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WO1996036608A1 - DERIVES DE CETONE α,β-INSATURES - Google Patents

DERIVES DE CETONE α,β-INSATURES Download PDF

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Publication number
WO1996036608A1
WO1996036608A1 PCT/JP1996/001330 JP9601330W WO9636608A1 WO 1996036608 A1 WO1996036608 A1 WO 1996036608A1 JP 9601330 W JP9601330 W JP 9601330W WO 9636608 A1 WO9636608 A1 WO 9636608A1
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Prior art keywords
group
substituent
atom
substituted
optionally
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English (en)
Japanese (ja)
Inventor
Masayuki Tanaka
Makoto Okita
Mitsuaki Miyamoto
Toshihiko Kaneko
Tetsuya Kawahara
Keishi Akamatsu
Kenichi Chiba
Hiroshi Obaishi
Hideki Sakurai
Shinya Abe
Seiichi Kobayashi
Takashi Yamanaka
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Eisai Co Ltd
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Eisai Co Ltd
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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
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a process for producing an ⁇ , 9-unsaturated ketone derivative having a novel structure, a medicament containing a,; 3-unsaturated ketone derivative, and a ⁇ -unsaturated ketone derivative. For useful intermediates.
  • IL-1 Kinyuichi Leukin 1
  • IL-1 is a bioactive protein produced from macrophages, monocytes, neutrophils, etc., and is involved in the maintenance of homeostasis in living organisms. Increased production induces abnormal immune responses and inflammatory reactions, which have a negative effect on living organisms.
  • IL-11 induces the production of collagenase and prostaglandin- 2 as well as various inflammatory cytokines and lymphokines, and is considered to be a central factor in inflammation and the immune system .
  • autoimmune diseases and inflammatory diseases represented by rheumatoid arthritis is becoming clear.
  • IL-1 was detected in synovial fluid from patients with rheumatoid arthritis and rheumatoid arthritis, and the IL-1 value in plasma from rheumatoid patients was lower than that in healthy human plasma.
  • the IL-11 level was significantly higher in comparison with the worsening and resolving symptoms, and the production of IL_1 from synovial tissue was dependent on the degree of inflammation of synovial tissue and bones of joints. Correlation with the degree of destruction has been found.
  • the present inventors have attempted to treat and prevent diseases such as autoimmune diseases such as rheumatoid arthritis and inflammatory diseases mainly by suppressing the production of IL-11. .
  • Rheumatoid arthritis is a chronic inflammatory disease of unknown cause, and non-steroid anti-inflammatory drugs and steroids are used as pharmacological treatments.
  • Non-steroidal anti-inflammatory drugs represented by indomethacin have an analgesic effect but do not show any improvement in the progression of the disease state, and also inhibit the production of 1L-1 Shina No.
  • Steroids on the other hand, have one of their pharmacological effects, which suppresses the production of inflammatory inflammation sites, such as IL-11, and has a strong anti-inflammatory effect.
  • the utility is not enough. Therefore, there has been a demand for the development of a drug which exerts an IL-11 production inhibitory effect and prevents and treats a condition mediated by IL-11.
  • the present inventors have conducted intensive studies on compounds having an inhibitory effect on the production of IL-1, and as a result, have found that the following cr, -unsaturated ketone derivatives have an excellent action. It was completed.
  • Japanese Unexamined Patent Publication (Kokai) No. 2-256565 discloses a group of compounds having an antagonistic effect on leukotriene D4 as quinoline derivatives. There are no examples reported, and the compound according to the present invention has a structure different from that of the compound disclosed in the above publication. Furthermore, in the publication of No. 073/0724, a nitrogen-containing heterocyclic compound having a phosphodiesterase inhibitory action is disclosed. -1 There is no description or suggestion that the compound has an inhibitory action on production, and the compound group disclosed in this publication has a different structure from the compound group of the present application.
  • the present invention relates to an ⁇ , ⁇ monounsaturated ketone derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof:
  • ring B represents an aromatic ring which may have a substituent.
  • R 2 has a hydrogen atom, a halogen atom, a lower alkyl group optionally substituted by a halogen atom, a cycloalkyl group optionally containing a hetero atom, and a substituent.
  • Aryl group, optionally substituted heteroaryl group, optionally substituted arylalkyl group, optionally substituted heteroaryl group A real alkyl group, a formula X— (wherein X is a group represented by the formula 10— or a formula
  • R represents a hydrogen atom, a lower alkyl group optionally substituted with a halogen atom, an alkoxyalkyl group, an optionally substituted aryl group, or an optionally substituted substituent It means a heteroaryl group, an arylalkyl group which may have a substituent or a heteroarylalkyl group which may have a substituent. ), An alkoxyalkyl group, an alkoxy bovine alkoxyalkyl group, or a mono- or di-substituted aminoalkyl group.
  • R 3 may have a hydrogen atom, a lower alkyl group optionally substituted with a halogen atom, a cycloalkyl group optionally containing a hetero atom, an alkoxyalkyl group, and a substituent.
  • Aryl group, heteroaryl group optionally having a substituent, arylalkyl group optionally having a substituent, aryloxyalkyl group optionally having a substituent, substitution A heteroarylalkyl group which may have a group, a heteroaryloxyalkyl group which may have a substituent, a carboxylalkyl group or an acyl group which may be protected. .
  • R 2 and R 3 together form a ring with the carbon atom to which R 2 and the group represented by the formula R 30- are bonded and the oxygen atom to which R 5 is bonded. Is also good.
  • the ring in addition to the nitrogen atom of oxygen atom to which R 3 is attached, the oxygen atom May include a sulfur atom or may have a substituent. ] Means the group selected from the group shown by these.
  • R 1 has the formula R 4
  • R 4 and R s are the same or different from each other, and may include a hydrogen atom, a lower alkyl group which may be substituted with a halogen atom, a hetero atom, a cycloalkyl group or a halogen atom.
  • R ⁇ 5 > represents a substituted or unsubstituted arylalkyl group or a substituted or unsubstituted heteroarylalkyl group. Together with the carbon atom to which they are bonded, they may form a ring which may further contain a nitrogen atom, an oxygen atom or a sulfur atom. May be.
  • R 6 is a hydrogen atom, a lower alkyl group which may be substituted with a halogen atom, a cycloalkyl group which may contain a hetero atom, an aryl group which may have a substituent, a substituent Teroa aryl group to which may have a which may have a substituent ⁇ Li Ruarukiru group, terrorism a Li one Ruarukiru group to which may have a substituent, wherein one OR 1 1 (
  • R 11 is a hydrogen atom, a lower alkyl group optionally substituted with a halogen atom, a cycloalkyl group optionally containing a hetero atom, a hydroxyalkyl group, a cyanoalkyl group.
  • R 12 R 13 may form a ring which may further contain a nitrogen atom, an oxygen atom or a sulfur atom together with the nitrogen atom to which they are bonded. Further, this ring may have a substituent. ), An aryl group which may have a substituent, a heteroaryl group which may have a substituent, and an arylalkyl which may have a substituent. A heteroarylalkyl group which may have a group or a substituent. ⁇ .
  • the aromatic ring which may have a substituent in the definition of B in the general formula (I), the aromatic ring means a 5- to 6-membered ring which may contain an oxygen atom, a sulfur atom or a nitrogen atom.
  • the aromatic ring may contain an oxygen atom, a sulfur atom or a nitrogen atom. The following can be mentioned, for example.
  • This platform, (e), is more preferred.
  • R 'R s R 9 and R' °, identical or different hydrogen atom, hydroxyl group, C b Gen atoms, c b Gen may be substituted with atoms lower alkyl group, substituted with C b Gen atoms Lower alkoxy groups, cycloalkyls that may contain heteroatoms, cycloalkyls that may contain heteroatoms, alkyl alkyl groups that may contain heteroatoms, and alcohol Groups, cyano groups, mecapto groups, and alkyl groups are replaced with halogen atoms
  • An alkylthio group which may be substituted, an alkyl rusulfinyl group wherein the alkyl may be substituted by a halogen atom, an alkylsulfonyl group wherein the alkyl may be substituted by a halogen atom, a substituent
  • An arylthio group which may have a substituent, an arylsulfur group which may have a substituent, an
  • ⁇ pigen atom in the definition of R 2 , R 7 , R S , R 9 , and R 10 means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, Means
  • R 2, R 3, R ⁇ are substituted with C b Gen atoms in R s, R 5, R 7 , R 8, R 3, R 1 0, R ".
  • R 1 2, R 1 3 and R 1 4 In the lower alkyl group which may be substituted, a lower alkyl group is a straight-chain or branched alkyl group having 1 to 8 carbon atoms, for example, a methyl group, an ethyl group, an n-propyl group, an i-alkyl group.
  • halogen atom means that one carbon atom of the above lower alkyl group has one halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Or a compound having two or more bonds, for example, a trifluoromethyl group, a 1,1-dichloromethyl group, a 2,2-dichloromethyl group, 1 , 2-cycloethyl group and the like.
  • a cycloalkyl optionally containing a heteroatom at R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R, R ′ °, R ′ ′′, R 12 and R 13 The group means a cyclic alkyl group having 3 to 8 carbon atoms, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cycloalkyl group. It means a octyl group and the like. Of these, preferred are those having 3 to 6 carbon atoms.
  • the cycloalkylalkyl group optionally containing a hetero atom means a lower alkyl group in which the above-mentioned cycloalkyl group is bonded to any carbon atom.
  • it means a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylethyl group, a cyclohexylpropyl group, a cycloheptylmethyl group, a cyclohexylmethyl group, and the like.
  • R 4 , R 5 , R ′, R 8 , R 9, and the lower alkoxy group which may be substituted with a halogen atom at 1 ° refer to a lower alkoxy group having 1 to 8 carbon atoms.
  • Direct or branched alkoxy groups such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, i- Butoxy, t-butoxy, n-pentyloxy, i-pentyloxy, neopentyloxy, 1-methylbutoxy, 2 — methyl butoxy group, 1,1 dimethyl oxypropoxy group, 1, 2 — dimethyl propoxy group, n —hexyloxy group, 1 — methyl pentyloxy group Group, 2—methylpentoxy group, 3—methylpentyloxy group, 1, 1—dimethylbutoxy group, 1, 2 — Dimethyl butoxy, 2, 2 — dimethyl Tilbutoxy, 1,3—
  • halogen atom means that one of the above-mentioned lower alkoxy groups has at least one halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Means two or more bonds, for example, a trifluoromethoxy group, a 1,1-dichloro ethoxy group, a 2,2-dichloro ethoxy group, 1, 2-dichloroethoxy group and the like.
  • the Shiano alkyl groups found in the R 1 1 definition is one which Xia amino group is bonded to any carbon atom of the lower alkyl group.
  • a hydroxyalkyl group defined in the definition of R 11 means a hydroxyl group bonded to any carbon atom of the above lower alkyl group.
  • the alkoxyalkyl group found in the definition of R 2 , R 3 , R 4 , R 5 , R 7 , R ′, R 9 , R ′ °, R ′′, and R ′′ is any of the above lower alkyl groups Means that a lower alkoxy group as defined above is bonded to the carbon atom.
  • alkoxy bovine alkoxy group '' defined in the definitions of R 7 , R 8 , R 9 and R 10 means that the above-mentioned lower alkoxy group is attached to any carbon atom of the above-mentioned lower alkoxy group. I do.
  • alkoxyalkyloxy as defined in the above definition means that the above-mentioned lower alkoxy group is bonded to any carbon atom of the alkoxy in the above-mentioned alkoxyalkyl group.
  • the acyl group found in the definitions of R 3 , R 7 , R 8 , R 9 , R ′ °, R 12 and R 13 is, for example, acetyl, propionyl, no, 'relyl, a Groups derived from aliphatic saturated monocarboxylic acids, such as sol- eryl, pivaloyl, lauroyl, and stearoyl; acryloyl, propioloinole, and metacryloinole. Groups derived from aliphatically unsaturated carboxylic acids, such as, benzoyl, isocrotonyl, oleoyl, benzoyl, etc.
  • One S— Groups derived from carbocyclic carboxylic acids such as naphthoyl, tonoleoil, hydroatroboyl, cinnamoyl, foil, tenol, nicotinol, and a Groups derived from heterocyclic carboxylic acids, such as sonicotinoyl, glycoroyles, lactoyl, glyceroinole, troboinole, benzyloyl, salicylo Examples include groups derived from hydroxycanolevonic acid and alkoxycarboxylic acid, such as inole, anisinole, parixyl, veratroinole, vironilole, and galloinole. However, preferably, acetyl, propionyl, vivalyl, benzoyl, toluoyl, glycoroyl, salicyloyl, nicotinoyl and the like are mentioned. Kill.
  • the term “carboxyalkyl” means a carboxyl group bonded to any one of the carbon atoms of the above lower alkyl group.
  • the protection of the carboxyl group in this case means a case where a lower alkyl group, an arylalkyl group or the like has an ester bond, or a case where an amide is formed. In short, anything that can be removed in vivo by a substituent to form a carboxyl group is included in the protection of the carboxyl group.
  • An optionally protected carboxyl alkenyl group defined in the definitions of R 7 , R 8 , R 9 and R ′ ° means a carboxy group bonded to any carbon atom of the alkenyl group. I do.
  • the alkenyl in this case means an alkenyl group having 2 to 8 carbon atoms and having one or more double bonds.
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R ′′, R 12 , R 13 , R ′ 4 may have a substituent.
  • An aryl group in a good aryl group means a phenyl group, a 1-naphthyl group, a 2_naphthyl group or an anthracenyl group, and preferably a phenyl group. Can be mentioned.
  • the heteroaryl group which may have a substituent in R 13 and R ′ 4, the heteroaryl group preferably contains 1 to 4 nitrogen, oxygen, or sulfur atoms.
  • a 5- or 6-membered ring or a condensed ring for example, a pyridyl group, a cyenyl group, a furyl group, a benzoimidazolyl group, a benzothiazolyl group or a quinolylisoquinolyl group. And preferably a pyridyl group.
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R, R ′ °, R ′ ′′, R 12 , R 13. , R ′ 4 may have a substituent.
  • aryl has the same meaning as the above aryl group
  • alkyl has the same meaning as the above lower alkyl group.
  • R 2 R 3, R ⁇ , R 5, R ⁇ , R 7, R 8, R 9, R l R ' ⁇ R l 2, R 13, Teroa Li to an optionally substituted in R 14
  • heteroaryl has the same meaning as the above heteroaryl group
  • alkyl has the same meaning as the above lower alkyl group.
  • R 7, R 8, R 9 and R ' In the aryloxy group which may have a substituent as defined in the above, the aryloxy group has the same meaning as the above aryl group.
  • arylalkyloxy group which may have a substituent as defined in the definitions of R 7 , R 8 , R 3 and R ′ °, arylalkyl has the same meaning as described above.
  • R 7 , R s , R 9 and R 1 ( a heteroarylalkyl group which may have a substituent as defined in the definition of 1 has the same meaning as the above. .
  • ⁇ Riruoki Shiarukiru group which may have a substituent which is in the definition of R 3, and ⁇ Li Lumpur, have the same meaning as above ⁇ Li Lumpur.
  • the alkyl in this case has the same meaning as the lower alkyl. That is, aryloxyalkyl means that aryloxy is bonded to any carbon atom of the above lower alkyl.
  • a Li Ruoki Shiaruki Le group to be substituted for in the definition of R 3 A Heteroa Li Lumpur, have the same meaning as te lower Li Lumpur to said - Further, this
  • base alkyl has the same meaning as the lower alkyl. That is, heteroaryloxyalkyl means that heteroaryloxy is bonded to any carbon atom of the above lower alkyl.
  • R 5 together with the carbon atoms to which they are attached, other nitrogen atom, Retribution C one A ring which may contain an oxygen atom or a sulfur atom may be formed. Further, this ring may have a substituent.
  • The, and R 5, a carbon atom bonded - cord to a connexion nitrogen atom means a 5-6 membered ring Rukamata does not contain an oxygen atom or a sulfur atom one or more And preferably a cyclohexane ring, a pyridin ring, a pyrrolidine ring, and a saturated pyridine ring.
  • R 12 and R 13 may be taken together with the nitrogen atom to which they are bonded to form a ring which may additionally contain a nitrogen, oxygen or sulfur atom. May have a substituent.
  • R 2 and R 3 together to form a ring together with the oxygen atom groups represented by R 2 and wherein R 3 0- is bonded carbon atoms and R 'are combined binding
  • This ring may contain a nitrogen atom, an oxygen atom or a sulfur atom in addition to the oxygen atom to which R 3 is bonded, or may have a substituent.
  • R 2 and R 3 taken together R 2 and R 3, as the R 2 carbon atoms to which they are attached constitute a carbon atom to which the oxygen atom and the oxygen atom R 3 is attached is sintered stand atoms inclusive This means that a ring may be formed. Further, the formed ring may or may not contain one or more oxygen, sulfur or nitrogen atoms in addition to the oxygen atom to which R 3 is bonded. Specific examples include the following.
  • alkyl is an alkyl sulfonyl group which may be substituted with a halogen atom, wherein alkyl is the lower alkyl It has the same meaning as the group.
  • alkylsulfinyl group which may be substituted with a halogen atom in the alkyl defined in the definitions of R 7 , R 8 , R 9 and R 10
  • the alkyl has the same meaning as the lower alkyl group described above.
  • “alkyl may be substituted with a halogen atom” means that a halogen atom as defined above may be bonded to any carbon atom of the alkyl.
  • a trifluoromethylsulfinyl group and a jib-opening methylsulfinyl group there can be mentioned a trifluoromethylsulfinyl group and a jib-opening methylsulfinyl group.
  • alkyl has the same meaning as the above lower alkyl group.
  • the expression "alkyl may be substituted with a halogen atom” means that a halogen atom as defined above may be bonded to any carbon atom of the alkyl.
  • a trifluoromethylthio group a dibutyl moethylthio group and the like.
  • R ′, R 8 , R 9 , R ′ ⁇ R 12 and R 13 which may have a substituent, in the arylsulfonyl group, aryl is the same as the above aryl group. It has meaning and preferably includes phenyl.
  • heteroaryl refers to the above heteroaryl. It has the same meaning as the group.
  • R 7, R 8, R 9 and R ' In the arylsulfinyl group which may have a substituent as defined in the above definition, aryl means R 7 , R s , R 9 having the same meaning as the above aryl group. And R '. In the heteroaryl sulfinyl group which may have a substituent as defined in the above definition, the heteroaryl has the same meaning as the above heteroaryl.
  • R 7, R s, R 9, R ' In the arylthio group optionally having a substituent and the heteroarylthio group optionally having a substituent, which are defined in the definition,
  • aryl and “heteroaryl” have the same meaning as defined above for the aryl group and the heteroaryl group.
  • R ' in mono Wakashi Ku is disubstituted by Itemoyoia Mi-alkyl groups found in the definitions of R 8, R 9, R 1 0 and R ", and the ⁇ Mi-alkyl, the lower Arukiru Further, the term "amino or di-substituted" means that the amino group is bonded to any one of the carbon atoms of the above. One or two substituents may or may not be bonded to the group.
  • the mono Wakashi Ku good mosquito Rubamo I le group which is disubstituted found in the definition of R 1 2 and R 1 3, the nitrogen atom constituting the force Rubamoi Le, 1 or 2 substituents Means that they may or may not be bonded.
  • the alkyl group is defined as a group in which the compound is bonded to any of the above carbon atoms of the lower alkyl. What you mean.
  • aryl group optionally having substituent (s) "heteroaryl group optionally having substituent (s)" " ,
  • arylalkyloxy group "Optionally substituted arylalkyloxy group”, “optionally substituted heteroarylalkyloxy group”, “mono- or di-substituted And mono- or di-substituted alkyl groups, and mono- or di-substituted aminoalkyl groups.
  • substituted means a hydroxyl group, a halogen atom, a lower alkyl group optionally substituted with a halogen atom, a lower alkoxy group optionally substituted with a halogen atom, a halogen atom.
  • alkylsulfonyl group which may be substituted with a halogen atom
  • an alkylsulfonyl group which may be substituted with a halogen atom
  • an arylthio group which may have a substituent
  • a group which has a substituent Good reel reel sulfonyl group Te ⁇ ⁇ Li Ruchio group to which may have a group, it may also have a substituent Iete Russia A Li Rusu sulfo group,
  • the protecting group means an alkyl group, an arylalkyl group and the like.
  • a mono- or di-substituted radical group "a mono- or di-substituted radical group”, and “mono- or di-substituted radical group”.
  • ⁇ amino alkyl group which may be substituted '', those which are di-substituted and which form a ring together with the nitrogen atom to which these substituents are bonded are also encompassed in the present invention.
  • This ring may have a substituent and may of course have an oxygen atom, a sulfur atom, and a nitrogen atom.
  • the pharmacologically acceptable salt is a conventional non-toxic salt, specifically, an alkali metal salt such as a sodium salt and a calcium salt, a calcium salt, and a magnesium salt.
  • Alkaline earth metal salts such as sodium salt, ammonium salt, trimethylamine salt, N, N '— organic base salts such as dibenzyldiethylenediamine salt, hydrochloride, hydrogen bromide
  • Inorganic acid salts such as acid salts, sulfates and phosphates, formates, acetates, trifluoroacetates, maleates, tartrates, methansulfonates, benzenesulfonates
  • organic acid salts such as toluene sulphonate; salts with amino acids such as arginine salts and orditin salts.
  • the compounds of the present invention can be easily produced by a commonly used method.
  • the following is an example of a method for producing the compounds of the present invention.
  • the compound represented by can be produced by the following method,
  • R 1 , R 2 , R 3 , R 7 , R 8 , R 9 and R 10 each have the meaning described above, and R ′ and R b each represent a lower alkyl group. And Z represents a halogen atom.
  • the aldehyde compound represented by the general formula (1) is added to the phosphane, phosphoric acid ester and phosphonium represented by the general formulas (2), (3) and (4), respectively. Any of the salts is reacted by a conventional method according to the Zittig reaction, or a methylketone compound represented by the general formula (5) is converted by a conventional method. Then, the desired compound (6) is obtained by reacting with an aldol reaction.
  • reaction solvent used in the reaction of the aldehyde compound (1) with phosphorane (2) examples include dichloromethane, benzene, tetrahydrofuran, And dimethoxetane.
  • the reaction temperature is appropriately selected from the range of 0 ° C. to the boiling point of the solvent.
  • the c aldehyde compound (1) and the phosphoric acid ester (3) or the phosphonium salt (4) The reaction with) gives favorable results when carried out in the presence of a base.
  • bases examples include sodium hydride, potassium hydride, sodium amide, Sodium methoxide, sodium ethoxide, potassium t-. Butoxytide, methyl lithium, n-butyl lithium, etc. Is mentioned.
  • the solvent examples include hydrocarbon-based organic solvents such as benzene, ether-based organic solvents such as tetrahydrofuran and dimethyl beef, dimethylformamide, and dimethylsulfoxide. I can give it.
  • the reaction temperature is in the range of about 178 ° C to the boiling point of the solvent, preferably in the range of about 120 ° C to room temperature.
  • Examples of the base used in the aldol reaction between the aldehyde compound (1) and the methylketone compound (5) include lithium hydroxide, sodium hydroxide, and the like. Hydroxic acid lime, sodium methoxide, calcium t-butoxide and the like can be mentioned.
  • reaction solvent examples include alcohols such as methanol and ethanol, tetrahydrofuran, water, and a mixed solvent thereof.
  • the reaction temperature is in the range of about 120 ° C. to the boiling point of the solvent, but is preferably in the range of about room temperature to about 60 ° C.
  • the target substance in which R 3 is a hydrogen atom that is, the compound (7) in which the 4-position of the bovine norrin ring is a hydroxyl group can also be produced by the following method.
  • R ′, R 2 , R ′, R s , R and R 11 have the above-mentioned meanings, respectively, and R 15 represents a hydroxyl-protecting group.
  • a compound represented by the general formula (9), in which a hydroxyl group is protected by an appropriate protecting group, is used as a starting material, and is deprotected by a conventional method to obtain a target substance (7).
  • the protecting group include a methoxymethyl group, an ethoxymethyl group, a methoxyethoxymethyl group, a benzyloxymethyl group, a phenyl-12-yl group, and a pyran-12- Examples thereof include a methyl group and a t-butyldimethylsilyl group, and the most preferred group includes a methoxymethyl group.
  • solvent for this reaction water or a solvent miscible with water, for example, ether organic solvents such as tetrahydrofuran and dioxane, methanol, and ethanol And alcohol-based organic solvents, such as acetonitrile and acetonitrile.
  • solvents that are immiscible with water for example, esters such as ethyl acetate, and aromatic hydrocarbons such as benzene and toluene can also be used.
  • acids as deprotecting agents are hydrochloric acid, sulfuric acid, methansulphonic acid, p-toluenesulphonic acid, D-10-camphorsulphonic acid Acid, acetic acid, trifluoroacetic acid and the like.
  • the base where the protecting group is t-butyldimethylsilyl group is used as a deprotecting agent.
  • Tetrabutylammonium fluoride can be used.
  • the reaction temperature is in the range of about 140 to the boiling point of the solvent, but is preferably in the range of about room temperature to the boiling point of the solvent.
  • R 3 is a group other than a hydrogen atom, an acyl group, an optionally substituted heteroaryl group and an optionally substituted aryl group.
  • the target substance can also be produced by the following method.
  • R 1 , R 2 , R 7 , R e , R 9, and R ′ ° each have the above-mentioned meaning
  • R 18 is a hydrogen atom, an acyl group from the definition of R s.
  • Hal means a halogen atom, except for a group, a heteroaryl group which may have a substituent and an aryl group which may have a substituent.
  • compounds represented by the general formula (7) in which R 3 is a hydrogen atom include, for example, sodium carbonate, aluminum carbonate such as sodium carbonate, sodium hydride, and the like.
  • R "-Hal is allowed to act to obtain the target compound (10) represented by the formula (10).
  • reaction solvent used examples include ketones such as acetone and methylethylketone, N, N-dimethylformamide, dimethylsulfoxide and the like. It is in the range of 40 ° C to the boiling point of the solvent, but preferably in the range of room temperature to the boiling point of the solvent.
  • the target substance in which R 3 is an acyl group that is, the compound (11) in which the 4-position of the quinoline ring is an acyloxy group can also be produced by the following method.
  • R 1 , R 2 , R 7 , R 8 , R 9, and R 1 each have the meaning described above, and R 17 represents an acyl group.
  • the compound represented by the general formula (7) in which R 3 is a hydrogen atom can be converted into a desired acid by a conventional method, for example, a reactive acid derivative such as a desired carboxylic acid, an acid halide, or an acid anhydride.
  • a reactive acid derivative such as a desired carboxylic acid, an acid halide, or an acid anhydride.
  • the reaction is carried out at a temperature in the range of about 0 ° C to the boiling point of the solvent in the presence of a silylating agent and a deoxidizing agent such as pyridine or tritylamine, and represented by the formula (11).
  • a silylating agent and a deoxidizing agent such as pyridine or tritylamine
  • reaction solvent examples include dichloromethan, curoform form, tetrahydrofuran, and the like.
  • the compound (14) wherein R 3 is a hydrogen atom and R 2 is an alkylsulfinyl group or a tautomer thereof (15) is
  • it can also be manufactured by the following method: 1 1 cow 1
  • R 1 , R 7 , R ′, R 9 , R ′, and R 15 each have the meaning described above, and R 1S represents an alkyl group.
  • a quinoline derivative represented by the general formula (12) and having an alkyne ruthio group at the 3-position is oxidized using an oxidizing agent such as hydrogen peroxide or m-cyclo ⁇ -perbenzoic acid.
  • an oxidizing agent such as hydrogen peroxide or m-cyclo ⁇ -perbenzoic acid.
  • a 3-alzylsulfinylquinoline derivative represented by the general formula (13) is obtained, which is then deprotected by a conventional method to obtain a target substance (14).
  • the solvent for the oxidation reaction is appropriately selected from water, dichloromethane, black form and the like.
  • Reaction temperature 20. It is in the range of C to the boiling point of the solvent, but preferably in the range of about 0 ° C to room temperature.
  • the obtained 3 -alkylsulfinylquinoline derivative (13) is treated in the same manner as in the production method B to treat the compound (9), whereby the target compound represented by the general formula ( The compound represented by 14) or the general formula (15) can be obtained.
  • the compound (17) or a tautomer (18) in which R 3 is a hydrogen atom and R 2 is an alkyl sulfo group is, for example, It can also be manufactured by a method.
  • R 1 , R 7 , R 8 , R 9 , R′R 15 and R ′′ each have the meaning described above.
  • a quinoline derivative represented by the general formula (12) and having an alkylthio group at the 3-position thereof is oxidized using an oxidizing agent such as an excess amount of hydrogen peroxide or m-c ⁇ ⁇ perbenzoic acid.
  • an oxidizing agent such as an excess amount of hydrogen peroxide or m-c ⁇ ⁇ perbenzoic acid.
  • a 3 -alkylsulfonylquinoline derivative represented by the general formula (16) is obtained, which is then deprotected by a conventional method to obtain a target substance (17).
  • the solvent for the oxidation reaction is appropriately selected from water, dichloromethane, black form and the like.
  • the reaction temperature is in the range of about ⁇ 20 ° C. to the boiling point of the solvent, preferably in the range of about 0 ° C. to room temperature.
  • the compound (6 ′) having A force ⁇ ( ⁇ ) or (t) can be produced by the following method.
  • R 1 , R 2 , R 7 , R 8 , R 9 , R 10 , R ′, R ”and ⁇ have the above-mentioned meanings, and ⁇ represents an oxygen atom or sulfur.
  • ⁇ represents an oxygen atom or sulfur.
  • an aldehyde compound represented by the general formula (1 ') is added to the aldehyde compound represented by the general formula (2), (3) and (4) in the same manner as in production method ⁇ .
  • the target compound (6,) can be obtained by reacting the methyl ketone compound represented by the following formula by an aldol reaction according to a conventional method.
  • the compound represented by the above general formula (1) or (1 ′), which is a starting material for producing the compound represented by the general formula (6) or (6 ′), is excellent as a pharmaceutical. It is extremely useful as an intermediate for producing the ⁇ , ⁇ monounsaturated ketone derivative of the present invention having an action.
  • the compound represented by the general formula (1) or (1 ′) can be easily produced by a generally used method. Next, an example of the manufacturing method will be described. As described above, a compound having a quinoline ring, in which the 4-position is a hydroxyl group, is in a tautomeric relationship with a 4-quinoline derivative. Preparation of starting materials 1
  • R S is a hydrogen atom, an acyl group or a heteroaryl group which may have a substituent.
  • a compound other than an aryl group which may have a substituent may be produced, for example, by the following method.
  • R 19 represents a lower alkyl group
  • R 2 ° is the same as above. From the definition of R 3 , it means a group excluding a hydrogen atom, an acyl group, an optionally substituted teraryl group and an optionally substituted aryl group.
  • the first step is to add 4-hydroxyquinoline _ 2-carboxylic ester derivative (19) or (20), for example, sodium carbonate, carbonated lithium.
  • Aruka and Li metal carbonates such as, by Al force Li metal salts, such as hydrogen kana Application Benefits ⁇ beam be present as a base, is reacted with Ha port Gen compound (R 2 ° -Hal), 4 -
  • Ha port Gen compound R 2 ° -Hal
  • 4 - This is a step of obtaining an alkoxyquinoline-2-ester carboxylate derivative (21).
  • the halogen atom in the halogen compound include a chlorine atom, a bromine atom, and an iodine atom.
  • the solvent examples include ketones such as acetone and methylethylketone, N, N-dimethylformamide, dimethylsulfoxide and the like.
  • the reaction temperature ranges from about ⁇ 40 to the boiling point of the solvent, preferably from about room temperature to the boiling point of the solvent.
  • the 4-alkoxyquinoline 12-carboxylic acid ester derivative (21) obtained in the previous step is reduced by a conventional method, for example, using diisobutylaluminum hydride.
  • 2-—Hydroxymethylquinoline derivative (22) is obtained.
  • solvents include dichloromethane, getylether, tetrahydrofuran, tonolenene and the like.
  • the reaction temperature is in the range of about 178 ° C to about 30 ° C, preferably in the range of about 178 ° C to about 0 ° C.
  • the desired quinoline 1-2-potassium represented by the general formula (23) is oxidized.
  • a sialaldehyde derivative is obtained.
  • the oxidizing agent include manganese dioxide, dimethyl sulfoxide and the like.
  • the reaction solvent include alcohols such as methanol and ethanol, aceton, ether, acetonitrile, benzene, dichloromethan, and cross-linked form. And ethyl acetate.
  • the reaction temperature is appropriately selected within the range of about 0 ° C. to the boiling point of the solvent.
  • the compound (21) is converted from the compound (21) to the compound (23) by using the 4-hydroxyquinoline-12-force sulfonic acid ester derivative (19) or (20). )) To give an aldehyde derivative represented by the general formula (26) or (27).
  • R 21 is an alkyl group or an aryl which may have a substituent.
  • R 21 is an alkyl group or an aryl which may have a substituent.
  • a 4-hydroxy-2-methyl quinoline derivative (28) or a tautomer thereof (29) is prepared by a conventional method, for example, bipyridine-triethylamine.
  • an acid acceptor such as an acid anhydride
  • a reactive acid derivative such as desired mosquitoes Rubo phosphate or Sanha androgenic compound, from 0 e C to the boiling point of the solvent
  • the solvent include dichloromethane, chloroform-form, N, N-dimethylformamide, tetrahydrofuran and the like.
  • the reaction can be performed without solvent
  • the 4 — acyloxy 2 — methylquinoline derivative (30) obtained in the previous step is oxidized by a conventional method, for example, using selenium dioxide to obtain the desired compound represented by the general formula (31) ) 2 — carboxy aldehyde derivative can be obtained.
  • Examples of the solvent used in this case include dioxane, toluene, and xylene.
  • the reaction temperature ranges from about 80 to the boiling point of the solvent.
  • R 3 may have a hydrogen atom, an acyl group or a substituent.
  • the compound which is a group other than an aryl group and an aryl group which may have a substituent can be produced, for example, by the following method.
  • R 2 , R 7 , R 11 , R 9 , R ′, and R 2 have the meanings described above, respectively, and Hal represents a halogen atom.
  • the 4-hydroxyquinoline-12-carboxy aldehyde derivative (26) or a tautomer thereof (27) is converted to the compound (21) of the production method 1 of the starting material.
  • the halogen compound R 2 ° -Hal By reacting with the halogen compound R 2 ° -Hal in the same manner as in the production, the desired 4 -alkoxyquinoline- 12 -carboxyaldehyde derivative (23) is obtained.
  • the 4-hydroxyhydroxylinoline—2-carboxysyl aldehyde derivative (26) or its tautomer (27) used as the starting material is It can also be manufactured by the following method.
  • the 4—hydroxyquinoline 2—carboxylate ester derivative (19) or its tautomer (20) used as a starting material is, for example, It can be manufactured by the following method. ( 34 )
  • R 2, R 7, R 8, R 9, R '° and R 1 S are each as defined before SL, respectively.
  • the aniline derivative represented by the general formula (33) is condensed by dehydration condensation with the oxaza-mouthed acetic acid diester derivative represented by the general formula (34).
  • the solvent include hydrocarbons such as cyclohexane, benzene, and toluene, and alcohols such as ethanol and propanol.
  • the reaction may be performed without a solvent.
  • the acid include hydrochloric acid, sulfuric acid, acetic acid, p-toluenesulfonic acid and the like.
  • the reaction temperature is in the range of about room temperature to the boiling point of the solvent, preferably in the range of about 80 ° C. to the boiling point of the solvent.
  • the condensate (35) obtained in the previous step is heated at a high temperature, preferably 200, without solvent or using a high boiling point solvent such as diphenyl ether. Heat at a temperature in the range of C to the boiling point of the solvent to allow intramolecular cyclization and the desired 4-hydroxyquinoline-12-carboxylate ester derivative (19) or its tautomerism This is the step of obtaining the body (20).
  • the 4-hydroxy 2-methyl quinoline derivative (28) or a tautomer thereof (29) used as a starting material can be produced, for example, by the following method. Can be manufactured.
  • R 2 , R 7 , R ?, R 9, and Rie each have the meaning described above, and R 22 represents a lower alkyl group.
  • the aniline derivative represented by the general formula (33) and the acetate acetate derivative represented by the general formula (36) are dehydrated in the same manner as in the production method 6 of the starting material.
  • the desired 4-hydroxy-2-methylthioquinoline derivative (28) or its tautomer (29) is obtained.
  • the compound in which R 2 is a halogen atom is produced, for example, by the following method. You can do that too.
  • R 7 , R 8 , R 9 , R ′, and R ′ 9 each have the meaning described above, and Hal represents a halogen atom.
  • 4-hydroxyhydroxyquinoline-2-carboxylate derivative (38) or (39) in which the 3-position is a hydrogen atom can be converted to chlorine, sulfuryl chloride, bromine, iodine monochloride.
  • a halogenating agent such as nitrogen
  • the desired 4-hydroxy-l-3logenoquinoline-l- 2-carboxylic acid ester derivative (40) or (41) is obtained. I can do it.
  • Acetic acid can be used as the solvent.
  • the reaction temperature is appropriately selected from about room temperature to the boiling point of the solvent.
  • a compound in which R s is a halogen atom is produced, for example, by the following method. You can also.
  • R 2 , R ′, R 9 , R 1C and R 18 each have the above-mentioned meaning, and Hal represents a halogen atom.
  • a 4-hydroxyhydroxyquinoline-2-ether ester derivative (42) or a tautomer thereof (43) in which the 6-position is a hydrogen atom is converted into a compound similar to the starting material production method 8
  • R 2 and R 19 have the above-mentioned meanings, respectively, and R 23 and R 2 ⁇ are the same or different from each other, and represent a lower alkyl group or an alkoxyalkyl group, respectively.
  • R 25 and R 25 are the same or different from each other, and each have a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group which may have a substituent, and a substituent.
  • R 25 and R ie are Together with the attached nitrogen atom, it forms a ring containing another oxygen, sulfur or nitrogen atom.
  • a quinoline-2-carboxylic acid ester derivative represented by the general formula (46) or a tautomer thereof (47) is converted to a chlorometer methyl ester by using chlorometer methyl ester.
  • the compound is treated in the same manner as in the production of the compound (21) of the production method 1 of the starting material. In this way, a 4-methoxyethoxyquinoline-12-potassium ester ester derivative (48) can be obtained.
  • the ester derivative (48) obtained in the previous step is treated with a conventional method, for example, using tetrafluoro n-butylammonium to remove the silyl group, and the 7- This is a process for obtaining a hydroquinone ester derivative (49).
  • Tetrahydrofuran can be mentioned as an example of the solvent.
  • the reaction temperature is in the range of about ⁇ 20 ° C. to the boiling point of the solvent, preferably in the range of about 0 ° C. to room temperature.
  • the obtained 7-hydroxyalkylquinoline 1-2-potassium ester ester derivative (49) was added to methyl chloride in a conventional manner in the presence of a deoxidizing agent such as tridiamine.
  • a deoxidizing agent such as tridiamine.
  • the compound is reacted with tansulfonyl and then reacted with the amine.
  • the desired 7-aminoaminoalkylquinoline-12-potassium ester derivative (50) or (51) can be obtained.
  • the solvent used in this case include tetrahydrofuran and N, N-dimethylformamide.
  • the reaction temperature is appropriately selected within a range from about 0 to the boiling point of the solvent. Production method for starting materials 1 1
  • the reduction stage material producing method 1 of the starting material (2 1) Chi sales of, the R 7, R 8, R 9 and R 10
  • An example of a specific production method for a compound that is a hydroxyalkyl group, an alkoxyalkyl group or an alkoxyalkoxyalkyl group, which is any of O96 / 36608, is as follows.
  • R 2 , R 1 ′ and R 2 ° have the same meanings as above, and R 28 is the same or different from each other and represents a hydrogen atom or a lower alkyl, respectively.
  • R 29 represents an alkyl group or an alkoxyalkyl group, Hal represents a halogen, and n represents an integer of 1 to 4.
  • a quinoline-2-ester dicarboxylic acid derivative represented by the general formula (52) is treated in the same manner as in the production of the compound (49) in the production method 10 of the starting material. This is the step of removing the silyl group to obtain a hydroxyalkyl bovine alkyllin derivative (53).
  • the obtained hydroxyquinoline derivative (53) was halogenated using an alkali metal hydride such as sodium hydride or potassium hydride as a base.
  • an alkali metal hydride such as sodium hydride or potassium hydride
  • the solvent used include N, N-dimethylformamide.
  • the reaction temperature is appropriately selected from the range of about 0 ° C. to the boiling point of the solvent.
  • R 2 and R 2 ° have the above-mentioned meanings respectively, Hal means a halogen atom, and R 3 ° means a lower alkyl group.
  • the first step is a step of synthesizing a silyl ether derivative (56) from a 2-hydroxymethylquinoline derivative represented by the general formula (55) by an ordinary method.
  • a silyl ether derivative (56) is obtained.
  • the silyl ether derivative (57) can be obtained.
  • silyl ester derivative (57) obtained in the previous step is treated in the same manner as in the production of the compound (49) in the production method 10 of the starting material, whereby The desired 2-hydroxymethylquinolinine derivative (58) can be obtained.
  • any of R 7 , R s , R 9, and R 10 of the compound represented by the general formula (22) is an alkoxycarbonylyl group.
  • Ru as der below 0
  • the alcohol beef sika rubonibine represented by the general formula (57) is used.
  • the quinolinine derivative is subjected to catalytic hydrogenation by a conventional method, for example, using palladium carbon, an alkoxycarbonyl benzoylquinoline derivative (59) can be obtained.
  • the reaction solvent include alcohols such as methanol and ethanol, ethyl acetate, and tetrahydrofuran.
  • the reaction temperature ranges from 0 ° C to room temperature. is there.
  • the alkoxycarbonyl benzoylquinoline derivative (59) obtained in the preceding step can be treated in the same manner as in the production of the compound (49) in the production method 10 of the starting substance.
  • — Hydroxyquinoline derivative (60) can be obtained.
  • R 2 , R 7 , R ′,, R ′ °, and R 19 each have the meaning described above, and R 3 ′ is an aryl which may have a substituent.
  • a 4-hydroxyhydrinoline-12-carboxylate ester derivative represented by the general formula (19) or a tautomer thereof (20) Can be obtained by a conventional method, for example, by heating and refluxing in an excess of oxine chloride without a solvent, to obtain a 4-cycloquinoline-12-monocarboxylic acid ester derivative ( This is the step of obtaining 1).
  • the first step comprises the following steps: the 4-chloroquinoline-2-2-carboxylate derivative (61) obtained in the preceding step and a phenyl compound which may have a substituent. Is heated at a temperature of 150 ° C. to 200 ° C. in the absence of a solvent to obtain the desired quinoline 1-2-potassium ester derivative (62). This is the step of obtaining.
  • R 2 is The compound which is a lucoxymethyl group or an alkoxyalkoxymethyl group can also be produced, for example, by the following method.
  • R 7 , R ′, R 9 and R ′ have the meanings described above, respectively, and R 32 represents an alkyl group, an alkoxyalkyl group, a cycloalkyl group, or a substituent.
  • a 3-hydroxymethylquinoline derivative (63) is used as a base with an alkali metal hydride such as sodium hydride or lithium hydride.
  • an alkali metal hydride such as sodium hydride or lithium hydride.
  • Te reacted Ha b gain down compound (R 32 -Hal), 3 - a Al breath caulking Chirukino to obtain a re-emission derivative (6 4).
  • solvents include .N, N-dimethylformamide.
  • the reaction temperature is in the range of from about 0 ° C to the boiling point position of the solvent, Ru is appropriately selected 0
  • the 3-alkoxymethylquinoline derivative (64) obtained in the preceding step is subjected to a demethoxymethylation reaction under acidic conditions to obtain the desired 4-hydroxy behic acid 3-alcohol.
  • This is a step for obtaining a xymethylquinoline derivative (65) or a tautomer thereof (66).
  • solvents are water and water-miscible solvents, for example tetrat-drofuran, methanol, ethanol, acetate and acetonitrile, Is mentioned.
  • a solvent immiscible with water for example, ethyl acetate can also be used.
  • acids include hydrochloric acid, sulfuric acid, methansulphonic acid, p-toluenesulphonic acid, D-10-camphorsulfonic acid, acetic acid, trifluroacetic acid.
  • the reaction temperature is in the range of about ⁇ 40 ° C. to the boiling point of the solvent, and preferably in the range of room temperature to the boiling point of the solvent.
  • R 2 is The compound that is silaminomethyl or sulfonylaminomethyl can also be produced, for example, by the following method.
  • R 33 may have a hydrogen atom, an alkyl group, or a substituent.
  • An aryl group, an arylalkyl group which may have a substituent, a heteroaryl group which may have a substituent, or may have a substituent R 3 ⁇ and R 35 represent an alkyl group, an aryl group which may have a substituent or a hetero group which may have a substituent, respectively.
  • a 3-hydroxymethylquinoline derivative (63) is reacted with lithium chloride and methanesulfonyl chloride in the presence of a base such as cholidine by a conventional method. Then, the hydroxyl group is converted into a chlorine atom, and then the obtained compound is reacted with amine to obtain a 3-aminomethylquinoline derivative (67).
  • a base such as cholidine
  • the solvent used in this case include N, N-dimethylformamide.
  • the reaction temperature is in the range from 140 ° C to the boiling point of the solvent, preferably in the range from 0 ° C to 50 ° C.
  • the 3-aminomethylquinoline derivative (67) obtained in the previous step is combined with a reactive acid derivative such as an acid anhydride and a haptic halide, or a halogenated sulfonate. , Trimethylamine N-methylmorpholine, etc., and reacts with the reaction mixture to give a 3 -acylaminomethyltylquinoline derivative (68) or 3 -sulfonylaminoline.
  • the quinolino derivative (69) is obtained.
  • the solvent include dichloromethane, tetrahydrofuran and N, N-dimethylformamide.
  • the reaction may be performed without a solvent.
  • the reaction temperature is in the range of ⁇ 40 ° C. to the boiling point of the solvent, preferably in the range of 0 to 50.
  • the starting material is prepared by using the 3-aminosulfonylamino derivative (68) or 3-sulfonylaminomethylquinoline derivative (69) obtained in the previous step.
  • the desired 4—hydroxyl3—acylaminomethyl quinoline derivative (70%) ) Or a tautomer thereof (72) or a 4-hydroxy-3-sulfonylaminomethyl quinolinine derivative (71) or a tautomer thereof (73) This is the process to obtain.
  • R 7 , R s , R 9, and R lc each have the meaning described above, and R 36 represents a lower alkenyl group.
  • the condensate (753) is obtained by dehydrating the aniline derivative represented by the general formula (33) and the malonic acid diester derivative represented by the general formula (74). ).
  • the solvent used in this case include cyclohexane, benzene, and toluene.
  • the reaction may be performed without a solvent.
  • acids include hydrochloric, sulfuric, and p-toluenesulfonic acids.
  • the reaction temperature is appropriately selected within the range from room temperature to the boiling point of the solvent.
  • ester derivative (78) obtained in the previous step can be converted to a lithium hydride using a conventional method, for example, using tetrahydrofuran or getyl ether as a solvent.
  • a conventional method for example, using tetrahydrofuran or getyl ether as a solvent.
  • the desired 3 -hydroxymethylquinoline derivative (63) can be obtained.
  • the compounds used as the starting material (3 3) of, R 7 and R '. Is a lower alkoxy group or an alkoxyoxy group, and R 9 is a lower alkyl group or an alkoxyalkyl group.
  • Specific examples of the production method are as follows. It is.
  • R 3 ′ and R 3a are the same or different and represent a lower alkyl group or an alkoxyalkyl group, respectively, and R 3 * is a hydrogen atom, a lower alkyl group or Hal means a halogen atom.
  • a nitric acid reagent such as nitric acid
  • the solvent include water, tetrahydrofuran, hexane, dichloromethane and acetic acid, and a mixed solvent thereof.
  • the reaction temperature is about 150.
  • the temperature is in the range of C to 50, preferably in the range of about ⁇ 20 ° C. to room temperature.
  • the 2-trobenzene derivative (80) obtained in the previous step is reacted with a methyl chloroformate according to a conventional method in the presence of a base such as tritylamine. Then, the obtained compound is reduced with sodium borohydride to convert the carbonyl group of the nitrobenzene derivative into a methylene group. In this way, a nitrobenzene derivative (81) obtained by reducing the carbonyl portion can be obtained.
  • the solvent used in the reaction with ethyl chloroformate include tetrahydrofuran, and the solvent used in the reduction with sodium borohydride may be used. Examples include water, methanol, ethanol and tetrahydrofuran, and mixed solvents thereof.
  • the reaction temperature is in the range of about 120 ° C to room temperature.
  • the nitrobenzene derivative (81) obtained in the previous step is treated according to a conventional method with lithium carbonate, sodium hydride and lithium hydride.
  • a good example of the solvent is N, N-dimethylformamide.
  • the reaction temperature ranges from about 0 ° C. to the boiling point of the solvent, preferably from about room temperature to the boiling point of the solvent.
  • dialkoxystrobenzen derivative (82) is subjected to catalytic hydrogenation using a catalyst such as palladium carbon or stannic chloride in a conventional manner. Treatment to reduce the nitro group and obtain the desired aniline.
  • the phosphorus derivative (83) is obtained.
  • the reaction solvent include alcohols such as methanol and ethanol, ethyl acetate and tetrahydrofuran.
  • the reaction temperature is in the range of 0 ° C to room temperature.
  • R 9 and R 1D are each a lower alkyl group
  • R 8 is a hydrogen atom
  • R 7 is a lower alcohol.
  • the nitrofynol derivative represented by the general formula (84) is used in the production method 18 of the starting material to produce the compounds (82) and (83) from the compound (81). By treating in the same manner, the desired aniline derivative (86) is obtained.
  • R 9 and R 1D are each a lower alkyl group
  • R 8 is a hydrogen atom
  • R 7 is a fluorine atom.
  • R 43 and R ′′ are the same or different from each other, and each represents a lower alkyl group.
  • a nitranilinine derivative represented by the general formula (87) is treated by a conventional method, for example, with sodium nitrite in concentrated hydrochloric acid to form a diazonium salt. Then, the obtained compound is treated with borofluoric acid to obtain diazonium borofluoride (88).
  • a fluoronitrobensen derivative (89) By pyrolyzing the obtained borohydride of diazonium (88), a fluoronitrobensen derivative (89) can be obtained.
  • the solvent used at that time include a high boiling point solvent such as xylene.
  • the reaction may be performed without a solvent.
  • the fluorinated benzene derivative (89) obtained in the preceding step is treated in the same manner as the compound (82) of the production method 18 of the starting material, whereby the desired fluorinated compound is obtained.
  • the lower linyline derivative (90) can be obtained.
  • the compound (33) used as the starting material In the method 6 for producing the starting material, the compound (33) used as the starting material, the compound (33) used as the starting material In the method for producing a compound in which R 9 is a carbamoyl group, R 7 and R 10 are the same or different from each other and are each a lower alkoxy group or an alkoxy alkoxy group, and R 8 is Taking a compound which is a hydrogen atom as an example, a specific method for producing the compound is as follows.
  • R 4 S and R ⁇ e are the same or different and are each a lower alkyl group or an alkoxyalkyl group, and Hal is a halogen atom.
  • R 47 and R 48 are The same or different from each other, means a hydrogen atom, a lower alkyl group, an aryl group which may have a substituent or a heteroaryl group which may have a substituent, Alternatively, together with the nitrogen atom to which R 47 and are attached, it meant that the oxygen atom, forms a ring containing a sulfur atom, a nitrogen atom c)
  • a benzaldehyde derivative represented by the general formula (91) is converted to a compound (80) in the same manner as in the production of the compound (80) and the compound (82) in the production method 18 of the starting material. In this order to obtain dialkoxytrobenzaldehyde derivatives (93).
  • dialkoxystrobenzaldehyde derivative (93) is oxidized by a conventional method, for example, using sodium hypochlorite, chromic acid or permanganate.
  • Benzoic acid derivative (94) can be obtained.
  • the reaction solvent water, dimethyl sulfoxide or the like is used, and the reaction temperature is in a range of 0 ° C to 50 ° C.
  • the dibenzobenzoic acid derivative (94) obtained in the previous step is converted into an acid halide using a conventional method, for example, using thionyl chloride.
  • a conventional method for example, using thionyl chloride.
  • a nitro benzoate amide derivative (95) can be obtained.
  • the reaction solvent used in this case include dichloromethane, tetrahydrofuran, getyl ether and ⁇ , ⁇ -dimethylformamide.
  • the reaction temperature is in the range of from 120 ° C to the boiling point of the solvent, preferably in the range of from 0 ° C to room temperature.
  • the nitr ⁇ -benzoic acid amide derivative (95) obtained in the preceding step is treated in the same manner as in the production of the compound (83) in the production method 18 of the starting material, This is the step of reducing the nitro group to obtain the desired aniline derivative (96).
  • One square In the method 6 for producing a starting material among the compounds (33) used as the starting material, among the compounds in which R 9 is a carbamoylalkyl group, R 7 and R 10 are the same or different from each other;
  • An example of a specific production method for a compound in which R 8 is a hydrogen atom, each of which is a lower alkoxy group or an alkoxy alkoxide group, and R 8 is a hydrogen atom is as follows.
  • the ditrobenzoaldehyde derivative represented by the general formula (93) is converted into a phosphate ester derivative (97), sodium hydride, lithium hydrogen hydride, and sodium hydroxide.
  • an amide compound (98) is obtained by reacting in the presence of a base such as toxide or potassium t-butoxide.
  • reaction solvents include tetrahydrofuran, N, N-dimethylformamide, and dimethoxetane, and the reaction temperature is in the range of 120 ° C to room temperature.
  • the amide derivative (98) obtained in the previous step is treated in the same manner as in the production of the compound (59) in the production method 13 of the starting material, to give the desired aniline. This is a step of obtaining a phosphorus derivative (99).
  • the aniline derivative (107) as a starting material is For example, it can be manufactured by the following method.
  • R 23 and R 2 ⁇ have the same meanings as above, R 49 represents a lower alkyl group, and Hal represents a halogen atom.
  • a nitrobenzene aldehyde derivative represented by the general formula (100) is converted to phospholane (101) and phosphate ester (l) by a conventional method.
  • the unsaturated ester derivative (104) is obtained by reacting the salt with a phosphonium salt (103) by a Wittig reaction.
  • solvents are dichloromethane, macroform, N, N-dimethylformamide, dimethoxetane, tetrahydrofuran and ethanol.
  • reaction temperature is in the range of about ⁇ 40 ° C. to the boiling point of the solvent, preferably in the range of about 0 ° C. to 50 ° C.
  • the unsaturated ester derivative (104) obtained in the previous step is reduced by a conventional method using a reducing agent such as diisobutylaluminum hydride to give an alcohol derivative.
  • a reducing agent such as diisobutylaluminum hydride
  • the solvent include dichloromethane, getyl ether, and tetrahydrofuran.
  • the reaction temperature is from ⁇ 78 to the boiling point of the solvent. It is appropriately selected within the range.
  • the alcohol derivative (105) obtained in the previous step is subjected to t-butylchlorodimethylsilylsilyl ester by a conventional method using imidazoletriethylamine or the like as a base.
  • R 7 and R ′ ° are different from each other. Identical or different, each is an alkoxy group or an alkoxyalkoxy group, and a compound in which R 8 is a hydrogen atom is described as an example. It is as follows.
  • the nitrogen aldehyde derivative represented by the general formula (93) is converted to sodium hydrogen hydride, aluminum lithium hydride, dihydrogen hydride by a conventional method.
  • This is a step of obtaining a nitrobyl alcohol derivative (108) by reacting with a reducing agent such as isobutyl aluminum.
  • a reducing agent such as isobutyl aluminum.
  • the reaction solvent include methanol, ethanol, getyl ether, tetrahydrofuran, and dichloromethane.
  • the reaction temperature is appropriately selected within a range from 178 to the boiling point of the solvent.
  • the 2-hydroxybenzyl alcohol derivative (108) obtained in the previous step was converted to an alkyl halide by the same method as in the production of the compound (64) in the production method 15 of the starting material.
  • a ditrobenzene derivative (109) can be obtained.
  • the two-necked benzene derivative (109) obtained in the preceding step is treated in the same manner as in the production of the compound (83) in the production method 18 of the starting material, whereby the desired aniline is obtained.
  • Derivative (110) can be obtained.
  • the compound represented by the general formula (1 ′) used as a starting material is produced, for example, by the following method.
  • the methyl group at the 2-position of the compound represented by the general formula (111) is converted in the same manner as in the formation of the compound (31) from the compound (30).
  • the desired compound (1 ′) can be obtained by conversion into a formyl group.
  • the compound (111) whose 2-position is a methyl group, which is used as a starting material can be produced, for example, by the following method.
  • a compound represented by the general formula (112) is heated in a conventional manner, for example, in acetic anhydride in the presence of sodium triethylamine acetate.
  • Ri and an object, a manufacturing method 2 7 c starting material compound No. 2-position is a methyl group and (1 1 1), can be easily obtained
  • R 2 , R 9 and R 1 ° are the same or different from each other, and
  • a specific example of a method for producing a compound in which R ′ is a hydrogen atom, R ′ is a lower alkoxy group or an alkoxyoxy group, and Y is an oxygen atom is a lower alkyl group. It is as follows.
  • An alkylated compound (117) can be obtained.
  • the halogen atom in the halogen compound used at this time include a chlorine atom, a bromine atom and an iodine atom.
  • solvents include acetate and N, N-dimethylformamide.
  • the reaction temperature is in the range of 0 ° C. to the boiling point of the solvent, preferably room temperature.
  • the resulting monoalkoxy benzene derivative (117) is reduced by a conventional method, for example, using zinc-amalgam or hydrazine, whereby the carbonyl group is converted to a methylene group.
  • a 2,3-dial bovine rufanol derivative (118) can be obtained.
  • the resulting 2,3-dialkylphenol conductor (118) was converted to chloromethyl teremate in the presence of a base such as hydrogenated sodium, N, N-diisoprovirethylamine.
  • the methoxyl methoxybenzene derivative (119) can be obtained by treating with nitrobenzene.
  • the obtained methoxymethoxybenzene derivative (119) is reacted with a strong base, for example, n-butyllithium, and then N, N-dimethylformamide is acted on the obtained compound.
  • a benzaldehyde derivative (120) can be obtained by using an ether such as ether or tetrahydrofuran as a solvent.
  • the reaction can be carried out at a temperature in the range of from 78 ° C. to 30 ° (:, preferably, from ⁇ 30 ° C. to room temperature).
  • the obtained benzaldehyde derivative (120) is reacted with an organometallic compound, and then the obtained alcohol is oxidized according to a conventional method. In this way, the ketone derivative (121) can be obtained.
  • organometallic compound include alkyl lithium (R 2 CH 2 Li) and a Grignard reagent (R 2 CH 2 Mg ⁇ Ha 1).
  • the solvent include ether and tetrahydrofuran.
  • the reaction temperature is in the range of 178 ° C to 50 ° C, preferably in the range of 178 ° C to room temperature.
  • Examples of the oxidizing agent used for oxidizing the obtained alcohol derivative include manganese dioxide, permanganate, cuprate, and dimethyl sulfoxide.
  • Examples of the reaction solvent include alcohols such as methanol and ethanol, acetone, dichloromethan, cross-hole form, ethyl acetate, pyridin and N , N-dimethylformamide.
  • the reaction temperature is appropriately selected within the range from ice cooling to the boiling point of the solvent.
  • the obtained ton derivative (122) is subjected to a deprotection treatment according to a conventional method, and the methoxymethyl group is converted to a hydroxyl group, whereby the desired ketone compound (122) is obtained.
  • the reaction solvent include water and a solvent miscible with water, for example, ethers such as tetrahydrofuran and dioxane, alcohols such as methanol and ethanol. And acetone.
  • Examples of acids as deprotecting agents include hydrochloric acid, sulfuric acid, methansulphonic acid, p-toluenesulphonic acid, D-10-camphorsulphonic acid, acetic acid and acetic acid. Trifluoroacetic acid.
  • the reaction temperature is in the range from 140 ° C. to the boiling point of the solvent, preferably from room temperature to the boiling point of the solvent.
  • IL-1 interleukin-1
  • test compound is dissolved in dimethyl sulfoxide, and the resulting dimethyl sulfoxide solution is dissolved in 10% so that the final concentration of dimethyl sulfoxide becomes 0.1%.
  • RPMI-164 culture medium 0.5 ml
  • lipopolysatride light was added to a final concentration of 10 ng / m1, and cultured at 37 ° C, 5% C02Z9 5% air for 18 hours.
  • the culture supernatant was filtered through a Millipore filter, and the obtained filtrate was used as a sample for extracellular IL-11 measurement.
  • a new culture solution (0.5 ml) is added to the adherent cells, the cells are disrupted by ultrasonication, the culture solution containing the obtained disrupted cells is passed through a miribofilter, and the obtained filtrate is filtered. It was used as a sample for measuring intracellular IL-1.
  • IL-11 ⁇ and IL-1 / 3 were quantified using a commercially available enzyme immunoassay (ELISA) kit (Cayman).
  • ELISA enzyme immunoassay
  • the potency of the test vehicle was expressed as 50 % IL-1 production inhibitory concentration (IC 50 , unit: ⁇ ).
  • 1,1-Dimethylpropargylamine is reacted with an appropriate acid chloride, a reactive acid derivative or a sulfonyl chloride compound, and the obtained compound is then reacted with (b) of Synthesis Example 2.
  • treatment with silver oxide and sulfuric acid gave the compounds listed in Table A.
  • the obtained mixture was stirred at 170 ° C for 1 hour, and thereto was added hexamyl triphosphate (32ral 178 mmol) and methyl iodide (9.5 ml 154 mmol) to obtain a mixture.
  • the resulting mixture was stirred for 1 hour.
  • a saturated aqueous solution of ammonium chloride was added to the reaction solution, and the resulting mixture was extracted with ethyl acetate.
  • the organic phase was washed with water and dried over anhydrous magnesium sulfate.
  • the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography chromatography (5% ethyl acetate Z hexane). In this way, the title compound (17.0 g, yield 92%) was obtained as a colorless oil.
  • i02-g02 f 'P) 66' L '(HI' ⁇ ? 8 + ⁇ ' ⁇ ) 6 ⁇ ' L '(HI' ZH6 f
  • ⁇ -NR 400MHz, CDC1 3 ) ⁇ ; 0.19 (s.6 ⁇ ), 1.01 (s.9 ⁇ ), 2.72 (s, 3 ⁇ ), 3.68 (s.3 ⁇ ).
  • the suspension was filtered, and the filtrate was dried over anhydrous magnesium sulfate.
  • the solvent was distilled off under reduced pressure to obtain yellow crystals (5.9 g).
  • the resulting crystals (2.9 g :), imidazole (1.0 g, 14.71) and t-butyldimethylchlorosilane (2.0 g, 13.3 mraol) N, N-dimethylforma
  • the mid (50ral) solution was stirred at room temperature for 3 hours. Water was added to the obtained reaction solution, and the obtained mixture was extracted with ethyl acetate. The organic phase was washed with water and dried over anhydrous magnesium sulfate.
  • the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography.
  • the organic phase was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the obtained residue was dissolved in tetrahydrofuran (25 ml), and morpholin (1.3 mU, 14.9 mmol) and a catalytic amount of tetraethylammonium iodide were added to the solution.
  • the mixture was heated and refluxed for 5.5 hours.
  • the reaction solution was filtered, the insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure.
  • the obtained residue was dissolved in N, N-dimethylformamide (lOral), and potassium carbonate (1.7 g, 12.3 mmol) and benzyl chloride were added to the solution under ice-cooling.
  • Example 126 When (d) of Example 126 was treated in the same manner as (c) and (d) of Example 120, the title compound was obtained as yellow crystals.
  • the reaction mixture was extracted with ethyl acetate.
  • the organic phase was washed with a saturated saline solution and dried over anhydrous magnesium sulfate.
  • the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography chromatography (70% ethyl acetatehexane). In this way, the title compound (0.3 g, yield 28%) was obtained as yellow crystals.

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Abstract

Cette invention concerne des dérivés de cétone α,β-insaturés ou des sels de ces dérivés acceptables sur le plan pharmacologique, les deux étant utiles en tant que médicament, lesquels dérivés correspondent à la formule générale (I), où, premièrement, la fraction de noyau A représente (a), (b), (c) ou (d) où B représente un noyau aromatique éventuellement substitué; R2 représente hydrogène, halogéno, alkyle inférieur éventuellement halogéné, etc.; et R3 représente hydrogène, alkyle inférieur éventuellement halogéné, cycloalkyle ayant éventuellement un ou plusieurs hétéroatomes, alcoxyalkyle, aryle éventuellement substitué, hétéroaryle éventuellement substitué, etc.; et où, deuxièmement, R1 représente un groupe correspondant à la formule suivante (II) dans laquelle R4 et R5 sont différents ou non et représentent chacun hydrogène, alkyle inférieur éventuellement halogéné, etc.; et R6 représente hydrogène, alkyle inférieur éventuellement halogéné, cycloalkyle ayant éventuellement un ou plusieurs hétéroatomes, aryle éventuellement substitué, hétéroaryle éventuellement substitué, etc.
PCT/JP1996/001330 1995-05-18 1996-05-20 DERIVES DE CETONE α,β-INSATURES Ceased WO1996036608A1 (fr)

Applications Claiming Priority (2)

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JP7/142394 1995-05-18
JP7142394A JPH08311032A (ja) 1995-05-18 1995-05-18 α，β−不飽和ケトン誘導体

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999025697A1 (fr) * 1997-11-19 1999-05-27 Kowa Co., Ltd. Nouveaux derives de pyridazine et medicaments contenant ces composes comme principe actif
US6313346B1 (en) * 1999-03-26 2001-11-06 Air Products And Chemicals, Inc. Catalyst compositions for the production of polyurethanes
WO2002083644A1 (fr) * 2001-04-12 2002-10-24 Meiji Seika Kaisha, Ltd. Derives de quinoline halogenes et agents d'elimination des ectoparasites
US6680282B2 (en) * 1997-06-02 2004-01-20 Meiji Seika Kaisha, Ltd. 4-Quinolinol derivatives and agrohorticultural bactericides containing the same as active ingredient
US6822098B2 (en) * 2000-08-29 2004-11-23 Yamanouchi Pharmaceutical Co., Ltd. Ester or amide derivatives
US7307089B2 (en) 2005-07-27 2007-12-11 Roche Palo Alto Llc Aryloxy quinolines and uses thereof

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7605289B2 (en) * 2005-06-17 2009-10-20 Amgen, Inc. Benzamide derivatives and uses related thereto
MX2010003449A (es) * 2007-09-26 2010-04-27 Astellas Pharma Inc Derivado de quinolona.

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4158663A (en) * 1977-07-15 1979-06-19 Warner-Lambert Company Process for the production of 2-substituted chromones
EP0017332B1 (fr) * 1979-03-20 1985-07-31 FISONS plc Composés hétérocycliques à activité pharmaceutique, procédés pour leur préparation et compositions les contenant
JPH02256665A (ja) * 1988-12-17 1990-10-17 Meiji Seika Kaisha Ltd ２，３―ジ置換―４―ヒドロキシキノリン誘導体及びその製法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4158663A (en) * 1977-07-15 1979-06-19 Warner-Lambert Company Process for the production of 2-substituted chromones
EP0017332B1 (fr) * 1979-03-20 1985-07-31 FISONS plc Composés hétérocycliques à activité pharmaceutique, procédés pour leur préparation et compositions les contenant
JPH02256665A (ja) * 1988-12-17 1990-10-17 Meiji Seika Kaisha Ltd ２，３―ジ置換―４―ヒドロキシキノリン誘導体及びその製法

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6680282B2 (en) * 1997-06-02 2004-01-20 Meiji Seika Kaisha, Ltd. 4-Quinolinol derivatives and agrohorticultural bactericides containing the same as active ingredient
US7067668B2 (en) 1997-06-02 2006-06-27 Meiji Seika Kaisha, Ltd. 4-quinolinol derivatives and fungicides containing the same as an active ingredient used for agriculture and horticulture
WO1999025697A1 (fr) * 1997-11-19 1999-05-27 Kowa Co., Ltd. Nouveaux derives de pyridazine et medicaments contenant ces composes comme principe actif
US6348468B1 (en) * 1997-11-19 2002-02-19 Kowa Co., Ltd. Pyridazine compounds and compositions containing the same
US6313346B1 (en) * 1999-03-26 2001-11-06 Air Products And Chemicals, Inc. Catalyst compositions for the production of polyurethanes
US6380274B1 (en) * 1999-03-26 2002-04-30 Air Products And Chemicals, Inc. Catalyst compositions for the production of polyurethanes
US6822098B2 (en) * 2000-08-29 2004-11-23 Yamanouchi Pharmaceutical Co., Ltd. Ester or amide derivatives
US7183412B2 (en) 2000-08-29 2007-02-27 Astellas Pharma Inc. Ester or amide derivatives
WO2002083644A1 (fr) * 2001-04-12 2002-10-24 Meiji Seika Kaisha, Ltd. Derives de quinoline halogenes et agents d'elimination des ectoparasites
US7022855B2 (en) 2001-04-12 2006-04-04 Meiji Seika Kaisha, Ltd. Halogen-substituted quinoline derivatives and ectoparasite control agent
CN1310889C (zh) * 2001-04-12 2007-04-18 明治制果株式会社 卤素取代的喹啉衍生物及外寄生虫防治剂
US7307089B2 (en) 2005-07-27 2007-12-11 Roche Palo Alto Llc Aryloxy quinolines and uses thereof

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