WO1996006084A1 - Novel quinolylamine derivative, process for production thereof, and use thereof as antiarrhythmic agent - Google Patents

Abstract

A novel quinolylamine derivative represented by general formula (I) and a salt thereof, useful as an antiarrhythmic agent, wherein R1 represents methyl, ethyl or phenyl; R2, R4 and R5 represent each hydrogen; R3 represents methanesulfonamido; and Z represents N-methyl-N-(4-methanesulfonamidophenethyl)aminomethyl, 4-methanesulfonamidophenetylamino or N-(2-hydroxyethyl)-N-(4-methanesulfonamidophenethyl)amino.

Description

 Specification

 Novel quinolylamine derivatives, their production and use as antiarrhythmic agents

 The present invention relates to a quinolylamine derivative useful as an antiarrhythmic agent. More specifically, the present invention relates to a quinolylamine derivative represented by the following general formula (I) and a salt thereof, which have a blocking effect on potassium channels, for example, useful as an antiarrhythmic agent.

In the above formula,

And one of Z represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a nitro group, a lower alkyl group, a lower alkoxy group, an aryl group or a group of the general formula — NR ₁₄ R ₁₅ or one C OR ₁₃ ; And R ₁₃ is a group of the general formula —NR _ie R ₁₇ (where R ₁₆ and R ₁₇ each independently represent a hydrogen atom or a lower alkyl group), a hydroxyl group or a lower alkoxy group, and R ₁₄ and R ₁₅ are each independently a hydrogen atom, a lower alkyl group, a lower alkylsulfonyl group, a lower Arukanoiru group or an optionally substituted Araruki group,

 And the other one of Z is a general formula

-(CH ₂ ) _ffl -NA-Y_ Represents a group of

R ₂ , R ₃ , R ₄ and R ₅ are each independently a hydrogen atom, a lower alkyl group, a halogen atom, a lower alkoxy group, a nitro group, a hydroxyl group, a cyano group, a lower alkanol group, a hydroxy lower alkyl group, A lower alkylsulfonyl group or a group of the general formula 1 NR ₁₈ R ₁₉ or 1 C 0 NR ₂₀ R ₂₁ or containing one or two hetero atoms selected from the group consisting of nitrogen and oxygen 6 R ₁₈ and ₉ each independently represent a hydrogen atom, a lower alkyl group or a lower alkylsulfonyl group, and R _{2 ()} and R ₂₁ each independently represent a hydrogen atom or Represents a lower alkyl group,

■ 0

Is a heterocycle or a general formula

Represents a group of

R ₇ , R ₈ , R ₉ , R _{1 ()} and each independently represent a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a sulfonyl group or a general Shiki NR ₂₄ shows a group of R ₂₅ or one S 0 ₂ NR ₂₂ R _23, wherein R ₂₂ and R ₂₃ each independently represents a hydrogen atom or a lower alkyl group, R "and R ₂₅ are each independently Represents a hydrogen atom, a lower alkyl group or a lower 'alkylsulfonyl group, and R ₆ represents a hydrogen atom, a lower alkyl group, a cyclo lower alkyl group, a lower alkanol group. Or a hydroxy lower alkyl group,

A represents a group of the general formula — (CHR ₁₂ ) _n — or 1 (CH ₂ ) „— 0—, wherein R ₁₂ represents a hydrogen atom or a hydroxyl group, and n represents a constant of 1 to 4, or

-N-A- R6 can also form a piperidine ring,

m represents a number of 0, 1 or 2, provided that when m is hydrogen, m is not 1. The present invention includes a method for producing the quinolylamine derivative represented by the general formula (I) and a salt thereof, and a use thereof as an antiarrhythmic agent.

Background art

Potassium channels, which are one of the mechanisms that regulate systemic physiological actions, are distributed in whole body cell lines, including one cell of the kidney, myocardium, etc., and therefore exhibit a pharmacological action that regulates potassium channels. Are used for the treatment of various circulatory diseases, for example, as antidiabetic agents, antiarrhythmic agents and the like. Numerous compounds and the like are known in the prior art for such potassium channel blocking agents and the like. For example, glibenclamide, an oral antidiabetic agent that blocks the potassium channel present in the kidney's ^ 1 cells, blocks the ATP-dependent potassium channel in the ^ 1 ^ cells and thereby induces insulin-induced insulin. It has been reported that the drug exerts a hypoglycemic effect upon release, and this effect is considered to be a common mechanism of action for oral antidiabetic drugs having a sulfonyl-peryl structure as a basic skeleton. The literature (Eur 0 pean Journ alof Pharmacology, 141, 243-251 (1987); British Journalof Pharmacology., 93, 61-68 (1988)] 4-Substituted benzoic acid It is known that the body performs the same function. On the other hand, compounds that block potassium channels in the heart muscle show an antiarrhythmic effect, and are associated with Baugan Williams (see: Anti-Ati-Rhythmic Action, EM Vaughan Willi ams, Acemic Press, 1980). )), It is classified as a class III antiarrhythmic agent. As an example of such a compound, a compound represented by the following general formula (A) has recently been proposed as an antiarrhythmic agent in JP-A-63-201167 and EP-A-0281254.

R one NHS0 ₂ (d- C ₄ alkyl group), an NH ₂ or N0 _2,

1 ^ is a _4- alkyl group,

 H e t is a general formula

Where

R ₂ is a hydrogen atom, CH ₃ or C ₂ H ₅ ,

R ³ is N 0 ₂ , CH ₃ or one NHS 0 ₂ (d-C alkyl group);

X is 0, S or NR ^4, where R ⁴ is hydrogen atom or CH _3,

However, if one of R and R ³ is NO ₂ , the other is NH ₂ . However, the prior art potassium channel blocker antiarrhythmic agents, etc., including the above-mentioned compounds, which have been clarified so far, are not always satisfactory in their action, or those exhibiting a certain level of activity may have serious side effects. And the like. For this reason, there is an urgent need for the development of a powerful antiarrhythmic drug that has excellent side effects of blocking potassium channels but has almost no side effects and can be used safely.

 Therefore, the present inventors have studied various compound species for their ability to block potassium chloride channels and their usefulness as antiarrhythmic agents. As a result, the present inventors have identified a specific novel compound of the general formula (I) as defined above. It has been confirmed that the quinolylamine derivative and its salt exhibit a strong power channel blocking action with few side effects, and have completed the present invention.

Disclosure of the invention

 Accordingly, the present invention relates to a novel quinolylamine derivative of the general formula (I) and a salt thereof.

In the above formula,

One of R) and Z is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a nitro group, a lower alkyl group, a lower alkoxy group, an aryl group or a group of the general formula --NR ₁₄ R ₁₅ or one C OR ₁₃ Wherein R ₁₃ is a group of the general formula —NR _ie R ₁₇ (where R ₁₆ and R ₁₇ each independently represent a hydrogen atom or a lower alkyl group), a hydroxyl group or a lower alcohol RM and R ₁₅ each independently represent a hydrogen atom, a lower alkyl group, a lower alkylsulfonyl group, a lower alkenyl group or an optionally substituted aralkyl group; and One is a general formula

Represents a group of

R ₂ , R ₃ , R ₄ and R ₅ are each independently a hydrogen atom, a lower alkyl group, a halogen atom, a lower alkoxy group, a nitro group, a hydroxyl group, a cyano group, a lower alkanol group, a hydroxy lower alkyl group group, a lower alkylsulfonyl group or formula over NR, ₈ R! ₉ or 1 C 0 NR ₂₀ R ₂ ! Or a 6-membered hetero ring containing one or two identical or different hetero atoms selected from a nitrogen atom or an oxygen atom, wherein R ₁₈ and R! ₉ are each independently Represents a hydrogen atom, a lower alkyl group or a lower alkylsulfonyl group, and R _{2 ()} and R ₂₁ each independently represent a hydrogen atom or a lower alkyl group;

-0

Is a heterocycle or a general formula

Represents a group of

R ₇ , R ₈ , R ₉ , R _{1 ()} and RH each independently represent a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a sulfonyl group or formula shows an NR ₂₄ group R ₂₅ or one S 0 ₂ NR ₂₂ R _23, wherein R ₂₂ and R ₂₃ each independently represents a hydrogen atom or a lower alkyl group, R ₂₄ and R ₂₅ are each Independently represents a hydrogen atom, a lower alkyl group or a lower alkylsulfonyl group,

 Re represents a hydrogen atom, a lower alkyl group, a cyclo lower alkyl group, a lower alkanoyl group or a hydroxy lower alkyl group,

A represents a group of the general formula — (CHR ₁₂ ) „— or 1 (CH ₂ ) _n — 0—,

 2 represents a hydrogen atom or a hydroxyl group, n represents an integer of 1 to 4) or

-N-A- R6 can also form a piperidine ring,

m represents a number of 0, 1 or 2, provided that when is a hydrogen atom, m is not 1. In the expression of various substituents in the present invention, the following meanings are given unless otherwise limited.

 The halogen atom means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. The lower alkyl group refers to a linear or branched alkyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an i-propyl group, n-butyl group, i-butyl group, s-butyl group, t-butyl group and the like.

The lower alkoxy group means a chain chain or branched alkoxy group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as a methoxy group, an ethoxyquin group and an n-propoxy group. Examples thereof include i-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, and t-butoxy.

 The aryl group means a group obtained by removing one hydrogen atom from an aromatic hydrocarbon, and examples thereof include a phenyl group, a tolyl group, a xylyl group, a biphenyl group, a naphthyl group, an anthryl group, and a funananthryl group. Represents a phenyl group.

 The lower alkylsulfonyl group means a group in which a sulfonyl group is bonded to a lower alkyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as methylsulfonyl group, ethylsulfonyl group, and n-propylsulfonyl. Group, i-propylsulfonyl group, n-butylsulfonyl group, i-butylsulfonyl group, s-butylsulfonyl group, t-butylsulfonyl group and the like.

 The lower alkanoyl group means an alkylcarbonyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms in the alkyl group, and includes, for example, an acetyl group, a brovionyl group, an n-butyryl group, and i— Examples thereof include a butyryl group, a phenolyl group, an isovaleryl group, and a pivaloyl group.

The aralkyl group which may be substituted is a group in which a lower alkyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, is substituted with an aralkyl group. The group may be substituted with one or more substituents. Examples of the substituent include a halogen atom, a hydroxyl group, a cyano group, a nitro group, a lower alkyl group, a lower alkoxy group, an amino group, and a sulfonylamino group. And lower alkylsulfonylamino groups, lower alkylaminosulfonyl groups, sulfonic acid groups, N-lower alkyl lower alkylsulfonylamino groups, and the like. Examples of such groups include benzyl, phenethyl, phenyl, phenyl, p-methylphenyl, p-methylbenzyl, p-methylphenpropyl, 0-methylphenoline, m-methinolephenethyl group, p-ditrophenethyl group, p-2-trobenzyl group, p-ditrophenpropyl group, 0-ditrophenethylenol group, m- Nitrophenethyl group, p-aminophenethyl group, p-aminobenzyl group, 0-aminophenethyl group, m-aminophenethyl group, p-fluorophenethyl group, p-fluorobenzyl group, 0-fluorophenethyl Group, m-fluorophenethyl group, p-chlorophenethyl group, p-chlorobenzoyl group, 0-chlorophenethyl group, m-chlorophenethyl group, p-hydroxyphenethyl group, p-hydroxy group Benzyl group, 0-hydroxyphenethyl group, m-hydroxyphenethyl group, p-methylsulfonylaminophenethyl group, p-ethylsulfonylaminophenethyl group, pn- Propylsulfonylaminophenethyl group, p-i-propylsulfonylaminophenethyl group, p-n-butylsulfonylaminophenethyl group, p-methylsulfonylaminobenzyl group, p Methylsulfonylaminophenpropyl, p-aminosulfonylphenethyl, p-aminosulfonylphenprovir, p-aminosulfonylphenbutyl, p-methoxyphenethyl, p-methoxybenzyl, 0-methyl Toxiphenethyl group, m-methoxyphenethyl group, 0-cyanophenethyl group, p-cyanophenethyl group, m-fluoro-p-methylsulfonylaminophenethyl group, p-fluoro-0-methylsulfonylaminophenethyl group, p-dimethylamino Sulfonylphenethyl group, p-dimethylaminosulfonylphenylpropyl group, ρ-dimethylaminosulfonylphenylbutyl group, 2,6-Jodo 4-methylsulfonylaminophenethyl group, 3,4-dimethoxyphenethyl group, 3 , 4-Dimethoxybenzyl group, 3.4-Dimethy Shifuwenpurobiru group, such as p- methylsulfonyl § Mino one m- two Torofuenechiru group.

A hydroxy lower alkyl group is a group in which any hydrogen atom of a lower alkyl group is substituted with at least one hydroxyl group, for example, a hydroxymethyl group, a 1-hydroxyshethyl group, a 2-hydroxyquinethyl group, 1.2-dihydroxyxyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 1.2-hydroxypropyl pill, 2,3-dihydroxypropyl pill Groups, 1, 2, And a 3-trihydroxypropyl group.

 A 6-membered hetero ring containing one or two identical or different hetero atoms selected from a nitrogen atom or an oxygen atom is a hetero ring having one nitrogen atom as a hetero atom, one oxygen atom Hetero ring with two nitrogen atoms as hetero atoms, hetero ring with two oxygen atoms as hetero atoms, one nitrogen atom and one oxygen atom as hetero atoms Heterocycle in the term atom, meaning a saturated or unsaturated 6-membered heterocycle, such as a piberidine ring, a pyridine ring, a pyran ring, a tetrahydropyran ring, a piperazine ring, a pyrazine ring, or a pyrimidine. Ring, pyridazine ring, morpholine ring, oxazine ring and the like. Heterocyclic group means a saturated or unsaturated 3- to 6-membered ring group containing at least one nitrogen atom, oxygen atom or iodo atom as a hetero atom, such as an aziridinyl group, an azetidinyl group, Pyrrolidinyl group, piperidinyl group, pyridyl group, pyrrolyl group, imidazolyl group, imidazolidinyl group, pyrazolyl group, vilazolidinyl group, vilazolinyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolidinyl group, piperazinyl group, piperazinyl group, piperazinyl group, piperazinyl group A pyridazinyl group, a triazinyl group, a thiadianyl group, a morpholinyl group, a chenyl group, a furyl group, a vinylyl group, a furazanyl group and the like. Preferably, a pyridyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group and the like are mentioned.

 The cyclo lower alkyl group means a cyclic alkyl group having 3 to 7 carbon atoms, preferably 3 to 6 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

As mentioned above, the compound of the general formula (I) according to the present invention has a strong power channel blocking action as an antiarrhythmic agent belonging to class III, and has an action potential in myocardium and conductive tissue. Prolongs the period, thus increasing refractory to extra stimuli. They have effects on the atria, ventricles and conductive tissue both in vitro and in vivo. It is useful in the prevention and treatment of various types of ventricular and supraventricular arrhythmias, including atrial and ventricular fibrillation. These compounds do not alter the rate at which impulse (impu1 se) is conducted, and therefore have a tendency to promote or exacerbate arrhythmias compared to other antiarrhythmic agents (mostly class I) currently used conventionally. Less neurological side effects. Some of these compounds have some positive inotropic activity, and are particularly useful for patients with impaired heart pump function.

 Desirable compounds in the compound of the general formula (I) of the present invention include:

Is a hydrogen atom, a hydroxyl group, a cyano group, a lower alkyl group having 1 to 6 carbon atoms, a lower alkoxy group having 1 to 6 carbon atoms, a phenyl group, a halogen atom or a group of the general formula-NR ₁₄ R ₁₅ or one COR ₁₃ Wherein R ₁₃ is a group of the general formula NR ₁₆ R ₁₇ (where R ₁₆ and R ₁₇ are each independently a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms), a hydroxyl group or a lower alkoxy group of from 1 to 6 carbon each, independently of R, ₄ and R i ₅ represents a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms, lower Arukirusu Ruhoniru group having 1 to 6 carbon atoms, alkyl A lower alkanol group having 1 to 6 carbon atoms or a lower alkyl group having 1 to 6 carbon atoms substituted with a substituted or unsubstituted phenyl, and Z represents a general formula

-( ^CH 2) mbian A— YJ

 β6

Represents a group of

R ₂ , R ₃ , R ₄ and R ₅ are each independently a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms, a halogen atom, a lower alkoxy group having 1 to 6 carbon atoms, a nitro group, a hydroxyl group, No, the number of carbon atoms in the alkyl moiety! Substituted with a lower alkanoyl group or hydroxyl group that is up to 6 Lower alkyl group of indicated number 1-6 carbon atoms, or a lower alkylsulfonyl group or formula chromatography NR ₁₈ R ₁₉ or one CONR _{2 ()} group R ₂₁ from 1 to 6 carbon, a piperazinyl group, a piperidinyl group, or A morpholinyl group, wherein R ₁₈ and R ₁₉ each independently represent a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms or a lower alkyl sulfonyl group having 1 to 6 carbon atoms, and R ₂₀ and R ₂₁ represent Each independently represents a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms,

R ₆ is substituted with a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms, a cyclo lower alkyl group having 3 to 6 carbon atoms, a lower alkyl group having 1 to 6 carbon atoms in the alkyl portion, or a hydroxyl group. Represents a lower alkyl group having 1 to 6 carbon atoms,

-0

Is a pyridyl group or a general formula

Represents a group of

R ₇ , R ₈ , R ₉ , R _{1 ()} and R are each independently a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms, a lower alkoxy group having 1 to 6 carbon atoms, a halogen atom, a cyano group. indicates nits port group, a hydroxyl group, a sulfonyl group or formula chromatography NR ₂₄ group R ₂₅ or one S0 ₂ NR ₂₂ R _23, wherein independently each R ₂₂ and R ₂₃ is a hydrogen atom or 1 to carbon atoms 6 represents a lower alkyl group, wherein R ₂₄ and R ₂₅ each independently represent a water purple atom, A represents a lower alkyl group or a lower alkylsulfonyl group having 1 to 6 carbon atoms, and A represents a group of the general formula — (CHR ₁₂ ) „— or 1 (CH ₂ )„ — 0—, wherein R ₁₂ represents Represents a hydrogen atom or a hydroxyl group, n represents an integer of 1 to 4,

m is 0 or 1, provided that when is a hydrogen atom, m is not 1.

 Among the above desirable compounds, particularly desirable compounds of the general formula (I) are

Represents a hydrogen atom, a hydroxyl group, a cyano group, a nitro group, a lower alkyl group having 1 to 6 carbon atoms, a methoxy group, a phenyl group, a chlorine atom or a group of the general formula NR ₁₄ R ₁₅ or one COR ₁₃ , wherein R is ₁₃ is a group of the general formula -NR ₁₆ R ₁₇ (where R _ie and R ₁₇ are each independently a hydrogen atom or a methyl group), a hydroxyl group or a methoxy group, and R ₁₄ and R ₁₅ are each Independently represents a hydrogen atom, a methyl group, a methylsulfonyl group, an acetyl group, or a P-nitrophenethyl group;

Z is the general formula

Represents a group of

R ₂ , R ₃ , R ₄ and R ₅ are each independently a hydrogen atom, a methyl group, a fluorine atom, a chlorine atom, a methoxy group, a nitro group, a hydroxyl group, a cyano group, an acetyl group, a hydroquinethyl group, and a carbon atom. or indicating the number 1 to a lower alkylsulfonyl group or formula chromatography NR of 6, ₈ R, ₉ or group one C ONR ₂₀ R _21, shows a piperazinyl group, & piperidinyl or Moruhori two group, wherein R ₁₈ and R ₁₉ is each independently a hydrogen atom, a lower alkylsulfonyl group having 1 to 4 carbon methyl group or C ^ to, R ₂ o and R ₂₁ each independently represents a water atom or a methyl group, O 96/06084

 14

Re represents a hydrogen atom, a lower alkyl group having 1 to 3 carbon atoms, a cyclopropyl group, a cyclopentyl group, an acetyl group or a hydroxyxetyl group;

■ 0 is 2-pyridyl or general formula

Represents a group of

R ₇ , R ₈ , R ₉ , R ₁₀ and RH each independently represent a hydrogen atom, a methyl group, a methoxy group, a fluorine atom, an iodine atom, a cyano group, a nitro group, a hydroxyl group, a sulfonyl group or NR ₂₄ R ₂₅ or a group of S 0 ₂ NR ₂₂ R ₂₃ , wherein R ₂₂ and R ₂₃ each independently represent a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms, and R ₂₄ and R _{23 25} each independently represents a hydrogen atom, a methyl group or a lower alkylsulfonyl group having 1 to 4 carbon atoms;

A represents a group of the general formula — (CHR ₁₂ ) _n — or one (CH ₂ ) „— 0—, wherein R ₁₂ represents a hydrogen atom or a hydroxyl group, n represents an integer of 1 to 4,

m is 0 or 1, provided that when is a hydrogen atom, m is not 1.

 Other desirable compounds of the general formula (I) according to the present invention are

Is the general formula

R 6 Represents a group of

 Z represents a lower alkyl group having 1 to 6 carbon atoms,

R ₂ , R ₃ , R ₄ and R ₅ each independently represent a hydrogen atom or a group of the general formula —NR ₁₈ R ₁₉ , wherein R ₁₈ and R ₁₉ each independently represent a hydrogen atom or a carbon atom 1-6 lower alkylsulfonyl groups;

-0 is a general formula

Represents a group of

R ₇ , R ₈ , R ₉ , R _{1 ()} and RH are each independently a hydrogen atom, a lower alkoxy group having 1 to 6 carbon atoms or a general formula

1 NR ₂₄ R ₂₅ or 1 S 0 ₂ NR ₂₂ R _{23 represents} a group, wherein R ₂₄ and R ₂₅ each independently represent a hydrogen atom or a lower alkylsulfonyl group having 1 to 6 carbon atoms, R ₂₂ and R ₂₃ each independently represent a lower alkyl group having 1 to 6 carbon atoms;

R ₆ represents a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms,

A general formula chromatography (CHR) "one or one _{(CH 2)} Π - 0- of a group, wherein R ₁₂ represents a hydrogen atom, or n is an integer from 2 to 4

-NA- Form a piperidine ring with

m is a compound showing the number of 0, 1 or 2.

Among the above-mentioned other desirable compounds of the general formula (I), a particularly desirable compound is 1 ^

 R 6

Represents a group of

 Z represents a methyl group,

R ₂ , R ₃ , R 4 and R ₅ each independently represent a hydrogen atom or a group of the general formula —NR ₁₈ R ₁₉ , wherein R ₁₈ and R ₁₉ each independently represent a hydrogen atom or methylsulfonyl Represents a group,

-0 is a general formula

Represents a group of

R ₇ , R ₈ , R ₉ , R ₁₀ and RH each independently represent a hydrogen atom, a methoxy group or a group of the general formula -NR ₂₄ R ₂₅ or -SO ₂ NR ₂₂ R ₂₃ , wherein R ₂₄ and R ₂₅ each independently represent a hydrogen atom or a methylsulfonyl group; R ₂₂ and R ₂₃ each independently represent a methyl group; R e represents a hydrogen atom or a methyl group,

A represents a group of the general formula-(CHR _{1 2} ) _n -or 1 (CH ₂ ) _n -0-, wherein R ₁₂ represents a hydrogen atom, n represents an integer of 2 to 4, or- NA-

Forming a piperidine ring with ^R 6,

m is a compound showing 0 or 2;

 The compound of the general formula (I) according to the present invention can further form a pharmaceutically acceptable salt. Such pharmaceutically acceptable salts include acids which form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, Inorganic acids such as hydroiodic acid, and organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid or trifluoroacetic acid, dalconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, etc. And acid addition salts formed with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or naphthalenesulfonic acid. Specific examples of such salts include hydrochloride, hydrobromide, hydroiodide, maleate, fumarate, lactate, tartrate, citrate, dalconate, benzoic acid Salt, methanesulfonate, benzenesulfonate, p-toluenesulfonate and the like can be mentioned. The present invention further relates to a process for producing a novel quinolylamine derivative represented by the above general formula (I) and a salt thereof. According to the method of the present invention, the quinolylamine derivative of the general formula (I) and a salt thereof are

(A) reacting a compound of the following general formula (II) or a salt thereof with a compound of the following general formula (III) or a salt thereof, 6/06084

 18

(B) A compound of the following general formula (Ib) or a salt thereof is produced by reducing a compound of the following general formula (Ia) or a salt thereof to produce a compound of the following general formula (Ib) or a salt thereof. Reacting with an alkane sulfonyl halide to produce a compound of the following general formula (Ic) or a salt thereof,

 (C) reacting a compound of the following general formula (Id) or a salt thereof with an amine derivative of the following general formula (VI) or a salt thereof to produce a compound of the following general formula (Ie) or a salt thereof,

(D) A compound of the following general formula (VII) or a salt thereof is produced by protecting the hydroxy group of the substituent R ₆ with a compound or a salt thereof of the following general formula (Ia-1), VII) or a salt thereof is reduced, reacted with an alkanesulfonyl halide to obtain a compound of the following general formula (VIII) or a salt thereof, and then deprotected to obtain a compound of the following general formula

It can be produced by a method characterized by producing the compound (Ic-11) or a salt thereof.

 The above method in the present invention can be shown by the following reaction scheme.

Method A

 (Π) (III)

• α) Method B

-NO (la)

t ^A

(lb)

Method C

(Id) (VI)

(Ie)

Method D

^[ 6a

 (Ia-1)

In the above reaction scheme,

Z, R ₂ , R ₃ , R ₄ , R ₅ , Re, -V 3, A, R _I4 , R ₁₅ and m are as defined in relation to general formula (I) above,

One of R _1P and Z _P is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a nitro group, a lower alkyl group, a lower alkoxy group, an aryl group or a general formula-NR ₁₄ R ₁₅ or A group of C0R ₁₃ , wherein R ₁₃ is a group of the general formula —NR ₁₆ R (where R _ie and R ₁₇ each independently represent a hydrogen atom or a lower alkyl group), a hydroxyl group or a lower alkoxy group R ₁₄ and R ₁₅ each independently represent a hydrogen atom, a lower alkyl group, a lower alkylsulfonyl group, a lower alkanol group or a lower alkyl group, and one of R _1P and Z _{P is} a group represented by the general formula: -(CH ₂ ) _m — represents a group of R,

 R is a reactive leaving group, for example, a halogen atom such as a chlorine atom, a bromine atom, an iodine atom, an alkane sulfonyloxy group such as a methanesulfonyloxy group, a benzenesulfonyloxy group, or a group such as a toluenesulfonyloxy group And

One of R ₁₈ , and R _ig , is a hydrogen atom, the other is a lower alkylsulfonyl group, one of R ₂₄ , and R ₂₅ , is a hydrogen atom, and the other is lower. An alkylsulfonyl group,

R ₆ is a hydroxy lower alkyl group,

 R is a protected hydroxy lower alkyl group, and Ha 1 is a halogen atom.

 Hereinafter, each of the methods A to D for producing the compound of the general formula (I) according to the present invention will be described more specifically.

Method A

 According to the method A of the present invention, the compound of the general formula (I) or a salt thereof can be produced by reacting the quinolyl derivative of the general formula (III) or a salt thereof with the amine derivative of the general formula (III) or a salt thereof. .

The reaction of Method A can be desirably performed in an organic solvent, generally in the presence or absence of an acid acceptor. This reaction The organic solvent is not particularly limited as long as it does not adversely affect the reaction and is an organic solvent, and is preferably an alcohol solvent such as methanol or ethanol, or a halogenated hydrocarbon solvent such as chloroform or methylene chloride. The reaction is carried out using dimethyl sulfoxide, dimethylformamide, acetone or the like. Book The reaction can be further performed in the presence of a water-soluble base, particularly when the reactive leaving group R is a halogen atom, that is, a chlorine atom, a bromine atom, or an iodine atom. It may be advantageous to do When the reaction is carried out in the presence of an acid acceptor, water-soluble bases include pyridine, triethylamine, potassium carbonate, potassium bicarbonate, potassium iodide, sodium methoxide, 1.8-diazabicyclo

 [5.4.0] It is desirable to use a normal water-soluble base such as Ndeque 7-Dene (DBU).

 The reaction of method A can be carried out in a relatively wide temperature range, but is generally carried out at room temperature to elevated temperature, preferably at the reflux temperature of the solvent used or at a temperature of 50 to 150 ° C. The reaction is generally carried out for 0.5 to 24 hours, preferably 1 to 15 hours. After the reaction is completed, the reaction product can be separated and purified by a post-treatment method commonly used in the art, if necessary, for example, a method such as column chromatography or recrystallization.

Method B,

 According to the method B of the present invention, in the first step, the compound of the general formula (la) or a salt thereof is reduced to obtain a compound of the general formula (Ib) or a salt thereof, and in the second step, Can react a compound of the general formula (lb) or a salt thereof with an alkane sulfonyl halide to produce a compound of the general formula (Ic) or a salt thereof.

The initial reaction in the first step can be carried out using an ordinary method commonly used in the art to reduce a dinitro group to an amino group. Such passing the original method touch the medium, such as platinum, palladium, carbon-like palladium, carbon like platinum, indirect reduction method is «source using hydrogen in the presence of a catalyst such as Raney nickel or SnC 1 _2, Z The method includes a direct reduction method using a chemical reducing agent such as n, Na ₂ S, aluminum amalgam, chromium (I) chloride, sodium thiosulfite, lithium aluminum hydride, and the like. In the general reaction, the catalyst is generally used in a ratio of 0.1 to 10 mol, preferably 1 to 5 mol, per 1 mol of the compound (Ia). The reaction is generally carried out under normal pressure, but may be carried out under slightly elevated pressure. The reaction time is generally between 0.5 and 24 hours, preferably between 1 and 15 hours.

 The compound of the general formula (Ib) produced by the first step reaction can be separated as an intermediate, but it can be used as it is in the second step reaction without separation if necessary.

 In the second step of method B, the compound of the general formula (Ic) is reacted with the compound of the general formula (Ib) produced from the first step, with an alkanesulfonyl halide, for example, alkanesulfonyl chloride or bromide. To manufacture.

 This second step reaction can be carried out preferably in the presence of an acid acceptor. Examples of the acid acceptor that can be used for such a purpose include pyridine, triethylamine, potassium carbonate, potassium bicarbonate and the like. Particularly preferably, the reaction is carried out in the presence of pyridine. The reaction temperature is not particularly limited, but it is generally desirable to carry out the reaction at room temperature. In general, the reaction is carried out for 1 to 15 hours, preferably 2 to 5 hours. After the reaction is completed, the reaction product can be separated and purified, if necessary, by a method commonly used in the art, such as a post-treatment reaction, for example, column chromatography, recrystallization and the like.

Method C

 According to the method C of the present invention, the compound of the general formula (Ie) or a salt thereof is reacted with the amide derivative of the general formula (VI) or the salt thereof to produce the compound of the general formula (Ie) or a salt thereof. Can be

The reaction of Method C can be desirably performed in an organic solvent, generally in the presence of an acid acceptor. Any organic solvent which does not adversely influence the reaction can be used as the organic solvent in this reaction, and alcohols such as methanol and ethanol are preferable. The reaction is carried out using a halogenated hydrocarbon solvent such as methyl solvent, chloroform and methylene chloride, dimethyl sulfoxide, dimethylformamide and the like. This reaction is further advantageously carried out in the presence of a water-soluble base, and an acid acceptor and sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate suitable for such a purpose are used. Metal hydroxides, such as sodium methoxide, carbonates, bicarbonates or alkoxides, pyridine, triethylamine, 1,8-diazabicyclo [5.4.0] pentacouene (DBU), etc. Ordinary water-soluble bases such as the following are preferably used.

 The reaction of Method C can be carried out in a relatively wide temperature range, but is generally carried out at room temperature to elevated temperature, preferably at the reflux temperature of the solvent used or at a temperature of 50 to 150 ° C. The reaction is generally carried out for 0.5 to 24 hours, preferably for 1 to 15 hours.

 After the reaction is completed, the reaction product can be separated and purified, if necessary, by post-treatment methods usual in the art, for example, column chromatography, recrystallization and the like.

Method D

Human mud Kin alkyl group in the reaction R _e in method D of the invention (R _e,) was reacted to protect, and Method B, except for performing the deprotection reaction after the reaction is completed Do the same.

 Hydroxy protecting groups desirably used in this reaction include ordinary hydroxy monoprotecting groups that can be easily removed by hydrolysis, for example, acetyl groups such as acetyl and propionyl groups.

—Free hydroxyl groups present in the compound of general formula (Ia-1) can be easily prepared by reacting the compound of general formula (Ia-1) with an acyl halide, for example, an acetyl chloride such as acetyl chloride. Can be protected. In this case, acyl halide is used in an amount of 1 to 5 mol, preferably 1 mol, per 1 mol of the compound of the general formula (Ia-1). Use in a ratio of up to 3 moles.

 The reduction reaction of the compound of general formula (VII), which is a hydroxy-protected compound, and the reaction with the alkane sulfonyl halide are carried out as described in Method B.

 The compound of the general formula (VIII) thus produced can be easily deprotected by base hydrolysis. Bases used for such base hydrolysis include alkali metal hydroxides such as sodium hydroxide and lithium hydroxide, and alkaline earth metal waters such as magnesium hydroxide and calcium hydroxide. Alkaline earth metal hydrides such as oxides, calcium hydride, etc., alkali metal hydrides such as sodium hydride, sodium methoxide, sodium ethoxide, potassium t-butoxide, etc. Alkali metal carbonates such as alkali metal alkoxide, sodium carbonate, potassium carbonate and the like, or alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate can be mentioned. Such a base hydrolysis reaction can be usually carried out in the presence of a solvent that does not adversely affect the reaction, for example, a solvent such as water, an alcohol such as methanol or ethanol, or a solvent such as tetrahydrofuran.

 After the reaction is completed, the reaction product can be separated and purified, if necessary, by a post-treatment method known in the art, for example, a method such as column chromatography or recrystallization.

Since the quinolylamine derivative of the general formula (I) and the pharmaceutically acceptable salt thereof according to the present invention have a potent potassium channel blocking action as described above, they are used, for example, as clinically useful antiarrhythmic agents. can do. In cases where the compounds are to be used clinically, they can be formulated and used in dosage forms well known in the pharmaceutical manufacturing art. Accordingly, the present invention further provides an antiarrhythmic agent composition comprising as an active ingredient a novel quinolylamine derivative of the general formula (I) or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of the present invention may be further prepared by using a well-known pharmaceutically acceptable carrier in a conventional manner in a pharmaceutical field, for example, tablets, capsules, troches, solutions, suspensions and the like. In the form of preparations for oral administration such as preparations, solutions for injection or suspensions, or dry powders for injection, which are ready-to-use and ready for use at the time of injection with distilled water for injection Can be formed into a dosage form.

 Carriers used for such purposes are well known in the pharmaceutical art, for example, in the case of formulations for oral administration, binders, lubricants, disintegrants, excipients, solubilizers There are a dispersing agent, a stabilizing agent, a suspending agent, a pigment, a fragrance, etc. In the case of an injection, there are a preservative, a soothing agent, a solubilizing agent, a stabilizing agent, a tonicity agent and the like. Pharmaceutical preparations thus produced can be administered orally or parenterally, for example, intravenously, intramuscularly or subcutaneously.

 When the quinolylamine derivative of the general formula (I) of the present invention is administered for the treatment and prevention of arrhythmia, the dosage may be varied depending on the condition, weight, age and the like of the patient. 1) to 6 Omg / day in 1 to 3 divided doses.

 [Example]

 The present invention will be more specifically described by the following examples and experimental examples, but the present invention is not limited thereto.

 Example 1 Production of N- [4- (412-trophenethylamino) -1 6-methanesulfone J-do 2-quinolylmethyl] 1-N-methyl-4-1-methanesulfonamide phenylamine

(1) 15 g (0.086 mol) of 6-ditroquinoline is dissolved in 100 ml of methylene chloride, and the resulting solution is stirred at room temperature while stirring at room temperature. 26.0 g of m-chloroperoxybenzoic acid (60%) (0.090 mol) was added slowly followed by stirring at room temperature—night. The precipitate was washed twice with 10% K ₂ CO ₃ solution. Drying later gave 14.3 g of product. 10 g of this product was separated, dissolved in POC 13 10 Om 1, stirred at the flowing temperature for 1 hour, cooled, and then gradually poured into ice water. The mixture was basified with an aqueous sodium hydroxide solution, and the generated precipitate was filtered and subjected to column chromatography using a mixed solvent of n-hexane and ethyl acetate 2: 1 as an eluent. Then, 7.02 g of the target compound 4-chloro-6-nitroquinoline was obtained.

 ^ -NMR (CDC "): 9.20 (s, 1 H), 8.97 (d, 1Η), 8

55 (dd, 1Η), 8.29 (d, 1 H). 7.67 (d. 1 H) (2) 4.92 g of 4-monochloro-6-nitroquinoline obtained in (1) above (0.033 mol) and dry ice Aseton _{F e S0 4 · 7H 2 0} 9. 22 g of (0.033 mol) was slowly added sulfuric acid 17. 7m 1 was dissolved in methanol 30 Om 1 Cooled to 0 ° C in bath. Was added dropwise _{H 2 0 2 (30%)} 19. 3ml (0. 199 mol) 1 hour over 30 minutes to the reaction mixture while maintaining the same temperature, the mixture was further搜拌30 min at 0 ° C, Neutralized with 10% potassium hydroxide solution. The reaction mixture was filtered, the base solution was extracted with chloroform, the extract was concentrated under reduced pressure, and the column was eluted with a 1: 1 mixed solvent of ethyl acetate and n-hexane as eluent. Chromatography gave 1.9 g of the desired compound 4-monochloro-6-nitro-2-quinolylmethanol as a crude product. The product was used for the next reaction without further purification.

(3) 0.5 g (2.99 mimol) of 4-monochloro-6-nitro-2-quinolyl methanol and 0.44 ml of triethylamine prepared from the above (2) were dissolved in methylene chloride 3 Om1. after the residue methanesulfonyl want such stirring at room temperature the resulting reaction solution black line de 0. 24 ml (3. 14 Mi Rimoru) _c reaction mixture was added dropwise to after concentration under reduced pressure was stirred at room temperature Column chromatography using a 1: 1 mixture of n-hexane and ethyl acetate as eluent 96/06084

Then, 0.43 g of the target compound (4-monochloro-6-nitro-2-quinolylmethyl) methanesulfonate was obtained.

_{• H-NMR (CDC 1 3} ):. 9. 19 (. S 1H), 8. 57 (d, 1 H), 8 25 (d, 1 H), 7. 86 (s, 1 H), 5 50 (s, 2H), 3.20 (s, 3H)

 (4) 10 g (0.044 mol) of 4-12-trophenethyl bromide was dissolved in 50 ml of a 40% methylamine-methanol solution, the mixture was stirred overnight, and then compressed under reduced pressure. The residue was acidified with 3N HCl, extracted with ethyl acetate, the extract was discarded, further basified with aqueous sodium hydroxide, extracted with ethyl acetate, dried over anhydrous magnesium sulfate and then under reduced pressure. This was reduced to give 4.8 g of the desired compound N-methyl-4-nitrophenethylamine.

Ή-NMR (CH ₃ OH): 8.23 (d. 2H. A r H), 7.58 (d, 2 Η, A r Η). 3.32 (m, 2H, A r -CH ₂ ) 3.17 (m, 2 H, N-CH ₂ -CH ₂ ), 2.76 (s, 3H, N-CH ₃ )

 (5) The above (3) product (4-monochloro-6-twotro-2-quinolylmethyl) methanesulfonate 0.43 g (l. 36 mimol) and the above product (4) N-methyl-4 0.49 g (2.72 mmol) of 12-trophenethylamine was dissolved in a mixed solvent of 10 ml of methanol and 10 ml of methylene chloride, and the resulting solution was stirred at the reflux temperature for 15 hours. After that, the mixture was concentrated under reduced pressure. The residue was subjected to column chromatography using a 2: 1 mixed solvent of ethyl acetate and hexane as an eluent to obtain the target compound N— (4-chloro-6-nitro-2-quinolylmethyl) -1N —0.44 g of methyl-412 trophenethylamine was obtained.

_{^ -NMR (CDC 1 3):} 9. 12 (s, 1H, quinoline Dan), 8. 5 (dd, 1H , quinoline each other), 8. 16 (m, 3H , A r Dan + Kino Li emissions H 7.56 (s.1H.quinoline H), 7.33 (d, 2H, Ar 96/06084

30

Η), 3.87 (s, 2Η. Quinoline- ^ J ^-), 2.96 (t, 2Η, Ar-CH _2- ), 2.8 (t, 2H, Ar-CH ₂ CH ₂ ), 2.45 (s, 3H, N-CH ₃ )

 (6) After dissolving 1.26 g (6.6 mimol) of SnC12 in an appropriate amount of concentrated hydrochloric acid, the product of the above (5), N- (4-monochloro-6-nitro-2- -Quinolyl methyl) -N-methyl-412-tropenetylamine 0.44 g (l.1millimol) is gradually added and stirred for 1 hour while heating at 40-50 ° C in a water bath. Was continued. Thereafter, an aqueous sodium hydroxide solution was added to make the mixture basic, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure to obtain 0.55 g of a product. Without purification, the product was continuously dissolved in 20 ml of pyridine, and 0.26 ml of methanesulfonyl chloride was added dropwise with stirring, followed by stirring overnight. The mixture was poured into water, basified again with an aqueous sodium bicarbonate solution, extracted with ethyl acetate, concentrated under reduced pressure, and the residue was eluted with a 9: 1 mixed solvent of chloroform and methanol as eluent. And subjected to column chromatography to give 0.48 g of the desired compound N- (4-chloro-6-methanesulfonamide 2-quinolylmethyl) -N-methyl-41-methanesulfonamide phenethylamine Was.

_{'H-NMR (CDC 1 3} ):. 8. 05 (d, 1 H, quinoline且), 7. 97 (s, 1 H, keno Li down Dan) 7. 64 (dd, 1 H , reluctant emissions且), 7. 55 (s, 1 H. reluctant emissions Dan), 7. 10 (m. 4H , A r H), 3. 81 (s, 2H. Kino Rin _{CH 2) ,. 3. 13 (s} , _{3H, S0 2 CH 3).} 3. 0 (s, 3H, S0 2 -CH 3), 2. 82 (t, 2H. A r CH ₂ CH ₂ ) .2.71 (t, 2H, A r-CH ₂ ), 2.4 (s, 3 H. N-CH ₃ )

 (7) N- (4-chloro-6-methanesulfonamide-12-quinolylmethyl) -N-methyl-4-1-methanesulfonamide dophenethylamine, which is the product of the above (6) 0.48 g (0.96 0.332 g (1.93 mimol) of and 4-12 trophenethylamine were dissolved in methanol and heated in an oil bath while evaporating the methanol to 12 (heated to TC. 30 at the same temperature). After stirring for 1 minute, let it cool down. In the first step, use a 3: 1 mixed solvent of chloroform and methanol as the eluent. In the second step, use a 5: 1 mixed solvent of methylene chloride and methanol as the eluent. And subjected to column chromatography to give the title compound N- [4-1 (412-trifluoroethylamino) -1-6-methanesulfonamido-2-quinolylmethyl] -N-methyl-4-methanesulfonamideヱ netilamine 0.29 g was obtained.

'H-NMR (MeOH - d 4): 8. 05 (d, J = 8. 7H z, 2H, A r H), 7. 73 (s, 1H, quinoline H), 7. 65 (d, J = 9 Hz, 1H, quinoline, etc. 7.51 (d, 1H, quinoline). 7.

41 (d, J = 8.7 Hz, 2H, ArH), 7.03 (m, 4H, ArH), 6.54 (s, 1H, quinoline), 3.64 (m, 4H , Kino Li down one CH _2, Kinorin _{NH- CH 2), 3. 07 (} m. 2H, -CH 2-A r -N0 2), 2. 94 (s, 3H, CH 3 SQ 3 NH), 2 . 81 (s, 3H, CH ₃ SQ ₂ ), 2.62.2.8 (m. 4H. CH ₂ CH _2- Ar NH), 2.33 (s, 3H, N-CH ₃ )

^{IR (KB r, cm '1} ): 3300-3400 (NH), 1160 - 1350 (S0 2 - N)

MS: 628 (M +)

Melting point: 109-112 ° C 96/06084

32

Example 2 Production of N- (6,7-dichloro-4-methyl-2-quinolylmethyl) 1 N dimethyl-4 1 methanesulfonamide phenethylamine salt _ ^ salt

 (1) Dissolve 24.3 g (0.15 mol) of 3.4 dichloroaniline in 120 ml of ethanol and add 67.58 g of iron chloride (ΙΠ) hexahydrate (0.25 mol) to the resulting solution. Mol) and 5.0 g (0.037 mol) of zinc chloride (II). The reaction mixture was heated at 60 to 65 ° C., and 10 ml (0.125 mol) of methyl vinylketone diluted in ethanol 3 Om1 was added dropwise over 2 hours. The mixture was stirred while heating at a reflux temperature for 3 hours, cooled to room temperature, and then neutralized with a 10% aqueous sodium hydroxide solution. The mixture was extracted three times with black hole form, the combined organic layers were dried over anhydrous sodium sulfate and concentrated 'under reduced pressure', and the residue was purified on silica gel using methylene chloride as eluent. The fraction containing the target compound was purified by column chromatography, collected and evaporated under reduced pressure to obtain 6.7-dichloro-4-methylquinoline (12.3 g) in a solid state.

Melting point: 149-153

_{^{! H-NMR (CDC 1 3}} ):. Δ 8. 77 (d, 1 H), 8. 22 (s, 1 Η) 8. 09 (s, 1Η), 7. 26 (d, 1 H), 2.68 (s. 3H)

(2) 6.0 g (0.038 mol) of 6,7-dichloro-4-methylquinoline was added to 50 Om 1 of methanol, and 2 Om 1 of concentrated sulfuric acid was gradually added thereto. The reaction mixture was allowed to cool to _{Fe S0 4 * 7H 2 0 10} g (0. 036 mol) was added to 0 ° C. Here was added dropwise _{30% H 2 O 2 2 Oml} , 0 ° C for 20 minutes stirring _c of the insoluble solid沈濺product is neutralized produced with 15% water oxidation power tumefaciens solution was removed by據過after the The solution was concentrated under reduced pressure and extracted three times with ethyl acetate. The organic layers were combined, washed with a saturated aqueous salt solution, and dried over anhydrous sodium sulfate. The residue was purified by column chromatography on silica gel using a 2: 1 mixed solvent of n-hexane and ethyl acetate as eluent to obtain a residue containing the target compound. The fractions were collected and evaporated under reduced pressure to obtain 4.12 g of the target compound 6.7-dichloro-2-hydroquinquin-4-methylquinoline in a solid state.

 啦 points: 139-154

_{'H-NMR (CDC 1 3} ) δ 8. 19 (s. 1 H). 8. 07 (s, 1 H), 7. 15 (s, 1H), 4. 86 (s. 2H), 4. 16 (b s. 1 H), 2.67 (s, 3H)

 (3) Dissolve 2.4 g (0.01 mol) of 6,7-dichloro-2-hydroquininemethyl-4-methylquinoline produced in (2) above in 30 ml of methylene chloride and 2.2 ml of thionyl chloride ( 0.03 mol) was added. The reaction mixture was passed for 2 hours 30 minutes and poured onto crushed ice. The mixture was neutralized with sodium bicarbonate and extracted three times with methylene chloride. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel using methylene chloride as eluent. The fractions containing the desired product were collected and evaporated under reduced pressure to obtain 0.93 g of the desired compound 2-chloromethyl-6,7-dichloro-4-methylquinoline in a solid state. Melting point: 138-143 ° C

^{! H-NMR (CDC ")} : 5 8. 18 (s, 1 H), 8. 07 (s, 1 H), 7. 46 (s, 1H), 4. 75 (s, 2H), 2. 69 (s. 3H)

(4) 0.39 g (l. 5 mimol) of 2-chloromethyl-6.7-dichloro-4-methylquinoline produced from (3) above and 2- (4-methanesulfonamidophenyl) -n-methylethyl 0.356 g (l. 6 mimol) of the amine were suspended in 1 Oml of methanol. The resulting suspension was stirred under heating at the flowing temperature for 3 hours, then cooled at room temperature and concentrated under reduced pressure. Saturated sodium bicarbonate solution was added to the residue, and the mixture was extracted three times with chloroform. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure, and the residue was treated with chloroform and methanol. : 1 Purified by column chromatography on silica gel using the solvent mixture as eluent, the fractions containing the desired product were collected and evaporated under reduced pressure. The residue was dissolved in methylene chloride (70 ml), and thereto was added getyl ether (7 Om1) and then 2.5 ml of a 1 NHC1-detyl ether solution. The resulting solid was dried over iS and dried to give 0.29 g of the title compound N- (6,7-dichloro-4-methyl-2-quinolylmethyl) -1-N-methyl-4-methanesulfonamidophenethylaminami hydrochloride. Was.

Melting point: 205-215

_{^{! H-NMR (CD 3 OD}} + DMSO-d 6):.. 5 8. 38 (d, J = 2. 8H z, keno Li down Dan), 8. 28 (d J = 2. 8Hz 1 H, Quinoline and), 7.46 (s. 1Η, quinoline and), 7.29 (d, J = 8.δΗ, 2Η, ArΗ), 7.22 (d, J = 8 .5 Hz, 2H.A r H). 4.75 (s, 2H, quinoline CH ₂ -N) .3.54 (bs, 2H, NCHzCHaA r), 3.17 (t.J = 8. OH z, 2 H. NCH ₂ C_ l A r), 3.10 (s. 3 H, SQ ₂ CH ₃ ), 2.95 (s, 3 H, quinoline CH ₃ ), 2.76 (s, 3H. NCH ₃ )

IR (KB r, cm " ¹ ): 3440 (NH), 1160 (S = 0)

MS: 452 (M ⁺ )

 Example 3 Production of N- (6-methanesulfonamido 4-methyl-2-quinolylmethyl) -1-N-methyl-4-1-methasulfamidophenethylamine dihydrochloride

(1) 42.5 g (0.35 mol) of 41.2 troarinline, 135.1 (0.5 mol) of iron chloride (III) hexahydrate, and 10 g (0.5 mol) of zinc chloride (Π) 073 mol) was heated to 60-65 ° C. in 25 Om 1 of ethanol. To this mixture was added dropwise 20 g (0.238 mol) of 3-penten-2-one over the course of 3 hours at the same temperature, and the mixture was stirred under flowing temperature for 3 hours while heating. Evaporate the solvent under reduced pressure and remove After adding 00 ml and water 300 ml, the mixture was neutralized with a 10% aqueous sodium hydroxide solution, and the resulting insoluble solid precipitate was removed by filtration. The at solution was extracted three times with a black hole form, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using methylene chloride as eluent to collect fractions containing the desired product, and the solvent was evaporated under reduced pressure to produce the desired product in solid state. The product 2,4-dimethyl-6-ditroquinoline was obtained in an amount of 19.8 g.

^! H-NMR (CDC "): δ 8.91 (s, 1H), 8.43 (d, 1 H), 8.10 (d, 1 H). 7.29 (s. 1 H), 2 . 80 (s, 3H). 2. 75 (s, 3H)

 (2) A solution prepared by dissolving 19.0 g (0.094 mol) of 2,4-dimethyl-6-ditroquinoline prepared in (1) above in 400 ml of methylene chloride was added with 60% 3- 40.5 g (0.141 mol) of black peroxybenzoic acid were added. The reaction mixture was stirred at room temperature for 2 hours, 120 ml of a 1 N aqueous solution of sodium hydroxide was added, the mixture was stirred for 20 minutes, and extracted three times with methylene chloride. The combined organic layers were dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a 15: 1 mixture of ethyl acetate and methanol as eluent to collect the fractions containing the desired product and to remove the solvent. Evaporation under reduced pressure gave 15.2 g of the target compound 2.4-dimethyl-6-ditroquinoline N-aged oxide as a yellow solid.

Melting point: 188-192

_{'H-NMR (CDC 1 3} ):. Δ 9. 00 (d, 1H), 8. 90 (s, 1 Η), 8. 50 (d, 1Η) 7. 34 (s, 1H), 2. 74 (s, 6H)

(3) 2.4 g (0.014 mol) of 4-dimethyl-6-ditroquinoline N-oxide prepared from (2) above and 4-toluenesulfonyl chloride 3. 87 g (0.021 mol) were heated in 30 ml of methylene chloride at reflux overnight. The reaction mixture was cooled, and a saturated aqueous solution of sodium bicarbonate was added. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel using methylene chloride as eluent to collect the fractions containing the desired product and evaporating the solvent under reduced pressure to afford the solid target. 2.21 g of compound 2-chloromethyl-4-methyl-6-nitroquinoline was obtained.

Melting point: 169—171

_{Ή-NMR (CDC 1 3)} :. Δ 8. 90 (. S 1 H), 8. 42 (d, 1 Η), 8. 12 (. D 1H), 7. 55 (s, 1 H) 4 . 74 (s. 2H)

, 2.77 (s, 3H)

 (4) 15 g (0.065 mol) of 4-12 trofunetyl bromide was added to 50 ml of a 40% methylamine-methanol solution cooled in a refrigerator, stirred overnight, and concentrated under reduced pressure. Thereafter, 100 ml of ethanol was added to the residue, and the residue was compressed again. To the residue was added 10 Om 1 of a 1 NHC 1 solution, and the mixture was extracted with ethyl acetate. The aqueous layer was separated, made basic with 2N NaOH 9 Oml, and extracted three times with ethyl acetate. The organic layers were combined, washed with a saturated aqueous salt solution, and dried over sodium sulfate. Hydrochloride gas was added thereto to produce a hydrochloride, and the solvent was evaporated under reduced pressure. C The product was recrystallized from ethanol, and the target compound in the solid state was obtained. 1 212 g of trophenethyl-N-methylamine hydrochloride 10.7 g I got

Melting point: 222-227 ° C

 • H-NMR (DMSO-de): <5 8.23 (d, 2H) '7.57 (d. 2H) .3.23 (m, 2H). 3.06 (t, 2H), 2 . 59 (s, 3 H)

(5) To 10 ml of methanol was added 69 mg of sodium gold and stirred for 20 minutes. To this, 0.65 g (3 mmol) of 4-nitrophenyl-N-methylamine hydrochloride produced from the above (4) was added, and the mixture was stirred for 20 minutes. To the reaction mixture was added 2-chloromethyl-4-methyl-6-nitroquinoline 0.115 S (0.5 mmol) produced from the above (3), and the mixture was stirred under reflux for 4 hours while heating. The mixture was cooled and concentrated under reduced pressure. To the residue was added 50 ml of a saturated aqueous sodium bicarbonate solution, and the mixture was extracted three times with methylene chloride. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel using a 1: 2 mixed solvent of n-hexane and ethyl acetate as eluent, and the fractions containing the desired product are collected. Was evaporated under reduced pressure to obtain 16 Omg of an oily target compound N- (4-methyl-6-ditro-2-quinolylmethyl) -1-N-methyl-4-12-trophenethylamine.

_{'H-NMR (CDC 1 3} ) δ 8. 85 (s, 1 H). 8. 39 (d, 1 H). 8. 07 (m. 3H), 7. 27 (m. 3H), 3. 79 (s. 2H), 2.90 (t, 2H), 2.73 (t, 2 H), 2.64 (s. 3H), 2.36 (s, 3H)

(6) 0.16 g (0.42 mimol) of N- (4-methyl-6-ditro-2-quinolylmethyl) -1-N-methyl-4-12-trophenethylamine prepared from (5) above was added to ethyl acelacete After dissolving in 20 ml of methanol, 2 Om 1 of methanol was added. 10% PdZC 10 Omg was added to the reaction mixture, and the mixture was stirred under hydrogen gas at normal pressure for 4 hours. The insoluble material was removed after washing thoroughly with methanol based on it. The combined solution and washing solution were concentrated under reduced pressure, dried under high vacuum, and 3 ml of pyridine and 0.5 g of K ₂ C 0 ₃ were added to the residue. 'The reaction solution was cooled in an ice water bath, and 0.21 g (l. 87 mimol) of methanesulfonyl chloride was gradually added. After the mixture was stirred at room temperature for 4 hours, 5 ml of methanol was gradually added. The solvent was evaporated under reduced pressure and the residue was poured into saturated aqueous sodium bicarbonate. The mouth of the mixture The mixture was extracted three times with form, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a 9: 1 mixture of chloroform and methanol as eluent to give a fraction containing the desired product. The collected and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, hydrogen chloride gas was introduced, and the solvent was evaporated under reduced pressure. The title compound in the solid state N- (6-methanesulfonamido 4-methyl-2-quinolylmethyl) -1-N-methyl- 4-Methanesulfonamide phenethylamine dihydrochloride (56 mg) was obtained.

Melting point:〉 135 ° C (decomposition)

_{Ή-NMR (DMSO- d 6)} :.. Δ 10. 87 (bs, 1 H. N + H), 10 37 (. S 1 H, S0 2 NH), 9. 76 (s 1 H, S0 2 NH), 8.07 (d, J = 9.0 Hz, quinoline), 7.74 (d, J = 9.OHz, 1 H. quinoline), 7.24 (d. J) = 8. 5H z, 2 H. A r H) 7. 18 (d, J = 8 5H z 2H, A r H) 4. 67 (s 2H, N- CH 2 -..... reluctant emissions) , 3. 39 (m. 2 H , NCH 2 CH 2- A r), 3. 13 (m. 5 H, S 0 2 CH 3 + NCH 2 CH 2 A r), 2. 96 (s. 3H, S O2CH3), 2.90 (s, 3H, quinoline-CH ₃ ), 2.67 (s, 3H, NCH ₃ )

 I R (KB r, cm_3: 3420 (NH) .1155 (S = 0)

 MS: 292 (M + —184). 184 (M + —292)

 Example 4 N- (6-methanesulfonamide 4-methyl-2-quinolyl)

N-Isoprovir-1 41 Manufacture of methansulfonamide

(1) 3 g (0.013 mol) of 4-12 trophenethylpromide and 7.68 g (0.13 mol) of isobroviramine were added to 40 ml of methanol, and then allowed to flow for 3 hours. After evaporating the solvent, add 40 ml of black form 0.1 NHC 1 The solution was acidified to pH about 4 and the aqueous layer was separated and extracted with ethyl acetate.c The aqueous layer was basified again with saturated sodium hydroxide solution to pH about 10, and then extracted with ethyl acetate. After drying over anhydrous sodium sulfate and evaporating, 1.28 g of N-isopropyl-141-tropenetylamine, which was a target compound, was obtained.

One _{NMR (CDC 1 3):.} Δ 8. 15 (d, 2H), 7. 38 (d, 2H) 2. 91 (s, 4H), 2. 82 (m, 1 H), 1. 05 ( d, 6H) (2) 1 g (4.4 mimol) of 2-chloro-4-monomethyl-16-nitroquinoline and N-isopropyl-14-nitrotropenetyla prepared from (1) above 1.84 g (8.8 mmol) of min was added to 2 ml of dimethyl sulfoxide, and the mixture was heated at 80 for 3 hours. Ethyl acetate was added to the reaction mixture, and extracted three times with water. The ethyl acetate layer was dried over anhydrous sodium sulfate and then evaporated. The residue was purified by column chromatography on silica gel using a 2: 1 mixed solvent of n-hexane and ethyl acetate as eluent. The fractions containing the product were combined and evaporated, and the residue was added to a mixed solution of 30 ml of chloroform and 3 Om1 of methanol.1 g of PdZC was added, and the mixture was stirred under hydrogen gas at room temperature for 2 hours. did. The precipitate was removed by filtration, dried and dried with anhydrous sodium sulfate, evaporated and the residue was purified by column chromatography on silica gel using ethyl acetate as eluent. The product was purified again by thin layer chromatography for purification using ethyl acetate as an eluent. The fractions containing the desired product were combined and evaporated, yielding 85 mg of the desired compound N- (6-amino-4-methyl-2-quinolyl) -1-N-isopropyl-14-aminophenethylamine. Was.

_{• H-NMR (CDC 1 3} ): δ 8. 66 (s, 1 H), 8. 25 (d, 1 Η), 8. 14 (d, 2Η), 7. 62 (d, 1 Η), 7.43 (d, 2H), 6.81 (s, 1Η), 4.61 (m, 1Η), 3.71 (t, 2Η) , 3.07 (t, 2H). 2.60 (s, 4H). 1.23 (d. 6H) (3) N- (6-amino-4-methyl-2-quinolyl) produced from (2) above 1 N-Isopropyl-4-aminoaminophenethylamine 8 Omg (0.2 mmol) was added to 2 ml of pyridine, cooled at 0 ° C, and 0.09 g of methanesulfonyl chloride was added dropwise at room temperature. Heated for 2 hours. Then, add 4 ml of methanol to the reaction mixture, evaporate with ethanol, add ethyl acetate, wash with saturated sodium bicarbonate, and wash three times with water. Thereafter, the ethyl acetate layer was dried over anhydrous sodium sulfate, and the residue was subjected to thin-layer chromatography for purification using a 2: 1 mixed solvent of n-hexane and ethyl acetate as an eluent. It was purified by applying. The fractions containing the desired product are combined and the solvent is evaporated to give the title compound N- (6-methanesulfonamido 4-methyl-2-quinolyl) -1-N-isopropyl-14-methanesulfonamide as a foam. 6 Omg of enethylamine was obtained.

_{Ή-NMR (CDC 1 3)} :. Δ 7. 60- 7. 67 (. M, 2Η, quinoline且), 7. 31 (.. D , J = 9. 0Hz 1H quinolin且) 7.26

(d, J = 8.3Hz, 2H, ArH), 7.1 (d.J = 8.3Hz, 2H, ArH), 6.73 (s.1H, quinoline H), 6.39 ( _{bs, 1H, NHS0 2),} 6. 36 (s, 1H, N Dan _{S0 2), 4. 7 2 (} m, 1H, NCH (CH 3) 2), 3. 58 (tt, J = 7. 9Hz , 2 H, NCH ₂ CH ₂ A r), 2.87-2.94 (m, 8H, SQ ₂ CH ₃

X2 + NCH ₂ CH ₂ Ar), 2.53 (s, 3 H.quinoline-CH ₃ ), 1.18 (d, J = 6.6 Hz, 6H, CH (CH ₃ ) ₂ )

IR (KB r, cm- ¹ ): 3270 (NH), 1155 (S = 0)

MS: 490 (M ⁺ )

Example 5 N- (6-n-butanesulfonamide 4-methyl-2-quinolyl) Production of methanesulfonamide phenethylamine

(1) In an 10 ° C in H ₂ S0 ₄ 50 m 1 2-chloro-4-methylquinoline 20 g (0. 1 13 mol) was added fuming nitric acid 21. 3 g (0. 338 mol) and H ₂ S0 ₄ 15 m l Was dropped at 110 ° C. over 30 minutes. The reaction mixture was stirred at 110 C for 30 minutes, then the temperature was raised to room temperature, stirred for 1.5 hours, and poured on crushed ice. The mixture was basified to about pH 10 with sodium hydroxide solution and extracted with methylene chloride three times. The combined organic extracts are dried over anhydrous sodium sulfate and evaporated, and the residue is purified by column chromatography on silica gel using methylene chloride as eluent to give the product. The fractions containing were collected and evaporated to give 3 g of the desired compound, 2-chloro-14-methyl-6-nitroquinoline.

_{'H-NMR (CDC 1 3} ):. Δ 8. 94 (s, 1 Η), 8. 51 (d, 1 Η), 8. 15 (d, 1 Η) 7. 42 (s, 1 Η) . 2. 82 (s, 3Η)

(2) 1.5 g (6.7 mimol) of 2-chloro-4-monomethyl1.6-ditroquinoline produced from (1) above and 4-g of 4-aminophenethylamine hydrochloride 1. (0.010 mol) was added to 15 ml of dimethylsulfoxide, and 3 g (0.020 mol) of 1,8-diazabicyclo [5.4.0] induec-7-ene (DBU) was added thereto. Thereafter, the reaction mixture was stirred at 80 ° C. for 1.5 hours, a saturated sodium bicarbonate solution and ethyl acetate were added, and the mixture was stirred. The organic layer was washed with water and saturated brine, and then washed with ethyl acetate. Layer was dried over anhydrous sodium sulfate, and the residue was purified by column chromatography on silica gel using a 1: 1 mixed solvent of n-hexane and ethyl acetate as the eluent. _{c The} fractions containing the desired product were collected and the solvent was evaporated, yielding the desired compound N— (4-Methyl-1-6—2tro-2-quinolyl) -14-aminophenethylamine 1.488 (488). _{-NMR (CDC 1 3): δ} 8. 61 (s, 1 H), 8. 22 (d, 1 Η) , 7.61 (d, 1H), 6.96 (d, 2H). 6.57 (d. 2H), 6.41 (s, 1H), 4.99 (bs, 1H), 3.69 (q, 2H), 3.47 (bs, 2H), 2.80 (t, 2H), 2.51 (s, 3H)

 (3) Add 1 g (3.1 mimol) of N- (4-methyl-6-ditro-2-quinolyl) -14-aminophenethylamine produced from the above (2) to 10 ml of pyridine. Here, 0.71 g (6.2 mmol) of methanesulfonyl chloride was added dropwise. After stirring the reaction mixture at room temperature for 3 hours, 2 ml of methanol was added, and the mixture was distilled under reduced pressure together with ethanol. Then, ethyl acetate and saturated sodium bicarbonate solution are added, and the organic layer is washed with water and saturated brine. After the ethyl acetate layer was dried over anhydrous sodium sulfate and evaporated, the residue was added to a mixed solution of 25 ml of chloroform and 5 Om1 of methanol. 1 g of PdZC was added thereto, and the mixture was stirred under hydrogen gas at room temperature for 3 hours. The precipitate was removed by filtration, and the solution was dried to obtain 0.78 g of N- (6-amino-4-methyl-2-quinolyl) -14-methanesulfonamide phenethylamine, which was the target compound.

Ή-NMR (DMSO-d _e ): <5 9.58 (bs, 1 H), 7.32 (d.

 1H), 7.23 (d. 2Η), 7.15 (d, 2H), 6.91 (d, 1H), 6.81 (s, 1H), 6.66 (b s. 1H), 6.53 (s, 1H), 5.02 (bs, 2H) .3.51 (m, 2H), 2.93 (s.3H), 2.84 (m, 2H), 2.36 (s , 3H)

(4) 0.75 g (0.002 mol) of N- (6-amino-4-methyl-2-quinolyl) -14-methanesulfonamide phenethylamine prepared from (3) above was added to 1 Om 1 of pyridine, and the mixture was added. 0. After cooling to C, 0.63 g (0.004 mol) of butanesulfonyl chloride was added dropwise. Thereafter, the reaction mixture was stirred at room temperature for 3 hours, 2 ml of methanol was added, and then the mixture was evaporated with ethanol. The ethyl acetate and saturated sodium bicarbonate solution are added and the ethyl acetate layer is washed with water and brine. The ethyl acetate layer was dried over anhydrous sodium sulfate and the residue was purified by column chromatography on silica gel using a 7: 1 mixture of chloroform and methanol as eluent. The eluate is evaporated again and the residue is subjected to column chromatography again on silica gel using a 1: 2 mixed solvent of n-hexane and ethyl acetate as eluent, containing the desired product The resulting fractions were collected and the solvent was evaporated, yielding 0.658 g of the title compound N- (6-n-butanesulfonamide 4-methyl-2-quinolyl) -14-methanesulfonamide dophenethylamine.

Melting point: 98 ° C

^{! H-NMR (DMS 0- d} 6) δ 9. 58 (b s. 2 H, NHS 0 2 X 2), 7. 55 (s, 1 H. quinoline Dan). 7. 50 (d. J = 8.9 Hz, 1H, quinoline and 7.37 (d, J = 8.9 Hz. 1H, quinoline and), 7.25 (d, J = 8.5 Hz, 2H, Ar H), 7.15 (d, J = 8.5 Hz, 2H.A r H), 6.90 (bs, 1 H, NHCH

₂ CH ₂ ), 6.63 (s. 1H, quinoline), 3.57 (m, 2H. NHCH ₂ CH ₂ ), 3.04 (t. J = 7.7 Hz, 2 H, CH ₂ CH) ₂ S 〇 ₂ ), 2.94 (s, 3H, SQ ₂ CH ₃ ). 2.85 (t, J = 7.1 Hz, 2 H, NHCH ₂ CH ₂ Ar), 2.42 (s, 3 H. quinoline CH ₃ ), 1.67 (m, 2H.S 0 ₂ CH ₂ CH ₂ CH ₂ ). 1.32 (m

2H, S0 ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 0.83 (t, J = 7.3 Hz, 3H, CH 2 CH ₂ CH ₃ )

IR (KB r. Cm '): 3400. 3290 (NH). 1160 (S = 0) S: 490 (M ⁺ )

Example 6 N ^ (6-Methanesulfonamide_4-phenyl-2-quinolyl). Production of Miacetate into Methanesulfonamide Phenylethylamine

 (1) 6.4 ml (0.07 mol) of aniline and 14.5 ml (0.084 mol) of ethyl benzoylacetate were stirred in 100 ml of dimethylformamide under flowing air for 2 hours. After the reaction mixture was cooled to room temperature, it was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted three times with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a 1: 1 mixture of n-hexane and ethyl acetate as eluent to collect the fractions containing the desired product. The mixture was concentrated under reduced pressure to obtain 10.1 g of N-phenylbenzoyl acetoamide, which was the target compound in a solid state.

Melting point: 105-109 ° C

 Ή-NMR (CDC "): <5 9.27 (bs, 1 H). 8.05 (d. 2H)-7.53-7.65 (m, 5H). 7. 34 (t. 2H) , 7.11 (t, 1H), 4.12 (s, 2H).

 (2) Add 10 g (0.042 mol) of N-phenylbenzoylacetamide produced from (1) above to concentrated sulfuric acid 2 Om 1 cooled in an ice water bath, and gradually heat Then, the mixture was stirred at 85 ° C for 1 hour. Cool the reaction mixture to room temperature and pour onto crushed ice. The mixture was stirred for 1 hour, and the resulting solid was filtered, washed twice with water and dried to obtain 4.54 g of the target compound, 2-hydroquinone- 4-fufurinquinoline, in a solid state.

Melting point: 253—261 ° C

 'H-NMR (CDC "): <12.61 (b«, 1 H), 7.47-7.5

7 (m. 8H), 7.17 (m, 1 H), 6.71 (s. 1 H)

(3) 3.54 g (0.016 mole) of 2-hydroxy 4-fur X dilquinoline produced from (2) above was mixed with acetoic anhydride and glacial acid in a 3: 1 mixed solvent of 25 m To 1 It was melted and cooled to 20 ° C. 1.56 ml (0.032 mol) of 86% fuming nitric acid diluted in 15 ml of glacial acetic acid was added dropwise to the reaction solution, and the mixture was stirred at 120 to 115 ° C for 30 minutes and gradually heated to 15 ° C. Stirred for 30 minutes. 50 ml of methanol was gradually added thereto, and the mixture was stirred for 30 minutes, concentrated under reduced pressure, added with water, and extracted three times with ethyl acetate. The combined organic layers were washed with a saturated aqueous salt solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography on silica gel using ethyl acetate as eluent. The fractions containing the desired product were purified by applying the compound, and the fractions containing the desired product were collected and evaporated under reduced pressure to obtain 1.93 g of the target compound, 2-hydroxy-6-twotro-4-phenylquinoline, which was a solid state. . Melting point:> 270 ° C

 • H-NMR (CDC 13 + DMSO-de): o 12.31 (b s. 1 H), 8.39 (s, 1 H). 8.27 (d, 1 H), 7.44-7 .58 (m, 6H), 6.64 (s, 1H)

(4) 2-arsenide Dorokishi 6 two Torrox 4 one Fuwenirukinorin 0. 53 g (2 millimeter mol) was stirred for 3 hours while flow through in POC l ₃ 2m 1. The reaction mixture was cooled at room temperature, and 10 ml of chloroform was added. The reaction solution was poured onto crushed ice, sodium carbonate was added to adjust the pH to 9, and the mixture was extracted three times with black-mouthed form. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was added with n-hexane, stirred, filtered and dried to obtain 0.53 g of 2-chloro-6-twotro 4-phenylphenylquinoline as a solid compound.

Melting point: 213-218 ° C

^J H-NMR (CDC "): <5 8.84 (s, 1 H) .8.52 (d. 1 H) .8.22 (d, 1H), 7.61 (m, 3H) .7 . 52 (m. 3H)

(5) 48 mg (2.1 mi atoms) of metallic sodium was added to 10 ml of methanol and stirred for 20 minutes. Here, 4 12-trophenethylamine hydrochloride 0.43 g (2. (1 mmol), stirred for 20 minutes, and evaporated under reduced pressure. The residue was thoroughly dried under high vacuum, and to this was added 0.20 g (0.7 mimol) of 2-chloro-6-nitro-4 4-fuylquinoline prepared from (4) above. 2 ml of dimethyl sulfoxide was added to the reaction mixture, and the mixture was stirred at 70 to 80 for 1.5 hours. After cooling to room temperature, 20 ml of methanol was added and stirred. The resulting solid is washed with methanol and aqueous methanol, dried and dried, and the target compound in the solid state, N- (6-2-troth-4-phenyl-12-quinolyl) -14-nitrophenethyla 0.24 g of min was obtained.

Melting point: 225—229 ° C

Ή Ή - NNMRR (fC CD ΠC C 11 3): δ 8 R 58 «(Cs ς, 1 H) 8 31 (d, 1H), 8. 19 (d, 2H), 7 79 (d, H) 7.54 (m, 3H) .7.44 (m, 4H), 661 (s.H) 5.11 (b s.1 H

), 3.93 (q, 2H), 3.17 (t ₍ 2H)

 (6) N- (6-nitro-2-4-quinolinol) produced from (5) above is obtained from 0.24 g (0.58 mimol) It was suspended in a mixed solvent of 10 ml of acetate and 10 ml of methanol. 0.20 g of 10% PdZC was added to the resulting suspension, and the mixture was stirred under an atmosphere of hydrogen gas for 1 hour. After that, the suspension was passed through Celite (Ce1ite) -545 and thoroughly washed with methanol. Later the insoluble solid was removed. The solution was evaporated under reduced pressure to obtain 0.19 g of N- (6-amino-4-phenyl-2-quinolyl) -14-aminophenethylamine as an oily target compound.

_{Ή-NMR (CDC 1 3)} δ 7. 62 (d. 1 H), 7. 46 (m. 5Η), 7. 04 (m, 3Η), 6. 82 (s, 1 Η), 6. 64 (d, 2Η), 6.47 (s.1Η), 4.89 (bs, 1H), 3.67 (q.2H), 3.59 (bs, 4Η), 2.87 (t.2H) ) (7) 0.19 g (0.54 mimol) of N- (6-amino-4-phenyl-2-quinolyl) -14-aminophenethylamine produced from (6) above was added to pyridine 5 m1 and cooled in an ice-water bath. To the reaction solution, 0.13 ml (1.6 mmol) of methanesulfonyl chloride was added dropwise, and the mixture was stirred at room temperature for 3 hours. To the mixture was gradually added 1 Om1 of methanol, and the mixture was concentrated under reduced pressure. After that, a saturated aqueous solution of sodium bicarbonate was added to the residue, and the mixture was extracted three times with chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a 15: 1 mixture of chloroform and methanol as eluent, and the fractions containing the desired product were collected and collected under reduced pressure. Evaporated. The residue was dried under a high vacuum to obtain 0.23 g of N- (6-methansulfonamide 4-phenyl-2-quinolyl) -14-methanesulfonamide phenethylamine, which was a foamed target compound. Was.

 (8) 100 mg (0.2 mimol) of N- (6-methanesulfonamide 4-phenyl-2-quinolyl) -14-methanesulfonamide produced from the above (7) in methanol Was added to the solution, and INacetoacid Z-methanol (1lm 1) was added. The mixture was stirred for 1 hour and evaporated under reduced pressure. The residue was dried under high vacuum to obtain 96 mg of the title compound N- (6-methanesulfonamido 4-phenyl-2-quinolyl) -14-methanesulfonate in the form of foam in 96-mg form. .

'H-NMR (DMSO-d e): δ 9. 53 (. Bs, 2H S0 2 NHX2), 7. 37- 7. 60 (m, 8H, reluctant emissions且and ArJi), 7. 28 (d, J = 8. 5H z, 2H, A r H), 7. 16 (d. J = 8. 5H z, 2H, A r H), 7. 07 (bs, 1 H, NHCH 2 CH 2), 6 . 70 (s, 1 H. reluctant emissions Dan). 3. 62 (m. 2H , NHCH 2 CH 2), 2. 91 (m, 8H. SO 2 CH 3 X 2 + NH CH 2 CH 2 A r) , 1. 9 1 (s, 1.5H, 1/2 CHsCOOH)

 I R (KB r, cm-ri: 3270 (NH), 1160 (S = 0)

MS: 510 (M ⁺ )

 Example 7 Production of N- (4-ethyl-6-methanesulfonamide-12-quinolyl) -1-N-methyl-4-1-methanesulfonamide dophenethylamine

 (1) 5 g (0.054 mol) of aniline and 7.7 ml (0.054 mol) of 3-keto n-ethyl valerate were dissolved in 40 m of dimethylformamide, and the mixture was stirred at reflux temperature for 2 hours. After cooling the reaction mixture, 200 ml of water was poured, and the formed precipitate was filtered and dried to obtain 5.5 g of the target compound N-fuyuniru 3-keto n monovalerate amide. .

 (2) N-phenyl 3-keto n-valeramide produced from (1) above 4.

After dissolving 59 g (0.024 mol) in 10.23 ml of sulfuric acid, the resulting solution was heated to 85 ° C in a water bath and stirred for 2 hours. After cooling the reaction solution, the mixture is poured into ice water, and the resulting precipitate is dissolved in methylene chloride by filtration, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and concentrated under reduced pressure. 2.90 g of 2-hydroxyquinoline was obtained.

_{^{! H-NMR (CDC 1 3}} ) δ 7. 73 (d, 1Η, quinoline each other), 7. 4 7 (m, 2H, quinoline Dan), 7. 23 (t, 1 H. quinoline且), 6. 62 (s, 1H. Quinoline), 2.92 (m, 2H, quinoline-CH ₂ CH ₃ ), 1.37 (t, 3H, quinoline-CH ₂ CH ₃ )

(3) ice water to cool the the manufactured from (2) a 4 Echiru 2- hydroxycarboxylic quinoline 0. 82 g (4. 73 Mi Rimoru) After stirring for 1 hour through flow temperature in addition to the POC 1 ₃ 30 ml Poured into. The mixture was neutralized with sodium hydroxide solution and extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was subjected to column chromatography using a 1: 1 mixture of ethyl acetate and hexane as eluent. The mixture was combined to give 0.8 g of the desired compound 2-chloro-4-ethylquinoline.

_{Ή-NMR (CDC 1 3)} :. Δ 8. 04 (m, 2 H, reluctant emissions H), 7. 7 4 (m , 1 H, reluctant emissions且), 7. 6 (m 1 H , Keno Li emissions H). 7. 29 (s , 1H, quinoline Dan), 3. 13 (m, 2H . quinoline one C H2CH3), 1. 43 (m . 3H, Kinorin CH ₂ ^ Ji ₃₎

 (4) A mixture of 5 ml of sulfuric acid and 5 ml of nitric acid was cooled to 0 ° C, and 2 g (0.010 mol) of 2-chloro-4-ethylquinoline prepared from (3) was gradually added thereto, and the temperature was gradually increased. After stirring for 1.5 hours while gradually raising the temperature to room temperature, cold water was poured and neutralized with a sodium hydroxide solution. The mixture was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. The residue was subjected to column chromatography using a 1: 3 mixed solvent of ethyl acetate and hexane as an eluent. 0.81 g of the desired compound 2-chloro-4-ethyl-6-nitroquinoline was obtained.

_{'H-NMR (CDC 1 3} ):. Δ 8. 96 (s, 1 H. keno Li down Dan), 8. 4 9 (. D d 1H, quinoline且), 8. 16 (d 1H, reluctant , 7.41 (s, 1H, quinoline), 3.21 (m, 2H, quinoline)

-CH ₂ CH ₃ ). 1.46 (m, 3H, quinoline-CH ₂ CH ₃ )

 (5) 0.3 g (1.27 mimol) of 2-chloro-4-ethyl-6-ditroquinoline and 0.5 g of N-methyl-4-12-tropenetylamine prepared from (4) above (77 mmol) was dissolved in 100 ml of methylene chloride, heated to 60 to 70 ° C. while evaporating the solvent, stirred at the same temperature for 2 hours, and then poured into water. The precipitate formed was filtered and washed with ether to obtain 0.26 g of the desired compound N- (4-ethyl-6-nitro-2-quinolyl) -1-N-methyl-412-tropenetylamine. Was.

_{^{1 H- NMR (CDC 1 3)}} :. Δ 8. 76 (s, 1 H, reluctant emissions Dan), 8. 3 (dd, 1H , reluctant emissions H), 8. 16 (d, 2H, A rH) . 7. 7 1 (d, 1H, quinoline), 7.43 (d, 2H, ArH), 6.8 (s, 1H, quinoline), 4.02 (t, 2H. Ar-CH ₂ CH ₂ . N), 3. 01-3 15 ( m, 7H, A r -CH 2, Kinorin _{CH 2 CH 3. N - CH 3} ), 1. 39 (t, 3 H, Kino Li Hmm CH ₂ CH ₃₎

 (6) 0.26 g (0.68 mimol) of N- (4-ethyl-6-nitro-2-quinolyl) -N-methyl-4-nitrophenethylamine prepared from (5) above was mixed with methanol. Methylene chloride was dissolved in 20 ml of a 1: 1 mixed solvent, 0.15 g of 10% PdZC was added to the resulting solution, and the mixture was stirred under a hydrogen atmosphere at room temperature for 2.5 hours. After filtering the reaction mixture, the solution was concentrated under reduced pressure to obtain 0.21 g of a product. This product was dissolved in pyridine 2 Om 1 without further purification, and 0.15 ml of methanesulfonyl chloride was gradually added dropwise thereto, followed by stirring at room temperature overnight. The mixture was poured into a solution of water and saturated sodium bicarbonate and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to column chromatography using a 9: 1 mixed solvent of chloroform and methanol as the eluent, and a 3: 1 mixed solvent of ethyl acetate and n-hexane was continuously used as the eluent. And then subjected to column chromatography again to obtain 0.23 g of the title compound N— (4-ethyl-6-methanesulfonamide 2-quinolyl) -1-N-methyl-14-methanesulfonamide phenethylamine. .

Melting point: 69-72 ° C

_{• H-NMR (CDC 1 3} ): δ 7. 69 (.. D, J = 8 35H z 2H, quinoline且), 7. 37 (d, J = 7. 5H z, 1H, quinoline且) 7.

25 (d, J = 9, 65 Hz, 2H, Ar H), 7.16 (d, J = 9.

55Hz, 2H, ArH), 6.68 (s, 1H, quinoline), 3.

87 (t, J = 7. 1 H z, 2H, -NHCH 2 CH 2 A r), 3. 13 (s, 3H, SO2CH3), 2. 99 (s, 3H, S0 2 CH 3), 2. 9 6-2. 91 (m. 7H. Quinoline CH ₂ CH ₃ , N-CH ₃ , CH ₂ CH ₂ -Ar), 1.34 (t, J = 7.5 Hz. 3H. Quinoline CH ₂ CH ₃

)

IR (KB r, cm-R: 1160 (— S0 ₂ — N—)

MS: 477 (M +)

 Example 8 Production of N- (6-methanesulfonamido 4-methyl-2-quinoline) -N- (2-hydroxyxethyl) -14-methanesulfonamide dophenethylaminin hydrochloride

 (1) A mixture of 30 ml of sulfuric acid and 23 ml of nitric acid was cooled to 15 ° C with dry ice and acetone, and 10 g (0.056 mol) of 2-methylene-4-methylenequinoline was gradually added thereto. Thereafter, the mixture was stirred for 1 hour while gradually increasing the temperature of the mixture to room temperature. After confirming the completion of the reaction by thin-layer chromatography, the reaction mixture was poured into ice water, neutralized with sodium hydroxide solution, and the precipitate was filtered. Stirred at temperature for 1 hour. The product was filtered and dried to obtain 1.7 g of the objective compound 2-chloro-6-ditro-4-methylquinoline.

(2) To 30 ml of ethanolamine was added 5 g of 412-tropenetilbamide, and the mixture was stirred at room temperature overnight. After adding 200 ml of water to the reaction mixture and extracting with ethyl acetate, the extract was concentrated under reduced pressure. The residue was subjected to column chromatography using a 9: 1 mixed solvent of chloroform and methanol as eluent to give the target compound N- (2-hydroxyxetyl) -141-tropenetylamine 4 7 g ο

_{Ή-NMR (CDC 1 3)} :.. <5 8. 17 (dd, 2 H, A r H) 7. 38 (dd, 2H, A r H) 3. 64 (m, 2 H. N-CH _{... 2 CH 2 OH)} 2 93 (m 4H, CH 2 -N-CH 2), 2. 81 (m, 2H, A r - H 2 -) (3) 1 g (4.5 mmol) of 2-chloro-4-methyl-6-ditroquinoline produced from (1) above and N- (2-hydroquinethyl) produced from (2) above 1.88 g (9 mmol) of 12-trophenethylamine was dissolved in 30 ml of methanol, and the resulting solution was heated to 110 ° C. while evaporating the methanol in an oil bath. After stirring at the same temperature for 1 hour and cooling, water was poured and extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was subjected to column chromatography using a 4: 1 mixed solvent of ethyl acetate and hexane as an eluent to give the target compound, N- (4-methyl-6- There was obtained 0.73 g of nitro 2- (quinolyl) -1-N- (2-hydroxyxetil) -141-tropenetylamine.

_{1H-NMR (CDC 1 3)} :. Δ 8. 71 (s, 1 H, keno Li down且) 8. 3 2 (d, 1H , quinoline Li down Dan), 8. 18 (d, 2 H, A 7.66 (d. 1H, quinoline), 7.43 (d, 2H, ArH), 6.76 (s. 1H, quinoline), 3.88 (m, 4Η, Ar CH ₂ CH ₂ N, -CHzOH), 3.74 (m. 2 H. CH, CH ₂ OH), 3.14 (t, 2H. Ar CH _2- ), 2 . 64 (s, 3H, quinoline CH ₃ )

(4) N- (4-methyl-6-nitro-2-quinolyl) -1-N- (2-hydroxyxethyl) produced from (3) above 0.74 g of trophenethylamine

(1.8 mmol) was dissolved in 50 ml of methylene chloride, 0.513 ml (3.7 mmol) of triethylamine was added, and 0.226 ml (3.7 mmol) of acetyl chloride was continued. It was slowly added dropwise. The reaction mixture was stirred at room temperature for 2 hours, then poured into water and extracted with methylene chloride. The extract was concentrated under reduced pressure, washed with ethyl acetate 2 Om 1, and the desired compound N- (2-acetoxethyl) 1 N— (4-methyl-16-nitro-2-quinolyl) 14 61 g of ditrophenethylamine.

_{Ή-NMR (CDC 1 3)} : δ 8. 74 (. S 1 H, keno Li down H), 8. 3 2 (dd, 1H, quinoline), 8.18 (d, 2H, ArH), 7.7 (d, 1H, quinoline), 7.44 (d, 2H, ArH), 6 . 8 4 (s, 1H, quinoline), 4.31 (t, 2H. CH ₂ OC (0) CH ₃ ), 3.96 (t. 2H. N-CH ₂ CH ₂ -A r ). 3.76 (t, 2H, N-CH2CH2OA c), 3.15 (t.2H, Ar -CH _2-

), 2.67 (s, 3H, quinoline-CH ₃ ). 2.04 (s, 3H,

 (5) N- (2-acetoxitytyl) -N- (4-methyl-2-6-nitro-2-quinolyl) -14-nitrotropenetylamine produced from (4) above 0.5 g (1. Was dissolved in 50 ml of methanol, 0.25 g of 10% PdZC was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours, filtered and concentrated under reduced pressure. This was directly dissolved in pyridine (1 Om1) without purification, and 0.27 ml of methanesulfonyl chloride was gradually added dropwise, followed by stirring overnight at room temperature. The reaction mixture was concentrated under reduced pressure to remove pyridine, and the residue was added with sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was not further purified, but 3NHC 118 Om1 was poured and heated in a water bath at 80 ° C and stirred for 1 hour.c The mixture was cooled, neutralized with sodium hydroxide solution and allowed to stand at room temperature overnight. After that, the precipitate is passed through, washed with getyl ether and ethyl acetate, dried, and dried to obtain the desired compound N— (2-hydroxyoxethyl) -1-N— (6-methanesulfonamide 4-methyl-2-quinolyl) 0.36 g of 1-4-methanesulfonamide phenethylamine was obtained.

Ή-NMR (DMSO): δ 7.59 (s, 1H, quinoline), 7.51 (d, 1H, quinoline), 7.4 (d. 1H, quinoline), 7.2 (d, 2H, ArH), 7.15 (d, 2H.ArH), 6.94 (s, 1H, quinoline ϋ), 3.78 (m, 2Η, N-CH, CH ₂ -OH ) .3.57 (m, 4H, N-CH ₂ CH ₂ Ar + N-CH ₂ CH ₂ OH), 2.94 (s, 3H.S0 ₂ CH ₃ ), 2.9 (s, 3H, S0 ₂ -CH ₃ ), 2.86 (t, 2H, Ar CH ₂ )

 (6) N- (2-hydroxyethyl) -1-N- (6-methansulfonamide 4-methyl-2-quinolyl) -14-methanesulfonamide phenethylamine prepared from (5) above 0.36 g Was dissolved in 3 ml of a mixed solvent of methanol, ethyl acetate and methylene chloride (1: 1: 1), and 10 ml of 1 NHC dissolved in ethyl ether was added dropwise to the resulting solution, followed by stirring at room temperature for 20 minutes. After that, the mixture was concentrated under reduced pressure. The residue was dissolved in 10 ml of methanol, and an excess (about 10 ml) of ethyl ether was added to the residue for crystallization to give the title compound N- (6-methanesulfonamide 4-methyl-2-quinolyl) -1-N- (2-hydroxyxethyl) 14 0.35 g of methanesulfonamide pentaethylamine dihydrochloride was obtained.

Melting point:〉 203 (decomposition)

'H-NMR (DMSO-d ₆ ): δ 10.14 (brs, 1 H, NH S 0; CH ₃ ). 9.67 (s, 1 H, NHSQ ₂ CH ₃ ), 8.4 (br s.

1H, quinoline), 7.69 (s. 1H, quinoline alternately). 7.62 (d, J = 8.8Hz, 1H. Quinoline and), 7.33 (m. 3Η) 2 A r Η, quinoline ϋ), 7.12 (d, J = 8.4 Hz, 2H, A r H) .4.06 (brm, 2H, CH ₂ CH ₂ OH), 3.83 (brm , 2H, CHzCHzOH), 3. 68 (brm, 2H, N-CH 2 C

_{H 2 - Ar), 3. 05} (s, 3H, S0 2 - CH 3), 2. 94 (t, J = 6 6Hz, 2H, Ar -. CH 2 CH 2 - N), 2. 84 (s 3H, S0 ₂ "CH ₃ ), 2.59 (s, 3H, quinoline-CH ₃ )

^{IR (KB r, cm- 1)} : 3600, 1160 (S0 2 -N), 1320 - 13 40 (NC) MS: 493 (M +)

 Example 9 Production of N- (6-methanesulfonamide-1-methyl-2-quinolyl) -14-methanesulfonamide dofetylamine

 (1) After dissolving 15 g (74 mimol) of 4 12-tropenetylamine hydrochloride in a mixed solvent of 400 ml of methanol and 10 Om1 of ethyl acetate, 10%

After adding 6 g (5.6 mimol) of Pd / C and stirring under hydrogen gas for 3 hours, the mixture was filtered and concentrated under reduced pressure to obtain the target compound, 4-aminoaminoethylamine hydrochloride 11.7 g was obtained.

'H-NMR (DMS 0- d ₆ ): δ 7.9-8.2 (m. 2 H), 6.8-7.0 (d, 2H), 6.4-6.6 (d, 2H), 3. 2-3. 4 (brs, 2H). 2. 4-2. 6 (br s. 2H)

 (2) 15 g (67 mimol) of 2-chloro-4-methyl-6-nitroquinoline and 17.4 g (0.1 mol) of 4-aminophenethylamine hydrochloride prepared from (1) above were added to dimethyl sulfoxide. 30.7 g (0.2 mol) of 1,8-diazabicyclo [5.4.0] indene 7-ene was added to the solution prepared by dissolving in 30 Om1. The reaction mixture was stirred at 80 ° C for 2 hours, cooled to room temperature and added to water. The resulting crystals were washed with an aqueous solution of sodium bicarbonate, water and hexane in that order to obtain 15 g of the target compound N- (4-methyl-6-twotro-2-quinolyl) -14-aminophenethylamine.

(3) N- (4-Methyl-1-nitro-1-quinolyl) —4-aminophenethylamine (10.5 g, 0.033 mol) produced from the above (2) was added to ethyl acetate. Was dissolved in 55: 1 mixed solvent of methanol and methanol, and 4 g of 10% PdZC was added to the resulting solution. After introducing hydrogen gas into the reaction mixture at room temperature and reacting for 2 hours, the reaction mixture was concentrated under reduced pressure, followed by concentration under reduced pressure to obtain the desired compound N- (6-amino-4-methyl-2-quinolyl) -14-aminophenethylamine 9.5 g were obtained. (4) 9.5 g (0.032 mol) of N- (6-amino-4-methyl-2-quinolyl) -14-aminophenethylamine produced from the above (3) was added to 10 Om 1 of pyridine to give 0 After cooling with C, 11.2 g (0.097 mol) of methanesulfonyl chloride was slowly added dropwise over 30 minutes. After the reaction mixture was stirred at the same temperature for 1 hour, 50 Om1 of water was added and extracted with 30 Om1 of ethyl acetate. After the extract was dried over anhydrous magnesium sulfate and concentrated, the residue was subjected to column chromatography using a 9: 1 mixed solvent of chloroform and methanol as eluent to give the title compound N in the form of foam. — (6-Methanesulfonamido-1-methyl-2-quinolyl) 11.4 g of methanesulfonamidophenethylamine was obtained.

1H—NMR (CD ₃ OD): δ 7.66 (d, J = 2.3 Hz, 1 H, quinoline), 7.63 (d. J = 8.9 Hz, 1H. Quinoline). 7 42 (dd, J = 8.5 Hz. 1 H, quinoline). 7.26 (d. J = 8.5 Hz. 2 H, Ar H), 7.17 (d, J = 8.7 H) z, 2H. Ar H), 6.6 (s. 1H, quinoline), 3.67 (m, 2Η, NHCH ₂ CH ₂ ), 2.92 (s, 6Η, CH ₃ S0 ₂ NHX2) . 2. 9

1 (t. 2H, NHCH ₂ CH), 2.50 (s. 3 H. Quinoline mono CH 3)

 I R (KB r, cnr: 3240 (NH), 1160-1130 (S = 0) MS: 448 (M +)

 Example 10 N— (6-methanesulfonamide 4-methyl-2-quinolyl)

 (3-Hydroxypropyl) Production of 1,4-methanesulfonamide and phenethylamine

(1) 5 g (21.9 mimol) of 4-12 trophenethylpromide was gradually added to 30 ml (0.39 mol) of 3-amino-11-propanol and stirred at room temperature for 3 hours. The reaction mixture was added to 100 ml of water and extracted with 100 ml of ethyl acetate. Was. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 3.9 g of the target compound, N- (3-hydroxypropyl) -141-trophenethylamine.

 (2) 2-Chloro-4-monomethyl-16-ditroquinoline 0.5 g (2.24 mimol) and N- (3-hydroxypropyl) 1-42 prepared from (1) above After reacting 2 g (8.9 mmol) of trophenethylamine at 110 ° C. for 2 hours, the reaction mixture was added to water, neutralized with an aqueous solution of sodium bicarbonate, and extracted with 50 ml of ethyl acetate. After concentration of the extract, the residue was subjected to column chromatography using cyclohexane, ethyl acetate and methanol in a 7: 3: 1 mixed solvent as eluent to obtain the target compound N_ (4-methyl- 0.52 g of —nitro-12-quinolyl) -N— (3-hydroxypropyl pill) -141-tropenetylamine was obtained.

Melting point: 185-189 ° C

_{^{! H-NMR (CDC 1 3}} ):. Δ 8. 65 (s, 1 H) 8. 26 (d, 1 H), 8. 13 (. D 2H) 7. 58 (d, 1H), 7. 35 (d. 2H)

, 6.70 (s, 1H), 3.74 (m, 4H), 3.47 (m.2H). 3.05 (m.2H). 2.59 (s, 3H), 1. 78 (m, 2H)

(3) N- (4-methyl-6-nitro-2-quinolyl) -1-N- (3-hydroxypropyl) -14-2 tropenetylamine prepared from (2) above 0.72 g (1 .75 mmol) in 20 ml of methylene chloride, 0.49 ml of triethylamine was added to the resulting solution, and 0.25 ml of acetyl chloride (3.5 mmol) was added for 30 minutes. It was added dropwise. After stirring the reaction mixture for 2 hours, water was added, and the mixture was extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and concentrated to the desired compound, N- (3-acetoxypropyl). N— (4-Methyl-6-Nitro-2-quinolyl) 1-4-Nitrophenethylamine 0. 1 1 g was obtained.

 (4) N— (3-Acetoxypropyl) —N— (4-Methyl-6-Diitro-2-quinolyl) produced from (3) above 1.4-g Trophenethylamine 1.lg

(2.43 mmol) was dissolved in 50 ml of a mixed solvent of ethyl acetate and black form, 0.5 g of 10% PdZC was added to the resulting solution, and the mixture was stirred under hydrogen gas for 6 hours. The mixture was filtered and concentrated under reduced pressure. The residue was dissolved in pyridine (20 ml), and methanesulfonyl chloride (0.53 g, 6.9 mmol) was gradually added. After the reaction mixture was stirred at room temperature for 2 hours, water was added, and the mixture was extracted with ethyl acetate. The extract was concentrated and the target compound, N- (6-methanesulfonamido 4-methyl-12-quinolyl) -N- (3-acetoxoxypropyl) -14-methanesulfonamidophenethylamine 0.42 g was obtained.

_{• H-NMR (CDC 1 3} ):. Δ 69 (s, 1 H) 7. 61 (d, 1 H) 7. 46 (. D 1 H) 28 (d, 2H) 7. 18 (d, 2H ), 6.85 (s, 1H) 4.12 (m, 2H) 3, 84 (m, 2H), 3.62 (m.2H) 2.98 (m, 5H) 2.86 (m, 2H) 2.57 (s, 3H) 2.05 (s. 3H). 1]. 95 (m. 2H) (5) N- (6-methanesulfonamide 4) produced from (4) above 1-Methyl 1-2-quinolyl) 1 N- (3-acetoxypropyl) -14-methanesulfonamide phenethylamine 0.32 g (0.58 mimol) dissolved in 15 ml of ethanol to form a solution After adding 1 lml of 3N HCl, the mixture was passed at room temperature for 3 hours and evaporated under reduced pressure to remove ethanol. The reaction mixture was neutralized with aqueous sodium bicarbonate solution, extracted with ethyl acetate, and the extract was concentrated. The residue was subjected to column chromatography using a 9: 1 mixed solvent of chloroform and methanol as an eluent to give the title compound N— (6-methanesulfonamide 4-methyl-21-quinolyl) -1-N— ( 3-Hydroxypropyl) 1-41 Methanesulfonamide 0.23 g of netilamine was obtained.

Poll point: 205— 211 C

^{J H-NMR (CDC ")} : δ 9. 59 (. S, 2H NHS0 2 CH 3 X2).

 7.58 (d, 1H, J = 2.4 Hz, quinoline), 7.51 (d, 1H, quinoline), 7.41 (d, 1H, J = 2.4 Hz, quinoline)

H), 7.28 (d, 2H, J = 8.4 Hz, ArH) .7.15 (d, 2H, J = 8.5 Hz, ArH), 6.93 (s, 1 H , Quinoline), 4.69 (brm, 1 H.HOCH ₂ ) .3.73 (m.2H.N CH ₂ CH ₂ CH ₂ OH), 3.56 (m, 2H, NCH ₂ CH ₂ A r ), 3.43 (m, 2H, N-CH ₂ ). 2.96 (s, 3H, CH ₃ SQ ₂ NH

2.91 (s, 3H. CH ₃ SQ ₂ NH), 2.86 (m. 2H, Ar CH ₂ ), 1.70 (m, 2H, CH ₂ CH ₂ CH ₂ OH)

IR (KB r, cm " ¹ ): 1160 and 1330 (S = 0)

 M S: 507 (M- + 1)

 [Example 11] N- (6-methanesulfonamide 4-phenyl-2-quinolyl)

-N- (2-Hydroxyshetyl) 1-4-Methanesulfonamide Dophenethylamine Production of hemiacetate

 (1) 2-Chloro-6-1-2-row 4-Phenylquinoline 285 mg (1 mmol) and N- (2-hydroxyxethyl) 1-412 trophenethylamine 63 Omg (3 mmol) in dimethyl sulfoxide lm 1 And heated for 3 hours at 80-90. The reaction mixture was cooled at room temperature, 15 ml of methanol was gradually added, and the mixture was stirred. After stirring for 1 hour, the solid formed is passed through, washed with methanol, washed with knees and dried to dry the target compound as a yellow solid, N— (6-2-trow 4-phenyl-2-quinolyl) -1-N— ( 2-Hydroxityl) 0.32 g of 1,4-trophenethylamine was obtained.

_{! H-NMR (CDC 1 3} ): <5 8. 53 (. Q 1 H), 8. 30 (d, 1 H) 8.14 (d, 2H) .7.72 (d.1H) .7.56 (m, 3H), 7.38 (m, 4H), 6.73 (s, 1H), 3.86 -3.96 (m, 6H), 3.15 (t, 2H)

 (2) N- (6-nitro-4-1-phenyl-2-quinolyl) -1-N- (2-hydroxyxetyl) produced from (1) above 0.32 g of trophenethylamine

(0.7 mimol) was dissolved in 10 ml of form of black mouth and cooled in an ice-water bath. To the reaction mixture was added 0.07 ml (0.93 mmol) of acetyl chloride, and gradually 0.14 ml (1 mmol) of triethylamine was added. The mixture was stirred at room temperature for 2 hours, and then saturated aqueous sodium bicarbonate solution (30 ml) was added. Extracted three times with black-mouthed form. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a 2: 1 mixture of n-hexane and ethyl acetate as eluent to collect the fractions containing the desired product. The solvent is evaporated under reduced pressure and the target compound, a yellow solid, is N- (6-nitro-4-4-phenyl-2-quinolyl) -1-N- (2-acetoxethyl) 1-412 trophenethylamine 0.31 g was obtained.

Melting point: 153-157 ° C

_{Ή-NMR (CDC 1 3)} :. Δ 8. 58 (. S 1 H) 8. 31 (d, 1H), 8. 17 (d, 2Η) 7. 78 (. D 1H) 7. 56 (m , 3H), 7.44 (m, 4H), 6.85 (s, 1H) 4.33 (t. 2H), 3.99 (t, 2H), 3.82 (t. 2H) 3.17 (t. 2H)

'2.02 (s, 3H)

 (3) N- (6-two-row 4-one-Fe-2-ru-quinolyl) -N- (2-acetoxicetil) 1-412-tropenetylamine prepared from (2) above 0.31 g

(0.62 mmol) was suspended in a mixed solvent of 15 ml of ethyl acetate and 15 ml of methanol, and 0.30 g of 10% PdZC was added to the resulting suspension. The reaction mixture was stirred under a hydrogen gas atmosphere for 2 hours, and the generated insoluble solid was removed by filtration. The concentrated solution is concentrated under low pressure, and the residue is purified by column chromatography on silica gel using a 15: 1 mixed solvent of chloroform and methanol as eluent to give the desired product. Is collected and evaporated under reduced pressure to give the target compound in the form of an oil, N- (6-amino-4-phenyl-2-quinolyl) -1-N- (2-acetoxityl) -14-aminophenethylamine 0.18 g was obtained.

_{Ή-NMR (CDC 1 3)} :.. Δ 7. 61 (d, 1 H), 7. 48 (. M 5 Η) 7. 02 (. M 3Η), 6. 82 (s, 1 Η) 6 71 (s, 1Η), 6.62 (d. 2Η), 4.33 (t, 2Η), 3.82 (t. 2H)

, 3.77 (t.2H) .3.59 (b s.4H) .2.86 (t.2H), 2.04 (s, 3H)

(4) N- (6-amino-4-phenyl-2-quinolyl) -N- (2-acetoxicetyl) -Aminofeneethylamine 0.18 g (0. (4 mmol) was dissolved in 2 ml of pyridine, and the resulting solution was cooled in an ice-water bath. 0.1 ml (1.3 mmol) of methanesulfonyl chloroform was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 3 hours. Thereafter, 5 ml of methanol was gradually added, and the mixture was concentrated under reduced pressure. To this mixture were added 50 ml of chloroform and 5 Om1 of a saturated aqueous solution of sodium bicarbonate, and the mixture was stirred for 10 minutes and extracted three times with chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel using a 15: 3: 1 mixed solvent of methylene chloride, ethyl acetate and methanol as eluent to fractionate containing the desired product. Is collected and evaporated under reduced pressure to obtain the oily target compound N- (6-methanesulfonamide 4-1-phenyl-2-quinolyl) -N- (2-acetoxicetyl) -14-methanesulfonamide phenethylami 0. 15 g were obtained.

_{• H-NMR (CDC 1 3} ) δ 7. 75 (d, 1H), 7. 45-7. 54 (m, 5H), 7. 23 (d. 2H), 7. 15 (d. 2H). 6.78 (s, 1H), 6.64 (s, 1H) .6.53 (s, 1H) .4.31 (t, 2H) .3.84 (m, 4H), 2.93- 3.01 (m, 8H)

(5) N— (6-methanesulfonamide 4-1-fluoro-2-quinolyl) produced from (4) above N— (2-acetoxicetyl) 1-41-methanesulfonamide phenethylamine 0 15 g (0.25 mmol) was dissolved in 2 Om1 of methanol, and 1 ml of 1N NaOH was added to the resulting solution. The reaction mixture was stirred at room temperature for 1 hour, 1N acetonic acid methanol solution (lm 1) was added, the mixture was concentrated under reduced pressure, and the residue was diluted with 50 ml of chloroform and 50 ml of a saturated aqueous sodium bicarbonate solution. In addition, the mixture was stirred for 10 minutes. The reaction mixture was extracted three times with a black hole form, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a 15: 1 mixture of chloroform and methanol as eluent, and the fractions containing the desired product were collected and collected under reduced pressure. Concentrated. The residue was dissolved in 3 ml of methanol, 0.2 ml of cold acetic acid was added, and the mixture was stirred for 2 hours, concentrated under reduced pressure, dried under high vacuum, and concentrated in a foam state. The title compound N- (6-methanesulfonamide 4-1 There was obtained 0.10 g of phenyl acetate 2-N-quinolyl-N- (2-hydroxyxetil) -141 methanesulfonamide dophenethylamine hemiacetate.

^ -NMR (DMS 0- d ₆ ): δ 9.61 (bs. 1 H. NHS 0 ₂ ). 9.55 (bs, 1 H, NH S 0 ₂ ). 7.44-7.61 ( m, 8H, quinoline H + quinoline Ph H), 7.28 (d, J = 8.4Hz, 2H.. A r H). 7.15 (d, J = 8.4Hz, 2H.A r H). 6.90 (s, 1H. Quinoline H). 3.84 (t, J = 7.25 H z. 2H, 63

CH2CH2OH), 3.61 (bs, 4H, N-CH2CH2-A r + N- CH2CH2OH), 2.90 (m.8 H.N-CH ₂ CH ₂ -A r + S0 ₂ CH ₃ X2), 1 . 91 (s, 4.5H, 1.5 CH3COOH)

IR (KB r, cm " ¹ ): 3260 (NH), 1150 (S = 0)

MS: 556 (M + +2)

 [Example 12]

 The following compounds and the like can be produced by a method similar to the methods of Examples 1 to 11 above.

 (1) N— (6-methanesulfonamide-14-methyl-12-quinolyl) -14- (2-propanesulfonamide) phenethylamine (foam)

_{Ή-NMR (DMS 0- d 6} ): δ 9. 58 (. S 1 H. NHS 0 2), 9.

52 (bs, 1 H, NHS O2), 7.49 (s, 1 H. quinoline). 7.44 (d, J = 8.8 Hz. 1 H, quinoline). 7. 31 (d, J = 8.8 Hz, 1H, quinoline). 7.16 (d, J = 8.5 Hz, 2 H, Ar H), 7.10 (d, J = 8. 5 H z. 2H, A r H). 6. 89 (bs, 1 H, NHCH 2 CH 2), 6. 57 (s, 1 H, keno Li down且), 3. 50 (m. 2H _{, NHCH 2 CH 2), 3.} 08 (m, 1 H, S0 2 CH (CH 3) 2), 2. 89 (s, 3H. S0 2 CH 3). 2. 7

7 (t, J = 8. OH z. 2H. CH ₂ CH ₂ Ar). 2.36 (s, 3 H quinoline-CH ₃ ), 15 (d, J = 6.8 Hz. 6 H. S 0 ₂ CH (CH ₃ ) 2)

IR (KB r, cm ' ¹ ): 3400, 3260 (NH),] 50 (S = 0) S: 476 (M ⁺ )

(2) N— (6-Methanesulfonamide 4-methyl-2-quinolyl) 1-port mouthsulfoneamide phenethylamine Melting point: 78. C

_{Ή-NMR (CDC 1 3)} :. Δ 7. 65 (m, 2H, quinoline Li down且), 7. 3 5 (.. D, 1 H, J = 9 1 H z Keno Li down且) 7. 25 (d, 2H, J = 8.7Hz, ArH), 7.15 (d, 2H, J = 8.4Hz, Arand), 6.47 (s, lH, 3.75 (brd, 2

_{H. HNCH 2). 3. 0 (} t, 2H, A r CH 2). 3. 0 (s, 3H, S 0 2 CH 3), 2. 95 (t, 2H. S0 2 CH 2). 2 5 (s. 3H, quinoline CH ₃ ), 1.85 (m, 2 H, S 0 ₂ CH ₂ CH ₂ CH ₃ ), 1.0 (t, 3H, S0 ₂ CH ₂ CH ₂ CH ₃ )

 I R (KB r. Cm "'): 1330, 1 150 (S = 0)

MS: 476 (M ⁺ )

 (3) N— (6-Methanesulfonamide 4-methyl-2-quinolyl) 1 N—Bu mouth pill 1-4-Methanesulfonamide phenethylamini dihydrochloride

Melting point: 223-225 ° C

• H-NMR (CD ₃ OD): δ 7.85 (d. J = 8.8 Hz, quinoline), 7.8 (s, 1 Η, quinoline and), 7.65 ( m, 1H, quinoline H), 7.25 (d. J = 6.3Hz. 2H. ArH). 7.1 (m. 3H, Ar] i + quinoline and). 4. 1 (m. 2H. -NCH 2 CH 2 CH 3), 3. 7 (m. 2H, N-CH2-CH2- A r), 3. 05 (s, 6 H, S 0 2 CH 3 X2 ). 2.75 (m, 2H, Ar CH ₂ ) .2.6 (s

3H, quinoline CH ₃ ) .1.8 (m. 2H, N-CH ₂ CH ₂ CH ₃ ), 1.2 (m. 3H, N-CH 2 CH ₂ CH ₃ )

IR (KB r, cm " ¹ ): 1 1 70, 1 350 (S = 0)

MS: 49 1 (M +)

(4) N— (6-Methanesulfonamide 4-methyl-2-quinolyl) Clopropyl-41-methanesulfonamide phenethylamine (foam)

_{JH- NMR (CDC 1 3):} δ 7. 63 (m, 2H, quinoline Li down且), 7. 3 3 (. D , J = 8. 8Hz, 1H keno Li down Dan), 7. 03-7 . 19 (m, 5H, A r H + S0 2 NH), 6. 72 (bs, 1 H, S0 2 NH), 6. 61 (s, 1 H, keno Li down Dan), 3. 93 (t , J = 7.6 Hz,

2H, NCH ₂ CH ₂ ), 2.94 (s, 3H, SQ ₂ CH ₃ ), 2.89 (t, J = 7.6 Hz, 2H.NCH ₂ CH ₂ A r), 2.86 (s, _{3H, SQ 2 -CH 3),} 2. 53 (s, 3H, keno Li Hmm _{CH 3), 2. 48 (m} , 1 H, cyclopropyl Dan), 0. 84 (m, 2 H, cyclopropyl且), 0.58 (m, 2H, cyclopropyl H)

IR KB r, cm ' ¹ ): 1150 (S = 0). 3420 (NH)

MS: 488 (M +)

 (5) N- (6-Methanesulfonamide 4-methyl-12-quinolyl) -1-N-methyl-41-methanesulfonamide phenethylamine

Melting point: 75-79 ° C

^{! H-NMR (CDC 13 +} TMS): δ 7. 82- 7. 05 (. M, 7Η keno Li down ϋ + Α r Dan), 6. 65 (s, 1 H, keno Li down '且) 3.85 (t, 2H,-N (CH ₃ ) CH ₂ CH _2- ), 3.10 (s. 3H. CH ₃ S0 _2- ), 2.95 (s. 3H, CH ₃ S 0 _2-) ), 3.00 (t, 2H, one N (CH ₃ ) CH ₂ CH ₂ ), 2.85 (s, 3H. N-CH ₃ ), 2.4

5 (s. 3H, Kino Li Hmm CH ₃₎

IR (KB r, cm- ¹ ): 1150 (S = 0).

MS: 462 (M +)

(6) N- (6-Fluoro-4-methyl-2-2-quinolyl) -14-methanesulfone amide phenethylamine Melting point: 54 ° C

^{J H- NMR (CDC 13):} .. Δ 7. 65 (m, 1 H, keno Li down且) 7. 4 5 (. M 1 H. Keno Li down且), 7. 3-7 25 (m , 3H, keno Li emissions H + A r H), 7. 2 (d, 2H. J = 8. OH z, A r H), 3. 7 (q, 2H, J = 6. 4H z, NHCH 2 ), 3.0 (s, 3H, S0 ₂ CH

3), 2.95 (t, 2H, J = 6.3Hz, Ar CH ₂ ), _2.5 (s, 3H, quinoline CH ₃ )

IR (KB r, cm- ¹ ): 1330.150 (S = 〇)

M S: 374 (N)

 (7) N- [6- (N-methyl-methanesulfonamide) -14-methyl-2-quinolyl] -14-methanesulfonamide phenethylamine

Melting point: 89-91 ° C

_{^{! H-NMR (CDC 1 3}} ): δ 7. 76 (. S 1 H, keno Li down且), 7. 6 8 (. D 1 H, keno Li down且), 7. 48 (d, 1 H 7.23 (d. 2H, ArH). 7.12 (d, 2Η, ArH). 6.

46 (s, 1 H, quinoline and) .3.7 δ (m. 2 (, NCH ₂ CH ₂ ), 3.38 (s, 3Η, CH ₃ -SQ ₂ NCH ₃ ), 3.0 (s, 3Η, Ν HS Q ₂ CH ₃ ), 2.96 (m, 2Η. NHCH ₂ CH ₂ ), 2.89 (s, 3Η, SQ ₂ NCH ₃ ). 2.53 (s.3H, quino Li Hmm _{CH 3) IR (KB r,} cm '1):. 3400, 2900 (CH, aliphatic) 1325 (S = 0)

 MS: 462 (M +)

 (8) N— (6-ethanesulfonamido 4-methyl-2-quinolyl) 1-4-methansulfonamide dophenethylamine

Melting point: 0.70 ° C (decomposition) _{- NMR (DMS 0- d e)} :. Δ 9. 66 (s, 1 H, NHS 0 2) 9. 60 (s, 1H, N Dan _{S0 2), 7. 56 (s} , 1 H, Keno Li 7.51 (d, J = 8.8 Hz, 1 H, quinoline H). 7.38 (d, J = 8.9 Hz, 1 H, quinoline and), 7.26 (d, J = 7.2 Hz, 2H, ArH), 7.16 (d, J = 7.0 Hz, ArH), 6.94

_{(brs, 1 H, NHCH 2} ), 6. 63 (s, 1 H, keno Li down Dan). 3. 57 (t, 2H , NHCH2CH2), 3. 06 (q. 2H, CH 3 CH 2 S 0 _{2), 2. 95 (s,} 3H, NHSQ 2 CH 3), 2. 86 (t, 2H, J = 7. OH z, NHCH2CH2), 2. 43 (s, 3H, keno Li Hmm CH _3), 1.21 (m, 3H. NHSQ ₂ CH ₂ CH ₃ )

IR (KB r, cm— ¹ ): 3260 (NHS 0 ₂ ), 1320 and 1145 (S = 0)

 MS: 462 (iM +)

 (9) N- [6-Methanesulfonamide 4-((N, N-dimethylamino) -121-quinolyl] -14-methanesulfonamide-phenethylamine

Melting point: 128-130 ° C

Ή-NMR (DMSO-de) :. <5 9. 58 (brs, 1 H, S 0 2 NH) 9. 52 (brs, 1 H, S0 2 NH), 7. 66 (s, 1 H. Keno 7.44 (d, J = 8.9 Hz, 1H, quinoline), 7.32-7.24 (m, 3H, quinoline H, Ar and). 15 (d,

J = 8.4Hz. 2H, Ar H), 6.8 (m, 1H, NH), 6.21 (s, 1H, quinoline). 3.54 (t, J = 5.8Hz _{. 2H, N -CH 2 CH 2} -A r). 2. 94 (s. 3H. S0 2 CH 3). 2. 91 (s. 3H, S O2CH3), 2. 86-2. 81 (m. 8H. Quinoline N (CH ₃ ) ₂ Ar CH ₂ ) .. IR (KB r, cm_ Re: 1310 - 1320 (N - C ), 1160 (S0 2 - N)

MS: 477 (M ⁺ )

 (10) N- (6-Methanesulfonamide 2-quinolyl) 14-Methanesulfonamide phenethylamine (foam)

Ή-NMR (DMSO-de) : δ 9. 53 (s, 1 H. S0 2 NH), 8.

29 (s, 1 H, S0 2 NH), 7. 79 (d, J = 8. 9H z, 1H, quinoline Li down Dan), 7. 48 (d. J = 8. 9Hz, keno Li down且) 7.42 (s. 1 H. quinoline and), 7.34 (d, J = 8.9 Hz. 1 H, quinoline and). 7.24 (d, J = 8.3 Hz, 7.13 (d, J = 8.3Hz, 2H, ArH), 7.01 (bs.1H, NHCH2CH2) ■ 6.74 (d.J = 8.9 Hz, 1 H, quinoline H), 3.56 (m, 2 H, NHCH ₂ CH ₂ ) .2.93 (s, 3H.SQ ₂ CH ₃ ) .2.91 (s. 3 H, SQ ₂ CH ₃ ), 2, 8 δ (t.J = 7.3 Hz, 2H.NHCH ₂ CH ₂ A r)

IR (KB r, cm- ¹ ): 3410. 3260 (NH), 1150 (S = 0)

MS: 250 (M ⁺ -184). 184 (M +-250)

 (11) N— (6-methanesulfonamide 4-methyl-2-quinolyl) 1-41 butanesulfonamide phenethylamine (foam)

_{^{. 1 H_NMR (DMSO-d 6}} ): δ 9. 64 (s, 1 H, NHS0 2) 9. δ 7 (. S 1 H, NHSO2) - 7. 56 (s, 1 H, keno Li down Dan) , 7.51 (d, J = 8.8 Hz, 1H. Killindan), 7.37 (d. J = 8.8 Hz. 1H, quinoline and), 7.23 (d, J = 8 . 4H 2, 2H, A r H). 7. 14 (d. 'j = 8. 4 H z. 2H, A r H), 6. 97 (bs, 1 H, NHCH 2 CH 2). 6. 63 (s, 1 H. quinoline WO 96/06084 PCT / JP 5/01137

69

Η), 3.55 (m, 2Η. NHCH ₂ CH ₂ ), 3.02 (t, J = 7.7 Hz, 2H, SQ ₂ CH ₂ -CH ₂ ), 2.95 (s, 3 H. S0 ₂ CH 3), 2.84 (t, J = 6.8 Hz, CH ₂ CH ₂ Ar), 2.42 (s, 3H, quinoline-CH ₃ ), 1.63 (m. 2H, S0 ₂ CH ₂ CH ₂ CH 2), 1.31 (m, 2H, CH ₂ CH ₂ CH ₃ ), 0.82 (t, J = 7.3 Hz, 3 H, CH ₂ CH ₂ CH ₃ )

 I R (KB r. Cm-): 3420, 3270 (NH), 1150 (S = 0)

MS: 490 (M ⁺ )

 (12) N- (6-Methanesulfonamide 4-methyl-2-quinolyl) 1 4-

10 (N-methyl-methanesulfonamide) phenethylamine dihydrochloride (foam)

Ή-NMR (CD ₃ OD): ό7.8 (m, 2 H, quinoline H). 7.67 (s, 1 H. quinoline), 7.25 (m, 4 H, A r H). 6. 8 (s . 1 H, Dan keno re down). 3. 75 (m, 2H , NHC_H 2 _). 3. 1 (s. 3H, CH 3 SQ 2 NH), 2. 96 (t, J ^ 6.8 Hz, NH CH ₂ CH ₂ ) .2.92 (s, 3H, CH ₃ S0 ₂ N <), 2.67 (s, 3H.> N-CH ₃ ), 2.52 (s, 3H, quinoline CH ₃ )

IR (KB r, cur ¹ ): 1150 and 1340 (S = 0) '

 MS: 462 (M *)

 (13) N- (4,7-Dimethyl-2-quinolyl) -14-methanesulfonamide phenetinoreamin

 Melting point: 51- 53 ° C

'Η—NMR (MeOH-d): o 6.9-7. · 8 (m, 7H.ArH + quinoline), 6.5 (s. 1Η, quinoline) .3 6 (m, 2H, N. H-CH ₂ CH ₂ Ar), 2. 6-3. '0 (m, 5H.S0 ₂ CH ₃ + CH ₂

1 Ar), 2.3.2.4 (s, 3 H. quinoline 1 CH ₃ ) IR (KB r, cm_ re: 3230, 3400 (NH), 1160 (—SO ₂ -N)

 MS: 369 (M +)

 (14) N- (4,7-Dimethyl-16-methanesulfonamide 2-quinolyl) — 4-Methanesulfonamide phenethylamine

Melting point: 175-178 ° C

_{lH-NMR (CDC 1 3)} :.. 0 7. 7 (s, 1 H, keno Li down Dan) 7. 45 (. s 1 H , keno Li down Dan), 7. 05-7 2 (m, 4 H, Ar H), 6.35 (s, 1 H, quinoline), 3.6 (t, 2 Η. NH-CF ^ CH ₂ -Ar), 2.8-2. 98 ( _{. m, 8 H, SQ 2} CH 3 A r-CH 2 one _{CH 2 -.), 2. 45} (s, 3 H. keno Li emissions _{CH 3), 2. 35 (s} , 3H keno Li Hmm CH ₃ )

IR (KB r, cm- Li: 3220-3390 (NH), 1140 ( S 0 2 -N) MS:. 278 (M + - 186) 186 (M + - 278)

 (15) N- [7- (n-butanesulfonamide) 1-4-methyl-2-quinolyl] 1-N-methyl-4-1-methanesulfonamide phenethylamine dihydrochloride

Melting point:> 120 ° C (decomposition)

¹ H—NMR (MeOH-d ₄ ): δ 7.8—7.78 (m, 2H, quinoline H), 7.17-7.1 (m. 3H, quinoline and Ar) H). 7.02 (d, J = 8.4 Hz, 2H. Ar H). 6.77 (s, 1 H, quinoline). 3.97 (t, J = 6.5 Hz, _{. 2H, N-CH 2 CH} 2 A r), 3. 24-3 13 (m, 5H, S_〇 _{2 CH 2 -... CH} 2 CH 2 CH 3 S0 2 CH 3) 2. 95 (t 2H Ar CH ₂ CH ₂ N), 2.65 (s. 3 H, N-CH ₃ ). 2.49 (s, 3 H. quinoline CH ₃ ). 1.7 (m, 2 H, _{CH 2 CH 2 CH 2 CH 2} S0 2 - NH), 1. 35 (m, 2 H. C 71

H ₃ CH ₂ CH ₂ CH ₂ S0 ₂ NH), 0.82 (t, J = 7.4H z. 3H, CHaCHzCHzCHzS 0 ₂ NH)

^{IR (KB r, cm "1} ): 1120-1140 (S0 2 -N)

MS: 504 (M ⁺ )

 (16) N- (6-Methanesulfonamide 4-methyl-2-quinolyl) -1- (3,4-dimethoxyphenethyl) amine

Melting point: 71.7 ° C

_{^{! H- MR (CDC 1 3)}} :. Δ 7. 61 (m, 2 H, Dan keno Li down), 7. 2 9 (. D , J = 2 5H z 1 H, Dan keno Li down) 6. 73 (m, 3H. A r H), 6. 39 (s 1 H, keno Li down Dan), 4. 77 (b s. 1 H, HCH 2 CH 2), 3. 79 (s, 6H. CH _{3 OX2), 3. 67 (m} , 2 H, NHCH 2), 2. 92 (s, 3 H, CH 3 S 0 2 NH). 2.

85 (t. J = 6. 8H z. 2H, NHCH 2 CH 2), 2. 45 (s. 3

H, quinoline CH ₃ )

IR (KB r, cm. ¹ ): 3400 (NH). 1 160 and 1320 (S = 〇)

 (17) N- (6-Methanesulfonamide 4-methyl-2-quinolyl) -N-methyl-3,4-dimethoxyphenethylamine

Melting point: 162-163 ° C

_{'H-NMR (CDC 1 3} ): δ 7. 65 (.. D, J = 8 1 H z 1 H. Keno Li down且), 7. 5 δ (s, 1 Η, keno Li down Dan), 7.25 (d, J = 4.6 Hz, 1 H,. Quinoline), 6.65 (m, 3 H. ArH). 6.6 (s. 1 H, quinoline ϋ) 3.3.8 (t. J = 7. OH z. 2 H. N -CH, 3.75 (s, 6H, OMe X2), 3.05 (s, 3H. S O2CH3). 2.85 ( s. 3H, N-CH ₃ ). 2. S (t, J = 7 Hz, 2H, Ar— CH ₂ ), 2.4 δ (s, 3 H, quinoline one CH

)

IR (KB r, cm " ¹ ): 1620 (aromatic C = C), 1160 (S = 0) MS: 430 (M ⁺ + 1)

 (18) N— (6-Fluoro-4-methyl-2-quinolyl) -141-aminosulfonylphenethylamine

Melting point: 187-188 ° C

'H-NMR (DMS 0- d ₆ ) δ 7.8—6.8 (m, 7 H, quinoline and ArH), 6.6 (s, 1 H, quinoline and), 3.6 (t, 2 —, — NCH ₂ CH ₂ A r), 29 (t, 2H. -NCH ₂ CH ₂ A r), _2.5

(s, 3H, quinoline — CH ₃ )

 I R (KBr, cm-R: 3400 (NH), 320, 1160 (S = 0) MS: 360 (M ++ 1)

 (19) N- (8-Fluoro-4-methyl-12-quinolyl), 141-aminosulfonylphenethylamine

Melting point: 177-179 ° C

^{!. H-NMR (CDC 1} 3 + DMSO-d 6 + D 2 0):. Δ 7 "68 (d, J = 7 Hz, 2 H, A r H) 6. 95 - 7. 50 (m, 5H, quinoline + ArH), 6.51 (s, 1H. Quinoline), 3.67 (t. J = 7 Hz, NHCH ₂ CH ₂ ), 2.99 (t. J = 7Hz. 2 H, NHCH 2 CH 2), 2. 45 (s, 3H, keno Li Hmm CH ₃₎

IR (KB r, cm " ¹ ): 3380, 3320 <NH), 1160 (S = 0)

MS: 359 (M ⁺ )

(20) N— (4-dimethylamino 7-methyl-2-quinolyl) 1-4-dimethylaminosulfonylphenethylamine Melting point: 168.5 ° C

Ή-NMR (CD ₃ OD): δ 7.8-6.9 (m, 7H. Quinoline H + ArH), 6.1 (s, 1H, quinoline), 3. 7 (t, 2H. NCH 2), 3.1 (t, 2H, Ar CH ₂ ). 2. 9 (s. 6H, Ar-S0 ₂ 1 N (CH ₃ ) ₂ ), 2.45 ( s. 6H, quinoline N (CH ₃ ) ₂ ), 2

. 3 (s. 3H. Quinoline CH ₃ )

IR (KB r, cm ' ¹ ): 1340, 1160 (S = 0)

MS: 412 (M ⁺ )

 (21) 1- (2-Pyridyl) 1-2- [N- (6-Methanesulfonamido 4-methyl-12-quinolyl) amino] ethane

Melting point: 172-173 ° C

Ή-NMR (DMS 0- d ₆ ): δ 7.58 (s 1 H, CH ₃ S 0 ₂ NH-), 8.53 (d, 1 Η, pyridine). 7 71 (t, 1 H, 7.49 (s, 1H, quinoline), 7.39 (d. 1H. Quinoline). 7.56 (s. 1H, quinoline), 7.56 (s. 1H, quinoline). 31 (s, 1 H

7.23 (d, 1H, pyridin), 6.96 (s, 1H.-NH-), 6.62 (s.1H, quinoline), 3.73 (t, 2H, -NHCH ₂ CH _2- ), 3.10 (s.3H, CH ₃ SQ ₂ ) .3.06 (t, 2H, -NHCH ₂ CH _2- ), 2.42 (s.3H Quinoline CH ₃ )

IR (KB r, cm " ¹ ): 3400 (NH)

MS: 356 (M ⁺ )

 (22) N— (6-methanesulfonamide 4-methyl-2-quinolyl) 1-41 methanesulfonamide benzylamine

Melting point: .88—88. tH—NMR (CD3OD): δ 7.08-7.7 (m. 7 H, Ar + quinoline), 6.6 (s. 1H, Ar H), 2.9 (s, 6H, CH ₃ SQ ₂ NHX2) .2.5 (s, 3H, quinoline CH ₃ )

IR (KB r, cm— ¹ ): 1330 and 1150 (S = 0), 3130 (NH) MS: 156 (M + —278)

 (23) N— (6-Methanesulfonamide-1-methyl-2-quinolylmethyl) 1-N-methyl-4-1-methanesulfonamide benzylamine hydrochloride

Melting point:> 154 ° C (decomposition)

^{J H-NMR (DMSO-de} ):... Δ 10. 84 (bs, 1 H, N + H) 10 30 (s, 1 H. S0 2 NH), 10. 02 (s 1 H, S0 2 NH),

8.11 (d, J = 8.9 Hz. 1H. Quinoline), 7.86 (s. 1 Η. Quinoline), 7.74 (d. J = 8.9 Hz, 1 H. Quinoline H), 7.60 (m, 3H.quinoline and + ArH) .7.28 (m, 2H.ArH), 4.55 (s, 2H, N-CH ₂ -.. quinoline) 4. 41 (s, 2H, N-CH2-A r), 3. 12 (s, 3H S0 2 CH 3),

3.02 (s, 3H, S0 ₂ CH ₃ ), 2.76 (s, 3H, quinoline I), 2.66 (s, 3H, NCH ₃ )

IR (KB r. Cm- ¹ ): 3400 (NH), 1150 (S = 0)

MS: 278 (M +-184), 184 (M +-278)

 (24) N- (6-Methanesulfonamido 4-methyl-2-quinolylmethyl) -N-methyl-4-cyanophenethylamine

Contact point: 51. 4-52. 2 ° C

_{- NMR (CDC 1 3):} δ 8. 04 (d, J = 9. OH z, 1 H, keno Li down且), 7. 80 (s, 1H , quinoline Li down且), 3. 80 (s , 2H, CH2NCH3), 3.0 & (s, 3H, CH ₃ S OzNH) .2.90 (m _{. 2H, NCH 2 CH 2)} . 2. 74 (m, 2H. NCH 2 CH 2), 2. 6 1 (s. 3H, CH 2 NCH 3), 2. 40 (s. 3 H, Kino Li Hmm CH ₃ )

IR (KB r, cm ' ¹ ): 3260 (NH), 2240 (C≡N), 1160 (S = 0)

MS: 409 (NH ⁺ )

 (25) N— (4-methyl-6-methanesulfonamide 2-quinolylmethyl) 1-N-methyl-4-methanesulfonamide propylamine

Melting point: 62-64 ° C

Ή-NMR (CD ₃ OD): <5 7.9 (d. J = 9.1 Hz, 1H, quinoline H), 7.8 (d, J = 2.3 Hz. 1 H. quinoline) 7.55 (d. J = 2.3 Hz, 1 H, quinoline and), 7.4 (d. J = 2.4 Hz, 1 H, quinoline). 6.96 ( m, 4H, A r H) . 3. 7 (s, 2H, quinoline Li emissions _{CH 2), 2. 95 (s} , 3H, SQ 2 CH 3). 2. 75 (s, 3H, SQ 2 CH 3 ). 2.61 (s, 3H,-N (CH ₃ ) C

H ₂ ), 2.55-2.35 (m.4H.I N (CH ₃ ) CH ₂ CH ₂ CH _; Ar), 2.30 (s, 3 H, quinoline CH ₃ ), 1. 75 (m, 2H.I N (CH ₃ ) CH ₂ CH ₂ CH ₂ -A r)

IR (KB r, cm- ¹ ): 1340. 1160 (S = 0)

^{MS: 491 (M + + 1} )

 (26) 1- (4-Methanesulfonamidophenokine) 1-2- [N- (6-Methanesulfonamido 4-methyl-2-quinolylmethyl) -1-N-methylamino] ethane (foam)

Ή-NMR (DMS 0-d ₆ ): δ 10.05 (b s. 1 H, S 0 ₂ NH), 9.35 (b s. 1 H, S 0 ₂ NH). 7.93 (d, J = 9. OH z, 1H, quinoline and), 7.78 (s, 1H, quinoline), 7.59 (d, J = 9.0 Hz, 1H, quinoline j, 7.46 (s, 1H Quinoline and) 7.13 (d, J = 9.0 Hz, 2H, ArH), 6.92 (d, J = 9. OHz, 2H, ArH), 4 . 10 (t. J = 5. 8 Hz, 2H, NCH 2 CH 2 0), 3. 79 (s, 2H, quinoline Li down _CH ₂

N), 3. 07 (s, 3H, SO2CH3), 2. 87 (s, 3H, S0 2 CH 3) ■ 2. 81 (t. J = 5. 8Hz, 2H, NCH 2 CH 2 0), 2 . 60 (s, 3 H, Kino Li Hmm _{CH 3), 2. 30 (s} , 3 H, NCH 3) IR (KB r, cm "1): 3270 (NH), 1155 (S = 〇)

^{MS: 493 (M + + 1} )

 (27) 1— [4- (N-methylmethanesulfonamide) phenoxy] —3— [N— (4-methyl-2-quinolyl) amino] propane

Melting point: 133

_{'H-NMR (CDC 1 3} ):. Δ 7. 65 (. D 1 H, Dan keno Li down) 7. 6 (d, 1 H. keno Li down Dan), 7. 49 (t, 1 H, Kino Lin),

7.25 (m, 2H. ArH). 6.85 (d, 2H, ArH), 6.41 (s. 1H, quinoline), 4.0 (t. 2H. CH) ₂ -〇), 3.6 (t, 2H, NHCH ₃ ), 3.2 (s, 3H, SQ ₂ CH ₃ ), 2.75 (s, 3H, N (CH ₃ ) S0 ₂ CH ₃ ), 2. 55 (s, 3H, keno Li down _{-CH 3), 2. 13 (m} , 2H, NHCH 2 CH 2 CH 2 - 0)

I R (KB r, cm 're: 1340. 1140 (S = 0)

MS: 399 (M ⁺ )

 (28) 1— (2-Fluoro mouth—4-Methanesulfonamidophenoquine) 1-31- [N— (4-Methyl-2-quinolyl) amino] propane

Melting point: '76 -78 ° C _{Ή-NMR (CDC 1 3)} :. <5 7. 65 (d, J = 8. 1Hz, 1 H, Dan keno Li down), 7. 6 (d, J = 8 3Hz, 1H, quinoline Li down且). 7.

45 (t, J = 7.1Hz, 1H. Quinolin). 7.2 (m, 2H, ArH), 7.05 (d, 1H, ArH), 6.45 ( s, 1 H, quinoline), 4.1 () = 5.51 ^ 2,211, CH ₂ -0), 3.65

(t, J = 6.3Hz. 2H. NHCH ₂ ), 2.9 (s, 3H, S02-CH ₃ ), _2.5 (s, 3H, quinoline ^ ϋ ₃ ). 2. 1 ( m. 2Η, C

IR (KB r, cm ' ¹ ): 1330, 1150 (S = 0)

MS: 404 (NH ⁺ )

 (29) 1— (3-Methoxy-1-41-methanesulfonamide phenoquine) 1-3— [N- (4-Methyl-2-quinolyl) amino] propane

Melting point: 114 ° C

_{• H-NMR (CDC 1 3} ):. Δ 7. 68 (d, J = 7. 9Hz, 1 H. keno Li down Dan), 7. 6 (d, J = 8 2Hz, 1H, quinoline Li down Dan ) .7.4

5 (t, J = 4.1 Hz, 1 H, quinoline). 7.35 (d, J = 8.4 Hz, 1 H, quinoline), 7.2 (d, J = 7.5Hz, 1H, ArH), 6.55 (d.J = 2.5Hz.2H.ArH).

(t, J = 5. 5Hz, 2H, CH 2 - 0), 3. 75 (. s, 3H OCH 3), 3. 65 (. q, J = 6 1Hz, 2H, NHCH 2), 2. 8 (s,

3H, S O2CH3) .2.5 (s.3H, quinoline CH ₃ ), 2.1 (m, 2 H, CH ₂ CH ₂ CH ₂ )

 I R (KB r. Cm-R: 1310, 1160 (S = 0)

MS: 416 (M ++ 1)

(30) 1— (2—Methoxy 14 1 Methanesulfonamide phenoxy) 1 3 1 [N- (4-methyl-2-quinolyl) amino] propane hydrochloride Melting point: 60-63 ° C

^{! H-NMR (MeOH-d} 4):. Δ 8. 0 (. D, J = 8 1Hz, quinoline H) 7. 78 (. M 2 H, Kino Li down且), 7. 5 (t, 1Η. Quinolin ϋ), 6.96 (m, 2Η, A r H), 6.88 (d, J = 2Hz

, 1 H, quinoline Dan), 6. 78 (d, J = 8. 5 H z, 1 H, A r H), 4. 18 (t, J = 5. 6Hz, 2H. CH 2 CH 2 OA r), 3.7 7-3. 83 (m, 5 H, A r OCH ₃ , NH-CH ₂ — CH ₂ -CH ₂₀ ), 2.89 (s, 3H, SQ ₂ CH ₃ ), 2 67 (s, 3H, quinoline CH ₃ ), 2.34 (t, J = 5.8 Hz, 2H, NHCH ₂ CH ₂ CH ₂ Q

)

IR (KB r. Cm "'): 1230-1260 (CH _30- A r), 3230-3370 (NH)

MS: 415 (M ⁺ )

 (31) i— (4-Methanesulfonamide dophenoxy) 1-3— [N-methyl- (4-methyl-2-quinolyl) amino] propane

Melting point: 109

_{• H-NMR (CDC 1 3} ):. Δ 7. 65 (d, 1 H, quinoline Dan), 7. 5 5 (d, 1H, Dan keno Li down), 7. 5 (d 1H, quinoline 7. 13-7.05 (m, 3H, ArH2H + quinoline 1H), 6

.8 (d, 2Η, ArH), 6.65 (s, 1H, quinoline), 3.95 (t, 2H, CHz-O), 3.75 (t, 2H, N (CH ₃ ) CH ₂ ), 3.15 (s, 3H, SQ ₂ CH ₃ ), 2.85 (s, 3H, N (CH ₃ :) CH ₂ ), 2.4 (s, 3H, -CH ₃ ), 2.1 (m, 2H, CH2 1 ^ 2Cri2) IR (KB r, cm- '): 1320. 1150 (S = 0)

^{MS: 400 (M + + 1} )

 (32) 1— (4-Methanesulfonamide phenoquine) 1—3— [N— (4-methyl-2-quinolyl) amino] propane

Melting point: 165—167 ° C

Ή-Ni R (DMSO-d ₆ ): δ 9.27 (bs, 1 H, NH), 8.17 (1 H, quinoline), 7.69 (d. 1 H, quinoline and ), 7.40 (m.2H, quinoline). 7.00 (m, 4H, ArH), 6.56 (s, 1H, quinoline). 4. 07.. (t, 2 H , CH 2 - 0) 3 50 (. t 2H, NH-CH2-CH2-CH2O), 2. 81 (s, 3

_{. H, NHSQ 2 CH 3)} 2. 40 (s, 3H, keno Li down _{- CH 3), 2. 01 (} m, 2H, NHCH 2 CH 2 CH 2 Q)

IR (KB r.cm ' ¹ ): 3400 (NHCH ₂ ) .3300 (NHS 0 ₂ ), 1 335 and 1150 (S = 0) "

MS: 385 (M ⁺ )

 (33) 1— (4-Aminosulfonephenokine) -1- [N— (4-Methyl-2-quinolinyl) amino] propane

Melting point: 173-17.3 17 ° C

 Ή-NMR (DMSO-de): δ 7.62 (d. 2H, Ar H). 7.42 (s, 1 H, quinoline), 7.19 (m. 3 H. quinoline) ),

6. 98 (m, 2H, A r H). 6. 59 (s. 1 H. Keno Li down Dan), 4. 10 (t, 2 H, CH 2 Q). 3. 5 Ί (t, 2 H, NCH ₂ CH ₂ CH ₂₀ ), 2.45 (s.3H. Quinoline CH ₃ ). 2.05 (m, 2H

^{IR (KB r, cm '1} ):. 3450 (NH), 3340 (A r S0 2 NH 2) 1 335 and 1160 (S = 0)

MS: 371 (M ⁺ )

 (34) 1— (4-Methanesulfonamidophenoxy) 1-3— [N— (6-Methoxy 4-methyl-21-quinolyl) amino] propane

Melting point: 52-57 ° C

Ή-NMR (CD ₃ OD): δ 7.57 (d, J = 1.5 Hz, 1 H, quinoline), 7.18 (m, 4 H, quinoline and + A ri), 6. 93 (d, 2H. A r H), 6. 65 (s, 1 H, keno Li down Dan), 4. 11 (t, J = 6. 2Η ζ. 2Η, OCH 2 CH 2), 3 .88 (s. 3 Η. C Η3Ο), 3.62 (m. 2Η, NH-CH ₂ ), 2.87 (s, 3H.

H3S 0 ₂ NH), 2.52 (s, 3H, quinoline CH ₃ ), 2.13 (m, 2H, OCH ₂ CH ₂ CH ₂ )

IR (KB r, cm " ¹ ): 1320. 1150 (S = 〇), 3405 (NH) MS: 415 (M ⁺ )

 (35) N- (4-methyl-2-quinolyl) 1-4- (4-methanesulfonamide phenyl) butylamine (foam)

_{Ή-NMR (CDC 1 3)} :.. Δ 7. 00 - 7. 80 (. M, 8H keno Li down且+ A r H) 6. 41 ( . S, 1H keno Li down Dan) 4.30 ( b s. 1H, NHCH ₂ ) .3.42 (b s.2H,, NHCH ₂ CH ₂ ), 2.89 (s, 3H.S O2CH3), 2.40-2.60 (m. 5H , Quinoline

-CH ₃ + CH ₂ CH ₂ Ar), 1.65 (bs, 4H, NHCH ₂ CH ₂ CH 2 CH 2)

IR (KB r. Cm " ¹ ): 3410, 3270 (NH). 1155 (S = 0) MS: 383 (M ⁺ )

(36) N— (6-methanesulfonamide 4-methyl-2-quinolyl) (4 one methanesulfonate Ami Dofuweniru) Puchiruami emissions (foam) Ή-NMR (DMSO-d e):. Δ 9. 55 (s, 1 H, NH), 7. 54 (s 1 H, quinoline且), 7.46 (d, J = 8.7 Hz, 1 H, quinoline and). 7.35 (d, J = 8.7 Hz, 1 H, quinoline). 7.18 (d, J = 8.6Hz, 2H, ArH) .7.11 (d.J = 8.

6Hz, 2H, A r H) , 6. 61 (s, 1 H. keno Li down Dan), 3. 3 7 (b s . 2H, NCH 2 CH 2), 2. 94 (s, 3H, SQ 2 -CH ₃ ), 2.92 (s, 3H, SQ ₂ CH ₃ ), 2.59 (m, 2H. NCH ₂ CH ₂ CH ₂ CH ₂ ), 2.41 (s, 3H, quinoline CH ₃₎ ), 1.62 (bs, 4H, NCH ₂ CH ₂ CH ₂ CH ₂ )

 I R (KB r, cm- '): 3410. 3260 (NH), 1160 (S = 0) MS: 398 (MH + -79), 79 (MH + -398)

 (37) N— (2-methyl-4-quinolyl) 4-methansulfonamide phenylamine

Melting point:> 100 ° C (decomposition)

Ή-NMR (DMSO-de): δ 8.10 (d, 1H, quinoline), 7.78-6.85 (m, 5H, quinoline H + Ar). 6. 70-6. 30 (m, 3H. Quinoline Ji + A r), 3.32 (q, 2H. NH—CH ₂ CH ₂ ) '2.92 (s.3H, SQ ₂ CH ₃ )' 2.85 (t . 2H, NHCH2CH2), 2. 40 (s, 3H, keno Li Hmm CH ₃₎

 I R (KB r, crrr): 3320 (NH)

MS: 355 (M ⁺ )

 (38) N— (2-Methyl-4-quinolyl) 1-41 (N, N-dimethylaminosulfone) phenethylamine

Melting point: 227. 6— 229. 9 ° C. «Η-NMR CDMSO-d _e ): δ 8.10 (d, 1 H, quinoline and), 7.00 to 7.50 (m, 8H, quinoline + Ar) i), 6 . 35 (s, 1 H, Dan keno Li down), 3. 50 (q. 2H . NCH 2 CH 2), 3. 10 (t, 2 H, NCH 2 CH 2), 2. 55 (s, 6H , S 0 ₂ N (CH ₃ ) ₂ ), 2.45 (s, 3H, quinoline CH ₃ )

IR (KB r, cm " ¹ ): 3220 (NH), 1160 (S = 〇)

MS: 262 (M +-107), 107 (-S〇 ₂ N (CH ₃ ) ₂ )

 (39) N- (6-Methanesulfonamide 2-methyl-4-quinolyl) -14-Methanesulfonamide dophenethylamine

Melting point: 140-143 ° C (decomposition)

_{^ -NMR (DMSO- d 6):} ... Δ 7. 81 (s, 1H, quinoline Li emissions H) 7 66 (d, J = 7. 21Hz, Dan keno Li down), 7. 41 (d J 7.29 (d, J = 8.4 OH z. 2H, Ar H), 7.15 (d, J = 8.4 OH z) 7.00 (bs, 1 H, NHCH ₂ -CH ₂ ), 6.40 (s, 1 H. key / day). 3.37 (t. 2H, NHCH _{2 ... CH 2) 3. 04} (s 3 H, CJ S 02-) 2. 94 (s, 3H CJisSO, -...) 2. 92 (t, 2H, NHCH 2 -CH 2) 2. 45 (s, 3H, quinoline CH ₃

)

 I R (KB r.cm '): 3420 (NH)

MS: 369 (M ⁺ -79)

 (40) N— (6-Methanesulfonamide 2-methyl-1-quinolyl) 1N—Methyl-4-methanesulfonamide phenethylamine

Melting point: 80- 85 ° C

Ή-NMR (MeOH-d ₄ ): δ 7.84 (d, J = 2.4 Hz, 1H, 83 Bruno Li down Dan), 7. 69 (d, J = 9. 0Hz, 1 H, quinoline且), 7. 35 (dd, J , = 9. OH z, J 2 = 2. 4Hz, 1H, 7.05 (d, J = 8.4Hz, 2H.ArH), 6.97 (d, J = 8.4Hz, 2H.ArH), 6.70 (s, 1 H, quinoline and), 3.48 (t, 2Η. Ν (CH ₃ ) CH ₂ CH ₂ ), 2.95 (s. 3 H, CH ₃ S 0 _2- ), 2. 90 (t. 2H, N (CH ₃ ) CH ₂ CH ₂ ), 2.87 (s, 3H, CH3-SO2), 2.77 (s, 3H, N-CH ₃ ), 2.47 (s , 3 H, quinoline CH ₃ )

 I R (KB r, cm-: 1150 (S = 0)

MS: 462 (M +)

 (41) 1— (4-Methanesulfonamidophenoquine) 1 3— [N— (2-Methyl 4-1-quinolyl) amino] propane

Ή-NMR (DMSO-de): δ 8.10 (d, 1H, quinoline H), 7.75-6.78 (m, 7H, quinoline + Αr), 6.35 (s , 1 H. keno Li down Dan). 4. 00 (t, 2H . CH2O), 3. 30 (q. 2H. NHCH 2). 2. 75 (s, 3 H, SQ 2 CH 3), 2. 40 (s, 3 H, quinoline Li down one _{CH 3), 1. 95 (m} . 2 H. NHCH 2 CH 2 CH 2 0)

IR (KB r, cm— ¹ ): 1260 (A r-1 0-alkyl), 3340 (ΝΗ) MS: 385 (M ⁺ )

 (42) 1- (4-Methanesulfonamidophenoxy) 1-3- [N- (6-Methanesulfonamido-2-methyl-4-quinolyl) amino] propane

Melting point: 132-136 ° C

Ή-NMR (MeOH-d ₄ ): δ 7.70 (d. 1Η, quinoline), 7.65 (s. 1 H, quinoline H), 7.49 (d, 1 H. quino) Lin H 96/06084

84

), 7.19 (d.J = 8.90 Hz. 2 H.A r H), 6.94 (d.J = 8.90 Hz, 2H, A r H), 6.46 (s, 1 H. quinoline and), 4.11 (t, J = 5.7 Hz, 2H, NH CH ₂ CH ₂ CH ₂ Q), 3.60 (t, J = 5.7 Hz, 2H, NH CH ₂ CH ₂ CH ₂ Q), 2.95 (s, 3H, CH ₃ SQ ₂ NH) .2.87 (s, 3H, CH ₃ SQ ₂ NH) .2.44 (s, 3H, quinoline CH ₃ ) , 2.21 (m, 2H, NHCH ₂ CH ₂ CH ₂ Q)

IR (KB r. Cm " ¹ ): 3240 (NH), 1260 (A r-alkyl)

MS: 399 (M ⁺ -79)

 (43) N- (2-Methyl-12-quinolyl) -14-Methanesulfonamide dophenbutylamine

Melting point: 183-185 ° C

^ -NMR (DMSO-de): δ 8.15 (d, J = 6.8 Hz, 1 H, quinoline), 7.68 (d, J = 9. OH z, 2H. Ar) H), 7.54 (bs, 1H, quinoline). 7.34 (d. J = 8.0 Hz, 1H, quinoline and), 7.11-7.20 (m. 3H) 7.01 (bs, 1 H, NH) .6.33 (s. 1 H. quino,) and 3.33 (bs, 2 Η. NHCH _{2 CH 2). 2. 93 (s} , 3 H, SO2CH3). 2. 40-2. 70 (m. 5H, CH 2 CH 2 Ar + onboard Li Hmm _{CH 3) 68 (bs, 4H} . CH 2 CH 2 CH ₂ CH ₂ )

IR (KB r, cm " ¹ ): 3350 (NH), 1150 (S = 0)

MS: 383 (M +)

 (44) 4- (3,4-Dimethoxyphenyl) 1-1-1 [2- (2-Methyl-4-quinolyl) ethyl] piperidine dihydrochloride

Bill point: 132-134 ° C ^l H-NMR (MeOH-d ₄ ): δ 8.6 (d, 1 H, quinoline), 8.12-8.25 (m, 2H, quinoline), 7.95-8.05 (m, 2 H, quinoline), 6.8-6.98 (m, 3H. Ar H), 3.75-4.00 (m, 1 OH, piperidine H + ArOCH ₃ X2) , 3.64 (t, 2H, CH ₂ —piperidine and), 3.29 (t, 2H, quinoline-CH _2- ), 3.0 (s, 3H, quinoline CH ₃ ) , 2.90 (m. 1 H, piperidine), 2.1.2.3 (m, 4 H, piperidine H)

IR (KB r, cm " ¹ ): 1240-1260 (COA r)

MS: 234 (M +-156), 156 (M ⁺ -234)

 (45) 4— [2 -— [N- (2-hydroxy-4-methyl-7-quinolyl)] aminoethyl] benzenesulfonamide

Melting point: 235- 238 ° C

'H-NMR (DMSO-de): δ 12.19 (s, 1 H, OH), 7.06-8.04 (m, 7 H, quinoline H + Ar H + NH— CH ₂ CH ₂ ), 6

22-6. 64 (m. 3H, quinoline H + SQ ₂ NH ₂ ), 5.87 (s, 1 H, quinoline), 3.22 (b s. 2H. NHCH ₂ CH ₂₎ ) '2.90 (t.2H, NHCH ₂ CHz), 2.24 (s, 3H, quinoline-one CH ₃ )

IR (KB r, cm ' ¹ ): 3415, 3380 (NH ₂ ), 3280 (OH) .1155 (S = 0)

MS: 357 (M +)

 [Example 13]

The following compounds were further produced in substantially the same manner as in Examples 1 to 11 above. · (1) N- [4- (N, N-dimethyl) amino-6-methanesulfonamido 2-quinolyl] -N-methyl-4-methanesulfonamidophenethylamine trihydrochloride

Melting point: 148-151 ° C

 (2) N— (4-acetamide 6-methanesulfonamide 2-quinolyl) 1-41 methanesulfonamide

MS: 492 (M +)

 (3) N- (4-amino 6-methanesulfonamide 2-quinolyl) 1-41 methanesulfonamide dophenethylamine

Melting point: 80 ° C (decomposition)

 (4) N- (7-hydroxy-4-methyl-2-quinolyl) -1-N-methyl-14-methanesulfonamide phenethylamine

Melting point: 169—171 ° C

 (5) N- (6,7-difluoro-4-methyl-2-quinol) -1-N-methyl — 4-methanesulfonamide phenethylamine

Melting point: 168—169 ° C

 (6) N— (6-n-butanesulfonamido 4-methyl'-12-quinolyl) 1-N-methyl-14-methanesulfonamide phenethylamini dihydrochloride

Melting point: 54-56

 (7) N— (4.6-dimethyl-2-quinolyl) -141-aminosulfonylphenethylamine

Melting point: 173-175 ° C

 (8) N- (4.8-Dimethyl-2-quinolyl) 1-41-aminosulfonylphenethylamine

Melting point: 178. 8— 180. 9 (9) N— (8-amino-4-methyl-2-quinolyl) -141-aminosulfonyl phenethylamine

Melting point: 228 ° C (decomposition)

MS: 356 (M +)

 (10) N- (4-methyl-6-nitro-2-quinolyl) -14-aminosulfonylphenethylamine

Melting point: 218. 5-221. 2 ° C

 (11) N- (6-amino 4-methyl-2-quinolyl) 1-4-aminosulfonyl-norethenelamin

MS: 3 δ 6 (Μ +)

 (12) Ν- (4-Methyl-2-quinolyl) monophenylamine hydrochloride

iMS: 299 (M +)

 (13) N- (4-Methyl-2-quinolyl) -1-Methylphenethylamine hydrochloride MS: 276 (M +)

 (14) N— (6-Methoxy-4-methyl-2-quinolyl) 1-41-aminosulfonylphenethylamine

Melting point: 213.6-216 ° C (decomposition)

 (15) N- (7-Methoxy-4-methyl-2-quinolyl) 1-aminosulfonylphenethylamine

Melting point: 147—149.5 ° C

M S: 371 (M *)

 (16) 1- (4-aminosulfonylphenoquine) 1- 2- [N- (4-methyl-2-quinolyl) amino] ethane

Melting point: .191. 5-193. 0 ° C (17) 1- (4-12-tropoxy) 1-2- [N- (4-methyl-2-quinolinyl) amino] ethane

Melting point: 140. 1-142. 4 ° C

 (18) 1- (4-amino-phenoxy) 1-2-CN- (4-methyl-12-quinolyl) amino] ethaneni hydrochloride

Melting point: 212 ° C (decomposition)

 (19) 1— (4-Methanesulfonamide phenoxy) 1-2— [N— (4-methyl-2-quinolyl) amino] ethane

Melting point: 157.0-158.0 ° C

 (20) 1- (4-122-tropinoquine) -1 3- [N- (4-methyl-2-quinolinyl) aminopropane

Melting point: 123.0-123.2

 (21) 1- (4-aminophenoxy) 1-3- [N- (4-methyl-2-quinoline) amino] propane

Melting point: 110. 3—112. 6 ° C

 (22) 1— (4-Methanesulfonamide phenoxy) 1—2— [N— (4—methyl 2-quinolyl) —N—methylamino] ethane

 MS: 385 (M +)

 (23) N— (4-methyl-2-quinolyl) amino sulfonic acid

Melting point:> 250 ° C

 (24) N— (6-Methoxy-4-methyl-2-quinolyl) 1-4-methylphenethylamine hydrochloride

Melting point: 182.1-183.5 ° C (decomposition)

(25) 1- (4-Methanesulfonamidophenoquine) 1-3- [N- (6-Methanesulfonamido 4-methyl-2-quinolyl) amino] propane Melting point:> 61. ° C (decomposition)

 (26) N- (6,7-Dimethoxy-4-methyl-2-quinolyl) -1-aminosulfonylphenethylamine

Melting point: 112-116. 6 ° C

 (27) N— (6-Methoxy-4-methyl-2-quinolyl) 1-4-Methylphenethylamine hydrochloride

Melting point: 176.3-177.9 ° C (decomposition)

 (28) 1— (4-Methanesulfonamide phenoquine) 1-41 [N- (4-methyl-2-quinolyl) amino] butane

Melting point: 106.3-109.2 ° C

 (29) 1— (4-aminosulfonylphenoxy) 1-3— [N— (6-methanesulfonamide 4-methyl-2-quinolyl) amino] propane

Melting point: 167.8 ° C

 (30) N- (6-methanesulfonamido 4-methyl-2-quinolyl) 1-41 methanesulfonamidophenylpropylamine

Melting point: 79.0-82.5 ° C

 (31) N— [4- (4-Methanesulfonamidophenethyl) amino-2-quinolyl] 1-4-methanesulfonamidophenethylamine

Touch point: 120.5-123.0

 (32) 1— (4-Methanesulfonamide phenoxy) 1-2— [N- (6-Methanesulfonamide 4-methyl-2-quinolyl) amino] ethane

Melting point: 89.5 ° C (decomposition).

 (33) N- (4-Isopropyl-12-quinolyl) -14- (N, N-dimethylaminosulfonyl) phenethylamine

MS: 397 (M ⁺ ) (34) 1— (4-Methanesulfonamide phenoxy) 1-41 [N— (6-Methanesulfonamide 4-methyl-2-quinolyl) amino] butane

Melting point: 62-70 ° C

 (35) N— (6-Methanesulfonamide 7-Methoxy-14-methyl-2-quinolyl) -14-Methanesulfonamide phenethylamine

Melting point: 105.8-107.2 ° C

 (36) N- (6-Methanesulfonamide 4-methyl-12-quinolyl) -14-Ethanesulfonamide diphenylamine

Melting point: 85.7 ° C (decomposition)

 (37) N- (7-hydroxy-6-methanesulfonamide 4-methyl-12-quinolyl) -14-methanesulfonamide phenethylamine

Melting point: 91.5 ° C (decomposition)

 (38) N— (6-n-butanesulfonamido 4-methyl-2-quinolyl) 1-4-isopropaneamide diphenylamine

Melting point: 86.7-88.9 ° C

 (39) N— (6-n-butanesulfonamide 4-methyl-2-quinolyl) 1-3,4-dimethoxyphenethylamine

MS: 457 (M +)

 (40) N- (6-n-butanesulfonamido 4-methyl-2-quinolyl) -N-methyl-3.4-dimethoxyphenethylamine

MS: 471 (M +)

 (41) N- (8-Fluoro-4-methyl-2-quinolyl) -N-methyl-41-methylsulfonamide

Melting point: 100.3-103. 9 ° C

(42) N- (6.7-Dimethoxy-4-monomethyl-1-2-quinolyl) -1-N-methyl 1 4 1 Methanesulfonamide Dophenethylamine

Melting point: 164.5-165.6 ° C

 (43) N— [7— (4-chlorobenzyloxy) 1-4-methyl-2-quinolyl] 1-N-methyl-4 methanesulfonamide dophenethylamine

Melting point: 153.9-155.1 ° C

 (44) 1- (2-Fluoro-4-methanesulfonamide phenoxy) 1-3- [N- (4-methyl-2-quinolyl) -1-N-methylamino] propane

MS: 417 (M +)

 (45) 1- (4-Methanesulfonamidophenokine) 1-2- [N- (6,7-Dimethoxy-4-methyl-2-quinolyl) -1-N-methylamino] ethane

MS: 446 (M +)

 (46) N— (6-benzenesulfonamide 4-methyl-2-quinolyl) 1-4—methanesulfonamide phenethylamine

MS: 511 (M ++ 1)

 (47) N— (6-methanesulfonamide 4-isopropyl-12-quinolyl) —4-methanesulfonamide phenethylamine

Melting point: 158 ° C (decomposition)

 (48) N- (6,7-dichloro-1-methyl-2-quinolyl) -14-methanesulfonamide phenethylamine

Melting point: 66.2-68.3 ° C

 (49)-(6-Methanesulfonamide 4-methyl-2-quinolyl) 1-41 cyanophenetylamine hydrochloride

^{MS: 381 (M + + 1} )

(50) N— (6-Methanesulfonamide 4-methyl-2-quinolyl) 1-N-methyl-14-cyanophenethylamine hydrochloride MS: 394 (M +)

 (51) N- (8-Nitro-1-methyl-2-quinolyl) 1-aminosulfonylphenethylamine

Melting point: 224-227

MS: 386 (M ⁺ )

 (52) N- (4-Methyl-2-quinolyl) -141-aminosulfonylphenpropyramine

Melting point: 158-160 ° C

 (53) N— (4-Methyl-2-quinolyl) -141-aminosulfonylfemptylamine

Melting point: 168.4-169.5 ° C

 (54) N- (4-Methyl-12-quinolyl) -14-(, N-dimethylaminosulfonyl) phenylpropylamine

Melting point: 1_49-152 ° C

 (55) N— (4-aminocarbonyl-12-quinolyl) -14-aminosulfonyl phenethylamine

Melting point: 234—235 ° C

 (56) N- (4-carboxy-2-quinolyl) 1-aminosulfonylphenethylamine

Melting point: 336- 337 ° C

 (57) N- (4-Hydroxy-2-quinolyl) -1- 4-aminosulfonylphenethylamine

Melting point: 192 ° C

(58) N— (4-Methyl-12-quinolyl) -1-N-acetyl-41-aminosulfonylphenethylamine Melting point: 210- 211

 (59) N- (4-acetylamido 2-quinolyl) 1-4 aminosulfonylphenethylamine

Melting point: 164 ° C

 (60) N- (4-amino-2-quinolyl) 1-4-aminosulfonylphenethylamine

Melting point: 270-271 ° C

 (61) N— (4-cyano 2-quinolyl) 1-aminosulfonylphenethylamine

Melting point: 159.7-160.8 ° C

 (62) N— [4- (N, N-dimethyl) amino-2-quinolyl] —4-aminosulfonylphenethylamine

Melting point: 182-186 ° C

 (63) N— (4-Methoxy-1-2-quinolyl) 1-4-aminosulfonylphenethylamine

Contact point: 143 ° C

 (64) N— [4-(N, N—dimethylamino) carboxy-2-quinolyl-1--1-aminosulfonylphenethylamine

Melting point: 115-115.9 ° C

 (65) N— (4-chloro-2-quinolyl) 1-4-aminosulfonylphenethylamine

Melting point: 137

 (66) N- (4-Methyl-2-quinolyl) 1-4-methoxyphenethylamine hydrochloride

Melting point: 96—96.8 ° C (67) N- (4-Methyl-2-quinolyl) 1-4-fluorophenylethylamine hydrochloride

Melting point: 207—208 ° C

 (68) N- (4-tallow 2-quinolyl) 1-4-aminosulfonylphenylamine

Melting point: 214—217 ° C

 (69) N— (4-methylamino-2-quinolyl) 1-aminosulfonylphenethylamine

Melting point: 160—161. 1 ° C

 (70) N— (4-Methoxycarbonyl-12-quinolyl) -14-aminosulfonylphenethylamine

Melting point: 130-132 ° C

 (71) N- (6-methanesulfonamide 4-methyl-2-quinolyl) 1-4-aminosulfonylphenethylamine

Melting point: 135 ° C

 (72)-(6-Acetyl-4-methyl-2-quinolyl) 1-aminosulfonylphenylamine

Melting point: 267.3-268. 7 ° C

 (73) 1- (4-Methanesulfonamidophenokine) 1-2-Hydroxy-3- (N- (4-methyl-2-quinolyl) amino) propane

Melting point: 97-99 ° C

 (74) N- [6- (N-methylaminocarbonyl) 1-4-methyl-12-quinolyl) 1-4-aminosulfonylphenethylamine

Melting point: 246-248 ° C

(7.5) N— (6-methoxycarbonyl-2-methyl-2-quinolyl) 1-4 Minosulfonylphenylamine

Melting point: 171-173 ° C

 (76) N- (6-cyano-4-methyl-2-quinolyl) -14-aminosulfonylphenethylamine

Melting point: 196—197

 (77) N- (6-Hydroxymethyl-4-methyl-2-quinolyl) 1-41-aminosonolephoni lephenetinoreamin

Melting point: 131 ° C

 (78) N— (6-aminocarbonyl 4-methyl-2-quinolyl) 1-41-aminosulfonylphenethylamine

Melting point: 90. 2 -94. 9 ° C (decomposition)

 (79) N— [4- (N, N-dimethyl) amino-2-quinolyl] —41- (N, N-dimethyl) aminosulfonylphenethylamine

Melting point: 101-103 ° C

 (80) N— [4- (N, N-dimethyl) amino-2-quinolyl] —4- (N, N-dimethylaminosulfonyl) phenylpropylamine

Melting point: 151 ° C

 (81) N- (4-Methyl-12-quinolyl) -1-Methanesulfonamidophen propylamine

Melting point: 137 ° C

 (82) N— (4,7-Dimethyl-2-quinolyl) 1-41-aminosulfonylphenethylamine

M S: 35 δ (M +)

(83) N— (4-Methyl-12-quinolyl) -14-Hydroxyphenethylamine MS: 278 (M +) · " (84) N- (7-Fluoro-4-methyl-2-quinolyl) -1-aminosulfonylphenethylamine

MS: 359 (M +)

 (85) N— (7—piberidino 4-methyl-2-quinolyl) 1-41-aminosulfonylphenethylamine

 MS: 424 (M +)

 (86) N— [7— (4-morpholino) 1-4-methyl-12-quinolyl] —4-aminosulfonylphenethylamine

 MS: 426 (M +)

 (87) N- (5-Chloro-4-methyl-7-methylaminocarbonyl-12-quinolyl) -14-aminosulfonylphenethylamine

MS: 432 (M +)

 (88) N- (7-Aminocarbonyl 5-5-chloro-4-methyl-2-quinolyl) 1-41-aminosulfonylphenethylamine-melting point: 282-283 ° C

MS: 418 (M +)

 (89) N— (5-chloro-4-methyl-17-methylaminocarbonyl-2-quinolyl) -14-methanesulfonamide dophenethylamine

MS: 447 (M ++ 1)

 (90) N- (7-Aminocarbonyl 5-chloro-4-methyl-2-quinolyl) 1-41-methanesulfonamide phenethylamine

MS: 433 (M ++ 1)

 (91) N— (7-aminocarboyl 5- 5-chloro-1-methyl-2-quinolyl) 1-412 trophenethylamine

MS: 384 (M +) (92) N- (7-aminocarboyl 5- 5-chloro-4-methyl-2-quinolyl) 1-4-aminophenethylamine

MS: 354 (M +)

 (93) N— (5-Chloro-7-cyan-4-methyl-2-quinolyl) 1-4-aminosulfonylphenethylamine

 I R (KB r, cm-ri: 2220 (-C≡N)

Melting point: 245—249 ° C

 (94) N— (7-aminocarbonyl 5-chloro-4-methyl-2-quinolinole) 4-dimethylaminosulfonylphenethylamine

MS: 446 (M +)

 (95) N- (2-Methanesulfonyloxy-4-methyl-7-quinolyl) 1-41-dimethylaminosulfonylphenethylamine

MS: 463 (M +)

 (96) N— (5-Chloro-4-methyl-7-methylamino-2-carbonyl 2-quinolyl) 1-4-dimethylaminosulfonylphenethylamine

MS: 460 (M +)

 (97)-(4-acetamido 2-quinolyl) 1 -41 methanesulfonamide phenethylamine

Ή-NMR (DMSO-d _e ): 9.70 (s, 1 H). 9.47 (s. 1 H), 7.93 (d. 1Η), 6.93-7.57 (m, 9H ), 3.49

(b s, 2H), 2.83 (s, 5H), 2.13 (s. 1 H)

IR (KB r, cm ' ¹ ): 1150 (S = 0)'

 (98) N- '(8-methanesulfonamide 4-methyl-2-quinolyl) 1-41 methanesulfonamide phenethylamine

MS: 448 (M +) (99) N— (4,7-dimethyl-2-quinolyl) 4-methansulfonamide fenbutylamine hydrochloride

MS: 397 (M +)

 (100) N— [4-Methyl-6- (2-isopropylsulfonamide) 1-2-quinolyl] -14-methanesulfonamide phenethylamine

MS: 476 (M +)

 (101) N- (6-Ethane sulfonamide 1-4-methyl-12-quinolyl) 1-4 1-n-butane sulfonamide phenethylamine

'H-Ni R (CDC 1 3):.. 7. 65 (s, 2 H), 7. 39 (. D 1 H) 7 19 (. M 4H), 6. 57 (bs, 1 H). 6.46 (s, 1 H),

4.90 (b s.1H), 3.74 (b s.2H), 3.10 (m, 4H), 2.95 (t.2H), 2.52 (s, 3H), 1. 81 (m, 2H), 1.39 — (m. 5H), 0.91 (t. 3H)

 (102) 1- (2-Fluoro-4-methanesulfonamide phenoxy) 1-3- [N- (6-Methanesulfonamido-4-methyl-2-quinolyl) -1-N-methylamino] propane

iH—NMR CCDC "): 7.60 (m, 2H), 7.35 (d, 1H), 7.03 (d. 1Η) .6.80 (m.3H), 6.49 (bs, 4.07 (t, 2H). 3.89 (t, 2H), 3.20 (s, 3H), 3.00 (s, 3H), 2.95 (s, 3H), 2. 50 (s, 3H),

2.17 (m. 2H)

 (103) N— (7-Fluoro-4-methyl-2-quinolyl) -1-N-methyl-4-methanesulfonamide phenethylamine

MS: 387 (M +)

(104) N— (6-Methanesulfonamide 4-methyl-2-quinolyl) N 99-Methyl-4-1 methanesulfonamide dophenbutylamine

MS: 491 (M ++ 1)

 (105) N- (6-Methanesulfonamide 1-4-methyl-2-quinolyl) 1 N 1 cyclopentyl-4 1 methanesulfonamide dophenethylamine

MS: 517 (M ++ 1)

 (106) N- (6-Methanesulfonamide 1-4-methyl-2-quinolyl) 1-N-methyl-4-methanesulfonamide 3-nitrophenethylamine

MS: 507 (M +)

 (107) N— (6-Methanesulfonamide 4-methyl-12-quinolyl) -14-Methanesulfonamide doorlin

Melting point: 219—221

 (108) 1- [4- (N-methylmethansulfonamide) phenoxy] 1-3- [N- (4-methyl-2-quinolin) -1-N-methylamino] propane

Melting point: 143

 (109) 1- (3-Fluoro-4-methanesulfonamide) phenoxy 3- [N- (4-methyl-2-quinolyl) amino] propane

 MS: 403 (M +)

 (110) 1- (4-fluoro-2-methanesulfonamide) phenoxy-1-CN- (4-methyl-2-quinolyl) amino] propane

Melting point: 75.9-81.5 ° C

 (111) N— (4-methyl-6-n-propanesulfonamido 2-quinolyl) 1-41-methanesulfonamide phenethylamine

Melting point: 74 ° C

(112) 1- (2-Fluoro-4-methanesulfonamide phenoxy) 1-3- [N- (6-Fluoro-4-methyl-2-quinolyl) amino] propane MS: 421 (M ⁺ )

 (113) N— (6-n-butanesulfonamido 4-methyl-2-quinolyl) 1-41 n-butanesulfonamidophenethylamine

Melting point: 94-95

 (114) N- (6-n-butanesulfonamide 4-methyl-2-quinolyl)

— 4— n—propanesulfonamidophenethylamine

Melting point: 68.5 ° C (decomposition)

 (115) N— (6-Fluoro-4-methyl-2-quinolyl) -1-N-methyl-4 monomethanesulfonamide phenethylamini dihydrochloride

Melting point: 268-270

 (116) N— (6-Methanesulfonamido 4-methyl-2-quinolyl) -N-Ethyl-41-Methanesulfonamidophenethylamini hydrochloride

Melting point: 256 ° C

 [Experimental example] _

Experimental example 1

Prolonged effective refractory period (ERPC) using contractile force in papillary muscles isolated from guinea pigs-Right ventricular papillary muscles of male guinea pigs weighing 400 to 600 g were removed and the temperature was 34 ° C. in it is maintained, a gas mixture (95%: 5% = 0 2: C0 2) organ bath containing the Kureppu Sue Ringer solution saturated with _c was suspended (or gan ba th) - side transducers (tr an s du cer), the other side was fixed and 0.5 initial tension was applied. The isolated papillary muscle was subjected to electrical stimulation (frequency: 1 Hz, vibration width: 4 ms ec, voltage: W value xl. 5), and was stabilized for at least 2 hours while washing at 15-minute intervals. An early stimulus (extrast imu lu s. Frequency: 1 Hz, vibration width: 4 ms ec, voltage: M value x 1.5) is applied to the stabilized isolated papillary muscle to increase the contractile force. The effective refractory period used (ERP c) was measured. During the 3 Hz experiment, only the frequency was changed under the same conditions as l Hz, and the experiment was performed in the same manner. Each experiment compound was dissolved in a concentration of 10_ ² M 1 100% dimethyl sulfoxide (DMSO), was used by diluting with click Retsubusu one Ringer's solution. Concentration of 10 · ^beta Micromax: was measured ERP c of up to 1 hour after administration of the experimental compound (final DMSO concentration of 0.1%). The data are shown as the percentage change (%) after drug administration compared to before drug administration. The experimental results are shown in Tables 1 and 2.

 Table 1. ERP c elongation rate of compounds in the present invention

 Compound number Guangzhou (M)

(Example) Hz 10 · ⁶

 Example 1 3 130.1 + 3.49

 Example 2 3 130.6 + 2.75

 Example 3 3 133.5 + 1.35

 Example 4 3 125.8 + 2.33

 Example 5 3 123.9 + 2.80

 Example 6 3 135.5 + 2.91

 Example 7 3 130.7 + 0.65

 Example 8 3 133.5 + 3.96

 Example 9 3 128.0 + 1.51

 Example 10 3 133.1 + 2.36

Example 11 3 128.4 + 1.84 96/06084

102 Table 2. Rate of change of ERP c of compounds in the present invention

 (Average soil standard error)

Note) * E— 4031 = 4 '— [[1- [2- (6-methyl-12-pyridyl) ethyl] -14-piperidyl] carbonyl] methanesulfonanilide Compound is already being developed as an antiarrhythmic agent Due to the higher 3 Hz Z 1 Hz ratio compared to E-4031, it is a disadvantage of known class III antiarrhythmic drugs. Due to reverse pendency (reversed ep end en cy) This shows that it is an excellent antiarrhythmic agent with improved proarrhythmic effect (proar rhythmic effect).

Experimental example 2

Prolonged action potential duration (APD ₉₀ ) on papillary muscles isolated from guinea pigs

The right ventricular papillary muscle of a male guinea pig weighing 400 to 600 g was excised and fixed to an organ bath made by Aquinolé. In organ bath, the temperature is 34 ° mixed-gas (95%: 5% = 0 2: C0 2) which is maintained at C Kure' Pusu Ringer solution saturated were perfused with. After applying electrical stimulation (frequency: 1 Hz or 3 Hz; oscillation width: 2 ms ec, voltage: «value X1.5) to the fixed isolated papillary muscle and stabilizing for about 2 hours, 3M KC The action potential duration (APD ₉₀ ) was measured using a glass microelectrode (20-30ΜΩ) charged with one solution. Each of the experimental compounds was dissolved in 100% dimethyl sulfoxide (DMSO), and then diluted with a Klebs-Ringer solution to a concentration of 10_β ^β (final DMSO concentration: 0.1%) before use. The effect of prolonging the action potential holding time observed about 1 hour after drug administration was shown as a change rate (%) compared to that before drug administration. The experimental results are shown in Tables 3 and 4.

3. APD ₉₀ elongation rate of compound in the present invention Compound number Concentration (M)

(Example) H z 10- ⁶ N Example 12 18) 1 128.2 1

12-19) 122.9 1

9 137.6 7

12-C45) 1 122.5 1

12-C32) 1 128.7

 12-C33) 1 123.8 1

12-C37) 124.6

 12-C13) 1 128.9

 12-C41) 1 128.5 1

12-C38) 1 123.3 ι

12-C20) 1 134.3 1

12-C35) 1 128.5

 12-C22) 124.1 ι

12-C43) 122.4 1

12-C36) 142.9 3

12-C39) 131.3 3

3 1 135.7 2

12-C14) 122.7 1

12-C42) 1 124.9 1

12-C27) 1 120.4 1

12-C31) 1 137.3 1

12-C34) 1 121.0 1

12-C23) 1 136.2 1

12- (5) 1 146.6 3

12-C28) 1 132.0 2

12-C29) 1 121.0 1

12- (8) 1 126.8 1

5 1 143.5 2

12- (2) 1 128.5 1

12- (1) 1 123.3 1

12-C11) 139.6 1

12- (6) 132.2 1

12-C16) 137.0 3

12-C44) 130.1 3

12-C12) 133.6 1

12- (7) 136.0 1

12-C21) 141.1 1

12-C40) 121.7 1

12-C17) 126.8 4 Table 4. APD ₉₀ change rate of compounds in the present invention

 (Mean ± standard error)

Note)

 (1) The hydrochloride salt of N- (6-methanesulfonamido-4-phenyl-12-quinolyl) -14-methanesulfonamide phenethylamine, which is the compound of Example 6, was used.

 (2) * E— 4031 = 4 '— [[1- [2- (6-Methyl-2-pyridyl) ethyl 1-4-Piperidyl] carbonyl] methanesulfonanilide Industrial applicability

 From the above experimental results, the compound of the present invention exhibits several times higher t, 3Hz1Hz ratio than E-4031 which has been already developed as an antiarrhythmic agent. It is an excellent antiarrhythmic drug that has improved the proarrhythmic effect of reverse use dependency, which is a disadvantage of reversible use.

Claims

 Claims General formula (I)

(Wherein one of Ri and Z is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a nitro group, a lower alkyl group, a lower alkoxy group, an aryl group or a general formula

One NR ₁₄ R ₁₅ or One C0R ₁₃

Wherein R ₁₃ is a general formula

 -N R 16 R! 7

Group (wherein R ₁₆ and R ₁₇ are each independently a hydrogen atom or a lower alkyl group), a hydroxyl group or a lower alkoxy group, R _l4 and R ₁₅ are each independently a hydrogen atom, a lower alkyl A lower alkylsulfonyl group, a lower alkanoyl group or an optionally substituted aralkyl group,

And one of Z is a general formula

Represents a group of R ₂ , R ₃ , R ₄ and R ₅ are each independently a hydrogen atom, a lower alkyl group, a halogen atom, a lower alkoxy group, a nitro group, a hydroxyl group, a cyano group, a lower alkanol group, a hydroxy lower alkyl group, Lower alkylsulfonyl group,

-NR ₁₈ R ₁₉ or one C ONR ₂₀ R ₂₁

Or a 6-membered hetero ring containing one or two identical or different hetero atoms selected from a nitrogen atom or an oxygen atom, wherein R ₁₈ and R ₁₉ are each independently A hydrogen atom, a lower alkyl group or a lower alkylsulfonyl group; R _{2 ()} and R ₂₁ each independently represent a hydrogen atom or a lower alkyl group;

-0

Is a heterocycle or a general formula

11 represents a group of 10, wherein R ₇ , R ₈ , R ₉ , R ₁₀ and RH each independently represent a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, a nitro group, a cyano group, water Acid group, sulfonyl group or general formula

— NR ₂₄ R ₂₅ or one S 0 ₂ NR ₂₂ R ₂₃

Wherein R ₂₂ and R ₂₃ each independently represent a hydrogen atom or a lower alkyl group;

R ₂₄ and R ₂₅ are each independently a hydrogen atom, a lower alkyl group or a lower alkyl sulf A honyl group;

R _e represents a hydrogen atom, a lower alkyl group, a cyclo lower alkyl group, a lower alkanoyl group or a hydroxy lower alkyl group,

A is a general formula

One (CHR ₁₂ ) „-or one (CH ₂ )„-0- group (where R ₁₂ represents a hydrogen atom or a hydroxyl group, and n represents an integer of 1 to 4); or

Forms a piperidine ring with -N-A-R6, and m represents an integer of 0 to 2. However, when is a hydrogen atom, m is not 1) or a salt thereof.

 2.

 Is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a nitro group, a lower alkyl group, a lower alkoxy group, an aryl group or a general formula

One NR ₁₄ R ₁₅ or One COR ₁₃

Wherein R ₁₃ is a general formula

Group (wherein R _ie and R ₁₇ are each independently a hydrogen atom or a lower alkyl group), a hydroxyl group or a lower alkoxy group, R _l4 and R ₁₅ are each independently a hydrogen atom, a lower alkyl A lower alkylsulfonyl group, a lower alkanoyl group or an optionally substituted aralkyl group,

Z is a general formula

Represents a group of

-0

Is a heterocycle or a general formula

Wherein R ₇ , R ₈ , R ₉ , R ₁₀ and RH each independently represent a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, a nitro group, a cyano group, a hydroxyl group, Sulfonyl group or general formula

One NR ₂₄ R ₂₅ or One S 0 ₂ NR ₂₂ R ₂₃

Wherein R ₂₂ and R ₂₃ each independently represent a hydrogen atom or a lower alkyl group;

R ₂₄ and R ₂₅ each independently represent a hydrogen atom, a lower alkyl group or a lower alkylsulfonyl group,

R _E is a hydrogen atom, lower alkyl group, cyclo lower alkyl group, lower alkanoyl group Or a hydroxy lower alkyl group,

 A is a general formula

1- (CHR ₁₂ )-or 1- (CH ₂ ) „-0- (where ₂ represents a hydrogen atom or a hydroxyl group, and n represents an integer of 1 to 4) or

-N-A- R6

Together form a piperidine ring, and m represents an integer of 0 to 2. Provided that when m is a hydrogen atom, m is not 1) or a salt thereof.

 3.

Is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a nitro group, a lower alkyl group having 1 to 6 carbon atoms, a lower alkoxy group having 1 to 6 carbon atoms, a phenyl group or the general formula 1 NR ₁₄ R ₁₅ or 1 COR ₁₃

Wherein R ₁₃ is a general formula

-NR _I6 R ₁₇

Group (wherein R ₁₆ and R ₁₇ are each independently a hydrogen atom or a lower § alkyl group having 1 to 6 carbon atoms), a hydroxyl group or a lower alkoxy group having 1 to 6 carbon atoms, R ₁₄及fine R ₁₅ are each independently a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms, lower alkylsulfonyl group, lower alk force Roh I le group having a carbon number of 1-6 alkyl moiety of a carbon number 1 to 6 Or a lower alkyl group having 1 to 6 carbon atoms substituted with phenyl which may be substituted,

Z is a general formula

Represents a group of

R ₂ , R ₃ , R ₄ and R ₅ each independently represent a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms, a halogen atom, a lower alkoxy group having 1 to 6 carbon atoms, a nitro group, a hydroxyl group, a cyano A lower alkanol group having 1 to 6 carbon atoms in the alkyl group, a lower alkyl group having 1 to 6 carbon atoms substituted with a hydroxyl group, a lower alkyl sulfonyl group having 1 to 6 carbon atoms or

-NR ₁₈ R ₁₉ or one C〇NR ₂₀ R ₂₁

Or a piperidinyl group, a piperazinyl group or a morpholinyl group, wherein R ₁₈ and R ₁₉ are each independently a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms or a lower alkyl group having 1 to 6 carbon atoms. A lower alkylsulfonyl group; R ₂₀ and R ₂₁ each independently represent a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms;

-0

Is a pyridyl group or a general formula

11 ^R 10 Wherein R ₇ , R ₈ , R ₉ , R ₁₀ and each independently represent a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms, a lower alkoxy group having 1 to 6 carbon atoms, a halogen atom , Nitro, cyano, hydroxyl, sulfonyl or general formula

One NR ₂₄ R ₂₅ or One S0 ₂ NR ₂₂ R ₂₃

Wherein R ₂₂ and R ₂₃ each independently represent a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms, and R ₂₄ and R ₂₅ each independently represent a hydrogen atom or a carbon atom 1 Represents a lower alkyl group or a lower alkylsulfonyl group having 1 to 6 carbon atoms,

R ₆ is a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms, a cyclo lower alkyl group having 3 to 6 carbon atoms, a lower alkanol group having 1 to 6 carbon atoms in the alkyl portion, or a carbon number replaced by a hydroxyl group. Represents 1 to 6 lower alkyl groups,

A is a general formula

One (CHR ₁₂ ) „-or one (CH ₂ )„ —0—

(Where R ₁₂ represents a hydrogen atom or a hydroxyl group, and n represents an integer of 1 to 4),

m represents an integer of 0 to 2. However, when Rt is a hydrogen atom, m is not 1.) The compound according to claim 1 or 2, or a salt thereof.

 Four.

 Is a hydrogen atom, a chlorine atom, a hydroxyl group, a cyano group, a nitro group, a lower alkyl group having 1 to 3 carbon atoms, a methoxy group, a phenyl group or a general formula

-NR ₁₄ R ₁₅ or one COR ₁₃

Wherein R ₁₃ is a general formula

-NR _I6 R ₁₇

Group (wherein R _ie and R ₁₇ are each independently a hydrogen atom or a methyl group), a water group or main butoxy group, R ₁₄ and R ₁₅ are each independently a hydrogen atom, methyl A methylsulfonyl group, an acetyl group or a p-tropenetyl group, 96/06084

113

Z is a general formula

(CH ₉ 2) ½ -NA- Y

Represents a group of

R ₂ R ₃ , R ₄ and R ₅ are each independently a hydrogen atom, a methyl group, a chlorine atom, a fluorine atom, a methoxy group, a nitro group, a hydroxyl group, a cyano group, an acetyl group, a hydroxy group, and the number of carbon atoms 1 to 6 lower alkylsulfonyl groups or

-NR ₁₈ R ₁₉ or one CONR ₂₀ R ₂₁

Or a piperidinyl group, a piperazinyl group or a morpholinyl group, wherein R ₁₈ and R _ig each independently represent a hydrogen atom, a methyl group or a lower alkylsulfonyl group having 1 to 6 carbon atoms. R ₂₀ and R ₂₁ each independently represent a hydrogen atom or a methyl group;

-0

Is a 2-pyridyl group or a general formula

Wherein R ₇ , R _E , R ₉ , R ₁₀ and RH each independently represent a hydrogen atom, a methyl group, a methoxy group, a fluorine atom, a bromine atom, a nitro group, a cyano group, a hydroxyl group, Sulfonyl group or general formula

-NR ₂₄ R ₂₅ or one S0 ₂ NR ₂₂ R ₂₃

Wherein R ₂₂ and R ₂₃ each independently represent a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms, and R ₂₄ and R ₂₅ each independently represent a hydrogen atom, a methyl group or Represents a lower alkylsulfonyl group having 1 to 4 carbon atoms,

R ₆ represents a hydrogen atom, a lower alkyl group having 1 to 3 carbon atoms, a cyclopropyl group, a cyclopentyl group, an acetyl group or a hydroxyxetyl group;

A is a general formula

One (CHR ₁₂ ) n-or one (CH ₂ ) „-0- (where R ₁₂ represents a hydrogen atom or a hydroxyl group, and n represents an integer of 1 to 4);

m is 0 or 1, provided that, when is a hydrogen atom, m, is not 1.) The compound according to any one of claims 1 to 3, or a salt thereof.

 Five.

 Is a lower alkyl group, aryl group or '

Wherein RH and R ₁₅ each independently represent a hydrogen atom or an optionally substituted aralkyl group.

Z is the general formula one (C¾) _ra _ ^N + Yj

^R 6 Represents a group of

R ₂ , R ₃ , R ₄ and R ₅ are each independently a hydrogen atom, a halogen atom or

Wherein R ₁₈ and R ₁₉ each independently represent a hydrogen atom or a lower alkylsulfonyl group;

-0

Is the general formula

Wherein R ₇ , R ₈ , R ₁₀ and RH each represent a hydrogen atom, and R ₉ has the general formula NR ₂₄ R ₂₅

Wherein R _{2 <} and R ₂₅ each independently represent a hydrogen atom or a lower alkylsulfonyl group;

R ₆ represents a hydrogen atom or a lower alkyl group,

A is a general formula

5 (CHR ₁₂ ) n-wherein R ₁₂ represents a hydrogen atom and n represents 2; and m represents 0 or 1. 5. Or a salt thereof.

6. -1

 Five

 116

Is a lower alkyl group having 1 to 6 carbon atoms, a phenyl group or

 -R RIS

(Where R ₁₄ represents a hydrogen atom and R ₁₅ represents a p-diene phenethyl group) Z is a general formula

10 groups,

R ₂ , R ₃ , R ₄ and R ₅ are each independently a hydrogen atom, a halogen atom or

 One N I \ 18 19

(Where R ₁₈ represents a hydrogen atom, and R ₁₉ represents a lower alkylsulfonyl group having 1 to 6 carbon atoms),

-0

Is the general formula

25 represents a group, wherein R ₇ , R ₈ , R ₁₀ and R represent a hydrogen atom, and R ₉ represents a general formula 117

(Where R ₂₄ represents a hydrogen atom, and R ₂₅ represents a lower alkylsulfonyl group having 1 to 6 carbon atoms),

R ₆ represents a hydrogen atom or a lower alkyl group,

A is a general formula

6. (CHR ₁₂ ) „-wherein R ₁₂ represents a hydrogen atom, n represents 2 and m represents 0 or 1. 6. Or a salt thereof.

 7.

 R! Is a general formula

Represents a group of

 Z represents a lower alkyl group,

R ₂ , R ₃ , R ₄ and R ₅ are each independently a hydrogen atom or

 ~ N 18 19

Wherein R ₁₈ and R ₁₉ each independently represent a hydrogen atom or a lower alkylsulfonyl group,

-0 96/06084

118 is a general formula

Wherein R ₇ , R ₈ , R ₉ , R _L0 and RH are each independently a hydrogen atom, a lower alkoxy group or a general formula

One NR ₂₄ R ₂₅ or One S 0 ₂ NR ₂₂ R ₂₃

Wherein R ₂₂ and R ₂₃ each independently represent a hydrogen atom or a lower alkyl group; R ₂₄ and R ₂₅ each independently represent a hydrogen atom or a lower alkyl sulfonyl group; "

R ₆ represents a hydrogen atom or a lower alkyl group,

A is a general formula

— (CHR ₁₂ ) or one (CH ₂ )

(Where R ₁₂ represents a hydrogen atom or a hydroxyl group, and n represents an integer of 1 to 4) or

-N-A- R6

And m is an integer of 0 to 2), or a salt thereof.

 8.

Is the general formula 119

Represents a group of

 Z represents a lower alkyl group having 1 to 6 carbon atoms,

R ₂ , R ₃ , R ₄ and R ₅ are each independently a hydrogen atom or

 One N I 18 R 19

Wherein R ₁₈ and R ₁₉ each independently represent a hydrogen atom or a lower alkylsulfonyl group having 16 carbon atoms,

-0

Is the general formula

Wherein R ₇ , R ₈ , R ₉ , R ₁₀ and RH are each independently a hydrogen atom-a lower alkoxy group having 1 to 6 carbon atoms or a general formula

δ

120 One NR ₂₄ R ₂₅ or — S0 ₂ NR ₂₂ R ₂₃

Wherein R ₂₂ and R ₂₃ each independently represent a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms, and R ₂₄ and R ₂₅ each independently represent a hydrogen atom or a carbon atom 1 Represents a lower alkylsulfonyl group of from 6 to 6,

R ₆ represents a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms,

 A is a general formula

-(CHR ₁₂ ) n-or one (CH ₂ ) _n -0- group (where R ₁₂ represents a hydrogen atom or a hydroxyl group, and n represents an integer of 2 to 4); or

0

 Or a salt thereof, wherein the compound or a salt thereof forms a piperidine ring together with -N-A-R6, and m represents an integer of 0 to 2.

 9.

Ri is the general formula

0

Represents a group of

 Z represents a methyl group,

R ₂ , R ₃ , R ₄ and R ₅ are each independently a hydrogen atom or

5 -NR ₁₈ R ₁₉ Wherein R ₁₈ and R ₁₉ each independently represent a hydrogen atom or a methylsulfol.

-0

Is the general formula

Wherein R ₇ , R ₈ , R ₉ , R ₁₀ and each independently represent a hydrogen atom, a methoxy group or a general formula.

— NR ₂₄ R ₂₅ or one S0 ₂ NR ₂₂ R ₂₃

Wherein R ₂₂ and R ₂₃ each independently represent a hydrogen atom or a methyl group. R ₂₄ and R ₂₅ each independently represent a hydrogen atom or a methylsulfol group;

R ₆ represents a hydrogen atom or a methyl group,

A is a general formula

One (CHR ₁₂ ) π-or one (CH ₂ ) „-0- (where R ₁₂ represents a hydrogen atom and n represents an integer of 2 to 4); or

-NA- R6 δ

 Or a salt thereof, wherein the compound or a salt thereof forms a piperidine ring, and m represents an integer of 0 to 2).

 10. The compound according to claim 1, which is N- (2-hydroxyxethyl) -1-N- (4-methyl-16-methanesulfonamide 2-quinolyl) -14-methanesulfonamide phenethylamine or a salt thereof.

 11. (A) reacting a compound of the following general formula (II) or a salt thereof with a compound of the following general formula (III) or a salt thereof,

 (B) A compound of the following general formula (Ib) or a salt thereof is produced by reducing the compound of the following general formula (Ia) or a salt thereof to produce a compound of the following general formula (Ib) or a salt thereof. Is reacted with an alkane sulfonyl halide to produce a compound of the following general formula (Ic) or a salt thereof.

 (C) reacting a compound of the following general formula (Id) with an amine derivative of the following general formula (VI) or a salt thereof to produce a compound of the following general formula (Ie) or a salt thereof,

(D) A compound produced by protecting the hydroxy group of the substituent R ₆ with a compound of the following general formula (Ia-1) or a salt thereof to produce a compound of the following general formula (VII) or a salt thereof, and

(VII) is reduced and then reacted with an alkanesulfonyl halide to produce a compound of the following general formula (VIII) or a salt thereof, followed by deprotection to give a compound of the following general formula (Ic-11) or a salt thereof. A process for producing a quinolylamine derivative of the general formula (I) and a salt thereof, characterized by being produced.

0

Five (qi)

9a

 (III) (λ -V-HN

L £ U0iS6dT / LDd W090 / 96 ΟΛλ

1X

124

 20

twenty five 02

 q9. ST

(ΙΙΛ) ya ■ vN- ^ffl (

Β9, οι

Z. £ II0 / S6 «ir / XDd t« 09O96 O / ^ (In the above formula,

And one of Z represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a nitro group, a lower alkyl group, a lower alkoxy group, an aryl group or a group of the general formula —NR ₁₄ R ₁₅ or —COR ₁₃ ; in R ₁₃ is a group of general formula over NR ₁₆ R ₁₇ (wherein R ₁₆ and R ₁₇ are each independently a hydrogen atom or a lower alkyl group), a hydroxyl group or a lower alkoxy group, 1¾ ₁₄ and 1¾ ₁₅ are each independently a hydrogen atom, a lower alkyl group, a lower alkylsulfonyl group, a lower alk force Noiru group or an optionally substituted Araruki group,

 The other one of R! And Z is a general formula

Represents a group of

R ₂ , R ₃ , R ₄ and R ₅ are each independently a hydrogen atom, a lower alkyl group, a halogen atom, a lower alkoxy group, a nitro group, a hydroxyl group, a cyano group, a lower alkanol group, a hydroxy lower alkyl group, A lower alkylsulfonyl group or a group of the general formula 1 NR, ₈ R, _g or 1 CONR ₂₀ R ₂₁ or containing one or two hetero atoms selected from nitrogen and oxygen to 6 membered shows heterocycle, wherein R _l8 and ₉ are each independently a hydrogen atom, a lower alkyl group or a lower alkyl sulfonyl Le group, R ₂₀ and R ₂₁ are each independently a hydrogen atom Or shows a lower alkyl group.

-0 is a heterocyclic ring or single branch type 127

^R ll represents a group of ^R 10,

R ₇ , R ₈ , R ₉ , R _{1 ()} and RH each independently represent a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a sulfonyl group or formula chromatography NR ₂₄ shows a group of R ₂₅ or one S_〇 ₂ NR ₂₂ R _23, wherein R ₂₂ and R ₂₃ each independently represents a hydrogen atom or a lower alkyl group, R ₂₄ and R ₂₅ are each Independently represents a hydrogen atom, a lower alkyl group or a lower alkylsulfonyl group,

R ₆ represents a hydrogen atom, a lower alkyl group, a cyclo lower alkyl group, a lower alkanol group or a hydroxy lower alkyl group,

A represents a group of the general formula-(CHR ₁₂ ) _π -or 1 (CH ₂ ) _π -0-(where R, ₂ represents a hydrogen atom or a hydroxyl group, and η represents an integer of 1 to 4) Or

-Ν-Α-

^R 6

Together with each other to form a pyrididine ring, and m represents an integer of 0 to 2.

However, when R i is a hydrogen atom, m is not 1.

One of R _{1 P} and Z _P is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a nitro group, a lower alkyl group, a lower alkoxy group, an aryl group or one NR ₁₄ R ₁₅ or one C OR a group of _l3 , wherein R ₁₃ is a group of the general formula —NR ₁₆ R ₁₇ (where R ₁₆ and R ₁₇ each independently represent a hydrogen atom or a lower alkyl group), a hydroxyl group or a lower alkoxy group in and, R _l4 and R ₁₅ are each independently a hydrogen atom, a lower alkyl group, lower alk alkylsulfonyl group, a lower Arukanoiru group or an optionally substituted Ararukiru group,

 R1. And the other one of Z p is a general formula

One (CH ₂ ) _m -R

Where R represents a reactive leaving group;

One of R ₁₈ and R ₁₉ is a hydrogen atom, the other is a lower alkylsulfonyl group,

One of R ₂ and R ₂₅ is a hydrogen atom and the other is a lower alkylsulfonyl group;

R ₆ is a hydroxy lower alkyl group,

 R is a protected hydroxy lower alkyl group, and H a1 represents a halogen atom. )

12. A method for producing a ginolylamine derivative of the general formula (I) and a salt thereof, comprising reacting a compound of the following general formula (II) or a salt thereof with a compound of the following general formula (III) or a salt thereof.

(In the above formula,

 And Z represent a substituent at a corresponding position of the compound obtained when the compound of the general formula (II) or a salt thereof is reacted with the compound of the general formula (III) or a salt thereof,

One of R _1P and Z _P represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a nitro group, a lower alkyl group, a lower alkoxy group, an aryl group or one NR ₁₄ R ₁₅ or one COR ₁₃ group, wherein R ₁₃ is formula chromatography NR _ie groups R ₁₇ (wherein R _ie and R ₁₇ each independently represent a hydrogen atom or a lower alkyl group), a hydroxyl group or a lower alkoxy group, R _l4 and R _l5 Each independently represents a hydrogen atom, a lower alkyl group, a lower alkylsulfonyl group, a lower alkanol group, or an optionally substituted aralkyl group Indicates that

The other one of R _lP and Z _P is a general formula

One (CH ₂ ) _m -R

Where R represents a reactive leaving group;

R ₂ , R ₃ , R ₄ and R ₅ are each independently a hydrogen atom, a lower alkyl group, a halogen atom, a lower alkoxy group, a nitro group, a hydroxyl group, a cyano group, a lower alkanol group, a hydroxy lower alkyl group, A lower alkylsulfonyl group or a group of the general formula 1 NR R! ₉ or 1 COR ₂₀ R ₂₁ or a 6-membered group containing one or two identical or different hetero atoms selected from a nitrogen atom and an oxygen atom R ₁₈ and 1 ^ ₉ each independently represent a hydrogen atom, a lower alkyl group or a lower alkylsulfonyl group; R ₂₀ and R ₂₁ each independently represent a hydrogen atom or a lower Represents an alkyl group,

-〇

Heterocycle or general formula

Represents a group of

R ₇ , R ₈ , R ₉ , R _{1 D} and RH each independently represent a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom * a nitro group, a cyano group, a hydroxyl group, a sulfonyl group or Her shows the general formula chromatography NR _J R ₂₅ or over S0 ₂ NR ₂₂ group R _23, wherein R ₂₂ and R ₂₃ each independently represents a hydrogen atom or a lower alkyl group, R ₂₄ and R ₂₅ Each independently represents a hydrogen atom, a lower alkyl group or a lower alkylsulfonyl group;

R ₆ represents a hydrogen atom, a lower alkyl group, a cyclo lower alkyl group, a lower alkanoyl group or a hydroquinone lower alkyl group,

A represents a group of the general formula — (CHR _l2 ) _π — or one (CH ₂ ) „— (where ₂ represents a hydrogen atom or a hydroxyl group, and n represents an integer of 1 to 4); or

-N-A-

^R 6

Together form a piperidine ring, and m represents an integer of 0 to 2. However, 1 ^. M is not 1 if is a hydrogen atom. )

13. A compound of the following general formula (lb) or a salt thereof is produced by reducing the compound of the following general formula (la) or a salt thereof, and the resulting compound of the following general formula (lb) or!; A method for producing a quinolylamine derivative of the general formula (I) and a salt thereof, which comprises reacting with a sulfonyl halide to produce a compound of the following general formula (Ic) or a salt thereof.

(>δ>")

(In the above formula,

R ₂ , R ₃ , R ₄ , R ₅ and Z each represent a substituent at a corresponding position in the general formula (I c);

R, is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a nitro group, a lower alkyl group, A lower alkoxy group, an aryl group or a group of the general formula -NR ₁₄ R ₁₅ or a COR ₁₃ , wherein R ₁₃ is a group of the general formula -NR ₁₆ R ₁₇ (where R ₁₆ and R ₁₇ are each independently Represents a hydrogen atom or a lower alkyl group), a hydroxyl group or a lower alkoxy group, and R ₁₄ and R ₁₅ are each independently a hydrogen atom, a lower alkyl group, a lower alkylsulfonyl group, a lower alkanol group or a substituted R _e represents a hydrogen atom, a lower alkyl group, a cyclo lower alkyl group, a lower alkanol group or a hydroquinone lower alkyl group;

One of R _18a and R ₁₉ is a hydrogen atom, the other is a lower alkylsulfonyl group,

One of R ₂₄ and R ₂₅ is a hydrogen atom, the other is a lower alkylsulfonyl group,

A represents a group of the general formula — (CHR ₁₂ ) _n — or 1 (CH ₂ ) „— 0— (where ₂ represents a hydrogen atom or a hydroxyl group, and n represents an integer of 1 to 4); or

-N-A-

^R 6

Together form a piperidine ring, and m represents an integer of 0 to 2. However, when is a hydrogen atom, m is not 1.)

14. A compound of the following general formula (Ie) or a salt thereof is produced by reacting a compound of the following general formula (Id) with an amine derivative of the following general formula (VI) or a salt thereof. A method for producing a quinolylamine derivative represented by the general formula (I) and a salt thereof.

(In the above formula,

 And Z each represent a substituent at the corresponding position in general formula (Ie);

Ha 1 represents a halogen atom, R ₁₄ and R ₁₅ each independently represent a hydrogen atom, a lower alkyl group, a lower alkylsulfonyl group, a lower alkanol group or an optionally substituted aralkyl group; 135

R ₂ , R ₃ , R ₄ and R ₅ are each independently a hydrogen atom, a lower alkyl group, a halogen atom, a lower alkoxy group, a nitro group, a hydroxyl group, a cyano group, a lower alkanol group, a hydroxy lower alkyl group, A lower alkylsulfonyl group or a group of the general formula 1 NR ₁₈ R ₁₉ or 1 COR ₂₀ R ₂₁ or a 6-membered group containing one or two identical or different hetero atoms selected from a nitrogen atom and an oxygen atom to indicate the heterocycle, wherein R! ₈及beauty ₉ each independently represents a hydrogen atom, a lower alkyl group or a lower alkylsulfonyl group, R ₂ o and R ₂₁ are each independently a hydrogen atom or a lower Represents an alkyl group,

-0 heterocycle or general formula

Represents a group of

_{R 7, R 8, R 9} , R 1Q and R _u are each independently a hydrogen atom, a lower alkyl group, lower-grade alkoxy group, a halogen atom, a nitro group, Shiano group, hydroxyl group, sulfonyl group or generally Shiki NR ₂₄ shows a group of R ₂₅ or one S 0 ₂ NR ₂₂ R _23, wherein R ₂₂ and R ₂₃ each independently represents a hydrogen atom or a lower alkyl group, R ₂₄ and R ₂₅ are each independently Represents a hydrogen atom, a lower alkyl group or a lower alkylsulfonyl group, and R _e represents a hydrogen atom, a lower alkyl group, a cyclo-lower alkyl group, a lower alkanol group. Or a hydroxy lower alkyl group,

A represents a group represented by the general formula-(CHR ₁₂ ) _n -or 1 (CH ₂ ) _π -0-(where R and ₂ represent a hydrogen atom or a hydroxyl group, and η represents an integer of 1 to 4) Or

-Ν-Α-

Together with a piperidine ring, and m represents an integer of 0 to 2. However, when is a hydrogen atom, m is not 1. )

15. A compound of the following general formula (VII) or a salt thereof is produced by protecting the hydroxy group of the substituent R ₆ with a compound of the following general formula (Ia-1) or a salt thereof, The compound (VII) is reduced and then reacted with an alkane sulfonyl halide to produce a compound of the following general formula (VIII) or a salt thereof, followed by deprotection to give a compound of the following general formula (Ic-1) or a salt thereof A process for producing a quinolylamine derivative of the general formula (I) and a salt thereof, characterized by producing:

6a))

(In the above formula, R ₂ , R ₃ , R ₄ , R ₅ and Z each represent a substituent at a corresponding position in the general formula (I c -1),

Is a hydrogen atom, halogen atom, hydroxyl group, cyano group, nitro group, lower alkyl group, lower alkoxy group, aryl group or the general formula -NR! ₄ R! ₅ or 1 C 0 R! The _third group shows, where R ₁₃ is formula chromatography NR ₁₆ R group (wherein R ₁₆ and R ₁₇ are each independently a hydrogen atom or a lower alkyl group), a hydroxyl group or a lower alkoxy group R ₁₄ and R ₁₅ each independently represent a hydrogen atom, a lower alkyl group, a lower alkyl sulfonyl group, a lower alkyl group or an optionally substituted aralkyl group, and R or hydroxy lower An alkyl group,

R _6b is a protected hydroxy lower alkyl group;

One of R ₁₈ and R ₁₉ is a hydrogen atom, the other is a lower alkylsulfonyl group,

One of R ₂₄ and R ₂₅ is a hydrogen atom, the other is a lower alkylsulfonyl group,

A represents a group of the general formula — (CHR _I2 ) _π — or 1 (CH ₂ ) _n — 0— (where R, ₂ represents a hydrogen atom or a hydroxyl group,

n represents an integer of 1 to 4) or

-N-A- -N-B- or

 R6a "6b

Together form a pyridin ring, and m represents an integer of 0 to 2. However, if is a hydrogen atom, m is not 1. )

16. Any of paragraphs 1 to 10 together with a pharmaceutically acceptable carrier —An antiarrhythmic agent composition comprising, as an active ingredient, the compound of the general formula (I) or a salt thereof in one section.