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WO2006033422A1 - Compose de quinolizinone et utilisation de celui-ci en tant qu'inhibiteur de l'integrase du vih - Google Patents

Compose de quinolizinone et utilisation de celui-ci en tant qu'inhibiteur de l'integrase du vih Download PDF

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Publication number
WO2006033422A1
WO2006033422A1 PCT/JP2005/017556 JP2005017556W WO2006033422A1 WO 2006033422 A1 WO2006033422 A1 WO 2006033422A1 JP 2005017556 W JP2005017556 W JP 2005017556W WO 2006033422 A1 WO2006033422 A1 WO 2006033422A1
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WIPO (PCT)
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group
oxo
chloro
fluorobenzyl
pharmaceutically acceptable
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PCT/JP2005/017556
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English (en)
Japanese (ja)
Inventor
Motohide Satoh
Hisateru Aramaki
Hiroshi Nakamura
Masafumi Inoue
Hiroshi Kawakami
Hisashi Shinkai
Yuji Matsuzaki
Kazunobu Yamataka
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Japan Tobacco Inc.
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Publication of WO2006033422A1 publication Critical patent/WO2006033422A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/02—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing not further condensed quinolizine ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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 novel quinolizinone compound or a pharmaceutically acceptable salt thereof useful as an anti-HIV agent.
  • the present invention also relates to a novel use of certain quinolizinone compounds or pharmaceutically acceptable salts thereof as anti-HIV agents. More particularly, the present invention relates to an anti-HIV agent comprising a quinolizinone compound or a pharmaceutically acceptable salt thereof that exhibits an anti-HIV action particularly by integrase inhibitory activity.
  • Retroimmunores HIV (Huma n Immu nodeficiency Virus (tye 1)) is a causative virus of AIDS (Acquired I mm unodeficiency Syndrome). is there.
  • HIV targets a group of CD4 positive cells, such as helper T cells, macrophages, and dendritic cells, and destroys these immunocompetent cells, causing immunodeficiency.
  • CD4 positive cells such as helper T cells, macrophages, and dendritic cells
  • a drug that eradicates HIV in vivo or suppresses its growth is effective for the treatment or prevention of AIDS.
  • protease inside and outside the shell.
  • DNA is transcribed by reverse transcriptase to produce full-length double-stranded DNA.
  • the DNA moves into the host cell nucleus and is integrated into the host cell DNA by integrase.
  • the incorporated DNA is converted into mRNA by the host cell polymerase, and various proteins necessary for virus formation are synthesized from the mRNA by HIV protease and the like, and finally virus particles are formed.
  • Liberate These virus-specific enzymes are essential for the growth of HIV, attracting attention as a target for the development of antiviral agents, and several anti-HIV agents have already been developed.
  • zidopsin, didanosine, lamivudine, and the like as reverse transcriptase inhibitors, and indinavir, nelfinavir, etc. have already been sold as protease inhibitors.
  • multi-drug combination therapy that uses these drugs in combination is also used, for example, 'dual transcriptase inhibitor (zidovudine and didanosine) in combination, reverse transcriptase inhibitor (zidopudine and lamivudine) and protease inhibitor ( Three-drug combination with nelfinavir has been used clinically, and these multiple-drug combination therapy has become the mainstream of AIDS treatment (for example, Guide 1 inesforthe U seof An tiretroviral A gentsin HIV— Infected Ad ultsand Ad olescents (See Au gst 1 3, 200 1.)
  • W02004 / 046 1 15 describes the following compound A and the like as an anti-HIV agent having integrase inhibitory activity (WO 2004/046 1 15 pamphlet (1 page 34, Example 1— 9 See 9).
  • Special Table 2004-502771 Patent Family: WO 2002/004445
  • compound B etc. as an antiviral agent, particularly a drug against hepes / lespes virus
  • the following compound C is disclosed as an intermediate (see JP 2004-502771 (page 85, Example 7).).
  • Special Table 2004-502770 Patent Family: WO 2002/004444
  • compound D as an antiviral agent, particularly a drug against herpes virus (special table) 2004-502770 (see page 57, formula AI .8)).
  • WO 2004/019933 also describes the following compound D and the like as a therapeutic agent for atherosclerosis and restenosis (see WQ 2004/019 933 pamphlet (page 64, compound (52)) )
  • WO 2003/029253 Patent Family: EP 1437354 describes the following compound E and the like as compounds having antibacterial activity (see WO2003 No. 029253 pamphlet (page 54, Example 1 19)). )
  • antibacterial agents having a cyclic substituent at the 8-position of the quinolizinone skeleton (for example, pyrrolidine-1-yl group) are commonly found, the antibacterial agents are the same as the quinolizinone compounds disclosed in the present specification. Have different chemical structures and uses.
  • Patent Family No. 1 EP 157346
  • JPB 6 49701 gazette (see pages 15-16, Example 3 (1), (4))).
  • WO 2000/17197 describes the following compound H, compound i and the like as anticancer agents having an integrin inhibitory action and angiogenesis inhibitors (WO200 0/17197 pamphlet (pages 71-74) See compound XIII, page 102, compound XL I).
  • anti-HIV agents are effective for the prevention and treatment of the onset of AIDS, and in particular, compounds having an integrase inhibitory action can be effective anti-HIV agents.
  • an object of the present invention is to provide a drug having an anti-HIV action, particularly a drug having an integrase inhibitory action.
  • the present invention is as follows.
  • An anti-HIV agent comprising a quinolizinone compound represented by the following general formula [I] or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group A (wherein the heterocyclic group is at least selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom) A saturated or unsaturated ring group containing one heteroatom)
  • a heterocyclic group which may be substituted with 1 to 5 substituents selected from Group A (the heterocyclic group is as defined above), a cyano group, One OR a4 , one SR a4 , one NR a4 R a5 ,
  • R a4, R a 5 ⁇ Pi R a 12 are the same or different Dzute, hydrogen atom, ⁇ one 4 alkyl group, substituted by 1 to 5 substituents selected from the group A Also good.
  • R a6 is , alkyl group, 1 to 5 substituents which may be substituted with a substituent C 3 _ 10 carbocyclic group selected from the above-mentioned group a, or is substituted by 1 to 5 substituents selected from the group a Is a good heterocyclic group (the heterocyclic group is as defined above), and W is a Ci- 10 alkylene group.
  • R 2 is a hydrogen atom or the same alkyl group
  • Z is C 1 R 31 or a nitrogen atom
  • R 31 is a hydrogen atom, a cyano group, a hydroxy group, an amino group, a nitro group, a halogen atom, a Ci-4 alkyl group, a Ci- 4 alkoxy group, a 4 alkylsulfanyl group, a haloalkyl group, Or a haloalkyloxy group.
  • X is C—R 32 or a nitrogen atom
  • Y is C 1 R 33 or a nitrogen atom.
  • R 32 and R 33 are the same or different and each represents a hydrogen atom, a cyano group, a nitro group, a halogen atom, A C 3 _ i 0 carbon ring group which may be substituted by 1 to 5 substituents selected from the group A;
  • a heterocyclic group which may be substituted with 1 to 5 substituents selected from Group A above (the heterocyclic group is as defined above);
  • R a 7 and R a 8 are the same or different and each represents a hydrogen atom, a group selected from the group B, or a halogen atom and 1 to 3 substituents selected from the group B.
  • a C _ 0 alkyl group which may be substituted by R a 9 is a C _ 4 alkynole group, R a 1 ⁇ 3 and R a 11 are the same or different and each represents a hydrogen atom or an alkyl group Yes.
  • Ring Cy has the formula:
  • R 6 is a group represented by a group selected from group A (group A is as defined in (1) above);
  • 1 4 and 15 are the same or different and each is a hydrogen atom and a group selected from group A (group A is as defined in (1) above),
  • n 0 or an integer from 1 to 3, and when m is 2 or 3, the R 6 s may be the same or different from each other.
  • the anti-HIV agent according to (1) above which is a group represented by: (4) A quinolizinone compound represented by the following general formula [II] or a pharmaceutically acceptable salt thereof.
  • R 6 is a group selected from Group A below.
  • Shiano group phenyl group, a nitro group, a halogen atom, ⁇ 4 alkyl group, 'halo C - 4 Arukinore group, halo C _ 4 Arukiruokishi group,
  • 31 and 1 32 are the same or different and are a hydrogen atom, a Ci-4 alkyl group, or a benzyl group, and R a3 is an alkyl group.
  • 1 4 and 1 5 are the same or different from each other, and are a hydrogen atom and a group selected from the above group A,
  • R 4 and R 5 may form a condensed ring together with the benzene ring they substitute,
  • each R 6 may be the same or different
  • Hydrogen atom A group selected from the following group B, or
  • Heterocyclic group optionally substituted by 1 to 5 substituents selected from Group A above
  • the heterocyclic group is a saturated or unsaturated ring group including at least one hetero atom selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom.
  • R A 4 , R a 5 and R a 12 are the same or different and each is substituted with a hydrogen atom, a di- 4 alkyl group, or 1 to 5 substituents selected from group A above. It's okay.
  • ⁇ R 2 is a hydrogen atom or an alkyl group,
  • Z is C—R 31 or a nitrogen atom
  • R 31 is preferably a hydrogen atom, Shiano group, hydroxy group, an amino group, a nitro group, a halogen atom, alkyl groups, C - 4 alkoxy groups, C Bok 4 alkylsulfanyl group, Haroji 4 alkyl group Or a non-alkyloxy group.
  • X is C 1 R 32 or a nitrogen atom
  • Y is C—R 33 or a nitrogen atom.
  • R 32 and R 33 are the same or different and each represents a hydrogen atom, a cyano group, a nitro group, a halogen atom,
  • a heterocyclic group which may be substituted with 1 to 5 substituents selected from Group A above (the heterocyclic group is as defined above);
  • C may be substituted with a halogen atom and 1 to 3 substituents selected from group B above.
  • 1 37 and 1 38 are the same or different and are each substituted with a hydrogen atom, a group selected from the above group B, or a halogen atom and 1 to 3 substituents selected from the above group B.
  • C ⁇ which is an alkyl group
  • R a9 is a C ⁇ 4 alkyl group
  • ! ⁇ and! ⁇ are the same or different and are a hydrogen atom or an alkyl group. . ⁇ ]
  • a heterocyclic group which may be substituted with 1 to 5 substituents selected from group A (the heterocyclic group and group A are as defined in (4) above);
  • R a 7 , R a8 , R a9 and R a10 are as defined in (4) above.
  • a heterocyclic group which may be substituted with 1 to 5 substituents selected from group A (the heterocyclic group and group A are as defined in (4) above);
  • Ci-ioalkyl group which may be substituted by a halogen atom and 1 to 3 substituents selected from group B (group B is as defined in (4) above),
  • a hydrogen atom, one OR a7 , or one NR a7 R a8 (R a7 and R a8 are as defined in (4) above.)
  • R a7 and R a8 may be the same or different and each may be substituted with 1 to 3 substituents selected from a halogen atom and gnoleop B.
  • Alkyl group (Group B is as defined in (4) above.)
  • the quinolizinone compound or a pharmaceutically acceptable salt thereof according to any one of (8) to (14) above.
  • R 4 and R 5 are the same or different
  • R a4 , R a5 , R a6 and R al2 are as defined in (4) above.
  • they may be substituted with 1 to 3 substituents selected from a halogen atom and group B Yes. 10 alkyl group (Group B is as defined in (4) above.)
  • R a4 , R a5 , R a 6 and R a 12 are as defined in (4) above.
  • R a4 , R a5 , R a 6 and R a 12 are as defined in (4) above.
  • R a 6 and R a 12 are as defined in (4) above.
  • 1 to 3 substituents selected from a haguchi atom and group B C- 10 alkyl group Group B is as defined in (4) above.
  • R 32 and R 33 are the same or different and are each a hydrogen atom or one OR a7 (R 37 is as defined in (4) above); ) As defined. ]
  • a pharmaceutical composition comprising the quinolizinone compound or a pharmaceutically acceptable salt thereof according to any one of (4) to (26) above and a pharmaceutically acceptable carrier.
  • An integrase inhibitor comprising the quinolizinone compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (26) as an active ingredient.
  • An antiviral agent comprising the quinolizinone compound according to any one of (4) to (26) above or a pharmaceutically acceptable salt thereof as an active ingredient.
  • An anti-HIV agent comprising, as an active ingredient, the quinolizinone compound according to any one of (4) to (26) or a pharmaceutically acceptable salt thereof.
  • An anti-HIV comprising the quinolizinone compound according to any one of (1) to (26) above or a pharmaceutically acceptable salt thereof and one or more other anti-HIV active substances as active ingredients. Composition.
  • (32) Contains a quinolizinone compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (26) above as an active ingredient for multi-drug combination therapy with other anti-HIV agents.
  • a method for inhibiting integrase in a mammal comprising administering an effective amount of the quinolizinone compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (26) above to the mammal. .
  • a method for treating a viral infection in a mammal comprising administering to the mammal an effective amount of the quinolizinone compound according to any one of (4) to (26) above or a pharmaceutically acceptable salt thereof. Prevention or treatment method.
  • An anti-HIV composition comprising the quinolizinone compound or a pharmaceutically acceptable salt thereof according to any one of (4) to (26) above, and a pharmaceutically acceptable carrier.
  • An integrase-inhibiting composition comprising the quinolizinone compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (26) above, and a pharmaceutically acceptable carrier.
  • An antiviral composition comprising the quinolizinone compound or a pharmaceutically acceptable salt thereof according to any one of (4) to (26) above, and a pharmaceutically acceptable carrier.
  • composition according to (40) above and the description relating to the composition, which can be used for or should be used for the prevention or treatment of HIV infection Including commercial package.
  • An anti-HIV agent comprising a combination of the quinolizinone compound according to any one of (1) to (26) or a pharmaceutically acceptable salt thereof and another antiviral agent.
  • the compound of the present invention can be an effective drug for the prevention or treatment of AIDS as an anti-HIV agent having HIV inhibitory activity.
  • it can be a more effective anti-HIV agent when used in combination with other anti-HIV agents such as protease inhibitors and reverse transcriptase inhibitors.
  • having high P and harmful activity specific to integrase can be a safe drug with few side effects on the human body.
  • halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom, a chlorine atom or a bromine atom.
  • group A are particularly preferably a fluorine atom and a chlorine atom
  • R 32 and R 5 are more preferably a chlorine atom
  • “. ⁇ 4 alkyl group” means a linear or branched alkyl group having 1 to 4 carbon atoms, specifically, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isopropyl group, sec One butyl group and tert-butyl group are exemplified.
  • RR 31 and R a 6 are preferably a methyl group, an ethyl group, a propyl group, an isopyl pill group, and a tert-butyl group, and R 4 , R 5 , R 6 , R 6 ′, R 6 ′ ′, R preferred examples 6 ''' ⁇ beauty group a, a methyl group, Echiru group and Isopuropiru group, more in preferably a methyl group, preferably a R al and R a2, methyl group, Echiru group, and propyl group
  • An isopropyl group, more preferably a methyl group, and R a 3 , R a 9 , R al () and R al 1 are preferably methyl groups, and R a4 , R a 5 and R al 2 Preferred are a methylol group, an ethyl group and a tert-butyl group.
  • Halo CI- 4 alkyl group 1 to 9, preferably 1 to 3 of "Ji 4 alkyl group” defined above which is substituted with "halogen atom” defined above.
  • R 31 , RR 5 , R 6 , R 6 ′, R 6 ′ ′, R 6 ′ ′ and Group A are preferably trifnoreo oral methyl / re groups.
  • the ". 4 alkoxy group", the alkyl moiety is a Arukiruokishi group is ". ⁇ 4 alkyl group” defined above, specifically, main butoxy group, an ethoxy group, propoxy group, Isopuropokishi group, a butoxy group Isobutoxy group, tert-butoxy group and the like.
  • R 31 is preferably a methoxy group. ". Alkylsulfur group” means that the alkyl moiety is as defined above.
  • alkylsulfanyl group specifically, a methylsulfuryl group, an ethylsulfanyl group, a propylsulfanyl group, an isopropylsulfanyl group, a butinoresulphal group, an isoptinoresnolevanore group, a tert- Examples thereof include butylsunophaninole group.
  • R 31 is preferably a methylsulfanyl group.
  • haloalkyloxy group is a halo C i- 4 alkyloxy group in which the haloalkyl moiety is the “halo C i- 4 alkyl group” defined above.
  • Carbocyclic group means a saturated or unsaturated cyclic hydrocarbon group having 3 to 10 carbon atoms, and means an aryl group, a cycloalkyl group, a cycloalkenyl group, or a condensed ring thereof. To do.
  • aryl group examples include a phenyl group, a naphthyl group, a pentarenyl group, an azulenyl group, and the like, preferably a phenyl group and a naphthyl group, and particularly preferably a phenyl group.
  • cycloalkyl group examples include a cyclopropyl group, a cycloptyl group, a cyclopentinole group, a cyclohexinole group, a cycloheptinole group, a cyclooctyl group, an adamantyl group, a norbornanyl group, and the like.
  • cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are examples.
  • the “cyclanol alkenyl group” includes at least one, preferably one or two double bonds, and specifically includes a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, a cyclopentaenyl group, a cyclo Hexenyl group, cyclohexadenyl group (2,4-cyclohexagen-1-inole group, 2,5-cyclohexagen-1-inole group, etc.), cycloheptenyl group, cyclootatul group, etc. .
  • ring in which these “aryl group”, “cycloalkyl group” and “cycloalkenyl group” are condensed include indul group, indanyl group, 1,4-dihydronaphthyl group, 1, 2, 3, 4- Examples include tetrahydronaphthyl group (1, 2, 3, 4-tetrahydro-2-naphthyl group, 5, 6, 7, 8-tetrahydro-2-naphthyl group, etc.) and perhydronaphthyl group.
  • C 0 carbon ring group optionally substituted by 1 to 5 substituents selected from group A means 1 to 5, preferably 1 to 3 substituents selected from group A below.
  • C 3 — carbocyclic group as defined above, which may be substituted by, and includes unsubstituted “C 3 — i. Carbocyclic group”.
  • one OR al include a hydroxy group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, and a tert-butoxy group.
  • one SR al include a mercapto group, a methylsulfanyl group, an ethylsulfanyl group, a propylsulfanyl group, an isopropylsulfanyl group, and a tert-pentylsulfanyl group.
  • one NR al R a2 include amino group, methylamino group, ethylamino group, propylamino group, isopropylamino group, tert-butylamino group, dimethylamino group, jetylamino group, N-ethyl-1-N— Examples thereof include a methylamino group, an N-methyl-1-N-propylamino group, an N-isopropyl-1-N-methylamino group, and an N-benzyl-1-N-methylolamino group.
  • ⁇ one CONR al R a2 '' include a strong rubamoyl group, a methylcanolamoyl group, an ethylcarbamoyl group, a propyl-powered rubamoyl group, an isopropyl-powered rubamoyl group, a tert-butylcarbamoyl group, a dimethylcarbamoyl group, Examples thereof include a jetylcarbamoyl group and an N-methyl-N-ethylcarbamoyl group. '
  • one S0 2 NR al R a2 include sulfamoyl group, methylsulfamoyl group, ethylsulfamoyl group, propylsulfamoyl group, isopropylsulfamoyl group, tert-butylsulfamoyl group, dimethylsulfamoyl group.
  • examples include a famoyl group, a cetinolesnoyl group, an N-methyl-N-ethylsulfamoinole group, and the like.
  • one COR a 3 include a acetyl group, a propiol group, a pentyl group, an isoptylinole group, and a 2,2-dimethylpropionino group.
  • One NR al COR a3 J includes, specifically, an acetylamino group, a propio- ⁇ / amino group, a butyrylamino group, an isoptylylamino group, a 2,2-dimethylpropionylamino group, an N-acetylethyl N-methylamino group. Etc.
  • one S0 2 R a3 include a methylsulfur group, an ethylsulfur group, a propylsulfonyl group, an isopropylsulfonyl group, and a tert-butylsulfonyl group.
  • One NR al S0 2 R a3 J includes, specifically, a methylsulfonylamino group, an ethylsulfo2 / reamino group, a propylsulfonylamino group, an isopropylsulfonylamino group, and a tert-butylsulfonylamino group. N-methyl-N- (methylsulfonyl) amino group and the like.
  • One COOR al J includes, specifically, a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a tert-butoxycarbonyl group, and the like.
  • one NR a 2 COOR a 3 include methoxycarbonylamino groups, ethoxycarboamino groups, propoxycarbolamamino groups, isopropoxycarbonylamino groups, tert-butoxycarbonylamino groups, etc. Is mentioned.
  • Gnolepe A is preferably a cyano group, a phenol group, an etro group, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, an isopropyl group, a trifluoromethyl group, a trifluoromethyloxy group, Hydroxy group, methoxy group, ethoxy group, propoxy group, methylsulfanyl group, amino group, methylamino group, ethylamino group, isopropylamino group, dimethylamino group, jetylamino group, N-ethyl-1-N-methylamino group, N-methyl-N —Propylamino group, N-isopropyl-1-N-methylamino group, N-benzyl-N-methylamino group, strong rubamoyl group, methylcarbamoyl group, dimethylcarbamoyl group, sulfam
  • group A particularly preferred are a cyano group, a phenyl group, a nitro group, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, a trifluoromethyl group, a trifluoromethyloxy group, a hydroxy group, a methoxy group, Ethoxy group, methylsulfanyl group, amino group, methylamino group, dimethylamino group, jetylamino group, N-ethyl-1-N-methylamino group, N-methyl-N-propynoleamino group, N-isopropyl-1-N-methylamino group, N-benzylthio group N-methylamino group, dimethylcarbamoyl group, methylsulfamoyl group, dimethylsulfamoyl group, acetylylamino group, N-acetylylamino group, N-acetylylamino group, N-
  • the number of substituents is preferably 1 to 3 , and when “C 3-10 carbocyclic group” is a phenyl group, ring C y is preferably 2-position mono-substituted or 3-position mono-substituted. 2, 3-position di-substitution, 2, 4-position di-substitution, 2, 5-position di-substitution, 2, 6-position di-substitution, 2, 3, 4-position tri-substitution, 2, 3, 5-position tri-substitution, 2, 3 , 6-position tri-substitution, particularly preferably the 2- and 3-position di-substitution.
  • C 3 — i 0 carbon ring group optionally substituted by 1 to 5 substituents selected from group A include phenyl group, naphthyl group, 2-fluorophenyl group,
  • the ring Cy is preferably a phenyl group, a naphthyl group, a 2-chlorophenyl group, a 3-monophenyl group, a 2-bromophenyl group, a 3-promophenyl group, or a 2-ethynenyl group.
  • a phenylol group More preferably, a phenylol group, a 2-chlorophenol group, a 2-promofur group, a 2-ethylphenyl group, a 2-hydroxyphenyl group, a 2-ethoxyphenyl group, a 2,3-diphenylorophenyl group.
  • R 1 and Group B are preferably phenyl group, 3,4-dichlorophenyl group, 2-biphenylinole group, cyclopropyl group, 2-hydroxycyclopropynole group, succinylbutynole group, 2-hydroxyxic group.
  • R a 4 , R a 5 and R al 2 are preferably phenyl groups, and R a 6 is preferably a phenol group.
  • R 3 2 and R 3 preferably, a cyclohexyl group phenyl group or cycloalkyl.
  • “Heterocyclic group” means a saturated or unsaturated group (partially including at least one selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms, preferably 1 to 4 heteroatoms).
  • a condensed ring group with a carbocycle is meant.
  • Heterocyclic group which is a saturated monocycle includes pyrrolidinyl group, tetrahydrofuryl group, tetrahydrochelinole group, imidazolidinino group, virazolidinino group, 1,3-dioxanolinole group, 1,3-oxathiolanyl Group, oxazolidinyl group, thiazolidinyl group, piperidinyl group, piperazinyl group, tetrahydrobiaryl group, tetrahydrothiobiranyl group, dioxanyl group, morpholinyl group, thiomorpholinyl group, 2-oxopyrrolidinyl group, 2-oxopiperidinyl group 4-oxopiperidyl group, 2,6-dioxopiperidinyl group, and the like.
  • Preferable are pyrrolidinyl group, piperidinyl group, morpholinyl group and tetrahydrobiranyl
  • Examples of the “unsaturated monocyclic heterocyclic group” include pyrrolyl group, furyl group, enyl group, imidazolinole group, 1,2-dihydro-2-oxoimidazolinole group, virazolinole group, oxazolyl group, isoxazolyl group , Thiazolyl group, isothiazolyl group, 1,2,4 monotriazolyl group, 1,2,3-triazolyl group, tetrazolyl group, 1,3,4-o Xadiazolyl group, 1,2,4-4-oxadiazolyl group, 1,3,4-thiadiazolyl group, 1,2,4-thiadiazolinole group, furazalu group, pyridinore group, pyrimidinyl group, 3,4-dihydro-4 monooxopyrimidinole group , Pyridazinyl group, pyrazinyl group, 1,3,5-triazinyl group, imidazoliny
  • heterocyclic group that is a condensed ring examples include an indolyl group (for example, 2-indolyl group, 3-indolyl group, 4-indolyl group, 7-indolyl group, etc.), isoindolyl group, 1,3-dihydro-1, 3-dioxoisoindolyl group, benzofuranyl group (for example, 2-benzofuranyl group, 4-benzofuranyl group, 7-benzofuranole group, etc.), indazolinole group, isobenzofuranyl group, benzothiofur Groups (for example, 2-benzothiophenyl group, 4-benzothiophenyl group, 7_benzothiophenyl group, etc.), benzoxazolyl group (for example, 2-benzoxazolyl group, 4-benzoxazolyl group, 7-benzoxazolyl group, 7-benzoxazolyl group, etc.), benzoxazoly
  • benzimidazolinore group for example, 2-benzimidazolyl group, 4-benzimidazolinore group, 7-benzui) Midazolinol group, etc.
  • benzothiazolyl group for example, 2-benzothiazolyl group, 4-benzothiazolyl group, 7-benzothiazolyl group, etc.
  • indolizinyl group quinolyl group, isoquinolyl group, 1,2-dihydro-2-oxoquinolyl group , Quinazolinyl group, quinoxalinyl group, cinnolinyl group, phthalazinyl group, quinolizinyl group, prill group, pteridinyl group, indolinyl group, isosodolenore group, 5, 6, 7, 8-tetrahydroquinolyl group, 1, 2, 3, 4— Tetrahydroquinolyl group, 2-oxo-1,2,3,4-te
  • it is a condensed ring of a monocyclic 5-membered or 6-membered heterocyclic ring and a benzene ring.
  • an indolyl group a benzofuranyl group, a benzothiophenyl group, a benzimidazolyl group, a benzoxazolyl Group, benzothiazolyl group and benzo [1,3] dioxolyl group.
  • heterocyclic group optionally substituted by 1 to 5 substituents selected from group A means 1 to 5, preferably 1 to 3 substituents selected from “group A” defined above. It is a “heterocyclic group” as defined above which may be substituted by and includes an unsubstituted “heterocyclic group”.
  • heterocyclic group is preferably a monocyclic heterocyclic group containing 1 or 2 heteroatoms, or a heterocyclic group which is a condensed ring of these with a benzene ring.
  • heterocyclic group optionally substituted by 1 to 5 substituents selected from group A include 1-pyrrolidinyl group, 2-pyrrolidinyl group, 3-pyrrolidyl group, and 1-piperidinyl group.
  • Ring Cy is preferably a 2-pyridyl group and a 4-monopyridyl group
  • R 1 and group B are preferably 1 imidazolyl group, 2-pyridyl group, 2-benzothiophenyl group, morpholino group, and 4-methylthiazole-5 1 f group.
  • R a4 , R a5 and R al2 are preferably a tetrahydropyran-1-2-nore group, and R a6 is preferably a morpholino group.
  • R 32 and R 33 are preferably one pyrrolidyl group.
  • Ci-alkyl group optionally substituted by 1 to 3 substituents selected from halogen atom and group B is selected from “halogen atom” defined above and “group B” defined below. Or a Ci 10 alkyl group which may be substituted by a group of substituents, or an unsubstituted alkyl group.
  • the alkyl moiety represents a linear or branched alkyl group having 1 to 10 carbon atoms, specifically, a methyl group, an ethyl group, a propyl group, an isopropinole group, a ptynole group, an isoptinole group, a sec-ptyl group, tert 1-butylene group, pentyl group, isopentyl group, 1-methylbutyl group, 1-ethylpropyl group, 2-ethylpropyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, tert 1-pentyl group, hexyl group, isohexyl group, 1-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylolbutyl group, 1,3-dimethylbutyl group, 1-ethylbutyl group, 1-ethynole group 1-methylpropyl group, 1-ethy
  • R a4 , 1 35 and 1 ⁇ 12 are the same or different and are each a hydrogen atom, “. ⁇ 4 alkyl group” as defined above, or “1 to 5 substitutions selected from group A as defined above”.
  • a carbocyclic group ”or a“ heterocyclic group optionally substituted by 1 to 5 substituents selected from group A ”as defined above, and R a 6 is The “definition alkyl group” as defined above, the “C 3 ⁇ 0 carbocyclic group optionally substituted by 1 to 5 substituents selected from group A” as defined above, or “selected from group A as defined above” is 1 to 5 substituents indicates heterocyclic group "may be substituted by a substituent, W is shown a C! _ 10 alkylene group.
  • alkylene group refers to a linear or branched alkylene group having 1 to 10 carbon atoms, specifically, a methylene group, an ethylene group, a trimethylene group, a tetramethylene group,
  • Preferred is a linear or branched alkylene group having 1 to 6 carbon atoms, and particularly preferred is a linear or branched alkylene group having 1 to 4 carbon atoms.
  • one OR a4 include a hydroxy group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a tert-butoxy group, and a tetrahydropyran-2-yloxy group.
  • one SR a4 include a mercapto group, a methylsulfanyl group, an ethenolesnorefaninore group, a propinolesnorefaninore group, an isopropinolesnorefa-nore group, and a tert-butylsulfanyl group.
  • one NR a4 R a5 include amino group, methylamino group, ethylamino group, propylamino group, isopropylamino group, tert-ptylamino group, dimethylamino group, jetylamino group, N-ethylyl N— Methylamino group, N-methyl- N-propylamino group, N-isopropyl mono-N-methylamino group, N-benzylu-N monomethylamino group and the like can be mentioned.
  • ⁇ one CONR a4 R a5 '' include strong rubermoyl group, methylca / levermoyl group, ethylcarbamoyl group, propyl-strength rubamoyl group, isopropyl-strength rubamoyl group, tert-butylcarbamoyl group, dimethinorecanolevermoyl Group, jetylcarbamoyl group, N-methyl-1-N-ethylcarbamoyl group, phenylcarbamoino group and the like.
  • one S0 2 NR a4 R a5 include sulfamoyl group, methylsulfamoyl group, ethylsulfamoyl group, propylsulfamoyl group, isopropylsulfamoyl group, tert-butylsulfamoyl group, dimethylsulfamoyl group.
  • examples include a famoyl group, a dimethylsulfamoyl group, and an N-methyl-1-N-ethylsulfamoyl group.
  • one COR a 6 includes a acetyl group, a propionyl group, a butyryl group, an isoptylyl group, and a 2,2-dimethylpropionyl group.
  • one NR a4 COR a6 include acetylamino groups, propionylamino groups, petitylamino groups, isoptylylamino groups, 2,2-dimethylpropionylamino groups, N-acetylene ⁇ / one N-methinoreamino groups A benzoinoreamino group, a monoreforino force ruponylamino group, and the like.
  • one S0 2 R a6 include a methylsulfonyl group, an ethylsulfonyl group, a propylsulphonyl group, an isopropylsulfonyl group, a tert-butylsulfonyl group, and the like.
  • one NR a4 S0 2 R a6 include a methylsulfonylamino group, an ethylsulfonylamino group, a propylsulfonylamino group, an isopropylsulfonylamino group, a tert-butylsulfo-lumino group, an N-methyl group N— (methylsulfoel) amino group and the like can be mentioned.
  • one COOR a4 include a carboxyl group, a methoxycarbon group, an ethoxycarbonyl group, a propoxy group, a non-oxy group, an isopropoxycarbonyl group, and a tert-butoxycarbonyl group.
  • Specific examples of ⁇ one NR a5 COOR a6 '' include methoxycanreponinoreamino group, ethoxycarbonylamino group, propoxycarbonylamino group, isopropoxycarbonylamino group, tert-butoxycarbonylamino group, N- (tert-ptoxycarbonyl) 1 N-methylamino group and the like can be mentioned.
  • Examples include 3-ethylureido group.
  • NR a4 CO—COOR a5 J is an oxalylamino group.
  • ⁇ 0—W—OR a 5 examples include a methoxymethoxy group.
  • one NR a4 —W—OR a5 specifically, a 2-hydroxyethylamino group
  • one NR a4 —W—SO 2 NR a5 R al2 J include (sulfamoylmethyl) amino group, N-methyl-1-N- (sulfamoylmethyl) amino group, and the like.
  • one NR a4 CO—W—R a5 include a phenylacetylamino group.
  • one NR a4 CO—W—OR a5 include 2-hydroxyacetylenoamino group, 2-methoxyacetylamino group, 2-ethoxyacetylamino group, 2-phenol.
  • Examples thereof include a nonoxycetylamino group, (R) -2-methoxypropionylamino group, (S) -2-methoxypropionylamino group, 2-methoxy-2-methylpropionylamino group, and the like.
  • one NR a4 CO—W—COOR a5 include 3-carboxypropionylamino group and the like.
  • NR a4 CO—W—NR a5 COR a6 J includes a 2-acetylaminoacetylamino group and the like.
  • alkyl group that may be substituted with 1 to 3 substituents selected from a halogen atom and a group B” include a methyl group, an ethyl group, a propyl group, isopropyl / le ⁇ , petitnore, Isoptenole, sec-butinole group, tert-butenole group, Pentyl group, isopentyl group, 1-methylbutyl group, 1-ethylpropyl group, 2-ethylpropyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, tert-pentyl group, hexyl group, isohexyl Group, 1-methylpentyl group, 1,1 dimethyl butyl group, 1,2-dimethyl butyl group, 1,3-dimethyl butyl group, 1-ethyl butyl group, 1-ethyl -1-methylpropyl group, 1 _ethyl
  • R 1 is preferably a methylol group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isoptyl group, a tert-butyl group, a 2-fluoroethyl group, a 2, 2, 2-trifluoroethyl group, a 2- Hydroxyethyl group, 2-hydroxypropyl group, 3-hydroxypropyl group, 4-hydroxybutyl group, 5-hydroxypentyl group, 2, 3-Dihydroxypropyl, 2-hydroxy-1-methylethyl, 2-hydroxy 1,1-dimethylethyl, 2-hydroxy-1- (hydroxymethyl) ethyl, 1- (hydroxymethyl) propyl, 2-hydroxy 1-methylpropyl group,
  • 2-hydroxy-1-monophenyl group 2-hydroxy-1-2-phenylethyl group, 11- (hydroxymethyl) 1-2-phenylethyl group, methoxymethyl group, 2-methoxy shetinol group, methylsulfanylmethinole group, 2- (methylsulfanyl) Ethyl group, 2-Aminoethynole group, 2- (Dimethylamino) ethyl group, Carboxymethyl group, 2-Carboxyethyl group, 3-Carboxypropyl group, (Canolemomoyl) methyl group, 2- (Strylamoyl) ethyl group, Methylcarbamoyl Methyl group, dimethylcarbamoylmethyl group, 2- (phenylcarbamoyl) ethyl group, 2-oxopropynole group, methylsulfonylmethyl group, 2- (methylsulfonyl) ethyl group
  • Particularly preferred is an alkyl group branched at the 1-position, and / or an alkyl group substituted with a hydroxy group.
  • these particularly preferred substituents are optically active substances, the S form is more preferred.
  • R 32 and R 33 are preferably a methyl group, an ethyl group or a trifluoromethyl group.
  • R a7 and R a8 are preferably a methyl group, an ethynole group, a propyl group, an isopropyl group, a 2-hydroxyethyl group, a 3-hydroxypropyl group, and a hexylmethyl group, and more preferably Are a methyl group, an ethyl group and an isopropyl group, and particularly preferably a methinore group.
  • fused rings connection formed such with a benzene ring means a condensed ring of a benzene ring, a C 3 _ 10 carbocyclic or heterocyclic ring.
  • C 3 -. I carbocycle and means a ring constituting the “C 3 _ 10 carbocyclic group” defined above.
  • Heterocycle means a ring constituting the “heterocyclic group” defined above.
  • condensed ring R 4 and R 5 are connection formed such with benzene ring, preferably benzene ring and C 3 one 6 cycloalk Cikarang or condensed with C 3 _ 6 consequent opening alkene, or benzene ring and a condensed ring with the heterocyclic 5- or 6-membered monocyclic, specifically, among those defined in the "C 3 _ 10 carbocyclic group” and "heterocyclic group” includes a benzene ring Examples thereof include a ring constituting a condensed ring group.
  • one OR a7 include a hydroxy group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a tert-butoxy group, a tetrahydropyran-2-yloxy group, and the like.
  • one SR a7 include a mercapto group, a methylsulfanyl group, an ethylsulfanyl group, a propylsulfanyl group, an isopropylsulfanyl group, and a tert-butylsulfanino group.
  • one NR a7 R a8 include amino group, methylamino group, ethylamino group, propylamino group, isopropylamino group, tert-butylamino group, dimethylamino group, jetylamino group, N-ethyl-1-N -Methylamino group, N-methyl-N-propylamino group, N-isopropylmono-N-methylamino group, N-benzyl-N-methylamino group and the like.
  • one NR a7 COR a9 include an acetylamino group, a propionylamino group, a petitylamino group, an isoptylylamino group, a 2,2-dimethylpropionylamino group, an N-acetylethyl-N-methylamino group, and the like. It is done.
  • one COOR al include a strong lpoxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a tert-butoxycarbonyl group, and the like.
  • one N CH- NR a l0 R al l J, specifically,. Aminomethylene amino group, dimethylcarbamoyl ⁇ / ⁇ amino methylene ⁇ amino group, and the like.
  • the quinolizinone compound represented by these is preferable.
  • Halogen atom as defined above
  • di- 4 alkyl group as defined above
  • halo Ci 4 alkyl group as defined above
  • Halogen atom defined above, "Ji 4 alkyl group” defined above, the above-defined “halo CI- 4 alkyl group”,
  • R 6 ', R 6 ''and R 6 ''' are a hydrogen atom and a substituent selected from the group AJ force defined above, and R 4 and R 5 are as defined above. It is a group represented by
  • R 4 and R 5 are the same or different, preferably
  • R 4 preferably
  • Halogen atom "Ji 4 alkyl group” defined above as defined above,
  • t R 5 which is a hydrogen atom and the above-defined “halogen atom”, preferably Hydrogen atom, cyano group, phenylol group, nitro group,
  • Halogen atom the above-defined “ ⁇ 4 alkyl group” defined above,
  • Hydrogen atom a "Ji 4 alkyl group” of the "halogen atom” and the definitions defined above, particularly preferably “halogen atom” of the hydrogen atom and the definition.
  • R 6 preferably
  • Halogen atom the above-defined “ ⁇ 4 alkyl group” defined above,
  • halogen atom as defined above.
  • m is preferably 0 or 1, and more preferably 0.
  • R 6 'and R 6 ''' are the same or different, preferably a hydrogen atom and the above-defined “halogen atom”.
  • R 6 '' is preferably a hydrogen atom, “halogen atom” as defined above, “alkyl group” as defined above, “one S0 2 R a3 ” as defined above, “—OR al ” as defined above and above a “one SR al” definitions, more preferably, a hydrogen atom, “Harogu emissions atom” defined above, a "one SR al” in “CI_ 4 alkyl group” and the above defined hereinbefore defined, preferably in Japanese Is a hydrogen atom.
  • R 1 is preferably
  • One OR a4 as defined above (here, specifically preferred is a methoxy group)
  • “One NR a4 R a5 ” as defined above here, specifically preferred is an amino group, methyla Mino group, ethylamino group and dimethylamino group.
  • One NR a4 COR a6 defined above (here, specifically, preferably an acetylamino group)
  • One NR a4 —W—OR aS defined above (specifically, preferably a 2-hydroxy shetylamino group and an N-methyl-N- (2-hydroxyethyl) amino group),
  • C — i which may be substituted by 1 to 3 substituents selected from the group consisting of halogen atom and group B” as defined above.
  • Alkyl group which may be substituted with 1 to 3 substituents selected from halogen atoms and group B” as defined above
  • C- 10 alkyl group optionally substituted by 1 to 3 substituents selected from the group C and group B” as defined above.
  • group B in the “dialkyl group which may be substituted with 1 to 3 substituents selected from a halogen atom and group B” is as follows:
  • R 2 is preferably a hydrogen atom.
  • X is preferably C 1 R 32 .
  • Y is preferably C—R 33 .
  • Z is preferably C 1 R 31 .
  • R 31 preferably
  • Hydrogen atom a Shiano group, a hydroxy group ⁇ Pi above defined "CI_ 4 alkoxy group j, particularly preferably a hydrogen atom.
  • R 32 preferably
  • Alkyl group substituted with 1 to 3 substituents selected from halogen atom and group B “One OR a7 ” defined above (specifically, preferably a methoxy group), “one SR a7 ” defined above, “one NR a7 R a8 ” defined above,
  • R 33 Preferably as R 33 ,
  • heterocyclic group J which may be substituted with 1 to 5 substituents selected from group A
  • Alkyl group which may be substituted with 1 to 3 substituents selected from halogen atom and group B” in the above definition
  • Alkyl group which may be substituted with 1 to 3 substituents selected from halogen atom and group B” in the above definition
  • R 32 and R 33 is preferably a hydrogen atom and the other is “one OR a7 ” as defined above.
  • R 31 is a hydrogen atom and R 32 or R 33 is other than a hydrogen atom.
  • R a7 and R a8 are the same as or different from each other, and preferably, “C 1 -i which may be substituted with 1 to 3 substituents selected from the group consisting of a nodogen atom and group B as defined above. It is.
  • the compound [II] is preferably represented by the following general formula [II-1] or [II-2]:
  • the compound represented by the general formula [I] or a pharmaceutically acceptable salt thereof is preferably 7-(3-Chloro-2-Funole-born Robenzinore) —4 1-oxo 4H-quinolidine 1 3 ethyl rubonate (Example 1),
  • “Pharmaceutically acceptable salts thereof” are those that form non-toxic salts with the compounds represented by the above general formulas [I], [II], [II-1] and [II-12]. Any salt can be used, for example, inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid; oxalic acid, malonic acid, succinic acid, fumaric acid, lactic acid, malic acid, cono, succinic acid, tartaric acid, acetic acid, trisulfreo Oral organic acids such as acetic acid, darconic acid, ascorbic acid, methylsulfonic acid, benzylsulfonic acid; inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, ammonium hydroxide; methylamamine, jetylamine, Triethylamine, triethanolamine, ethylenediamine, tris (hydroxymethyl) methylamine, guanidine, choline,
  • Bases; lysine, arginine, can be obtained by reacting with amino acids such as ⁇ La Nin.
  • hydrates or hydrates and solvates of each compound are also included.
  • various isomers exist.
  • E isomers and Z isomers exist as geometric isomers, and when an asymmetric carbon atom exists, enantiomers and diastereomers as stereoisomers based on these exist, and tautomers exist.
  • those isolated and purified from various isomers, by-products, metabolites, and prodrugs are preferred, those having a purity of 90% or more are preferred, and those having a purity of 95% or more are more preferred. That's right.
  • prodrugs and metabolites of each compound are also included.
  • a “prodrug” is a compound of the compound of the present invention that has a group that can be chemically or metabolically decomposed and is restored to the original compound after administration to a living body and exhibits the original drug efficacy. Includes unconventional complexes and salts. 'Prodrugs are used, for example, to improve absorption in oral administration or to target sites.
  • modified site examples include highly reactive functional groups such as a hydroxyl group, a carboxyl group, an amino group, and a thiol group in the compound of the present invention.
  • hydroxyl-modifying group examples include a acetyl group, propionyl group, isobutyryl group, pivaloyl group, benzoinole group, 4-methinolevenozonore group, dimethinorecanolevainole group, sulfo group and the like.
  • Specific examples of the modifying group for the carboxyl group include an ethyl group, a bivalyloxymethyl group, a 1- (acetyloxy) ethyl group, a 1- (ethoxy-stroxyloxy) ethyl group, and a 1- (cyclohexyloxycarbonyl group).
  • Xyl) ethyl group carboxymethyl group, (5-methyl-2-oxo-1,3-dioxol-41-inole) methyl group, phenolino group, o-tolyl group and the like.
  • amino group-modifying group include: a hexylcarbamoyl group, a 3-methylthio-1-1 (acetinoreamino) propylcarbonyl group, a 1-sulfo-1- (3-ethoxy-1-hydroxyphenyl) methyl group.
  • 5-Methyl-2-oxo-1,4-dioyl-4-yl methyl group and the like.
  • the compound of the present invention is administered to mammals (human, mouse, rat, hamster, usagi, cat, innu, ushi, hidge, monkey, etc.) as an anti-HIV agent, integrase inhibitor, antiviral agent, etc. be able to.
  • the compound of the present invention When used as a pharmaceutical preparation, it is usually a pharmaceutically acceptable carrier, excipient, diluent, extender, disintegrant, stabilizer, preservative, buffer, emulsifier, fragrance, coloring.
  • the dose varies depending on age, weight, symptoms, therapeutic effects, administration method, etc., but is usually in the range of 0.0 lmg to 1 g per adult, once to several times a day. It is administered orally or in the form of injections such as intravenous injection.
  • anti-HIV agents need not only to temporarily suppress virus growth but also to maintain their effects so that the virus does not grow again. Therefore, long-term administration is required, and in order to maintain the effect for a long time such as at night, it is often necessary to increase the dose at one time. These long-term 'high doses' increase the risk of side effects.
  • one preferred embodiment includes one that has high absorbability by oral administration, and one that maintains the blood concentration of the administered compound for a long time.
  • Prevention of AIDS means, for example, the administration of a drug to a person who has HIV detected by screening, etc. and has no symptoms of AIDS; For example, the drug should be given to people who have not been eradicated of HIV and are concerned about the recurrence of AIDS. The drug may be given before HIV infection because of the danger of infection.
  • anti-HIV agents and other anti-HIV active substances used in combination therapy include anti-HIV antibodies, HIV vaccines, immune enhancers such as interferon, HIV Pozymes, HIV antisense drugs, HIV reverse transcriptase inhibitors, HIV protease inhibitors, HIV integrase inhibitors, virus-recognized host cell binding receptors (CD4, CXCR4, CCR5, etc.) and virus binding Inhibitors and the like can be mentioned.
  • HIV reverse transcriptase inhibitors include retrovir (R) (zidovudine), epivir (R) (lamivudine), zerit (R) (sarubudine), videx (R) (didanocin), hibid (R) ) (Zarcitabine), Zyadiene (R) (Ababa sulfate building), Viramune (R) (Nevirapin), Stockrin (R) (Efavirenz), Rescripter (R) (Delavirdine mesylate), Combivir
  • HIV protease inhibitors include Crixiban (R) (Indinavir sulfate adduct), Saquinavir, Inbilase (R) (Saquinavir mesylate), Novia (R) (Ritonavir), Viracet (R) (Nelfinavir Mesilate) Mouth Pinavir, Prose (R) (Amprenavir), Kaletra (R) (Litonavi Nore + Mouth Pinabinole), also: mo zenavirdi me sylate (L4 R— (4 a, 5 a, 6)] — 1, 3—Bis [(3-Aminophenyl) methinole] Hexahi Draw 5, 6-Dihydroxy-1,4,7-Bis (Phenenolemethinore)-2H-1, 3-Diazepine 2—one dimethanesulphon
  • HIV integrase inhibitors S-1360, L-870810, etc., DNA polymerase inhibitor or DNA synthesis inhibitor, Phos force building (R), AC H-126443 (L-2,, 3, 1-dehydro- 1-dioxy-1-5-fluorocytidine), Yente force building ((1 S, 3 S, 4 S) —9— [4-Hydroxy-3 -— (hydroxymethylenole) 1 2-methylenesic pentinole] guanine), ca 1 ano 1 ide A ([1 OR- (10 a, 1 1/3, 12)] — 1 1,12-dihydro 12-hydroxy 1,6, 10, 10, 1 1-tetramethyl-4-propyl 2H, 6 H, 10H-Benzo [1, 2— b: 3, 4-b ': 5, 6-b''] tripyran mono-2-one), calanolide B, NSC— 674447 (1, 1' — Zobisformamide), Iscador (viseum al ubm extract),
  • Interferon or interferon agonist Sumiferon (R), Multi Ferron (R), Interferon, Reticulose, human leukocyte interferon ⁇ , etc., CCR5 antagonist, SCH-351125, HI Vp 24 GPG—NH2 (Glyciloop Lilyricinamide), etc., as an agent that acts on HIV, and FP—21399 (1,4-one bis [3 1, [(2,4-dichlorophenyl) carbonylamino] as an HIV fusion inhibitor 1 2-Oxo 5, 8 —Dinatriumsulfinole] Naphthyl 2,5—Dimethoxyphene 1,4-Dihydrazone), T—1249, Synthetic Poly meric Co nstruetion No 3, pentafuside, FP—21399, PRO—542, En f uv irtide, etc.
  • IL-2 as an agonist or antagonist, interleukin 1, imnes (R), pro 1 eukin (R), Mu 1 tikine (R), On tak (R), etc., as a TNF- ⁇ antagonist
  • Tha 1 omid (R) (salidomide), remicade (R) (infliximap), sulfated cardan, etc., as a darcosidase inhibitor, Bu cast (R), etc., as a purine nucleoside phosphorylase inhibitor, penoledesine (2-amino-4-oxo-3H, 5H-7-[(3-pyridyl) methyl] pyrophlo [3,2-d] pyrimidine), etc., as an apoptotic agonist or inhibitor, Arkin Z (R) , P ana V ir (R) , Co enz yme Q 10 (2-deca (3-methyl-1-2-buterene) -1,5,6-dimethoxy-1-methyl-
  • Re v Ml 0 gene HIV Specific cytotoxic T cells (CTL immunotherapy, ACTG protocol 080 treatment, CD4—gene therapy), SCA binding protein, RB C-CD 4 complex, Mo teafingadolini um, G EM— 92, CN I— 1493 , (Sat) One FTC, Us hercel 1, D2S, Buifer G e 1 (R), V iva G e 1 (R) s G 1 yminoxvaginalgel, Sodium lauryl sulfate, 2F5, 2 F 5 / 2G 12 VRX— 496 Ad 5 gag 2, BG-777, IG IV-C, BILR-255 and the like.
  • “Other anti-HIV agents” and “other anti-HIV active substances” used in combination therapy with the compound of the present invention are preferably HIV reverse transcriptase inhibitors and HIV protease inhibitors. . Two, three, or more drugs can be used in combination. At this time, a combination of drugs having different action mechanisms is one of the preferred embodiments. It is also preferable to select drugs that do not have side effects.
  • Specific drug combinations include efavirenz, tenobuvir, emtricitabine, indinavir, nelfinavir, atazanavir, ritonavir + indinavir, ritonavir + oral pinavir, ritonavir + saquinavir, didanosin + lamivudine, zidopsin + Didanocin, Zidovudine + Lamivudine, Stavudine + Lamivudine, Emtriva and the combination of this quinolizinone compound [I] (Guidelinesfor the Us eof An tiretroviral Ag entsin HI V— Infected Ad u 1 tsand Ad olescent s.
  • a protective group is introduced into the functional group as necessary, and then removed in a post-process.
  • the functional group is treated as a precursor in each process, and converted into a desired functional group at an appropriate stage. Efficient production should be carried out by changing the order of each manufacturing method and process. '' In each step, post-reaction treatment can be performed by the usual method, and isolation and purification can be performed by crystallization, recrystallization, distillation, liquid separation, silica gel chromatography, preparative HPLC as necessary. A commonly used method such as the above may be appropriately selected and combined.
  • Ha I 1 represents a halogen atom such as a bromine atom, an iodine atom, or a chlorine atom, where a bromine atom and an iodine atom are preferred, and R 2A is independently defined as above.
  • Compound [1] is mixed with a strong base such as n-butyllithium, lithium diisopropylamide, lithium hexamethinoresilazide, sodium hexamethinoresilazide, etc. in tetrahydrofuran solvent under argon or nitrogen atmosphere, at ambient temperature or at room temperature. Subsequently, the compound [3] can be obtained by reacting with the compound [2] under cooling to room temperature.
  • a strong base such as n-butyllithium, lithium diisopropylamide, lithium hexamethinoresilazide, sodium hexamethinoresilazide, etc.
  • the mixing of each compound is preferably carried out gradually by dropping the order or dropping it.
  • Compound [4] can be obtained by reacting compound [3] with heating in a solvent.
  • a high-boiling solvent such as diphenenoleethenore, a mixture of diphenenoleetenore and bifuenore, for example, Dow the rm A (registered trademark) or a mixed solvent thereof. Is preferred.
  • Compound [4] can also be obtained by heating and refluxing compound [3] in a toluene solvent.
  • Ha I 2 represents a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, where a fluorine atom and a chlorine atom (especially a fluorine atom) are preferred, and R ei is a hydrogen atom or an alkyl atom.
  • halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, where a fluorine atom and a chlorine atom (especially a fluorine atom) are preferred, and R ei is a hydrogen atom or an alkyl atom.
  • R ei is a hydrogen atom or an alkyl atom.
  • Compound [6] is mixed with a strong base such as n-butyllithium, lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, etc. in tetrahydrofuran solvent under argon or nitrogen atmosphere, under cooling to room temperature. Then, the compound [7] can be obtained by reacting with the compound [5] under cooling to room temperature.
  • a strong base such as n-butyllithium, lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, etc.
  • the compound [8] can be obtained by converting the cyan group of the compound [7] into a carboxylic acid or a carboxylic acid ester by a conventional method.
  • the compound [8] (where R C1 is derived from the above alcohol solvent). It is an alkyl group of.
  • Compound [9] can be obtained by reducing one C0 2 R C1 group of compound [8] by a conventional method.
  • Solvents include ether solvents such as 1,4-dioxane and tetrahydrofuran; alcohol solvents such as methanol and ethanol; halogen solvents such as dichloromethane and chloroform; hydrocarbon solvents such as benzene and toluene; Examples thereof include a mixed solvent thereof.
  • the compound [8] is a carboxylic acid compound
  • a chloroformate such as isoptilucoracic formate and isopropylchloroformate and compound [8] It is also possible to obtain a mixed compound [9] by reacting to form a mixed acid anhydride and then performing the above reaction.
  • Compound [10] can be obtained by oxidizing the hydroxyl group of compound [9] by a conventional method. For example, by using oxalyl chloride in dimethyl sulfoxide or a mixed solvent of dimethyl sulfoxide and dichloromethane and cooling to room temperature, and then adding a tertiary amine such as triethylamine, the compound [9 ] May be oxidized.
  • oxalyl chloride dicyclohexyl hexylcarbodiimide, acid anhydride, sulfur trioxide, chlorine, etc. may be used.
  • Compound [12] can be obtained by reacting compound [10] with compound [11] in the presence of a base or an acid in a solvent under heating.
  • bases include pyridine, piperidine, triethylamine, carbonated potassium, sodium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, and the like.
  • acids include acetic acid, hydrochloric acid, nitric acid, sulfuric acid, and the like. Is mentioned.
  • Solvents include alcohol solvents such as methanol, ethanol, n-propanol, and isopropanol; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane, chlorohonolem, carbon tetrachloride, 1,2-dichloroethane, and the like. Halogen solvents; ether solvents such as 1,4-dioxane, jetyl ether, 1,2-dimethoxyethane, tetrahydrofuran, or mixed solvents thereof may be used. When piperidine is used as the base, acetic acid may be added to accelerate the reaction. ⁇ 6th process>
  • the compound [13] can be obtained by reacting the compound [12] in the same manner as in the second step of production method 1-1.
  • Ha 1 is a halogen atom such as a chlorine atom or a bromine atom
  • one B (OR C2 ) (OR C3 ) is —B (OH) 2 , — B (OMe) 2 , one B (O i P ro) 2 , 4, 4,
  • the solvent include ether solvents such as 1,4-dioxane, 1,2-dimethoxyethane, and tetrahydrofuran; hydrocarbon solvents such as benzene, toluene, hexane, and xylene.
  • Second step> Compound [15] in a solvent, in the presence of a catalyst, optionally in the presence of a ligand such as triphenyl / lephosphine or tri (2-furyl) phosphine, in an argon or nitrogen atmosphere, cooled or heated
  • a ligand such as triphenyl / lephosphine or tri (2-furyl) phosphine
  • Catalysts include bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium, dichlorobis (triphenylphosphine) palladium, dichlorobis (benzonitrolinole) palladium, dichloroethylenediamminepalladium, palladium acetate, tetrakis (triphenylphosphine) Palladium catalyst such as palladium; nickel catalyst and the like.
  • solvent examples include ether solvents such as 1,4-dioxane, 1,2-dimethoxetane, and tetrahydrofuran; hydrocarbon solvents such as benzene, toluene, hexane, and xylene.
  • ether solvents such as 1,4-dioxane, 1,2-dimethoxetane, and tetrahydrofuran
  • hydrocarbon solvents such as benzene, toluene, hexane, and xylene.
  • Compound [17] can be obtained by reacting compound [16] with boric acid or a borate ester in the presence of a base and a catalyst in an argon or nitrogen atmosphere under heating.
  • boric acid esters examples include pinacol borane and bis (pinacolato) diboron.
  • Pd (PPh 3 ) 4 P dC 1 2 (dppb), P dC 1 2 (dppf), P d C 1 2 (dppf) CH 2 C 1 2 , P d C 1 2 (PP h 3 ) 2 , P d (OA c) 2 , P dC l 2 , palladium black, palladium catalyst such as palladium carbon, and the like.
  • Examples of the base usually include ethylenediamine, sodium carbonate, barium hydroxide, potassium phosphate, cesium carbonate, sodium bicarbonate, sodium tert-butoxide, potassium tert-butoxide, triethylamine, and potassium acetate.
  • the compound [16] may be reacted with a borate ester such as triisopropyl borate or trimethyl borate in the presence of n-butyl lithium.
  • Examples of the solvent include dimethyl sulfoxide, 1,4-dioxane, tetrahydrofuran, toluene, dimethoxetane, water and the like.
  • Compound [I-1] can be obtained by subjecting compound [17] and compound [18] to the Suzuki reaction.
  • a solvent such as dimethylformamide, acetonitrile, alcohol solvents (methanol, ethanol), DME, tetrahydrofuran, toluene, water, or a mixed solvent thereof, tetrakistrif earth nylphosphine palladium, dichlorobistriphenylphosphine palladium ( 1 1)
  • Palladium catalysts such as palladium acetate and triphenylphosphine
  • nickel catalysts such as sodium chloride, nickel chloride, 1,3-bis (diphenylphosphino) propanenickel (II), sodium carbonate, carbonic acid
  • a base such as potassium, hydrogen hydrogen carbonate, sodium hydrogen carbonate, potassium phosphate, triethylamine, fluoride fluoride, cesium fluoride, sodium hydrogen phosphate, cesium carbonate, etc.
  • Compound [I one 1] can be obtained.
  • the reactivity may be increased by adding salt, lithium or the
  • Compound [1-1] is hydrolyzed in a solvent at room temperature or under heating under basic conditions such as sodium hydroxide, hydrous hydroxide, lithium hydroxide, or acidic conditions such as hydrochloric acid or sulfuric acid.
  • basic conditions such as sodium hydroxide, hydrous hydroxide, lithium hydroxide, or acidic conditions such as hydrochloric acid or sulfuric acid.
  • Solvents include alcohol solvents such as methanol, ethanol, n-propanol, and isopropanol; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; 1,4-dioxane, jetyl ether, 1,2-dimethyl Examples include ether solvents such as toxetane and tetrahydrofuran; polar solvents such as dimethylformamide, dimethyl sulfoxide and acetonitrile; water or a mixed solvent thereof.
  • R P1 is a hydroxyl-protecting group, and other symbols are as described above.
  • Compound [19] can be obtained by introducing a protecting group into the hydroxyl group of compound [9] obtained in the same manner as in the third step of production method 1-2 by a conventional method.
  • Protecting groups for hydroxyl groups include: acetyl group, methoxycarbonyl group, methoxymethyl group, methoxyethoxymethyl group, trimethylsilyl group, tert-ptyldimethylsilyl group, tert-ptyldifursillinole group, tetrahydropyran —The Yil group.
  • R P1 is a tert-butyldimethylsilyl group
  • the compound [9] may be reacted with tert-butyldimethylsilyl chloride in the presence of imidazole in a dimethylformamide or toluene solvent at room temperature.
  • R P1 is a methoxycarbonyl group
  • the compound [9] may be reacted with chloromethyl carbonate in the presence of pyridine in a chloroform solvent at room temperature or at room temperature.
  • R P1 is a tetrahydropyran-2-inole group
  • the compound [9] may be reacted with dihydropyran in the presence of pyridinium p-toluenesulfonate in a chloroform solvent under cooling.
  • compound [9] may be allowed to react at room temperature by adding dimethoxymethane and ihyniline pentanoate under cooling in a chloroform solvent.
  • Production Method 1 13 Compound [15] obtained in the same manner as in Step 1 of Step 1 and Compound [19] are reacted in the same manner as in Production Method 1-3 of Step 2 to obtain Compound [20]. Can do.
  • Compound [21] can be obtained by removing the hydroxyl-protecting group of compound [20] by a conventional method and reacting in the same manner as in Step 4 of Production Method 1-2.
  • R P1 is a tert-butyldimethylsilyl group
  • the protecting group is removed by treatment with tetraptylmonium fluoride in a tetrahydrofuran solvent at room temperature, or at room temperature to warming.
  • a method such as treatment with acetic acid-water-tetrahydrofuran may be used.
  • Compound [1-1] can be obtained by reacting Compound [21] with Compound [11] in the same manner as in Production Process 1-2, Step 5. '
  • step 2 Production method 1 to obtain compound [22] by reacting compound [15] obtained in the same manner as in step 1 of 3 with compound [5] in the same manner as in production method 1-3, step 2 Can do.
  • the compound [24] can be obtained by converting the cyan group of the compound [23] into a formyl group by a conventional method.
  • reduction using a reducing agent such as diisoptylaluminum hydride catalytic reduction using hydrogen gas at room temperature to reflux temperature in the presence of a metal catalyst such as palladium carbon or raney nickel, etc.
  • a metal catalyst such as palladium carbon or raney nickel
  • compound [23] can be reacted by adding a metal catalyst such as Raney nickel and sodium phosphinate under cooling in an organic solvent such as a mixed solvent of pyridine, water, and acetic acid.
  • a metal catalyst such as Raney nickel and sodium phosphinate under cooling
  • an organic solvent such as a mixed solvent of pyridine, water, and acetic acid.
  • Step 4> 'Compound [1-1] can be obtained by reacting Compound [24] with Compound [11] in the same manner as in Step 5 of Production Method 1-2.
  • Compound [1-2] can be obtained by reacting compound [1-1] in the same manner as in Production Method 1-3, Step 5.
  • n 1 is an integer of 1 to 10, and each symbol is as described above.
  • the hydroxyl-protecting group R P1 may be removed by a conventional method at an appropriate time.
  • R P1 when R P1 is a tetrahydropyran-2-yl group, it may be removed by adding paratoluenesulfonic acid or hydrochloric acid in an alcohol solvent such as methanol or ethanol and reacting at room temperature or under heating conditions.
  • an alcohol solvent such as methanol or ethanol
  • Compound [26] can be obtained by reacting Compound [25] in the same manner as in Production Process 2, Step 1.
  • Compound [27] can be obtained by cyanating compound [26] by a conventional method.
  • compound [26] and a cyanide agent such as potassium cyanide and sodium cyanide under heating in a solvent such as acetonitrile, tetrahydrofuran, dimethylformamide, dimethylsulfoxide; or cyanotrimethylsilane and tetrabutylammonium fluoride
  • a solvent such as acetonitrile, tetrahydrofuran, dimethylformamide, dimethylsulfoxide; or cyanotrimethylsilane and tetrabutylammonium fluoride
  • n 2 and n 3 are each independently an integer of 1 or more, n 2 + n 3 is an integer of 2 to 10 and are represented by group A (benzyleno group) and group B (— (C n3 H 2n3 ) 1 OR pl ) are in opposite configurations to each other.
  • group A benzyleno group
  • group B — (C n3 H 2n3 ) 1 OR pl
  • the group A is up (in this case, the compound [29] is R )
  • other symbols are as described above.
  • Compound [29] is mixed with a strong base such as n-ptynolethium, lithium diisopropylpropyamide / lithium hexamethyldisilazide in tetrahydrofuran solvent under argon or nitrogen atmosphere and cooled to room temperature, and then cooled to Compound [30] can be obtained by reacting with compound [28] at room temperature.
  • a strong base such as n-ptynolethium, lithium diisopropylpropyamide / lithium hexamethyldisilazide
  • the mixing of each compound is preferably carried out gradually by cooling under cooling.
  • compounds [28] and [29] are prepared in ether solvents such as dioxane, tetrahydrofuran, etc .; in the presence of triethylamine and dimethylaminopyridine in the presence of triethylamine and dimethylaminoviridine in a solvent solvent such as dichloromethane and chloroform. You may make it react. ⁇ Second process>
  • Compound [32] can be obtained by reacting compound [30] with compound [31] in the presence of titanium tetrachloride and diisopropylethylamine in a solvent under cooling to room temperature.
  • the solvent examples include hydrocarbon solvents such as toluene and xylene; halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane.
  • hydrocarbon solvents such as toluene and xylene
  • halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane.
  • the hydroxyl-protecting group of the compound [32] can also be converted into a protecting group more suitable for the subsequent steps by a conventional method.
  • the compound [32] can be obtained by reducing the compound [32] with lithium aluminum hydride in a solvent under cooling to room temperature in an argon or nitrogen atmosphere.
  • the solvent examples include ether solvents such as dioxane and tetrahydrofuran; alcohol solvents such as methanol and ethanol; halogen solvents such as dichloromethane and chloroform; hydrocarbon solvents such as benzene and toluene or mixed solvents thereof. Can be mentioned.
  • Ha 1 1 is preferably bromine or iodine
  • compound [36] can be obtained by halogenating compound [35] by a conventional method.
  • compound [35] is reacted with a halogenating agent such as N-prosuccinimide and N-dosuccinimide in a solvent such as trifluoromethanesulfonic acid, acetic acid, concentrated sulfuric acid, dimethylformamide, or the like at room temperature or under heating.
  • a halogenating agent such as N-prosuccinimide and N-dosuccinimide
  • a solvent such as trifluoromethanesulfonic acid, acetic acid, concentrated sulfuric acid, dimethylformamide, or the like
  • R 1 ′ is C which may be substituted with a halogen atom and 1 to 3 substituents selected from the above-mentioned group B.
  • An alkyl group, and the other symbols are as described above.
  • Compound [22] can be obtained by reacting compound [5] with compound [15] in the same manner as in the second step of production method 1-13.
  • Compound [37] can be obtained by reacting compound [22] with acetonitrile in the same manner as in the first step of production method 1-2. Instead of acetonitrile, the reaction is carried out using NC—CH 2 —COOR a13 (R al3 is an alkyl group such as a methyl group, an ethyl group, or a tert-butyl group), and then
  • Compound [39] can be obtained by reacting compound [37] with compound [38] in a solvent in the presence of a base in the presence of a base.
  • Examples of the base include carbonated lithium, sodium carbonate, sodium hydroxide, hydroxylated lithium, and lithium hydroxide.
  • Solvents include alcohol solvents such as methanol ⁇ ⁇ , ethanol, ⁇ -propanol, and isopropanol; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane, carbon tetrachloride, 1,2-dichloroethane Halogen solvents such as 1, 4-dioxane, jetinolele ether, 1,2-dimethoxyethane, tetrahydrofuran, etc. ether solvents; dimethylformamide, dimethyl sulfoxide, acetonitrile etc. polar solvents; water or their A mixed solvent etc. are mentioned.
  • alcohol solvents such as methanol ⁇ ⁇ , ethanol, ⁇ -propanol, and isopropanol
  • hydrocarbon solvents such as benzene, toluene, hexane, and xylene
  • Compound [40] can be obtained by reacting compound [39] in the same manner as in Step 3 of production method 3-1.
  • Compound [1-3] can be obtained by reacting compound [40] with compound [1 1] in the same manner as in Production Process 1-2, Step 5.
  • Compound [1-4] can be obtained by reacting compound [1-3] in the same manner as in Production Process 1-3, Step 5.
  • n4 is an integer of 1 to 10, and the other symbols are as described above.
  • Compound [1-5] obtained by the above production method is replaced with 1,4-dioxane, tetrahydrofuran, etc.
  • the compound [1-6] can be obtained by reacting with a compound [41] in the presence of triethylamine and diphenylphosphoryl azide in a solvent such as a hydrocarbon solvent such as toluene or xylene. it can.
  • Compound [42] can also be obtained by isolation during the reaction.
  • R C4 is an alkyl group such as a methyl group, an ethyl group, or a tert-butyl group (preferably a tert-petitanol group), and one COR C5 group is an acetinole group, a trifnoreo methylcarbonyl group, This is an acyl group that can be removed from a hydroxyl group such as benzoyl, and other symbols are as described above.
  • Compound [1-7] can be obtained by reacting compound [1-6] in the same manner as in Production Method 1-13, Step 5.
  • Second step> Compound [1-8] can be obtained by treating compound [1-7] by a conventional method.
  • R a ⁇ Stert-butyl group it is treated with trifluoroacetic acid at room temperature; treated at room temperature with ethyl acetate or methanol solution, with hydrogen chloride monoacetate solution; at room temperature in tetrahydrofuran, Treatment with hydrochloric acid; treatment at room temperature with methanol dichloride in methanol can be used.
  • Compound [I I 9] can be obtained by reacting compound [1-6] in the same manner as in Step 2 of production method 6-2.
  • Compound [45] can be obtained by reacting Compound [1-9] with Compound [43] and Compound [44] in a solvent such as toluene at room temperature or under heating. '' ⁇ 5th process>
  • Compound [1-10] can be obtained by reacting Compound [45] in the same manner as in Production Method 1-13, Step 5.
  • R P2 is a hydroxyl-protecting group
  • R al4 is _W—OR a 5 or one R a 4 , and other symbols are as described above.
  • Compound [47] is obtained by reacting Compound [5] with Compound [46] using a Darrieard reagent such as isopropylmagnesium chloride in an atmosphere of argon or nitrogen, in a solvent, cooled to room temperature, and the like. be able to.
  • a Darrieard reagent such as isopropylmagnesium chloride in an atmosphere of argon or nitrogen, in a solvent, cooled to room temperature, and the like. be able to.
  • solvent examples include ether solvents such as 1,4-dioxane, 1,2-dimethoxetane, and tetrahydrofuran; hydrocarbon solvents such as benzene, toluene, hexane, and xylene.
  • ether solvents such as 1,4-dioxane, 1,2-dimethoxetane, and tetrahydrofuran
  • hydrocarbon solvents such as benzene, toluene, hexane, and xylene.
  • Compound [47] in a solvent, a tertiary amine such as triethylamine, disopropylethylamine, N-methylmorpholine, carbonated lithium carbonate, inorganic base such as sodium carbonate, etc.
  • Compound [49] can be obtained by reacting with compound [48] under heating in the presence of.
  • Solvents include: halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, and tetrachloroethylene; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; 1,4-dioxane, jetyl ether 1, 2-dimethoxyxane.
  • Ether solvents such as tetrahydrofuran; polar solvents such as dimethylformamide, dimethyl sulfoxide, acetonitrile, and aceton.
  • Compound [50] can be obtained by reacting compound [49] with compound [15] in the same manner as in production method 1-13, second step.
  • the compound [51] can be obtained by removing the hydroxyl-protecting group R p 2 of the compound [50] by a conventional method in the same manner as in the method described in Step 3 of Production Method 2.
  • R P2 is preferably one having little influence on R a 14, and examples thereof include a tert-butyl dimethylsilyl group.
  • Compound [52] can be obtained by reacting compound [51] in the same manner as in Production Process 1-2, Step 4.
  • R P3 is an alkyl group such as a methyl group or an ethyl group, a acetonide group formed by two one OR 1 " 3 groups, a hydroxyl protecting group such as a methylene acetal,
  • OR c 6 is a leaving group such as a mesyloxy group
  • R c7 is a protecting group for an amino group, and other symbols are as described above.
  • Compound [55] can be obtained by converting the hydroxyl group of compound [54] into a leaving group by a conventional method.
  • R c6 is a mesyl group
  • a method such as treatment with mesyl chloride in a solvent such as tetrahydrofuran or black mouth form in an argon atmosphere in the presence of a base such as triethylamine, pyridine, dimethylaminopyridine, etc. Use it.
  • the compound [56] can be obtained by reacting the compound [55] with a metal azide salt such as lithium azide in a dimethyl sulfoxide solvent in an argon atmosphere.
  • Compound [57] can be obtained by reacting compound [56] in an ether solvent such as 1,4-dioxane or tetrahydrofuran and an aqueous solvent in the presence of triphenylphosphine resin.
  • an ether solvent such as 1,4-dioxane or tetrahydrofuran
  • an aqueous solvent in the presence of triphenylphosphine resin.
  • Compound [58] can be obtained by introducing a protecting group into the amino group of compound [57] by a conventional method.
  • Examples of the protecting group for the amino group include a tert-butoxycarbonyl group, a benzyloxycarbonyl group, and a trifluoroacetyl group.
  • Rc 7 when Rc 7 is a tert-butoxycarbonyl group, it may be treated with tert-butoxycarbonyl chloride at room temperature or under cooling, or with di-tert-butyl dicarbonate in a tetrahydrofuran solvent.
  • Compound [59] can be obtained by reacting compound [58] with compound [15] in the same manner as in production method 1-3, step 2.
  • Compound [60] can be obtained by removing the protecting group for the hydroxyl group of compound [59] by a conventional method.
  • two one OR P3 together form a acetonide group it may be treated with trifluoroacetic acid under heating in methanol and an aqueous solvent, or with acetic acid-water under heating.
  • Compound [60] can be obtained by treating compound [60] with a periodate such as sodium periodate or potassium periodate under cooling.
  • Compound [62] can be obtained by reacting Compound [61] with Compound [1 1] in the same manner as in Production Method 1-12, Step 5.
  • Compound [1-12] can be obtained by removing the protecting group of the amino group of compound [62] by a conventional method.
  • M 1 is an alkali metal such as sodium, potassium or lithium (preferably sodium)
  • M 2 is an alkali metal such as sodium, potassium or lithium (here preferably lithium
  • R P4 is a protecting group for a hydroxyl group
  • R c8 is an alkyl group such as a methyl group or an ethyl group, and other symbols are as described above.
  • Compound [63] can be obtained by reacting Compound [22] with Compound [34] in the same manner as in Production Process 1-2, Step 1.
  • Compound [64] can be obtained by hydrolyzing compound [63] in an alcoholic solvent such as methanol or ethanol under acidic conditions such as concentrated hydrochloric acid or concentrated sulfuric acid. In alkaline hydrolysis using bases such as sodium hydroxide, this power oxidization power lithium, lithium hydroxide, etc. in the solvent of ethylene dalycol, compound [63] force, compound [65] or hydroxyl group is protected with R P1 Compound [65] can also be obtained.
  • Compound [64] can be obtained by reacting compound [64] in the presence of a base in a solvent.
  • Examples of the base include sodium hydrogen carbonate, potassium carbonate, sodium carbonate, sodium hydroxide, lithium hydroxide, lithium hydroxide and the like.
  • the solvent examples include ether solvents such as dioxane and tetrahydrofuran; alcohol solvents such as methanol and ethanol; water or a mixed solvent thereof.
  • Compound [6 6] can be obtained by introducing a protecting group into the hydroxyl group of compound [65] by a conventional method.
  • the protective group to be introduced is preferably a protective group that is removed under high load or under special conditions in order to obtain the compound [70], and examples thereof include a tertiary t-butyldimethylsilyl group.
  • Compound [67] can be obtained by hydrolyzing the group introduced into the carboxyl group of compound [66] in the fourth step under basic conditions.
  • reaction may be performed in the same manner as in the third step of production method 9, and conditions that do not affect RP4 are preferred.
  • Compound [69] can be obtained by reacting compound [67] with compound [68] in a solvent.
  • Solvents include alcohol solvents such as methanol, ethanol, n-propanol, and isopropanol; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; 1,4-dioxane, jetyl etherol, 1, 2— And ether solvents such as dimethoxyethane and tetrahydrofuran; polar solvents such as dimethylformad, dimethyl sulfoxide, and acetonitrile. '' ⁇ Seventh process>
  • Compound [70] can be obtained by reacting compound [69] in the same manner as in Step 3 of production method 1-2.
  • Compound [71] can be obtained by reacting compound [70] in the same manner as in production method 1-12, step 4.
  • Compound [1-13] can be obtained by reacting Compound [71] with Compound [1 1] in the same manner as in Production Method 1-12, Step 5.
  • Step 6 of production method 1-2 the same reaction as in Step 6 of production method 1-2 can then be carried out.
  • Compound [1-14] can be obtained by removing the hydroxyl-protecting group of compound [1-13] by a conventional method.
  • Compound [1-15] can be obtained by reacting compound [37] with compound [2] in the same manner as in Production Method 1-1. .
  • Compound [72] can be obtained by reacting compound [37] with heating in the presence of a base in the same manner as in Step 2 of production method 1-2.
  • the compound [74] can also be obtained directly by reacting in the presence of an acid in an alcohol solvent in the same manner as in the second step of production method 1-2.
  • Compound [74] can be obtained by subjecting compound [72] and compound [73] to an esterification reaction by a conventional method.
  • Compound [1-16] can be obtained by reacting compound [74] with compound [2] in the same manner as in Production Method 1-1.
  • Lithium diisopropinorea mono mono (tetrahydrofuran) (1.5M hexane solution) (3.2 m 1, 4.8 mm o 1) in tetrahydrofuran (2 m 1) solution under argon flow at 60 ° C Below C, a solution of 5-bromo-2-methylpyridine (750 mg, 4.4 mmo 1) in tetrahydrofuran (8 ml) was added dropwise. After stirring at the same temperature for 1 hour, ethoxymethylenemalonate jetyl (881 1, 4.4 mm o 1) was added dropwise at 160 ° C.
  • the compound (536 mg) obtained in the first step was dissolved in Dow therm A (3 ml) and stirred with heating at 200 ° C. for 2 hours. After cooling, hexane was added to the reaction solution, and the mixture was stirred at room temperature for 20 minutes. After filtration, the residue was dried under reduced pressure to obtain the desired product as a brown solid (23 lmg, yield about 18% 2).
  • the compound obtained in the third step (76 mg) was dissolved in dimethoxyethane (0.76 l), and 3-chloro-2-fluorobenzylbutamide (189 mg, 1.1 m mo 1) under an argon stream. , Tetrakistriphenylenolephosphinepalladium (8 mg, 0.005 mmol), 1.2 M aqueous sodium hydrogen carbonate solution (1.1 ml, 0.92 mm o 1) and ethanol (0.38 ml) were added. The mixture was heated and stirred at 80 ° C for 30 minutes. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction solution, and the layers were separated.
  • Example 2 The compound obtained in Example 1 (14 mg, 0.039 mm o 1) was dissolved in tetrahydrofuran (2 ml), ethanol (lml) and water (lml), and lithium hydroxide monohydrate (4 mg, 0. 098mmo 1) was added and stirred at room temperature for 3 hours.
  • the reaction mixture was acidified with 1N hydrochloric acid, and extracted with ethyl acetate.
  • the organic layer was washed with water and saturated brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was slurried with a mixed solvent of hexane and aceton. After filtration, the filtrate was dried under reduced pressure to obtain the desired product (8 mg, yield 62%) as a yellow solid.
  • Lithium diisopropylamide (2.0 M heptane Z tetrahydrofuran / ethylbenzene solution) at 78 ° C in a tetrahydrofuran (15 m 1) solution of ptyronitrile (1.47 g, 21. 31 mmo 1) under an argon stream ( 1 1. 37 ml, 22.74 mmol) was added dropwise and stirred for 15 minutes.
  • a solution of 5-promo-2-fluorine pyridine (2.50 g, 14.2 lmmo 1) in tetrahydrofuran (15 m 1) was added dropwise at 78 ° C, stirred for 1 hour, and warmed to room temperature. Stir for 5 hours.
  • the compound obtained in the first step (2. O O g, 8.89 mm o 1) was dissolved in ethanol (18 ml), concentrated sulfuric acid (6 ml) was added, and the mixture was heated to reflux for 45 hours.
  • the reaction solution was added to ice water and extracted with ethyl acetate.
  • the organic layer was washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine in that order, and then dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain the desired product (2.12 g, yield 88%) as a pale yellow oily solid.
  • the compound obtained in the 6th step (15 Omg, 0.463 mm o 1) was dissolved in dimethyl sulfoxide (3 ml), and bis (pinacolato) diboron (129 mg, 0.5 lmmo 1), potassium acetate in an argon stream. (136 mg, 1.39 mm o 1) and P d C 12 (dppf) (12 mg, 0.014 mm o 1) were added. After stirring for 2 hours at 80 ° C, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a brownish brown crude product (207 mg).
  • the compound (207mg) obtained in the 7th step was dissolved in dimethoxyethane (2ml), and 3-chlorodi-2-fluorobenzylbromide (517mg, 2.32mmo1) ethanol ( lm l) solution, followed by tetrakistriphenylphosphine palladium (27 mg, 0.023 mm o 1), 1.2 M aqueous sodium hydrogen carbonate solution (2. 30 ml, 2.78 mm o 1), 80 The mixture was stirred with heating at ° C for 30 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate.
  • Example 3 the compound (15 mg, 0.039 mmo 1) was dissolved in tetrahydrofuran (2 ml) and ethanol (1 ml), and lithium hydroxide monohydrate (4 mg, 0.097 mmo 1) and water (1 ml) were dissolved. ) And stirred at room temperature for 15.5 hours. A 10% aqueous citrate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and purified by HPLC. The obtained solid was dissolved in ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate.
  • the compound (2.54 g, 11.4 Ommo 1) in the first step was dissolved in acetonitrile (2 3m 1), and cyanotrimethylsilane (3. O Oml, 22.8 Ommo 1) and tetraptylammonium were dissolved.
  • Add fluoride (1M solution in tetrahydrofuran) 22. 80 ml, 22. 80 mm o 1).
  • the mixture was heated and stirred at C for 3.5 hours.
  • Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • N-Butyllithium (2.59M n-hexane solution) in a solution of the compound obtained in the second step (1.67 g, 4.93mmo 1) in tetrahydrofuran (8ml) under argon flow at 60 ° C or below ( 3. 8ml and 9.86mmo 1) were added dropwise and stirred for 30 minutes.
  • a solution of 5-hydrobromo-2-fluoropyridine (867 mg, 4.93 mm o 1) in tetrahydrofuran (8 ml) was added dropwise at a temperature not higher than 1700 ° C. After completion of the addition, the mixture was warmed to room temperature and stirred for 1.5 hours. did.
  • the compound obtained in the 5th step (1 96 mg, 0.59 mmo 1) is dissolved in dimethinorephonolemamide (2.4 m 1) and t-butyldimethylsilyl chloride (108 mg, 0.7 2 mmo 1) and Imidazole (53 mg, 0.78 mmol 1) was added, and the mixture was stirred at room temperature for 10 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate.
  • Zinc powder (1 1 g, 175 mmo 1) was suspended in tetrahydrofuran (30 ml) under a stream of anoregon, and 1,2-dipromotane (0.1 ml, 1.2 Ommo at 60 ° 0) 1) and trimethylsilyl chloride (0.29 ml, 2.4 mmo 1) were added, and the mixture was heated and stirred for 30 minutes.
  • the compound obtained in the 6th step (689 mg, 1.55 mm o 1) was dissolved in tetrahydrofuran (5 ml) and dichlorobis (triphosphine) palladium (II) (55 mg, 0.078 mmo 1) under an argon stream. And 1M bromide 3-chloro mouth 1-fluo benzyl zinc tetrahydrofuran solution (2.30 ml, 2.3 Ommo 1) was added dropwise and heated to reflux for 30 minutes. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Example 5 The compound obtained in Example 5 (97 mg, 0.2 Ommo 1) was dissolved in ethanol (2 ml), and p-tonoleensnorephonic acid 'monohydrate (2 mg, 0.010 mm o 1) was added. The mixture was heated and stirred at 50 ° C for 1.5 hours. Water and chloroform were added to the reaction solution, and the layers were separated. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain the desired product (49 mg, yield 61%) as a yellow solid.
  • Example 6 The compound obtained in Example 6 (49 mg, 0.12 mmo 1) was dissolved in tetrahydrofuran (3 ml), ethanol (1 ml) and water (lml), and lithium hydroxide 1 hydrate (25 mg, 0 60 mm o 1) was added and stirred at room temperature for 6 hours.
  • the reaction mixture was acidified with 1N hydrochloric acid, and extracted with ethyl acetate.
  • the organic layer was washed with water and saturated brine, and dried over magnesium sulfate. After filtration, the solution was concentrated under reduced pressure, and the residue was sonicated by adding jetyl ether. After filtration, it was dried under reduced pressure to obtain the desired product (40 mg, yield 88%) as a yellow solid. ,
  • the compound obtained in the first step (10.OO g, 38. 27mmo 1) is dissolved in dichloromethane (150ml), and titanium tetrachloride (4.41ml, 40. 17mmo 1) is added dropwise at 0 ° C for 10 minutes. Stir. Next, disopropylethylamine (6 ⁇ 92 ml, 40.17 mm o 1) was added dropwise at 0 ° C and stirred for 1 hour, and then benzylmethyl ether (10. 61 ml, 76. 52 mmo 1). Was added dropwise and stirred for 16 hours. A saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with black mouth form.
  • the compound obtained in the second step (9. 18 g, 24. 06 mmo 1) is dissolved in tetrahydrofuran (30 ml) and methanol (30 ml), and palladium hydroxide (containing 20 wt% palladium-carbon on water) (900 mg) is added. Hydrogen was added at 3 atm and stirred at room temperature for 2.5 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the desired product (7.09 g) as a white solid.

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Abstract

Cette invention concerne un médicament doté d'une activité anti-VIH, en particulier un médicament doté d'une activité inhibitrice de l'intégrase. L'invention concerne également un composé de quinolizinone représenté par la formule générale suivante [I] (dans laquelle les symboles sont identiques à ceux définis dans la description) ou un sel pharmaceutiquement acceptable de celui-ci. Le médicament est un agent anti-VIH contenant le composé ou le sel en tant que principe actif. Le composé a pour fonction d'inhiber l'activité de l'intégrase du VIH et est utile en tant qu'agent anti-VIH pour le traitement ou la prévention du SIDA. Cet agent anti-VIH peut être plus efficace lorsqu'il est utilisé en association avec un autre agent anti-VIH tel qu'un inhibiteur de la protéase ou un inhibiteur de la transcriptase inverse. L'agent anti-VIH possède une forte activité inhibitrice ciblant de manière spécifique les intégrases. Dès lors, cet agent peut constituer un médicament sûr pour le corps humain et présentant des effets secondaires réduits.
PCT/JP2005/017556 2004-09-21 2005-09-16 Compose de quinolizinone et utilisation de celui-ci en tant qu'inhibiteur de l'integrase du vih WO2006033422A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007148780A1 (fr) 2006-06-23 2007-12-27 Japan Tobacco Inc. Composé 6-(benzyle substituté par hétérocycle)-4-oxoquinoline et utilisation de celui-ci comme inhibiteur de l'intégrase du vih
WO2009051715A1 (fr) * 2007-10-18 2009-04-23 Merck & Co., Inc. Modulateurs allostériques positifs du récepteur m1 de la quinolizidinone
US7888375B2 (en) 2006-07-19 2011-02-15 The University Of Georgia Research Foundation, Inc Pyridinone diketo acids: inhibitors of HIV replication
JP2012184201A (ja) * 2011-03-07 2012-09-27 Nippon Zeon Co Ltd 環状エーテル化合物、非水系電池電極用バインダー組成物、非水系電池電極用スラリー組成物、非水系電池用電極及び非水系電池
JP2016531863A (ja) * 2013-09-27 2016-10-13 メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． Ｈｉｖインテグラーゼ阻害薬として有用な置換されたキノリジン誘導体

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05503709A (ja) * 1990-05-02 1993-06-17 アボツト・ラボラトリーズ キノリジノン型化合物
JP2004502770A (ja) * 2000-07-12 2004-01-29 ファルマシア・アンド・アップジョン・カンパニー 抗ウイルス剤としての複素環カルボキシアミド
WO2004046115A1 (fr) * 2002-11-20 2004-06-03 Japan Tobacco Inc. Composes 4-oxoquinoliniques et leur utilisation comme inhibiteur de la vih-integrase

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05503709A (ja) * 1990-05-02 1993-06-17 アボツト・ラボラトリーズ キノリジノン型化合物
JP2004502770A (ja) * 2000-07-12 2004-01-29 ファルマシア・アンド・アップジョン・カンパニー 抗ウイルス剤としての複素環カルボキシアミド
WO2004046115A1 (fr) * 2002-11-20 2004-06-03 Japan Tobacco Inc. Composes 4-oxoquinoliniques et leur utilisation comme inhibiteur de la vih-integrase

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007148780A1 (fr) 2006-06-23 2007-12-27 Japan Tobacco Inc. Composé 6-(benzyle substituté par hétérocycle)-4-oxoquinoline et utilisation de celui-ci comme inhibiteur de l'intégrase du vih
US7872004B2 (en) 2006-06-23 2011-01-18 Japan Tobacco Inc. 6-(heterocyclyl-substituted benzyl)-4-oxoquinoline compound and use thereof as HIV integrase inhibitor
EP2368880A1 (fr) 2006-06-23 2011-09-28 Japan Tobacco, Inc. Composé de 6-(benzyle substitué par hétérocycle)-4-oxoquinoline et utilisation de celui-ci comme inhibiteur de l'intégrase du VIH
US7888375B2 (en) 2006-07-19 2011-02-15 The University Of Georgia Research Foundation, Inc Pyridinone diketo acids: inhibitors of HIV replication
WO2009051715A1 (fr) * 2007-10-18 2009-04-23 Merck & Co., Inc. Modulateurs allostériques positifs du récepteur m1 de la quinolizidinone
US8258135B2 (en) 2007-10-18 2012-09-04 Merck Sharp & Dohme Corp. Quinolizidinone M1 receptor positive allosteric modulators
JP2012184201A (ja) * 2011-03-07 2012-09-27 Nippon Zeon Co Ltd 環状エーテル化合物、非水系電池電極用バインダー組成物、非水系電池電極用スラリー組成物、非水系電池用電極及び非水系電池
JP2016531863A (ja) * 2013-09-27 2016-10-13 メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． Ｈｉｖインテグラーゼ阻害薬として有用な置換されたキノリジン誘導体
JP2017105793A (ja) * 2013-09-27 2017-06-15 メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． Ｈｉｖインテグラーゼ阻害薬として有用な置換されたキノリジン誘導体

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