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WO1996010569A1 - Derive de quinoleine - Google Patents

Derive de quinoleine Download PDF

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Publication number
WO1996010569A1
WO1996010569A1 PCT/JP1995/001998 JP9501998W WO9610569A1 WO 1996010569 A1 WO1996010569 A1 WO 1996010569A1 JP 9501998 W JP9501998 W JP 9501998W WO 9610569 A1 WO9610569 A1 WO 9610569A1
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WO
WIPO (PCT)
Prior art keywords
added
mmol
carbon atoms
single bond
alkylene
Prior art date
Application number
PCT/JP1995/001998
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English (en)
Japanese (ja)
Inventor
Mitsuo Masaki
Masao Yamamoto
Kaoru Hara
Shinichi Yoshida
Original Assignee
Nippon Chemiphar Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nippon Chemiphar Co., Ltd. filed Critical Nippon Chemiphar Co., Ltd.
Priority to AU35784/95A priority Critical patent/AU3578495A/en
Publication of WO1996010569A1 publication Critical patent/WO1996010569A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Definitions

  • the present invention relates to novel quinoline derivatives.
  • the present invention particularly relates to a quinoline derivative which is effective as a novel anti-allergic agent having TXA 2 synthase P harmful activity and LTD 4 antagonistic activity.
  • brostaglandin PG.
  • Thromboxane TX
  • leukotriene LT
  • TXA 2 is a analogue of Bok Ronbokisan is known to be a potent blood / H3 ⁇ 4 simultaneously potent smooth muscle contractile agents If it is aggregated material. Therefore, the known TXA 2 synthase inhibitor (E) —3- [p— (1H-imidazole-11-ylmethyl) phenyl] propenoic acid (generic name: ozagrel) and its sodium salt are It is known that it is useful as a therapeutic agent for asthma or cerebral thrombosis (Japanese Patent Application Laid-Open No. 55-313). Ozagrel has the following chemical structure, and its structural features include an imidazole structure and an acidic group (carboxyl).
  • Substances having TXA 2 synthase inhibitory activity having similar characteristics include, in addition to ozagrel, 1- [3- (4-benzhydryl-1-1-biperazinyl) propyl] 13- (1H-imidazole-1-ylmethyl 1) H-indole-1-carboxylic acid (as described in WO 93/20065) and (E) -3- [3- (1H-imidazole-1-ylmethyl) 1-2-methyl-1 H—Indone-l-yl] propanoic acid (described in ⁇ Med. Chem. 1986, 29, p342) is known.
  • This branlukast has the following chemical structure, and its structural features are that it has an arylalkyloxyphenyl structure and an acidic group (tetrazole).
  • Compounds having similar characteristics include 5- [2- [4-1- (quinolin-12-ylmethyloxy) phenyloxymethyl] phenylmethyl] tetrazole (described in U.S. Pat. No. 4,939,011), quinoline 12-ylmethyoxyphenylalkanoic acid derivatives (described in European Patent Publication Nos.
  • An object of the present invention is to provide a novel compound having TXA 2 synthase inhibitory activity and LTD antagonistic activity.
  • the present inventor has been conducting research on antiallergic agents.
  • the inventors have found that all of the quinoline derivatives represented by (IV) to (IV) have both TXA 2 synthase inhibitory activity and LTD antagonism, and completed the present invention.
  • a 1 is one C0 2 R '', one CN, -CONHSOz R 12, one C0NR 13 R '4, -OR' 6, a tetrazolyl or substituted tetrazolyl, R 'l, R 13, R " Contact And R 16 are each a hydrogen atom, an alkyl or an alkali metal
  • R ′ 2 is a hydrogen atom, an alkyl, a haloalkyl, an aryl or an aralkyl
  • the S substituent of the substituted tetrazolyl is an alkyl, carboxyalkyl or alkoxycarbonyl
  • L is a single bond or an alkylene having 1 to 6 carbon atoms
  • X ' is a nitrogen-containing heterocyclic group
  • L' 2 is a single bond or an alkylene having 1 to 6 carbon atoms.
  • L 13 is a single bond or an alkylene having 1 to 6 carbon atoms; Y ′ is an oxygen atom or a sulfur atom; L ′′ is a single bond or 1 to 6 carbon atoms Is an alkylene of 6 Then, the two main ing from the broken line and the solid line means a single bond or a double bond)
  • a a is -C0 2 R a ⁇ -CN, -CONHSO ⁇ R 22 , one C0NR 23 R a4 , -OR ", a tetrazolyl or substituted Te Bok Razoriru, R 2l, R 23,
  • Contact and R 2S are each a hydrogen atom, an alkyl or an alkali metal
  • R 22 is a hydrogen atom, alkyl, haloalkyl, Ariru or Aralkyl
  • the substituent of the substituted tetrazolyl is alkyl, carboxyalkyl or alkoxycarbonylalkyl
  • L 21 is a single bond or an alkylene having 1 to 6 carbon atoms
  • X 2 is is nitrogen heterocycles ⁇
  • L 22 represents a single bond or a carbon atoms is alkylene of 1 to 6
  • L 23 represents a single bond or a carbon atoms is alkylene of 1 to 6
  • Y 2 represents an oxygen Is
  • a 3 are, -C0 2 R 31, one CN, -C0NHS0 2 R 32, one C0NR 33 R ", a -OR 86, tetrazolyl or conversion tetrazolyl, R 3 ', R 33, R”
  • R" is a hydrogen atom, alkyl, haloalkyl, aryl or aralkyl
  • the substituent of the substituted tetrazolyl is alkyl, carboxyalkyl or L 31 is a single bond or an alkylene having 1 to 6 carbon atoms
  • X s is a nitrogen-containing heterocyclic group
  • L 3Z is a single bond or 1 carbon atom.
  • L 33 represents a single bond or a carbon atoms is alkylene of 1 to 6;
  • Y 3 is an oxygen atom or a sulfur atom; and is a single bond or a carbon atoms 1 to 6 Is an alkylene) (IV)
  • a 4 shows an C0 2 R a ', one CN, -CONHSO2 R 42, one C0NR 43 R ", -OR 45, tetrazolyl or g conversion tetrazolyl, R, R', R"
  • L 41 is a single bond or an alkylene having 1 to 6 carbon atoms
  • X 4 is a nitrogen-containing heterocyclic group; is one CONH— or one NHCO—
  • L 43 is Is a single bond or an alkylene having 1 to 6 carbon atoms; is an oxygen atom or a sulfur atom; and is a single bond or an alkylene having
  • a 1 is a derivative of an acidic group or an acidic group, specifically -C0 2 R ll, one CN, -CONHSO2 R l2, -CONR, s R ' ⁇ -OR 15, tetrazolyl Or a substituted tetrazolyl.
  • One C0 2 and tetrazolyl preferably, a C0 2 R 11 forces particularly preferred.
  • R ′′, R 13 , R 14 and R 16 are each a hydrogen atom, alkyl or alkali metal.
  • the R ia represents a hydrogen atom, alkyl, haloalkyl, was Ariru or a Ararukiru.
  • the substituent of the substituted tetrazolyl is alkyl, carboxyalkyl or alkoxycarbonylalkyl.
  • the alkyl and alkoxy preferably have 1 to 6 carbon atoms. Examples of alkyl include methyl Le, ethyl and provir. Examples of alkali metals include sodium and potassium.
  • the haloalkyl preferably has 1 to 6 carbon atoms.
  • haloalkyl examples include chloromethyl, chloroethyl and fluoroethyl.
  • aryls examples include phenyl and naphthyl.
  • aralkyls examples include benzyl, phenethyl and benzhydryl.
  • the carboxyalkyl preferably has 2 to 7 carbon atoms.
  • carboxyalkyl examples include carboxyethyl.
  • the alkoxy portion and the alkyl portion of the alkoxycarbonylalkyl preferably have 1 to 6 carbon atoms, respectively.
  • alkoxycarbonylalkyl examples include ethoxycarbonylethyl.
  • L 1 ′ is a single bond or an alkylene having 1 to 6 carbon atoms.
  • a single bond or an alkylene having 1 to 3 carbon atoms is preferred, and methylene and ethylene are preferred.
  • L 11 is the 3-, 4-, 5- or 6-position of a benzo [b] furan ring, or the 2-, 3-, 4-, or 5-position of a 2,3-dihydrobenzo [b] furan ring Or it can be linked to position 6.
  • L '1 is Rukoto force to bind to the 5-position of the ring 5 particularly preferred.
  • X ′ is a nitrogen-containing heterocyclic group.
  • the nitrogen-containing heterocyclic ring preferably has 3 to 7 members, more preferably 5 or 6 members.
  • the number of nitrogen atoms contained in the heterocyclic ring is preferably 1 to 3.
  • the atoms constituting the heterocyclic ring are preferably composed of only a nitrogen atom and a carbon atom. Further, it is preferable that the heterocyclic ring is unsaturated and has aromaticity.
  • the complex may have a substituent. Examples of the substituent include alkyl.
  • the alkyl has preferably 1 to 6 carbon atoms. Examples of alkyl include methyl and ethyl.
  • Examples of the nitrogen-containing hetero II group include imidazolyl and pyridyl. Imidazolyl, particularly imidazolyl, is preferred.
  • L 12 is a single bond or alkylene having 1 to 6 carbon atoms.
  • a single bond or an alkylene force having 1 to 4 carbon atoms is preferable, and an alkylene force having 1 to 3 carbon atoms i is particularly preferable.
  • Lia is a single bond or alkylene having 1 to 6 carbon atoms.
  • Single bond or Is preferably a methylene atom, and a single bond is particularly preferred.
  • L 12 and L '3 to the benzene ring interposed, ortho, may be attached at any position of the meta and para.
  • V 1 is an oxygen atom or a sulfur atom.
  • An oxygen atom is preferred.
  • L is a single bond or an alkylene having 1 to 6 carbon atoms. Alkylene having 1 to 3 carbon atoms is preferable, and methylene or ethylene is particularly preferable. L" is 2-position of the quinoline ring. It is preferable to bind to
  • a double line consisting of a broken line and a solid line means a single bond or a double bond. It is preferred that the condensed ring containing an oxygen atom represented by the formula (I) be a benzo [b ⁇ furan ring].
  • a 1 and X 1 have the same meaning as in formula (I). “1” is 1 or 2. m is 1, 2 or 3. n is 1 or 2.
  • a 2 is a derivative of an acidic group or an acidic group, in particular one C0 2 R ", one CN, -CONHSO2 R 22, one C0NR 23 R 24, -OR 25, tetrazolyl or substituted tetrazolyl. one C0 2 R 2 'and tetrazolyl, and particularly preferably one C0 2 R 21.
  • R 21 , R 2a and R ′′ are each a hydrogen atom, an alkyl or an alkali metal.
  • R aa is a hydrogen atom, an alkyl, a haloalkyl, an aryl or an aralkyl.
  • the substituent of the substituted tetrazolyl Is an alkyl, carboxyalkyl or alkoxyl alkenylalkyl.
  • the alkyl preferably has 1 to 6 carbon atoms.Examples of alkyl include methyl, ethyl and Propyl. Examples of the alkali metal include sodium and potassium.
  • the haloalkyl preferably has 1 to 6 carbon atoms.
  • haloalkyl examples include chloromethyl, cloethyl, and fluoroethyl.
  • aryls include phenyl and naphthyl.
  • aralkyls include benzyl, phenethyl and Benzhydryl forces.
  • the carboxylalkyl preferably has 2 to 7 carbon atoms.
  • carboxyalkyl include carboxyethyl carb.
  • the alkoxycarbonyl and alkyl portions of the alkoxycarbonylalkyl preferably have 1 to 6 carbon atoms, respectively.
  • alkoxycarbonylalkyl examples include ethoxycarbonylethyl.
  • L 2 1 is a single bond or a carbon atoms is an alkylene of 1 to 3. Alkylene forces having 1 or 2 carbon atoms are particularly preferred.
  • L 2 1 is 3-position of the benzene ring, 4-position, can be attached to the 5-position or 6-position. L 2 1 is particularly preferably bound to the 4-position.
  • X 2 is a nitrogen-containing heterocyclic group.
  • the nitrogen-containing heterocycle is preferably a 3- to 7-membered ring, more preferably a 5- or 6-membered ring.
  • the number of nitrogen atoms contained in the heterocycle is preferably 1 to 3.
  • the atoms constituting the heterocyclic ring are preferably composed of only a nitrogen atom and a carbon atom. Further, the complex is preferably unsaturated and has aromaticity.
  • the heterocyclic ring may have a substituent. Examples of the substituent include alkyl.
  • the alkyl has preferably 1 to 6 carbon atoms. Examples of alkyl include methyl and ethyl.
  • Examples of the nitrogen-containing heterocyclic group include imidazolyl and pyridyl. Imidazolyl, especially imidazole-1-ylka, is preferred.
  • L 22 is a single bond or an alkylene having 1 to 4 carbon atoms. Alkylene having 1 to 3 carbon atoms is particularly preferred.
  • L 23 is a single bond or methylene. Single bonds are preferred. L 22 and L 23, to the benzene ring interposed, Ol Bok, may be attached at any position of the meta and para.
  • Y a is oxygen atom or sulfur atom.
  • An oxygen atom is preferred.
  • a 2 and X 2 have the same meaning as in formula ( ⁇ ). “1” is 1 or 2. m is 1, 2 or 3. n is 1 or 2.
  • a 3 is a derivative of an acidic group or an acidic group, in particular one C0 2 R ", one CN, -CONHSO2 R '2, -C0NR a3 R 3 ⁇ -OR 36.
  • one 0R the as, one C0 2 R 31 and Te Torazoriruka preferably, particularly preferred C0 2 R ai is.
  • a 3 may be coupled to the position of the arbitrary benzene ring.
  • a 3 is this a force i particularly preferably bonded to a position adjacent to the following L 32.
  • R 32 is a hydrogen atom, alkyl, haloalkyl, aryl or aralkyl.
  • the substituent is alkyl, carboxyalkyl or alkoxycarbonylalkyl, wherein the alkyl has preferably 1 to 6. Examples of alkyl include methyl, ethyl and propyl. Examples include sodium and potassium forces.
  • the haloalkyl preferably has 1 to 6 carbon atoms. Examples of haloalkyl include chloromethyl, chloroethyl and fluoro. Includes ethyl.
  • Examples of the above aryl include phenyl and naphthyl.
  • Examples of the above aralkyls include benzyl, phenethyl and benzhydryl.
  • the carboxyalkyl preferably has 2 to 7 carbon atoms.
  • Examples of carboxyalkyl include carboxymethyl and carboxyethyl.
  • the alkoxy and alkyl portions of the alkoxycarbonylalkyl preferably have 1 to 6 carbon atoms.
  • Examples of the alkoxycarbonylalkyl include ethoxycarbonylethyl.
  • L 3 ′ is a single bond or alkylene having 1 to 3 carbon atoms. Alkylene having 1 or 2 carbon atoms is particularly preferred. L 3 'can be bonded to any position on the benzene ring. L 3 ′ is particularly preferably a compound that binds to position 4 (the binding position of A 3 is position 1).
  • X 3 is a nitrogen-containing heterocyclic group.
  • the nitrogen-containing heterocycle is preferably a 3- to 7-membered ring, more preferably a 5- or 6-membered ring.
  • the number of nitrogen atoms contained in the heterocycle is preferably 1 to 3.
  • the atoms constituting the complex are preferably composed of only a nitrogen atom and a carbon atom. Further, it is preferable that the heterocyclic ring is unsaturated and has aromaticity.
  • the heterocyclic ring may have a substituent. Examples of the substituent include alkyl.
  • the alkyl has preferably 1 to 6 carbon atoms. Examples of alkyl include methyl and ethyl.
  • Examples of the nitrogen-containing heterocyclic group include imidazolyl and pyridyl. Imidazolyl, especially imidazole-11-yl, is preferred.
  • L 32 is a single bond or alkylene having 1 to 4 carbon atoms. Alkylenes having 1 to 3 carbon atoms are particularly preferred.
  • Y 3 is an oxygen atom or a sulfur atom.
  • An oxygen atom is preferred.
  • the ability to be methylene or ethylene is particularly preferred.
  • Particularly preferred quinoline derivatives are represented by the following formula (III-a):
  • a 3 and X 3 have the same meaning as in formula (III). “ ⁇ 1” is 1 or 2. m is 1, 2 or 3. n is 1 or 2. Further, the positional relationship between 1- (CH 2 ) possibly0- and-(CH 2 ) m- attached to the benzene ring is preferably a meta- (m) or para- (p) positional relationship.
  • a 4 is a derivative of an acidic group or an acidic group, one particular C0 2 R 4 is the 'one CN, -CONHSOa R 42, one CONR "R", -OR 46, tetrazolyl Or a substituted tetrazolyl.
  • One C0 2 R 4 one OR "and Te Torazoriru preferably one OR” force i particularly preferred.
  • R “, R”, R “and R” are each a hydrogen atom, an alkyl, a carbonyloxyalkyl or an alkali metal.
  • the substituent of the above substituted tetrazolyl is alkyl, carboxyalkyl or alkoxycarbonylalkyl.
  • the alkyl has preferably 1 to 6 carbon atoms. Examples of alkyl include methyl, ethyl and propyl. Examples of alkali metals include sodium and potassium.
  • the haloalkyl preferably has 1 to 6 carbon atoms. Examples of haloalkyl include chloromethyl, chloromethyl and fluormethyl.
  • Examples of the above aryl include phenyl and naphthyl.
  • Examples of the above aralkyls include benzyl, phenethyl and benzhydryl.
  • the carboxyalkyl preferably has 2 to 7 carbon atoms.
  • Examples of carboxyalkyl include carboxymethyl and carboxyethyl.
  • the alkoxy and alkyl portions of the alkoxycarbonylalkyl preferably have 1 to 6 carbon atoms.
  • Examples of the alkoxycarbonylalkyl include ethoxycarbonylethyl.
  • L represents a single bond or the number of carbon purple atom is alkylene of 1 to 3. Alkylene force of carbon atoms 1 to 2 i particularly preferred. L 4 1 may be any of a benzene ring It is particularly preferred that the bond to position 4 or 5 (the position of A4 binding is position 1).
  • X 4 is a nitrogen-containing heterocyclic group.
  • the nitrogen-containing heterocycle is preferably a 3- to 7-membered, more preferably a 5- or 6-page ring.
  • the number of nitrogen atoms contained in the heterocycle is preferably 1 to 3.
  • the atoms constituting the heterocyclic ring are preferably composed of only a nitrogen atom and a carbon atom. Further, the complex is preferably unsaturated and has aromaticity.
  • the heterocyclic ring may have a substituent. Examples of the substituent include alkyl.
  • the alkyl has preferably 1 to 6 carbon atoms. Examples of alkyl include methyl and ethyl.
  • Examples of the nitrogen-containing heterocyclic group include imidazolyl and pyridyl. Imidazolyl, especially imidazole-1-ylka, is preferred.
  • L is one C ONH— or one NHCO—.
  • L 4a is a single bond or methylene. Single bonds are preferred. And may be bonded to the intervening benzene ring at any of ortho, meta and para positions.
  • An oxygen atom is preferred.
  • L is a single bond or an alkylene having 1 to 3 carbon atoms. Methylene or ethylene is particularly preferable. It is preferably bonded to the 2-position of the quinoline ring.
  • a 4 , X 4 and L 42 have the same meaning as in formula (IV).
  • "1 J is 1 or 2.
  • n is 1 or 2.
  • One (CH a ) radical one and one L attached to the benzene ring is the same as the meta ( m ). Power 5 is preferred.
  • the quinoline ring to which L ", L", L "or is bonded may have a substituent.
  • substituent include halogen, alkyl and alkoxy.
  • halogen include chlorine, bromine and fluorine
  • the alkyl preferably has 1 to 6 carbon atoms
  • alkyl include methyl and ethyl. Has preferably 1 to 6.
  • alkoxy include methoxy and ethoxy.
  • Examples of the pharmacologically acceptable salts of the compounds of the present invention include acidic salts such as hydrochloric acid and acetic acid and basic salts such as alkali metals (eg, sodium and potassium).
  • acidic salts such as hydrochloric acid and acetic acid
  • basic salts such as alkali metals (eg, sodium and potassium).
  • the quinoline derivative represented by the formula (I) can be synthesized, for example, by the following synthetic route.
  • the compounds represented by formulas (II), (III) and (IV) can be synthesized by the same synthetic route.
  • the quinoline derivative of the present invention and a salt thereof both have an inhibitory action on tocopomboxane A 2 synthase and an antagonistic action on leukotriene D ⁇ . Therefore, it is possible to use the compounds of the present invention as a therapeutic agent or prophylactic agent for a disease TXA 2 or LTD 4 are involved.
  • the compound of the present invention is useful, for example, as a therapeutic or preventive agent for bronchial asthma, allergic disease, Sf inflammation, thrombosis, stroke, myocardial infarction, angina pectoris, ischemic cerebral circulation disorder.
  • the method of administering the compound of the present invention may be oral or parenteral.
  • Oral dosage forms include tablets, capsules, powders, granules and syrups.
  • Methods of parenteral administration include mucosal administration, body surface administration, vascular administration, and tissue administration.
  • mucosal administration use as eye drops, inhalant, spray or suppository.
  • intravascular or intravascular administration use as an injection.
  • the above-mentioned oral administration preparation can be produced using ordinary excipients, disintegrants, binders, lubricants, pigments and diluents.
  • an excipient glucose and lactose are generally used.
  • disintegrants include starch and calcium carboxymethylcellulose.
  • Lubricants include magnesium stearate and talc.
  • binders hydroxybutyl cellulose, gelatin and polyvinylidone are used.
  • Preparations for parenteral administration can also be produced in a usual manner.
  • ordinary distilled water for injection physiological saline or Ringer's solution may be used.
  • the dose of the compound of the present invention is 0.1 to 200 mg / day for injection and 1 to 500 mg / day for oral administration for normal adults.
  • the dosage will vary according to age, race, symptoms, etc.
  • the reaction solution was poured into water (500 mL), and the precipitated crystals were collected and washed with water (400 mL ⁇ 3).
  • the obtained crystals were dried under vacuum, dissolved in chloroform (200 mL) by heating, hexane (250 mL) was added while the solution was hot, and the solution was cooled to room temperature with stirring.
  • 2- (chloromethyl) quinoline hydrochloride (5.0 g, 23.4 mmol) was added to a mixed solvent of water (40 mL) and dichloromethane (10 mL), and sodium bicarbonate (2.38 g, 28.3 mmol) was added little by little, and the organic layer was separated. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 2- (chloromethyl) quinoline.
  • 2- (chloromethyl) quinoline hydrochloride (5. Og, 23.4 mmol) was added to a mixed solvent of water (40 mL) and dichloromethane (10 mL), and sodium bicarbonate (2.38 g, 28 (3 mmol) was added little by little, and the organic layer was separated. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 2- (chloromethyl) quinoline. This was dissolved in dry DMF (8 mL), added dropwise to the above reaction solution under ice-cooling, stirred at room temperature for one hour, poured into ice water (100 mL), extracted with black hole form (80 mL), and extracted with water. (40mLx2), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography.
  • the above compound (4) (0.30 g, purity: 97.9%, 0.57 mmol) is dissolved in ethanol, and a 1N aqueous sodium hydroxide solution (1. OmL) is added at room temperature, followed by stirring for 1 hour and 30 minutes. Thereafter, a 1N aqueous sodium hydroxide solution (0.43 mL) was further added, and the mixture was stirred for 13 hours and 30 minutes. Ethanol was distilled off under reduced pressure at 30. Water (4 mL) was added to the residue, and a 1N aqueous hydrochloric acid solution was added under ice-cooling until the pH reached 7.
  • the compound (3) (100 mg, 0.37 mmol) synthesized in Synthesis Example 4 was dissolved in dry DMF (1 mL), and the mixture was cooled on ice with 60% sodium hydride (15 mg, 0.38 mmol). ) was added, and the mixture was stirred for 30 minutes, and then dried DMF (4 mL) of the compound (9) (105 mg, 1.83 mmol) synthesized in Synthesis Example 1 was added dropwise. After stirring at room temperature for 21 hours and 20 minutes, the reaction solution was poured into ice water (14 mL), extracted with chloroform (8 mL ⁇ 3) while passing through a suitable filter, and washed with water (10 mL ⁇ 2).
  • Zanhama To the mixture was added water (10 OmL), and extracted with ethyl acetate (10 OmL). 0.5N hydrochloric acid was added to the aqueous layer to adjust the pH to 7, and then extracted with ethyl acetate (100 mL ⁇ 2). The extract was combined with the above ethyl acetate layer and dried over anhydrous sodium sulfate. The title compound (2) obtained by evaporating the solvent under reduced pressure was used for the next reaction as a crude product.
  • the reaction solution was poured into ice water (20 OmL), extracted with ethyl acetate (10 OmL X 2), washed with water (100 mL X 2) and saturated saline (100 mL), and dried over anhydrous sodium sulfate. It was dried in a realm.
  • the reaction solution was poured into ice water (150 mL), extracted with ethyl acetate (100 mL X 2), and washed with water (100 mL X 2) and saturated saline (100 mL). And dried over anhydrous sodium sulfate.
  • the extract was acidified by adding concentrated hydrochloric acid, and extracted again with ether (200 mL, 15 OmL). After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 9.40 g (yield: 37.4%) of the title compound (1) as pale brown crystals.
  • water 50 O mL
  • extracted with ether 500 mL
  • dried over anhydrous sodium sulfate and evaporated under reduced pressure to remove 6.4 O g of the crude product of the title compound (1) in brown. Obtained as crystals.
  • Acetonitrile (124 mL) was added to the above compound (1) (9.30 g, 60.7 mimol) and anhydrous potassium carbonate (12.6 g, 91.2 mimol), and dimethyl sulfide was added. (7.2 mL, 75.9 mol) was added, and the mixture was stirred at room temperature for 5 hours.
  • the solvent was distilled off under reduced pressure, a saturated aqueous solution of glycine (31 mL) was added to the residue, and the mixture was stirred at 50 for 1 hour. After cooling to room temperature, the mixture was extracted with ether (31 mL ⁇ 2), and washed with iN aqueous sodium hydroxide solution (15 mL). After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and 10.0 g (purity: 98.3%, yield: 96.9%) of the title compound (2) was obtained as a yellow oil. Obtained.
  • imidazole (3.42 g. 50.2 mmol) is dissolved in dry dimethylformamide (17 mL), and the mixture is cooled with ice and cooled to 60% sodium hydride (2.0, 50.3 mmol). Was added little by little, and the mixture was stirred at room temperature for 30 minutes.
  • the reaction solution was again ice-cooled, and a solution of the above-mentioned residue A in dry DMF (2 OmL) was added dropwise, followed by stirring at room temperature for 2 hours.
  • the reaction solution was poured into ice water (10 OmL), extracted with a black hole form (5 OmL x 2), washed with water (100 mL x 2), and dried over anhydrous sodium sulfate.
  • the above compound (4) was dissolved in 1.00 g (4.56 mmol) of dry dimethylformamide (3 O mL), and then cooled to 60% sodium hydrogen hydride under ice-cooling. mg (5.03 mmol) was added and stirred for 30 minutes. Then, ethyl ethyl bromoacetate (0.51 mL, 4.60 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 6 hours. The reaction solution was poured into ice water (200 mL), extracted with ethyl acetate (100 mL X 2), and washed with water (100 mL X 2) and saturated saline (100 mL).
  • the above compound (7) (5.30 g, 18.1 millimol) was dissolved in methanol (50 mL), and the mixture was dissolved in ice-cooled 1N aqueous sodium hydroxide solution (54.3 mL) and Methanol (10 O mL) was added, and the mixture was stirred at room temperature for one hour.
  • the solvent was distilled off under reduced pressure, and water (100 mL) and 1 N hydrochloric acid were added to the residue to adjust the pH to 7.
  • the precipitated crystals were filtered, washed with water (50 mL ⁇ 2), and dried under reduced pressure to obtain 74 g (yield: 93%) of the title compound (8) as pale yellow crystals.
  • Zinc dust (50.0 g, 1.67 mol), copper sulfate (70 mg, 0.44 mmol), and sodium hydroxide (16.0 g, 0.67 mol) were added to water (6 OmL). Suspended. Under ice-cooling, gradually add 4-aminophthalimide (25.0 g, 0.15 mol), add water (7 OmL), and add 10 to 70-80 * C. Time Heated. Insolubles were removed by filtration through celite. Concentrated hydrochloric acid was added to the resulting aqueous solution under ice-cooling to adjust the pH to 2, and the mixture was heated under reflux for 2 hours. After cooling, sodium carbonate was added to adjust the pH to 8, and the precipitated crystals were collected to quantitatively obtain 22.9 g of the title compound (1) as light brown crystals.
  • the above compound (4) (127 mg, 0.48 mmol) was dissolved in methanol (2.5 mL), 10% palladium / carbon (13 mg) was added, and the mixture was heated to room temperature under a hydrogen atmosphere at room temperature. Stirred for hours. The insolubles were separated, and the resulting solution was concentrated under reduced pressure to obtain 124 mg of a colorless oily substance.
  • the compound (5) was eluted with a mixed solvent of the following solvent: 11.5 mg (yield 81%) as a colorless oil.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Nouveau dérivé de quinoléine utile pour le traitement des maladies en rapport avec la thromboxane T2 ou la leucotriène D4 et utile comme remède contre l'ictus cérébral, l'asthme bronchique ou les maladies allergiques. Ce nouveau dérivé de quinoléine présente une structure chimique caractéristique dans laquelle un groupe acide ou un dérivé d'un tel groupe est lié à un groupe benzofurane (ou phényle) comportant un groupe hétérocycle par l'intermédiaire de groupes de liaison constitués d'alkylène (soit -NHCO- soit -CONH-) de phénylène et d'alkylène.
PCT/JP1995/001998 1994-09-30 1995-09-29 Derive de quinoleine WO1996010569A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU35784/95A AU3578495A (en) 1994-09-30 1995-09-29 Quinoline derivative

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JP26115094 1994-09-30
JP6/261150 1994-09-30

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WO1996010569A1 true WO1996010569A1 (fr) 1996-04-11

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0799826A1 (fr) * 1996-04-02 1997-10-08 Kowa Co. Ltd. Dérivés de phenylene heteroaryle substitués, leur préparation et leur utilisation comme antagonistes de récépteur de leukotriène
WO2003016254A1 (fr) * 2001-08-09 2003-02-27 Ono Pharmaceutical Co., Ltd. Composes derives d'acide carboxylique et medicaments comprenant ces composes comme principe actif
EP1424101A3 (fr) * 2002-11-29 2004-08-18 NOZAKI, Masako Utilisation d'un antagoniste du leucotriène c4/d4 pour la préparation d'un médicament pour le traitement ou la prévention d'une inflammation ou septicémie du cerveau
JP2008515971A (ja) * 2004-10-12 2008-05-15 デコード ジェネティクス イーエイチエフ 閉塞性動脈疾患のためのスルホンアミドぺリ置換二環式化合物

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05345778A (ja) * 1991-10-24 1993-12-27 Lilly Ind Ltd 薬剤組成物

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05345778A (ja) * 1991-10-24 1993-12-27 Lilly Ind Ltd 薬剤組成物

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0799826A1 (fr) * 1996-04-02 1997-10-08 Kowa Co. Ltd. Dérivés de phenylene heteroaryle substitués, leur préparation et leur utilisation comme antagonistes de récépteur de leukotriène
US5885987A (en) * 1996-04-02 1999-03-23 Kowa Co., Ltd. Phenylene derivatives
US6011033A (en) * 1996-04-02 2000-01-04 Kowa Co., Ltd. Phenylene derivatives
WO2003016254A1 (fr) * 2001-08-09 2003-02-27 Ono Pharmaceutical Co., Ltd. Composes derives d'acide carboxylique et medicaments comprenant ces composes comme principe actif
RU2315746C2 (ru) * 2001-08-09 2008-01-27 Оно Фармасьютикал Ко., Лтд. Производные карбоновых кислот и фармацевтическое средство, содержащее их в качестве активного ингредиента
US7491748B2 (en) 2001-08-09 2009-02-17 Ono Pharmaceutical Co., Ltd. Carboxylic acid derivative compounds and drugs comprising these compounds as the active ingredient
US7786161B2 (en) 2001-08-09 2010-08-31 Ono Pharmaceutical Co., Ltd. Carboxylic acid derivatives and pharmaceutical agent comprising the same as active ingredient
EP1424101A3 (fr) * 2002-11-29 2004-08-18 NOZAKI, Masako Utilisation d'un antagoniste du leucotriène c4/d4 pour la préparation d'un médicament pour le traitement ou la prévention d'une inflammation ou septicémie du cerveau
JP2008515971A (ja) * 2004-10-12 2008-05-15 デコード ジェネティクス イーエイチエフ 閉塞性動脈疾患のためのスルホンアミドぺリ置換二環式化合物

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