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WO1996006084A1 - Nouveaux derives de quinolylamine, son procede de production et son utilisation comme agent antiarhythmique - Google Patents

Nouveaux derives de quinolylamine, son procede de production et son utilisation comme agent antiarhythmique Download PDF

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Publication number
WO1996006084A1
WO1996006084A1 PCT/JP1995/001137 JP9501137W WO9606084A1 WO 1996006084 A1 WO1996006084 A1 WO 1996006084A1 JP 9501137 W JP9501137 W JP 9501137W WO 9606084 A1 WO9606084 A1 WO 9606084A1
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Prior art keywords
group
hydrogen atom
general formula
lower alkyl
alkyl group
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PCT/JP1995/001137
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English (en)
Japanese (ja)
Inventor
You Sup Chung
Dong Ick Kim
Gee Ho Jeon
Kab Sig Kim
Shigeru Tanabe
Toshiro Kozono
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C & C Research Labs.
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Priority to AU26299/95A priority Critical patent/AU2629995A/en
Publication of WO1996006084A1 publication Critical patent/WO1996006084A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms

Definitions

  • 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.
  • 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.
  • 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 ;
  • 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,
  • 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
  • R 2 () and R 21 each independently represent a hydrogen atom or Represents a lower alkyl group
  • A represents a group of the general formula — (CHR 12 ) n — or 1 (CH 2 ) casual— 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
  • n 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.
  • 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.
  • antidiabetic agents 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.
  • 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.
  • 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
  • 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,
  • 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.
  • the present invention relates to a novel quinolylamine derivative of the general formula (I) and a salt thereof.
  • 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
  • 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
  • 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;
  • 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 ) argue— or 1 (CH 2 ) n — 0—,
  • n represents an integer of 1 to 4)
  • -N-A- R6 can also form a piperidine ring
  • n represents a number of 0, 1 or 2, provided that when is a hydrogen atom, m is not 1.
  • m represents a number of 0, 1 or 2, provided that when is a hydrogen atom, m is not 1.
  • 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.
  • 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.
  • 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.
  • lower alkylsulfonylamino groups lower alkylaminosulfonyl groups, sulfonic acid groups, N-lower alkyl lower alkylsulfonylamino groups, and the like.
  • 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
  • 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 hydroxymethyl 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.
  • 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 A pyridazinyl group, a triazinyl group,
  • 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.
  • 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:
  • 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
  • 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!
  • 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,
  • 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.
  • 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 ) seldom— or 1 (CH 2 )phon — 0—, wherein R 12 represents Represents a hydrogen atom or a hydroxyl group, n represents an integer of 1 to 4,
  • n is 0 or 1, provided that when is a hydrogen atom, m is not 1.
  • 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.
  • 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
  • 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 ) casual— 0—, wherein R 12 represents a hydrogen atom or a hydroxyl group, n represents an integer of 1 to 4,
  • n is 0 or 1, provided that when is a hydrogen atom, m is not 1.
  • 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;
  • 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
  • CHR A general formula chromatography "one or one (CH 2) ⁇ - 0- of a group, wherein R 12 represents a hydrogen atom, or n is an integer from 2 to 4
  • n is a compound showing the number of 0, 1 or 2.
  • a particularly desirable compound is 1 ⁇
  • 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,
  • 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-
  • n 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.
  • 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.
  • 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, t
  • 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 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,
  • 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
  • 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
  • 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
  • a halogen atom such as a chlorine atom, a bromine atom, an iodine atom
  • an alkane sulfonyloxy group such
  • R 18 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.
  • R 6 is a hydroxy lower alkyl group
  • R is a protected hydroxy lower alkyl group, and Ha 1 is a halogen atom.
  • 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.
  • 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.
  • water-soluble bases include pyridine, triethylamine, potassium carbonate, potassium bicarbonate, potassium iodide, sodium methoxide, 1.8-diazabicyclo
  • DBU Ndeque 7-Dene
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • an alkanesulfonyl halide for example, alkanesulfonyl chloride or bromide.
  • This second step reaction can be carried out preferably in the presence of an acid acceptor.
  • the acid acceptor that can be used for such a purpose include pyridine, triethylamine, potassium carbonate, potassium bicarbonate and the like.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a solvent such as water, an alcohol such as methanol or ethanol, or a solvent such as tetrahydrofuran.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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 )
  • ⁇ -Ni R (DMSO-d 6 ): ⁇ 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
  • the isolated papillary muscle was subjected to electrical stimulation (frequency: 1 Hz, vibration width: 4 ms ec, voltage: W value xl.
  • 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).
  • electrical stimulation frequency: 1 Hz or 3 Hz; oscillation width: 2 ms ec, voltage: «value X1.5
  • the action potential duration (APD 90 ) was measured using a glass microelectrode (20-30 ⁇ ) charged with one solution.
  • APD 90 elongation rate of compound in the present invention Compound number Concentration (M)
  • 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.

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Abstract

Nouveau dérivé de quinolylamine représenté par la formule générale (I), et sel de ce dérivé, utile comme agent antiarhythmique. Dans cette formule, R1 représente méthyle, éthyle ou phényle; R2, R4 et R5 représente chacun hydrogène; R3 représente méthanesulfonamido; et Z représente N-méthyl-N-(4-méthanesulfanomidophénéthyl)aminométhyle, 4-méthanesulfonamidophénéthylamino ou N-(2-hydroxyéthyle)-N-(4-méthanesulfonamidophénéthyl)amino.
PCT/JP1995/001137 1994-08-19 1995-06-07 Nouveaux derives de quinolylamine, son procede de production et son utilisation comme agent antiarhythmique WO1996006084A1 (fr)

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AU26299/95A AU2629995A (en) 1994-08-19 1995-06-07 Novel quinolylamine derivative, process for production thereof, and use thereof as antiarrhythmic agent

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998054148A3 (fr) * 1997-05-30 1999-03-04 Isis Innovation Agents antiarythmiques
WO1999055677A1 (fr) * 1998-04-29 1999-11-04 Smithkline Beecham Plc Quinolones utilisees comme inhibiteurs de mrs et bactericides
US6211376B1 (en) 1996-09-10 2001-04-03 Pharmacia & Upjohn Company 8-hydroxy-7-substituted quinolines as anti-viral agents
JP2005519876A (ja) * 2001-11-27 2005-07-07 メルク　エンド　カムパニー　インコーポレーテッド ２−アミノキノリン化合物
JP2008523042A (ja) * 2004-12-09 2008-07-03 ゼンション・リミテッド 化合物
WO2010020981A1 (fr) * 2008-08-19 2010-02-25 Universiteit Leiden Modulateurs allostériques du récepteur de l'adénosine a3
US8420664B2 (en) 2006-01-26 2013-04-16 The United States Of America, Represented By The Secretary, Dept. Of Health And Human Services A3 adenosine receptor allosteric modulators
JP2021525752A (ja) * 2018-05-31 2021-09-27 シー・アンド・シー・リサーチ・ラボラトリーズＣ＆Ｃ Ｒｅｓｅａｒｃｈ Ｌａｂｏｒａｔｏｒｉｅｓ 複素環誘導体及びその使用

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JPS62142167A (ja) * 1985-10-03 1987-06-25 アメリカン・ホ−ム・プロダクツ・コ−ポレイシヨン 抗炎症および抗アレルギ−剤用新規置換ベンゼン誘導体
JPS62255474A (ja) * 1986-04-16 1987-11-07 フアイザ−・リミテツド 抗不整脈剤
JPS63201167A (ja) * 1987-02-07 1988-08-19 ファイザー・リミテッド 杭不整脈薬
JPH02223558A (ja) * 1988-11-02 1990-09-05 Kaken Pharmaceut Co Ltd フェニルアルキルアミン誘導体及びこれを有効成分とする抗真菌剤

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JPS62142167A (ja) * 1985-10-03 1987-06-25 アメリカン・ホ−ム・プロダクツ・コ−ポレイシヨン 抗炎症および抗アレルギ−剤用新規置換ベンゼン誘導体
JPS62255474A (ja) * 1986-04-16 1987-11-07 フアイザ−・リミテツド 抗不整脈剤
JPS63201167A (ja) * 1987-02-07 1988-08-19 ファイザー・リミテッド 杭不整脈薬
JPH02223558A (ja) * 1988-11-02 1990-09-05 Kaken Pharmaceut Co Ltd フェニルアルキルアミン誘導体及びこれを有効成分とする抗真菌剤

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6500842B1 (en) 1996-09-10 2002-12-31 Pharmacia & Upjohn Company 8-hydroxy-7-substituted quinolines as anti-viral agents
US6211376B1 (en) 1996-09-10 2001-04-03 Pharmacia & Upjohn Company 8-hydroxy-7-substituted quinolines as anti-viral agents
US6252080B1 (en) 1996-09-10 2001-06-26 Pharmacia & Upjohn Company 8-hydroxy-7-substituted quinolines as anti-viral agents
US6310211B1 (en) 1996-09-10 2001-10-30 Pharmacia & Upjohn Company 8-hydroxy-7-substituted quinolines as anti-viral agents
WO1998054148A3 (fr) * 1997-05-30 1999-03-04 Isis Innovation Agents antiarythmiques
US6320051B1 (en) 1998-04-29 2001-11-20 Smithkline Beecham Plc Quinolones used as MRS inhibitors and bactericides
WO1999055677A1 (fr) * 1998-04-29 1999-11-04 Smithkline Beecham Plc Quinolones utilisees comme inhibiteurs de mrs et bactericides
JP2005519876A (ja) * 2001-11-27 2005-07-07 メルク　エンド　カムパニー　インコーポレーテッド ２−アミノキノリン化合物
JP2008523042A (ja) * 2004-12-09 2008-07-03 ゼンション・リミテッド 化合物
US8420664B2 (en) 2006-01-26 2013-04-16 The United States Of America, Represented By The Secretary, Dept. Of Health And Human Services A3 adenosine receptor allosteric modulators
US9326978B2 (en) 2006-01-26 2016-05-03 The United States Of America, Represented By The Secretary, Dept. Of Health And Human Services A3 adenosine receptor allosteric modulators
WO2010020981A1 (fr) * 2008-08-19 2010-02-25 Universiteit Leiden Modulateurs allostériques du récepteur de l'adénosine a3
JP2021525752A (ja) * 2018-05-31 2021-09-27 シー・アンド・シー・リサーチ・ラボラトリーズＣ＆Ｃ Ｒｅｓｅａｒｃｈ Ｌａｂｏｒａｔｏｒｉｅｓ 複素環誘導体及びその使用
JP7558066B2 (ja) 2018-05-31 2024-09-30 シー・アンド・シー・リサーチ・ラボラトリーズ 複素環誘導体及びその使用

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