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WO2014098054A1 - Agent antiviral - Google Patents

Agent antiviral Download PDF

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Publication number
WO2014098054A1
WO2014098054A1 PCT/JP2013/083686 JP2013083686W WO2014098054A1 WO 2014098054 A1 WO2014098054 A1 WO 2014098054A1 JP 2013083686 W JP2013083686 W JP 2013083686W WO 2014098054 A1 WO2014098054 A1 WO 2014098054A1
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Prior art keywords
group
substituent
pyrano
dimethyl
chromen
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English (en)
Japanese (ja)
Inventor
晋也 木村
誠治 岡田
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Saga University NUC
Kumamoto University NUC
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Saga University NUC
Kumamoto University NUC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D201/00—Preparation, separation, purification or stabilisation of unsubstituted lactams
    • 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

Definitions

  • the present invention relates to a drug having an antiviral action. More specifically, the present invention relates to a tricyclic coumarin compound (GUT-70) having an anti-HIV virus action and a derivative thereof.
  • GUT-70 tricyclic coumarin compound
  • AIDS Acquired immunodeficiency syndrome
  • HAV human immunodeficiency virus
  • CD4 and chemokine receptors CXCR4 or CCR5 CD4 and chemokine receptors CXCR4 or CCR5 as receptors. It is a serious infectious disease that infects T cells and macrophages, destroys the immune cells, and subsequently acquires immunodeficiency.
  • 3′-azido-3′-deoxythymidine a synthetic 3′-deoxynucleoside
  • ddI 3′-dideoxyinosine
  • More than 20 different compounds such as 2 ′, 3′-dideoxycytidine (ddC), 3′-fluoro-3′-deoxythymidine (FLT), saquinavir (SQC) and the like are used as anti-HIV agents.
  • a multi-drug combination therapy High Active Antitherapy; HAART
  • HAART High Active Antitherapy in which a plurality of anti-HIV agents are combined and administered to AIDS patients has been introduced, and HIV infection is also regarded as a chronic disease.
  • anti-HIV agents are effective in the HIV life cycle, such as inhibiting HIV DNA synthesis or preventing HIV from entering host cells, they are effective against latent HIV infection. The effect is not recognized.
  • due to problems such as side effects caused by these anti-HIV agents and the appearance of drug-resistant viruses the number of cases in which HAART is difficult to continue for a long time is increasing.
  • none of the existing commercially available anti-HIV agents have an anticancer effect, and the development of new anti-HIV agents having different action mechanisms is urgently required.
  • Non-patent Document 1 a tricyclic coumarin compound extracted from Brazilian Hypericum grass
  • Patent Document 2 various derivatives with chemical modification using GUT-70 as a lead compound were synthesized, and they had cancer cell growth inhibitory activity, prevention of cancer, neurodegenerative diseases, autoimmune diseases, infectious diseases, etc. It has been reported that it is effective for treatment and the like (Patent Document 2).
  • An object of the present invention is to provide an antiviral agent having a new mechanism of action, particularly an anti-HIV agent.
  • GUT-70 has a growth inhibitory action that inhibits the proliferation of HIV-1 by suppressing the replication or transcription of HIV-1
  • GUT-70 has a cell membrane inhibitory action that reduces the fluidity of cell membranes and inhibits membrane fusion of HIV-1 env expressing cells, and inhibits HIV-1 intracellular entry.
  • GUT-70 was also found to inhibit HIV-1 infection against both CXCR4 and CCR5 receptors. Based on these findings, the present inventors have completed the present invention.
  • R 1 represents hydrogen, an alkyl group, a cycloalkyl group, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, an aryl group which may have a substituent, a substituent A heterocyclic group which may have a group, an amino group which may have a substituent, an alkoxy group, an alkylcarbonyl group, an arylcarbonyl group which may have a substituent, and a substituent.
  • R 16 , R 17 and R 18 are the same or different and each represents hydrogen, an alkyl group, a cycloalkyl group, an aryl group which may have a substituent, a heterocyclic group which may have a substituent, or a dialkyl.
  • An amino group or an alkenyl group which may have a substituent Means a structure represented by R 2 is hydrogen, an alkyl group, an aryl group which may have a substituent, a halogen atom, a cyano group, a cycloalkyl group, an alkylcarbonyl group, an arylcarbonyl group which may have a substituent, a carboxyl group , Alkoxycarbonyl group, thiol group, alkylthio group, arylthio group which may have a substituent, alkylsulfonyl group, arylsulfonyl group which may have a substituent, amino which may have a substituent Carbonyl group, optionally substituted aminosulfonyl group, optionally substituted aryloxycarbonyl group, amino group, alkylamino group, dialkylamino group, acylamino group, alkylsulfonylamino group or substituted An arylsul
  • R 19 and R 20 are the same or different and each represents hydrogen, an alkyl group, a cycloalkyl group, or an aryl group which may have a substituent, or C—R 19 R 20 represents C ⁇ O
  • R 21 and R 22 are the same or different and are each a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, an alkyl group, a cycloalkyl group, an aryl group which may have a substituent, or an alkoxy group.
  • R 3 represents hydrogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, or an aryl group
  • R 4 represents hydrogen or OR 4a (wherein R 4a represents hydrogen, an alkyl group, an alkenyl group, an alkynyl group or an aryl group), and OR 4a together with R 3 represents the general formula (2):
  • R 19 and R 20 are the same or different and each represents hydrogen, an alkyl group, a cycloalkyl group, or an aryl group which may have a substituent, or C—R 19 R 20 represents C ⁇ O
  • R 21 and R 22 are the same or different and are each a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, an alkyl group, a cycloalkyl group, an aryl group which may have a substituent, or an alkoxy group.
  • R 2 is OR 2a when R 4 is hydrogen; When R 4 is OR 4a R 2 is not OR 2a; formula:
  • R 5a and R 5b is the same or different and is hydrogen, an alkyl group which may have a substituent, an aryl group which may have a substituent, a halogen atom, a cyano group, a hydroxy group, a cycloalkyl group, an alkoxy group.
  • R 6 and R 7 are the same or different and each represents hydrogen or an optionally substituted alkyl group, or C—R 6 R 7 represents C ⁇ O, R 8 Means an oxo group or an alkyl group;
  • R 9 represents hydrogen or an alkyl group
  • R 10 represents hydrogen or an alkyl group
  • R 11 represents an arylcarbonyl group which may have a substituent.
  • R 13 represents hydrogen or an aryl group which may have a substituent
  • R 14 represents hydrogen or an alkyl group which may have a substituent
  • An antiviral agent comprising as an active ingredient a compound represented by the meaning of a group or a pharmaceutically acceptable salt thereof.
  • R 1 ′ is hydrogen, a heterocyclic group, an optionally substituted amino group, a heterocyclic carbonyl group, a cycloalkylcarbonyl group, a cycloalkenylcarbonyl group, or the general formula (1 ′):
  • R 16 ′ , R 17 ′ and R 18 ′ are the same or different and each represents hydrogen, an alkyl group or an aryl group which may have a substituent.
  • Means a structure represented by R 2 ′ means an alkoxy group;
  • R 3 ′ means hydrogen or an alkyl group;
  • R 4 ′ represents OR 4a ′ (wherein R 4a ′ represents an alkyl group), and OR 4a ′ together with R 3 ′ represents the general formula (2 ′):
  • R 19 ′ and R 20 ′ are the same or different and each represents an alkyl group, and the broken line represents a condensed portion with a benzene ring]
  • R 5a ′ and R 5b ′ are the same or different and each represents hydrogen or an optionally substituted alkyl group) or a group represented by the formula (b ′ ):
  • the compound represented by the general formula (I) is: 5-methoxy-2,2-dimethyl-6-[(2E) -2-methylbut-2-enoyl] -10-propyl-2H, 8H-pyrano [2,3-f] chromen-8-one, 5-methoxy-2,2-dimethyl-6- (2-methylbutanoyl) -10-propyl-2H, 8H-pyrano [2,3-f] chromen-8-one, 5-hydroxy-2,2-dimethyl-6- (2-methylbutanoyl) -10-propyl-2H, 8H-pyrano [2,3-f] chromen-8-one, 5-hydroxy-2,2-dimethyl-6-[(2E) -2-methylbut-2-enoyl] -10-propyl-2H, 8H-pyrano [2,3-f] chromen-8-one, 5-hydroxy-2,2-dimethyl-6-[(2E) -2-methylbut-2-enoyl] -10-propyl-2H, 8H
  • the compound represented by the general formula (I) is: 5-methoxy-2,2-dimethyl-6-[(2E) -2-methylbut-2-enoyl] -10-propyl-2H, 8H-pyrano [2,3-f] chromen-8-one, 6-cyclobutylcarbonyl-2,2-dimethyl-5-methoxy-10-propyl-2H, 8H-pyrano [2,3-f] chromen-8-one, or 6-cyclohexylcarbonyl-2,2-dimethyl-
  • the antiviral agent according to [1] which is 5-methoxy-10-propyl-2H, 8H-pyrano [2,3-f] chromen-8-one.
  • the compound represented by the general formula (I) has the following structural formula: 5-methoxy-2,2-dimethyl-6-[(2E) -2-methylbut-2-noyl] -10-propyl
  • the antiviral agent according to [1] which is -2H, 8H-pyrano [2,3-f] chromen-8-one.
  • the other anti-HIV agent is at least one selected from the group consisting of a reverse transcriptase inhibitor, a protease inhibitor, an integrase inhibitor, a DNA polymerase inhibitor, and a DNA synthesis inhibitor.
  • Antiviral agent Use of the compound according to [1] to [5] for the manufacture of a medicament for inhibiting HIV replication in an HIV-infected patient.
  • Cancer is acute myeloid leukemia, acute lymphoblastic leukemia, Kaposi sarcoma, Hodgkin lymphoma, non-Hodgkin lymphoma, leiomyosarcoma, choriocarcinoma, multiple myeloma, soft tissue tumor, small cell lung cancer, chronic myelogenous leukemia , Thyroid cancer, osteosarcoma, head and neck cancer, esophageal cancer, non-small cell lung cancer, breast cancer, colon cancer, stomach cancer, biliary tract cancer, brain tumor, malignant melanoma, kidney cancer, pancreatic cancer, liver cancer, cervical cancer, testicular cancer
  • the use according to [11] selected from the group consisting of skin cancer and anal cancer.
  • a method for treating a viral infection comprising administering an effective amount of the compound according to [1] to [5] to a patient in need thereof.
  • the method according to [13], wherein the virus is a retrovirus.
  • the method according to [14], wherein the retrovirus is HIV.
  • the method according to [13] to [16], wherein the patient suffers from cancer, other infectious disease or immune disease.
  • Cancer is acute myeloid leukemia, acute lymphoblastic leukemia, Kaposi sarcoma, Hodgkin lymphoma, non-Hodgkin lymphoma, leiomyosarcoma, choriocarcinoma, multiple myeloma, soft tissue tumor, small cell lung cancer, chronic myelogenous leukemia , Thyroid cancer, osteosarcoma, head and neck cancer, esophageal cancer, non-small cell lung cancer, breast cancer, colon cancer, stomach cancer, biliary tract cancer, brain tumor, malignant melanoma, kidney cancer, pancreatic cancer, liver cancer, cervical cancer, testicular cancer
  • the method according to [17] which is selected from the group consisting of skin cancer and anal cancer.
  • FIG. 1-1 shows the results of a flow cytometer in which GUT-70 inhibited HIV-1 replication in cells infected with HIV-1.
  • FIG. 1-2 shows the results of GUT-70 inhibiting HIV-1 replication in cells infected with HIV-1.
  • the vertical axis represents the percentage (%) of p24 positive cells, and the horizontal axis represents the number of culture days.
  • FIG. 1-3 shows the results of GUT-70 inhibiting HIV-1 replication in cells infected with HIV-1.
  • the results of measuring the concentration of p24 in the cell culture supernatant after culturing cells infected with HIV-1 for 7 days are shown.
  • the vertical axis represents the p24 concentration (ng / ml), and the horizontal axis represents the GUT-70 concentration.
  • FIG. 1-1 shows the results of a flow cytometer in which GUT-70 inhibited HIV-1 replication in cells infected with HIV-1.
  • FIG. 1-2 shows the results of GUT-70 inhibiting HIV-1 replication in cells
  • FIG. 2 shows that GUT-70 reduced cell membrane fluidity.
  • the vertical axis represents the fluorescence polarization P value, and the horizontal axis represents time (minutes).
  • FIG. 3-1 shows the results of a flow cytometer in which GUT-70 inhibited membrane fusion of HIV-1 env expressing cells (24 hours after culture).
  • FIG. 3-2 shows the results of GUT-70 inhibiting membrane fusion of HIV-1 env expressing cells.
  • the vertical axis represents the cell fusion ratio (%), and the horizontal axis represents the GUT-70 concentration ( ⁇ M).
  • FIG. 4 shows a fluorescence microscopic image in which GUT-70 inhibited membrane fusion of HIV-1 env expressing cells (after 48 hours in culture).
  • FIG. 5-1 shows the results of a flow cytometer in which GUT-70 inhibited HIV-1 infection of HUT78 cells (48 hours after infection).
  • FIG. 5-2 shows that the expression of intracellular p24 (HIV-1 gag) in HUT78 cells infected with HIV-1 decreased when GUT-70 was added.
  • FIG. 5-3 shows the results of a flow cytometer in which GUT-70 inhibited HIV-1 infection of TZM-bl cells (48 hours after infection).
  • FIG. 5-4 shows that the expression of intracellular p24 (HIV-1 gag) in TZM-bl cells infected with HIV-1 decreased when GUT-70 was added.
  • FIG. 6-1 shows a flow site in which HIV-1 production was suppressed in a dose-dependent manner when GUT-70 was added to HIV-1 latent cell line U1 in which HIV-1 production was induced by addition of PMA or TNF- ⁇ .
  • the meter result is shown.
  • FIG. 6-2 shows that the percentage of p24 positive cells in the cells decreased in a dose-dependent manner when GUT-70 was added.
  • FIG. 6-3 shows that the expression of p24 (HIV-1 gag) in the cell culture supernatant decreased in a dose-dependent manner when GUT-70 was added.
  • FIG. 7-1 shows that after pretreatment of TZM-bl cells with GUT-70, infection with HIV-1 strain NL-4.3 and culturing for 24 hours, GUT-70 suppressed HIV-1 infection.
  • FIG. 7-2 shows the results of suppression of HIV-1 transcription when GUT-70 (10 ⁇ M) was added to HIV-1 latent cell line U1 in which HIV-1 production was induced by addition of TNF- ⁇ .
  • GUT-70 or NF- ⁇ B inhibitor (10 ⁇ M Bay 11-7085 (Bay in the figure) or 20 nM Bortezomib (Bor in the figure)) was added, and Tat-Rev mRNA after 24 hours of culture was added. The result measured by quantitative RT-PCR is shown.
  • FIG. 7-3 shows the results of suppression of HIV-1 transcription when GUT-70 (10 ⁇ M) was added to Molt-4 cells infected with HIV-1 strain NL4-3.
  • FIG. 8 shows a Western blot image in which GUT-70 suppressed phosphorylation of NF-kappaB p65.
  • FIG. 9-1 shows a gel shift assay image in which GUT-70 inhibited the DNA binding activity of NF-kappaB by addition of TNA- ⁇ .
  • FIG. 9-2 shows a diagram in which HIV-1 transcription is inhibited by NF-kappaB suppression by GUT-70. The vertical axis shows the relative luciferase activity when con is 1.
  • Halogen in the present specification includes fluorine, chlorine, bromine and iodine.
  • alkyl group in the present specification means a linear or branched alkyl group, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, Neopentyl, tert-pentyl, hexyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl and the like can be mentioned, and among them, a C 1 -C 6 alkyl group is preferable.
  • alkyl group optionally having substituent (s) refers to an alkyl group optionally having 1 to 5, preferably 1 to 3 substituents at substitutable positions. means.
  • substituents include a carboxyl group, a dialkylaminocarbonyl group (eg, dimethylaminocarbonyl), an optionally substituted heterocyclic carbonyl group (described later), and an optionally substituted group.
  • An aryl group (described later), an alkyloxycarbonyl group (eg, methoxycarbonyl, ethoxycarbonyl), an alkenylcarbonyloxy group (eg, isobutenylcarbonyloxy) and the like can be mentioned.
  • alkenyl group in the present specification is a linear or branched alkenyl group such as vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, but-3-en-1-yl, penta -4-en-1-yl, hex-5-en-1-yl and the like, among which a C 2 -C 6 alkenyl group is preferable.
  • the “optionally substituted alkenyl group” refers to an alkenyl group optionally having 1 to 5, preferably 1 to 3 substituents at substitutable positions. means. Examples of such a substituent include a hydroxy group, a dialkylamino group (described later), and an aryl group (described later) which may have a substituent.
  • alkynyl group in the present specification is a linear or branched alkynyl group such as ethynyl, prop-2-yn-1-yl, but-3-yn-1-yl, penta-4 -In-1-yl, hex-5-in-1-yl and the like can be mentioned, among which a C 2 -C 6 alkynyl group is preferable.
  • optionally substituted alkynyl group means an alkynyl group optionally having 1 to 5, preferably 1 to 3 substituents at substitutable positions. means. Examples of such a substituent include a hydroxy group.
  • cycloalkyl group examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like, and among them, a C 3 -C 6 cycloalkyl group is preferable.
  • aryl group examples include phenyl, naphthyl (eg, 1-naphthyl, 2-naphthyl), biphenylyl, anthryl, phenanthryl, etc.
  • a C 6 -C 14 aryl group is preferable.
  • C 6 -, more preferably 10 aryl group include a phenyl group and the like are generally used.
  • the “aryl group optionally having substituent (s)” refers to an aryl group optionally having 1 to 5, preferably 1 to 3 substituents at substitutable positions. means.
  • Examples of such a substituent include a halogen (eg, bromine, chlorine), a cyano group, a nitro group, a hydroxy group, an aminocarbonyl group, an acetyl group, a carboxyl group, an alkoxycarbonyl group (described later), and a substituent.
  • a halogen eg, bromine, chlorine
  • a cyano group e.g., a cyano group
  • a nitro group e.g, a nitro group
  • an aminocarbonyl group e.g., an acetyl group
  • carboxyl group e.g., an alkoxycarbonyl group (described later)
  • alkoxy group examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy Hexyloxy, 2-ethylbutoxy and the like, among which a C 1 -C 6 alkoxy group is preferable.
  • heterocyclic group in the present specification includes an aromatic heterocyclic group and a non-aromatic heterocyclic group.
  • examples of the aromatic heterocyclic group include 4 to 7 members (preferably 5 or 5) containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom as a ring constituent atom.
  • examples of the condensed aromatic heterocyclic group include a ring corresponding to the 4- to 7-membered monocyclic aromatic heterocyclic group and a 5- or 6-membered aromatic heterocyclic ring containing 1 or 2 nitrogen atoms.
  • aromatic heterocyclic group examples include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3, 4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, Monocyclic aromatic heterocyclic groups such as pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl; and benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, 1H-indazolyl
  • non-aromatic heterocyclic group examples include 4 to 7 members (preferably 5 or 6 members) containing 1 to 4 heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms in addition to carbon atoms as ring constituent atoms.
  • Monocyclic non-aromatic heterocyclic group and condensed non-aromatic heterocyclic group examples include a ring corresponding to the 4- to 7-membered monocyclic non-aromatic heterocyclic group, and a 5- or 6-membered aromatic containing 1 or 2 nitrogen atoms.
  • 1 or 2 rings selected from a heterocyclic ring eg, pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine
  • a heterocyclic ring eg, pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine
  • a 5-membered aromatic heterocyclic ring containing 1 sulfur atom eg, thiophene
  • benzene ring examples thereof include a group derived from a condensed ring and a group obtained by partial saturation of the group.
  • non-aromatic heterocyclic group examples include azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl and the like
  • Non-aromatic heterocyclic groups and isochromanyl, dihydrobenzopyranyl, dihydroquinolyl, isochromenyl, chromenyl (2H-chromenyl, 4H-chromenyl), 1,2,3,4-tetrahydroisoquinolyl, 1,2,3 , 4-tetrahydroquinolyl, 2,3-dihydrobenzofuranyl, condensed non-aromatic heterocyclic groups such as benzo
  • heterocyclic group optionally having substituent (s) in the present specification means a heterocyclic ring optionally having 1 to 5, preferably 1 to 3 substituents at substitutable positions. Means group. Examples of such a substituent include halogen (described above), alkyl group (described above), aralkyl group (eg, benzyl), heterocyclic group (described above), and alkoxy group (described later).
  • the “optionally substituted amino group” refers to an amino group (monoalkylamino group, simply alkylamino) monosubstituted by an alkyl group (preferably a C 1 -C 6 alkyl group).
  • a substituted amino group (monoarylamino group) or a disubstituted amino group (diarylamino group), an amino group substituted with an optionally substituted aminocarbonyl group (described later), an alkenylcarbonyl group ( Examples include an amino group substituted with a later-described amino group and an amino group substituted with a heterocyclic carbonyl group (described later).
  • Examples of the halogenated alkyl group include a trifluoromethyl group.
  • optionally substituted amino group include methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamino, C 1 -C 6 alkylamino groups such as isopentylamino, neopentylamino, tert-pentylamino, hexylamino, and di (C 1 -C 6 ) alkyl such as dimethylamino, diethylamino, N-ethyl-N-methylamino amino group, phenylamino, 1-naphthylamino, 2-naphthylamino, C 6 -C 14 arylamino group such as trifluoroacetic phenylamino, diphenylamino, di (C 6 -C 14) aryl amino groups such as din
  • alkylamino group and “dialkylamino group” have the same meanings as those exemplified as the “amino group optionally having substituent (s)” described above.
  • alkylcarbonyl group “alkenylcarbonyl group”, “alkoxycarbonyl group”, “arylcarbonyl group optionally having substituent”, “cycloalkylcarbonyl group” and “having substituent”
  • aminocarbonyl group which may optionally be represented by the above-mentioned “alkyl group”, “alkenyl group”, “alkoxy group”, “aryl group optionally having substituent”, “cycloalkyl group” and “ It means a carbonyl group substituted with an “amino group optionally having substituent (s)”.
  • alkylcarbonyl group is preferably a C 1 -C 6 alkyl-carbonyl group, specifically, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2,2 -Dimethylpropanoyl and the like.
  • alkenylcarbonyl group is preferably a C 2 -C 6 alkenyl-carbonyl group, and specifically includes vinylcarbonyl, 1-propenylcarbonyl, 2-propenylcarbonyl, 2-butenylcarbonyl, 3-butenylcarbonyl. Etc.
  • alkoxycarbonyl group is preferably a C 1 -C 6 alkoxy-carbonyl group, and specifically includes methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, and sec-butoxycarbonyl, tert-butoxycarbonyl and the like.
  • cycloalkylcarbonyl group is preferably a C 3 -C 6 cycloalkyl-carbonyl group, and specifically includes cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, cyclooctylcarbonyl and the like. Is mentioned.
  • the “optionally substituted arylcarbonyl group” is preferably a C 6 -C 14 aryl-carbonyl group, and specific examples include benzoyl, 1-naphthoyl, 2-naphthoyl and the like.
  • the “optionally substituted aminocarbonyl group” means, for example, an alkylamino group (preferably an amino group mono- or di-substituted with C 1 -C 6 alkyl) or an arylamino group Means a carbonyl group substituted with (preferably an amino group mono- or di-substituted with a C 6 -C 14 aryl group), specifically, methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropyl Aminocarbonyl, n-butylaminocarbonyl, isobutylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, isopentylaminocarbonyl, hexylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, di-n-propylaminocarbonyl, di Soprop
  • cycloalkenylcarbonyl group means a carbonyl group substituted with a C 3 -C 6 cycloalkenyl group such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and the like.
  • heterocyclic carbonyl group in the present specification means a carbonyl group substituted with the above-mentioned “heterocyclic group”.
  • heterocyclic group examples include a ring corresponding to the aromatic or non-aromatic heterocyclic group exemplified as the heterocyclic group.
  • heterocyclic carbonyl group examples include benzofuranylcarbonyl, thienylcarbonyl, benzimidazolylcarbonyl, pyrimidinylcarbonyl, 1-pyrrolidinylcarbonyl, piperidinocarbonyl, 1-piperazinylcarbonyl, morpholinocarbonyl, thiomorpholino Examples include carbonyl and the like.
  • the term “heterocyclic carbonyl group optionally having substituent (s)” in the present specification refers to a heterocyclic ring optionally having 1 to 3 substituents at substitutable positions in addition to the carbonyl group. Means a carbonyl group. Examples of such a substituent include halogen (described above), alkyl group (described above), aralkyl group (eg, benzyl), heterocyclic group (described above), and alkoxy group (described later).
  • Examples of the “substituent” in the “carboxyl group optionally having a substituent” in the present specification include an alkyl group (described above), an aryl group (described above), an aralkyl group (eg, benzyl, phenethyl) and the like. Can be mentioned.
  • alkylthio group and the “arylthio group optionally having substituent (s)” are each substituted with the above-mentioned “alkyl group” and “aryl group optionally having substituent (s)”.
  • the “alkylthio group” is preferably a C 1 -C 6 alkylthio group, and specific examples include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio and the like.
  • the “arylthio group optionally having substituent (s)” is preferably a C 6 -C 14 arylthio group optionally having substituent (s), and specific examples include phenylthio, naphthylthio and the like.
  • alkylsulfonyl group” and the “arylsulfonyl group optionally having substituent (s)” are substituted with the “alkyl group” and “aryl group optionally having substituent (s)”, respectively.
  • alkylsulfonyl group is preferably a C 1 -C 6 alkylsulfonyl group, specifically, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, tert- And butylsulfonyl.
  • arylsulfonyl group optionally having substituent (s) is preferably a C 6 -C 14 arylsulfonyl group optionally having substituent (s) such as phenylsulfonyl, naphthylsulfonyl and the like. Is mentioned.
  • Examples of the “optionally substituted aminosulfonyl group” include (C 1 -C 6 ) alkylamino-sulfonyl group, di (C 1 -C 6 ) alkylamino-sulfonyl group, and (C 6 -C 14). ) Arylamino-sulfonyl group, di (C 6 -C 14 ) arylamino-sulfonyl group, and the like.
  • methylaminosulfonyl ethylaminosulfonyl, n-propylaminosulfonyl, isopropylaminosulfonyl, n- Butylaminosulfonyl, isobutylaminosulfonyl, tert-butylaminosulfonyl, n-pentylaminosulfonyl, isopentylaminosulfonyl, hexylaminosulfonyl, dimethylaminosulfonyl, diethylaminosulfonyl, di-n-propylaminosulfonyl, diisopropylaminosulfur Examples thereof include phonyl, di-n-butylaminosulfonyl, diisobutylaminosulfonyl, ditert-butylaminosulfonyl, di-n-pentylaminosulfonyl, diisopent
  • examples of the “aryloxy group which may have a substituent” include phenoxy, 1-naphthyloxy, 2-naphthyloxy and the like.
  • aryloxycarbonyl group which may have a substituent examples include phenoxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl and the like.
  • acylamino group means —NHCOR ′ ′′ (wherein R ′ ′′ means the above “alkyl group” or the above “optionally substituted aryl group”). Group), for example, acetylamino, propionylamino, butyrylamino, benzoylamino and the like.
  • alkylsulfonylamino group in the present specification means a sulfonylamino group substituted with the above “alkyl group”, specifically, for example, methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, isopropyl
  • alkylsulfonylamino group substituted with the above “alkyl group specifically, for example, methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, isopropyl
  • Examples include sulfonylamino, n-butylsulfonylamino, isobutylsulfonylamino, tert-butylsulfonylamino, n-pentylsulfonylamino, isopentylsulfonylamino,
  • arylsulfonylamino group optionally having substituent (s) in the present specification means a sulfonylamino group substituted with the above “aryl group optionally having substituent (s)”, specifically Includes phenylsulfonylamino, naphthylsulfonylamino and the like.
  • R 1 is preferably (i) hydrogen, (ii) an alkenyl group which may have a substituent, (iii) an alkynyl group which may have a substituent, (iv) A heterocyclic group which may have a substituent, (v) an amino group which may have a substituent, (vi) an alkoxy group, (vii) an alkylcarbonyl group, and (viii) a substituent.
  • R 16 is preferably hydrogen or an alkyl group
  • R 17 and R 18 are preferably the same or different and each is an aryl group optionally having hydrogen, an alkyl group or a substituent.
  • R 2 is preferably hydrogen, a hydroxy group or an alkoxy group.
  • R 2a means hydrogen, an alkyl group, an alkenyl group, an alkynyl group or an aryl group which may have a substituent
  • R 1 and the substituent may be substituted.
  • a ring represented by the general formula (2) which may be present is formed.
  • R 4 is not OR 4a (wherein R 4a represents hydrogen, an alkyl group, an alkenyl group, an alkynyl group, or an aryl group).
  • R 19 and R 20 are preferably alkyl groups, and R 21 and R 22 are preferably hydrogen.
  • OR 2a forms a ring represented by the general formula (2) which may have a substituent together with R 1
  • the compound represented by the formula (I) is a compound represented by the following general formula. is there.
  • R 3 is preferably hydrogen, an alkyl group or an alkoxy group.
  • R 4 is preferably hydrogen, a hydroxy group or an alkoxy group.
  • R 4 together with R 3 forms a ring represented by the general formula (2).
  • R 4 is hydrogen, R 2 is OR 2a (wherein R 2a is as defined above), and when R 4 is OR 4a , R 2 is not OR 2a .
  • R 19 and R 20 are preferably alkyl groups, and R 21 and R 22 are preferably hydrogen.
  • OR 4a forms a ring represented by the general formula (2) which may have a substituent together with R 3
  • the compound represented by the formula (I) is a compound represented by the following general formula: is there.
  • X 1 is preferably O or NH
  • R 5a and R 5b are preferably the same or different and have hydrogen, an alkyl group which may have a substituent, or a substituent.
  • R 6 and R 7 are preferably the same or different and each represents an alkyl group. It is also preferred that C—R 6 R 7 forms C ⁇ O.
  • R 8 is preferably an oxo group or an alkyl group,
  • the bond represented by is a single bond or a double bond.
  • R 9 is preferably hydrogen
  • R 10 is preferably hydrogen
  • R 11 is preferably an arylcarbonyl group which may have a substituent.
  • X 2 is preferably N
  • R 12 is preferably an amino group which may have a substituent.
  • R 13 is preferably an aryl group
  • R 14 is preferably an alkyl group.
  • R 1 ′ is hydrogen, a heterocyclic group, an optionally substituted amino group, a heterocyclic carbonyl group, a cycloalkylcarbonyl group, a cycloalkenylcarbonyl group, or the general formula (1 ′):
  • R 16 ′ , R 17 ′ and R 18 ′ are the same or different and each represents hydrogen, an alkyl group or an aryl group which may have a substituent.
  • Means a structure represented by R 2 ′ means an alkoxy group;
  • R 3 ′ means hydrogen or an alkyl group;
  • R 4 ′ represents OR 4a ′ (wherein R 4a ′ represents an alkyl group), and OR 4a ′ together with R 3 ′ represents the general formula (2 ′):
  • R 19 ′ and R 20 ′ are the same or different and each represents an alkyl group, and the broken line represents a condensed portion with a benzene ring]
  • R 5a ′ and R 5b ′ are the same or different and each represents hydrogen or an alkyl group which may have a substituent, or a group represented by formula (b ′) :
  • the compound represented by the above general formula (I) can be produced by the method disclosed in Patent Document 1 or Patent Document 2.
  • the compound represented by the general formula (I) may be referred to as the compound (I) or the compound of the present invention.
  • “Pharmaceutically acceptable salt thereof” refers to any non-toxic salt formed from the compound of the present invention.
  • inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid; oxalic acid, malonic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, glucone Acids, organic acids such as ascorbic acid, methyl sulfonic acid, benzyl sulfonic acid; inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, ammonium hydroxide; methylamine, diethylamine, It can be obtained by reaction with organic bases such as triethylamine, triethanolamine, ethylenediamine, tris (hydroxymethyl) methylamine, guanidine, choline, cincholin and the like; or amino acids such as lysine, arginine
  • compound (I) has an isomer such as an optical isomer, a stereoisomer, a positional isomer, or a rotational isomer
  • any one isomer or a mixture of isomers is included in compound (I). Is done.
  • compound (I) has an optical isomer
  • the optical isomer resolved from the racemate is also encompassed in compound (I).
  • Each of these isomers can be obtained as a single product by a known synthesis method or separation method (concentration, solvent extraction, column chromatography, recrystallization, etc.).
  • Compound (I) may be crystalline or amorphous.
  • the compound (I) is a crystal, it is included in the compound (I) regardless of whether it is a single crystal form or a mixture of crystal forms.
  • the crystal can be produced by crystallization by applying a crystallization method known per se.
  • Compound (I) may be labeled with an isotope (eg, 3 H, 14 C, 35 S, 125 I, etc.) and the like.
  • an isotope eg, 3 H, 14 C, 35 S, 125 I, etc.
  • the compound of the present invention has an antiviral action and is useful as an antiviral agent.
  • the virus targeted by the compound of the present invention is preferably a retrovirus.
  • retrovirus include viruses that maintain their life by transcription of RNA, such as human immunodeficiency virus (HIV) such as human immunodeficiency virus type 1 (HIV-1), human T Examples include cellular leukemia virus (HTLV), hepatitis virus (HBV, HCV, etc.) and the like.
  • HIV is useful for HIV infection.
  • HIV infection refers to a pathological condition infecting HIV including AIDS, symptomatic or asymptomatic HIV infection (including AIDS-related syndrome: ARC).
  • the antiviral agent of the present invention can be used as a drug for treating various retroviral infections including HIV infection.
  • Treatment includes treatment aimed at amelioration, alleviation or cure of symptoms.
  • the treatment of HIV infection includes treatment aimed at amelioration, alleviation or cure of symptoms due to HIV infection, prevention or delay of the onset of AIDS.
  • suppression of increase or decrease in the number of CD4 positive lymphocytes, suppression of increase or decrease in NK cell activity, prevention, improvement, alleviation or cure of ARC, prevention or delay of the onset of AIDS, prevention of opportunistic infections Includes treatment aimed at ameliorating, alleviating or healing, improving AIDS symptoms, alleviating or healing.
  • Symptoms of ARC include lymphadenopathy, loss of appetite, diarrhea, weight loss, fever, malaise, rash, bronchial asthma and the like.
  • the compound of the present invention can inhibit the proliferation of HIV-1 by inhibiting the replication and / or transcription of HIV-1. More specifically, the compound of the present invention can suppress activation (phosphorylation) of NF-kappaB p65. In addition, the compound of the present invention can inhibit the transcription of HIV-1 and inhibit its replication by inhibiting the DNA binding of NF-kappaB. Moreover, since the compound of the present invention can exert the above-mentioned inhibitory action in HIV-1 latently infected cell lines, it is useful for the treatment of HIV-1 latent infection. Furthermore, HIV-1 is infected by binding of env expressed on the surface of HIV-1 to a host cell, but the compound of the present invention decreases the fluidity of cell membrane and expresses env of HIV-1. Known anti-HIV agents because they can inhibit cell membrane fusion, inhibit HIV-1 intracellular entry, and HIV-1 infection to both CXCR4 and CCR5 receptors It is useful as an anti-HIV agent having a different mechanism of action.
  • the compound of the present invention also has an anticancer activity, it can be used for cancer (eg, malignant lymphoma (Hodgkin lymphoma, non-Hodgkin lymphoma, etc.)), leukemia (acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, etc.
  • cancer eg, malignant lymphoma (Hodgkin lymphoma, non-Hodgkin lymphoma, etc.)
  • leukemia acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, etc.
  • Sarcoma (Kaposi sarcoma, soft tissue sarcoma such as leiomyosarcoma, malignant peripheral nerve tumor, malignant bone tumor such as osteosarcoma), multiple myeloma, choriocarcinoma, soft tissue tumor, lung cancer (small cell lung cancer, non-small cell) Lung cancer, etc.), thyroid cancer, head and neck cancer, esophageal cancer, breast cancer, colon cancer, stomach cancer, biliary tract cancer, brain tumor, malignant melanoma, kidney cancer, pancreatic cancer, liver cancer, cervical cancer, testicular cancer, melanoma, skin It can be suitably applied to patients suffering from cancer or anal cancer.
  • autoimmune diseases eg, systemic lupus erythematosus and rheumatoid arthritis
  • infectious diseases eg, opportunistic infections
  • the content of the compound of the present invention in a medicament containing the compound of the present invention as an active ingredient is usually about 0.01 to about 99.9% by weight, preferably Is from about 0.1 to about 50% by weight.
  • a medicament containing the compound of the present invention as an active ingredient may be referred to as the medicament of the present invention for convenience.
  • the compound of the present invention is blended with a pharmaceutically acceptable carrier, solid preparations such as tablets, capsules, granules and powders; liquid preparations such as syrups and injections; patches, ointments, plasters and the like It can be appropriately formulated as a transdermal absorption agent; an inhalant; and a suppository. Also in a form that can be performed continuously for any length of time that is therapeutically effective, such as intravenous instillation, skin patches, subcutaneous pumps, polymer implants; or administration using nanosphere formulations. May be administered.
  • the medicament of the present invention may be administered orally or parenterally, and the above-described compounds may be used alone or in combination of two or more.
  • various organic or inorganic carrier substances commonly used as pharmaceutical materials can be used as the pharmaceutically acceptable carrier. Specifically, excipients, lubricants, binders, disintegrants in solid preparations, solvents, dissolution aids, suspending agents, isotonic agents, buffering agents, soothing agents, etc. in liquid preparations can do. Moreover, formulation additives such as preservatives, antioxidants, colorants, sweeteners and the like can be used as necessary.
  • excipients include lactose, sucrose, glucose, starch, sucrose, microcrystalline cellulose, licorice powder, mannitol, sodium bicarbonate, calcium phosphate, calcium sulfate and the like.
  • lubricants include magnesium stearate, stearic acid, calcium stearate, purified talc, colloidal silica and the like.
  • binder examples include crystalline cellulose, sucrose, mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like.
  • disintegrant examples include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium and the like.
  • the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like.
  • solubilizer examples include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
  • suspending agents include, for example, surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate; polyvinyl alcohol, polyvinyl pyrrolidone, Examples include sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the like.
  • surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate
  • polyvinyl alcohol polyvinyl pyrrolidone
  • examples include sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the like.
  • the isotonic agent include sodium chloride, glycerin, D-mannitol and the like.
  • buffers such as phosphate, acetate, carbonate and citrate.
  • soothing agent include benzyl alcohol.
  • Preferable examples of the preservative include paraoxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
  • Preferable examples of the antioxidant include sulfite and ascorbic acid.
  • Preferable examples of the colorant include tar pigment, caramel, iron sesquioxide, titanium oxide, riboflavin and the like.
  • Preferable examples of the sweetening agent include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin, simple syrup and the like.
  • the compound of the present invention can be administered to mammals including humans, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, pigs, etc., preferably humans.
  • the dose of the compound of the present invention depends on age, body weight, general health condition, sex, meal, administration time, administration method, excretion rate, drug combination, and the degree of the medical condition being treated at the time of the patient, It is decided in consideration of these and other factors.
  • the dose varies depending on the target disease, symptom, administration subject, administration method, and the like. ), More preferably about 1 to 3 mg / kg (body weight) is preferably administered once or in 2 to 3 divided doses.
  • the compound of the present invention can be administered alone to obtain a desired effect, or is used in combination with other antiviral agents (eg, other anti-HIV agents) and other agents useful for the treatment of viral infections. be able to. Since the compound of the present invention has a mechanism of action different from that of the conventional antiviral agent, there is a possibility that an effect that could not be obtained with the conventional antiviral agent may be obtained. It is possible to avoid problems such as side effects that have been a concern. For example, even in the presence of strains resistant to any of the other conventional anti-HIV agents, the compounds of the present invention can effectively modulate virus growth.
  • other antiviral agents eg, other anti-HIV agents
  • drugs that can be used in combination with the compounds of the present invention include HIV reverse transcriptase inhibitors, HIV protease inhibitors, HIV integrase inhibitors, DNA polymerase inhibitors or DNA synthesis inhibitors, interferons or interferon agonists HIV antisense drugs, anti-HIV antibodies or other antibodies, HIV vaccines or other vaccines, interferons or interferon agonists, CCR5 antagonists, drugs acting on HIV p24, HIV fusion inhibitors, IL-2 agonists or It is selected from antagonists, purine nucleoside kinase inhibitors, apoptosis agonists or inhibitors, cholinesterase inhibitors, immunomodulators and the like. Two or three or more drugs can be used in combination. Combination of drugs having different mechanisms of action is one embodiment of the present invention. In addition, the selection of medicaments without duplication of side effects is another embodiment of the present invention.
  • HIV reverse transcriptase inhibitors include Retrovir® (zidovudine or AZT), Epivir® (lamivudine or 3TC), Zelit® (sanylvudine), Widex® (Didanocin), Hibit (registered trademark) (zarcitabine), Ziagen (registered trademark) (abacavir sulfate), Viramun (registered trademark) (nevirapine), Stoclin (registered trademark) (efavirenz), Lescriptor (registered trademark) (mesyl) Delavirdine acid), Combivir (registered trademark) (zidovudine + lamivudine), Tridivir (registered trademark) (abacavir sulfate + lamivudine + zidovudine), Coactinone (registered trademark) (emivirin), Phosphonovir (registered trademark), Kobilacil (Registered trademark), Alob (3′-fluoro-3′-de
  • HIV protease inhibitors include: Crixiban® (Indinavir Sulfate Ethanolate), Saquinavir, Inbilase® (Saquinavir Mesylate), Norvir® (Ritonavir), Viraccept® (Nelfinavir mesylate), lopinavir, Prose (registered trademark) (amprenavir), Kaletra (registered trademark) (ritonavir + lopinavir), mozenavir dimesylate (dimethanesulfonic acid [4R- (4 ⁇ , 5 ⁇ , 6 ⁇ ) )]-1--3-bis [(3-aminophenyl) methyl] -hexahydro-5,6-dihydroxy-4,7-bis (phenylmethyl) -2H-1,3-diazepin-2-one), tipranavir (3 ′-[(1R) -1-[(6R) -5,6-dihydro-4-hydroxy 2-oxo-6-one),
  • the HIV integrase inhibitor can be S-1360, L-870810, and the like.
  • DNA polymerase inhibitors or DNA synthesis inhibitors are: Focavir®, ACH-126443 (L-2 ′, 3′-didehydro-dideoxy-5-fluorocytidine), Entecavir ((1S, 3S, 4S) -9 -[4-hydroxy-3- (hydroxymethyl) -2-methylenecyclopentyl] guanine), calanolide A ([10R- (10 ⁇ , 11 ⁇ , 12 ⁇ )]-11,12-dihydro-12-hydroxy-6,6, 10,11-tetramethyl-4-propyl-2H, 6H, 10H-benzo [1,2-b: 3,4-b ′: 5,6-b ′′] tripyran-2-one), calanolide B, NSC -67447 (1,1'-azobisformamide), Iskadol (viscum alubm extract), Rubutecan, etc.
  • the HIV antisense drug can be HGTV-43, GEM-92, etc.
  • the anti-HIV antibody or other antibodies are NM-01, PRO-367, KD-247, Citrine®, TNX- 355 (CD4 antibody), AGT-1, PRO-140 (CCR5 antibody), anti-CTLA-4 Mab, etc.
  • HIV vaccines or other vaccines include ALVAC®, AIDSVAX®, Lemune (registered) Trademark), HIV gp41 vaccine, HIV gp120 vaccine, HIV gp140 vaccine, HIV gp160 vaccine, HIVp17 vaccine, HIVHp24 vaccine, HIVp55 vaccine, AlphaVax vector system, Canarypox gp160 vaccine, AntiTat, MVA-F6 ef vaccine, HIV rev vaccine, C4-V3 peptide, p2249f, VIR-201, HGP-30W, TBC-3B, etc. PARTICLE-3B, Antiferon (interferon - ⁇ vaccines) and the like.
  • the interferon or interferon agonist may be Sumiferon (registered trademark), Multiferon (registered trademark), Interferon- ⁇ , Reticulose, human leukocyte interferon ⁇ , and the like.
  • the CCR5 antagonist can be SCH-351125 or the like.
  • the medicament acting on HIV p24 can be GPG-NH2 (glycyl-prolyl-glycinamide) and the like.
  • the HIV fusion inhibitor is FP-21399 (1,4-bis [3-[(2,4-dichlorophenyl) carbonylamino] -2-oxo-5,8-disodium sulfonyl] naphthyl-2, 5-dimethoxyphenyl-1,4-dihydrazone), T-1249, Synthetic®Polymeric®Construction®No3, pentafuside, FP-21399, PRO-542, enfuvirtide and the like.
  • the IL-2 agonist or antagonist may be interleukin-2, Imnes®, proleukin®, Multikine®, Ontac®, and the like.
  • the TNF- ⁇ antagonist can be Saromide® (thalidomide), Remicade® (infliximab), curdlan sulfate, and the like.
  • the ⁇ -glucosidase inhibitor may be Bucast® or the like.
  • the purine nucleoside phosphatase inhibitor may be perdecine (2-amino-4-oxo-3H, 5H-7-[(3-pyridyl) methyl] pyrrolo [3,2-d] pyrimidine).
  • Apoptotic agonists or inhibitors are: Arkin Z®, Panavir®, coenzyme Q10 (2-deca (3-methyl-2-butenylene) -5,6-dimethoxy-3-methyl -P-benzoquinone) and the like.
  • the cholinesterase inhibitor may be Cognex® or the like, and the immunomodulating agent may be Immunox®, Prokine®, Met-enkephalin (6-de-L-arginine- 7-de-L-arginine-8-de-L-valineamide-adrenorphine), WF-10 (10-fold diluted tetrachlorodecaoxide solution), Perthon, PRO-542, SCH-D, UK-427857, AMD -070, AK-602, etc.
  • Neurotrophin registered trademark
  • Lidakol registered trademark
  • Answer 20 registered trademark
  • Ampurigen registered trademark
  • Anticort registered trademark
  • Inactivin registered trademark
  • PRO-2000 RevROM10 gene
  • RevROM10 HIV specific cytotoxic T cells
  • RBC-CD4 complex motexafingadolinium
  • GEM-92 CNI ⁇ 1493, ( ⁇ ) -FTC
  • Ushercell D2S
  • BufferGel® BufferGel®
  • VivaGel® Glyminox ⁇ vaginal gel
  • sodium lauryl sulfate 2F5, 2F5 / 2G12, VRX-496
  • Ad5gag2, BG-777, IGIV -C BILR-255, etc. It may be used in combination therapy with compounds.
  • each dose varies depending on age, body weight, symptom, therapeutic effect, administration method, etc.
  • the doses clinically used for each drug can be used, but additive or synergistic effects can be expected by the combined use. Therefore, the dose of each drug can generally be reduced.
  • the compound of the present invention has an anticancer activity and is also effective for inflammation, autoimmune diseases, infectious diseases, etc., HIV infection affected by cancer, inflammation, autoimmune diseases, infectious diseases, etc. It can be suitably administered to a patient.
  • the compound of the present invention can be used in appropriate combination with an anticancer agent, an anti-inflammatory agent or an immunotherapeutic agent.
  • anticancer agents examples include antimetabolites (eg, methotrexate, 5-fluorouracil, etc.), alkylating agents (eg, cyclophosphamide, ifosfamide, etc.), platinum anticancer agents (eg, cisplatin, carboplatin, etc.), topoisomerase, etc.
  • Inhibitors eg, etoposide, etc.
  • anticancer antibiotics eg, mitomycin, adriamycin, etc.
  • plant-derived anticancer agents eg, vincristine, vindesine, taxol, etc.
  • tyrosine kinase inhibitors eg, gefitinib, imatinib, etc.
  • humanized antibodies eg, Herceptin
  • Anti-inflammatory agents include acetaminophen, phenacetin, ethenamide, sulpyrine, antipyrine, migrenin, aspirin, mefenamic acid, flufenamic acid, diclofenac sodium, loxoprofen sodium, phenylbutazone, indomethacin, ibuprofen, ketoprofen, naproxen, oxaprozin, flurbi Profen, fenbufen, pranoprofen, fructophenine, epilysole, tiaramid hydrochloride, zaltoprofen, gabexate mesilate, camostat mesilate, urinastatin, colchicine, probenade, sulfinpyrazone, benzbromarone, allopurinol, sodium gold thiomalate, sodium hyaluronate , Sodium salicylate, morphine hydrochloride, salicylic acid, atropy ,
  • immunotherapeutic agents include microorganisms or bacterial components (eg, muramyl dipeptide derivatives, picibanil, etc.), polysaccharides having immunopotentiating activity (eg, lentinan, schizophyllan, krestin, etc.), cytokines obtained by genetic engineering techniques (Eg, interferon, interleukin (IL), etc.), colony stimulating factor (eg, granulocyte colony stimulating factor, erythropoietin, etc.) and the like can be mentioned. Among them, IL-1, IL-2, IL-12 and the like are preferable.
  • the administration of the drug used in combination with the compound of the present invention can be administered simultaneously with the compound of the present invention, but may be administered separately. When administered simultaneously, it can also be produced as a single pharmaceutical preparation.
  • pharmaceutically acceptable carriers, excipients, diluents, extenders, disintegrants, stabilizers, preservatives, buffers, emulsifiers, flavoring agents, colorants, sweeteners, Mixed with thickeners, straighteners, solubilizers, other additives etc. it is generally water, vegetable oil, alcohol (eg ethanol or benzyl alcohol), polyethylene glycol, glycerol triacetic acid, gelatin, carbohydrates (eg , Lactose, starch, etc.), magnesium stearate, talc, lanolin, petrolatum and are known to contain tablets, pills, powders, granules, suppositories, injections, eye drops, liquids, capsules Formed into drugs, lozenges, aerosols,
  • two types of preparations obtained by separately formulating a compound to be used in combination with the compound of the present invention are administered simultaneously by the same route of administration, and the drug to be used in combination with the compound of the present invention is formulated separately.
  • Administration of the two preparations obtained by the same administration route with a time difference in the same administration route, simultaneous administration of the two preparations obtained by separately formulating the compound of the present invention and the drug used together in different administration routes examples include administration of two kinds of preparations obtained by separately formulating the compound of the present invention and a drug used in combination with different administration routes with a time difference.
  • the compound of the present invention is also effective in preventing the growth of retrovirus in an in vitro solution.
  • Human, animal and microbial cell cultures such as T lymphocyte cell cultures, are utilized for a variety of well-known purposes such as research and diagnostic procedures, including calibrators and controls.
  • the compound of the present invention is in an effective concentration that prevents inadvertent or undesired replication of retroviruses that may be inadvertently or inadvertently present in the cell culture. It can be added to the liquid.
  • viruses can be originally present in cell culture, for example HIV can be present in human T lymphocytes long before it can be detected in blood or through exposure to the virus.
  • the use of the compounds of the present invention prevents potentially lethal retrovirus exposure to unintentional or inadvertent researchers or doctors.
  • the compounds of the present invention can also be used effectively in in vitro screening methods to identify additional anti-HIV agents that may be beneficial in combination therapy with the compounds of the present invention for treating HIV infection.
  • a test compound is added to an HIV-infected cell culture in combination with the compound of the present invention, retrovirus replication in the cell culture is measured, and a standard sample (eg, a sample not containing the test compound, only the test compound) is measured. Containing samples, or other variants thereof).
  • a standard sample eg, a sample not containing the test compound, only the test compound
  • a standard sample eg, a sample not containing the test compound, only the test compound
  • T cell line Molt-4 obtained from RIKEN CELL BANK
  • T cell line HUT78 T cell lines Jurkat-HXBc2 and Jurkat-522F / Y (all from NIH AIDS Research & Reference Reagent Program IV, H -1 latency cell line U1 (obtained from NIH AIDS Research & Reference Reagent Program), TZM-bl cells (obtained from NIH AIDS Research & Reference Reagent Program) were used.
  • the HIV-1 strain NL4-3 obtained from NIH AIDS Research & Reference Reagent Program
  • GUT-70 provided by Saga University
  • PMA SIGMA-ALDRICH, ST.
  • TNF- ⁇ (Pepro Tech) were used.
  • Molt-4 cells were cultured in a medium supplemented with RPMI-1640 (Wako Pure Chemical Industries) with 10% fetal bovine serum (FCS, Thermo Scientific HyClone, South Logan, Utah, USA).
  • T cell line HUT78 is cultured in a medium supplemented with RPMI-1640 (Wako Pure Chemical Industries) with 10% fetal calf serum (FCS, Thermo Scientific HyClone, South Logan, Utah, USA), 100 U / mL penicillin and 50 ⁇ g / mL streptomycin. did.
  • Jurkat-HXBc2 cells and Jurkat-522F / Y cells were prepared using RPMI-1640 (Wako Pure Chemical Industries), 10% fetal calf serum (FCS, Thermo Scientific HyClone, South Logan, Utah, USA), 200 ⁇ g / mLG418 mL, 200 ⁇ g / mLG418 The cells were cultured in a medium supplemented with mycin and 1 ⁇ g / mL tetracycline.
  • U1 cells were cultured in RPMI-1640 (Wako Pure Chemical Industries) supplemented with 10% fetal calf serum (FCS, Thermo Scientific HyClone, South Logan, Utah, USA), 100 U / mL penicillin and 100 ⁇ g / mL streptomycin.
  • TZM-bl cells were cultured in a medium supplemented with 10% fetal calf serum (FCS, Thermo Scientific HyClone, South Logan, Utah, USA), 100 U / mL penicillin and 100 ⁇ g / mL streptomycin in DMEM (Wako Pure Chemical Industries).
  • Example 1 Suppression of HIV-1 Replication
  • the T cell line Molt-4 was infected with the HIV-1 strain NL4-3 by the spinoculation method (J. Virol., Vol. 74, p. 10074-10080, 2000). .
  • the cells were seeded at 1 ⁇ 10 5 cells / well in a 12-well microplate and cultured for 3 days. 0 to 10 ⁇ M of GUT-70 was added to the cells. Further, the cells were cultured for 4-7 days, stained with a FITC-labeled anti-p24 antibody (Beckman-Coulter, the same applies below) and using an LSR-II flow cytometer (BD Bioscience, San Jose, CA, the same applies below). The percentage of cells expressing p24 was analyzed.
  • the p24 antigen is a structural protein of HIV-1 virus, and the degree of HIV-1 replication can be measured by detecting the protein.
  • the results are shown in FIGS. 1-1 and 1-2.
  • mock indicates (HIV-1 and GUT-70 are not added), and con indicates (HIV-1 is added and GUT-70 is not added). Addition of GUT-70 suppressed HIV-1 replication.
  • the amount of p24 Gag protein in the cell culture supernatant on the 7th day of the culture was quantified by ELISA using an HIV-1 p24 antigen ELISA kit (Tropical Technology Center, Okinawa, Japan). did.
  • the results are shown in Fig. 1-3.
  • the horizontal axis represents the concentration of GUT-70 ( ⁇ M), and mock indicates (no GUT-70 added). Addition of GUT-70 suppressed HIV-1 replication.
  • T cell HUT78 (2.5 ⁇ 10 6 cells) was labeled with a final concentration of 2 ⁇ 10 ⁇ 6 M DPH (1,6-diphenyl-1,3,5-hexatriene; Wako Pure Chemicals) at 37 ° C. After incubation, light was shielded for 30 minutes. After labeling with DPH, the cells were washed with PBS and prepared with PBS to 2.5 ⁇ 10 6 cells / mL.
  • GUT-70 was added to the cells so that the final concentrations were 0, 10, and 50 ⁇ M, and the fluorescence polarization for 10 minutes after the addition was measured with a spectrofluorometer (F4500; Hitachi). The results are shown in FIG. If the rotation of the fluorescent molecule is large and the fluidity of the cell membrane is high, the fluorescence polarization P value is low. Conversely, if the rotation of the fluorescent molecule is small and the fluidity of the cell membrane is low, the fluorescence polarization P value is high. . In the T cells, the fluidity of the cell membrane was reduced by the addition of GUT-70 in a dose-dependent manner.
  • Example 3 Membrane inhibition of HIV-1 env expressing cells
  • the inhibitory effect of GUT-70 on cell membrane fusion was examined.
  • the T cell lines Jurkat-HXBc2 and Jurkat-522F / Y that had been cultured in the presence of tetracycline were washed with PBS to remove tetracycline and cultured for 3 days.
  • 2 ⁇ 10 6 Jurkat-HXBc2 and Jurkat-522F / Y cells were stained with PKH 26 Red Fluorescent Cell Linker Kit (SIGMA-ALDRICH, ST. Louis, MO) and used as a control T cell line (Molt- 4) was stained using PKH 67 Green Fluorescent Cell Linker Kit (SIGMA-ALDRICH, ST. Louis, Mo.) (Cytometry, vol. 47, p. 100-106, 2002).
  • FIG. 3-1 The results of calculating the degree of cell membrane fusion are shown in FIG. 3-2. Further, after 48 hours, observation with a fluorescence microscope was performed with Biozero (KEYENCE, Japan). The results are shown in FIG. GUT-70 inhibited membrane fusion of HIV-1 env expressing cells.
  • Example 4 Inhibition of HIV-1 infection by GUT-70 The inhibitory effect of GUT-70 on HIV-1 infection was examined. GUT-70 was added to T cell HUT78 (5 ⁇ 10 6 cells / mL) at 0, 10, 30, 50 ⁇ M and cultured at 37 ° C. for 1 hour. The cells were infected with HIV-1 strain NL4-3 (HIV-1 gag protein p24 concentration; 200 ng / mL), washed 1 hour later with PBS, and further cultured for 48 hours.
  • HIV-1 strain NL4-3 HIV-1 gag protein p24 concentration; 200 ng / mL
  • the cells were stained with a FITC-labeled anti-p24 antibody (Beckman-Coulter, the same applies hereinafter) as usual, and after LUT-II flow cytometer (BD Bioscience, San Jose, CA, the same applies below) after GUT-70 treatment. Intracellular p24 was detected. The results are shown in FIGS. 5-1 and 5-2.
  • TZM-bl cells (3.5 ⁇ 10 6 cells / mL) were infected with HIV-1 strain NL4-3 (HIV-1 gag protein p24 concentration; 50 ng / mL), and the same GUT- Intracellular p24 after 70 treatment was detected. The results are shown in FIGS. 5-3 and 5-4.
  • Example 5 Suppression of HIV-1 proliferation in HIV-1 latently infected cell line U1 U1 cells were seeded in a 6- well microplate at 1 ⁇ 10 6 cells / well, and 100 ng / mL PMA or 10 ng / mL TNF- ⁇ was added and cultured for 24 hours to induce HIV-1 production (J. Immunol., vol. 140, p. 1171-1122, 1988, Biol. Pharm. Bull., vol. 31, p. 2334-). 2337, 2008). GUT-70 was added to the system to a final concentration of 1, 3, 10 ⁇ M. The results are shown in FIGS. 6-1 and 6-2. HIV-1 production was suppressed in a dose-dependent manner with GUT-70.
  • the amount of p24 Gag protein in the cell culture supernatant was quantified using the HIV-1 p24 antigen ELISA kit (Tropical Technology Center, Okinawa, Japan) as described above. The results are shown in Fig. 6-3.
  • Example 6 Transcriptional repression of HIV-1 TZM-bl cells (CD4 and CCR5 were introduced into a HeLa cell line, and luciferase under the HIV-1 promoter was added to a 6- well microplate at 1 ⁇ 10 6 cells / well. And a cell line into which the ⁇ -galactosidase gene was introduced separately) and 0.2 ⁇ h of GUT-70 was added after 0.2 hours as a pretreatment. 2 ng / mL or 10 ng / mL of HIV-1 strain NL4-3 is infected by spinoculation method (J. Virol., vol. 74, p. 10074-10080, 2000), and the cells are seeded in a 24-well microplate. did.
  • Example 7 Inhibition of HIV-1 NF-kappaB Activation It is known that there are two NF-kappaB binding regions in the LTR region of HIV-1. Therefore, an HIV-1 latently infected cell line U1 was prepared in the same manner as in Example 5. To the cells, 10 ng / mL TNF- ⁇ and 10 ⁇ M GUT-70 were added. Those not added were prepared for comparison. Separate the nuclear extract from the cells after addition (+) and non-addition (-) of GUT-70, load 10 ⁇ g of nuclear protein onto 10% SDS-polyacrylamide gel, and separate by electrophoresis. Transferred to PVDF membrane.
  • the membrane was reacted with anti-p-65 monoclonal antibody (Santa Cruz, CA), anti-pp-65 monoclonal antibody (Santa Cruz, CA), anti-HSC70 antibody (Santa Cruz, CA), 0.5, 2, 4 6, 12, 24 hours later, activation of NF-kappaB was detected (Biol. Pharm. Bull., Vol. 31, p. 2334-2337, 2008).
  • GUT-70 inhibited the activation (phosphorylation) of NF-kappaB by addition of 10 ng / mL TNF- ⁇ . The results are shown in FIG.
  • Example 8 Inhibition of DNA Binding and Transcriptional Suppression of NF-kappaB
  • an HIV-1 latently infected cell line U1 was prepared, and 10 ng / mL TNF- ⁇ and 10 ⁇ M GUT-70 were added. . 0.5, 1 hour, 4 hours later, nuclear extracts were separated from U1 cells after GUT-70 addition (+) and non-addition (-), respectively, and DNA binding activity of NF-kappaB was detected by gel shift assay (Int. J. Cancer, vol. 125, p. 1464-1472, 2009). Furthermore, the transcriptional activity of the cells after 2, 4 hours was measured by luciferase assay in the same manner as in Example 4 (Biol. Pharm. Bull., Vol. 31, p. 2334-2337, 2008). It was suggested that GUT-70 inhibits NF-kappaB DNA binding and represses transcription. The results are shown in FIG.
  • GUT-70 has the effect of inhibiting the replication and transcription of HIV-1 and also reduces the fluidity of the cell membrane, and inhibits the entry of HIV-1 into the cell as well as the cell membrane fusion inhibitory action. It has also been shown to have an effect.
  • An anti-HIV agent having such a mechanism of action is not known, and the compound of the present invention having a new mechanism of action provides a new possibility for the treatment of AIDS.
  • the compound of the present invention has a growth inhibitory action against HIV, a fluidity lowering action of cell membrane, a cell membrane fusion inhibitory action, etc., and can be applied to the AIDS treatment field. Moreover, since the compound of the present invention also has an anticancer activity, it can be applied not only to HIV infection but also to patients with malignant tumors, and is thus extremely useful clinically.

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Abstract

La présente invention a pour objet de résoudre le problème consistant à fournir un agent antiviral et, plus particulièrement, un agent anti-VIH, doté d'un mécanisme de fonctionnement innovant. La présente invention concerne un médicament qui constitue un agent antiviral comprenant un composé représenté par la formule générale (I) ou un sel pharmaceutiquement acceptable de ladite composition en tant qu'ingrédient actif, ledit médicament ayant un effet inhibiteur de prolifération, un effet réducteur de fluidité de membrane cellulaire, un effet inhibiteur de fusion de membrane cellulaire, etc. sur le VIH. Dans la formule générale (I), chaque symbole est tel que défini dans la description.
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