.39 (5H.

m), 7.60-7.74 (IH, m), al 3-a
42 (3H, m), a64 (I Hla, J=5
．． 9Hz), 9.18 (IHlbr), 9.39 (I
H, br) Example 31 The same procedure as in Example 29 was performed to obtain colorless crystals of 1-(:N-(
5-isoquinolinesulfony/V)tyrosyl)-4-(3
-Phenylpropioni) V) Piperazine was obtained.

Melting: 172-178℃ Engineering R (KBr) cm-': 1630.1510
．． 1440.1320.1225.1150.1128 +1(-NMR(CDCt3-G!D30D, δp
pm): 2.50-3.47 (14H, m),
4.26 (IH, t, J=7.!+Hz), 6.32 (
2H, dlJ=a3Hz), 6.62 (2H, dlJ
:8.3H2), 7.15-7.34 (5H, m), 7
．． 62 (IH, t, J=7.8Hz), 8.17 (1
H1d, J=7.8H2), 8.24~ax3 (
2H.

m), a5 B (I H, d, J=5.4Hz)
, 9.26 (IHSs) Example 32 1-(N,O-bis(5-inquinolinsulfonylpi)v)piperazine 301 mg of the ↑■ product obtained in Example 28 and 6-phenylpropyl bromide 95η total dimethyl Formamide 5
- dissolved in potassium carbonate 66η and sodium iodide 7
After adding 2trq and stirring at 80°C for 7 hours, add 30d of 1 brine of saturated food and extract with 40rRt of acetic acid/ethyl acetate.
The resulting residue was washed with 30 ml of saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was applied to a silica gel column and purified with chloroform-methanol/L/(40:1) to give a yellow anonymous substance. The target product 2f 6117 was obtained.

lH-NMR (CDCt3, Jppm): 1.60
~1.95 (6H.

m), 2.06 to 2.29 (2H, m),
2.5 3 ~ i2 0 (8H.

m), 4.28 (IH, m), 5.98 (IH, a%
．． T=9.3Hz), 6, 64 (2H, a, J
= 8.3Hz), 6.86 (2H, dl, r
= a3Hz), 7.1 4 ~ 7.35 (5H, m
), 7. S? (1H, t.

J=7.8Hz), 7.62(IH, t, , r=7
．． 8Hz), al2(f!(, d, J=a3Hz
), a23 to a29 (4H, m), a5 2 (
I H%d, :J=5.9Hz), a6a(1H
, a, y=6,4Hz), aa 2 (I H,
a, J=6.4Hz), 9.28 (IH.

S), 9.42 (IH, s) Example 33 1-(N-(5-isoquinolinesulfonyl)tyrosyl)
-4-(S-phenylpropyl)piperazine 216 µ of the anonymous substance obtained in Example 32 was dissolved in methanol 3-, 2N aqueous caustic potassium solution α6- was added, and after heating and refluxing for 10 hours, 30 d of saturated brine was added. Then, a mixture of chloroform-isopropane (5:1) 1 volume soot 2[]r
After 2 times of HL + extraction with nt, the residue was dried with r flow + 1 magnesium and concentrated under reduced pressure, and the resulting residue was applied to a silica gel column and chloro-gamma-methanol.
(40:1 to 10:1) to give yellow anhydrous substance 7
4η is 1tJ.

IR (KBr)z-”: 1630, 1510,
1440, 1320.

1230, 1150, 1128' H-NMR (CDCt,, δppm): L6
5 ~ 1.83 (2H, m), 2,0 0 ~ 2.3
7 (6H, m), 2.5 7 ~ 2.811
(4H, m), 3,02 ~ 3.42 (4H
, m), 4.31 (IHSm), 6.3o (2H1d
, J=a31(Z), 6.4 1 (I H, d
, J==9. ! +Hz), 6, 65 (2H%
dS. T=a3Hz), 7.15 ~ 7.37 (5H
.

m), 7.60 (IH, tSJ=7.8Hz
), al6(IH%d.

J=axHz), a2 3 ~a3 3 (2H,
m), ass(1H.

br), 9.33 (IH, br) Reference Example 12 1-(N-(t-butoxycarp/l/sz2/L/)tyrosyl]-4-phenylpiperazine N-(t-butoxycarponi)V) Tyrosine 1977,
N-phenylpiperazi:/. -2.52, N-hydroxybenzotriacy)v 1b, 1? e A 50-tetrahydrofuran solution of Do(1!1a7?) dissolved in 100 d of tetrahydrofuran was added dropwise under ice cooling for 20 minutes, and the mixture was stirred for 1 hour. Combine L/300- and F solutions, concentrate under reduced pressure, dissolve in ethyl acetate 500 + ILt, wash 6 times with saturated sodium bicarbonate aqueous solution, once with white saline solution, dry over magnesium sulfate, and concentrate under reduced pressure 11 times. The residue obtained by condensing .
1:2 to 1:1) were combined and condensed under reduced pressure. The obtained residue was dissolved in ethyl acetate/L/100d,
After leaving it in the refrigerator overnight and separating the insoluble matter, the liquid F was dried under reduced pressure, azeotropically with benzene, and dried under reduced pressure to obtain the colorless and heavy target product 40. Obtained OS'.

IR(KBr)m': 1700.1620.12
20'H-NMR (DMSO-(16, δppm):
1.33 (9H, s), 2.6~! i, 1(6H, m
), 3.4-5.7 (4H, m), 4.55 (IH, m
), 6.64 (2H,a, ,T=a2Hz),a
8o(1H.

t,, T=7.3H2), 6.90 (2H,a, J
=7.9uz), 7.02(2H, d%J=a2H2)
, 7.22 (2H, aa, J=73.7, 9 HZ
), 9.16 (1H, s) Reference Example 15 1-(2-(t-butoxy)vdanylamino)-1-
(p-Hydroxypheni)V)Propyl]-4-phenylpiperazine Under water cooling, 230 m of tetrahydrofuran of lithium aluminum hydride a02! :il aluminum chloride 2 at night
Aete Az 230-solution of a02 was added dropwise to the solution over 50 minutes, and after 15 minutes, the non-grained body 40. obtained in Reference Example 12 was added dropwise to the solution. O
A solution of 250 td of tetrahydrofuran was added dropwise over 15 minutes, and the temperature was returned to room temperature.
rt and stirred for 25 minutes. The insoluble matter was separated from house to house, the insoluble matter was washed with tetrahydrofuran, the liquid from the furnace was combined with the solution, and the residue obtained by concentrating under reduced pressure was applied to a silica gel column and chloroform-methanol/l/(20: The fraction obtained in 1) was concentrated under reduced pressure. Add 10 ethyl acetate to this
0 Int was added, and the precipitated crystals were collected in a furnace, and the filtered crystals were washed with the mother liquor five times and further with n-hexane three times, and then dried under reduced pressure to obtain colorless crystals of the desired product, 24.1 i/.

Melting point: 199-202°C (decomposition) 'H-NMR (DMsO-ao, δppm): 1
-33 (9H, s), 2.2-2.8 (8H, m)
, 3.09 (4H, brs), 572 (1H, m)
, 6.5-7.0 (7H, m), 7.20 (2H, 1
t, J=a3Hz), 9.1o(1a,s) Engineering R(KBr)cm': 1690.1500.1
230 Reference Example 14 1-[2-amino-3-(p-hydroxypheni/L/
) 7'lopyl]-4-phenylpiperazine Reference Example 1
To a suspension of 2562 ethyl acetate/L/100 of the crystals obtained in step 3 was added 30
After stirring for 1 hour and 50 minutes, excess hydrogen chloride was removed under reduced pressure, and 200% of water was added for extraction. The ethyl acetate lv layer was further extracted with a 1N aqueous hydrochloric acid solution (50°C), the combined aqueous layers were neutralized with solid sodium bicarbonate (pH 7,4), the resulting crystals were collected in a furnace, washed with water and benzene, and added with phosphorus pentoxide. The product was dried under reduced pressure in a f-dicator to obtain the desired product 16.95' in the form of colorless crystals.

Melting point: 270°C or higher' NieR (KBr) crrl-': 1600.1470
．． 1230'H-NMR (DMso-ao, δppm
): 2.2-3.5 (13H.

m), 6.7-6.8 (3HSm), 6.90 (
2H1a1. T=a5Hz), 7.07(2H, a%,
T=a3H2), 719(2H1t1:r=7.6H2
), 8.00 (2H, brs), 9.41 (IHSb
rs) Example 34 N-(1-(1)-(5-isoquinolinesulfonyloxy)benziJV-2-(4-phenylpiperazinyl)ethyl)-5-isoquinolinesulfone 1-stylamide Reference Example 14 was carried out. 22.962 crystals obtained with tetrahydrofuran 700 mtf & cloudy? 5-isoquinolinesulfonyl chloride/ti acid bB under water cooling.
5 to 1y was added over 5 minutes, and then triethylamine 103- was added dropwise over 30 minutes, and the mixture was returned to room temperature and stirred at 4'' for 2 hours. Extracted with and 230-, combined 17
The extracted solution was washed with saturated saline, dried over magnesium sulfate, and dried under reduced pressure. The yellow anonymous substance obtained was applied to a silica gel column, and chloroform-methanol/v (jOD: 1 to 50:
1) to yield yellow, I:j (heavy target product 45.5
? I got it.

Engineering R (KBr) Crn-': 1600.1500
．． 1130IH-NMR ((:!DO43, δppm
): 2.0-3.0 (12H, m), 3.30
(IH, m), 5.51 (IH, brs), 6.7~
7.8 (11H, m), 8.20 (1H, a, J
=EL2Hz), a28(2H.

d%y=z7Hz), a4-a5 (2H, m), a5
3(IJ(.

a, J=:tlHz), 8.67 (I H, d,
, T=6.1 Hz), aa1(11(, dSJ=6
．． 1 Hz), 9j5(IH,e),? , 42(1)
1. El) Real') J1ζ Example 35 N-(1-(p-(5-isoquinolinesulfonyloxy)benzitV)-2-(4-phenylpiperazinyl)ethyl)-N-methyl-5-inquinolinsulfonic acid Amide Example 34 was carried out to obtain 200 d of anhydrous 25.02 ml of dimethylformamide (60 ml of sodium hydride 1.645 ml was added to solution B in three portions under water cooling, and after 5 minutes, methyl iodide 5 .14 ml was added dropwise over 2 minutes and stirred for 1 hour.The reaction solution was poured into ice water (400 m/j) and 200-1200 mg of ethyl acetate.

The combined extracts were extracted 31 times with saturated saline, dried with 1 ml of magnesium sulfate, concentrated under reduced pressure, and the resulting residue was applied to a silica gel column and purified with chloroform-methanol. The objective product 2.0.25' of Huangba non-grained substance was obtained.

'H-NMR (CDCl2, δppm): 2.3
0 (IH, dd, , T=6, 8, 12.2Hz),
2.39 to 2.52 (5H, m), 2
．． 68 (IH, da, , T:=7.3, 14.2H
z), 2.86 (3H, e), 2, 8 9 ~ 3.0
1 (5H, m), 4.18 (IH, m), 6.
6t (2H, d, J=a3Hz), aa3~6.9
2(su, m), 7.26(2H, t%J=7.8
Hz), 7.57 (IH, tS.T=7.8Hz),
7, 60 (1H, t, , T=7.8Hz), alo
(1H, a, , r=a3Hz), a2 3 ~a
2 8 (3H, m), 8.33 (IH, dd.

J = 1.0, 7.3Hz), a5 6 (I H,
dSJ=5.9Hz), a58(1H, d, ,
T=5.9Hz), aa3(1H%a, y=5,9
Hz), 9.27 (IH, s), 9.4 1 (I
Hla, , T=1.0Hz) Engineering R (KBr) crn-': 1620, 1
500, 1370, 1325, 160 Su J Rikii Example 3 6 N-1: t-(p-hydroxybenzi/l/) -
2-(4-phenylpiperazinyl)ethyl
-N-Methyl/l/-5-isoquinolinesulfonic acid 7mide obtained in Example 55; , 7S', 240 mg of methanol, 60 Tnt. of tetrahydrofuran.
, 2 hours with 29° of aqueous caustic soda solution and 50°C for 2 hours.
After refluxing, the reaction solution was poured into saturated brine, extracted three times with 200% chloroform, washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was applied to a silica gel column and chloroform-methanol/L/
(50:1), yellow amorphous crystals (Book 1 0.
9 S' was obtained, ethanol 54- was added thereto, and the mixture was pressed for 1 hour at room temperature and 1υ for 30 minutes with water cooling, and the resulting crystals were purified by p
The product was taken, washed three times with mother liquor and twice with benzene, and dried under reduced pressure to obtain the target product a25' in the form of light-colored crystals.

Melting point: 201°C IH-NMR (cnct3, δppm): 2.
49 (IHSad, , T=: 6, 8, 9. 8 H
Z ), 2.5 2 ~ 2.7 7 ( 7 H, m
), 2.95 (IH.

da1J=4.4, 14.2Hz), 3.02 (3H,
El), 3.14 (4H1t, J=4, 9Hz),
4.03 (1H, m), 6.26 (2H, d, , r
=a3Hz), 6.61 (21(, d, J=8
．． 8Hz), &86(11(1t1J.=6
．． 8Hz), b. q 1( 2H, a, :r=7
, 3Hz), 7.27 (2H, t1J=7.8Hz)
,y. 6o(+H.

t, J = 7.3) (Z), al 1 (I HScl
, , T=5.9Hz ), &1 4 ( IH, d
, J=6.4Hz), a3s(1H, aa, J=
1, 0, 7. 5 HZ), aa 7 (1H%
d, :f=6.5Hz), 927 (IH, 8) Engineering R (KBr)c+r+-': 1600, 151
0, 1445, 1320, 1205, 1150, 112
5 Example 57 1CN(1-(p-hydroxybendi/L/)-2-(4-phenylpibe) Vagini) V) Ethi IV) -5-Isoquinoline sulfonic acid amide was obtained as a colorless; 1jj (heavy substance).

IH-NM, R (CDC13, δppm): 2
．． 25-2.55 (6)(.

m), 2.65 (I H, dd, J=13.7, &
85H2), 2.79 (I Hldd, J=13.7
．． 6.85Hz), 2.82~! ,,0(4)1゜m)
, 3.37 (I H, quintet, J=6.8
5Hz), 6.42 (2H, d, J=a57Hz
), 6.69 (2)1. d, , T=a57Hz)
, 6.84 (2H%d, J=8.57Hz), 6
．． 85 (IH.

tS, T=a57H2), 7.26 (2H,t, J
=a57Hz), 7.69(11H1tS, r:=7
．． 42Hz), A22 (1H, d,, T=7, 99H
z), a38 (I H, dl, T: 6.28Hz)
, A43(I Hlad,, J=7.42.1.0H
z), A59(1)! , (1,, T=6.28H2)
,9. ! +4 (IH, a, J=1.0H2) Example 3
8 N-C1-(p-methoxypendinov)-2-(4-phenylpiperazine)V)ethyl)-N-methyl-5-isoquinolinesulfonic acid amide 1 of the crystals obtained in Example 36
．． 51f was dissolved in 20ml of a mixed solvent of dimethylformamide-tetrahydrofuran (1:1), 140JIv of 604 sodium hydride was added to a water bath stirring knife, and the mixture was stirred for about 30 minutes. After the foaming stopped, methioiodide (VA90I) was dissolved.
ml was added, and the mixture was further stirred at room temperature overnight. After adding water to the reaction solution, the mixture was extracted three times with 50d of methylene acetate, washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. / (100:1) to obtain the target product 1.55 F as a pale brown oil.

"H-NMR (CDC11, δppm): 2.45
(IHSdd, J=7.1.13.8H2), 2.6
(sH, m), 2.5s (1H, m), 2.88 (IH
, s), 2.95 (3H, 8), 3J5 (4H, m),
3.74 (3H, S), t2 (1H1m), 6.5 (
2)1. a, :r=a5Hz), 6.9(5H,
m), 7.2 s (2 Hlm), 7.55 (I H,
t, J=7. '5Hz), an 7 (I H,'
(1, J near, 5H2), A22 (IHSdSJ=6.
4Hz), A56 (IHScl, , r=6.4Hz)
, 9.22 (jH, s) Engineering R (KBr) a+s-': 1600.1510.
1320.1240.1150.1130 Example 59 Reference Example 12 except that varini 1-(2-pyrimidi/L/)piperazine dihydrochloride was used instead of N-phenylpiperazine
~14, the same procedure as in Example 34 was carried out to obtain colorless poly((heavy N-(1-Cp-(5-isoquinolinesulfonyloxy)benzyl)-2-(4-(2-pyrimidyl)piperazinyl)ethyl) -5-isoquinoline sulfonic acid amide was added.

IH-NMR (CDC43, δppm): 1.
8-1.96 (2H.

m), 1.96-2.24 (4H, m), 2.8 (1
)! , aa, J=13.7.6.85Hz), 2.
92 (I H, (1(IS:r=1s7.4.57H
z), 3.0 to 3.47 (5H, m), 5.49 (
I H%br), 6.47 (I HSt%J=4,5
7Hz), 6.70 (2H, a%, r=a57Hz
), 6.94 (2I (1ti%J=a57Hz), 7.
64 (IH, t, J = varnish 2H2), 7.70 (IH
,tS :r-7,42Hz), al7~a35(5
H, m), A37-448 (2H.

m), A52 (1H,, d,, J=5.71H2), a
6s (1u.

dSJ=6.28H2), 8.82 (1)(, dl,
T=6.28H2), 9.37(IH,s), 9.42
(IHScl.
-2-(4-(2-pyrimidi/L/)piperazinyl]ethyl)-5-isoquinolinesulfonic acid amide was obtained.

'H-NMR (CDCt, δppm): 2.
05-2.55 (6H1m), 2.66 (I H,
aa, :r=13.13.6.85)(z), 2.8
2 (IHSd(11, T=I A13, A28H2),
52-3.7 C5H, m), 6.42 (2H, d,
, T=7.9 H(Z), 6.46(IH,t,:
r=4,. 57Hz), /1.72(21(,d%J=
799Hz), 76B (IH, t, J near, 42Hz)
, a20 (I H, dl, r=8.57Hz), a2
7 (2H, d, J: 4.57H2), a, 55 ~ [
3,50 (2H, m), A57 (IH, d,, T=5.
71H2), 931 (1H 1 day) Example 41 The amorphous group of Example 39 was operated in the same manner as in Example 35 to produce colorless and heavy N-(1-(p-(5-isoquinolinesulfonyloxy)benzyl)) -2-[4-(2-pyrimidyl)hiverazinyl]ethyl)-N-mefl-5-isoquinolinesulfonic acid amide was obtained.

"H-NMR (CDCl2, δppm): 2.1
5-2.36 (5H.

m), 2.44 (I Hlad, J=15.7.6
．． 85H2), 2,71(IH,aaSJ=13.1
3.6.85H2), 2.8-2.95 (jHSm)
, 2.87 (3H, s), 3.5-6 (4H, m), 4
．． 17 (I H, quintet1J=6.85Hz
), 6.4a (1h (, t1J=4.85Hz), 6.
6s (2H, a, :r=q, 14Hz), 6.
92 (2H, d, :r=9.14Hz), 7.58
(IH, t, , T=6.85Hz), 7, t, 1(
IH,t, J=6.85Hz), &13(IHS
a, J=7.42)IZ), a18-a38(61(
, m), a56 (I H, d, , r=6.28 H
z ), asa (1H, a, , T=6.28Hz),
8.84 (11(,d, :f=6.28Hz),
9.28 (IH, s), 9.42 (IH, (1, J: 1
．． 0H2) Example 42 In fact, Case 41 '7) A colorless non-baric substance was prepared in the same manner as in Example 36 to produce N-(1-(p-hydroxybenzyl)-2-C4-(2-hyrimidyl). ) Piperazinyl]ethyl)-N-methylfury 5-isoquinoline sulfonic acid 7mide was obtained.

IR(KBr)crn”: 1585.1510.1
555.1325.1255, 1130'H-NMR (aDC43, δppm): 2.4
~2.65 (6H, m), 2.70 (IH, dd,,
T=13.15.6.28H2), 2.97(IH, d
d, ,T=13. j 5.5.71Hz), 3.03
(31(,S), 5.77(4H,t, J=4.57
Hz), 4.04 (IH, m), 6.28 (2H, d
, J=a57Hz), 6.49(1HSt1J=5
．． 14Hz), 6.62 (21(,d, J=a57
Hz), 7.62 (I H, t, J=7.42H2
), all (1HSa%J=6.2aHz), al 5
(1H, d, J=7.42Hz), a30(2)
(.

d, J=5.14 Hz), as2(1HSad,
J=v, 42.10Hz), &48 (I H,d,
, T=6.2811s ), 9.28 (IH.

8) Example 13 N-(t-)゛Toxica! N-(1-benzyl-2-(4- Phenylhiberanoni/I/)ethyl-N-methy)v-5-isoquinoline sulfonic acid amide was obtained as a pale yellow solid.

Engineering R (KBr) cm-': 1595.1490
．． 1300, 1220, 120”H-NMR (ODO2J, δppm): 2.4
5 (jH, dd, J=6.6.13Hz), 2.7
(1H, dd, J=8.13H2), 2.55(5[
(, m), 3.0 (5H1m), 4.5 (1H, m),
6.84.6.9 (Total 3H1m), 7.0
(5H, brs), 7.25 (2H, m), 7.5
(1H, t, J=7.5Hz), aOS (1H, dSJ
=8Hz), 8.2 (I H,a, J=7.5Hz
), a, s (I HSa, J=8H2), 8.5
5 (j H, a, , T=6.IHz), 9.23(
IH, s) real example, + 4 N-feni,! Yellow crystalline N-(
1-Cp-(5-isoquinolinesulfony, I-reoxy)
benzyl-2-(4-(2-pyridyl)hyperanonyl)
Ethi/L/ ) -5-isoquinoline sulfonic acid amide ol? tfc.

Engineering R (KBr) crn-': 1615.1590.
1480.1450.1370.1510.1150.
1130'H-NM, R (cDctl, δppm)
: 1.93-2.21 (6H.

m), 2.77 (I HSaa, J=7.3.14
．． 2Hz), 2.83~500 (3HSm), i02~
3. j9 (2H, m), 3.29 (IH, m), 5.4
6 (IHSbr), 6.47 (IH%d, IJ=8
．． 8Hz), 6.62 (IH, aa, J=4.9
．． 7.3 HZ), 6.69 (2H, d, J:a8H
z), 6.92 (2Hld, J=a8Hz), 7.4
4 (I H, clad, J=1.0.8, 8.7.
3 Hz), 7.64 (1HSt, J=7.8Hz)
, 7.70 (IH, aa, J=7.3, a3uz),
AI! l (I H, adS, T=1.0.4.9H
2), a22 (I H, dl, T=a3Hz), a
2B (21 (1d,, T = 7, 3 HZ), a43 (
2H, m), a53 (I Hld, , T=5.9H
z), a67 (IH, d1J=6.5Hz), s, a
1(+I(S(1°, T=5.9Hz), ?, 55
(N(,a,,T=1.0Hz), 9.42(I HS
Example, t 5 Generation of actual Mi example 44 * was operated in the same manner as in Example 35 to generate N
-(1-Cp.-(5-isoquinolinesulfonyluoquine)benzyl), -2-(4-(2-pyridyl)biverazinyl)-N-methyl-5-isoquinolinesulfonic acid amide was obtained.

ER(KBr)m': 1590.1480
．． 1430.1370.1310, 1130"H-NMR (CDC43, δppm): 2.2
5-2.50 (6H.

m), 2.69 (I H, aa, J=7.s, 1
4.2H2), 2.86 (3H,s), 2.88 (I
H, da, J=14.2.10.2Hz), Goro
(4H, m), 4.18 (IHlm), 6.55-6.
65 (4H, m), 6.90 (2H, d1J=13
．． 8Hz), 7.47 (IH.

dad, , T=1.0.13, a8Hz), 7. s
s (I HladS, T=73, a3Hz), S6
0 (I H%t, , T=7.8Hz), all(
jH1dSJ=a5Hz), a17(11(, act,
, T=1.0.4.9Hz), a22~a27 (3
HSm), 8.33 (IH.

(ld, J=1.C17,,'l Hz), aS
6 (I H, d, , T=5.9H2), aS8 (I
HSa,,T=5.9Hz),aa4(1H,a,:r
=6, 4 I(Z), 9.28(IH,e), 9.4
1(jH,s) run + Zl ~ 16 runs] - The product of 15 was operated in the same manner as in Example 36 to obtain N-(1-(p-hydroxybendi)V )-2-(:
4-(2-viridi/I/) biverazini, I]ena/L
/ ) -N-methy1V-5-isoquinoline sulfone amide was obtained.

Engineering R (KBr) crn-': 1590.147
5.1445.1320.1230.1150.112
5 1H-NMR (CDC13, δppm): 2.48
(IHSdd, J=3.4, q, 4 HZ), 2
．． 50-2.75 (6HSm), 2.95 (IH.

ddS, T=4.9.14.7H2), 3,02(3H
, s), 5,49 (4H1t, J=4.9H2), to
6 (1HSm), 6.27 (2H, aS, 7==a3H
2), 6.62 (2H, a, J=asuz), 6.6
1 to 6.66 (2H, m), 7.43 (I Hld
(id, J=1.0, s3, a8Hz), v, s 1(
IH, aaS, T near, 3, a3Hz), alo ~a
16 (2H, m), al 9 (I H, dd, , T
=tO14,3H2), a32 (I H, cldl,
T=1.0.7.3 HZ), aa B (I H,
d%, T=6.4 Hz), 9.28 (1H, s) Example 47 Caterpillars using N-pheniI rebiverazine (Cn-<m-chloropheni/L/)piperazine are reference examples 12
~14, by operating in the same manner as in Examples 34 to 56, pale yellow island-like rJ-(2-C4-(m-chlorophenyl)hiverazinyl)-1-(p-hydroxybendi)V)ethyl]-N -Mef-5-isoquinolinesulfonic acid amide was obtained.

Engineering R (KBr) LM': 1590.1320
．． 1230.1130'H-NMR (CDC13, δp
pm): 2.5 (1H, da%'J=12.0.1o
Hz), 2.5-2°8 (2H, m), 2.6-2.7
(4H, m), 2.9 s (I H, d+i, J=4
．． 5.158Hz), 50(3H,s), 3.15(4
H1m), 4.0 (I HSm), 6.22 (2H,
a, J=8.0H2), 6.55(2H,d,, T=a
OHz), 6.77 (I H, aa, J=as, 2
．． 2Hz), 6.8 (I H, a.

J=aoHz), 6.85 (1-HSd, J=2゜2H2), 716 (IH,t, J=aOHz),
7.6 (IHlt, J=7.8Hz), al (IH
, (lS, T: 6.IHz), s, 1s (I H,a
, J=a1Hz), a3(IH,d,, T=7.3+
(z), aas(1H, a.

J:6.4Hz),? . 2B (IH, s) Example 48 N-Phenyl/L/ Piperazine substitute: briK? J-(p
-Fluorofueni)v) Piperazine was used, and the same procedure as in Examples 12 to 14 and Example 34 was repeated to obtain a colorless island-like N-(2-C4-.(p-fluorophene)v)pibewononyl)-1. -(p-(5-inoquinolinesulfonyl)benzyl]enal)-5-isoquinolinesulfonic acid amide was obtained.

Engineering R (KBr) cm-': 1610,1500.
1370.1+20°1210.1130.860.8
20'H-NMR (CDC13, δppm): 2.0
~2.3 (5H, m), 2.4 ~ 2.9 (6H, m
), 3.3 (IH, m), 6.6-6.75 (4H
, m), 6.85-7.0 (4HSm), 7.65
(IH, t, J=a1H2), 7.7 (IH, t,
J=a4Hz), a2(IH, d1J=&3Hz), a
3 (IH, d, , T=varnish 8H), aa (1n.

a, J:43H2), aa(IH, (1, J knee 6,
IHz), aS (IH, d, J=6.1), 8.
65 (I H, d, , T=6.1 Hz), aa
(1H, a, , T-6, 3H2), 9.3 (1H,
9.4 days), 9.4 days (IF 5 days) Example 49 The anhydrous body obtained in Example 48 was methylated according to the procedure of Example 35 to give pale yellow power ((island-like N-(2-(4
-(1)-fluorofenyl)-pivefudinil)-1
-Cp-(5-isoquinolinesulfityloxy)bendiρ]ethyl)-N-methyl-5-isoquinolinesulfonic acid amide.

ER (K, Br) cm': 1620.1
510.1370.1530.1210.1140'H-NMRCcDat3, δppm): 2.3
(I H, da, , T ~12.1.6.5H2)
, 2.45 (4H, m), 2.4-2.6 (I H
.

m), 2.67 (I H, dd, J=13.8.7
．． 8Hz), 2.75-3.0 (5H1m), 4.17
(IH, m), 6.6 s (2HSa.

J=a6H2), 6.7-7.0 (6H, m), z
, 57 (1aSt.

J=aoHz), 7.60(1)(, t%, T=7.6
H2), &1(1H,d, J=aO,)Iz),a
2-a35 (4H, m), a55 (I H, a, J:
5.4 Hz), as 6 (I H, d, , T=
aI H2), 8.85 (I HSd, J=6.3
Hz), 9.27 (IHl(1,, r=0.7Hz)
, 9.40 (IH, a, , T = 1.0H2) 1 row of fallen turtles 50 The clean body 160η obtained in Example 19 was dissolved in methano-IV 2 td j' according to the procedure of Example 36. 2
After adding 0.5-liter of normal caustic soda and refluxing for 2 hours, it was cooled and extracted three times with chloroform. It was purified with chloroform-methanofluoride (100:2) on a column to give a pale yellow, non-baric N-(1-(p-hydroxybenzi/L/)-2-(4-(p-fluorophenic/I/)-
hiberazinyl]ena/L/)-N-meryl-5-isoquinolinesulfonic acid amide 105η.

IR(KBr)cM-': 1610.1500.
1520.1230.1150.1150.820 II (-NMR (ODCll, δppm): 2.4
~2.6 (zH, m), 2.6 ~ 2.8 (I H, m
), 2.8~! L, O (I H, m ), 2.75 (
4H, m), S, 05 (IHSm), xl (1u, m)
,6. ．． 5 (2H.

d, , r=8.311), &67(2H1d, , r
=a3. Hz), 6.87 (2HSaa, y=a3.
10. IHz), 6.95 (2H.

tl, T2a3Hz), 7.6 (IH,da, ,
T=7.6, aoHz), 8.12 (I H%d,
, T=9.0H2), a13(IHSd, , T=6,
IH2), a3(IH, d%, r=73H2), as(
1HSa.

, T:6. IH2), 9.25 (IHSs) Example 51 Using Valini N-(m-methylphenyl)piperazine instead of N-phenyl lebibeozine, etc. 3 Examples 12 to 14,
The same procedure as in Examples 34 to 36 was repeated to obtain a pale yellow non-grained N-(1-(p-hydroxybenziN)-2-(4
-(m-methylphenyl)-hiverazinyl]-ethyl/V
) -N-methy/V-5-isoquinolinesulfonic acid amide.

IR (KBr) cm-, 1: 1600.1440.
1320.1210.1190.1150.1120 IH-NMR (c:ocz3, δppm): 2.3
0 (3HS13), 2.55 (4H, m), 2.96
(I HSdd, , T=11./), zlHz),
2.5-2.9 (3H, m), 2.9 (5H1s
), 5L1 (4H, m), 4.3 (1H, m), 6.
8(2J(, (1%, T=8.3H2), 7.0(2H
, d, J=a3Hz), 7.0-7.15(3H, m
), y, x (1H, m), S55 (I Hlt, ,
T=7.8H2), al(IH, dSJ=7.8Hz
), a2-a3 (2Hlcomplex), 8.5
8 (I H, (1,, T=6.I Hz), 9.2
5 (IH, s) Example 52 Reference Example 12 to
14. Repeat the same procedure as in Example 34 to obtain yellow; I! Convex N-117(p-(5-isoquinolinesulfonyloxy)benzi)V-2-C4-(p-methoxyphenyl)piveranonyl]-5-inquinolinesulfonic acid amide .

Engineering R (KBr)tM”: 1615.1500.15
60.1150' H-NMR (C!DCt3, δpp
m): 1.96-2.22 (6H.

m), 2.39-2.52 (2H, m), 2.52
~2.67 (2H.

m), 2.77 (I H, aa%J=7.3.14.
2Hz), 2.90 (IH, aa, J=4.4.1
4.2H2), 3.27 (IH%m), xl6 (3a,
e), 5.50 (1H, br), 6.70 (4H.

aSJ=a8Hz), 6.82 (2H, d%J=a8
Hz), 6.94 (2H, d, J=a8Hz)
, 7.65(IH,t, J=7.8I(Z), 7.7
0 (IH, t1J=7.3Hz), 8.21 (IH, a
, J=axHz), a2q (2H,a, , T=7
．． 8Hz), a40~1lL43(2H,m), as
3 (I H, a, :r=s, qHz), a6a (
I Hla, , T=6.4H2), aa1 (IH.

d, J = 5.9Hz), 9.36 (IHLB), 9
．． 42(IH,s) Example 53 The non-grainy substance obtained in Example 52 was treated with methyl iodide in the same manner as in Example 35 to obtain yellow [13 pure N (1-
(p-(s-isoquinolinesuluatonyloxy)benzyl)-2-C4-(p-methoxypheny)V)piperazinyl]ethyl)-N-methytV-5-isoquinolinesulfonic acid amide was obtained.

Engineering R (KBr) cm-': 1665.1615
．． 1505.1565.1320.1130'H-NMR (CDC13, δppm): 2.3
0 (11(, dd, J=6.8.12.21(z)
, 2.37-2.51 (5H,m), 2.68 (I
H, [1(1,, T=7.3.14.2Hz), 2.8
5(3H,s), 2.78-2.97(5T(,m
),! 1.77 (+a, s), 4.16 (IH, m),
6.62 (2H1d, J=a3Hz), 6.82
(4H.

8), 6.90 (2H, a, J=a3Hz), 7
．． 57 (1H, t.

, T=7.8Hz), 7.60(IHSt, , T=7
．． 8Hz), all(IT(, dl, T=EL51(z
), 13.2S ~ &28 (3H, m), C53 (I
H, ad, , r=1.0.7.3H2), C56(I
H,d.

, T=6.4H2), C58(IH, (1,, T=,6
．． 4Hz), C83 (IH, cl, J=5.9Hz)
, 9.27 (1H, d, , r=1.0Hz), 9.
41 (IHSa, J=1.0Hz) Example 54 The anhydrous body obtained in Example 53 was subjected to alkaline hydrolysis in the same manner as in Example 36 to obtain yellow crystals of N-(1-(p-hydroxybenzi/L). / ) -2-C4-(p-methoxyphenylene/L/)hiberagini~]ethyl)-N-methy/
L/-5-isoquinoline sulfonic acid amide was obtained.

Melting point: 157-160°C (decomposition) Engineering R (KBr) crn': 1615.1510.
1445.1320°1305.1240.1125'H-NMR (cDat, δppm): 2.4
6-2.74 (7H.

m), 2.88~xoz(su, m), xoo(3u,
s), C77 (3H, e), to6 (iH, m), 6.
s o (2H, a.

, T=a5Hz), C65(2H%a, J=a3Hz
), 6.83 (2H, (1,, T=9.3Hz), 6
．． 88 (2HSa, , T=9.314Z), 7.57
(IH, ad, , T=7.3, axuz), C12 (
IH.

d, , T=a3Hz), als (I H, a, J
=6.4H2), ax 2 (1HSaa, J=to
, 7.3 HZ), C50 (IH, d.

J = 6.4 Hz), 9.26 (IH, s) Example 55 The anhydrous body obtained in Example 52 was alkaline hydrolyzed in the same manner as in Example 37 to give yellow crystals of N-(1-(p-hydroxy BenzitV) -2-(4-(p-methquinphenyl)
Add hiberazinyl]ethyl)-5-isoquinolinesulfonic acid amide.

Melting point: 200-208°C (decomposition) Engineering R (KBr) crn': 1615.1590.
1510.1450.1340.1250.1150.
1160.1025'H-NMR (CDC!/, 3, δ
ppm): 2.20-2.44 (6H.

m), 2.58-2.82 (6H, m), x3x(
1H, m), 3.77 (!IH1El), 5.55 (I
H,'br), 6.47(21(1d.

J==asH2), 6.76 (21(Sd, J=a
3Hz), t, 78 (2HSd, J=6.8Hz)
, 6.83 (2H, d, , T=6.8Hz), 7.
70 (IH, t, J=7.8Hz), C21 (IH,
dS, T=&3Hz), C40(IH,d, ,r
=6.4Hz), C44(1H,d(1%, T=i,
C17, 3Hz), C64 (I H, (1, J=6.4
H2), y, 34 (1a, s) Example 56 Reference Examples 12 to 14 except that N-(2-methoxyphenyl)bibewodine was used in place of N-phenylpiperazine,
The obtained 9N-(1-
Cp-(5-isoquinolinesulfonyloxy)benzyl)-2-[4-(2-methoxypheni)V)bibewodinyl]ethyl)-N-methy)v-5-isoquinolinesulfonylamide 800 Iqf, alkali as in Example 36 N-[1-(p-hydroxybenzyl)-2-(4-(2-methoxyphenyl)
-hibewodinyl]ethyl)-N-methytV-5-isoquinolinesulfonic acid amide 504η was obtained.

Engineering R (KBr) cm-': 1610.1590.1
500.1320.1230.1130'H-NMR (CDC13, δppm): 2.5 (
1) (, aal, r=13.8.10.0Hz), 2.
55-2.8 (2H, m), 2.9-3.0 (IH
, m), 2.7 (4u, m), 1n (4H, m), 505 (3H, El), 3[6 (3H, s), 4.0 (IH
, m), 6.23 (2H1d, J=a3I(Z), 6
．． 57 (2H, a, , r=&3H2), 6.8-7.
1 (4Hlm), 7.6 (IH, t, J=aOH
2), C14 (1H, a, J=a1Hz), C16 (
IH,d, ,T=7,9 Hz), C35(IH
, drl, , T=7.4.1.0Hz), 9.30(
IH, θ) Example 57 1-[2-amino-3-(p
−? : )'Roxipheni/V) 7"ropil]-4
- Phenylpibeodine and 1-naphthalenesulfonyl chloride are reacted according to Example 64, and the product is further treated with methyl iodide in the same manner as in Example 35 to give a colorless and sterile N-methy)V-N-( 1-(p-(α-naphthalenesulfonyloxy)bencyl)-2-(4-phenylpiperazinylmide) was obtained.

IH-NMFj (CDCl2, δppm): 2.2
6 (IH, dd,, T = 12, 56, 6.85Hz),
2.42 (4H, m), 2.48 (IH.

d(lSJ=f 2.5 6, 6.8 5Hz), 2
．． 68 (I H, aa, J=14, 85, 6.
asHz), 2.84 (I H, aa, , T=
1 4.8 5, &8 5Hz), 2.85 (3H,
s), 2.92 (4H, m), 4, 1 2 (I H
, quintet , , T=6.8 5f(z)
, &56(2H, d, , T=a01(Z), b.7
8 ~ 6.9 2 (s H, m), 7.26 (
2H,t,,T=aOHz),7. 4 2 (2H
, t, , r=a0 1(z), 7, 46 ~ 7.5
8 (21 (Sm), 7.68 (IH, dt, , r=
aO, toHr), 7.7 7・~7.9 0 (2
H, m), 7.90 ~ a07 (3H, m), a12
(IH, dSJ=a57Hz), 8.17(1)1.

dd,, r=a57, tOHz), a45(IH, m)
, aa4(1) (, dl, r = 9.14 Hz) Example 58 The anonymous body obtained in Example 57 was alkaline hydrolyzed in the same manner as in Example 36 to obtain colorless power ((convex N-(1 -(p-hydroxybendi)v)-2-(4-phenylpiperazinyl)methyiv)-N-methyl-α-naphthalenesulfonic acid amide was obtained.

Engineering R (KBr) cm-1: 1595, 1315, 1
310, 1225, 1150, 1120 IH-NMR (CDCl2, δppm): 2.3
7 (IH, dd, , T=13, 70, 6.asnz)
, 2.4 7 (4H, +n), 2.55 (LH.

dd, , T=1 &70, 6.85Hz), 2.7
2 (I H, aa, :r=i4.28, 6.8
5Hz), 2.8 5 (I H, ad, , T=
1 4.2 8, 6, 8 5Hz), 2.89 (3H,
s), 2.9 7 (4H, m), 4, 27 (IH
,'quintet, ,T:6.85Hz),5.
10 (IH, br), 6.57 (2H1a, , T=7
, 9 9Hz), 6.78~ta9 (3H%m), &
L1(2)1,a,,T=7.99Hz),7,25(
2H, t, J = 7.99Hz), S43 (IHSt, J
==7,42Hz), 7.50 ~7.63(2HSm
), y. a6 (1H.

dd,, T=7.99, tOHz), 7.98(IH,
(1, , T=7.42Hz), a22 (1a%aa
1. T=7.42, toaz), 8.56(1H,
aa, J=7.9 q, t O H Z ) Reference example 1
5 1-((2-Amino-3-(p-hydroquine)phenyl)proyl)-4-penzyloxylponylbibefudin Manufactured in the same manner as Reference Example 11 1-(N-t-butoxycarbonyltyrosyl )-4-(penzyloxybenzene)
V) Pibewodine 1.41F with methiacetic anhydride/L' 5
．． 6-, 4 mol hydrogen chloride dissolved in ethyl acetate Q11.254 was added dropwise over 2 minutes while stirring under water cooling, and the mixture was stirred at room temperature for 2 hours. After the reaction, the bath was distilled off under reduced pressure, and extracted with a mixed solvent of chloroform-methanol/L/(9:1) 30 and 20. After washing with saturated saline, drying over anhydrous magnesium sulfate, and filtration, the solvent was distilled off under reduced pressure. ) to obtain colorless and sterile target product 700q.

'H-NMR (CDCl2, δppm): 2
．． 2 ~ 2.8 (8H, m), i19 (IH,
m), 3.50 (7) (, brs), 5.13 (2H.

θ), 6.7 1 (2H, d, J=a5Hz
), y. o2(2H, a.

y=asuz), 7.35 (5H, s) True, Scary Example 59 Honyloxy)bencyl]ethinov)-5.-isoquinolinesulfonic acid amide 21 ((680~) obtained in Reference Example 15 was dissolved in 18 ml of anhydrous tetrahydrofuran, 5-isoquinolinesulfonyl chloride 2 was added, and the mixture was cooled with water and stirred. After adding 3.20-ml of triethylamine dropwise over 1 minute, the mixture was stirred at room temperature for 2 hours and 30 minutes.The reaction solution was diluted with 50-chloroform, washed with water, and the washings were extracted with 20 ml of chloroform. The liquids were combined, washed with saturated saline, dried over magnesium sulfate, filtered, and the molten soot was distilled off under reduced pressure. The residue was applied to a silica gel column and purified with chloroform-Mekno 1lz (100:1). A pale yellow, island-like target product 987 was obtained.

Engineering R(KBr)tM': 1700.1620.15
00.1370.1250.1130'H-NMR (C!D(, t3, δppm): 1.
8-2.2 (6H, m), 2.7-3.4 (7H, m
), 5.05 (2H, El), 5.36 (IH.

bre), 6.67 (2H,a, J=EL4Hz
), 6.89 (2H.

d, J=a4Hz), 7.2~7.4 (5H1m)
, 7.62 (1H1d, J=7.7Hz), 7.69
(IH, d, J=7.7Hz), a2~a5 (5H
1brs ), &52 (I H, d, J=6.2H
z), a68 (IHld, J=6.2Hz), a8
1 (IH, d, , T=5.9H2), 9.34 (I
HSs), 9.41 (IH, 8) Example 6O N-(2-(4-penzyloxycargenyl biverage A)
/L/)-1-cp-c5-isoquinolinesulfonyloxy)benzylcoethyl)-N-methy/l/-5-isoquinolinesulfonamide 8 obtained in Example 59
52■ was dissolved in 2j((water dimethylformamide a5-), 59 Iq of 60% sodium hydride was added under stirring under water cooling, and 1151 tl of methyl iodide was further added, and the mixture was stirred under water cooling for 2 hours. After adding 30 ml of ice water, extract with 20.20 ml of methylene acetate,
The extracts were combined, washed with saturated brine, dried over magnesium sulfate, heated to P temperature, and then the solvent was distilled off under reduced pressure. ) to obtain pale yellow, island-like target product 679.
I got ~.

Engineering R (KBr) Iyn': 1700.1620.1
500.1370°1240.1130'H-NMR (cDcz3, δppm): 2.23
(5H,brs), 2.3-2.9 (3H,m),
2.83 (3H, s), 3.25 (4H.

brs), 4. o9 (1a, m), s, 11 (2H
,8),6.60(2H%d, ,r=a71(Z),
6.86 (2H1a, J=a7Hz), 7.34 (5
H, brs), 7.5-7.7 (2H, m), al2
(IH, d, J=a2Hz), al ~ a3 (4HS
m), a56 (2H, m), a84 (I H, d,,
J=6. I H2), 9.2-9 (I H.

8), 9.41 (IH, θ) Example 61 N-(2-((4-benzenesulfony)v)piperazinyl)-1-Cp-(5-isoquinolinesulfonyloxy)benzylcoethyl)-N- Methyl/l/-5-isoquinolinesulfonic acid amide 2j1 obtained in Example 60 (3 rnl of 30 hydrogen bromide/acetic acid f8 solution was added to the 480η of the convex body, and after stirring at room temperature for 1 hour and 20 minutes, ether/l/- 1150
- was added and stirred, the precipitate was collected, and after washing with ether,
After drying under reduced pressure, N-[1-[p-(5
-isoquinolinesulfonyloxy)benzylco-2-piperazinyl-ethyl 1-N-methyl 1v-s-isoquinolinesulfonic acid amide hydrobromide salt 567 ml was obtained.

' H-NMR (DMSO-i, + D20, δpp
m): 506 (3H, s), 3.46 (32H, br
s), 4.24 (1a, bre), 6.08 (2H
Sd, J=8.5Hz), &74 (2H,d,
J=8.5H2), 7.9! + (2H, m), a25
(I H, d, J=6.7Hz), a35 (11(
, d, , T=7.3Hz'), as ~&s (51
(.

m), 9.05 (IH, d1J=6.4Hz),
9.86 (2H.

brs) 550~ of the crystals obtained above were suspended in anhydrous tetrahydrofuran 10-, and while stirring with water cooling, benzenesulfonyl chloride 8471 and hydrethylamine 7671 tl were added thereto, followed by stirring at room temperature for 2 hours and 20 minutes. After adding 3° of chloroform and 20° of water to the reaction solution and separating the layers, the aqueous layer was extracted with 20 I/11 chloroform, the chloroform layers were combined, washed with saturated brine, dried over magnesium sulfate, filtered, and reduced under reduced pressure. The residue obtained by distilling off the solvent was applied to a silica gel column, and chloroform-methanol/l/(100:1
) to obtain the target product 331q in the form of pale yellow islands.

IR(KBr)m-': 1620.1500.14
40.1550° 170' H-NMR (CDC!t3, δppm): 2.
+ ~2.5 (6T (, m), 2.5--2.8 (
6H, m ), 2.78 (31 (113), 4.0 s
, (IH.

m), 6.60 (2H, d, , T=a7Hz), 6.
F33 (2H, d.

J=a7Hz), 7.37(1H,t, ,T=7.8
Hz), 7.5. ~Za (6H, m), 7.98 (IH
, a, , T=7.9H2), a1~as(4u, m)
, a4q (I H, a, :r=6.1Hr+),
a55 (I H, d, , T=6.I Hz), &8
4 (I HS (1, J-6, 1Hz), 9.17 (I
H,s), 9.42 (1H1B) Example 62 N-(2-C(4-benzenesulfony)v)pibefujini~)-1-(p-hydroxybenzyl)-ethyl)-
N-methy/V-5-isoquinoline sulfonic acid amide 1 g of the anhydrous substance 2211I obtained in Example 61 was dissolved in methanol 2
．． 69ml of tetrahydrofuran, dissolved in a mixture of 0.66ml of tetrahydrofuran, added with 2N caustic solution α35-, refluxed for 3 hours and 30 minutes, and then added with 20% of chloroform)vum30+d and 10% ammonium chloride aqueous solution. Separate the layers, extract the aqueous layer with 20-chloroform, combine the chloroform layers, and
Wash with 0 Japanese saline solution, dry with magnesium sulfate, filter,
The residue obtained by distilling off the solvent under reduced pressure was coated with silica gel and mixed with taloloform-methanol/L/(100:1).
It was purified with y(((rapidly heated island-like target substance 146q).

Engineering R (KBr) crn-': 1620.1510.
1440.1320, 160 IH-NMR (cDcz3, δppm): 2.3~
2.5 (2H, m), 2.60 (4H, bre), 2.
6-2.8 (2H, m), 2.95 (3H 1 day),
3.01 (4HSbrs), 3.92 (II(, br
s), 6.21 (2H, dSJ=a2Hz), 6.
51 (2H, dSJ=a2Hz), 7.4-7.8
(6H, m), ao3 (IH, d,, T=6, IHz)
, ao 9 (11(,d, ,T=8.2H2),a
24 (IH.

dcISJ=1.2.7.5 HZ), a40 (1
H, d, , T=5.8Hz), a68 (1H1brs
), 9.23 (IH, brs) Reference Example 16 0-benzyl-N-benzyloxycarbonyltyrosinol 0-benzi/L/-N-benzyloxyca)V i-nyltyrosine methyl ester)V 27.25 ? was dissolved in a mixed solvent of 185TRt of ethanol and 122% of tetrahydrofuran, and hydrogenated with 5.82y of lithium chloride while cooling with water. 5.2y of IJ boron was added, and the mixture was stirred at room temperature for 18 hours. After adding 500 g of Japanese saline solution to the reaction solution, it was extracted twice with 300 mt of chloroform, dried over magnesium sulfate, and subjected to l-layer separation under reduced pressure to obtain 25.4 g of the desired product as colored crystals.

'H-NMR (CDO43, δppm): 2.7
9 (2H, d, J=7, 4 HZ), 3.51~3
．． 79 (2) ISm),! L89 (IH, m), 4.9
3 (IH, br), 5.04 (2f (, S), 5.08
(21(.

B), 6.90 (2HSd, , T=a6 Hz)
,7. + 1 (2'i(, d.

, T=IIH*), 7.26-7.46 (5H%m) Reference Example 17 1-(2-benzyloxycarbonylamino-3-(p
-Penzylleoquinphenyl)Furohi/shi]-4-(
t-Butquin force/L/Mnil) Piperazine Reference Example 16
Dissolve 5.62 of the crystals obtained in 70gK of carbon tetrachloride! n
Then, 4.52 g of triphenylphosphine was added, and the mixture was heated under reflux for 20 hours. Insoluble materials were removed, and the residue obtained by concentrating the filtrate under reduced pressure was applied to a silica gel column and purified with hexane-ethyl acetate/L/(6:1) to give 2-benzyloxy as colorless crystals. Carbonylamino-3-(p-benzyloxyphenyl)proyl chloride 4.965' was obtained.

IH-NMR (cnaz3, δppm): 2.
76-2.90 (2H.

m), 156-A30 (2H, m), 4.39 (IH,
m), 5.03 (2H, s), 5.05.5.13 (
Total 2 H, each S), 6.85.6.89
(Total 2 H, each d1 each J = axHz),
7.00.7.09 (Total 2H, each d, each J = a3Hz), 7.23-7.45 (5H, m) /) Dissolved in dimethylformamide 40- with piperazine 2.237, methioiodide A/1.8? and potassium carbonate 1.66? Add and heat at 120°C for 3 hours. After adding 100 fld Warawa water brine to this, hl+ was added twice with chloroform/+0rnt, and <I7. The residue obtained by drying and concentrating under reduced pressure was applied to a silica gel column and purified with hexane-ethyl acetate (2:1) to obtain the desired product in the form of colorless islands.
I got it.

'H-NMR (CDC13, δppm): 1.4
5 (9H1s), 2.22-2.49 (6H,, m
), 2.82(2)! Sm), l 6 (4H, m),
594 (IH, m), 4.83 (IH, br), ao3
(2H1θ), 5.09 (2H, s), 6.88 (2H
1dSJ=a3Hz), 7.06(2H,d, ,T
=a3Hz), 7.30-7.45 (5H, m) Example 63 N-(2-[4-(t-ptoxycarboni)v)piperazinyl]-1-(p-(5-isoquinolinesulfonyloxy)benzyl ] Ethyl/Sh)-5-isoquinolinesulfonic acid amide Reference Example 17 yielded 21 ((1.62 of the convex body was converted into methanol/
Dissolved in l/25-5 palladium/carbon 1.0
After stirring in a hydrogen atmosphere for 20 hours, the insoluble matter was removed in a furnace, and the P solution was concentrated under reduced pressure. Tetrahydrofuran 30- was added to dissolve the residue, and 5-isoquinolinesulfonyl chloride was added to this under water cooling. Hydrochloride (2.85') ethylamine (4 ml) was added and stirred in a room 11m for 3 hours.

After adding 100 TPLt of water to the reaction solution, it was extracted twice with 70% of chloroform, dried over magnesium sulfate, and condensed for 0 hours. :1) to obtain yellow 7j ((1.279 islands of the desired product).

IH-NMR (C!DO63, δpp+n): 1
．． 40 (9H, s), 175-2.18 (6H, m),
2.15-3.117 (6H, m), 3.27 (IH
, m), 5.35 (IH, br), /), 1117 (2
T(.

a, J=a3Hz), 6.90 (2H,d, ,T
=a3Hz), 7.6s (I Hlt, , T=7
．． 8H2), 7.69 (IH, tS: r = 7, 81 (Z
), &21 (1) IS(1,, T=a3Hz),
8.27-a32 (2H, m), 8.37-JL41
('2F11m), &53(IL al, T=6<+H
z), a69 (I H%(1,, T=6.?I(Z
), aa 2 (I H, d, J=6.4Hz),
9.36 (IH, s), 9.43 (IH, s) Example 64 The non-weighted 940 μ obtained in Example 63 was mixed with tetrahydrofuran 7,5 rat and dimethylphoremamide 7,5-
Dissolved in a mixed solvent of 0.11 ml of 60% sodium hydride and 67% of methyl iodide under water cooling,
Press at room temperature for 1 hour. Add saturated fi water to the reaction solution 50-
The extract was washed with saturated brine, dried over magnesium sulfate, concentrated under reduced pressure, and the resulting residue was applied to a silica gel column and chloroform-methanol. 1v (60:1) to give a yellow island-like N-(2-(4-(t-ptoxycarboni)v)
)piperazinyl)-Cp-(5-isoquinolinesulfonyloxy)benzyl]ethyl/thi)-N-methy/l/-5
-Isoquinoline sulfonic acid amide 725~ was obtained.

IH-NIAR (cDcz3, δppm): 1.4
4 (9H, e), 2.21 (5H1m), 2.40
(I Hlaa, :r=b, 9.12, 6H2), 2
．． 15 (I H, daS, J=7.4.14.3 [(
Z), 2,83 (I H, dd, J-6, 9, 14,
3HI2), z, a4(su;s), 3.17(9H1
m), 4.12 (IH, m), 6.60 (2I (, d1
J=a8[(Z), 6.86(2H,d, , T=a8
Hz), 7.58 (I H%t, , T=7.8Hz
), 7.63 (I H,t, J=7.8 Hz),
al3 (IH, d, J=a3H2), a21-a30
(4T(.

m), as 6 (1)1. tl, J=6.9Hz
), &57(1)! , d.

J = 5.9Hz), aa 4 (I HSd, J =
5.91Hz), 9.29(IH,s), 9.42(
IH, Japan) Example 65 To Qtl; convex body 720IIq obtained in Example 64, a solution of 4N hydrogen chloride in vinegar vr-chill was added, and after stirring at room temperature for 1 hour, it was concentrated under reduced pressure and Acid soda saturated aqueous solution 3
0-, then taloloform-isopropanol (
5:1) mixture 1'6 K 20- twice. The extract was dried over magnesium sulfate and dipped under reduced pressure to give a yellow island-like N-(1-(p-(5-isoquinolinesulfonylleoquine)benzyl]ethyl/V-2-piperazinyl)-N- Methyl-5-isoquinolinesulfonic acid amide 6201F!9 was obtained.

IH-NMR (CDC13, δppm): 218
~2.28(5)T.

m), 2.37 (1H, dd, , r=7.5.12
．． 7Hz), 2.65 (4H, m), 2.66 (I
HSdd, J=7. ．． 5.14.8H2), 2.83
(31 (1s), 2.86 (I H, aa, J=5
．． 4.14.8Hz), 4.13 (IHSm), b, 6
1 (2H, a, :r= a, 8Hz), 6.89 (2
H1 (1% J = aaHz), 7.59 (IH.

t, J=7.8Hz), 7.63(IH, t, J=
7.8[(Z),[3,12(IH,IcLmiJ=aS
Hz), a23-a35 (4E(.

m), as b (I Hla, , T=5.9 H2
), &5B (IH, d.

, T=6.4Hz), aa 3 (I H%d, J=
6.9Hz), 929 (IH113), 9.42 (
I HlS) Example 66 Anonymous 620w1 obtained in Example 65 was dissolved in methylene chloride 10
- Dissolved in benzyl chloroform under water cooling - )0
．． 29+aj,) Re-chill-a-min 0
, 4- and stirred under ice-cooling for 2 hours.
After adding 〇-, it was extracted twice with 20 rag 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/L/(60:1) to give Example 60.
A pale yellow anonymous substance 660η having the same 'H-NMR spectrum was obtained.

Example 67 650 Ing of the anhydrous substance obtained in Example 66 was converted into methanol, 'l
/ 6 ml, added 1N aqueous sodium hydroxide solution 2-, heated under reflux for 2 hours, dried 30rnt of saturated brine over magnesium sulfate, concentrated under reduced pressure, and applied the resulting residue to a silica gel column. Chloroform-methanol Purification yields yellow sterile N-(2-(4-benzyloxyca!reponylbiberagini,v)-1-(p-hydroxybenzyl)ethyl)-N-methyl-5-isoquinolinesulfonic acid Amide 336■ was obtained.

Engineering R (KBr)cnt-': 169! l, 151
0, 1425, 1320, 1235, 1120'H-NMR (0.OOt,, δp pan )
: 2.3 9 ~2.5 5 (ro) (, m)
, 2, 6 4 (I H, dd, J=6.4, 1
2.7Hz), 2.87 (IH.

dd, J=4.4, tt6Hz), 2.97 (3H,
S), 3L44 (4H, m), 4.03 (11, m),
5.13 (2H, s), 6, 28 (2H, dSJ=a
3Hz), 6.6 2 (2H, dSJ=8, 3H
z ), 7.36 (sH, s), 739 (1H1d.1
, J=73, 7. 8)! Z ), ao 9 (
+ HSa, J:=5.9Hz), a13(I
H, dS: J=7.8Hz), a26(IH, d
, , T=7.314z), a4 B (I H,
d, ff = 5.9Hz), 9.27 (IH, s) Example 68 In fact, the protective group of Bibewodin was removed from the anionic substance obtained in Kokuma 63 according to Example 65, and the rest was prepared according to Examples 66 and 67. N-(2.-(4-penzyloxycarbonylpiverazinyl)-1-(p-hydroxybenzyl)ethyl)-5-isoquinolinesulfonic acid amide was obtained in the same manner as above.

IR (KBr)crn-': 1670, 15
10. 1425, 1320.

1230, 1150, 1125, 993IH-NMR
(CT)O/! ．． ,, δppm): 2.07 to 2.
23 (4H.

m), 2.3 0 (I HSddSJ=6.3, 1
A2Hz), 2.39 (I H, aa, J=7.
8, 13.2Hz), 2.62 (I H, dd
.

J=6.8, 14.2Hz), 2.76(1H,
aa, J=6.4, +4. + [(Z), 3.110
~3.38 (5H, m), 5. +19 (2H.

day), 6.4 1 (2 i(, d, J=8 i
Hz), 6. 6 9 (2 1(, rj.

, T=a13Hz), z33(5H1S), 7.68
(jI(Sdd.

J=7.3, a3Hz), a2 1 (I H, d
, J=a3Hz), a35(IH, d, J:5
．． 9Hz), a40(1)(1dd, , T=1.0,
7. 3 H Z ), &61 ( I H, d,
J = 5.9 Hz), 9, 34 (IH, θ) real/l (i Example 69 N- (1-(p-hydroquinbenzyl)-2-(4
-(3-phenylprohy/L/)hiverazinyl]ethyl)-5-inquinolinsulfonic acid amide was skewered.

Engineering R (KBr)6n': 1610, 1510,
1445, 1320, 1150, 1150, 995' H-NMR (CDCl2, δppm): 2
．． 00 ~ 2.20 (4H1m), 2.2 6 (I
HSaa, J=5.9, 12.7Hz), 2.36
(IH, (1(1, , T=7.8, 12.7Hz
), 2.4 6 - 2.6 0 (2H, m), 2.
6 2 ~ 2.7 7 (2H, m), 2.8
5-3. OD (2H, m), Aoo ~14
1 (5H, m), 5.24 (IHlbr), 6,
4s (2H, d, J=43Hz), 6.7
1 (2H, d, J=&3Hz), 7. 1
5 ~ 7.3 4 (5H, m), z69 (1H1
dd1J=73, a3Hz), a20(11(Sd,
, T=7.8Hz), a34 (I H, aS.
T=5.9Hz), a4o(1H, aa, :r=
1, 0, 7.3Hz), a63 (IH, br), 9.
12 (IH.

br) ￥ 70 yen A yellow sterile N-(1-(p-hydroxybenzyl)-2
-(4-phenylaminocarbonylhiberazini)V)ethyl]-5-isogynoline sulfonic acid amide was obtained.

'H-NMR (CDC43+ CD30D, δppm
): 2.37 (IH, dd, J=a13.14.
2Hz), 2.65 (I H, da, , T=5.4
．． 13.7Hz), 2.73~3.20 (4H, m
), 540-3.95 (7H, m), 6.12 (2H
, d, J=a3H2), 6.50(2H, dSJ=a
3Hz), 7.05 (IHSm), 7.25-7j8 (
4H, m), 7.67 (IH, aa, :r=v, 8
, a3Hz ), a21 (I HSd, , r=7.
8Hz), axl (1H1 (1%J:6.8H2),
a53 (IH, 'br), 9.2 s (1H, br) Example 71 The same procedure as in Example 6B was carried out except that varynipenzyl isocyanate instead of benzyl lyloroformate was reacted to give a yellow color; l! 11; Island-like N-(2-(4-benzylaminocarboxypiperazinyl)1-(p-hydroquinbenzyl)ethyl)-5-isoquinolinesulfonic acid amide was obtained.

IH-NMR (CD043-C!D30D, δpp
m): 2.40-2.71 (2H1m), 2.76
~&23 (4H, m), 3.4°O ~ &80 (7H%m
), 4.39 (2H,s), 6.08 (2H,tll
, T=a3Hz), 6.46 (2H, a%y=asH
z), 7.20-7.38 (5H, m), 7.63 (
IH%t, J near, 8H2), a17(1H, (1,,
r==a3Hz), a29 (2H1d%J=6.9
Hz), a52 (1H, br), 9. ';1(IH,
br) Seed Blood Example 72 The yellow pHHf obtained in Example 67 and bacterial cells 2001119 were dissolved in 5-chloroform and mixed with methanol/L/1Tn.
Then, an ether solution of diazomethane was added under ice-cooling, and the mixture was stirred for 1 hour and 60 minutes. The reaction mixture was concentrated as it was, and the resulting residue was filtered with silica gel.
Closed with chloroform-methanol (80:1 to 50:1) to give N-(2-(4-penzyloxytriponylbiperazine/l/)-1-(p-methoxybenzi)v
) Ethyl)-N-methy/I/-5-isoquinoline sulfonic acid amide 103η was obtained.

Engineering R(KBr)m': 1692.1508.14
20.1320.1255.1120'H-NMR (ODC4,, δppm): 2j
2-2.45 (5H.

m), 2.55-2.65 (2H, m), 2.78
~2.90 (I Hlm ), 2.92 (3H, 8)
, 3.57 (4H, m), 3.73 (5H 1 day), 4.
16 (1HSm), 5.11 (2H,s), 6.50
(2H, a.

y==asuz), 6.82 (2H, dS, T=a3
Hz), 7.55 (5H, s), 7.55 (IH, t
,,T=7.8Hz),ao? (1H, d, J=a3H
z), als(1u, a,, T=6.4H2), a22
(1)1. d,, T=7.5H2), ass(1H, a
, :r=6.4H2), 9.24(IH,s) Example 73 The product obtained in Example 68 was operated in the same manner as in Example 72 to obtain Luponyl biverazine/V)-1-(p-methoxybenzi)ethyl-5-isoquinoline sulfonic acid amide was obtained.

"H-NMR (CDO63, δppm): 1.97
~2.17 (4H.

m), 2.19 (11(, dd, , T=4.4, I
A7Hz), 2.28 (I H, ad, , T=6.8
．． 13.7 HIJ), 2.70 (IHlda.

, :T=6.8.14.2](z), 2. [12(1)
i, dtll, r=5.4.14.2Hz), 1.5
(2HSm), 315 (2)1. m),! +, 5
4' (IHSm), 3.74 (3H10), s, o7 (
2H1s), 5.3^(IH,br), 6.59(2H
,d,,r=a8Hz),6.85(2H,d,J=a
3Hz), 7.27-7.37 (5H, m), 7.68
(IHlaa, J=7.3.7.81(Z), alB(
IH, d.

J=a3Hz), a39(IH, d%, r=5.9H2
), a42 (I H, dd, J=1.0, 7. a H
Z), 8.67 (IH, a, , T=5.9Hz
), 9.33 (IH, θ) Example 74 N-(2-(4-penzoylpiverazini)V)-1-C
p-(5-isoquinolinesulfonyloxy)benzylcoethyl)-N-methy/V-5-isoquinolinesulfonic acid amide Crystals 764η of the intermediate of Example 61 were suspended in tetrahydrofuran 7-, and benzoyl chloride 1351 was suspended under water cooling.
After 1.5 minutes, 1.1-triethylamine was added and stirred for 1 hour. Chloroform and water were added to the reaction solution, which was then extracted three times with 50 ml of chloroform, washed with saturated brine, dried over magnesium sulfate, concentrated under reduced pressure, and dried under reduced pressure to obtain a pale yellow residue with 0. B2f was coated with silica gel and eluted with chloroform-methano/L/(100:1) to obtain colorless 2j1 (198 cm of island-like target product).

Engineering R (KBr) cm-1: 1620.1370.11
301)! -NMR (cDcz3, δppm): 2
．． 2-2.8 (10H, m), 2.84 (3H, s)
, A1-3.7 (4) 11m), 4.14 (IH.

m), 1. ．． 61 (2H, d, J=a6Hz),
6.85 (2HSa.

'J=a6Hz), 7.5~a6 (14,HSm)
, a84 (IH.

d, J=5.8H2), 9.30(IH,s), 9.
43(IH,El) Example 75 N-(2-(4-penzoylpiverazini)v) -1-
(p-Hydroxybendi/I/)ethyl)-N-methyl-5-isoquinoline sulfonic acid amide Anonymous substance obtained from Shinjima 74 349 ■(methano-)V 4 ml, tetrahydrofuran 17! , 2N caustic soda 0.5 ++
t7! was added, and after refluxing for 2 hours, chloroform, water, and salt were added, and chloroform 507! Extracted three times. The extract was washed with saturated saline, dried over magnesium sulfate, and evaporated under reduced pressure to obtain a yellow oil, Inumo 0.25 S', which was applied to a silica gel column and chloroform-methanol/L/(50
: From the elution area in 1)) IQ color rapidly heating island-like object 145η
I got it.

Engineering R (KBr) cm-': 1610.1440.
11201H-NMR (ODC13, δppm):
2.6-2.9 (8H,,m), 2.99 (3H
, s), 12-3.9 (4H, m), 4.00 (IH
.

m), 6.25 (2H1d, , T=a5I(Z), 6
．． 56 (2H, d.

, T=a5H2), 7.41(5)(, Eri, 7.59
(I H, t, y=7, q HZ ), &08 (
I H, dl, r=6.1 H2), 8y15(II(
.

d,, r=7.9Hz), a25 (IH1dSJ=7.
9Hz), a46 (1nSa, J=a1Hz), y,
29 (1H, s) Example 76 Pencil is added to the intermediate crystal 470■ of Example 6. Pencil is used instead of chloride! Lefonyl chloride 113IIg
A colorless, island-like N-(2-(4-pendylsulfonylpibewodini/L/)-1-(p-hydroxybenzibenzi) was prepared in the same manner as in Example 74 and then in Example 75, except that /
l/)ethyl]-N-methy/L/L5-isoquinoline pphonic acid amide 116q was obtained.

Engineering R (KBr) an-': 1610.1320.
1150'H-NMR (cDcz3, δppm):
2.5-2.9 (8H, m), 2.94 (3H, 13
), 3.0 to 3.2 (4H, m), 4. o3(1H.

m), 4.20 (2H, 8), 6.26 (2H1d,
I=8.2Hz), 6.56 (2I(Sd, J
=a2Hz), 7.40 (5H, 8), 7.60 (I
H, t, J=7.9Hz), 8.07(IHSa
,, T=6.4Hz), al 5 (I H, d, J
=7.9Hz), a22(IH,a,,r=7,9
HZ), 8.46 (I H,d, J=6.4Hz
), 9.29 (IH.

8) Example 77 5-isoquinolinesulfonic acid chloride was added to the intermediate crystalline 382 cape of Example 61 in place of V chloride.
Colorless island-like N-(1-(
p-HydroxybendiA/)-2-(4-(5-isoquinolinesulfony/I/)pibewodinyl]ethylA/)-N
-Methyl-5-isoquinolinesulfonic acid amide 172■
was corrected.

Engineering R (KBr) cln-': 1610.1320.
1150'H-NMR (aDC2,, δppm):
2.3-2.8 (8H, m), 2.90 (3H, s),
3.0~s, 2 (4H, m), 3.95 (1H1m)
, 6.29 (2H, d, J=a6Hz), 6.5
5 (2H, d.

, y==a6Hz), 7.5(1(IH,t,:f=7
．． 9Hz), 775 (I H,t, J=7.9Hz
), an-al(2H%m), a17(1H, aSJ=
7.9Hz), a26 (I H, d, J = 7.9
Hz), a3-a5 (2H1m), aS 3 (I H
, (1, J=6.I Hz), a7o (1H, aS,
T-41H2), 9.19 (IHSS), 9.59 (I
H, 8) Example 78 5-isoquinoline sulfonyl chloride, prefecture acid salt noshirowa υ
The procedure of Example 59 and then Example 60 was repeated except that α-naphthalenesulfonyl chloride was reacted with α-naphthalenesulfonyl chloride to obtain a colorless, island-like N-(2-(4-benzyloxycarboxylate) 2μpiberazini/l'). -t -1'' p -(a-naphthalenesulfonyloxy)bendiA/)ethyl)-N-
MeflV-〇-naphthalenesulfonic acid amide was obtained.

Engineering R (KBr) cy++-”: 1700.1365
．． 1.130.860°65 IH-NMR (CjDO13, δppm): 2.05
~2.25 (5H.

m), 2.41 (I HSda, , T=13.13
．． 6.85Hz), 2.55-2.8 (2H, m)
, 2.84 (3H, s), 3.05-3.25 (4H,
m), 4.05 (I H, quintet, 'J
=6.85Hz), 5.11 (2H,s), 6.57
(2H, a1J=8.57H2), 6.82 (2H,
d%, r=a57Hz), 7.25-7.60 (9H,
m), 7.60-a20 (8H, m), 8.42 (IH
.

m), a82 (IH, d, J near, 9.9Hz) 1
1i Example 79 The sterile body obtained in Example 78 was subjected to alkaline hydrolysis in the same manner as in Example 62 to obtain a colorless island-like N-(2-(4-benzi/
L/oxycarbonylbibewojini/I/)-1-(p-
Hydroxybendi/I/)ethyl]-N-methyl-α-
Naphthalenesulfonic acid amide was obtained.

Engineering R (KBr) cm': 1695.1670.
1310.1240, 120') (-NMR (CD063, δppm): 2
．． 15-2.4 (5H, m), 2.48 (IH
, (1 (1, J=12.56.7.42H2), 2.6
~z, as (2H, m), 2.87 (3H, s), 51
5-S, 35 (4H, ro), 4.20 (I H, q
uintet, , 7=6.85Hz), 5.10(
2H, 8), 5.15 (IH, br), 6.58 (2
HSd.

, r=7.991(z), 6.89 (21(1d,,
T=7.99H2), 7.33(5H,s), 7.44
(IH, tS, r=7.42Hz), 7. t7~7.6
5 (2HSm), 7.8-7.93 (1) 11m), 7
．． 99(1)1゜d, J=7.99Hz), al
5 (I H, dal, r=6.85.1.0Hz),
a45~&6 (I H%m) Example 8O N-(1-(p-(s-isoquinolinesulfonyloxy)benzi)V-2('-phenylhomopiperazinyl)ethyl)-5-isoquinolinesulfonamide 1-[2-amino-3-(p-hydroxypheni)V)
1-[ instead of propyl-4-phenylpiperazine
The procedure was repeated in the same manner as in Example 34 except that 2-amino-3-(p-hydroxypheni)V)propy/L/)-4-phenylhomopiperazine was used to obtain a yellow lice island-shaped target product. Ta.

IR(KBr)cy-': 1620.1600.1
365.1135'H-NMR (CDCl2.δppm
): 2.10-2.36 (7H.

m), 2.6s (I Hlaa, , r=aa, 1i
7Hz), 2.76 (I H, dd, J=4.9.1
3.7H2), 2.99-A29 (6H.

m), 6.53 (2H, d, , T==a3Hz)
, 6.60 (2H, (1°J=aaaz), 6.64
(IH,t, J=7.3Hz), &80(2)(,a
, J=aaHz), 7.17 (IL t, , T
=a81(Z), 7.62 (I H, tl, T==7
．． 8Hz), 7.66(II(, t, J=7, 8H
Z), &18 (I H, dSJ=a3Hz), a
26 (2H.

d,, T=7.3H2), &37~a38(2H1m)
, a53 (IH, d, , T=5.9Hz), &67 (
I H, d%, T = 6.4 Hz), &82 (I
H,d, ,T=5.9Hz), 9.53(IH,s
), q, 42 (I H, θ) Example 81 The sterile body obtained in Example 80 was treated with methyl iodide according to Example 35 to obtain N-(1-(p-(5- isoquinolinesulfonyloxy)benzyl)-2-(4-
Phenylhomopiperazine A/)ethyl)-N-methy/I
/-5-isoquinolinesulfonic acid amide was obtained.

IR(KBr)tM-': 1620.1600.15
00.1365, 135'H-NMR (CDCjt3, δppm): 1.
70 (2H, m), 2.57 (I H, dd, J=
48.11.7H2), 2.40-2.65 (6H, m
), 2.76 (I H, aa%, T=4.9.157
) (Z), 2.84 (3H, s), s, 2s ~x42
(aH, m), 3.98 (1H, m), 6.51-6.
65 (5H, m), tl7 (2HSa, :r=asu
z), 7.16(21(,t, J=7.8H2), 7
．． s 4 (IH, d(1,, T=7.3, a3Hz
), 7.59 (IH, t, J=7.13Hz), aO
a (I H, a, J=7.8Hz), &18~a
26 (an, m), a55 (IH, 6SJ=5.9H2
), a55 (IH, dd, J=1.0.6.3Hz)
, a84 (I H, d, , T=6.3Hz), 9.
26 (IH, s), 9.41 (IH, d, , T=1
．． 0H2) The following two compounds were obtained by alkali hydrolyzing the sterile bodies obtained in Examples 80 and 81 according to Example 56.

Example 82 N-(1-(P-hydroxybendi/V)-2-(
4-Phenylhomopiperazine)V)Ethyl]-5-isoquinolinesulfonic acid amide Value Color Crystalline Melting point: 170-178°C (decomposition) Engineering R(KBr)cTn': 1615.1600.
1505.1365, 1520.1205.1155.
1130'H-NMR (1:!DC43, δppm):
1.79 (2H, m), 2.44 (I HSaa,
y=ax, 13.7Hz), 2.50~2.72 (7
H.

m), s2. s (1HSm), x5o ~! L45 (4
H, m), 6.24 (2H%a, J=a3Hz)
, 6.51 (2H,a, J=a3Hz), 6.66
(2H, aSy=axHz), C68 (IH.

t, J=7.3 Hz), 7.23 (2H, aa
SJ=7.3.8. ．． 5H2), 7.64 (I Hl
t, J near, 8Hz), C19 (1a1a1.T=
7.8Hz), C27 (+HSaSJ=6.+Hz),
C34 (IH.

dd, J=1.0.7.3 HZ), C55(I
H, dS, T = 6.4 Hz), 9.33 (IH, br
s) Example 83 N-[1-(p-hydroxybendi/l/)-2-
(4-phenylhomopiperazinyl)ethyl]-N-methyl-5-isoquinoline sulfonic acid amide Huangbai anomaly IR (KBr) crn': 1615.1600.1
500.1560.1320.1210.1150.1
125')(-NMR (CDC13, δppm):
1.93 (2H,, m), 2.40 (I H, aa,
: r=q, s, 14.2Hz), 2.56 (IH.

da, J=a8.12.7Hz), 2.70(2H, m
), 2.80-2.92 (4H, m), 5.00 (3H
Se), 3.46-i53 (4H, m), 3.85 (
IH, m), 6A 9 (21(, d, , T=8.!
IHz), 6.51 (2H, a, y=asHz),
6.65 (IH.

t, J=71H2), 6.69(2H1a,:r=a
3Hz), 7, 21 (2H, aa, J=7.3, a
8Hz), 7.58 (2H.

t, , T=7.3Hz), 8.07 (1H,a, ,
T=6.4 H2), al 2(IHld, J=&3H
z), C27 (1H, aa,, T=1.0.7.3H
Z ), a4s (I H, a, J=5.9H2),
9.27 (IHSs) Reference Example 18 Nt-Ptoxycarboni N-4-hydroxypiperidine 4-piperidone monohydrate hydrochloride z141 was dissolved in 50 ml of dimethylformamide. Diisopropylethylamine 25-,
Di-t-butyl dicarbonate 952 was added, and after stirring for 4 hours, water was added and saturated with sodium chloride, and then chloroform 300
hl+ was released twice in rnt. The extract was dried over magnesium sulfate and the solvent was distilled off under reduced pressure to obtain a residue 962.
was dissolved in 100 m/l of ethanol-zLz, and 1.8 jf of 1-lium borohydride was added to the solution under water-cooling and stirring, followed by stirring for 1 hour and 30 minutes, and then for 30 minutes at room temperature.

After adding saturated brine to the reaction solution, it was made alkaline with sodium bicarbonate, extracted twice with chloro7trum 600 td, and the hi extract was dried over magnesium formate, and the solvent was distilled off under reduced pressure to obtain a residue. into a silica gel column (=l L
, hexane-ethyl acetate (2:1) to obtain colorless and sterile target product a031.

'H-NMR (CDC43, δppm): 1.35
~1.6 (2H, m), 145 (9H, s), 1.75
~1.95 (2H, m), 3.0 s (2H, ad
(1, J=1 il 3.10.2B, 4.00H2)
, 3.75-3.95 (3f(Sm) Reference Example 19 4-(p-methylpenzyloxy)hyperidine Reference ('
The anonymous 2.02 obtained from 21118 was dissolved in dimethylformamide 20-, and 0.481 of 60 sodium hydride was added under stirring while cooling with water, the water bath was removed, and 30
Stir for 1 minute, and then add 1.54 g of p-methylbenzyl chloride.
F was added and stirred for 18 hours. The reaction solution was poured into ice, saturated with sodium chloride, evaporated twice with chloroform (150°C), dried over magnesium sulfate, the solvent was distilled off under reduced pressure, the residue was applied to a silica gel column, and hexane-acetic acid Purification by tV (5:1) gave N-t-P1-quincarboni)V-4-p-methylbenzyloxyhyheridine 1.275'. This was dissolved in ethyl acetate/l 15- and a 3N hydrogen chloride/ethyl acid solution 12- was added while entraining at room temperature, followed by stirring for 17 hours and the solvent was distilled off under reduced pressure.

The resulting residue was dissolved in water, made alkaline with sodium bicarbonate, saturated with common salt, and dissolved in chloroform 20
After bending twice at 0ml and drying with magnesium sulfate, the solvent was distilled off under reduced pressure to obtain Jlli color 2ha (convex object Q3).
QIRg was obtained.

'H-NMR (CDC63, δppm): 1.55
~1.8 (2H, m), 1.9 ~ 2.15 (2H, m
), 2.34 (3H,s), 2.81 (2H.

ddd, J=13.13.10.28.4.0OH2
), 3.17 (2H.

addSJ=11.42.7.42.4.0OHz),
3.56 (IH.

Septet line 1,7471Hz), 4.50 (2H, 8),
S, Ol (+H, brs), 7.14 (2HSd, J=
7.99Hz), 722(2H, (11J=7.99H
2) Reference Example 2O N-t-butoxycarbonyl-o-(2-methoxyethoxymethy)V) Tyrosine methyl ester N-t-7"
) Oxypower/L/M Nyltyrosine Methyl Esoste Add 60% sodium hydride under cooling stirring, remove the water bath, stir at room temperature for 30 minutes, then cool with water again and add methoxyethoxymethyl chloride 5, 4? f), and the mixture was stirred for 15 hours while gradually returning the temperature to room temperature. The reaction solution was poured into water, saturated with sodium chloride, and extracted twice with chloroform 800-. The extract was dried over magnesium sulfate, and after cooling, the solvent was distilled off under reduced pressure. The resulting residue was applied to a silica gel column and purified with hexane-ethyl acetate/L/(4:1) to give 2
((Color 2! 1 (convex object 1 3. 8 5 ? obtained.

+ 1(-NMR (CDC!t, , δppm):
1.46 (9H, e), 3, 02 (2) (, m),
3.37 (3H, θ), 3.5 ml (21(.

m), 3.71 (3H, 8), 17 5 - 3.8 5
(2H, m), 4, 54 (IH, m), 4.9
5 (IH, m), 5.24 (2H, E+), 6, 96 (
2HSa, , r=9.71Hz), 7.0 4 (
2H, a%: r = 9, 71Hz) Reference Example 21 2-(N-t-butoxycarbonylamino)-1-chloro-3-(p-(2-methoxymethoxy)phenyl]propane 8 Example 20 The weightless body 15852 obtained in
0 ml, dissolved in 60 mt of tetrahydrofuran, and 3.0 ml of lithium chloride was added under water cooling and stirring. 1 1 SF, sodium borohydride 2. 7 7? was added, the water bath was removed, and after stirring at room temperature for 16 hours, saturated brine was added, made alkaline with sodium bicarbonate, and 80% chloroform was added.
Extracted twice at 0d. The extract was dried over magnesium sulfate and the solvent was distilled off under reduced pressure to obtain Nt-putquine carboni/V-0-(2-methoxyethoxymethy)V)tyrosinol 11,75SF. This was dissolved in carbon tetrachloride (120 trrlK M ), triphenylphosphine (10 gtJJ11), heated for 3 hours, and then heated at 80° C. for 17 hours. The solvent was distilled off under reduced pressure,
The residue was applied to a silica gel column, chloroform-methanol (100:1), then hexane-ethyl acetate/l/
(4:1) and colorless '+! ! (Akira's objective 7,
2 2 5' was obtained.

'H-NMR (cDct, δppm): 1.4
3 (9H, s), 2, 7 5 ~ 2.9 ( 2 H
lm), 3.38 (3H, s), 54 ~ 3.65 (
4H, m), 3.75 - 3.9 (2H, m), i
．． oa (1u, m), 4, 79 (1H, m), 5.26
(2H, +3), 6.9 9 (2H, d.

J = 9.71) (Z), 7.1 6 (2L dl, T =
9.71Hz) Reference Example 22 N-(2-(t-butoxycarbonylamino)-3-C
p-(2-Methoxyethoxymethquine)phenyl]proyl)-4-(p-methylbenzylleoquine)piperidine The anonymous t56f obtained in Reference Example 21 was dissolved in dimethylformamide 25-, and The weightless body obtained in Reference Example 19 was 0. 83F, 0671 potassium chloride, and 0.67F sodium iodide were added, and after stirring at 100°C for 2 hours, saturated brine was added, and the mixture was extracted twice with chloroform 150-. The residue obtained by drying with magnesium sulfate and distilling off the solvent under reduced pressure was applied to a silica gel column and purified with chloroform-methanol/lz (100:1) to obtain 490 η of the target product in the form of colorless islands. Obtained.

')! -NMR (cDczJ, δppm): 1.
42 (9H, e), 1.5-1.7 5 (3H,
m), 1.75 ~ 2.0 (2F (, m), 2.1
1-2.3 (3H%m), 2.3! l(3[(,e),
2.55 to 2.95 (4H.

m), A2 5 ~ 3.5 (IH, m), s
．． 3a (su, s), 55-56s (2u, m), A7
5-i5 (3H, m), 4.49 (2H
, s), 4. A4 (IHSm), 5.25 (2H%s)
, 6.96 (2HSd%J=9.7 1 Hz)
, 7.09 (2J dSJ=9.71Hz), 7.14
(2 [(, d, , T:=9.71Hz), q. 2
s ( 2 H, (L, J: 9.7 1 Hz
) Example 84 N-(1-Cp-(5-isoquinolinesulfonyloxy)benzyl)-2-(4-(p-methylbenzyloxy)piperidinocoethyl)-5-isoquinolinesulfonic acid amide Obtained in Reference Example 22 490 to 1 trL of ethyl acetate
3N hydrogen chloride ethyl acetate/I/solution 5- was added to the room under stirring, and the mixture was stirred for 1 hour.

After evaporating the solvent under reduced pressure, the resulting residue was made alkaline by adding an aqueous solution of sodium bicarbonate, saturated with common salt, washed with a small amount of methanol, and diluted with 100% chloroform.
Extracted twice with ml. The entire extract was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue N-[2-amino-5
-(p-hydroxyphenyl/L/)]propyIL/-4
-(1)Methylbenzyloxy)piperidine is obtained.

The residue was dissolved in tetrabitrofuran and stirred at room temperature.
-Isoquinoline sulfonyl chloride/Shin et al. Salt
545 η, TRI ECHIL AMIN 4
After stirring for 18 hours, make it alkaline by adding an aqueous solution of sodium bicarbonate, and add 100 IIq of chloroform.
Extracted twice with m1. The extract was dried with magnesium (IVI), the solvent was distilled off under reduced pressure, the residue was applied to a silica gel column, and the extract was diluted with chloroform-methanol (30:1).
) to obtain colorless, island-like target product 572.

'H-NMR (CDC13, δppm): 1.0
~1.33 (3H1m), 1.33~154 (IH%m
), 1.59-1.88 (2H%m), 1, 88-2.
25 (4H, m), 2.33 (3H10), 2.7
1 (IT(, dd, J=14.28.6.85H2)
, 2.91 (I H, da.

J=14.28.4.57Hz), 518(2[(, m
), 4.34 (2H18), 6.68 (2H, a, J
=9.14H2), 6.90(2H1d, J=9.1
4 Hz), 7. ti(4H,s), 8.13(IH,
t.

J near, 42Hz), 8.18 (IHSt, , T = near, 42Hz), 9.19 (IH, d, J = 7.42H
2), 8.27 (2)(,a, ,T=7.42H2
), a4o (1H,aa, :r=7.q q,to
Hz), 8.44 (I H, d, J=6.85H2
), a52 (I Hla, , T =6.28H2)
, aAB(IH, d, J=6.28T(z), aa1
(I H, d, J=4.28Hz), 9. ,')4
(IH, 8), 9.41 (1)! , s) Example 85 N-(1-(p-hydroxybendi)v) -2-(4
-(1)-Methylbenzyloxy)piperidinocoethyl)-isoquinoline sulfone 1-shun amide The non-grained 400 cape obtained in Example 84 was dissolved in methanol 2:5m/2.5ml/tetrahydrofuran and 1N caustic soda solution. 4-
was added and heated under reflux for 2 hours. After cooling, the reaction solution was diluted with water to make it citric and acidic, then made alkaline with sodium bicarbonate, and then extracted twice with 100 mtf of chloroform. The extract was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was filtered onto a silica gel/L/column.
Purification with chloroform-meth/-tV (20:1) gave Qiq color, IjjlH crystalline island-like 172η.

'H-NMR (C!DCjt3, δppm): 1.
2-1.75 (4H, m), t85-215 (2H,
m), 2.2-2.58 (4'ASm), 2.52
(31(,s), 2.58-2.85 (2H,m)
,! 1.15~! ,,4(2u,m),4.41(2i
, s), 4.8 (2H1br), 6.42 (2HSdS
J==9.14Hz), 6.68(2H,a, :r=
9.14Hz), 7.14 (2H, d, J=7.4
2Hz), 7.19 (2H, ti, J=7.42H2
), 7.67 (IH, t, , T=7.42H2), a
19 (IH, d, J near, 42+(z), 8.33.4
50(2H, m), a5 B (1[(, d, , T=
6.28′H2), 9.33(IH1θ) Example 86 N-(2-(t-butoxycarbonylamino)-5-(
p-(2-methoxyethoxymethoxy)phenyl]proyl)-4-(p-methy/L//<ndyloxy)piperidine instead of N-[2-(1-butoxypropyl)/
A colorless island-like N-( 1-Cp-s-isoquinolinesulfonyloxy)benzyl]-2-(4-(3,4
-dichlorobenzyloxy)piperidinocoethyl)-5
-Isoquinoline sulfonic acid amide was obtained.

'H-NMR (CD(!/!,, , δppm):
0.95-1.17 (IH, m), 1.17-154
(2HSm), 1.34-1.91 (2H,m), 1
．． 91-2.30 (4H, m), 2.72 (I
H, aa, :r=13.1 s, 7, 42 HZ)
, 2. l'l 9 (I H, dd, , T=13.1
3.4.5nH2), 3.20(2'H,m), 4.3
3(2[(,8), 6.6s(2HSa.

J=9.14Hz), 6.92(2H,d, J=9.
14H+g), 7.10(11(, ad, J=914
．． 1.71H2), z, 56 (1H, a.

J=1.71)(Z), 7.58(IH, cl, J=
9.14H2), 7.64(IH,t,,T=7.42
)(Z), 7. /+8(1T(,t1J=7.42Hz
), a2o(iH, d, J=7.42Hz), &28(
2H1d,, T near, 42Hz), a39 (I H%
d, iS, r=7.42.1. o, uz), a, 1 s
(I H,a, :r=6.z 8Hz), a53
(1H,d,,T=6.28[(z),a69(IH,
dS, T=6.28Hz), aa0(IHSdS, T=
6.28 Hz), 9.35 (IH%s), 9.42 (I
H, e) Engineering R (K', I'3r) tv2'
: 1615.1375.1130.860 Example 87 The anhydrous substance obtained in Example 86 was subjected to alkaline hydration according to Example 85/) 144 and 9jl? Color;i! +? crystalline N
-[1-(p-hydroxybenzyl) -2-[,4-
(4-dichlorobenzyloxy)piperidinoconi-
1-t)-5-isoquinolinesulfonic acid amide was obtained.

Engineering R(KI3r)cyn-': 1/+15, 1
375, 1130.860'H-NMR (ODOl3,
δppm): 1.2~t8(4H,m), 19~2
．． 2 (2[(,m), 2.2~2.6(4H,m
), 2. /12(IH, d4, J=14.28.6.8
5Hz), 2.75 (I H, dd.

, T=14.28.6.28Hz), x29(2q, m
), 4.33 (2H, br), 4.39 (';'H, s
), 6.3 a (2HSa1.T=as7H2), 6
．． l, 7 (2H, d, J=a57Hz), 71
2(II(, da, J=a57, t71H2), 7.3
8(1f(,d.

, 7=a57Hz), 7. ,! +9 (IL d, 1.
r=171H2), 7.67(IH,t,J:=7.4
2Hz), a 20 (1[(, d%, T=7.42H
z),a,57(1x(,dS,T=6.28H2),
8,4゜(I H,aa, :r=7.42.1.0H
z), 8.58 (IH, d, , T=6.28Hz)
, 942 (IH, s) Reference Example 25
-benzyloxycarbonylamino-5-(p-benzyloxyphenylamino-5-(p-benzyloxyphenylamino)) was prepared in the same manner as in Reference Example 21 except for using g-benzyltyrosine methyl ester. /l/)-j-chloropropane was obtained.

'H-NMR (ODOlt3, δppm): 2.7
~2.95 (2H, m), 3.4 q (I H, a
a, :r=1ta 2.3.43Hz), 3.63(
IH, ad, J=11.42.4.0OHz), 4.
13 (IH, m), 5.00 (IH, m), 5.04 (
2H, 8), 5.10 (2H, +3), 6.92 (2H
,dS,T=7.99H2),7.15(2H,d,
, T=7,99 HZ), 7.3~7.5 (51(
, m) The same as in Reference Example 2I by adding N-phenylpiperazine to the obtained anonymous body (colorless due to drug manipulation); 1 (convex 1-
(2-(benzyloxyca)V gnylamino)-3-
(I)-pencyloxyphenyl)furovir)-4-phenylpiperazine was obtained.

'H-NMR (ODOl3, δppm) 2 2.54 (2H, d, , T=6.85Hz)
, 2.4~2.7 (4HSm), 2.75~! 1.
0 (2H.

m), 3.1a (4HSt, J=5.14Hz),
&99(1H.

m)1. s, 9o (1H, m), 5.04 (2H, s)
, 5.10 (2H.

day), 6.75-7.0 (5:(, m), 7.09(
2H, dl, T=a57H7), 7.2-7.5 (12
a, m) Example 88 N-[1-[(p-penzyloquine)benzyl]-2-
(4-phenylpiperazinyl)ethyl)-5-isoquinolinesulfonic acid amide 1-Substituted-4-phenylpiperazine obtained in Reference Example 23 5
Dissolve 00η in acetic acid 1-, add 2 ml of 30% aqueous bromide/1-tonic acid solution under stirring at room temperature, stir for 10 minutes, pour the reaction solution into water, and add Kyowa sodium thiosulfate solution. , Saturated bicarbonate of soda water (after making alkaline with BM,
Extracted twice with 150-chloroform. The extract was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to a silica gel column and stirred with chloroform-methanol-1-30:1 to give 1-(2-amino-3). -(p-
7255 ml of benzyloxyphenyl)propyl)-4-phenylpiperadi was obtained. Dissolve this 2'55INi in tetrahydrofuran and stir at room temperature.
-Isoquinoline sulfonic acid chloride/hydrochloric acid 41? s
~, 178 Iq of triethylamine was added and stirred for 16 hours. After adding brine to the reaction solution, it was made alkaline with Shigeishi Yumuri's solution, extracted twice with chloroform 150-, dried over the shun magnesium, and the solvent was distilled off under reduced pressure. The resulting residue was applied to a silica gel column and purified with chloroform-methanol (SO:1) to give a colorless and sterile N-(1-[(4-benzyloxy)benzyl]-
2-(4-phenylbiverazini)V)ethyl)-5-
280 Ing of isoquinoline sulfonic acid amide was obtained.

'H-NMR (ODC13, δppm): 2.1~
2.5 (6H, m), 2.7-3. o (6H, m)
, 3b37 (1H, m), 4.99 (2H.

B), 5.5 (IHlbr), 6.71 (2H, d,
, T=a57Hz), 6.81 (34(,t, J
=a57Hz), 6.90 (2H, (1,,7=a5
7Hz), 7.24 (2)1. t, , r=a5
7Hz), 7.3-7.5 (5H, m), 7.68 (I
H, t, J=7.42Hz), a17 (1n, d,
J=7.99 Hz), a4B1u, a, :r=
6.28Hz), a46 (I H, d, J=6.
85Hz), &67(1H, dS:r=6.28Hz
), 9i2(IT(,e) Example 89 N(2-(4-(44-dichlorobenzyloxy)piperidino)-1-(p-(5-isoquinolinesulfonyloxy)bencyl]ethyl)-N-methy/ V-5-isoquinoline sulfonic acid amide After reading 1.70 r of the anhydrous substance obtained in Example 86 in dimethyl,
The ice water bath was removed and each item was stirred in the chamber for 4 hours.

Add ethyl acetate/I/150- to the reaction solution, wash 5 times with water, extract the washings with ethyl acetate 50-, combine the resulting oil extracts, wash with saturated 4iX water, and dry over magnesium sulfate. , the residue obtained by distilling off the molar fraction under reduced pressure was applied to a silica gel column (silica gel: Fuji Davison Chemical Co., Ltd. BW-820).
MH) with methanol/chloroporm! I
! A colorless and sterile target product 1.301 was obtained.

Engineering F, (CHCL3)cm': 2920.2
810.1618.1583.1563.1450.9
86.9021 H-NMR (cDat3, δppm)
: 1.30-1.52(2)(.

m), t6o ~1.78 (2H, m), 1.95 ~ 2
12 (2H.

m), 2.15-3.00 (6H1m), 2.84 (3
HSs), s, 31 (1n, m), 4.1o (1u, m
), 4.42 (2H, 8), 6.58 (2HSbrdS
J=asHz), 6.87 (2H1brd.

J=a5Hz), 7.14 (I H, aa, y=a
3, t9Hz), 7.39(IH, d, J=a3Hz
), 7.41 (IHSa, :r=1.9H2), 7
．． 53-7. /15 (2H1m), all (IH, d.

y=a, 5Hz), a28~a3 (3H, m), &
32 (IH.

(id,, T=7.5.1.2Hz), a54 (I
H,brd, J=6.1H2), a57 (I H,
d, J=6. I Hz), ass(1a.

a, y=6. i Hz), 9.2 a (I Hl
a, J=1.0H2), 9.41 (IH, a1J=1
．． 0H2) Actual 7dli Example 9O N-(2-(4-(3,4-dichlorobenzyloxy)
piperidino)-1-(p-hydroxybendi)V)ethy)v)-N-methyl-5-isoquinolinesulfonic acid amide Dissolving the anonymous 1.04F obtained in Example 89 in dimethylsulfoxide 10- 152q of caustic soda under stirring
2 water-resistant solution was added, heated to 80° C., and stirred for 2 hours. Add ethyl acetate 150- to the reaction solution, then add water 100+
m! Read twice with /) t,, wash solution with ethyl acetate) V 5
The mixture was extracted with 0 ml of ethyl acetate, combined with ethyl acetate, washed with brine for both phases, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. - By interlayering with chloroform, 650 mg of an island-shaped target product was obtained.

IH-NMR (cDcz3, δppm): j, 50
~1.67 (2H.

m), 1.75 to 1.94 (2H, m), 2.15 to
2.30 (2H.

m), 2.40-2.96 (6H, m)1. aOO
(3H,e),! ,,Ro9(jHlm),3.96(I
H, m), 4.47 (2H, e), 6.26 (2H,
brd, J=a51(z), 6.61 (2H,b
rd.

J=asuz), 6.9 C1~7.10 (I Hl
b, r), 7.16 (1H.

d, il, T=a3.1.9Hz), 7. ．． 11 (I
H, dS, T=a3Hz), 7.44 (I H, a
, J:=1.9Hz), 7.60 (IHSd-
1, J=aO17,5Hz), &09 (I H,br
d, J=6.1 Hz), a+ 4 (I H, b
rd, 1. T=aOI(z), a31 (i H, dd
.

J=7.5.1.2H2), a47 (1H1d, J
=6.1 Hz), 9.28 (IH, brs) Example 91 N-[2[4-(3,4-dichlorobenzyloxy)piperidine)-1-(p-methoxybenzi)v)ethyl)- N-Methyl V-5-isoquinoline sulfonic acid amide 350 mg of the anhydrous substance in Example 90 was dissolved in 10 d of dimethyl holemamide, and 82 ml of methyl iodide was dissolved under stirring under ice cooling.
．． After adding 8 mg and stirring for 50 minutes, the ice water bath was removed and the mixture was stirred at room temperature for 2 hours. Ethyl acetate/I/100r on the reaction surface
nt and washed 5 times with 50% water, the washing water was ethyl acetate/
Oil comes out with v50-, wash with water and then 1!11=
Acid ethyl alcohol) The V layers were combined, washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. MHI.

Colorless 2j1 (island-shaped target object 2971rpg) was obtained.

Engineering R (OHO43) c1n': 2910.2865
．． 1615.1585.1322.1125.9861
H-NMR (CDC4, δppm): 1.58
~1.60 (2H.

m), 1.69-1.85 (2H, m), 2.06-2
．． 22 (2H1m), 2.36 (1H, dcl,
J=13.0.7jHz), 2.51~2.76 (4
HSm), 2.88 (IH, m), 2.93 (3H, B
), 3.34 (IHSm), 3.73 (3H,s), 4
．． 13 (IHSm), 4.44 (2H, s), 6.50
(2H, dm, J=a8Hz), 6.83 (2
H, dm, J=8.8Hz), 7.14 (I Hl
dd, , T=80, j, 9Hz), 7.40 (1H
1a,, T=8.0H2), 7.43(I HXd,
J=1.9H2), 7.56 (I H, ddSJ=a
3.7, 3 HZ), an s (I H,brd,
J=8.3Hz), 8.29(+H, dd, J=
7.3.1.2Hz), ass(1H1a, J=6.
3Hz), 9.23 (IH, brs) Example 92 1-[2-[2-amino-6-(p-hydroxyphenyl)propyl]-4-phenylhiberazine instead of
-amino-3-(p-hydroquinphenyl)propyl]
Example 34 and then the same procedure as in Example 35 except that -4-phenylpiperidine was used: Z-(,S-phenylpiperidino)
Enerzlz ) -N-methy)V-5-isoquinolinesulfonic acid amide was obtained.

'H-NMR (C!DC!t3, δppm): 115
〜175(4HSm), 180〜2.10(2I(,m
), 2.20~2.50 (3H,m), 2.60~
2.80 (2H, m), 2.5o-3,05 (3H
, m), 2.86 (3H, 8), 4.13 (I H,
d, J=6.85H2), 6.62 (2H,d,
J=7.99H2), 6.91 (2H,d, J=7
．． 99H2), 7.12 (2H1ddS, T=6.8
5.1.0H2), 7.16-7.40 (3H, m)
, 7.58 (IHSt, J=7.4.2) (z), 7.
61 (1H, t, J=7.42Hz), all (1H
.

a,, T=7.42Hz), 8.26 (5H, dd,
:J=6.85.1.0Hz), as 6(I Hl
aa, , T=7.42.1.0Hz), a56 (IH
, d, J=6.28H2), 8.59 (I H, d,
, T=6.28Hz), 8.83 (I H,d,
J = 6.28H2), 9.211 < -, H■,.

θ), 9.41 (I H, d, , r=1.0Hz
) Example 93 Implementation (! The anhydrous body obtained in A192 was alkaline hydrolyzed according to Example 36;
-Hydroxybendi iv) -2L(4-phenylpiperidino)ethyl)v) -N-methy/L/-5-isoquinoline ρphonic acid amide was obtained.

Engineering R (KBr) crn': 1615.1515
．． 1325.11251H-NMR (aDet3, δp
pm): t55~1.95 (5H1m), 2.22
(2H, dtS: f = 6.28.1.7 Hz),
2.55-2.60 (3H, m), 2.70 (I H
,da, ,T=12.56.5.71H2), 2.8
~3.25 (3H1m), 3. o6 (3n, 8),
3.98 (IH, m), 6.23 (2H1d, J=8.
57H2), 6.59(21(,d,J=a57Hz)
, 7.1 s to 7.40 (5H.

m), 7.62 (IH1tSJ=7.42Hz), al
0'(IH%d.

J=6.85Hz), a16(1H,a, J=7.42
H2), ass(tH, da,, T=7.42.1.0
Hz), 8.47 (IHla, J=6.28Hz)
, a29 (IH, s) Example 94 1-, (2-amino-3-(p-hydroxyphenyl)
propy)v]-4-phenylpiperazine instead of 1-
[2-Amino-3-(p-hydroxybendi)V)proL" tvE -2j((electron) Terushima-like N-(2-(4,4-ethylenedioquinepiperidine)-1-Cp-(5-quinolinsulfonyloxy)benzyl]ethyl)-N-methyl-5-isoquinolinesulfonic acid amide was obtained.

'H-NMR (CDC43, δppm): 1.4~
16 (4H, m), 2゜22 (IH, ddS, T = 12
．． 56.6.85H2), 2.25-2.5(5H, m
), 2.6-2.8 (I HSm ), 2.8-2.
95 (I Hlm), 2.84 (jH,s), A90
(4H, s), 4.11 (IH.

q, , T=&85Hz), 6.61 (2HSd,
, T=a57Hz), 6.89 (2HSdSJ==
a57Hz), 7.61 (IH1t1J=7.42
Hz), 7.63 (IH, t, J=7.42Hz),
C12 (IH, d, J=7.42Hz), C26
(2H1d,, T=7.42Hz), C27 (IHSd
, J=7.42I(z), a3s(tH.

d, J=7.42Hz), C57(I H, d, :
J=6.28Hz), 8.58 (IH,d, :
r=6.28Hz), C84 (IH, d, , T=6
．． 28Hz), 9.29 (IH, s), 9.42 (IH
, s) Real; l/Ii Example 95 N -(1-Cp-(5-isoquinolinesulfonyloxy)benzyl)-2-(4-oxopiperidino)ethyl/$/)-N-methy/L'-5-isoquinoline 2.57 F of the product of sulfonic acid amide Example 94 was dissolved in 50 m of 3N hydrochloric acid.
The mixture was dissolved in 200ml of chloroform, heated for 6 hours, cooled, made alkaline with saturated aqueous sodium chloride AM, and extracted twice with 200% chloroform. The extract was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, the resulting residue was applied to a silica gel column, and chloroform-methanol/l/(5
0: 1) TeM! 11'JI.

I got the electric island-shaped objective 2.22?

'H-NMR (CDC43, δppm): 2.1
~2.25 (4H, m), 2.31 (I H, dc
lSJ=13.13.6.851(Z), 2.4-2.
65 (6H, m), 2.65-2.85 (I H, m
), 2.79 (5H18), 4.10 (I H,
q, J=6.85Hz), 6.52 (2HSd.

J=7.71H2), 6.78(2H,d, J=7.
71Hz), 7.49(1H,t, ,T=7.42H
2), 7.55 (I Hlt,, T=7.42Hz)
, C05 (IH%d, , r=7.99Hz), a10
~a20 (3H, m), C20 (IHS (1, J=7.
42) TZ), C46(I H, d, , r=6.28
H2), C4B (I H, d, ': J=6.28H
z), EL76 (I H, d, , T=6.2814
z), 92o (1H.

8), 9.34 (IH, 8) Example 96 N-[2-C4-(N'-benzyl-N'-methylamino)piperidino)-1-Cp-(5-isoquinolinesulfonyloxy)benzylcoethyl )-N-Methi/L'
-5-isoquinoline/lephonic acid amide 1.09 of the product of Example 95 was added to methanol/L/15 mA
Dissolve in 4% J at room temperature, press benzylmethylamine 2
70 μm and 120 μm of sodium cyanoborohydride were added, and stirring was continued for 18 hours. An aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted twice with 150-chloroform. The extract was dried over magnesium monoformate, and the solvent was distilled off under reduced pressure. The resulting residue was applied to a silica gel column and purified with chloroform-methanol/L/(30:1) to give 9H1 A target object of 380η was obtained.

'I(-NMR(CDC23, δppm): 1.0
~1.45 (2H1m), 1.4 s ~1.6 s
(IH,m), 1.65-2.0 (5H,m),
2.13 (sH, e), 2.15-2.45 (3H,
m), 2.5-2.9 (4H, m), 2.84 (3)
(,8), 3,49 (2H1s), 4.07 (I H
lcl, , T=&85Hz), 6.61 (2H,
a, : r=7, 99 HZ ), /), 89 (2H,
(1, J = 7.99Hz), 7.28 (5HS s),
7.58 (IH, t, J=7.42Hz), 7.60
(IH%t, J=7.42Hz), all (IH
, d, J=7.99Hz), C25(I H, d, J
-=6.28Hz), C26 (2HSd, , T=7
．． 42Hz), 8.34 (I H,aa, :r=y
, 42.1.0H2), 8.55 (11(,a,
, T=6.28H2), C57(IH, d1J=6.2
8H2), C83 (IHla, J=6.28Hz)
, 9.26 (1H,S), 9.41 (1H 1 day) Example 97 N-(2-(4-(N-benzyl-N-methylamino)
piperidino)-1-(p-hydroxybendi/L/)
Ethyl)-N-methyl-5-inginoline sulfonic acid amide 380 μ of the anhydrous substance obtained in Example 96 was mixed with 2 ml of tetrahydrofuran and 2 ml of Mekno IV, and 1N aqueous sodium hydroxide solution was added to the mixture for 3 hours. After heating to reflux, the reaction solution was cooled, poured into water, made acidic, made alkaline with sodium bicarbonate, washed with a small amount of methanol, and extracted twice with 100 ml of chloroform. was dried over Jide M magnesium, the solvent was distilled off under reduced pressure, the resulting residue was applied to a silica gel column, and chloroform-methanol/L/(20:1
) to obtain colorless, island-like target product 147a7.

'H-NMR (CDC13, δppm): 1.35
~t95 (4H.

m), 1.95-2.25 (2H, m), 2.19 (3
H, s), 2.6~2.7 (4H, m), 2.75~
3.15 (3H, m), 3.01 (3N1 day), &
57 (2H, s), 3.95 (IH, m), 6.25 (
2N%d1J=EL3Hz), 6.58(2HS(11
J=assHz), 7.2-7.4 (5NSm), 7
．． 60 (IH, t, J=7, 57 HZ), al
1 (I H, cl, J=5.86Hz), 8.1
2 (IH, d, J=a06Hz), a32 (IH
, d, , T=7.33Hz), 8.46 (I H,
(1%, r=6.35H2), 9.28 (IHlB) Example 98 P
H(<black-skinned island-like N-(2-(4-(N-benzylamino)piperidino)]-1-(p-hydroxybenzi/I/
)ethyl A/)-N-methy)v-5-isoquinolinesulfonic acid amide was obtained.

'H-NMR (cDcz3, δppm): 1.2~
1.6 (2H, m), t 7-2.0 (2Hlm)
, 2.0-2.3 (2Hlm), 2.35-2.7
(4)1. m), 2.7-l 5 (5H, m), 3
．． 0(3H,s), 3.83(2H1s), 3.95(
IHSm), 6.24 (2H, d.

J=7.99H2), 6.56 (2H,d, 'J=
7.99Hz), 732 (5H, m), 7.59 (I
H,t, J==7.42Hz), alo(1HSd,
, T: 6.28H2), al 2 (I H, d,
, T=7.42Hz), a30(IHld, , T=7
．． 42Hz), a46 (1H, a, , r=&28Hz
), 9°26 (IH, El) Example 99 N-(2-(4-hydroxypiperidino)-1-(p-
(5-isoquinolinesulfonyloxy)benzylcoethyl)-N-methyl-5-isoquinolinesulfonic acid amide
After adding 35.2 μl of sodium chloride in small portions under stirring at room temperature, stirring was continued for 2 hours, the solvent was distilled off under reduced pressure, and the resulting residue was purified with silica gel. Attach to the column, ・Chloroform-methanol tv (1o
o: 4) to obtain the desired product 116 as a pale yellow oil.
n1 was obtained.

Engineering R (KBr) am-': 1620.1500.
1370.1320.1130.860'H-NMR (CDC6,, δppm): 1.2~
1.4 (2N1m), ts ~ta (4H,m),
1.9~2.1 (2N1m), 2.25 (IH, d4
．． J=12°6.7.3H2), 2.4 (I H,
aal:r=12.7.7.1)1'Z),2.7 (
j H, dd, J=13.8.7.0H2), 2.8
~2.95 (IH,m), 2.55 (IH,br
s), 2.83 (3H, s), 5.55 (IH, m),
4.1 (I H, m), &6 (2H, a, J=as
nz), 6.87 (2HSd1J=a5Hz), 7.
6 (IHlt, J=a3H2), 7.6 ri (I
H, t, , T=7.8Hz), a12 (I H%a
, , r=asaz ), a23 (IHSd.

, T=5. IH2), a26 (1)1. l, ,T
=5.1 Hz), as(1H, (ldSJ=1.2
, 53Hz), a54 (I H,d, , r=4.1
Hz), as 7 (I I(, (1, J-4, 1Hz
), aas (1a1a.

, T=6.1H2), 9.28(11(,8), 9.4
(IH,s)1;^:1soj(1;Example 100 N-(2-(4-hydroxypiperidino)-1-Cp-
(5-isoquinolinesulfonyloxybenzyl)ethyl/
l/) - N-Methyl/L/-5-isoquinolinesulfonic acid amide 1501 ng of the oil obtained in Example 99 was added to methanol-l
After dissolving the mixture in 3- and 10-ml aqueous solution of caustic soda 1- and heating for 2 hours, the solvent was distilled off under reduced pressure, and citric acid was added to the residue to make it acidic.

After making the solution alkaline by adding an aqueous solution of sodium bicarbonate, it was extracted three times with chloroform (20%), dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel preparated thin layer chromatography. 2j ((
Dark complexion, island-shaped eyes, 87cm white.

Engineering R (KBr)z-': 1610, 1510, 1
320, 1150, 125′ H-NMR (CDCjt3, δppm): 1
．． 4-1.7 (2H, m), 1, 8-2.
0 (2 H, m), 2.1 to 2, 4 (4N1m
), 2.3 to 2.6 (IH, m), 2.7 (I
HSdci, , T=1 2.7, 4.8Hz), 2,
8 (I HSaa, J=1 4.6, 4.7Hz
), 2.95(11(.

da, J=12, 2.5Hz), 2.99 (3H, s)
, 3.7 (IH.

m), 3. ．． 9 (1H, m), 6.15 (2H, a,
J:8.3Hz), 6.5 (2H,a, J=a
3Hz), 76 (in, t, , T=7.6Hz)
, an (I H, aS, T=6.I Hz), a,
1s (1H, a.

J=a3Hz), a35(IHldd, J=7.3.1
．． 0Hz), a4 (I HSd, J=6.1 Hz
), 9.24 (IH, Japan) Example 101 N-(1-(p-hydroxybenzyl)-2-(4-hydroquinpiperidino)ethyl)-N-methyl-5-isoquinolinesulfonic acid amide implementation Ethyl acetate-methanol/L/(
1) Dissolve in 5-! 'N18L/, diazomethane ether'fRM a! di Add the amount and leave it overnight with one item ii
t Shita. The solvent in the reaction solution was distilled off under reduced pressure, and the resulting residue was subjected to silica gel preparative deep layer chromatography, and preparatively purified with chloroform-Mechnot/L/(20:1) to give a colorless and sterile 80. I got 4 ■.

Engineering R (KBr) crn': 1510.1320.1
240.1150.1120.1031 03011(-N (CDC13, δppm):
13-15 (2H,m), 1,7-2.0 (4H
, m), 2.0-2.3 (2H, m), 2.35
(1■], dd, J=13.0.7.1 HZ),
2.55 (I H,aa, :r=10.0.6.9
H2), 2.62 (I H,da, , T=10.3
．． 7.3Hz), 2.89 (I HlddS, T=1
4.8.6.3Hz), 2.6-2.75 (1HSm)
, 2.93 (3H18), s, 6 (1H, m), 4.1
2 (1H, m), 3.73 (5H, o), 6.5 (2
HSa, y=8.7Hz), 6.84 (I H,d
, J=a7Hz), 7. s 6 (IH, t,
, T=8.0I(Z), 81 (I H,d, ,T=
a3Hz ), a2(U(,d, ,T=6.1Hz
), a3(I HSa, J=7.3Hz), aS5(
1)(, (ISJ=6.IHz), 9.24(IH,s
) Blood Example 102 N-[1-(p-acetoxybenzyl)-2-(4-acetoxypiperidino)ethyl)-N-methyl-5-isoquinolinesulfonamide Obtained by carrying out Example 100 230ml of anhydrous material was dissolved in 2rntK of pyridine, 1me of acetic anhydride was added, and the mixture was allowed to stand overnight at room temperature. After adding 20ml of ice water and stirring for about 1 hour, the mixture was extracted twice with 20ml of ethyl acetate. The extract was washed with saline, dried over magnesium sulfate, the solvent was distilled off under reduced pressure, the resulting residue was applied to a silica gel column, and chloroform-methanol/I/(10
0:1) and colorless: i! i? Crystalline island-like object 234
．． I got 3η.

Engineering R(KBr)cy-': 1760.1730.1
360.1320°1240.1215, 4th article 120
0.1030'■q-NMR (cDat3, δppm)
: 1.58(3H,El), 2.03(3■(,8
), 2.30 (3H, B), 2.91 (3H, s), 1
．． 4-ta (4H, m), 2.2-2.9 (4H, m)
, 4.2 (IH.

m), 4.7 (IHSm), 6.77 (2H,a,
J=6.6H2), 6.8 (2H,d, I=6.6
H7), 7.5 (I HSt, J=aQHz), a
l(11(,d, ,T=8.1 Hz), a2(1
H1d1J near, 4H2), 8.29(iH%d, J
=6.1Hz), aS7(IH,a, J=6.IH2
), q, 27 (I H2S) Example 103 N-(2-(t-butoxycarbonylamino)-3-(
Instead of p-(2-methoxyethoxymethquine)phenyl]propyl)-4-(p-methylbenzyloxy)piperidine, similarly synthesized N-(2-(t-butquincarbonylamino)-3-(p -(2-Methoxyethquinmethoxy)phenyl]propyl)-4-acetoxypiperidine was prepared in the same manner as in Example 84.
((Color 1 (1 (convex N-(2-(4-acetoquine piperidino)-1-[:p-(5-inginolinesulfonyloxy)benzyl]ethitV) -5-isoquinolinesulfonic acid amide Profitable.

'H-NMR (CDC43, δppm): 0.8~
1.05 (IH, m), 1.2-155 (3H, m),
1.6-2.15 (5HSm), 1.99 (6I(,0
), 2.15-2.33 (I H,m ), 2.73
(11(.

dal, T=13.13.6.85Hz), 2.89
(I H, dd, J=13, i3, JAS7Hz),
3.22 (IH, m), 4.51 (IHlm), 5.4
3 (IH, br), 6.70 (2H, d, , T=a
57H2), 6.91 (I H%d, , T=a57
Hz), 7.66(1)(.

t, J=7.42 Hz), 7.68(1)(,(
11, T = 7.42Hz), 13.20 (IHlaS,
T=7.42H2), a30(2H1d, J=7.4
2Hz), 7.39 (IHSaa, J=7.42.
10H2), a42 (I H, d, J: 6.28H
2), aS3 (IH, d, J=b, 2qHz), a7
0 (I H, d, :J=6.28Hz), aa1
(I H,a, :r=6.28H2),? ,! +4(
IH, 13), 9.43 (IH, s) Example 104 N-(2-(4-hydroxypiperidino)-1-Cp-
(5-isoquinolinesulfonyloxy)benzylcoethyl)-5-isoquinolinesulfonic acid amide Example 1.52 of the product of Example 103 was dissolved in methanol 8-, and 1N aqueous sodium hydroxide solution 8- was added under stirring at room temperature. After continued stirring for 2 hours, water was added and the mixture was extracted twice with 100 mj of chloroform. The extract was washed with saturated brine, dried over magnesium chloride, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in chloroform-methanol/1/
(30:1) was eluted on a silica gel column as I'81 to obtain a crystalline target product of F1 (color, 1jtq).

'H-NMR (cvct3, δppm): 0.6~
0.9 (IH, m), 1.05 to 1j (IH, m),
1.3-1.5 (2H1m), 1.5-1.9 (3H,
m), 1.9 = 2.2 (2H, m), 2.2~2
．． 4 (11(.

m), 2.72 (I H, da, , T=1 570
．． 6.85Hz), 2.89 (I Hlad, ,T
=1 a2 ), 4.57Hz),! L19 (1H, m
), A46(IHlm), 6.72 (21(, (1,
, T=8.57Hz), 6.72 (2HSd, ,T
= a57H2), 7.66 (IH.

t, J=7.42Hz), 7.69(IH, t, J
=7.42Hz), a21(I H,a, J=7.9
9H2), a29 (2H%(1,, T=7.42 H
z), a41 (IH, d, J==7.99Hz),
a44 (I H, d, J=6.28H2), a53
(I H, d, , T=6.28Hz), 8.69 (
IH, d, J=6.28H2), a81 (IH.

dSJ=6.28Hz), 9.35 (IHSs), 9
．． 42(1H,s) Example 105 N-3,4-dichlorobenzyl-N-C1-(p-hydroxybendi/V)-2-(4-hydroxypiperidino)ethyl]-5-isoquinoline spone Acid amide 400 η of the anhydrous substance obtained in Example 104 was dissolved in dimethylformamide 5/8, and 3,4-dichlorobenzyl chloride 130–. After adding 28 μm of sodium hydride, the mixture was returned to room temperature and kept pressed for 18 hours. Add 1) brine to the reaction solution, extract twice with 100% chloroform, wash the oil extract with 11% brine, dry over magnesium sulfate, and remove the solvent under reduced pressure to obtain a residue. was applied to a silica gel column, and N-(3,4-dichlorobenzyl)-N-(2-(4-hydroxypiperidino)-1-1:p-(5 228 ml of -isoquinolinesulfonyloxy)benziethyl)-5-isoquinolinesulfonic acid amide was collected.

Dissolve the 2213 mq obtained above in methanol 1.5 + Rt, add 1 N caustic soda aqueous solution, heat for 3 hours, cool, dilute with water, and make it acidic with citric acid. The mixture was made alkaline with sodium bicarbonate and extracted twice with 100-chloroform. The extract was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, the resulting residue was applied to a silica gel column, and chloroform-methanol (2
0:1) to obtain colorless, island-like target substance 162 Misaki.

'H-NMR (ODC13, δppm): 1.2~
t6 (2HSm), 1.6-2.0 (3H, m), 2.
0–2.2 (2Hl, m), 2.4–2.9 (5
H, m), 3.5 (IHSm), 4.21 (I H,
q, J=6.08Hz), 444 (monthly work, aSJ: 1
1S, 36Hz), 4.66 (IHla, , T=1
6.11 H2), 6.51 (2T(,d, J=8
．． 55H2), 6.79 (2H, a, J=8.55)1
z), 7.17 (IH, ddSJ=a30, t96Hz
), 7.25 (I H,d, , T=5.06Hz
), 7.33 (1H, dSJ=1.96Hz), 7.5
7 (IT(1t, :r7.57Hz), al 2
(I H, d, J: a3Hz), a25 (1H1
d, J=6.10H2), a3x(1H1aa, J=7
．． 32.0.98Hz), a50 (I H, a, J
=5.86Hz), 921 (IH 1 day) Example 106 N-[1-(p-hydroxybenzyl)-2-(4-hydroxypiperidino)ethyl/L/]-H-p-)
f /l / / I got it.

'H-NMR (ODOt3+CD30D, δpp
m): 12 to 155 (2HSm), 1.5 5
~2.15 (5H, m), 2.33 (
! IH, s), 2.33-2.85 (5H, m)
, 3.5 (IHSm), 18 (IH.

q1J=6.59Hz), 4.52 (I H, d,
ff=15.63Hz), 4.78 (IHS, (
1, J=15.62Hz), 6.36 (2H1a,
: r=aO5Hz), 6.66 (2H, d, J=13
．． 06Hz), 7.08 (2H, d,, T=7.5/I
Hz), 7.29 (2H1(1,:r=z,57In)
, 7.60 (IH, t, J = 7.57 Hz), al2 (
I Hld, J=a06Hz), a2 B (I H, d
, J~6.10Hz), 8.39 (IH,c
l, , r=7.32H2), [8(IH, (lS, T
==6.35Hz),y,2o(1H,s) Example 10
7 N-(2-(4-hydroxypiperidino)-1-(p-
(5-isoquinolinesulfonyloxy)benzylcoethyl)-N-methy71/-s-isoquinolinesulfone-shunamide real JA1 After treating the anionized substance obtained in Example 103 with methyl iodide according to Example 89, Example 104 The same weightless substance as in Example 99 was obtained by alkaline hydrolysis according to the method.

'H-NMR (CDCl3, δppm) -1,2G
~1.42(2)1. m), 1.68(2)(, m)
, 2.01 (2H, m), 2.22 (I H, da.

J=7.3.13.2H2), 2.40 (IT(,
ad, , T=7.5.13.2Hz), 2.43~2
．． 60 (2H, m), 2.66 (1H, da,
J=6.8.15.7Hz), 2.84(3H,s),
2.85 (I H% ad.

J=6.4.1&7Hz), 3.58(IH, m), 4
．． 10 (IH.

m), b, b 1 (2HSa, J=a8Hz), 6.
a a (2I(Sa, J=F3.8Hz), 7.5
9 (181t1J=7.8Hz), 7.63(IH,t
, J = near, 8Hz), al 2 (I H, d, J
= a5H2), a23 to a35 (4H, m), a55
(I H, d, J: 6.4H2), a58 (IH%d
, J=6.4Hz), a83(IH,d, J=5.9
Hz), 9.29 (IHSs), 9.42 (IH, 8)
Reference Example 24 1-(N-penzyloxycarbonyltyrosy)V)-4
-Phenylpiperazine N-penzyloxylponylnarosine 12.31 and N
- phenylpiperazine 6.62 to methylene chloride 150r
Melt into nt! Ishi, DI:IC! a45' was added and stirred at room temperature for 5 hours. The precipitated insoluble matter was separated and the furnace liquid was concentrated under reduced pressure. The residue obtained was applied to a silica gel column and washed once with hexane-ethyl acetate (1:1 to 1:2) to obtain a colorless Terushima-like object. Things 10, 5? I got it.

lH-NMR (CDCl2, δppm): 2.6
3 (IH, m), 2.88-3.24 (6HSm), 3
．． 48 (IH, m), 3.68 (2H1m), 4.8
8 (IH, m), 5.07 (I H, a, J=12
．． 7Hz), 5.11 (I H, d, J=12.
7Hz), s, 34 (1uSbr), 5.67 (I
H, a, , T=8.8H2), 6.71 (2HS
(1, J = 8.34 (z), 6.84 (2H, d,
J=a31(z), 6.90(IHlt, J=75H
z), 7.04 (2L d, J=a3H2), 7.26
(2H%tSJ=7.3Hz), 7.34 (5H, s)
Example 108 1-[:N,O-bis(5-isoquinolinesulfonyl)
Tyroshi/L/]-]4-phenylpiveranone 4.59 ? was dissolved in 50 methanol, 3 tons of palladium on carbon was added, and under a hydrogen atmosphere,
It was pressed for 17 hours at room temperature. The resulting insoluble matter was removed from the furnace, the liquid was concentrated under reduced pressure, and the residue was suspended in chloroform (50%). 7, and triethylamine 10- were added sequentially, and then stirred at room temperature for 3 hours. Add 200% water to the reaction solution
ml, extracted twice with 100% chloroform, dried over magnesium chlorate, and concentrated under reduced pressure. 5. Refined in 1) to obtain a yellow snake-like object. 4 6? I got it.

L H-NMR (CI)O/:3, δppm):
2.50 to 2.90 (7H, m), 2,9 2-4
1 7 (21 (, m), &21 (IH, m), 4.
32 (IH, m), 5.99CIH1br), 6.65
(2H, dSJ=a811), 6.80 (2H,
d, J=7.8Hz), 6.89 (211,
(1.

, T=a8Hz), //>,94(IH, t, J=
7.3Hz), 7. 2 9 (2H, da, J=
7.3, a3Hz), 7.51 (IH.tSJ=
7, 8 H Z ), 7.59 (IH, dd, ,
T=7. ! l, a3Hz), aO9 ~a3 1 (
5L m), &50 (IH, a, , T=6.
4Hz), a6? (IHld., T=5.9Hz),
a81 (IH, d, , T=5, 9Hz), 9.2
8 (IH, s), 9.39 (IH, e) ￥ between electrodes 109 1-CN, O-bis (5-isoquinoline sulfony/V
) - N-Methyltyronyl]-4-phenylated/rebibewodin 2.27 t of the anonymous substance obtained in Example 108 was dissolved in dimethylformamide 50%, and 60% sodium hydride 160 mg and methyl iodide IV 0. 3 ml were added one after another, and the mixture was stirred for 1 hour and 30 minutes while cooling with water. 8 parts of water to the reaction solution
After adding 0-, it was extracted with 100 rnl of ethyl acetate, washed with 80 rnl of saturated brine, dried over magnesium sulfate, condensed under reduced pressure, and the resulting residue was applied to a silica gel column and extracted with chloroform-methanol. /L/(60:1
) to obtain a yellow island-like object 1.82.

Engineering R (KBr) crn-': 166B, 1475.
1360.1130'H-NMR (CDO43, δpp
m): 2.45 (I H, dd, J==4.6
, IAI) 1z), 2.63 (IH, m), 2.82~
3.07 (4H, m), 3.03 (3H%s), A1
5-3.29 (2H, m), 3.43-S, 65 (
4H,m), 5.11 (1H,da, ,T-4,
6,10,3H2), 6.76 (2H,d, J =
&6Hz), 6.85 (2H, d, J=aOHz)
, 6.88 (I H, t1J=a6Hz), 7.2
9 (2HSaa, J=ao, a6Hz), 7.49
(IH.

ad, , r=EL3.7.3H2), 7.70 (I
H, ad1J=a3.7, 5 HZ), IILl
6 (1)1. daSJ=1.0.7. ) H2), a
21 (2H, d, :J=8.5Hz), a3o(
1H,aa,,r=1.0.7.3HZ),a41
(I HSd, :f=6.4 Hz), a5/(
I H, d, J=6.4Hz), a68 (j H
SdSJ=6.4 Hz), aa0(IH, dSJ=6
．． 4Hz), 9.36 (IH, 8), 9.40 (IH1
θ) Example 110 1-CN-(5-isoquinolinesulfonyl)-N-)4
-7 retyrosyl] -4-phenylpibedine Example 109 obtained sterile f$ 1.151 with methanol/
#8 and 2N caustic soda water (Jl
After adding 112 ml and heating for 1 hour and 30 minutes, 100% of water was added, and then extracted twice with 50 ml of chloroform. I+Ie magnesium acid acid was dried and concentrated under reduced pressure, and the resulting residue was applied to a silica gel column.
Chloroform-methano-/l/(80:1-50:1)
Purified with colorless ;'! 820 cm of tE crystal-like islands were produced.

Engineering R (KBr) t:m': 1638.1590
11440.1326, 150 +1 (-NMR (cDat3, δppm): 2.5
6 (IH, dd, 'J=5.4.12.7Hz), 2.
61 (IH, m), 2.90~! L22 (3H, m)
, 115 (3H, s), 3.43 (ILm), 551~
3.71 (LHlm), 5.13 (I H, ddS,
T=5.9.9.81 (Z), 5.53 (IH, br)
, 6.62 (2H, d, , T=a8Hz), 6.
8, i (2H, d, , T=7.8Hz), 6.
89 (IH, t, J=7.3Hz), 6.90 (2H
, dS, T=a3H2), 7.26(2H.

t, ,T=7.87(Z),7.7σ(1)(,co
dSJ=7.3.13.3 H2), a21(IH, a
, J=a3Hz), a32(IH, dd, , T=1.
0.7.3 HZ), a38 (IH, d, J=5.
9Hz), a66 (IH, d, J=5.9Hz)
, 9.33 (IH%br) Example 111 The product of Example 108 was hydrolyzed with alkali in the same manner as in Example 110 to give a yellow island-like 1-(IJ-(5-isoquinolinesulfonyl)tyrosyl]-4 -Phenylpiperazine was obtained.

Engineering R (KBr) cIn-': 1630.1590
．． 1510.1440.1325.1220.1150
．． 1128' H-NMR (aDet3-OI) 30D
, δppm): 2.60 (IH.

m), 2.72-2.77 (2H, m), 2.88
(4H, m), 31o ~3. a 3 (3H, m),
4.37 (I H, t, J=7.8Hz), 6, A
O(2HSd, , T = a3Hz), 6.72
(2) (,d, J=a3Hz), 6.83(2H, (
1, J=7.8H2), 6.91(IH.

t, J=7,3)(z), 7.27(2H,d4.,
T=7.8, a 31-1z ), 7.6+(IH, a
a, , T=7.3, a3Hz), a17(IH, d1
J=a3Hz), as o (I H,aa, ,y=
to, 13H2), as s (I H, a, J=6
．． a Hz), ago(IH, d, J=6jHz)
, 9.24 (IH, s) Reference Example 25 To N-penzyloxyluponylhomobiverazine dimethylformamide 230- were added 252 of homopibefudine and 5.42 of sodium bicarbonate, and to this was added water 25-, and under stirring under ice-cooling, benzyl Oxycarbo=ρ chloride 101 was added dropwise, and the mixture was stirred overnight at room temperature. Dimethylformamide was distilled off under reduced pressure, and then chloroform was added to Wlt-C.
s 1Ej1. The solvent was distilled off under reduced pressure, and the resulting residue was transferred to a gel ram.
τ1 and VJ with chloroform-methanol-zv (9:1)
UiR and Tanbutsu r! 3 Liquid object 9? I got it.

ER(KBr)crn': 1695.142
0'n-NMR (aDC43, δppm): 1.8
(2H1m), 2.8-3.0 (4H, m), s4-3
．． 6s (4HSm), 5.15 (2H.

), 7.4 (5H, S) Reference Example 26 1-(:N-(t-butoxycarbonyl V ) -N
-Methyl]tyrosine IV-4-penzyloxyluponylhomopiverazine N-t-butoxycarbonyl-N-methyltyrosine 1.
02 was dissolved in 70 rug of methylene chloride, 793 η of N-benzyloxycarboxylhomopiverazine was added, and the mixture was stirred overnight while stirring at room temperature while adding DC 0857 η all at once. The solvent was distilled off under reduced pressure, and benzene was added to the resulting residue. After removing the insoluble matter, it was applied to a silica gel column and diluted with hexane-methyl acetate (6:4 to 6:5).
A yellow oily target substance of 1.06 F was eluted.

The following physical properties were measured for the acetyl form.

Engineering F ((KBr)cln-1: 1760.1695
．． 1215.1200' H-NldR (CDC43,
δppm): 1.3. j, 4 (Total 9
H.

S), 1.85 (IH, m), 2.3 (3H, 8) respectively
, 2.82 (3H, brs), 2.7-2.9 (2H
, m), 3.0-3.8 (8H.

m), 5.15 (2H,brs), 7.0 (2H
, a, J=a3Hz), 7.35 (5HSbrs) Reference Example 27 1- (s'-(p-acetoxyphenyl)-2'--
[n-(t-Ptoxycarbonyl/L/)-N-methylaminocopropyl)-4-penzyloxycarbony-homopiperazineProduct 5.561 obtained by carrying out Reference Example 26 was dissolved in anhydrous tetrahydrofuran 60 - Dissolved in 1.
Add 0 molar borane-tetrahydrofuran 20 m/
The mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and this was dissolved in 10 ml of pyridine, 5 rnt of acetic anhydride was added, and the mixture was left at room temperature overnight. Ice was added, the mixture was stirred for 4 times for 30 minutes, and then mixed twice with 60 ml of chloroform. After washing the extract with saturated brine and drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified with silica gel and chloroform-methanol-71z (100:1). A pale yellow r△ amorphous island-like target material of 2.02 was obtained.

Engineering R (KBr) crn”: 1760.16?0.
1215.1200'H-NMR (ODC!t3, δp
pm): 125.1.27 (Tota191 (, 4 days each), 1.6-1.9 (2HSm), 2.27 (
3HSs), 2.4-2.8 (11H,m), 3.
4-3.6 (4H, m), 5.13 (2H, bra),
6.97 (2HSd, J==a6Hz), zl(
2H, d, J=8.6Hz), 7.25.7.53
(Total 5 H.

4 days each) Central blood case 112 N-[1-(1)-acetoxybendi/V) -2-
(4-penzyloxycarbonyl homobiberazine/L/
) Ethyl)-N-methy1v-s-isoquinolinesulfonic acid amide The anionic 12 obtained in Reference Example 27 was converted into methylene chloride 28-
2.6-/cytidine2tnl', (7
2 ml of t-butyldimethylsilyltrifluoromethanesulfone was added to the mixture at room temperature with stirring.
Inhaled and expelled for 6 hours. Add ice to the reaction solution and then add 70m7 of ethyl acetate! The residue obtained by distilling off the solvent under reduced pressure was treated with 20 rats of tetrahydrofluff and added with 1.0 ml of tetrabutylammonium fluoride under suction and evacuation. A 0M tetrahydrofuran solution (4.28 Tnt) was added, and the mixture was stirred at room temperature for 40 minutes. After adding ice to this, it was evacuated twice with chloroform at 70rnt, the 1111 eluate was washed with saturated brine, dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the chloroform-methanol (95:5 ~90:10) from the fraction 1-[3'
-(p-acetoquinphenyl)-2'-(N-methylamine)propyl]-4-penzyloxylponylhomopiverazine 723η was obtained.

IH-NMR (cDat3, δ1>pm): 1.8
(2H, m), 2.3 (3H, s), 2.48 (3H
, d, J=2.017z), 2.35-3.8 (9
H, m), 14-3.6 (d H, m), 5.1 (
2B1B), 7.0 (2H, d%J=a5Hz),
7.2(2H,'brd, ,T=&5H2), 7.3
5 (5H, s) The obtained product 723η was dissolved in nomethylformamide 25r
After adding 401 mg of triethylamine to the solution, 564 η of 5-isoquinolinesulfonyl chloride hydrochloride was added to the mixture under water cooling No. 1, and the mixture was stirred at room temperature overnight. After adding water to the reaction solution, extract twice with ethyl acetate) v70-,
Wash the extract with saturated saline, dry with magnesium sulfate,
The residue obtained by evaporating the solvent under reduced pressure was applied to a silica gel column and purified with chloroform-methanol (100:1) to obtain a pale yellow sterile dog product 796.

'H-NMR (cnat3, δppm): 1. −
7 (2H, m), 2.3 (3H1s), 2.7-2.8
(s H,m), 2.90.2.91 (Total
5H, each θ), 3.3 to 3.55 (4HSm), 4
．． 1 (IHSm), 5.1 (2H,s), 6.7 (2
H, d, J=a3Hz), 6.9(2H, d, J=
a3Hz), 7.34, 7.36 (Total 5H,
8), 7.53.7.55 (Total IH.

t, J=7.6H2), al (I H, d, , respectively)
T=6.1 H2), al 8 (2HSd%J=&5
Hz), a55 (l)1. d, ,T=6.1
H2), 9.25 (IH,s) Implementation VA1115 N-[2-(4-penzyloxylponylhomopibewazini, v)-1-(p-hydroxybenzi)v)enal]-N-methy /v-5-Isoquinoline sulfone 1 Shunamide The non-weight aoomg obtained in Example 112 was dissolved in methanol 1
10 parts of caustic soda and 2 parts of sodium hydroxide were added thereto, and the mixture was stirred at room temperature for 10 minutes. The reaction solution was once made weakly acidic with a citric acid aqueous solution, then made weakly alkaline with a saturated sodium bicarbonate aqueous solution, and then oiled twice with 50rnt of chloroform.
After drying with magnesium fluoride, the solvent was distilled off under reduced pressure, and the resulting product was applied to a silica gel column to obtain the target product 339η of chloroform-methanol heat exchange.

Engineering R (KBr) cm': 1700, 1330
, 1210, i+50.

120 IH-NMR (C!DOt3, δppm): i.
8 (2H, m), i. 37.

L 3 8 (Total I H, each dd, J
= 1 0.0, 13.8Hz), 1, 5 5 (I
H, dd, J=1 3.8, 9.8Hz), 2.7
5 (dH.

m), 2.7-3.0 (2H, m), 3.0 (3H,
e), xs (4n.

m), 3.8 (IH, m), 5.13 (2I (, day),
&17(2H.

d, J=aOHz), 6.5 0, 6.5 1 (
Total 2H, each d1, y=aouz), 7.1
9, 7.50 (Total IH, each t, J= 7
．． 7 H Z ), an 3 ( I H, a, J
=6.1 Hz), a13(1H.aSJ=7.8H
z), a23 (IH, d,, T=7.IHz), 6, 4
3 (IH%d1,T=/1.IHz), 9
．． 24 (II (, s), 7, 35 (5H, s) Example 114 220 μ of the anhydrous substance obtained in Example 113 was dissolved in 2-acetic acid, and 25 μm of hydrogen bromide/vinegar: Shun?gt.6 After stirring at room temperature for 20 minutes, 40rnt' of dry ether was added and the resulting white precipitate was made alkali 4 with a saturated aqueous sodium bicarbonate solution, followed by chloroform-impropano-)V (5
: 1) Oil came out twice at 20-. The extract was dried over magnesium monoformate, and the solvent was distilled off under reduced pressure. The resulting residue was applied to a silica gel column and purified with chloroform-methanol (20:80-30:0) to give a pale yellow oil. N-(1-(p-hydroxy)benzyl-2-homopiperazinylethyl-N-methyl-5-isoquinolinesulfonic acid amide 67m7 was exhaled.

"H-NMR (ODCt3, δppm): 1.7
5 (2H, m), 2.3~in (1 2H, m
), 2.93 (3H, e), 3.96 (IH, m), 5
, 3Hz), al 2 (IH, d, J=a5Hz), 8
．． 2 (IH.

d, J=7.4Hz), 8.4 5 (I H, d
, J = 6.1 Hz), 9, 26 (IH, 8) Reference Example 28 1-benzyloxycarbonyl- -butoxycarbo-rutyrosyl) homopiperazine N-t-butoxycarbo-rutyrosyl 15.29P, N
-penzyloxylponyl homopibedine 1 2.
7 3 1 was dissolved in 7hydrofuran 28o-, and 1-hydroxybenzo)IJ7so/l/hydrate a09? was dissolved at room temperature under stirring. and DCO'+1.771 were added and stirred for 16 hours. The solvent was distilled off from the reaction solution under reduced pressure, and benzene was added to the resulting residue, the insoluble matter was suctioned out, the insoluble matter was washed with benzene, and the combined benzene layer was distilled off under reduced pressure to obtain the residue. Taroroformmumekno/l/ (100
: Created with 1) and colorless :'! fl; crystalline island-like 26.
I got 422.

'H-NMR (aDat3, δppm): 1.11
(9H, s), 1.5-2.0 (2H, m), 2.7
5-3. ,05 (2H,m), 505~3.7(8
H1m), 4.67 (IHSm), 5.1 o, 5.
12 (Tota12H, 8 each), s, 2s (1H,
m), 6.0 (IH, br), 6.68.6.72 (T
otal 2H1 each a%y=as7Hz), 7.02
．． 7.03 (Total 2H, each d1 J=a5
7 Hz), 7.32, 7.34 (Total 5H, 4 days each) Example 115 ) Benzyl]ethyl)-5-isoquinoline sulfone 5. The heavy body was dissolved in 20 ml of tetrahydrofuran,
1 mo/L/M run-tetrahydrofuran solution τ night 24-
was added and stirred for 15 hours at 7++N in a nitrogen atmosphere. After the reaction was completed, the solvent was distilled off under reduced pressure, and 52 ml of potassium hydroxide was added to the resulting residue, which was stirred at room temperature for 30 minutes and then extracted twice with 200 ml of chloroform. The extract was dried over magnesium sulfate and the solvent was distilled off under reduced pressure.
1-Penzyloquinyl-4-(2-(t-butoxycarbonylamino)-3-(p-hydroxyphenyl)furopi/di)homopiperazine in ethyl acetate/I/6-
A solution of 4N hydrogen chloride in ethyl acetate (50°C) was added thereto, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was distilled off under reduced pressure, and the residue was saturated; 1. Add r1 sodium bicarbonate aqueous solution,
After making it alkaline, it was extracted twice with 200ml of chloroform, the extract was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 1-[2-amino-3-(p-hydroxyphenyl)propyl]. -4-penzyloxylponylhomobiverazine 2.4! 5-isoquinoline sulfonyl was dissolved in 65% of tetrahydrofuran and heated in a room with stirring.
'Y1. '4 4. 9 tnl of ethylamine was added and the mixture was stirred for 16 hours.

Add 1 solution of sodium bicarbonate to the reaction solution and extract twice with 300 ml of chloroform. After drying the extract over magnesium sulfate, the solvent was distilled off under reduced pressure and the resulting residue was applied to a silica gel column. , chloroform-methano-/L
/ (20:1) fn lu L/ colorless and sterile object 2.26? I got it.

'H-NMR (cDat3, δppm-): 1.
43 (2HSm), 2.2 (6H, m), 2.7s (2
a, m), 2.9-3.4 (5HSm), 5.07
(2T(,s), 5.34(1H,br), 6.62
(2H, a.

J=B, 57H2), 6.8! , 6.86 (Tota'
12H, each d1, T=a57Hz), S32, 7.3
4 (Total 5H, each θ), 7.63 (11 (1
t%, T=&28Hz), 7.67 (IH, m), al
6 (I H, t, J=a28H2), 7.67(
IH,m), al 6 (IH,t, , T=7.4
2Hz), a22-ad5 (4H.

m), as 3 (I H, d%J=6.28H2),
a66 (1H1dd, T=6.57.1.0Hz),
as 2 (I H, a, J: 6.28Hz),? ,
31.9.34 (Total IH1 each), 9.4
2 (IH18) Prison Example 116 Dissolve 1.02 of the product of Example 115 in methanol (5), tetrahydro (7), and add 1N caustic soda (1).
0! d was added, heated under reflux for 2 hours, cooled, made acidic, made alkaline with sodium bicarbonate, added methanol to the precipitated insoluble matter, and dissolved twice with 100% chloroform. The extract was dried over magnesium sulfate, and the resulting residue was purified using a silica gel column (chloroform-methanol 20:1) to obtain Qi (rapidly heated islands of ir-(2-(4)). -penzyloxycarboni!lehomopiverazinyl)-1-(p-
458η of hydroxybenzyl)ethyl)-5-isoquinolinesulfonic acid amide was obtained.

'H-NMRCcDct3, δppm): 1.7
2 (2H, brs), 2.3-2.9 (8H, m)
, 3.1-3.7 (5HSm), 5.12 (2H18
), 6.27 (2)1. d, J=7.32Hz)
, 6.57 (2H.

d, J=7.32Hz), 7.6(IH,br),
7j3 (6H.

e), 7.63 (IH, t, , T=7.57H2),
ai7(1H1a.

J=a3t+z), a33(2H,d, , T=7.0
8Hz), a52 (1H, brs), 9.28 (IH,
brs) Example 117 N(1-Cp-(s-isoquinolinesulfonyloxy)
benzy/V)-2-homopiperazinylethyl)-5
-Isoquinoline sulfonic acid amide To 1.01 l of the product of Example 115 was added 30 hydrogen bromide dissolved in acetic acid at room temperature for 4 minutes, followed by further stirring for 24 hours. 100% of ether was added to the reaction solution and stirred for 30 minutes, and the precipitated salt was washed with ether in a suction furnace and dried in a desiccator.

Dissolve this in water, make it alkaline with sodium bicarbonate (make it raw, then extract it twice with 100 d of chloroform, and sap the extract.
The residue was dried over magnesium I12, and the solvent was distilled off under reduced pressure to obtain the desired product 830 in the form of colorless islands.

'H-NMR (aDcz3, δppm): 1.3
7 (2H, m), 2.1-2.9 (12H1m), 3
．． 22 (IH, m), 6.62 (2H, d.

,T=a79f(Z),6.87(2)ISd, ,T
=a54Hz), 7.64 (I H,t, J=7,
132Hz), 7.66 (IH, t, J=7.82
Hz), 8.18 (IH, d, , T=a51Hz),
a23-a36 (3H, m), a40 (I H, d,
J=6.35Hz), 8.55(IH,d,
, T=6.1 Hz), a67(IH, d, J=6.
11Hz), a81 (I H, d, 1=6.55H
2), 9.36 (IH, 8), 9.42 (IH, s) - Example 118 N-(1-(p-(s-isoquinolinesulfonyloxy)benzyl)-2-(4- (3-phenylpropioni)
V) Homopiperazinylethyl)-5-isoquinolinesulfonic acid amide 420 η of the 9+jζ crystal obtained in Example 117 was dissolved in methylene chloride 6-, and 125 η of 3-phenylpropionyl chloride and 100 ai of 1' ethyl amino were dissolved under stirring at room temperature.
1 YF was added and stirred for 17 hours.

The reaction solution was made alkaline with a saturated aqueous sodium bicarbonate solution, then evaporated twice with chloroform (50%), dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. /l/(
30:1) to obtain colorless; island-like target product 400η.

IT(-NMR(cvct3, δppm): 146
(2H, m), 1.9-2.4 (6H1m), 2. a
~2.6 (2H, m), 2.6 ~ 2.82 (2H,
m), 2.82-2.98 (2Hlm), 2.9
s ~ x12 (IH.

m), 3.12-5.53 (3H, m), 3.4 (
1H,t, :r=6.28H2), 6,61, 6.
63 (Total 2H, each d, J=&57H2
), 6.82, 6.85 (Tota12H, each d,
J=a57Hz), 7.1~7.35 (5H, m
),y,6,1(1H,t.

J=a28Hz), 7.66(IHSt, J'=a28
Hz), a1~a45 (5H, m), a, s 2
(1H, a, J=6°28Hz), 8.67 (I
H, da, , T=6.28, j, 0Hz), &82(
IH.

d, J=6.28Hz), 9.33.9.34(T
otal IH, each S), 9.42 (IH, Japan) Real i + li Example 119 N-(1-(1)-Hydroxybendi/L/ ) -2
-C4-(3-phenylpropioni)V) homopiperazinylethyl)-5-inquinolinesulfonic acid amide Obtained in Example 118: JIIQ crystalline 00η
IV 2 ml, dissolved in tetrahydrofuran 2-
After adding 1N caustic soda and heating under reflux for 5 hours to make it acidic, it was made alkaline with sodium bifusate, and the precipitated insoluble matter was removed with a small amount of heat. Dissolved in methanol] (then eluted twice with chloroform (50°C). After drying the extract over magnesium merate, the solvent was distilled off under reduced pressure, and the residue was applied to a silica gel column, and taloloform-methanol was dissolved. (30:1) and purified with 211 (color) 11
(We obtained a box-shaped object of 250η.

11(-NMR(cvat3, δppm):
1.64 (2H, m), 2.3~2.85 (
10H, m), 2.96 (2HXt1J=a3Hz
), 515-3.6 (5H1m), 6. ! +1.6.3
5 (Tota12H.

d, , T=a30H2), 6.57.6.61 (
Total 2H.

d, J=8.3 [)I-1z), 7.1~7 respectively
．． 4 (5HSm), 7.65 (IH, t%, r=a06
H2), 8.19 (IH, d, J=a23Hz), a
25-a4 (2H, m), a55 (IH, d, ,
T=6.28H2), 9.32 (IH,s) Reference Example 29 1-penzyloxycarbonyl, I-(N-t-ptoquine carbonyl 10-methyl) tyronylhomopibevodine Amorphous material 5.01 obtained by carrying out Reference Example 28 was mixed with 25 ml of tetrahydrofuran and 25 ml of dimethylformamide.
60% sodium hydride and 0.4% sodium hydride dissolved in water-cooled with stirring.
After adding No. 17, the mixture was returned to the room and stirred for 30 minutes. Next, 1,435' of methyl iocide was added, stirred for 16 hours, saturated brine was added, and the mixture was extracted twice with 300...l of chloroform. After drying the extract with magnesium oxide, the solvent was distilled off under reduced pressure.
100:1) to give the target compound 3,76 F (color; i = crystalline islands).

'H-NMR (CDC43, δppm): 1,4
1 (9H, s), 1.65-2.0 (2HSm), 2
．． 8-3.0 s (2H, m), 3.05-5.6
5 (8H, m), 3.77 (3H1B), 5.68 (I
H, m), 5.10 (2H, s), 5.23 (IH, m
), 6.79 (2H, d, J=8.3H2), 7.
11 (2H, dS, T==8.54Hz), 7.3
3 (5H1B) Reference Example 30 1-(N-t-butoxycarbonyl-O-methy)V) thyron)v-4-phenylacetyl homopiperazine Reference IMI 29 pjjlH crystal monomer 029
The mixture was mixed with 25-ml methanol, 250 ml of 54 palladium/carbon was added under ice-cooling, the temperature was returned to room temperature, and catalytic reduction was performed for 6 hours. After cleaning with methanol/distillate, the resulting methanol solution was distilled off under reduced pressure (N-t).
-Butoxycarbonyl-〇-methyl)tyrosine homopiperazine, 800 lbs., was obtained. This 400-.eta. was dissolved in 6-methylene chloride, 195 .mu. of phenylacetyl chloride and 190 .mu. of triethylamine were added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was made alkaline with Betsuwa heavy carbon; Ka soda aqueous solution, extracted twice with 100 ml of chloroform, the extract was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue. was applied to a silica gel column and purified with chloroform-meth/-Az (50:1) to obtain the desired product 433η in the form of colorless 7ijlH crystals.

'H-NMR (apC43, δppm): t41
(9H, s), 1.6-2, o(2H, m), 2.7
~3.75 (12H, m), 577°3,78 (T
otal 3 H1 each 8), 4.65 (11 (, m)
, 5.13° 5.2 A (Total I H, each,
za, J:=9.14Hz), 6.78°1, . 79
(Total 2H, each a1.7=9.71 Hz
), 7.08.

7, 11 (Total 2 H, each d1.T=9.7
1 HZ), 7.28 (5HSm) Example 120 1-4N-(5-isoquinolinesulfony)V)-〇-methyl]tyrosy)v-4-phenylacef tV Homopiperazine 31 (obtained in Reference Example 30) (Convex body 436~ is methiacetate JV
A solution of 4N hydrogen hydroxide in ethyl acetate dissolved in 1-5
After stirring at room temperature for 30 minutes, the bath soot was distilled off under reduced pressure, and an aqueous sodium bicarbonate solution was added to the resulting residue, which was extracted twice with 50+ nt of chloroform. The extract was dried with magnesium arsenate (after drying with magnesium arsenate, the solvent was distilled off under reduced pressure, 6 rnt of tetrahydrofuran was added to the obtained residue, and the mixture was incubated at room temperature with 5-isoquinolinesulfonyl chloride borate 275#).51. ) Add ethylamine 1,2-,
I pressed the camellia for another 18 hours. The reaction solution was made alkaline with an aqueous solution of sodium bicarbonate (IN) and 50% chloroform.
nt has released two songs! I1lc was dried over Shun magnesium, and the insoluble ■ was distilled off under reduced pressure.
chloroform-methanol (30:1
), TI′? Manufactured and colorless: Box-shaped object A59r
ng was improved.

'H-NMR (aDC43, δppm): 15~
1.9 (2HSm), 2.4-2.9 (3H%m
), 2.9-4.0 (9H, m), 5.67°3.
68. S, 70 (Total 3H, each θ), 4
．． 18 (IHlm), 6.18 (IHlm), 6.25
~6.5 (2H, m), 6.7 (2H, m), 7.
28 (5H, m), 7.54.7.56 (Total I
H, respectively t, , T = 7.81Hz), 8.09 (1H
,t, ,T=7.81Hz), al5~a3(2H
, m), 8.63 (IH, m), 9.22, 9.26 (
Total IH, 4 days each) Example 121 1-[N,O-dimethyl-N-(5-isoquinolinesulfonylcetylhomopiperazine) The anhydrous body obtained at 120 was dissolved in tetrahydrofuran 2.5 me, dimethylpho JV Amide 2.
5-, add 60 ml of sodium hydride under water cooling, return to room temperature, stir for 30 minutes, and dissolve methyl iodide Az1.
10η was added and the mixture was further stirred for 16 hours. After adding saturated saline to the reaction solution, it was extracted twice with 50 trt of chloroform. The product was purified with chloroform-methanol/1z (50:1) to obtain 348 .mu. of the desired product in the form of colorless islands.

'H-NMR (aDct, , δppm): 1
．． 5-2.0 (2H, m), 2.2-4.0 (12
H1m), 3.03.3.07. i08.3.19 (
Tota'l 3H, each 0), 5.71.3.73.
3.75 (Tota13H, each S), 49 (1H, m
), 6.5-6.78 (2H, m), 6.78-7.0
(2Hlm), 7.26 (5H1m), 7.68 (I
H.

m), a1 to a33 (2H1m), aa2 (1H1m)
, F, 66 (IH, m), 9. s2(1HSm) Example 122 1-benzyloxycarbonyl--bis(5-isoquinolinesulfony/I/)tyrosyl]
Homopiperazine Anonymous 6. obtained in Reference Example 28. a a y as ethyl acetate/
V 6-, add 60 rnl of 4N hydrogen chloride/ethyl acetate solution under stirring at room temperature, stir for 3 hours (17+), then evaporate the solvent under reduced pressure, and then add benzene and reduce the pressure. After adding 130+v+/'i of tetrahydrofuran to the island-like 1-penzyloxycarboni)v-4-tyrosylhomopiperazine hydrochloride obtained by distilling off the solvent, 5-isoquinoline! To the mixture were added 7.881 l of lefonyl chloride and 18 mj of triethylamine, and the mixture was stirred at room temperature for 18 hours. After making the reaction solution alkaline by adding saturated aqueous sodium bicarbonate solution, 700 d of chloroform was added.
The extract was dried over ii+Ie@magnesium, the solvent was distilled off under reduced pressure, the resulting residue was applied to a silica gel column, and chloroform-methanol/shock 30:1
) and purified to colorless 2j! (A convex object 5501 was obtained.

'H-NMR (CDCl2, δppm): 1.
65 (2H<m), 2.4-3, 8 (10H, m),
4.17 (IH, in), 5.1 (2H%m), 6, 0
2(11(, d, J=9.52Hz), 6.d 7
, 6.5 1 (Tota12H, each a, y=a
．． s 5Hz), l,, 7 5(2H, a, J
=8.5 sHz), 729, 7. 3 3 (To
tal 5 H, each θ), 7. 5 8.

7, 60 (Total IH, 1z t each,
J=aO 6Hz), a 1 to a 3 (5HSm)
, &52(IH,a,:r=b.11Hz), &64(
IH, aS:r=6.10Hz), a8 4
(I H%d, , T=5.37Hz), 9.29
(IH, s), 9.41 (IH, 8) OL Example 123 1-PendyloxycarbonyiV-d-(N-(5-isoquinolinesulfonyl)tyrosyl) Homopibewodine Example 122 1) Anhydrogen 5 ．． 50 S' in methanol/l/50 ml, tetrahydrofuran 30-
Add 60 ml of 1N caustic soda, heat under reflux for 2 hours, cool, and make the mixture acidic.
Make alkaline with sodium carbonate, dissolve the precipitated insoluble matter with a small amount of methanol, and then dissolve the aqueous layer in chloroform 4.
Extracted twice with 0 0 rnl. After drying the extract over magnesium sulfate, the solvent was distilled off under reduced pressure, the resulting residue was applied to a silica gel column, and chloroform-methanol (2
0:1) to obtain 2j ((French island-like object 5.12).

'H-NMR ((:!DOt3+CD30D, δpp
m): 1.82 (2H.

m), 2.48 (1H1m), 2.6 8 (I H
, a t, J=6.8 s, 5, 71 Hz), 3.
1 ~ 5.8 (8HSm), 4.1 6 (IH,
m), 5, 1 2, 5.1 3 (Total 2H
, 8), 614, 6.17 (Total 2H, a, .: r = assHz), 6.52, 6.55 (T
otal 2 H, each d, J = a5 5Hz)
, 733.

7, 3 5 (Total 5 H, 4 days each), 7
．． 61 (IH, m), ai 6 (IH, a,
J=ao 6Hz), a2~a45 (2H.

m), a53 (IH, a, J=6.1 1Hz),
q. 2 1 (IH, 8) Reference Example 31 N-Penzyloquine 1-(N -Penzyloquincarboni/L/) Tyroneruat-t-ptoxycarponylhomopiverazine is completed 411.

'H-NMR (a Det3, δppm
): 1.42, 1.44 (Tota19H
, respectively B), 1. 6 ~ 2.0 (2H, m
), 2.7~s-a (10H.

m), 4.75 (1 H, m), 5.0
4 (I H, a, :r= 1 1.4
2Hz), 5.13(1)(,d, J=11.12
Hz), 5.5 (IH.

m), 6.72 (2H, m), 7.02 (2H%m)
, 7.3a (sH.

S) Reference Example 32 1-(O-acetyl-N-benzyloxycarbonyl)
Tyroshi/V-4-t-butquincarbo-ruhomobipewodine 690η of the anhydrous substance obtained in Reference Example 31 was mixed with 7 m of pyridine.
Dissolve in 1 liter of Sakai and add 5.5-mL of acetic anhydride while stirring.
After stirring the reaction solution for an hour, the reaction solution was made alkaline by pouring it into an aqueous solution of sodium carbonate.
Extracted twice at t. The extract was washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified using a silica gel column using chloroform-methano-IV (100:1) as an eluent, and a colorless measurement was performed. A tall object of 670η was obtained.

'H-NMR (CDC13, δppm): 1.4
1.1.43 (Tota19H, 4 days each), 1.5-2
．． 0 (2H, m), 2.28 (3H, s), 2.8
~17 (10H, m), 4.7 (IH, m), 5.
05(II(.

dSJ==11.4Hz), 5.13(IH,d,
J=11.4Hz), 5.52 (IH, m), 6.
99 (2H, d, J = 7.42Hz), 7.21 (2
HXdSJ=7.42Hz), 73a(sH,s) Reference Example 33 1-(0-acetyl-N-penzyloxycarpho=/
L/)-F-rosi)va-(5-phenylfurovir)homopiperazine Obtained in Reference Example 32; i! Dissolve the IE crystal hexamer ■ in acid 1 ethyl/I/2-, add 5N hydrogen chloride/ethyl acetate solution 7- while stirring at room temperature, stir for 30 minutes, make alkaline with an aqueous sodium bicarbonate solution, and add salt. After saturation, the mixture was extracted twice with 100 ml of ethyl acetate. The extract was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 1-
(0-acetyl-N-penzyloxycarbony)V)
Tyrosylhomobiveozin A601rqf was dissolved in 60 parts of dimethylformamide and dissolved in 1 part of charcoal with stirring at room temperature.
50 ■, Sodium iodide 160 fIv, 1-Bromo-5-
210 ml of phenylpropane was added and stirred for 20 hours.

After adding saturated saline to the reaction solution, chloroform 10
Extracted twice with a low-pressure filter, dried all extracts with magnesium formate,
The /A residue obtained by evaporating the solvent under reduced pressure was applied to a silica gel column and purified with chloroform-methanol-7v (1oo:1) to give colorless F! Obtained 430 ■ of t+i crystal clear objects.

lH-NMR (CDC43, δppm): 1.5
~2.0 (6H, m), 2.26 (3H, 8), 2.3
~2.7 (6H, m), 2.9~xa (6H, m)
,4. (1 (IHSm), 5.03 (I H, d, ,
, T=11.99Hz), 5.12 (I H,d,
J=11.99Hz), 5.6 (IH.

m), 6°97 (2H, ddSJ=a57.1.0H
z), 7.1 to 3 (7HSm), 7.33 (5H, s
) Reference Example 34 1-(3-phenylfuropi)v)-a-tyrosylhomopiperazine Obtained in Reference Example 33; l! ! I: 430 cm of the box was dissolved in 5 Tnt of methanol, 120 μ of potassium carbonate was added while stirring at room temperature, and after stirring for 70 hours, saturated saline was added, the mixture was acidified with citric acid, and extracted twice with 100 d of chloroform. . The extract was 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 chloroform-methanol/l/(100:1) to obtain N-penzyloxycarboni)V) Tyrosyl-a-(3-phenylpropy)v) Homopiperazine 3
I got 95 ■. This is methano-)V 15 mj! 0.05 d of palladium and 5 d of palladium under ice cooling.
Add 150 μm of carbon, return to the chamber, and place in a hydrogen atmosphere for 8 hours. Suction filter the palladium and carbon. Combine the electrolytic solution with P solution using methanol, and place under reduced pressure. After distilling off the solvent, add 1 ton of water to the residue, make it alkaline with an aqueous bicarbonate solution, add a small amount of methanol to the precipitated insoluble matter, and add 80T of chloroform.
Extracted twice with nt. The extract was dried over magnesium oxide, and the solvent was distilled off under reduced pressure. The residue was applied to a phosphoric acid gel column and purified with chloroform-methanol (20:1) to give 180 ml of a colorless and heavy substance.

'H-NMR (CDC13, δppm): 1.7
5 (4H,'m), 2.3-2.8 (10H, m), 2
．． 9z (1u, m), 3.1~! 1.8 (4H.

m), 3.86 (I H, q, J=6.28Hz
), 6.65, 6.66 (Total 2 H, each d
S J = a57Hz), 6.99, 7.00 (Tota
12H, each Ad, T=8.57H2), 7.1-7.
35 (5H, m) Actually, Example 124 1-C1i -(5-isoquinolinesulfonyl)tyrosyl']-4-(3-phenylderohyde) 71 Electromopiverazine Anhydrous body 180~ obtained in Reference Example 34 was dissolved in tetrahydrofuran 4rnt 5-isoquinoline! and stirred at room temperature.
Lefonyl chloride h! (211!157), 0.2-triethylamine was added, and the mixture was stirred for 15 hours + W.

A solution of sodium chloride was added to the reaction surface, and the mixture was made alkaline with sodium bicarbonate, the resulting insoluble matter was made oily with a small amount of methanol, and the mixture was evaporated twice with chloroform (50°C). The extract was dried over magnesium b+ie acid, and the solvent was distilled off under reduced pressure. The residue was subjected to a silica gel column and preparative TLC to obtain a sterile target product 150 with a chloroform-methanol color.

'H-NMR (CDOt3+ C!D30D, δpp
m): 1.76 (IIH.

m), 2.3 to 2.8 (10H, m),
3.1~3.7 (4H, m), 4, ++ (1HS
m), 6.1 7, 6.1 9 (Total 2H
, respectively d1J=a57Hz), 6.53, 6.56(T
otal 2H, each d1J=a57Hz), 7. 1
~7. 4 (5H1m), 7.57, 7.59 (
Total IH, respectively t, J=a2sHz), a1
2 (1H.

a,, T=8.28Hz), ELl 5 ~ 8.3 5
(2H1m), a53(I H, dd, :f
=6.2 8, 1.0Hz), 9.18 (IH, S) Reference Example 55 1-[:N-(t-ptoxycarbony)v)-p
Nitrophenylalanine) v) - a (p-Methoxyphenylated/L/) Bibeodine N-(t-Ptokinka/L/GenyiV) -p-Nitrophenylalanine9. 0 Of is a 1@ solution of tetrahydrof9, 120, form, 100, and N-(p-methoxypheni)V) bibewadine dihydrochloric acidJu7.6EM'toN-hydroxybenzotriazole monohydrate 4,d4
f,)! J:r-f le
7 min 20 ml and Dcc
61 was added to the illJ, and after stirring at room temperature for 18 hours, it was concentrated under reduced pressure to a μ volume and 200 ml of 2.54 carbonic acid aqueous solution was obtained.
After adding 200m7 of chloroform! I released the song twice. 1 stream of oil extract: dried with magnesium acid, l under reduced pressure
Wash the crystals that precipitate with methanol and
H fm crystal object 1 0. I got 7 5 F.

'H-NMR CODOt3, δppm): 1.4
0 (9H, s), 2, 73 (111, m), 2.8
7 ~ 3 [0 (3H1m),! L04(1H,
dd, J=6.3, 13.2Hz), s. 17(
I HSaa, , y=73, 13.2Hz), 3.3
5 (1HSm), A55~! To. 70 (2H, m),
3.77 (3H18),! 1.81 (ILm), 4,9
2 (IH, m), 5.4 (I H1d1J==a8
Hz), 6. ax (4H.

S), 7.38 (2H, d, , T=a8Hz), a
1/+(2H1d1J=a8Hz) Reference Example 36 1-(N-(t-ptoxycarboni)v)-p
-aminophenyl awoni/l/ ) - 4 - (
(p-methoxyphenyl)hibewazine Crystal obtained from Reference Example 35 10. 7 5 f is a mixed solution of tetrahydrofuran 100- and methanol/l/20-, and to this, 5 ml and palladium/carbon 52 are added.
was added, and the mixture was stirred for 2 hours in a room under a hydrogen atmosphere. One flf't from which insoluble matter had been removed was concentrated under reduced pressure, and the resulting residue was applied to a silica gel column, followed by chloroform-methanol-lv (20:1-10).

:1) Purified colorless; +! t' Item Object 1 0.
0 81.

'H-NMR (CDCl2, δppm): 1. d
3 (9H, s), 2.42 (IH, m), 2.75
~3.00 (4H, m), 3.13 (1H1m), 3
．． a3 (IH, m), 3.57 (IHSm), 3.63
~x73 (2a, m), 3.76 (3H, ET), 4.
78 (IH, m), 5, 43 (IHSbr), 6.5
9 (2H, d, J=a3Hz), 6, 82 (
4H, s), 6.9 8 (2H, d, J=a3
Hz) Reference Example 37 1-(3-(p-aminophenyl71z)-2-
(t-butoxycarbonylamino)propyl]-4
-(p-methoxyphenyl)hiverazine lithium aluminum hydride2. 5/iS
' was suspended in tetrahydrofuran 75-, and to this was added 75tt of ether of aluminum chloride a912 (Liquid B) under water-cooling, and the weightless to, obtained in Reference Example 36, was further cooled with water.
A 100% solution of OSY in tetrahydrofuran was added dropwise over 20 minutes. After stirring in that state for 1 hour, add a small amount of water to stop the reaction, then 5a4p+@potash water'f8
i'& 70- and 200 m/chloroform were added, and insoluble matter was removed from the mixture using silica gel as an auxiliary agent. 20 insoluble matter
4 Wash with a chloroy11) L/mu solution of methanol, combine with the furnace liquid and concentrate under reduced pressure. Add 200% of a saturated aqueous bicarbonate solution to the residue, and then extract twice with 100% of chloroform. The resulting residue was dried over sulfuric acid and magnesium and concentrated under reduced pressure.
Purify with methanol (100:1) and extract
Crystalline target product 1722 was obtained.

'H-NMR (CDC13, δppm): 1.43
(9H, s), 2,30 (2H1, d, J=48Hz)
, 2.48~2°68 (8H, m), 2.78 (2H
, t, J==6.3Hz), io 6 (4H, t
, J=4.9Hz), 5.76(5H,e)1. &8
6 (IH, m), 4.59 (IH%br), 6.62 (
2) (, d, J=a3Hz), 6.82 (2H, d,
J = 9.3H2), 6.89 (2H, dSJ = 9
．． 3Hz), 6.98 (2H, dS, T=a3Hz)
Reference Example 38 1-(2-(t-butquincarbonylamino)-3-(
p-phthalimidopheni)V)propyl]-1-(p
-methoxyphenyl/l/)L'perazine 7. D? was dissolved in 70% chloroform, 2.66 F of anhydrous acid was added, and after refluxing with IAI heat for 1 hour, the mixture was evaporated under reduced pressure, 100% of toluene was added, and the mixture was further heated under reflux for 2 hours. The reaction solution was distilled off under reduced pressure to remove the solvent, and the resulting residue was applied to a silica gel column to give chloroform/methano/l/(100:1 to 50:1).
Purification was performed to obtain colorless crystals a912.

+ 1(-NMR(C!DC/, 3, δppm):
1.45 (9H, S), 2.37 (2H1d, , T=
6.8H2), 2.51-2.71 (4HSm), 2
．． 96 (2H1d, :J=5.4H2),! 1. o
9 (4n, t, J==4.9H2), 3.77 (31
(,8), 4.01 (IH, m), 4.66 (IH%b
r), 6.85 (2H, d, J=9.3Hz), 6.
90 (2H, d, J=9.3Hz), 7.36 (4H
Ss), 7.7 q (2HSad, , T=!1.4
．． 5.4Hz), 7.96 (2H, da, , T=6
．． 4, s, aHz) Example 125 N-(2-Ca-(p-methoxyphenyl)hiverazinyl)-1-(p-phthalimidobenzyl)ethytV)
-5-Inquinolinesulfonic acid amide Crystal a911 obtained in Reference Example 38 was mixed with 50 m7 of ethyl acetate!
Dissolve in 100 m of 4N hydrogen chloride/ethyl acetate solution.
7! was added and stirred at room temperature for 1 hour.

The reaction mixture was concentrated under reduced pressure, 200 ml of saturated aqueous bicarbonate solution was added to the resulting residue, extracted twice with 100 W Lt of 204 methanol/chloroform solution, and the extract was dried over magnesium sulfate and extracted once under reduced pressure. Crystalline aminofury was obtained. These crystals were suspended in 120% tetrahydrofuran and cooled with 5-isoquinoline! Lefonyl chloride tll' salt 5-Or and triethyl amino 20- were added, the mixture was returned to room temperature and stirred for 2 hours, 200-200 of water was added, and the precipitated crystals were collected by filtration. The furnace solution was extracted twice with 100% chloroform, dried over sulfuric acid and magnesium, purified under reduced pressure, and condensed. The resulting residue was combined with the previous crystals, and sequentially extracted with methanol, vinegar, ethyl vinegar, and hexane. Wash; 1iIQ color crystal object6. ．． 19
? I got it.

Melting point: 204-211℃ (decomposition) Engineering R (KBr) c +++ I: 1710.1510
, 1370.1235.1150.1130 IH-NMR (CDC13, δppm): 2.0
”r ~2..53 (6H,m), 2.16~2
．． 59 (2H, m), 2.59-2.72 (2I
(, m ), 2.8 s (I H, aaS, T = 7.
．． 5.13.7Hz), 3.1o (I H.

dd, 4,4.13.7Hz), 3. al(1H
, m), 77 (3H, 8), 5.63 (IH, br)
, 6.75 (2 Hld, , T=9, 3 HZ),
6.83 (2HSd, J = 9.3Hz), 7.20
(2H.

d, J=a8Hz), 7.29 (211, d, ,
T=a8Hz), 7.74(IH, t%, T=a3H2
), v, so (2H, aaS, T=5.4.5.4H
z), 7.96 (2H, aaS: r=s, a, 5.4+
1z), a2 a (I H, d1J=a3Hz),
a48-a52 (2H.

m), al2 (IHSa, , T-6, 4Hz)
, 9J6 (IH,s) Example 126 N-(2-(4-(p-methquinphenyl)piverazinyl)-1-(p-phthalimidobenzyl)ethyl/V)
-N-Methyl/l/-5-isoquinoline/I/otonic acid amide 4.71 SF of the crystals obtained in Example 125 was dissolved in 70 g of dimethylformamide, and cooled with water to give 60 g of accumulated sodium soum, Methyl iodide/l/1- was added one after another, and the mixture was pressed for 3 hours under the same condition. After stopping the reaction by adding a small amount of water, add 20% of a saturated ammonium chloride aqueous solution.
0 d, then extracted twice with 100 ml of chloroform, dried over +k r & magnesium, and tE under reduced pressure.
#i+'i To the residue obtained by
1.22 of -1 sodium acetate was added, and the mixture was stirred at 80°C for 1 hour. After the reaction mixture was dried to dryness under reduced pressure, 200 ml of ethyl acetate was added (3 ml), and this was mixed with Japanese lignite.
Soda water solution 100m1. 4. Sequential washing with 100% salt water; 4. Dry the bag with magnesium acid, and apply IJ under reduced pressure.
The residue obtained by A MUL was applied to a silicage gel,
The mixture was purified with chloroform (100:1) to obtain the desired product (4.84 F) as colorless crystals.

Melting point: 170-172℃ Engineering R (KBr) crn': 1710 161
0.1510,1375.1500.1235.114
5.1125'H-NMR (CDC13, δppm):
2. u3 (IH%dd, J=7.3.13.2Hz)
, 2.50-2.63 (a H,m ), 2.66 (
11(, dd, J=7.3, lX2Hz), 2.82(
111, ddSJ=6.8.14.2Hz), 2.86
~2.96 (4H, m), 2.97 (3H, s), io
2 (I H, ad, , T=6.8.14.2H2
), 3.77 (AH, e), 4.52 (1H, m), 6
．． 84 (IHSs), 715 (2) (1 (1,, T = 8
．． 8Hz), 7.22 (2HSa, :r-a8H2
), 7.61 (IH, t, J=7jHz), 7. s
1 (2H, aa, J=2.9.5.4Hz), 7.9
7 (2H, dd%, T=2.9.5.4Hz), al
3 (I H, d%J==a3Hz), a31 (
2H, d1J=6.1)iz), a60 (I H, d
, :f=6.5Hz), 9.23(IH.

B) Example 127 1.52 of the crystals obtained in Example 125 were converted into ethanol-iv
3 D d I/C1%i cloudy, hidden
Add 3 ml of chlorine, heat for 1 hour, add 100 ml of aqueous sodium chloride solution, and add 30 ml of chlorine.
Extracted twice with l. Dry the extract with magnesium sulfate,
The crystals obtained by concentrating under reduced pressure were mixed with ethyl acetate-methanol/V
Washing with a mixed solvent gives N-(+-(p-aminobenzi/I/)-2-(4-(p-methquinpheni)V)piperazinyl]ethyl/L/)-5-isoquinolinesulfonic acid as pale four-color crystals. Amide 1.142 is good.

Melting point: 210-217°C IR (KBr) cm-': 1615.1510
．． 1330.1245.1225.1150, 1130
, 1025'H-NMR (cDct3, δppm)
: 2.12-2.34 (6H.

m), 2.55-2.72 (5HSm), 2.8
s (IHSaa, J=4.9.14.2Hz),
5.31 (IH, nf), 3.52 (2H, br),
x77 (sals), 5.48 (IH, br), 6.4
3 (2H, d.

J=a5H2), 6.75(:)'t-1,d, J=
9.5 HZ ), 6.77 (2H, d, , r=a3
H2), 6.83 (2H, d, :J=9.5Hz),
7.70 (IHSt, J=7.8Hz), a2o(+
H, a, :r=asHz), B, a a (I H,
a, J=6.11 H2), aa7(1H1dcL,
, T=1.0.7.3H2), a68(IHla,
J=&4Hz), 9.35 (IH, s) Actual gun example 128 The 4.64 SF of the crystal obtained in Example 126 was ethanolized.
/V80- ji■ cloudy, hydrazine vitrate 8dr
In addition, after heating under reflux for 1 hour and 60 minutes, add 1 part of 10% caustic soda.
00- was added and extracted twice with chloroform 80-.

Dry the extract with magnesium sulfate, dry it under reduced pressure once, and remove the resulting residue from silica).
Remumeta/-/shiku 100:1~so:1) and yellow ('h, plif, convex N-[1-(p-
aminobenzyl)-2-Cd-(p-methoxypheni)
V ) Viperazininoriethi/V l -N-methy/v-
5-isoquinolinesulfonic acid amide 3.29f was obtained.

IR(KBr)tMt-': 1620.1510.
1315.1235.1150.1125 IH-NMR (ODC!t3, δppm): 2.4
3 (IH, daSJ=6.8.13.2H2), 2.5
5-2.66 (6H, m), 2.85 (IH, dd
, ,T=6.1! , 14.2H2), 2.87-2.
94 (a Hlm), 2.92 (3H, e), 3.
50 (2H, br), 5.77 (3H, S), t2o
(tu, m), 6.34 (2H1d, , r=8.3.
Hz), 6.75 (2H%aSJ=axHz), 6.8
4 (4H, s), 6.56 (IH, tSJ=7.3Hz
), ao 9 (I HSd, , T=a3Hz),
a24 (IHSdS, T=6.3Hz), a31
(IH, dd,, T=1.0.7.5Hz), a56
(I H, d, J=5.9Hz), 9.25 (I
H, d, , T=1.0Hz) Actually, 1 no *Iiuj
129 500 μm of the anonymous substance obtained in Example 128 was dissolved in 5-pyridine, and 5-inquinolinsulfonyl chloride was added to this.
305η of hydrochloride was added under water cooling, and the mixture was stirred for 20 minutes at room temperature and then for 1 hour at room temperature.
was added, and then extracted twice with 20-chloroform. The extract was dried over magnesium sulfate, subjected to L4 tree under reduced pressure, and the resulting residue was applied to a silica gel column, purified with chloroform-mekno/v (so: 1), and purified with yellow tris 3j ((island ρ).
N'-(1-1:p-(s-isoquinolinesulfonylaminobenzyl))-2-(4-(p-methoxypheni)
V) pivecdinyl]ethyl)-N-methyl-5-isoquinolinesulfonic acid amide 665η was obtained.

Engineering R (KI3r) cm-': 1615.15
jQ, j525.1225.1150.1150' H-111MR (cDct3, δppm): 2
．． 54 (1HSaa, J=7.3.12.7H2),
2.45~2.6 + (6H, m), 2.79~2
．． 94 (5H1m), 2.90 (3H, 8), 3.
77 (2H, s), to4 (1H, m), 6.55 (
2H, d, J=8.3Hz), 6.70(2H, d
SJ=a3Hz), 6.83(4H,a), 7.57
(2H, t, J=near, 8H2), 8.08~a 1
5 (3H.

m), 8.28~&,35 (2H,m), ado(
IH,d,,T=6.4Hz),a50(IHSd
, J==5jHz), a6i! (1H.

dS, T=6°4Hz), 9.29(H,s), 9.3
1 (1HSd1J=1.0Hz) Example 130 In Example 127, 200 tng of the tG crystal was mixed with pyridine 3
-, 5-isoquinolinesulfonyl chloride was added to it under water cooling, and after stirring for 2 minutes under water cooling and 1 hour at room temperature, it was stirred at room temperature for 1 hour.
Add 30 ml of Liaoen, then dilute with 20 ml of chloroform.
Extracted twice. The extract was dried over magnesium sulfate, layered under reduced pressure, and the resulting residue was filtered onto a silica gel column.
Chloroform-methano-/L/(50:1-25:1)
to give a yellow, unwhitened N-(1-(p-(s-isoquinolinesulfonylaminobenzi/I/))-2-(a-
(p-methoxypheni/I/)hiverazinyl]ethyl)
-5-isoquinolinesulfonic acid amide 270 was obtained.

Engineering R (KBr) crn': 1615.1505.1
560.1260.1150.1125 IH-NMR (ODCt3, δppm): 2.16
~2.55C6H,m), 2.49~2.81 (1,
H, m), 3.28 (IH, m), 16 (3H18)
, 6.69 (2H, d, J=a3H2), 6.73
(2H1d, J=9.3H2), 6.79 (2H, (
1,, T=a31(Z), 6.82(2HSa, ,
r=9.8Hz), 7.61 (IH%t, J=7.8
H2), 7.67 (I HltS, T near, 8Hz)
, al6 (IH.

d, J=a3Hz), al 9 (I H, d, J
==llLMMHz), a3! ~a48 (4H, m)
, a62 (2H, d, J=&4Hz), 9.33(
IHlB), 9.35 (IH,s) Example 131 N-C1-(p-CN-(5-isoquinoline sulfo=t
v) -N-(methylamino)benzyl])-2-[4-
(p-methoxyphenylhyperazine)
J-N-Methyl-5-isoquinoline sulfonic acid amide In Example 129, 503 my of the non-grained solid obtained at the delivery site was dissolved in 8 ml of dimethylformamide, and mixed with 6° sodium hydride 50 ~ and methyl iodide IV under ice cooling. Add 0.1-,
Stir for 1 hour under water cooling. Anti-1-shi 1-night saturated saline solution 3
While adding o-, 1h1: Extract with ethyl acid 30-,
The residue obtained by washing with saturated saline, drying with magnesium sulfate, and circulating iJ3 under reduced pressure was applied to a silica gel column, and chloroform-methanol, v (1oo:1) was added to Jej Shite Yellow 11I! '; Obtained island-like (') objective 488 capes.

Engineering R (KBr) crn-': 1610.1505
．． 1340.1520°1235.1145.1125 111-NMR (CDC1,, δppm): 2.3
2 (IH, dd, , T=6.4.13.2H2), 2
．． 41-2.56 (5H, m), 2.75-2.9
8 (6H, m), 2.88 (3H, s),! 23 (3'
H,s), 3.77(3H,s), 4.31(1H%m
), 6.82 (4HS8), /1.89 (2H, dl,
T=8.3Hz), 7.01 (2H,a, :r=a
xx(z), 7.63 (IH, tSJ=7.8Hz),
z64 (IHlt,, T=7.8H2), a02 (IH
Sa, J=5.9H2), al3(IHld,, T=
a3Hz), al 9 (t H, d, , T=a5H
2), a23 (f Hld, J = 7.5Hz)
, a34 (1H1d1J=6.3Hz), ad0~a4
7 (2H, m), a60 (IH, d.

J = 5.9 HZ), 9.28 (IHLB), 9.
29(IH,8) Example 132 N-(1-(p-(4-picolyloxy)benz I)
-2-(4-(2-pyrimidiJv)pibewodinyl]ethyl)-N-methytV-5-isoquinoline! Ref 1z
1001 rq of the anhydrous substance obtained in Example 42 was mixed with dry tetrahydrofuran-dry dimethylformamide (1:1) 1
4-picolyl chloride salt 9JjA3 dissolved in 0rnl
+ll, add 8 Ing, triethylamine 24
After adding ~, the mixture was stirred at room temperature for 30 minutes. then 6
Add 10 ml of sodium hydride, stir overnight in room n1A, add 20 ml of water, and add 20 ml of chloroform.
- Extracted twice.

The extract was washed with saturated brine, dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was applied to a silica gel cuff and mixed with chloroform-methanol (100:1).
-jjlH color measurement object 73 from both fractions eluted at
Got the cape.

NMR (cDcz3) δppm: 2.45 (4H,
complex), 2.5-2.75 (2H, com
plex), 2.95 (3H, 8), 3J5 (4H, c
complex), 4.22 (I H, complex
), 5.0 (2H, e ), 6.49 (I H,t
, J=4.26Hz), 6.6(2H,d, J=
aOHz), 6.9 (2H, d, J=13.Q)i
z ), 7.4 (2H, brd), 7.6 (I H,
t, J=a3H2), all(I H, d, J=8
．． 3Hz), e, 2s (I H,a, J=6.
64Hz), a3 (2H, d, , T=4.26H2)
, a37 (1a, ad, J=1.0.6.6H2),
8.57 (I H, d, , T=6.6H2), a6
5 (2H, bra), 9.25 (IH, d, J=1.
0Hz) Example 135 N-(1-Cp-(2-picolyloxy)benzyl)-
2-(4-(2-pyrimidi/L7)pibewadinyl]ethyl)-N-methy)L/-5-isoquinolinesulfonic acid amide 2-picolyl chloride hydrochloride instead of 4-picolyl chloride hydrochloride Except that the same amount was used, the same procedure as in Example 1 and fathom 2 was carried out to obtain a colorless, height-shaped target object of 74.4 mq.

NMR (CDC63) δppm: 2.45 (II,
comp'1ex), 2.5-2.9(2T(, co
complex), 2.98 (3H, s), 3,'75 (
4H, complex), 4.2 (I H, comp
lex), 5.13 (2H, 8), 6.46 (I H
,t, J=4.8Hz), 6.6s (2H,a,
J=a, GHz), 6.9 (21(,a, ,r
=a.

Hz), 7.15 (IH, complex), 7.5a
(2H, t.

J=6.914Z), 7.75(IH, complex
), al(1H.

d, J=aOHz), 8.2~a55 (2H, com
plex), a5 (I H, d, J=4.8Hz
), a58 (I H, d, J=&6Hz), EL6
(1)1. brs), 9.2s (1H,s) Example 1
34 N-(1-(1)-(4-picolyloxy)benzyl)
-2-(4-(2-pyridyl)piperazinyl)ethylv
) -N-Methyl/L/-5-isoquinoline M phonic acid amide) K (Example 1 Same as Example 132, except that the product of Example 46 was used in place of the anhydrous substance obtained in Example 42.) By gentle operation, a colorless, height-like target product was obtained in a yield of 5,354.

NMR(CD043)δppm: 2.5(4
H, complex), 2.5-2.75 (2H, co
mp'1ex), 2.95 (3H, s), 3.38 (4
H, complex), 4.22 (I H, comp
lex'l, 5.0 (2H, s), 6.58 (2H,
d, J=a6Hz), 6.6(2H,t, J=5
．． 7H2), 6.9 (2H, d, J=8.6Hz
), 7i5~7.5 (41 (, complex), 7.
58(11(, t, , T=ZQl(z), a07(
IH, a, J=aIHz), a17 (IH, bra
), a23 (IH, a, J=6.1Hz), a35 (
1H, dd, J=1.0.7.4H2), a57 (
1) (, d, , T-6, jHz), a63 (IH, b
rd), a6s (I H, a, J=5.8Hz),
9.2 (IH, d, J = 1.0 Hz) Example 135 L/)bibefudinir]ethyl)-N-methyl-5-isoquinoline sulfonic acid amide Fruit No. 1 Except that the product of Example 46 was used in place of the anhydrous form obtained in Example 42! The same procedure as in Blood Example 133 was carried out to obtain a colorless and sterile target product with a yield of 59.54.

NMR (CDC43) δppm: 2.5 (4H1co
complex), 2.5-2.9 (2H, complete
x), 2.95 (3H, El),! L38 (4H, co
mp'1ex), 4.22 (IH, comp'1ex)
, 5.12 (2H, s), 6.55-6.65 (2H,
complex), 6.54(2J(, (1,, T=&
6H2), 6.9 (2H, a, , r=a6Hz),
7.2-7.25 (1H, comp'1ex), 7.4
~7.7 (4H, complex), z65~s8 (
I H, complex), al(I H, a, :r
=7.7H2), a2(IH, br4), a27(I
H, d, 'J=6.6H2), a3 (I H, d,
J=6.6Hz), a57 (j H, d, :I
-6,5Hz), a6 (IH, brs), 9.73 (
1) T, s) Example 136 N-(2-aminoethyl)-N-(:2
-(4-Pendyloquine carbonyl biverazini tv)-
1-(p-methoxybenzene IV) -5-, r
Soquinoline Nurphonic Acid Amide 1.02 of the product obtained in Example 73 was dissolved in tetrahydrofucne s mt jC, and 685 mg of triphenylhonuphine and 340 ~ of N-t-butquin carbonylethanolamine were added thereto, and cooled on ice. While stirring 4'-1, a solution of diisoderobil azodical 1 levogishifut 530~ in tetrahydrofufun 3-1 was added dropwise. The water bath was removed, and the reaction surface was stirred at room temperature for 3 hours, then poured into water, made alkaline with sodium bicarbonate, extracted twice with chloroform 150, and the extract was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. . The obtained oil was dissolved in ethyl acetate/l/2-
Add normal hydrochloric acid / ethyl acetate / I / solution 50 - 30 at room temperature
Bay extrusion for 1 minute, add 100 ml of visual hydrochloric acid and 2 ml of ethyl acetate.
After washing twice, the material was alkalised with sodium bicarbonate and extracted twice with 150 ml of chloroform. This extract was dried over J-flow magnesium, and the solvent was distilled off under reduced pressure. The obtained oil was applied to a silica gel column, and the fraction eluted with chloroform-methanol-Jv (10:1 to 50:1) was collected. From the image, 400 cm of a colorless and sterile object was obtained.

Engineering R (KBr) crn-': 1 70 1, 151
41325, 1248, 1135, 763, +01 NMR (CDC43) δppm: 1.99 (2H
, brs), 2.1 s to 2.40 (sH, m),
2.55-2.80 (3H, m), 2.90-3.10
(2H, m), X 20~370 (6H+m)
, A73 (3H, 8), 4.98 (1H, m), 5.1
0(2H,s), 6.54 (2H,a, J=8.5
5H2), 6.77 (2H, d, J=a55Hz)
, 733 (5H, e), v, 62 (I H, aa,
, T=B, D6.7.57Hz), al4(fH,d,
J=a06Hz), a34 (I H, d, J:6.
10Hz), a39 (1H, a,, T=7.57H2
), 8.65 (I H,d, , T=6.10Hz
), 9.28 (IH,s) Example 137 N-(2-(4-penzyloxycarbonylbibefujini)v) -1-(I)-methoxybendi/I/)ethyl)-N- (2-dimethylaminoethyl/l/)-5-
Isoquinoline sulfonamide 6.085' of the product obtained in Example 73 was dissolved in 30 rnl of tetrahydrofuran and triphenylhonuphine 5.
．． Or, N, N-dimethylethanolamine 1.42
Add r, press water cooling 111.1, diisoderovir azozica! After dropping Levoxif-1-i2117) Tetrahydrofuran 10-F melt, remove the water bath and leave it at room temperature for 30 minutes.
I was confused about the time. After diluting the reaction solution with ethyl acetate,
Extract twice with 100 ml of normal salt, dilute the extract with bicarbonate)
After making it alkaline with IJum, add chloroform 1
00 m/te oil extraction twice, drying with magnesium monoformate,
The oil obtained by distilling off the solvent under reduced pressure was applied to a silica gel column, and chloroform-methanol (200:1~
A colorless and sterile target substance 4.99 F was obtained from the fraction eluted at 1oo:1).

Engineering R (KBr) on-1: 1703.1514.1
327.1247.1135.60ON M R (CD
013) δpptn: 2.10 to 2.45 (5H,
m), 2.26 (6H, e), 2.45-2.85 (
5H, m), 320-3.65 (6H, m), 3J3
(3H, [3), 4.00 (IH, m), 5.10 (2
H, El), 6.53 (2H, d, , T=a79H2
), 6.83 (2H, d, , T=a79H2), 7
．． 34 (5H, e), 7.56 (IH, dd, J=a0
5,7.57Hz), alo(1H9d, J=a05H
2), a31 (IH, d,, T=6.10Hz), a
35 (IH, d, , T = 7.57Hz), EL59 (I
H, d, J=6.1011z), 9.25(IH, s
) Example 138 N-(2-acetoxyethyl)-N-(2-(4-penzyloxycarponylpiverazini!V)-1-(p-methoxybendi)v)ethyl]-5-isoquinolinesulfonic acid Amide 1.02 of the product obtained in Example 73 was dissolved in tetrahydrone 5- and ethylene glyco/lemon acetate 22 was added in place of N-t-butoxycarbonylethanolamine.
(Mlp and) Riphenylhonuphine 685119 was added and the following procedure was carried out in the same manner as in Example 156 to obtain 600 ml of a colorless and sterile target product.

NMR(t,Dat,)δppm: 2.04
(3H, 8), 2.20-2.45 (5H, m), 2
．． 60-2.80 (5H, m), 3.20-3.4
0 (4H, m), &45~173 (2H, m), 574 (5H, El), 4.04 (IH, m), 4.27
(2H, t, J=6.3411), 5.10 (2H
, θ), 6.54 (2H, d, , T=a55Hz)
, 6.82 (2H, d, J=a55Hz), z!
+4 (5H.

S), 7.59 (IH, dd, J=a05, 7.57H
2), &13(1H2d, J=a05H2), a3o(
1H,a,,T=610H? ), a36 (IH, d,
J Near, 57Hz), 9.27 (IH.

e) Jirikishi side 139 N-(2-(4-penzyloxyluponylbibefudinyl)-1-(p-methoxybendi/I/)ethyl)-N
-(2-Hydroxyethyl)-5-isoquinoline sulfuric acid amide, the anhydrous form obtained in Example 138, was added to methano-IV
6 ml of tetrahydrone was dissolved in 3-ml of tetrahydrone, 1416 mt of 1N aqueous sodium hydroxide solution was added thereto, and the mixture was stirred at room temperature for 2 hours. After diluting the reaction solution with water, 50% chloroform
- twice, washed with saturated brine, dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting oil was applied to a silica gel column (=1 t, :1 to SO:1), a colorless and sterile target smg of ￥IA4o was obtained from both the elution fractions.

Engineering R(KBr)tM-': 1701.1514.1
433.1332.1249.1136NMR(ODC
43) δppm: 2.10 to 2.25 (3H, m
), 2.25~2.50 (4H,m), 2.50~
2.70 (I H,m), 3, 10-3.45 (
5H,m), 3.55~x,zs(2H,m),
346 (3H, El), 4.00-4.20 (2H,
m ), 5.08 (2H1s), around 5.4 (IH, b
r), 6.70 (2H, a, :ra79H2), &
79 (2H, d, , T=8.79Hz), 732
(5H,s), 7.73(IH,aa, J=aso,
7.32Hz), a22 (1H, a, J=a3H
2), 8.50 (IH, d, , T=7, !+2Hz)
, a63 (IH, d, J = 6.10H2), a72
(1H,a, ,T=6.10Hz), 9.34(I
H,El) Example 14O N-(2-(: 4-(5,4-dichlorobenzylamino)piperidino)-1-(p-methoxybenzyl)
Ethyl)-N-methyl-5-isoquinoline Nphonamide The anhydrous form obtained in Example 94 was subjected to alkaline hydrolysis, methyl iodide in dimethylformamide and tetrahydrofuran (1:1), and charcoal fI! Methylation by potassium,
Addition with 3N hydrochloric acid: N- obtained by refluxing
(1-(p-methoxybendi)v) -2-(4-oxopiperidino)ethyl)-N-methy/I/-5-isoquinoline sulfonic acid amide 3 (colorless, weightless) 3.342
Dissolve methanol-w 3o mt I (c, 1.89 ml of 44-dichlorobenzylamine, 0.6 ml of acetic acid
was added and stirred at room temperature for 3 hours. The anti-EM was cooled in a water bath, sodium cyanoborohydride 4501119 was added thereto, and the mixture was stirred for 30 minutes under water cooling and then for 1 hour at room temperature.

This solution was made alkaline with sodium bicarbonate (7)
'6, extracted twice with 150 chloroform, dried the extract over magnesium sulfate, distilled off the solution under reduced pressure, and the resulting oil was applied to a silica gel column. From the fraction eluted with (100:1 to 5o:1), the desired product 2.781 in the form of a mucous membrane was obtained.

Engineering R(KBr)cJn-': 1514.1327.
1249.1157.1130.826, 60 O NMR (aDcz,) δppm: 1.05
~1.40 (2H, m), 1.60 ~ 2.15 (4H,
m), 2.30-2.90 (8H, m), 2.93
(3H, s), 573 (5H, s), tl, 5 (1H,
m), 6.49 (2H, d, , T=a791(Z
), 6.8s (2H, a,, r=a79H2), 7.1
5 (IH, aa, J=a20, 1.95Hz), 7.3
8 (IH, d, J=a20Hz), 7.44 (IH
,d,,T=t95H2),7.56(1H,dd,,
T=:a06,757H2),a08(IH,d,,T
=&06H2), al9(IH,d,,T=&35Hz
), a29 (IH, d,, T=7.57Hz), a5
5 (IH, d, J=6.35Hz), 9.23 (IH
, e) *N M R (aDcz3) δppm:
2j7 (4H, t, J=5.99Hz), 2.413
~2.90 (8H,m), 2.94 (3H.

θ), 3.74 (3H, a), 4.23 (IH, m),
6.5B2I4. d,,T=&55Hz),6.83
(2H, d, J=a55Hz), 7.55 (IH, d
d,, r-432,7,50H2), al 0(IH,
d,, r=EL32H2), al9(IH, d,, T=
z, 5oHz), al 9 (I H, d, J=6.
1 DH, z ), a55 (IH, d, , 7=AlOH
z), 9.25 (IH, s) Example 141 N-(2-(4-CN-(翫4-dichlorobendi/L/
) -N-methylaminocopiperidino)-1-(p-mell-dibenzyl)ethyl)-N-methifle 5-isoquinolinesulfonic acid amide Example 140 , dimethylformamide jD=prli was dissolved, 60% sodium hydride 115η was added while stirring under water cooling, and 5% sodium hydride was added at the same temperature.
After reacting for 15 minutes at room temperature, it was cooled again with water, 405 μm of methyl iodide was added, and the reaction was continued at the same temperature for 5 minutes, then at room temperature for 2 minutes.
Allowed time to react. Pour the reaction solution into water and add 200 ml of ethyl acetate.
After washing the extract with homogeneous saline and drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting oil was transferred to a silica gel column (t L , chloroform-
1+11. Color measurement target aao#1
Got it on 9.

Engineering R(KBr)z-1: 1 5 1 4,
1529. 72+7.1157.1131.826.
60O NMR (cnaz3) δppm: 1.
10-2.10 (6H, rn), 2.14 (3H, s)
, 2.20-3.00 (7H, m), 2.93 (3
μ, θ), 3.46 (2H, e), 3j3 (3H, s)
,4.12(IH,m),6.51(2H,d,,T
= a55Hz), 6.85 (2H, d, J = EL55H
z), 7.15 (IH, aa, J=8.30, 1.7
1Hz), 7.37 (IH, d, J=lL30Hz)
, 7.42 (IH, d, , T=t71H2), 7.56
(IH, t, J=7.82Hz), a08(11(, (
1,, r near 82Hz), 8.20 (1) 1. d,,T
=6.11H2), EL30(IH,d,,T=7.8
2Hz), a56 (IH, d, J=6.11H2),
9.23 (IHIIll) [Effects of the Invention] The test methods and results for determining the effectiveness of the compounds according to the present invention are as follows.

Vascular smooth muscle relaxing effect (V, R, PDso) A rabbit was exsanguinated to death and opened, and the excised superior 11-momme artery was incised in a spiral shape according to a conventional method to prepare a strip specimen.
K of 37±0.5℃ through oxygen gas containing carbon dioxide gas
It was suspended under tension in the rebs-Heneeleit solution. After the strip specimen was contracted with potassium chloride and a constant tension was maintained, the target compound was administered at 1C. The muscle relaxant effect was expressed as a concentration of 50 times the contraction tension caused by chloride as a factor of 100.

Platelet pu W IrII system (P, A, I a,,
) Preparation of tip platelets (centrifugal washing method) The blood was collected from Yasuto Une and immediately mixed with 1/10 J o, 38 ml sodium citrate.
0XG for 10 minutes)
) and add 1/6 amount of ACD to this PRP? &(Sodium citrate 2.24, citric acid α8, glucose 2
．． 2. Add 2 ml (prepared before use) and centrifuge (1500XG,
The platelet pellet obtained by
PES quirode solution (salt 135mM 1,1 potassium chloride 2.7mM, magnesium hydride 1mM,
Glucone 0.11151, / 1 ml, HI! :
The cells were suspended in PmS 20mM, pH 7.4). After adding 1/6 m of ACD solution, further centrifugation (15,0
0XG for 5 minutes) corrected the platelet bet obtained by H1!
iPEs floating in Quirode solution, approximately 600,000 pieces/pl
Washed platelet floating IW solution.

Measurement of platelet aggregation reaction (specific value method) To 270 μt of washed platelet float t+lj'ld obtained in the previous section, add 3 ilt of each concentration of 1!11 compound dissolved in an appropriate solvent and incubate seedlings at 37°C for 2 minutes. After 1 heating, collage': / 20 p? /ml solution 3071t was added to Tekara, 4-channel aggregation analyzer (HFi MA
) The absorbance is measured using Laser 601 (manufactured by Niko Bioscience Co., Ltd.).

As a control for determining the effect of the test compound, the absorbance at the time of maximum aggregation by cofugen in the presence of the solvent used for the test compound was set as 100, and the absorbance at 111 when cofugen was added was set as 0.

Next, the percentage of inhibition was calculated from the absorbance at the time of maximum aggregation by cofugen when the test compound was added, and 504
The concentration of the test compound that causes inhibition is expressed as IC6°.

Oa2+PDE engineering Oso' (11M) Method for measuring calmodyulin-dependent phosphogesterase inhibitory effect 50, OmM) Lis J-fArC1 (p Ha O)
20 Jl 150mM Salt r Himagnesium 20 It 12mM
Calcium chloride 20 μL (or jOmM EQ-TA) 1 w/q+l bovine serum albumin (manufactured by Sigma) 2
071t phosphodiesterose
20 ti 1 carmodeulin
200ng test drug 10 II M~1m
Add 20μ of M to an appropriate agricultural level and make a total amount of 200μ with distilled water.
771.

Prepare the above solution in a test tube and add 4. #M (3H)
- cyclic guanosine monophosphate (2,5p
C3Iml) 201tt was added and treated at 30°C for 15 minutes, followed by heating in a boiling water bath for 3 to 5 minutes. After cooling this reaction solution in ice water, 5'-nucleotidase (manufactured by Sigma, Hebi fjJ) 2071? and again 30
After treatment at ℃ for 10 minutes, add about 2 - liters of water, and then add cation exchange resin (AG50W-X4. manufactured by Biohood).
Approximately 20 ml of the water scolumn was washed after adding the wash solution that had been poured into the column and washing the test tubes. 3N to this column
7 Pour aqueous ammonia 3- and collect the eluted liquid in a bottle, and add emulsified non-tillation liquid (AC!S-I) to this.
t, Amashi Arm Co., Ltd.) Add 1o-rrA7) H, 1
The radioactivity of [3H]-guanosine in the eluate was measured using a d3-1 Synnaration Counter p-Ls7500 (manufactured by Beckman). μM of
The concentration was calculated based on IC6°.

The calmodyulin-dependent phosphogesterase used in this experiment was partially purified from rat brain using a DFJAE-cellulose column, and the calmodyulin was prepared from bovine Ika by the TCA method.
The product purified by JW-7 Affinity Kahum was used.

F, a T A Id (ethylenebis(oxyethylenenitrilo))tetofacetic and.

9 Other compounds according to the invention include protein kinase A1
Although it had an inhibitory effect on enzymes such as myosin light chain kinase, protein kinase C1 cyclic AMP-dependent phosphogesterase, it had almost no effect on cardiac function.

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

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. A group such as lower alkyl; R_3 is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted aralkyl, or a group such as alkylene connected to the Ar ring; R_4 and R_5 are each hydrogen or together is oxo; Ar is a ring such as benzene or imidazole; Y is OH or N; A is CR_6R_7 or NR_6; n is 2 or 3; R_6 is hydrogen, substituted or unsubstituted hydroxyl group, substituted or groups such as unsubstituted phenyl, acyl, substituted alkoxycarbonyl, substituted carbamoyl, substituted amino, arylsulfonyl, aralkylsulfonyl, aralkyl, heterocycle; R_7 is hydrogen, alkoxy, or together with R_6, alkylenedioxy or oxo; Aromatic amino acid derivative represented by ). 2. General formulas ▲ Numerical formulas, chemical formulas, tables, etc. R_4R_5 are each hydrogen or together represent oxo; R_8 is hydrogen, lower alkyl, or a group such as alkylene linked to the Ar ring; A' is CR_9R_1_0 or NR_9; Ar is benzene or imidazole, etc.; a ring; n is 2 or 3; R_9 is a group such as hydrogen, substituted or unsubstituted phenyl, substituted hydroxyl group, substituted alkoxycarbonyl, heterocycle; R
(_1_0 represents a group that forms an acetal when combined with hydrogen, alkoxy, or R_9) Amino acid derivatives represented by the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (Y represents CH or N) A step of reacting a sulfonic acid or a reactive derivative thereof and a salt thereof or adding a reaction product to a reaction product, which is known per se (1) hydrolysis to liberate a hydroxyl group or an amino group; (2) a step of freeing a hydroxyl group or an amino group; (3) Step of acylating or substituted alkoxycarbonylation of the hydroxyl group or amino group; (4) Step of alkylating the hydroxyl group or amino group; (5) Amination or hydroxylation of the carbonyl group. (6) a step of reducing the nitro group and aminating it; (7) a step of carbonylating the acetal; a general formula characterized by sequentially reacting one or more of the above steps in combination or overlappingly; ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R_3 is hydrogen, substituted or unsubstituted lower alkyl,
Substituted or unsubstituted aralkyl, or a group such as alkylene connected to the Ar ring; A is CR_6R_7 or NR
_6; R_6 is hydrogen, substituted or unsubstituted hydroxyl group, substituted or unsubstituted phenyl, acyl, substituted alkoxycarbonyl, substituted carbamoyl, substituted amino, arylsulfonyl, aralkylsulfonyl, aralkyl, heterocycle, etc.; R_7 is A method for producing an aromatic amino acid derivative represented by hydrogen, alkoxy or R_6 together with alkylenedioxy or oxo; the others have the same meanings as above.