JPH04330057A - Anilinearylsulfonic acid amides and acid addition salt thereof allowable as medicine - Google Patents

Abstract

PURPOSE:To obtain a new compound having vascular smooth muscle relaxing action and action on enzyme system of living body, useful as a brain circulation improver, hypotensive agent, basodilator, treating agent for angina pectoris and antithrombotic agent, etc. CONSTITUTION:A compound expressed by formula I (R1 is 3-pyridyl, 8-quinolinyl or 7-(2-acetyl)-1,2,3,4-tetrahydroisoquinolinyl; R2 is H, 2-hydroxyethyl or 2- aminoethy; X is formula II, S-CH2CH=CH, etc.; R3 is lower alkoxy; (n) is 0-3) e.g. 8-[2-(phenyl-trans-2-propenyl)thiomethylphenyl]aminosulfonylquinoline. The compund expressed by formula I is obtained by reacting a compound expressed by formula III with a halogenated nitrobenzene and then reducing the reactional product and further reacting the reduced substance with a compound expressed by formula R1-SO2Cl.

Description

[Detailed description of the invention]

0001

[Industrial Application Field] The novel aniline arylsulfonic acid amides, in other words, the arylsulfonic acid anilide derivatives, or their pharmaceutically acceptable acid addition salts provided by the present invention have vascular smooth muscle relaxing effects. It is a powerful agent, and also has effects on the enzyme system of the living body, making it useful as a cerebral circulation improving agent, a vasodilator, an antihypertensive agent, a therapeutic agent for angina pectoris, and a prophylactic/therapeutic agent for thrombosis. The present invention relates to these novel arylsulfonic acid anilide derivatives or their acceptable acid addition salts, and methods for their production.

0002

BACKGROUND OF THE INVENTION Conventionally, regarding arylsulfonamide derivatives having a vascular smooth muscle relaxing effect, naphthalenesulfonamide derivatives have been disclosed in JP-A-62-87581, and isoquinolinesulfonamide derivatives have Japanese Patent Application Publication No. 58-121279,
Japanese Patent Publication No. 60-81168, Japanese Patent Publication No. 63-4886
No. 9, Japanese Patent Publication No. 2-27992, etc., it has been proposed as a useful compound and is well known.

0003

[Problem to be solved] However, there is room for improvement in the group of compounds proposed in the above-mentioned publications in terms of their production methods, pharmacological effects, and organ selectivity and safety of their effects as pharmaceuticals. It recognized.

[0004] Therefore, the present invention aims to enhance the efficacy as a drug and improve organ selectivity and safety by introducing various side chains into the core of arylsulfonic acid anilide (aniline arylsulfonic acid amide). The aim is to provide improved new compounds.

[0005]

[Solution] In order to solve such problems, the present invention provides the following formula 12:

[0006]

[Chemical formula 12]

[However, in the formula, R1 is a 3-pyridyl group, 8-quinolinyl group, or 7-(2-acetyl)-1,
2,3,4-tetrahydroisoquinolinyl group; R2 is hydrogen, 2-hydroxyethyl group or 2-aminoethyl group; X is the following formula 13:

[0008]

[Chemical formula 13]

The group represented by -S-CH2 CH=C
H- or -N(-R4)-CH2 CH2 -O-
(However, R4 represents hydrogen, a lower alkyl group, or an allyl group); R3 is a lower alkoxy group; n is 0
represents an integer of 3 to 3] (aniline arylsulfonic acid amides or arylsulfonic acid anilides) or pharmaceutically acceptable acid addition salts thereof.

[0010] Furthermore, in the present invention, the following formula 14:

[
0011

[Chemical formula 14]

[0012] A compound represented by the formula [wherein R3,

[0013]R1-SO2Cl

[In the formula, R1 has the same meaning as above]], and if necessary, further alkylation and reduction or deprotection are performed to form a salt. The gist of the present invention is also to provide a method for producing aniline arylsulfonic acid amides represented by the above formula 12 or non-toxic salts thereof, which are characterized by the following.

Furthermore, the present invention provides the following formula 16:

001
6]

[Chemical formula 16]

[However, in the formula, R1 has the same meaning as above; R5 is hydrogen, -CH2 COOEt or the following formula 17:

[0018]

[Chemical formula 17]

In the group represented by the following formula; R6 represents hydrogen or a hydroxyl group, R6 is replaced with a halogen or toluenesulfonyloxy group, and then
A method for producing aniline arylsulfonic acid amides represented by the above chemical formula 12, which comprises reacting with the compound represented by the above chemical formula 14, deprotecting or reducing if necessary, and then forming a salt. , its gist.

[0020] In this specification, the term "lower" such as lower alkyl groups refers to those having 1 to 4 carbon atoms, and the term "deprotection" refers to primary protection of reactive characteristic groups. This refers to the removal of a protective group, which is an atomic group, that was introduced for the purpose of reverting to the original characteristic group.

[0021]

[Specific Structure] By the way, regarding the compound represented by the above formula 12 according to the present invention, specifically, for example, the following compounds can be mentioned.

(1) 8-[2-(3-phenyl-tra
ns-2-propenyl)thiomethylphenyl]aminosulfonylquinoline (2) 8-{N-(2-hydroxyethyl)-[2-(
3-phenyl-trans-2-propenyl)thiomethylphenyl]amino}sulfonylquinoline (3) 8-[
N-(2-hydroxyethyl)-2-(N-methyl-2
-phenoxyethylamino)methylphenylamino]sulfonylquinoline (4) 8-{N-(2-hydroxyethyl)-2-[N
-Methyl-2-(2,6-dimethoxyphenoxy)ethylamino]methylphenylamino}sulfonylquinoline (5) 1-[2-(8-quinolinyl)sulfonylaminophenyl]methyl-4-(3-phenyl-trans-
2-propenyl)piperazine (6) 8-{N-(2-hydroxyethyl)-2-[N
-Methyl-2-(3,5-dimethoxyphenoxy)ethylamino]methylphenylamino}sulfonylquinoline (7) 8-{N-(2-hydroxyethyl)-2-[N
-Methyl-2-(3,4,5-trimethoxyphenoxy)ethylamino]methylphenylamino}sulfonylquinoline (8) 8-[N-(2-aminoethyl)-2-(N-methyl-2-phenoxy) ethylamino)methylphenylamino]sulfonylquinoline (9) 3-[2-(3-phenyl-trans-2-propenyl)thiomethylphenyl]aminosulfonylpyridine (10) 8-{N-(2-hydroxyethyl)- 2-[
N-methyl-2-(2,3,4-trimethoxyphenoxy)ethylamino]methylphenylamino}sulfonylquinoline (11) 8-{N-(2-aminoethyl)-2-[N-
Methyl-2-(3,4,5-trimethoxyphenoxy)
ethylamino]methylphenylamino}sulfonylquinoline (12) 1-{2-[7-(2-acetyl)-1,2,
3,4-tetrahydroisoquinolinyl]sulfonylaminophenyl}-4-(3-phenyl-trans-2-
propenyl)piperazine (13) 1-(3-phenyl-trans-2-propenyl)-4-[2-(3-pyridyl)sulfonylaminophenyl]methylpiperazine (14) 2-acetyl-7-[2-(3 -phenyl-t
rans-2-propenyl)thiomethylphenyl]aminosulfonyl-1,2,3,4-tetrahydroisoquinoline

[0023] Examples of acids that give pharmaceutically acceptable acid addition salts of the above compounds include inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid, and acetic acid, citric acid, succinic acid, and the like. Organic acids such as tartaric acid, lactic acid, fumaric acid, maleic acid and methanesulfonic acid can be mentioned.

The compound according to the present invention is designed and synthesized so that an aromatic ring is bonded to an arylsulfonamide compound of o-toluidine via a carbon chain containing nitrogen, oxygen, or sulfur. The above objectives have been fully achieved and all of these compounds are new.

Here, the compound represented by the above formula 12 provided by the present invention is, for example, the following formula 18 (wherein, X, R1, R2, R3, and n represent the same meanings as above) It can be synthesized according to the following.

[0026]

[Chemical formula 18]

That is, in Chemical Formula 18, the compound represented by formula (V) is first obtained by reacting o-nitrobenzyl chloride with the compound represented by formula (II), and this is further reduced. Then, by reacting with an arylsulfonyl chloride represented by formula (III), the amino form represented by formula (VI) was obtained.
) (R2=H) can be obtained. In addition, examples of the compound represented by formula (II) include cinnamyl mercaptan, cinnamyl piperazine, N-methyl-2-phenoxyethylamine, N-
Methyl-2-(2,6-dimethoxyphenoxy)ethylamine, N-methyl-2-(3,5-dimethoxyphenoxy)ethylamine, N-methyl-2-(3,4,5-
trimethoxyphenoxy)ethylamine, N-methyl-
Examples include 2-(2,3,4-trimethoxyphenoxy)ethylamine, N-(N,N-dimethylaminoethyl)-2-phenoxyethylamine, and the like.

[0028] In this reaction, an acid acceptor may be present. As acid acceptors, sodium bicarbonate,
Sodium hydroxide, potassium carbonate, sodium hydride,
Included are alkali metal compounds such as sodium methylate, organic tertiary amines such as pyridine, trimethylamine, triethylamine, triethylenediamine. In addition, reaction solvents include alkanols such as methanol and ethanol, halogenated hydrocarbons such as dichloromethane and chloroform, aromatics such as benzene, toluene, and pyridine, and tetrahydrofuran (THF).
), ethers such as dioxane, acetonitrile,
Dimethylformamide (DMF), dimethylsulfoxide (DMSO), etc. are used.

The amount of compound (II) to be used relative to o-nitrobenzyl chloride is preferably 1 to 10 times the mole, more preferably 1 to 3 times the mole, when an acid acceptor is present. , when no acid acceptor is present, a range of 2 to 10 times the mole is preferred.

[0030] When an acid acceptor is used, the amount used is 1 to 10 to o-nitrobenzyl chloride.
A range of 1 to 6 times the mole is preferred, and a range of 1 to 6 times the mole is particularly preferred. The reaction temperature is usually -30 to 150°C,
The temperature range is preferably from 0 to 120°C, particularly preferably from 0 to 80°C.

Furthermore, the reduction of the nitro compound (V) is carried out using 1 to 10 times the mole of sodium borohydride in the presence of palladium carbon containing 0.0001 to 1 times the mole of palladium. As the solvent, methanol, acetonitrile, dimethylformamide, dimethyl sulfoxide, etc. are used. The reaction temperature is usually -30 to 100°C, especially -2
A range of 0 to 50°C is preferred.

[0032] In addition, in this reaction, catalytic reduction may be carried out directly using hydrogen in place of the above-mentioned sodium borohydride. At this time, the hydrogen pressure is usually 1 to 10 atm, and the reaction temperature is is preferably 0 to 50°C.

Furthermore, as another reduction method, the reaction may be carried out using 3 to 10 times the molar amount of stannous chloride to the nitro compound (V) in 6 to 500 times the molar amount of concentrated hydrochloric acid. In this case, the reaction temperature is preferably 0 to 100°C. Furthermore, alkanols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, acetonitrile, ethyl acetate, etc. can also be used as reaction solvents.

Compound (I) (R2 = H) can be obtained by acid amidating the amino compound (VI) obtained by such reduction with an arylsulfonyl chloride represented by formula (III).

Examples of the arylsulfonyl chloride (III) used in this reaction include quinoline-8-sulfonyl chloride, pyridine-3-sulfonyl chloride, benzenesulfonyl chloride, 2-acetyl-1,2
, 3,4-tetrahydroisoquinoline-7-sulfonyl chloride and the like.

[0036] Furthermore, an acid acceptor may be present in this reaction. Acid acceptors include alkali metal compounds such as sodium bicarbonate, sodium hydroxide, potassium carbonate, sodium carbonate, potassium hydroxide, sodium methylate, organic tertiary compounds such as pyridine, trimethylamine, triethylamine, triethylenediamine, etc.
Examples include class amines. Reaction solvents include alkanols such as methanol and ethanol, halogenated hydrocarbons such as dichloromethane and chloroform, aromatics such as benzene, toluene and pyridine, ethers such as tetrahydrofuran and dioxane, acetonitrile and dimethylformamide. , dimethyl sulfoxide, etc. are used.

Acid chloride (
The amount of III) used is preferably in the range of 1 to 10 times the mole, more preferably 1 to 3 times the mole.

When an acid acceptor is used, the amount used is preferably from 1 to 10 equivalents, particularly preferably from 1 to 6 equivalents, relative to the aniline derivative represented by formula (VI). The reaction temperature is usually -30 to 150°C, and 0 to 150°C.
A temperature range of 120°C is preferred, and a range of 0 to 80°C is particularly preferred.

Furthermore, among the compounds represented by formula (I),
The compound in which R2 is CH2 CH2 OH further has (I)
It is obtained by alkylating the compound (R2 = H) with ethyl bromoacetate or ethyl chloroacetate, and then reducing it with sodium borohydride, lithium aluminum hydride, aluminum hydride, or the like. As a solvent in the alkylation reaction, THF, dioxane, methanol, ethanol, acetonitrile, DMF, DMSO, etc. are used, and when an acid acceptor is present, for example, potassium carbonate, sodium carbonate, sodium hydride, triethylamine, etc. are used. The amount used is amide compound (I) (R2
=H) is preferably 3 times the mole or less.

The reduction of the ester (VIII) obtained by such alkylation can be carried out using the above-mentioned metal hydride using 0.5 to 10 times the mole of the ester, and the solvent may be ether or THF. , dioxane, methanol, ethanol, etc. can be used. Furthermore,
The reaction temperature is preferably -30 to 80°C.

The compound represented by formula (I) (excluding R2=H) can also be synthesized according to Reaction 19 below.

[0042]

[Chemical formula 19]

That is, the formula (VI) in Reaction 18
Similarly to the reaction of the compound represented by formula (VII) to the compound represented by formula (VII) [R2=H in (I)], o
- After arylsulfonylamidation of toluidine, formula (VI
II) is alkylated in a similar manner to the reaction to formula (I).
X) After converting this into a compound represented by 1 to 10
React with twice the molar amount of N-bromsuccinimide (NBS) in benzene or carbon tetrachloride at 0°C to reflux temperature,
After forming the bromine compound (X), (VIII) was obtained in the same manner as the reaction from o-nitrobenzyl chloride to (V), and this was further converted into (I) (R2 = CH2 CH2 OH
) can be done.

Further, from compound (IX), according to the following reaction 20, (I) (R2 = CH2 CH2 NH
2) can also be done.

[0045]

[C20]

The reaction from (IX) to (XI) is carried out from (VIII) to (I) (R2 = CH
2 CH2 OH). (XI) is prepared by mixing 1 to 10 times the mole of p-toluenesulfonyl chloride and 1 to 1000 times the mole of an acid such as sodium hydride, pyridine, or triethylamine in a solvent such as chloroform, dichloromethane, ether, tetrahydrofuran, dimethylformamide, or pyridine. Tosylate (X
II). Furthermore, this was mixed with 1 to 10 times the molar amount of potassium phthalimide (protecting group-imparting compound) in a solvent such as benzene, DMF, DMSO, dioxane, etc.
(XIII) can be obtained by reacting at 0 to 200°C. From (XIII) to (XIV) to (XV
) is the reaction from (IX) to (X) in Reaction 19.
can be carried out in the same manner as the reaction to (VIII), and (XV) can be reacted with methanol, ethanol, water, DM
(I) (R2 = CH2 CH2 NH2) can be obtained by deprotection using hydrazine (or its hydrate) in a solvent such as F, dioxane, or DMSO at 0 to 100°C.

Furthermore, compound (I) (R2=H) is
It can also be synthesized according to the following formula 21.

[0048]

[C21]

From (VI) to (V
(XVI) was obtained in the same manner as in the reaction to II), and this was converted to tosylate (XVII) in the same manner as in the reaction from (XI) to (XII) in Reaction 20.
(I) (R2 = H) can be obtained in the same manner as the reaction from (X) to (VIII) in 9. Also,
(XVI) is prepared using THF, dioxane, methanol, ethanol, etc. as a solvent and a reaction temperature of 0 to 50% using 5 to 200 times the mole of hydrochloric acid or hydrobromic acid.
After converting (XVIII) at °C, converting (XVII) to (I
)(R2=H), (I)(R2
=H) can be obtained.

Furthermore, (I) (R2 = CH2 CH2
OH) can also be synthesized according to the following formula 22.

[0051]

[C22]

(XVI) in Reaction 18 is replaced by (I
) (R2 = H) to (VIII) in the same manner as (XIX) in Reaction 21, and then (X
VI) In the same manner as the reaction from (XVII), (XX) is obtained, and (VIII) is obtained in the same manner as in the reaction from (XVII) to (I) (R2 = H), and then reduction is performed, (I) (R2 = CH2 CH2 OH) can be obtained. In addition, (XIX) is converted to (XXI) in the same way as the reaction from (XVI) to (XVIII) in Reaction 21, and then from (XX) to (VIII).
(VIII) is obtained in the same manner as in the reaction, and by reducing this, (I) (R2 = CH2 CH2 OH) is obtained.

[0053]

[Examples] Some examples of the present invention will be shown below to clarify the present invention more specifically, but the present invention is not limited in any way by the description of these examples. It goes without saying that this is not the case.

[Production method] Example 1 8-[2-(3-phenyl-trans-2-propenyl)thiomethylphenyl]aminosulfonylquinolinecinnamyl mercaptan: 0.8 g was dissolved in 10 ml of toluene, and 20% water was added. After adding 15 ml of sodium oxide aqueous solution, o-nitrobenzyl chloride: 1
．． 0g was added, heated to 60°C, and reacted for 30 minutes. After cooling, the toluene layer was washed three times with water and dried over anhydrous sodium sulfate. After filtering this, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain 2.4 g of cinnamyl-2-nitrobenzyl sulfide as a pale yellow oil. This was dissolved in 10 ml of tetrahydrofuran, added to a solution in which 5.4 g of stannous chloride was dissolved in 8 ml of concentrated hydrochloric acid, and the mixture was stirred for 1 hour. The reaction mixture was neutralized with sodium hydrogen carbonate, extracted with ethyl acetate, dried over sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain 1.9 g of 2-aminobenzylcinnamyl sulfide. Obtained. this,
It was dissolved in 10 ml of pyridine, 1.8 g of 8-quinolinesulfonyl chloride was added, and the mixture was heated and stirred at 60° C. for 30 minutes. Thereafter, the solvent was distilled off under reduced pressure, and the residue was dissolved in dichloromethane, washed three times with water, dried over anhydrous sodium sulfate, filtered, and then the solvent was distilled off under reduced pressure and subjected to silica gel column chromatography. to obtain 3.2 g of the target product as pale yellow needle crystals (melting point: 137~
138℃). The NMR analysis results of this target product were as follows.

1H-NMR (CDCl3, δ, pp
m, TMS) 3.17 (2H, d, J=6Hz, -S-CH2CH
=CH-φ), 3.53(2H,s,φ-CH2-S
), 6.07 (1H, dt, J=15.8 and6
Hz, -CH2 CH=CH-φ), 6.40 (1H,
d, J=15.8Hz, -CH2 CH=CH-φ),
7.00-9.23 (15H, m, Ar), 8.76-
8.92 (1H, br, -NH)

Example 2 In place of 8-quinolinesulfonyl chloride in Example 1, 1.5g of 3-pyridinesulfonyl chloride was used to obtain 2.6g of the following compound. NM of this compound
The R analysis results were as follows. 3-[2-(3-phenyl-trans-2-propenyl)thiomethylphenyl]aminosulfonylpyridine (
As a hydrochloride, melting point 62-75℃, needle-shaped crystals)

[0057]
1H-NMR (CDCl3, δ, ppm, TMS) 3.17 (2H, d, J=6Hz, -S-CH2CH
=CH-φ), 3.43(2H,s,φ-CH2-S
), 6.07 (1H, dt, J=15.8 and6
Hz, -CH2 CH=CH-φ), 6.40 (1H,
d, J=15.8Hz, -CH2 CH=CH-φ),
7.00-9.00 (14H, m, Ar and-N
H)

Example 3 The following compound was prepared by using 2.5 g of 2-acetyl-1,2,3,4,-tetrahydroisoquinoline-7-sulfonyl chloride in place of 8-quinolinesulfonyl chloride in Example 1. 3.2 g was obtained as a colorless amorphous substance. The NMR analysis results of this compound were as follows. 2-acetyl-7-[2-(3-phenyl-trans
-2-propenyl)thiomethylphenyl]aminosulfonyl-1,2,3,4-tetrahydroisoquinoline

0
1H-NMR (CDCl3, δ, ppm,
TMS) 2.17(3H,s,-C(=O)-CH3),2.
68-3.13 (2H, m, Ac-N-CH2 CH2
-Ar), 3.27 (2H, d, J=6.0Hz, -
CH2 CH=CH-φ), 3.50-4.00 (4H
, m, Ac-N-CH2 CH2 -Ar and
Ar-CH2-S), 4.50-4.90 (2H,
m, Ac-N-CH2 -Ar), 6.17 (1H, t
d, J=6.4 and 15.6Hz, -CH2
CH=CH-φ), 6.50 (1H, d, J=15.
6Hz, -CH2CH=CH-φ), 6.73-7.
00 (1H, m, NH), 7.00-7.93 (12H
, m, Ar)

Example 4 8-{N-(2-hydroxyethyl)-[2-(3-phenyl-trans-2-propenyl)thiomethylphenyl]amino}sulfonylquinoline 1 g of the compound obtained in Example 1 was added to 15 ml of DMF. dissolved in
0.1 g of 60% sodium hydride was added and stirred for 30 minutes. Ethyl bromoacetate: 0.5 g was added, and the mixture was stirred for an additional 30 minutes. After that, ethyl acetate was added and the mixture was washed three times with water. The ethyl acetate layer was dried over sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. 20 ml of ethanol was added to the residue to dissolve it, and 10.3 g of sodium borohydride was added and stirred for 1 hour. Dichloromethane was added to the reaction mixture, washed three times with water, dried over sodium sulfate, filtered, concentrated under reduced pressure, and subjected to silica gel column chromatography to obtain 0.5 g of the desired product as a colorless amorphous substance. The NMR analysis results of the obtained target product were as follows.

1H-NMR (CDCl3, δ, pp
m, TMS) 3.17-4.79 (9H, m, φ-CH2 -S-C
H2 CH=CH-φ and -N-CH2 C
H2OH), 5.89-9.23 (17H, m, Ar
and -S-CH2 CH=CH-φ)

Example 5 Instead of cinnamyl mercaptan in Example 1,
Using 1.1 g of cinnamyl piperazine, 3.0 g of the following compound was obtained. The NMR analysis results of this compound were as follows. 1-[2-(8-quinolinyl)sulfonylaminophenyl]methyl-4-(3-phenyl-trans-2-propenyl)piperazine (melting point 168-170°C, needle-shaped crystals)

1H-NMR (CDCl3, δ, pp
m, TMS) 2.73-3.66 (10H, m, -CH2 ×4
in piperazine and φ-CH2
-N), 3.83 (2H, d, J=6Hz, -CH2
CH=CH-φ), 6.53 (1H, dt, J=16
and 6Hz, -CH2 CH=CH-φ), 6
．． 83 (1H, d, J=16Hz, -CH2 CH=C
H-φ), 6.83-9.20 (15H, m, Ar)

Example 6 In place of 8-quinolinesulfonyl chloride in Example 5, 1.5 g of 3-pyridinesulfonyl chloride was used to obtain 2.6 g of the following compound. NM of this compound
The R analysis results were as follows. 1-(3-phenyl-trans-2-propenyl)-
4-[2-(3-pyridyl)sulfonylaminophenyl]methylpiperazine (melting point 149-150°C, plate crystals)

1H-NMR (CDCl3, δ, pp
m, TMS) 2.33-3.00 (18H, m, -CH2 ×4
in piperazine), 3.18 (2H, d
, J=6Hz, -CH2 CH=CH-φ), 3.28
(2H, s, φ-CH2 -N), 6.35 (1H, d
t, J=16 and 6Hz, -CH2 CH=
CH-φ), 6.57 (1H, d, J=16Hz, -C
H2 CH=CH-φ), 6.93-9.20 (13H
, m, Ar), 9.34 (1H, broad s, -
NH)

Example 7 1-{2-[7-(2-acetyl)-1,2,3,4-
Tetrahydroisoquinolinyl]sulfonylaminophenyl}-4-(3-phenyl-trans-2-propenyl)piperazine o-aminobenzyl alcohol: 1.3 g to pyridine 1
Dissolve in 5 ml, 7-(2-acetyl)-1,2,3,
4-Tetrahydroisoquinolinesulfonyl chloride: 3
g was added thereto, and the mixture was heated and stirred at 60° C. for 1 hour. and,
After cooling, dichloromethane was added, washed with 10% hydrochloric acid, then with water, dried over sodium sulfate, filtered, concentrated under reduced pressure, dissolved in 20 ml of tetrahydrofuran, and further added with 20 ml of 47% hydrobromic acid. The mixture was heated and stirred at 50° C. for 1 hour. After cooling, dichloromethane was added, and the mixture was washed with water, sodium bicarbonate water, and water. The organic layer was dried over sodium sulfate, filtered, and then the solvent was distilled off under reduced pressure. The residue was dissolved in 20 ml of ethanol, 1.5 g of cinnamylpiperazine was added, and the mixture was heated under reflux for 1 hour. After cooling, ethanol was distilled off under reduced pressure, dissolved in dichloromethane, washed with sodium bicarbonate water and water, and the organic layer was dried over sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. Chromatography was performed to obtain 1.9 g of the target product as a colorless amorphous substance (as dihydrochloride, melting point 160-170°C, needle-shaped crystals). The NMR analysis results of this compound were as follows.

1H-NMR (CDCl3, δ, pp
m, TMS) 2.17 (3H, s, -C(=O)-CH3), 2.
23-3.10 (10H, m, -CH2 ×4 in
piperazine and Ac-N-CH2
CH2-Ar), 3.21 (2H, d, J=6.0
Hz, -CH2 CH=CH-φ), 3.29 (2H,
s, Ar-CH2-piperazine), 3.4
3-4.00 (2H, m, Ac-N-CH2 CH2
-Ar), 4.53-4.81 (2H, m, Ac-N-
CH2-Ar), 6.23 (1H, dd, J=6.0
and 16.0Hz, -CH2 CH=CH-
φ), 6.57 (1H, d, J=16.0Hz, -CH
2 CH=CH-φ), 6.91-7.83 (13H,
m, Ar and -NH)

Examples
8 8-{N-(2-hydroxyethyl)-2-[N-methyl-2-(3,5-dimethoxyphenoxy)ethylamino]methylphenylamino}sulfonylquinoline By the same procedure as in Example 7, o- Sulfonamide obtained by reacting aminobenzyl alcohol and 8-quinolinesulfonyl chloride: 3 g was dissolved in 30 ml of DMF,
420 mg of 60% sodium hydride was added and stirred for 30 minutes. Thereafter, 1.9 g of ethyl bromoacetate was added and stirred for 2 hours, and the reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, and washed with water. After drying over sodium sulfate and filtration, the solvent was distilled off under reduced pressure, and ether was added for crystallization to obtain 2.8 g of crude crystals. This was dissolved in 20 ml of pyridine, 2.2 g of p-toluenesulfonyl chloride was added, and the mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, dichloromethane was added to dissolve, washed with water, dried over sodium sulfate, the solvent was concentrated under reduced pressure, and ether was added to crystallize to obtain p-toluenesulfonic acid ester. I got 3g. 2-(3,5-dimethoxyphenoxy)ethylmethylamine: 2g in DM
After dissolving in 20 ml of F, the above p-toluenesulfonic acid ester was added and the mixture was heated and stirred at 90°C for 30 minutes. After cooling, the solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed with water, dried over sodium sulfate, filtered, and after the solvent was distilled off under reduced pressure, the residue was dissolved in Example 4. It was reduced in the same manner and crystallized from ethanol/petroleum ether to obtain 1.4 g of the desired product as colorless prism crystals (melting point 118-120°C). The NMR analysis results of this compound were as follows.

1H-NMR (CDCl3, δ, pp
m, TMS) 2.32 (3H, s, -N-CH3), 2.76-3
．． 69 (6H, m, φ-CH2 -N-CH2 CH2
-O and CH2 -CH2 OH or
CH2 CH2 OH), 3.78 (6H, s, -
OCH3 ×2), 4.07-4.46 (2H, t
like, J=6.5Hz, -N-CH2 CH2 -
O-φ), 4.76-5.28 (2H, m, -CH2
CH2OH or -CH2CH2OH),
6.05-9.27 (13H, m, Ar)

[0070]
Example 9 2-(2,6-dimethoxyphenoxy)ethylmethylamine: 2 g was used instead of 2-(3,5-dimethoxyphenoxy)ethylmethylamine in Example 8,
1.4 g of the following compound was obtained. The NMR analysis results of this compound were as follows. 8-{N-(2-hydroxyethyl)-2-[N-methyl-2-(2,6-dimethoxyphenoxy)ethylamino]methylphenylamino}sulfonylquinoline (melting point 141-142°C, prismatic crystal)

1H-NMR (CDCl3, δ, pp
m, TMS) 2.38 (3H, s, -N-CH3), 2.81-3
．． 76 (6H, m, φ-CH2 -N-CH2 CH2
-O and CH2 -CH2 OH or
CH2 CH2 OH), 3.84 (6H, s, -
OCH3 ×2), 4.07-4.46 (2H, t
like, J=7Hz, -N-CH2 CH2 -O-
φ), 4.76-5.36 (2H, m, -CH2 CH
2OH or -CH2CH2OH), 6.2
3-9.30 (13H, m, Ar)

Example 10 8-{N-(2-hydroxyethyl)-2-[N-methyl-2-(3,4,5-trimethoxyphenoxy)ethylamino]methylphenylamino}sulfonylquinoline Example 1 And by the same operation as 2, o-toluidine:
1.3g to 8-quinolinesulfonyl chloride: 3.2g
After reacting with ethyl bromoacetate: 2.4 g, the obtained N-ethoxycarbonylmethyl-o-toluidine-8-quinolinesulfonamide: 3.6 g and N-
Bromosuccinimide: 2.5g in 50ml of carbon tetrachloride
In addition to this, 0.2 g of benzoyl peroxide was further added, and the mixture was heated under reflux for 4 hours. After cooling, the solvent was distilled off, and the residue was subjected to silica gel column chromatography to obtain 2.6 g of crude bromo compound. This was dissolved in 50 ml of toluene, 2 g of N-methyl-2-(3,4,5-trimethoxyphenoxy)ethylamine and 1 g of triethylamine were added, and the mixture was heated and stirred at 80° C. for 1 hour. After cooling, washing with water and drying with sodium sulfate, the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography, and further reduced by the same operation as in Example 2. The product was subjected to column chromatography and crystallized from ethanol/petroleum ether to obtain the desired product 1.
Obtained 9g as prismatic crystals (melting point 113-115°C)
. The NMR analysis results of this compound were as follows.

1H-NMR (CDCl3, δ, pp
m, TMS) 2.33 (3H, s, -N-CH3), 2.53-5
．． 40 (10H, m, φ-CH2 -N-CH2 CH
2 -O and -CH2 CH2 OH), 3
．． 82 (3H, s, p-OCH3), 3.90 (6H
,s,m-OCH3 ×2),6.29-9.23(1
3H, m, Ar and -CH2 CH2 OH
)

Example 11 In place of N-methyl-2-(3,4,5-trimethoxyphenoxy)ethylamine in Example 10, N-
Methyl-2-(2,3,4-trimethoxyphenoxy)
Using 2 g of ethylamine, 1.8 g of the following compound was obtained. The NMR analysis results of this compound were as follows. 8-{N-(2-hydroxyethyl)-2-[N-methyl-2-(2,3,4-trimethoxyphenoxy)ethylamino]methylphenylamino}sulfonylquinoline (melting point 132-134°C, acicular Akira).

1H-NMR (CDCl3, δ, pp
m, TMS) 2.33 (3H, s, -N-CH3), 2.80-5
．． 30 (19H, m, φ-CH2 -N-CH2 CH
2 -O and -CH2 CH2 OH, -O
CH3 ×3), 6.26-9.23 (13H, m, A
r and -CH2 CH2 OH)

Example 12 8-[N-(2-aminoethyl)-2-(N-methyl-
2-phenoxyethylamino)methylphenylamino]
Sulfonylquinoline N-ethoxycarbonylmethyl- obtained in Example 10
o-Toluidine-8-quinolinesulfonamide: 4g was reduced in the same manner as in Example 2, and the obtained N-(2-hydroxyethyl)-o-toluidine-8-quinolinesulfonamide: 3.3g was reduced with pyridine. : Dissolve in 20ml,
Add p-toluenesulfonyl chloride: 2.2g to 1
Stirred for 6 hours. After the solvent was distilled off under reduced pressure, dichloromethane was added and dissolved, and the mixture was washed with water. Next, it was dried over sodium sulfate, the solvent was distilled off, and the residue was dissolved in DMF30.
ml, 3.5 g of potassium phthalimide was added thereto, and the mixture was heated and stirred at 100° C. for 1 hour. After cooling, the solvent was distilled off under reduced pressure, dissolved in ethyl acetate, and washed with water.
After drying with sodium sulfate, the solvent was distilled off under reduced pressure, and this was subjected to silica gel column chromatography. The obtained crystals were brominated in the same manner as in Example 10, and then N-methyl-2-phenoxy Ethylamine: 0.5g
Aminated with. Dissolve this in 30ml of ethanol,
After adding 20 ml of hydrazine hydrate, the mixture was heated under reflux for 2 hours, allowed to cool, the solvent was distilled off under reduced pressure, and the residue was dissolved in dichloromethane. After washing with water, drying over sodium sulfate, and filtration, the solvent was distilled off under reduced pressure and subjected to silica gel column chromatography to obtain 0.65 g of the desired product as a colorless amorphous substance. Furthermore, add 10 m of methanol to this
After adding 1 ml of saturated hydrogen chloride methanol solution, the solvent was distilled off under reduced pressure, and this was crystallized from ethanol to obtain the target monohydrochloride as colorless prism crystals (
melting point 228-240°C). The NMR analysis results of this compound were as follows.

1H-NMR (CDCl3, δ, pp
m, TMS) 1.92 (2H, s, -NH2), 2.13 (3H,
s, -N-CH3), 2.56 (2H, t, J=6H
z, -N-CH2 CH2 -O-φ or -N
-CH2 CH2 -NH2 ), 2.84 (2H, t
, J=6.5Hz, -N-CH2 CH2 -O-φ
or -N-CH2 CH2 -NH2 ), 3.
02-4.62 (6H, m, φ-CH2 -N-CH2
CH2 -O and -N-CH2 -CH2
-NH2), 6.47-9.24 (15H, m, A
r)

Example 13 Using 0.8 g of N-methyl-2-(3,4,5-trimethoxyphenoxy)ethylamine in place of N-methyl-2-phenoxyethylamine in Example 12, the following reaction was carried out. 0.81 g of compound was obtained. NMR of this compound
The analysis results were as follows. 8-{N-(2-aminoethyl)-2-[N-methyl-
2-(3,4,5-trimethoxyphenoxy)ethylamino]methylphenylamino}sulfonylquinoline (as dihydrochloride, melting point 173-175°C, prismatic crystal)

0
079 1H-NMR (CDCl3, δ, ppm,
TMS) 1.60 (2H, s, -NH2), 2.20 (3H,
s, -N-CH3), 2.50-3.00 (4H, m
, -N-CH2 CH2 -O-φ and -N
-CH2 CH2 -NH2 ), 3.81 (3H, s
, p-OCH3), 3.86 (6H,s,m-OCH
3 × 2), 3.50-4.54 (6H, m, φ-CH
2 -N-CH2 CH2 -O and -N-
CH2-CH2-NH2), 5.20-9.28
(12H, m, Ar)

Example 14 8-[N-(2-hydroxyethyl)-2-(N-methyl-2-phenoxyethylamino)methylphenylamino]sulfonylquinoline o-nitrobenzyl chloride: 1.8 g and methyl-(
Dissolve 1.5 g of 2-phenoxyethyl)amine in toluene, add 1 g of triethylamine, and stir at 50°C.
The mixture was heated and stirred for 0 minutes. After cooling, add toluene and dissolve with water.
After washing twice and drying with sodium sulfate, it was filtered and the solvent was distilled off. The residue was dissolved in 30 ml of methanol, 10% palladium on carbon was added, and 500 mg of sodium borohydride was added little by little, followed by stirring for 30 minutes. After filtration, the solvent was distilled off under reduced pressure, and the residue was dissolved in dichloromethane, washed three times with water, and dried over sodium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was dissolved in pyridine. Thereafter, the same procedure as in Examples 1 and 2 was carried out to obtain 2.4 g of the desired product as a colorless amorphous substance. The NMR analysis results of this compound were as follows.

1H-NMR (CDCl3, δ, pp
m, TMS) 2.31 (3H, s, -N-CH3), 2.66-3
．． 87 (6H, m, φ-CH2 -N-CH2 CH2
-O and -CH2 -CH2 OH o
r -CH2 CH2 OH), 4.23 (2H, t
, J=7Hz, -N-CH2 CH2 -O-φ), 4
．． 74-5.35(2H,m,-CH2CH2OH
or -CH2CH2OH)),6.66-
9.20 (15H, m, Ar)

The test methods and results for determining the effectiveness of the compounds synthesized in the above examples were as follows.

[Myosin light chain kinase (MLCK) inhibitory effect] Using chicken gizzard smooth muscle myosin light chain as a substrate,
Radioactivity from [γ-32P]ATP to substrate protein is measured. 250mM Tris-HCl (pH 7.0), 100m
20 μl each of M magnesium chloride and 2 mM calcium chloride, 40 μg of myosin light chain (myosin prepared from chicken gizzard smooth muscle), and 40 μg of myosin light chain kinase (prepared from chicken gizzard smooth muscle).
, 80 ng of calmodulin (prepared from bovine brain by TCA method and purified by calmodulin inhibitor W-7 affinity column), test drug (10 μM ~
Mix 20 μl of the above (adjusted to an appropriate concentration of 1 mM) in a test tube, and make the total volume 200 μl with distilled water.

[0084] 100 μM [γ-32P]AT was added to the above solution.
Add 20 μl of P (2.5 μCi/ml) and incubate at 30°C.
After treating for 15 minutes, 0.5 ml of 20% TCA is added to stop the reaction. After stopping the reaction, 3 ml of 5% TCA and 0.1 ml of 1 mg/ml albumin solution are added and centrifuged to fix the acid-insoluble protein at the bottom of the test tube. Furthermore, remove the supernatant, add 3 ml of 5% TCA, and centrifuge. This operation was repeated twice, and the precipitated protein was dissolved in 2 ml of 1N NaOH, placed in a vial containing approximately 10 ml, and added with 1 ml of emulsified scintillation fluid (ACS-II, manufactured by Amersham).
After adding 0ml, add liquid scintillation counter (
LS7500, manufactured by Beckman) in the eluate.
Radioactivity by γ-32P]ATP was measured.

[0085] 100% enzyme activity in the presence of calcium,
The μM concentration of the test compound giving 50% inhibition was calculated as the IC50 value, assuming that the enzyme activity in the absence of calcium was 0%, and is shown in Table 1 below. However, test compound 100μM
Those that did not show a 50% inhibitory effect were judged to have no effect.

[Calmodulin-dependent phosphodiesterase (Ca-PDE) inhibitory effect] 500mM Tris-HCl (pH 8.0), 50mM magnesium chloride, 2mM calcium chloride (or 10mM EGTA), 1mg/m
20 μl each of bovine serum albumin and calmodulin-dependent phosphodiesterase (partially purified from rat brain using a DEAE-cellulose column), calmodulin (prepared from bovine brain by the TCA method and purified using a calmodulin inhibitor W-7 affinity column) 200 μg of the test drug (10 μM
(adjusted to an appropriate concentration of ~1 mM) in a 20 μl test tube, and further adjusted to a total volume of 200 μl with distilled water.

[3H]-Cyclic guanosine monophosphate (2.5 μCi/ml) was added to the above solution.
) After adding 20 μl and treating at 30°C for 15 minutes,
Heat in a boiling water bath for 3-5 minutes. After cooling this reaction solution in ice water, 5'-nucleotidase (manufactured by Sigma,
After adding 20 μg of snake venom) and treating again at 30°C for 10 minutes, approximately 2 ml of water was added, and cation exchange resin (A
G50W-X4, manufactured by Bio-Rad) column and the solution used to wash the test tube was also added, and the column was washed with about 20 ml of water. Pour 3 ml of 3N ammonia water into this column, receive the eluate in a vial, and add 10 ml of emulsified scintillation liquid (ACS-II, manufactured by Amersham).
After adding ml, add liquid scintillation counter (L
S7500, manufactured by Beckman) in the eluate.
3H]-guanosine-induced radioactivity was measured.

[0088] Considering the enzyme activity in the presence of calmodulin as 0%, the μM concentration of the test compound that gives 50% inhibition is defined as IC.
It was calculated as a 50 value and shown in Table 1 below. However, if the test compound did not show a 50% inhibitory effect at 100 μM, it was judged as having no effect (EGTA is ethylene bisoxyethylene nitrilotetraacetic acid).

[Vascular smooth muscle relaxing effect] Japanese albino rabbits were exsanguinated to death, the abdomen was opened, and the extracted superior mesenteric artery was spirally incised in a conventional manner to prepare a strip specimen, and then 5% carbon dioxide gas was added. The specimen was suspended under tension in a Krebs-Hensleit solution at 37±0.5° C. through which oxygen gas containing oxygen was aerated. The strip preparations were contracted with 20 mM potassium chloride and, after maintaining constant tension, the compound of interest was administered cumulatively. The relaxation effect is based on the contraction tension caused by potassium chloride as 100%.
The concentration resulting in 50% relaxation is shown in Table 1 below.

[0090]

[Table 1]

[Effect on blood pressure and blood flow] Room temperature 23±
Male Wistar rats (body weight 200-300 g) were intraperitoneally injected with 75 mg/ml sodium pentobarbital (50 mg/ml Nembutal injection; manufactured by Dynabot) using a constant temperature and humidity room at 1°C and 55 ± 5% humidity. The patient was administered intravenously and anesthetized. The animal is fixed on a fixed table and an incision is made from the thorax along the midline of the pharynx to separate and expose the trachea. An incision is made in the exposed trachea below the thyroid gland, and a tracheal cannula is attached here. The left and right carotid arteries are each dissected 4 to 5 cm from the surrounding tissue without damaging the vagus nerve.

[0092] The upper end of the dissected left carotid artery is ligated, the lowermost end is held between arterial clamps, and an incision is made on the lower end side of the ligation point. A pressure transducer for blood pressure measurement (Blood Pressure Transducer Life Kit; manufactured by Nihon Kohden) is connected here,
Heparin saline (200 units/ml heparin)
Insert an arterial cannula filled with water and double ligate it to prevent it from coming off. Remove any air bubbles inside the cannula. Blood pressure measurement is recorded using a blood pressure measurement amplifier (AP-641G; manufactured by Nihon Kohden Co., Ltd.) and a thermal eye recorder (RTA-1100; manufactured by Nihon Kohden Co., Ltd.) via a pressure transducer.

[0093] The ablated right carotid artery was hooked to a blood flow transducer (Nihon Kohden, FI-005T, 0.5 mmφ), and a blood flow measurement amplifier (MF-26; manufactured by Nihon Kohden) and a DC amplifier (AD-641G) were used. ; manufactured by Nihon Kohden) and recorded with a thermal eye recorder.

A cannula for drug administration is inserted into the vein exposed through an incision in the skin of the left thigh. The test compound was dissolved in hydrochloride in 5% glucose or
% polysorbate 80 solution, neutralized with sodium bicarbonate, and administered through the left femoral vein in a volume of 0.1 ml per 100 g of animal.

[0095] The evaluation value of blood pressure lowering effect is as follows:
ED by determining the dose that lowers Hg from the dose-response regression line
Display as 30 values. Furthermore, the blood flow rate evaluation value was calculated by calculating the percentage of the blood flow rate at the time of maximum increase with respect to the blood flow rate before administration of the test compound, and is displayed in Table 2.

[0096]

[Table 2]

[Acute toxicity] Room temperature 23±1°C, humidity 55±
Male ddY mice (
Test animals (body weight 22-28 g) were divided into groups of 10 animals, several of the representative compounds according to the present invention were used as test compounds, and these were suspended in a 2% polysorbate 80 solution.
The above test animals were orally administered and observed for one week, and the acute toxicity values were calculated from the mortality rate and are shown in Table 3.

[0098]

[Table 3]

0099

Effects of the Invention As is clear from the above results, the compound according to the present invention is a new substance, has a smooth muscle relaxing effect, has a blood pressure lowering effect in vivo, and has low acute toxicity. Since it has been shown to be toxic, it is useful as a medicine such as an antihypertensive agent, a vasodilator, and a cerebral circulation improving agent. Furthermore, since it has the activity of inhibiting the activity of various phosphorylating enzymes, it is useful as a low-toxicity antitumor agent.

[C6]

[C6]

Claims (3)

[Claims] [Claim 1] The following formula 1: [Claim 1] [wherein, R1 is a 3-pyridyl group, 8-quinolinyl group, or 7-(2-acetyl)-1,2,3,4-
Tetrahydroisoquinolinyl group; R2 is hydrogen, 2-
hydroxyethyl group or 2-aminoethyl group;
The following chemical formula 2: A group represented by [chemical formula 2], -S-CH2 CH=CH- or -
N(-R4)-CH2 CH2 -O- (However, R4
represents hydrogen, lower alkyl group or allyl group); R
3 is a lower alkoxy group; n represents an integer of 0 to 3] and pharmaceutically acceptable acid addition salts thereof. [Claim 2] The following formula 3: [Chemical 3] [However, in the formula, X is a group represented by the following formula 4: [Chemical 4], -S-CH2 CH=CH- or -
N(-R4)-CH2 CH2 -O- (R4 represents hydrogen, a lower alkyl group, or an allyl group); R3
is a lower alkoxy group; n represents an integer of 0 to 3] is reacted with a nitrobenzyl halide, and after reducing this, the following chemical formula 5: R1 -SO2 Cl [However, in the formula , R1 is a 3-pyridyl group, 8-quinolinyl group or 7-(2-acetyl)-1,2,3,4-
[representing a tetrahydroisoquinolinyl group], and if necessary further alkylated, reduced or deprotected, and then formed into a salt. 6] [However, in the formula, R2 is hydrogen, a 2-hydroxyethyl group or a 2-aminoethyl group, and R1,
R3, R4, X and n each have the same meanings as above] A method for producing aniline arylsulfonic acid amides or non-toxic salts thereof. [Claim 3] The following chemical formula 7: [wherein, R1 is a 3-pyridyl group, 8-quinolinyl group, or 7-(2-acetyl)-1,2,3,4-
Tetrahydroisoquinolinyl group; R5 is hydrogen, -C
H2 COOEt or a group represented by the following chemical formula 8: [Chemical formula 8]; R6 represents hydrogen or a hydroxyl group] After replacing R6 with a halogen or a toluenesulfonyloxy group, the following chemical formula 9: [
[Formula 9] [wherein, X is a group represented by the following formula 10:
N(-R4)-CH2 CH2 -O- (However, R4
represents hydrogen, lower alkyl group, or allyl group)
; R3 is a lower alkoxy group; n represents an integer of 0 to 3]; further, if necessary, deprotection or reduction is performed, and then a salt is formed. 11: [Formula, R2 is hydrogen, 2-hydroxyethyl group or 2-aminoethyl group, and R1, R3,
R4, X and n each have the same meanings as above.] A method for producing an aniline arylsulfonic acid amide.