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WO2016056606A1 - Dérivé benzoisothiazolopyrimidine et sel de ce dernier, et inhibiteur d'infection virale et médicament - Google Patents

Dérivé benzoisothiazolopyrimidine et sel de ce dernier, et inhibiteur d'infection virale et médicament Download PDF

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Publication number
WO2016056606A1
WO2016056606A1 PCT/JP2015/078540 JP2015078540W WO2016056606A1 WO 2016056606 A1 WO2016056606 A1 WO 2016056606A1 JP 2015078540 W JP2015078540 W JP 2015078540W WO 2016056606 A1 WO2016056606 A1 WO 2016056606A1
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group
carbon atoms
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atom
salt
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Inventor
松岡　雅雄
和也 志村
藤井　信孝
浩章 大野
真也 大石
司 水原
志穂 岡崎
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Kyoto University NUC
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to a benzisothiazolopyrimidine derivative or a salt thereof, a virus infection inhibitor, and a pharmaceutical product.
  • an object of the present invention is to provide a novel compound having antiviral activity.
  • R 1 , R 2 , and R 3 each independently represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, or a carbon number
  • the virus infection inhibitor of the present invention comprises the compound of the present invention or a salt thereof.
  • the pharmaceutical product of the present invention is characterized by containing the compound of the present invention or a salt thereof.
  • the production method of the present invention uses at least one derivative of a pyrimidobenzothiazine-6-imine derivative (raw material A) and a pyrimidobenzothiazine-6-thione derivative (raw material B) as a synthetic raw material, Obtaining a thiophenol derivative from the raw material as an intermediate, and The method for producing the compound of the present invention or a salt thereof, comprising the step of oxidizing the intermediate.
  • the compound of the present invention has antiviral activity against HIV and the like, it can be used, for example, as a viral infection inhibitor and is extremely useful in the medical field.
  • FIG. 1 is a graph showing the relationship between the addition time of a drug sample after infection with HIV virus in Example 3 and the infection rate (%).
  • FIG. 2 is a graph showing the results of herpesvirus infection inhibition rate in Example 3.
  • a compound in which X 1 and X 2 are crosslinked is represented by the following formula (II).
  • R 1 , R 2 , and R 3 each independently represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, or a carbon number
  • R 4 is a methylene group, an ethylene group or an ethylidene group.
  • R 4 is a group having a structure represented by the following formula (2) or (3).
  • R 6 represents an alkyl group having 1 to 6 carbon atoms, a phenyl group or a benzoyl group, R 6 may be further substituted with a substituent, The substituent is an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkylcarbonyl group having 1 to 3 carbon atoms, an alkoxycarbonyl group having 1 to 3 carbon atoms, or an alkyl having 1 to 3 carbon atoms.
  • Y represents a methylene group or an oxygen atom, Y may be further substituted with a substituent, The substituent is an alkyl group having 1 to 6 carbon atoms or a halogen atom.
  • the aryl group or the heteroaryl group is a 5-membered ring or a 6-membered ring.
  • the aryl group has a structure represented by the following formula (1).
  • R 7 , R 8 , R 9 , R 10 and R 11 are each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a fluoroalkyl group having 1 to 6 carbon atoms, A fluoroalkoxy group having 1 to 6 carbon atoms, an alkylcarbonyl group having 1 to 3 carbon atoms, an alkoxycarbonyl group having 1 to 3 carbon atoms, an aminocarbonyl group, a halogen atom, a nitro group, a hydroxyl group, a cyano group, a methanesulfonylamino group, A benzoyl group or an alkylcarbonylamino group having 1 to 3 carbon atoms which may be substituted with a phenyl group; R 7 , R 8
  • R 2 is a hydrophobic functional group.
  • R 1 , R 2 , and R 3 are each independently a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkoxy group having 1 to 6 carbon atoms.
  • the halogen atom is a bromine atom
  • the alkyl group having 1 to 6 carbon atoms is a methyl group;
  • the alkoxy group having 1 to 6 carbon atoms is a methoxy group;
  • the aryl group having 5 to 10 carbon atoms is a phenyl group or a naphthyl group;
  • the aryl group having 5 to 10 carbon atoms substituted with an alkoxy group having 1 to 6 carbon atoms is a methoxyphenyl group;
  • the heteroaryl group having 1 to 10 carbon atoms is a furanyl group or a thiophenyl group;
  • An alkylcarbonylamino group having 1 to 6 carbon atoms is an acetylamino group,
  • the fluoroalkyl group having 1 to 6 carbon atoms is a trifluoromethyl group.
  • R 1 and R 3 are each independently a hydrogen atom
  • R 2 is a halogen atom, an alkoxy group having 1 to 6 carbon atoms, an aryl group having 5 to 10 carbon atoms, an aryl group having 5 to 10 carbon atoms substituted with an alkoxy group having 1 to 6 carbon atoms, 10 heteroaryl groups, nitro groups, or fluoroalkyl groups having 1 to 6 carbon atoms.
  • R 2 and R 3 are each independently a hydrogen atom
  • R 1 is a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an aryl group having 5 to 10 carbon atoms, a heteroaryl group having 1 to 10 carbon atoms, or 1 to 6 carbon atoms Of the fluoroalkyl group.
  • R 1 and R 2 are hydrogen
  • R 3 is the aryl group, the substituted aryl group, the heteroaryl group, or the substituted heteroaryl group.
  • any one of R 1 , R 2 and R 3 is the aryl group, the substituted aryl group, the heteroaryl group, or the substituted heteroaryl group. It is.
  • the substituent is an alkoxy group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 1 to 3 carbon atoms, a hydroxyl group, or a nitro group. is there.
  • the substituent is a methoxy group, a methoxycarbonyl group, a hydroxyl group, or a nitro group.
  • the substituted aryl group is a 3,4-methylenedioxyphenyl group or a naphthyl group.
  • the heteroaryl group is a pyridinyl group.
  • the heteroaryl group is a furanyl group, a thiophenyl group, an imidazolyl group, a pyrazolyl group, or a 1,2,3-triazolyl group.
  • X 1 is a thiol group, a hydroxyl group, or an amino group (—NH 2 ), X 2 is a nitrogen atom (—NH—).
  • the pharmaceutical product of the present invention is for viral infections, for example.
  • the virus is at least one virus selected from the group consisting of human immunodeficiency virus (HIV), human herpes virus, influenza virus and human hepatitis C virus (HCV).
  • HAV human immunodeficiency virus
  • HCV human herpes virus
  • influenza virus influenza virus
  • HCV human hepatitis C virus
  • the synthetic raw material is the pyrimidobenzothiazine-6-imine derivative (raw material A),
  • the thiophenol derivative is obtained as an intermediate by acid decomposition of the synthetic raw material.
  • the synthetic raw material is the pyrimidobenzothiazine-6-thione derivative (raw material B),
  • the synthetic raw material is alkali decomposed to obtain the thiophenol derivative as an intermediate.
  • the compound of the present invention or a salt thereof is referred to as the compound of the present invention unless otherwise specified, and the compound of the present invention can be read as the salt of the compound of the present invention.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • the alkyl group having 1 to 6 carbon atoms may be linear, branched, cyclic, or a combination thereof.
  • Examples of the alkyl group include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, pentyl group, hexyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, Examples thereof include a cyclopropylmethyl group and a cyclobutylethyl group.
  • an alkoxy group having 1 to 6 carbon atoms an alkylcarbonyl group having 1 to 6 carbon atoms, an alkylcarbonylamino group having 1 to 6 carbon atoms, a fluoroalkyl group having 1 to 6 carbon atoms, and an alkylsulfonyl group having 1 to 6 carbon atoms
  • the alkyl group having 1 to 6 carbon atoms is included in a part of the substituents such as a group
  • the alkyl group is the same, for example.
  • the indicated carbon number means the carbon number of the alkyl group, and does not include the carbon of the carbonyl group.
  • An aryl group is a monovalent aromatic hydrocarbon group.
  • the aryl group may further have a substituent, for example.
  • the aryl group may be, for example, monocyclic or polycyclic (fused ring) in which two or more monocycles are shared (fused).
  • Each ring may be, for example, a 5-membered ring or a 6-membered ring.
  • the number of carbon atoms of the aryl group is not particularly limited, and examples thereof include 5 to 60, 6 to 60; 5 to 20, 6 to 20; 5 to 10, 6 to 10, and the like.
  • Examples of the aryl group include a phenyl group, a naphthyl group, an anthracenyl group, a pyrenyl group, a fluorenyl group, and a biphenyl group.
  • the heteroaryl group is a group obtained by substituting any one or more carbons with another hetero atom in the monovalent aromatic hydrocarbon group.
  • the hetero atom include an oxygen atom, a sulfur atom, and a nitrogen atom, and the number of the hetero atoms is not particularly limited.
  • the heteroaryl group may further have a substituent, for example.
  • the heteroaryl group may be, for example, monocyclic or polycyclic (fused ring) in which two or more monocycles are shared (fused). Each ring may be, for example, a 5-membered ring or a 6-membered ring.
  • the number of carbon atoms of the heteroaryl group is not particularly limited and is, for example, 2 to 60, 3 to 60, 5 to 60, 6 to 60; 2 to 20, 3 to 20, 5 to 20, 6 to 20; 10, 3 to 10, 5 to 10, 6 to 10 and the like.
  • the heteroaryl group include a furanyl group, a thiophenyl group, a pyrrolyl group, an oxazolyl group, a thiazolyl group, an imidazolyl group, a pyridazolyl group, a pyridyl group, a benzofuryl group, a benzothienyl group, and a thienothienyl group.
  • the alkenyl group having 2 to 6 carbon atoms may be, for example, linear, branched, cyclic, or a combination thereof.
  • Examples of the alkenyl group include a vinyl group, a propenyl group, a butenyl group, a pentenyl group, a hexenyl group, a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, and a cyclopropenylmethyl group.
  • the alkynyl group having 2 to 6 carbon atoms may be, for example, linear or branched, and examples thereof include an ethynyl group and a propargyl group.
  • the alkylene group is a divalent group having one free valence from the hydrocarbons at both ends of the alkane chain (chain saturated hydrocarbon).
  • Examples of the linear alkylene group having 1 to 5 carbon atoms include a methylene group, an ethylene group, a trimethylene group, a tetramethylene group, and a pentamethylene group.
  • R 1 , R 2 and R 3 may be the same or different, and may be further substituted with a substituent.
  • R 1 and R 2 may be bridged, and R 2 and R 3 may be bridged.
  • a cyclic structure for example, a five-membered ring or a six-membered ring
  • the bridge formed by the adjacent substituents may include at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom or a sulfur atom.
  • R 4 represents a linear alkylene group having 1 to 5 carbon atoms or a hetero atom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, and R 4 represents Further, it may be substituted with a substituent.
  • R 4 is the alkylene group, the substituents on the alkylene group may be bonded to each other to form a crosslinked structure or a ring structure.
  • R 1 , R 2 and R 3 may be hydrogen atoms, any two may be hydrogen atoms, or any one may be a hydrogen atom.
  • Specific examples of the compound of the present invention for example, compounds in which all of R 1, R 2 and R 3 are hydrogen atoms, and is any one of hydrogen atoms of R 1, R 2 and R 3 and the remaining These are compounds in which the above two are substituents other than the hydrogen atom described above.
  • R 1 , R 2 and R 3 each independently represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or 2 to 6 carbon atoms.
  • An alkenyl group having 2 to 6 carbon atoms, an alkylene group having 2 to 6 carbon atoms, an aryl group, a heteroaryl group, a nitro group, an alkylcarbonylamino group having an alkyl group having 1 to 6 carbon atoms, 1 carbon atom Represents a fluoroalkyl group of ⁇ 6.
  • R 1 , R 2 and R 3 are, for example, an amino group, a mono- or dialkylamino group having 1 to 3 carbon atoms, an alkylcarbonylamino group having 1 to 3 carbon atoms, or a benzoylamino group.
  • R 1 , R 2 and R 3 may be further substituted with a substituent as described above.
  • the substituent is not particularly limited, and examples thereof include a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, and an alkynyl group having 2 to 6 carbon atoms.
  • the alkylcarbonyl group may be substituted with a phenyl group.
  • the position of the substituent is not particularly limited.
  • the substituent may be in the ortho position, the meta position, or the para position.
  • the aryl group or the heteroaryl group is preferably a 5-membered ring or a 6-membered ring.
  • Examples of the aryl group include a six-membered ring group having a structure represented by the following formula (1).
  • R 7 , R 8 , R 9 , R 10 and R 11 are each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a fluoroalkyl group having 1 to 6 carbon atoms, A fluoroalkoxy group having 1 to 6 carbon atoms, an alkylcarbonyl group having 1 to 3 carbon atoms, an alkoxycarbonyl group having 1 to 3 carbon atoms, an aminocarbonyl group, a halogen atom, a nitro group, a hydroxyl group, a cyano group, a methanesulfonylamino group, A benzoyl group, an aryl group, a heteroaryl group, or an alkylcarbonylamino group having 1 to 3 carbon atoms which may be substituted with a
  • heteroaryl group examples include groups having a structure in which at least one carbon atom constituting the six-membered ring in the formula (1) is substituted with a heteroatom.
  • hetero atom examples include a sulfur atom, a nitrogen atom, and an oxygen atom.
  • R 2 is preferably a hydrophobic functional group, for example.
  • the hydrophobic functional group include a phenyl group, a naphthyl group, a methoxyphenyl group (also referred to as anisyl group), and the like.
  • R 1 , R 2 and R 3 are each independently, for example, a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or 5 carbon atoms.
  • the halogen atom is a bromine atom
  • the alkyl group having 1 to 6 carbon atoms is a methyl group
  • the alkoxy group having 1 to 6 carbon atoms is a methoxy group
  • the aryl group having 5 to 10 carbon atoms is a phenyl group or a naphthyl group
  • the aryl group having 5 to 10 carbon atoms substituted with an alkoxy group having 1 to 6 carbon atoms is a methoxyphenyl group
  • the heteroaryl group having 1 to 10 carbon atoms is a furanyl group or a thiophenyl group
  • An alkylcarbonylamino group having 1 to 6 carbon atoms is an acetylamino group
  • the fluoroalkyl group having 1 to 6 carbon atoms is a trifluoromethyl group.
  • R 1 and R 3 are each independently a hydrogen atom
  • R 2 is a halogen atom, an alkoxy group having 1 to 6 carbon atoms, an aryl group having 5 to 10 carbon atoms, an aryl group having 5 to 10 carbon atoms substituted with an alkoxy group having 1 to 6 carbon atoms, 10 heteroaryl groups, nitro groups, or fluoroalkyl groups having 1 to 6 carbon atoms.
  • R 2 and R 3 are each independently a hydrogen atom
  • R 1 is a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an aryl group having 5 to 10 carbon atoms, a heteroaryl group having 1 to 10 carbon atoms, or 1 to 6 carbon atoms Of the fluoroalkyl group.
  • any one of R 1 , R 2 and R 3 is the aryl group, the substituted aryl group, the heteroaryl group, or the substituted heteroaryl group.
  • R 1 and R 3 are hydrogen, and R 2 is the aryl group, the substituted aryl group, the heteroaryl group, or the substituted heteroaryl group.
  • R 1 and R 2 are hydrogen, and R 3 is the aryl group, the substituted aryl group, the heteroaryl group, or the substituted heteroaryl group. is there.
  • the substituent is an alkoxy group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 1 to 3 carbon atoms, a hydroxyl group, or a nitro group.
  • the substituent is a methoxy group, a methoxycarbonyl group, a hydroxyl group, or a nitro group.
  • the substituted aryl group is a 3,4-methylenedioxyphenyl group or a naphthyl group.
  • the heteroaryl group is a pyridinyl group.
  • the heteroaryl group is a furanyl group, a thiophenyl group, an imidazolyl group, or a 1,2,3-triazolyl group.
  • X 1 is a thiol group, a hydroxyl group, or an amino group (—NH 2 ), and X 2 is a nitrogen atom (—NH—).
  • X 1 is more preferably a thiol group, and X 2 is more preferably a nitrogen atom (—NH—).
  • the compound of the present invention may not have R 4 in the formula (I).
  • the ring having R 4 is, for example, a five-membered ring.
  • R 4 is preferably, for example, an alkylene group having 1 to 6 carbon atoms.
  • alkylene include a methylene group (—CH 2 —), an ethylene group (—CH 2 —CH 2 —), an ethylidene group (CH—CH 3 ), and the like.
  • R 4 is a methylene group
  • the ring having R 4 is, for example, a six-membered ring
  • R 4 is an ethylene group
  • the ring having R 4 is, for example, a seven-membered ring.
  • R 4 may be further substituted with a substituent, for example, and examples of the substituent include the substituents as described above.
  • the substituent of R 4 may be crosslinked with an adjacent substituent.
  • the substituent at R 4 at the 5-position and the substituent at the 4-position or 6-position of the tetrahydropyrimidine ring may be bridged.
  • R 4 may be a group having a structure represented by the following formula (2) or (3), for example.
  • R 6 represents an alkyl group having 1 to 6 carbon atoms, a phenyl group or a benzoyl group, R 6 may be further substituted with a substituent, The substituent is an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkylcarbonyl group having 1 to 3 carbon atoms, an alkoxycarbonyl group having 1 to 3 carbon atoms, or an alkyl having 1 to 3 carbon atoms.
  • Y represents a methylene group or an oxygen atom, Y may be further substituted with a substituent, The substituent is an alkyl group having 1 to 6 carbon atoms or a halogen atom.
  • R 4 is, for example, a methylene group (—CH 2 —).
  • the compounds in Table 2 are specific examples of the compound of the formula (I).
  • the groups of R 1 , R 2 and R 3 are not particularly limited, and for example, the following table The groups shown in 3 to 6 may be used.
  • the compound of the present invention may be a compound in which X 1 and X 2 are cross-linked in the formula (I), and the compound is represented by the following formula (II), for example.
  • R 1 , R 2 , and R 3 each independently represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, or a carbon number
  • Amino group, mono- or dialkylamino group having 1 to 3 carbon atoms benzo
  • R 1 , R 2 , R 3 and R 4 are the same as those in the formula (I), and the above description can be used.
  • the five-membered isothiazole ring containing a sulfur atom and a nitrogen atom may be opened by breaking a nitrogen-sulfur bond.
  • the nitrogen atom derived from the nitrogen-sulfur bond may be substituted with an oxygen atom or a sulfur atom
  • the sulfur atom derived from the nitrogen-sulfur bond is substituted with an oxygen atom or a nitrogen atom.
  • An atom may be substituted.
  • the leftmost column is any one group of R 1 , R 2 and R 3 in the formula (II).
  • the remaining two groups are, for example, a hydrogen atom
  • R 4 is, for example, a methylene group (—CH 2 —).
  • Table 3 also shown a specific example of a compound having a group described in column of the left end R 2 or R 2 and R 3,.
  • H is a hydrogen atom
  • OMe is a methoxy group
  • Ph is a phenyl group
  • m-anisyl is an m-methoxyphenyl group
  • Br is a bromine atom
  • CH 3 is a methyl group
  • NO 2 is a nitro group
  • NHAc represents an acetylamino group (—NH—CO—CH 3 )
  • — (CH ⁇ CH) 2 — represents that R 1 and R 2 or R 2 and R 3 are bridged It shows that a benzene ring is formed (hereinafter the same).
  • the leftmost column is any one group of R 1 , R 2 and R 3 in the formula (II). In this case, the remaining two groups are, for example, a hydrogen atom, R 4 is, for example, a methylene group (—CH 2 —). In Table 4, specific examples of compounds having the group described in the leftmost column in R 1 or R 3 are also shown.
  • the leftmost column is one of R 1 , R 2 and R 3 in the formula (II).
  • the remaining two groups are, for example, a hydrogen atom
  • R 4 is, for example, a methylene group (—CH 2 —).
  • Table 5 also shown a specific example of a compound having a group described in column of the left end R 2.
  • the leftmost column is any one group of R 1 , R 2 and R 3 in the formula (II). In this case, the remaining two groups are, for example, a hydrogen atom, R 4 is, for example, a methylene group (—CH 2 —). In Table 6, specific examples of compounds having the group described in the leftmost column in R 2 are also shown.
  • examples of the salt of the compound of the formula (I) include a salt in a basic group such as a commonly known amino group or a salt in an acidic group such as a phenolic hydroxyl group or a carboxyl group. it can. The same applies to the salt of the compound of the formula (II).
  • Examples of the salt in the basic group include salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid; formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid , Salts with organic carboxylic acids such as tartaric acid, aspartic acid, trichloroacetic acid and trifluoroacetic acid; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid Etc.
  • mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid
  • formic acid acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid
  • salts in the acidic group include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine, N, N— Nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl- ⁇ -phenethylamine, 1-ephenamine and N, N′-dibenzylethylenediamine And salt.
  • preferable salts include, for example, pharmacologically acceptable salts.
  • the compound of the present invention includes, for example, an isomer (for example, an optical isomer, a geometric isomer, a tautomer, etc.), a hydrate, a solvation in the compound represented by the formula (I) or a salt thereof. And all crystalline forms. The same applies to the salt of the compound of the formula (II).
  • the compounds of the present invention exhibit activity against, for example, human immunodeficiency virus (HIV) and influenza virus, which are RNA viruses, and human herpesvirus, which is a DNA virus. For this reason, it is speculated that the compound of the present invention may inhibit a common site in the infection process of these viruses. In addition, it is speculated that the compound of the present invention may exhibit antiviral activity not only on these viruses but also on various viruses such as human hepatitis C virus (HCV). Many of the conventional antiviral agents target viral proteins, but the compounds of the present invention are effective against various viruses, and thus may act on host cells. It can also be expected to prevent infection.
  • HCV human immunodeficiency virus
  • influenza virus which are RNA viruses
  • human herpesvirus which is a DNA virus.
  • HCV human hepatitis C virus
  • viruses that can inhibit infection with the compounds of the present invention include human immunodeficiency virus (HIV) (for example, type 1 HIV and type 2 HIV), RNA viruses such as influenza virus, and DNA viruses such as herpes virus.
  • HIV human immunodeficiency virus
  • RNA viruses such as influenza virus
  • DNA viruses such as herpes virus.
  • herpes virus include human herpes virus.
  • Human herpesviruses include, for example, herpes simplex virus (HSV), and specific examples include herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2). For this reason, the compound of this invention can be used as a viral infection inhibitor, for example.
  • the compound of the present invention can inhibit the virus infection as described above, it can be used for the treatment of the DNA virus infection and the RNA virus infection, for example.
  • treatment includes, for example, prevention.
  • the compound of the present invention and a salt thereof can be synthesized, for example, by a known method or a combination thereof.
  • the following documents can be referred to.
  • the viral infection inhibitor of the present invention comprises the compound of the present invention or a salt thereof.
  • the virus infection inhibitor of the present invention is characterized by containing the compound of the present invention (or a salt thereof), and other configurations are not limited at all.
  • the description of the compound of the present invention or a salt thereof can be used for the virus infection inhibitor of the present invention, and in the above description, “compound or salt thereof” can be read as “virus infection inhibitor”.
  • the virus infection inhibitor of the present invention may contain other components in addition to the compound of the present invention, for example.
  • the other components are not particularly limited.
  • excipients for example, excipients, binders, disintegrants, disintegration inhibitors, caking / adhesion preventing agents, lubricants, absorption / adsorption carriers, solvents, extenders, isotonic agents.
  • Agent solubilizer, emulsifier, suspending agent, thickener, coating agent, absorption accelerator, gelation / coagulation accelerator, light stabilizer, preservative, moisture-proofing agent, emulsification / suspension / dispersion stability Agents, coloring inhibitors, deoxygenation / antioxidants, flavoring / flavoring agents, coloring agents, foaming agents, antifoaming agents, soothing agents, antistatic agents, buffer / pH adjusting agents, and the like.
  • the component is preferably, for example, a pharmaceutically acceptable component, and specifically, preferably a pharmaceutical additive.
  • the virus infection inhibitor of the present invention is, for example, an oral preparation (tablet, capsule, powder, granule, fine granule, pill, suspension, and the like, in addition to the compound of the present invention. Preparations, emulsions, solutions, syrups, etc.), injections, eye drops and the like.
  • the preparation can be formulated, for example, by a usual method.
  • Oral solid preparations such as tablets, powders, granules and the like include, for example, lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, crystalline cellulose, anhydrous dicalcium phosphate, partial alpha Excipients such as modified starch, corn starch and alginic acid; simple syrup, glucose solution, starch solution, gelatin solution, polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone, carboxymethylcellulose, shellac, methylcellulose, ethylcellulose, sodium alginate, gum arabic, hydroxypropyl Binders such as methylcellulose, hydroxypropylcellulose, water and ethanol; dried starch, alginic acid, agar powder, starch, crosslinked polyvinylpyrrolidone, crosslinked carboxyme Disintegrating agents such as sodium cellulose cellulose, carboxymethylcellulose calcium and sodium starch glycolate; disintegration inhibitors such as stearyl alcohol, stea
  • the tablet can be, for example, a tablet coated with a normal coating, for example, a sugar-coated tablet, a gelatin-encapsulated tablet, a gastric-coated tablet, an enteric-coated tablet, and a water-soluble film-coated tablet, if necessary.
  • a normal coating for example, a sugar-coated tablet, a gelatin-encapsulated tablet, a gastric-coated tablet, an enteric-coated tablet, and a water-soluble film-coated tablet, if necessary.
  • Capsules can be prepared, for example, by mixing the compound of the present invention with the above-mentioned various other components and filling them into hard gelatin capsules and soft capsules.
  • liquid formulations such as aqueous or oily suspensions, solutions, syrups and elixirs can be obtained.
  • Examples of the injection include diluents such as water, ethyl alcohol, macrogol, propylene glycol, citric acid, acetic acid, phosphoric acid, lactic acid, sodium lactate, sulfuric acid and sodium hydroxide; sodium citrate, sodium acetate and phosphoric acid PH adjusters and buffers such as sodium; stabilizers such as sodium pyrosulfite, ethylenediaminetetraacetic acid, thioglycolic acid and thiolactic acid; isotonic agents such as sodium chloride, glucose, mannitol or glycerin; sodium carboxymethylcellulose, propylene glycol Solubilizing agents such as sodium benzoate, benzyl benzoate, urethane, ethanolamine, glycerin; soothing agents such as calcium gluconate, chlorobutanol, glucose, benzyl alcohol; and ingredients such as local anesthetics Kill.
  • the injection can be prepared according to a conventional method using these pharmaceutical additives for
  • Eye drops include, for example, preservatives such as chlorobutanol, sodium dehydroacetate, benzalkonium chloride, cetylpyridinium chloride, phenethyl alcohol, methyl paraoxybenzoate and benzethonium chloride; borax, boric acid, potassium dihydrogen phosphate, etc.
  • preservatives such as chlorobutanol, sodium dehydroacetate, benzalkonium chloride, cetylpyridinium chloride, phenethyl alcohol, methyl paraoxybenzoate and benzethonium chloride
  • borax boric acid
  • potassium dihydrogen phosphate etc.
  • Thickeners such as methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, sodium carboxymethylcellulose and chondroitin sulfate; solubilizers such as polysorbate 80 and polyoxyethylene hydrogenated castor oil 60; sodium edetate And stabilizers such as sodium bisulfite; and isotonic agents such as sodium chloride, potassium chloride and glycerin.
  • the eye drop can be prepared according to a conventional method by appropriately blending these components.
  • the administration method of the preparation is not particularly limited, and can be determined as appropriate depending on, for example, the form of the preparation, the patient's age, sex and other conditions, and the degree of symptoms of the patient.
  • the dosage of the viral infection inhibitor of the present invention can be determined, for example, as the dosage of the compound of the present invention, which is an active ingredient. Specifically, the dosage, patient age, sex, disease form, other conditions, etc. It can be set appropriately according to. Specific examples include, for example, usually 0.1 to 500 mg of the compound of the present invention per day for an adult, divided into 1 to several times, and preferably 40 to 40 mg per day. 500 mg may be divided into 1 to several doses.
  • the pharmaceutical product of the present invention includes the compound of the present invention as described above.
  • the pharmaceutical agent of the present invention is characterized by containing the compound of the present invention or a salt thereof, and other configurations are not limited at all.
  • the description of the virus infection inhibitor of the present invention can be used for the drug of the present invention, and in the above description, “virus infection inhibitor” can be read as “medicament”.
  • the pharmaceutical product of the present invention is for viral infections, for example.
  • the virus is at least one virus selected from the group consisting of human immunodeficiency virus (HIV), human herpes virus, and influenza virus.
  • the production method of the compound of the present invention includes a pyrimidobenzothiazine-6-imine derivative (raw material A) and a pyrimidobenzothiazine-6-thione derivative (an intermediate production step of using at least one derivative of the raw material B) as a synthetic raw material and obtaining a thiophenol derivative from the synthetic raw material as an intermediate, and an oxidation step of oxidizing the intermediate are characterized.
  • the intermediate production step can also be referred to as, for example, a thiazine ring opening step in the raw material A and the raw material B.
  • the oxidation step of the intermediate can also be referred to as, for example, a step of cyclizing a thiophenol derivative obtained by opening a thiazine ring as a five-membered ring by oxidation.
  • a pyrimidobenzothiazine-6-imine derivative (raw material A)
  • it is preferably subjected to acid decomposition.
  • the acid decomposition the thiophenol derivative of the raw material A is obtained as an intermediate.
  • the conditions for the acid decomposition are not particularly limited.
  • a solvent containing an acidic substance and treat the raw material A in the solvent.
  • the acidic substance is not particularly limited, and examples thereof include trifluoroacetic acid.
  • the solvent is, for example, an organic solvent, an aqueous solvent, or a mixed solvent thereof.
  • the organic solvent is preferable, and examples thereof include ethanol, a mixed solvent of ethanol and chloroform, and the like. Specific examples include use of ethanol or a mixed solvent of ethanol and chloroform containing the trifluoroacetic acid.
  • a pyrimidobenzothiazine-6-thione derivative (raw material B) is used in the intermediate production step, it is preferably subjected to alkali decomposition.
  • alkali decomposition the thiophenol derivative of the raw material B is obtained as an intermediate.
  • the conditions for the alkali decomposition are not particularly limited.
  • a solvent containing an alkaline substance and treat the raw material B in the solvent.
  • the alkaline substance is not particularly limited, and examples thereof include sodium hydroxide.
  • the solvent is, for example, an organic solvent, an aqueous solvent, or a mixed solvent thereof.
  • the solvent include an organic solvent or a mixed solvent of an organic solvent and an aqueous solvent.
  • the organic solvent include methanol.
  • the mixed solvent include a mixed solvent of methanol and water. .
  • a specific example is the use of a mixed solvent of methanol and water containing sodium hydroxide.
  • the pyrimidobenzothiazine-6-imine derivative (raw material A) can be represented, for example, by the following formula (III).
  • R 1 ⁇ R 4 are the same as R 1 ⁇ R 4 in the formula (I), the both can be incorporated according in the compound or a salt thereof of the present invention.
  • the pyrimidobenzothiazine-6-thione derivative (raw material B) can be represented, for example, by the following formula (IV).
  • R 1 ⁇ R 4 are the same as R 1 ⁇ R 4 in the formula (I), the both can be incorporated according in the compound or a salt thereof of the present invention.
  • the treatment method of the present invention comprises the step of administering the compound of the present invention to a subject. Since the compound of the present invention has antiviral activity against the RNA virus and DNA virus as described above, it can be used for the treatment of these infectious diseases. In the present invention, the treatment includes, for example, prevention.
  • the administration method is not particularly limited, and examples thereof include oral administration and parenteral administration.
  • the above-mentioned description can be used for the administration method, dosage conditions, and the like.
  • the subject is not particularly limited, and examples thereof include humans and non-human animals. Examples of the non-human animals include mice, rats, guinea pigs, rabbits, sheep, pigs, cattle, cats, dogs, monkeys, baboons. And non-human mammals such as chimpanzees.
  • HPLC high performance liquid chromatography
  • a Cosmosil 5C18-ARII column (4.6 ⁇ 250 mm, manufactured by Nacalai Tesque, Inc.) was used. Elution was performed with a linear gradient of acetonitrile containing 0.1% (v / v) trifluoroacetic acid (TFA) at a flow rate of 1 mL / min, and the eluate was detected by UV (254 nm).
  • a Cosmosil 5C18-ARII preparative column (20 ⁇ 250 mm, manufactured by Nacalai Tesque, Inc.) was used.
  • Example 2 The various compounds synthesized in Example 1 were evaluated for anti-HIV virus activity.
  • Example 1 The various compounds synthesized in Example 1 were evaluated for anti-HIV activity. The evaluation was performed by the NCK assay based on the method described in the paper Journal of Clinical Microbiology, 2008, 46, 792-795 as shown below.
  • NCK45- ⁇ -Gal cells were seeded in a 96-well flat-bottom plate at 1 ⁇ 10 4 cells / well, cultured for 24 hours, and then replaced with a medium containing an appropriate dilution of the previous compound. Subsequently, HIV-1 (IIIB strain) was infected with 60 NCK units. After 48 hours of culture, the cells were fixed and HIV-1-infected cells were stained with X-gal and counted. The anti-HIV-1 activity of various compounds was calculated as EC 50 (50% effective concentration), the concentration that inhibits HIV-1 infection by 50%. Tables 7 to 9 show EC 50 values obtained using the compounds described above as the compounds of the examples.
  • each compound had an EC 50 of less than 2.2 ⁇ M, and about half of them showed a sufficiently low value of 1 ⁇ M or less. From these results, it was found that the compounds of Examples have excellent anti-HIV activity.
  • 1036J-152 in which m-methoxyphenyl group (m-anisyl group) is introduced as a hydrophobic functional group into R 2 in the above formula (II) is R 1 , R 2 and Compared with 1036J-129, in which all of R 3 are hydrogen atoms, the anti-HIV activity was improved by about 3 times, indicating that the anti-HIV activity was particularly excellent. Moreover, even if it used these compounds at the density
  • 1059D-13, 1059D-23, and 1059D-39 have about 6 times higher anti-HIV activity than 1036J-129, in which R 1 , R 2 and R 3 are all hydrogen atoms. And particularly excellent anti-HIV activity. From this, it was found that a more excellent anti-HIV activity can be realized by making R 2 a hydrophobic aryl group. It was also found that compounds other than 1059D-33 showed high safety without cytotoxicity even when used at a concentration of 10 ⁇ mol / L.
  • 1036J-167 which is a compound in which the isothiazole ring of 1036J-129 is opened, was also found to have equivalent excellent anti-HIV activity. From these results, it is suggested that the isothiazole derivative represented by the formula (II) may be ring-opened in a living body and exhibit antiviral activity as the thiophenol derivative represented by the formula (I). It was done. That is, the isothiazole derivative represented by the formula (II) can also be used as a prodrug of the thiophenol derivative represented by the formula (I).
  • Example 3 Of the various compounds synthesized in Example 1, 1036J-129 was evaluated for antiviral activity against various viruses.
  • DS5000 extract sulfate sodium salt, manufactured by Sigma
  • AZT 3′-azido
  • RAL raltegravir, manufactured by Selleck Chemicals
  • FIG. 1 is a graph showing the relationship between the addition time of a drug sample after virus infection and the infection rate (%).
  • 1036J-129 of Example compared the administration immediately after infection (0h) with the administration 2 hours after infection, and the latter (2h) was more infected than the former (0h). The rate (%) was high and the antiviral activity decreased. From these results, it was suggested that the compound of the present invention may act in the early stage of virus infection.
  • Vero cells derived from African green monkey kidney epithelial cells were used as target cells.
  • anti-HSV-1 activity and anti-HSV-2 activity of the drug samples were measured by plaque reduction assay (Plaque reduction assay). Specifically, the Vero cells were seeded in a 6-well plate at 5 ⁇ 10 5 cells / well and cultured overnight. Then, the obtained culture broth was replaced with 5% bovine serum-added DMEM to which a drug sample was added so as to be 1 ⁇ mol / L or 10 ⁇ mol / L, and HSV-1 (VR-3 strain) or HSV-2 ( UW268 strain) was infected with 100 PFU. The cells were cultured at 37 ° C. for 48 hours, fixed with methanol, stained with 0.1% crystal violet solution, and the number of plaques was measured.
  • DMSO dimethyl sulfoxide
  • FIG. 2 is a graph showing the infection rate (%).
  • (A) shows the infection rate of HSV-1
  • (B) shows the infection rate of HSV-2.
  • 1036J-129 of the example also has infection inhibitory activity against DNA viruses HSV-1 and HSV-2.
  • the MDCK cells were seeded in a 96-well plate at 1 ⁇ 10 4 cells / well and cultured overnight.
  • the well plate was washed with 0.1% bovine serum albumin-added DMEM, then added with 1% bovine serum albumin-added DMEM containing a drug sample, and human influenza A virus (A / PR / 8/34 strain) was added.
  • human influenza A virus A / PR / 8/34 strain
  • the cells were cultured at 37 ° C. for 72 to 96 hours, and then the number of viable cells was measured by the MTT [3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide] method.
  • Example 1 As the drug sample, 1036J-129 of Example 1 was used as an example, and anti-influenza virus activity was evaluated. In addition, as a control, the 1% bovine serum albumin-added DMEM without the drug sample was used instead of the medium to which the drug sample was added.
  • the anti-influenza virus activity is calculated by calculating the EC 50 (50% effective concentration) as the concentration that inhibits influenza virus infection by 50%, and the concentration at which 50% of the cells survive as CC 50 (50% cytotoxicity concentration). Calculated.
  • Example 1036J-129 also showed inhibitory activity against influenza virus.
  • the compound of the present invention since the compound of the present invention has antiviral activity against HIV and the like, it can be used, for example, as a viral infection inhibitor and is extremely useful in the medical field.

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Abstract

L'invention concerne un nouveau composé qui présente une activité antivirale. Le composé ou un sel de ce dernier, est caractérisé en ce qu'il est représenté par la formule (I). R1-R3 représentent indépendamment un atome H, un atome d'halogène, un groupe alkyle en C1-6, un groupe alcoxy en C1-6, un groupe alcényle en C2-6, un groupe alcynyle en C2-6, un groupe alkylène en C2-6, un groupe aryle, un groupe hétéroaryle, un groupe nitro, un groupe alkyl carbonyl amino avec un groupe alkyle en C1-6, un groupe fluoroalkyle en C1-6, un groupe amino, mono-ou di-alkyl amino en C1-3, un groupe benzoyl amino, un groupe azoture, un groupe carboxyle, un groupe alkyl carbonyle en C1-3, un groupe alcoxy carbonyle en C1-3, un groupe carbamoyle, un groupe naphtyle, un groupe hétéroaryle, un groupe styryle, un groupe alkylthio en C1-3, ou un groupe hydroxy alkyle en C1-6, pouvant être substitués par un substituant, et peuvent être identiques ou différents; R1 et R2, et R2 et R3 peuvent être réticulés, et une réticulation entre des substituants adjacents peut contenir un hétéroatome; R4 représente un groupe alkylène linéaire en C1-5 ou un hétéroatome, peut être substitué par un substituant, et lorsque R4 est un groupe alkylène, les substituants sur le groupe alkylène peuvent se lier l'un à l'autre pour former une structure réticulée ou une structure cyclique; X1 et X2 représentent indépendamment un hétéroatome, peuvent être substitués par un substituant, peuvent être identiques ou différents, et peuvent être réticulés.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3371195B1 (fr) * 2015-11-03 2021-04-21 Hochschule Darmstadt Inhibiteurs de hdac8 sélectifs et leurs utilisations
US11801251B2 (en) 2015-11-03 2023-10-31 Hochschule Darmstadt Selective HDAC8 inhibitors and their uses

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