WO1999042106A1 - Agent anti-hcmv - Google Patents

Agent anti-hcmv Download PDF

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Publication number
WO1999042106A1
WO1999042106A1 PCT/JP1999/000728 JP9900728W WO9942106A1 WO 1999042106 A1 WO1999042106 A1 WO 1999042106A1 JP 9900728 W JP9900728 W JP 9900728W WO 9942106 A1 WO9942106 A1 WO 9942106A1
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group
carbon atoms
formula
substituted
methoxy
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PCT/JP1999/000728
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English (en)
Japanese (ja)
Inventor
Masako Ishimura
Hidehiko Furukawa
Tetsushi Katsube
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Sankyo Company, Limited
Ube Industries, Ltd.
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Application filed by Sankyo Company, Limited, Ube Industries, Ltd. filed Critical Sankyo Company, Limited
Priority to AU25476/99A priority Critical patent/AU2547699A/en
Publication of WO1999042106A1 publication Critical patent/WO1999042106A1/fr

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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines

Definitions

  • the present invention relates to a herbal composition
  • a herbal composition comprising a quinoline carboxylic acid derivative having an activity of inhibiting the proliferation of Heldwill virus, especially human cytomegalovirus (hereinafter referred to as HCMV) as an active ingredient.
  • the present invention relates to a method for treating or preventing lupus infection (particularly HCMV infection).
  • HCMV human cytomegalovirus
  • the present inventors have studied the anti-HCMV activity of various quinolone carboxylic acid derivatives, and found that they were substituted with aryl or heteroaryl groups which may have a substituent in the molecule.
  • the present inventors have found that a quinolone carboxylic acid derivative which has enhanced lipid solubility and reduced antibacterial activity by introducing cyclic diamins can suppress virus growth in HCMV-infected cells.
  • a quinolone carboxylic acid derivative which is an active ingredient of the present invention is represented by the following general formula (Ia), (b) or (Ic).
  • X represents a hydrogen atom or a halogen atom
  • Y is a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, an amino group, or a mono- or dialkyl-substituted amino group substituted with 1 to 2 alkyl groups having 1 to 4 carbon atoms.
  • Z represents an optionally protected carboxy group or 5 —tetra 'zolyl group
  • R 2 represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms which may be substituted with a halogen, or 1 carbon atom which may be substituted with a halogen. Represents from 4 to 4 alkoxy groups] Denote the group,
  • W represents an oxygen atom or a sulfur atom
  • T is an alkylene group having 1 to 4 carbon atoms which may be substituted with alkyl having 1 to 4 carbon atoms or 2 to 4 carbon atoms which may be substituted with alkyl having 1 to 4 carbon atoms.
  • R 1 is a hydrogen atom; an alkyl group which may be substituted and has 1 to 4 carbon atoms [substituents of the alkyl group are hydroxy, carboxy, and nitrogen carbon atoms] to 4 alkoxy and carbon
  • R ⁇ and R 1 ° each represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, or some resins have R 9 and R 10 together. Together with the nitrogen atom to which they are attached, may optionally form a 3- to 7-membered saturated monocyclic ring containing a heteroatom selected from N, O and S), or The 5- to 6-membered heteroaromatic containing 1 to 2 heteroatoms selected from N, O and S, which may be substituted by R 0 , may be a C 6 to C 10 aryl group.
  • a 6 to 10-membered aryl group or a 5- or 6-membered heteroaromatic monocyclic group containing 1 or 2 heteroatoms selected from NO and S, or a fused benzene ring with these heteroaromatic monocycles Represents a fused heteroaromatic fused ring group
  • A represents a hydrogen atom or a halogen, hydroxy or an alkyl group having 1 to 4 carbon atoms which may be substituted with alkoxy having 1 to 4 carbon atoms, and G represents a nitrogen atom.
  • G represents a nitrogen atom.
  • G 1 represents a methylene group, a carbonyl group, an oxygen atom, a sulfur atom or one N (R 11 ) group (wherein R 11 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms) And p represents 0 or 1.] represents a group represented by
  • R is the formula (h) or the formula (i)
  • R 3 and R 6 are R 0 (R ° is halogen, nitro, hydroxy, alkyl having 1 to 4 carbon atoms, fluorine) Substituted with substituted alkyl of 1 to 4 carbons, alkoxy of 1 to 4 carbons, alkylthio of 1 to 4 carbons, amino and alkyl of 1 to 2 carbons of 1 to 4 carbons Selected from mono- or dialkyl-substituted aminos), aryl groups having 6 to 10 carbon atoms, selected from N, O and S A 5- or 6-membered heteroaromatic monocyclic group containing 1 or 2 heteroatoms or a heteroaromatic condensed ring group obtained by condensing these heteroaromatic monocycles with a benzene ring; R 4 , R 5 and R 7 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; R 8 represents a hydrogen atom, a hydroxyl group, An alkyl of 1 to 4 carbons, alk
  • preferred compounds include (Ia-3), (Ib-3), and (Ib-3). Ic-1 3), (Ia_4), (lb-4), (Ic-4), (Ia-5).
  • R 13 represents an alkoxy group having 1 to 4 carbon atoms (particularly, a difluoromethyoxy group), and R 13 has 1 to 4 carbon atoms which may be substituted with a hydrogen atom, a halogen atom, or a halogen (particularly, fluorine).
  • a ′ represents an alkyl group having 1 to 4 carbon atoms which may be substituted with a hydrogen atom or a halogen (especially, fluorine).
  • the compounds represented by the general formulas (la-3), (lb-3), (Ic-3), (Ia-4) or (Ia-6) are preferable.
  • the halogen atom of X in the general formulas (1a), (Ib) and (Ic) is preferably a fluorine, chlorine, bromine or iodine atom, and is preferably Is a fluorine or chlorine atom, and is more preferably a fluorine atom.
  • X in the general formulas (Ia), (Ib) and (Ic) is preferably hydrogen, fluorine or chlorine atom, and more preferably fluorine. And a chlorine atom, more preferably a fluorine atom.
  • Y represents a hydrogen atom; a halogen atom such as fluorine, chlorine, bromine or iodine; Alkynyl groups having 1 to 4 carbon atoms, such as propylinole, isopropyl, butyl, and isobutyl groups; amino groups; methylamino, methylamino, propylamino, isopropylamino Monoalkyl-substituted amino groups substituted by alkyl having 1 to 4 carbon atoms, such as amino and butyl amino groups; dimethylamino, getylamino, dipropylamino, diisopropinorea Alkyl-substituted amino groups substituted with an alkyl having 1 to 4 carbon atoms, such as amino and dibutylamino groups; and 7 to 14 carbon atoms, such as penzinolemino and phenylethylamino groups.
  • a halogen atom such as fluorine, chlorine, bromine or
  • Alkynyl groups having 1 to 4 carbon atoms such as butyl, butyl, and isobutyl groups; aralkyl groups having 7 to 14 carbon atoms, such as benzinole, 1-phenylethyl, and 1-naphthylmethyl group; C 1 -C 4 alkanoyloxyalkyl groups such as simetyl and bivaloyloxymethyl groups; 1 _ (ethoxycarbonyloxy) ethyl, 1 — (isopropoxycarbonyloxy)
  • An alkoxycarbonyloxyalkyl group having 1 to 4 carbon atoms such as ethyl group; N, N-dialkyl-substituted aminocarbonylcarbonyl group such as, N-dimethylaminocarbonylcarbonylmethyl group N-, N-dialkyl-substituted aminoalkyl groups such as 2-, (N, N-dimethylamino) ethyl group; 2-—morph
  • Z is preferably a carboxy group which may be protected, and more preferably a carboxy group.
  • the halogen atom of R 2 is fluorine, chlorine, bromine or iodine. And an atom, preferably a fluorine or chlorine atom.
  • Examples of the group include an alkyl group such as methyl, ethyl, propyl, iso, propyl, and butyl groups; fluoromethyl, diphnoleolomethyl, trifluoromethyl, 2-fluoroethyl, and 3-phenylole.
  • Mouth propyl a fluorine-substituted anoalkyl group such as 4-fluorobutyl group; chloromethylinole, dichloromethinole, trichloromethinole, 2—chloronetinole, 3—coutine Chlorine-substituted alkyl groups such as propyl and 4-ported robutyl groups can be mentioned, preferably an unsubstituted alkyl group or a fluorine-substituted alkyl group, and more preferably , Methyl, fluoro It is a methyl, difluoromethyl or trifluormethyl group, more preferably a trifluoromethyl group.
  • the alkoxy group having 1 to 4 carbon atoms which may be substituted by a halogen of R 2.
  • alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy and butoxy groups; fluoromethoxy, diphnoleolomethoxy, triphnoleolomethoxy, 2-phenylenoethoxy.
  • 2-Fluoropropoxy 3-Phenoleoxypropoxy
  • 4 -Fluorosubstituted alkoxy groups such as 4-fluorobutoxy
  • 2-chloroethoxy, 2-chloropropoxy 3 _ chloro
  • a chlorine-substituted alkoxy group such as 4-propoxy group, and preferably an unsubstituted alkoxy group or a fluorine-substituted alkoxy group (particularly, methoxy, ethoxy, Funorelomethoxy, difluoromethoxy, trifluoromethoxy or
  • 2-fluoroethoxy group more preferably methoxy, fluoromethoxy, difluoromethoxy or trifluoromethoxy group, more preferably methoxy, trimethoxy group. It is a fluoromethyoxy or difluoromethoxy group, most preferably a trifluoromethoxy or difluoromethoxy group.
  • R 2 is preferably a hydrogen atom; a halogen atom; An alkyl group having 1 to 4 carbon atoms which may be substituted by a fluorine atom; an alkoxy group having 1 to 4 carbon atoms which may be substituted by fluorine, and more preferably a fluoro group A methyl, difluoromethyl, trifluorenomethyl group, a methoxy, a phthalolomethoxy group, a diphnoreolomethoxy group or a trifluoromethoxy group, more preferably a methoxy, difluoromethoxy, trimethylol group.
  • a trifluoromethyl or trifluoromethyl group and most preferably a difluoromethoxy, trifluormethoxy or trifluoromethyl group.
  • the above-mentioned formulas (Ia) and (Ia) b ) And Q in (I c) is preferably a group represented by the formula (d) in which R 2 of the formula (d) is a difluoromethoxy, trifluoromethoxy or trifluoromethyl group.
  • W is preferably a sulfur atom
  • T is methylene or ethylidene.
  • (CH 3) an alkylene group having 2 to 4 carbon atoms which may be substituted by alkyl having 1 to 4 carbon atoms, such as a CH— group. And a CH—CH— or C (CH 3) —CH— group, and more preferably an ethylidene group.
  • methyl And alkyl groups such as ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl and t-butyl groups, and preferably a methyl, ethyl, propyl or isopropyl group. Still more preferably, it is a methyl or ethyl group.
  • the halogen atom which is a substituent of the substituted alkyl group having 1 to 4 carbon atoms of R 1 is fluorine, chlorine, bromine or iodine. And a fluorine atom, preferably a fluorine atom or a chlorine atom, and more preferably a fluorine atom.
  • the alkoxy group having 1 to 4 carbon atoms, which is a substituent of the alkyl group having 1 to 4 carbon atoms and is substituted by R 1 is methoxy.
  • the alkyl group include cyclopropyl pinole, cyclopentinole, cyclopentinole, and cyclohexyl groups, and preferably a cyclopropyl group.
  • the alkanoyloxy group having 2 to 5 carbon atoms which is a substituent of the alkyl group having 1 to 4 carbon atoms and is substituted by R 1
  • R 1 is preferably Examples thereof include a toxic, propionyloxy and butyloxy group, and an acetoxy group is preferred.
  • Examples of the four alkyl groups include the same groups as those described above as the alkyl group having 1 to 4 carbon atoms for R 1 , and are preferably a methyl or ethyl group. .
  • R 9 and R 10 in the above formula (e), which are the substituents of the substituted alkyl group having 1 to 4 carbon atoms of R 1 are the same as each other.
  • a 3- to 7-membered saturated monocyclic ring containing a hetero atom selected from N, O and S includes aziridino, Examples thereof include azetidino, pyrrolidino piperidino, morpholino, thiomorpholino and piperazino groups, and are preferably piperidino or morpholino groups.
  • R 1 is a substituent of a substituted alkyl group having 1 to 4 carbon atoms, and the formula (e) is preferably an amino.
  • Examples of the “aryl group having 6 to 10 carbon atoms” in the aryl groups include phenyl, 1.1-naphthyl, and 2-naphthyl groups, and preferably a phenyl group .
  • R 1 is a substituent of an alkyl group having 1 to 4 carbon atoms, and may be a substituent of N, O and S which may be substituted by R 0 described below.
  • a 5- or 6-membered heteroaromatic monocyclic group containing 1 or 2 selected heteroatoms, or a heteroaromatic condensed ring group obtained by condensing a heteroaromatic monocyclic group with a benzene ring hereinafter referred to as a heteroaromatic monocyclic group and 5 to 6-membered heteroaromatic monocyclic group containing 1 or 2 heteroatoms selected from N, O and S, or a complex thereof.
  • heteromatic condensed ring group in which an aromatic monocyclic group and a benzene ring are condensed are, for example, 2-chloro, 2-furyl, 2-oxazolyl, 2-thiazolyl, 2-imi Dazolyl, 2—pyridyl, 3—pyridyl, “4—pyridyl, 2—pyrimidur, 4 Nil, 5 — pyrimigel, 2 — pyrazur, 3 — pyridazinyl, 2 — benzoxazolyl, 2 — benzothiazolyl, 2 _ benzoimidazolyl, 3 — benzoisosoxazolyl, 3 — benzoisothiazolyl group, etc.
  • 2-pyridyl, 2-furidyl, 2-pyridyl or 2-pyrimidyl group and more preferably a 2-pyridyl group.
  • An aryl group having 6 to 10 carbon atoms which may be substituted by RO which is a substituent of a substituted alkyl group having 1 to 4 carbon atoms of R 1 in (Ia) and (Ib); RO and heteroaromatic ring groups
  • halogen atoms such as fluorine, chlorine, bromine, and iodine atoms
  • nitro groups hydroxy groups; methyl, ethyl, propyl, isopyl pill, butyl, s-butyl, isoptinole, t-alkyl group having 1 to 4 carbon atoms such as butynole; fluoromethyl, difluoromethyl, trif-noreolo-methinole, 2-phneoroletinol, 2-f Noro-propyno
  • R 1 as the whole optionally substituted alkyl group having 1 to 4 carbon atoms is preferably methylethynole, propyl or isopropyl.
  • Pill butyl, s-butyl, t-petit nole; 2-hydroxyxyl, 2-hydroxypro pinole, 3-hydroxy cypro pill; carboxymethyl, 1 carboxyethinole, 2-hex Funoleolo Mechinore, Kuroremechinore, 2 — Funoreolochinore, 2 — Kurorechinore, 2 — Fu, Mouth Moetinole, 2 — Edo Etinole, 3 — Funore 2-Propyl, 3-chloropropynole, 3-Bromopropynole, 4-phnoroleborobutyl, diphnoleolomethyl, trifnoroleolomethinole, 2,2,2—Trifnorleloethyl, cyclopropyrmetinole; 2-a 2-hydroxyacetoxypropyl, 3-acetoxypropyl; 2-aminopropyl, 2-methylaminoethyl, 2-d
  • methyl, ethyl, propyl, isopropyl 2—hydrokisechinole, canolepoxime chinole, 2—hnooleolotineol, 2—chloroetyl, 2,2,2—trifluoroetyl, 2— Acetoxyethyl, phenylmethyl, 2-phenylethyl, 2-pyridylmethyl, 2-dimethylaminoethyl or 2-morpholinoethyl group;
  • it is a methyl, ethyl, 2-hydroxyl or 2-fluoroethyl group.
  • R 1 is substituted with halogen.
  • the optionally substituted alkenyl group having 2 to 5 carbon atoms include butyl, 2-propyl, 1-butenyl, 2-buteninole, 3-buteninole, 3,3-dimethyl-1-2-propyl Nyl, 2 — phnoleolobininole, 2 — (2 — fluorinated) propionyl, 3,3 — diphnolero-2- 2-propininole, 3,3 Include, for example, bur, 2-propyl, 3,3-dimethinolate 2-propylenole or 3,3-dichloro-1--2-propyl, and more preferably bur and 2 —Propyl group.
  • Examples of the alkynyl group having 2 to 4 carbon atoms for R 1 in the general formulas (Ia) and (Ib) include ethur, 1-propiel, 2-propynyl and 2-butulyl. And a alkynyl group having 2 to 4 carbon atoms, preferably, an ethynyl or 2-propynyl group, and more preferably, a 2-propyl group.
  • the mono- or dialkyl-substituted amino group substituted by 1 to 2 alkyl groups having 1 to 2 carbon atoms of R 1 in R 1 is as follows.
  • Monoalkyl-substituted amino groups such as methylamino, ethylamino, propylamino, isopropylamino, and butylamino; dimethylamino, getylamino, dipropylamino, Examples thereof include dialkyl-substituted amino groups such as diisopropylamino and dibutylamino groups, and are preferably methylamino, ethylamino or dimethylamino groups, and furthermore, Preferably, it is a methylamino group.
  • the cycloalkyl group having 3 to 6 carbon atoms which may be substituted with a halogen of R 1 includes propinole, cyclopentinole and cyclopentinole.
  • the alkoxy group having 1 to 4 carbon atoms for R 1 includes alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy and butoxy groups. And preferably a methoxy, ethoxy or propoxy group, and more preferably a methoxy or ethoxy group.
  • R 1 of R 1 in R 1 in the general formula (Ia) or (Ib) may be substituted by a “C 6 to C 10 aryl group”.
  • a 5- to 6-membered heteroaromatic monocyclic group containing 1 to 2 heteroatoms selected from N, O and S As the ⁇ heteroaromatic condensed ring group in which ring and are fused '', those similar to the above-mentioned substituents for the substituted alkyl group having 1 to 4 carbon atoms for R 1 can be mentioned.
  • R 1 of R 1 in R 1 in the general formulas (la) and (C 10 ) may be a C 6-10 aryl group and a heteroatom selected from N, O and S A 5- or 6-membered heteroaromatic monocyclic group containing 1 or 2 or a heteroaromatic condensed ring group obtained by condensing a heteroaromatic monocycle with a benzene ring.
  • R 1 is a substituent of an alkyl group having 1 to 4 carbon atoms and is substituted with R 0.
  • R 1 in the general formulas (la) and (I b) is preferably a hydrogen atom; methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl; Kisechil, 2—hydroxypropyl, 3—hydroxypropyl; carboxymethyl, 1—canoleboxyshchinole.
  • butyl groups such as butyl groups; fluoromethyl, chloromethyl, difluoromethyltinole, triphenylolenomethylinole, 2—chloroenolenole, 2—chloroeneoleno 2—bromochinole, 2—bromoenolepropinole , 3-phenolic propinole, 2-phenolic butyl, 3-fluorobutynole, 4-nitrophenol-substituted alkyl group such as 4-phenolylenobutyl; Methyl, 2—hydroxyethyl, 3—hydroxypropyl, 4—hydroxy-substituted alkyl group such as hydroxybutyl group; methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, 2— Examples include an alkoxy-substituted alkyl group such as methoxyl, 3-methoxypropyl, and 4-methoxybutyl, and preferably a methyl, fluoromethyl
  • the formula (g) is a group represented by the formula (g), and an alkyl group having 1 to 4 carbon atoms of R 11 of G 1 —N (R 11 ) — of the formula (f)
  • R 11 of G 1 —N (R 11 ) — of the formula (f) examples include methyl, ethyl, propyl, isopropyl, butyl, etc., and preferably a methyl or ethyl group
  • G 1 in the formula (f) is preferably Is an oxygen atom or a sulfur atom, and is more preferably an oxygen atom.
  • ⁇ in formula (I) Preferably, it is 1.
  • R 0 is a substituent of the substituted alkyl group having 1 to 4 carbon atoms of R 1 in the aforementioned general formulas (Ia) and (Ib).
  • R of the optionally substituted heteroaromatic ring group is a substituent of the substituted alkyl group having 1 to 4 carbon atoms of R 1 in the aforementioned general formulas (Ia) and (Ib).
  • heteroaromatic group represented by R 3 and R 6 in the formulas (h) and (i) of R in the general formulas (Ia), (Ib) and (Ic) include, for example, 2-phenyl, 2-furyl, 2-oxazolyl, 2-thiazolyl, 2-imidazolyl, 2 _ pyridyl, 3 _ pyridyl, 4-pyridyl, 2-pyridyl -Pi, 4-pyrimidinyl, 5 -pyrimidinyl, 2 -pyrazil, 3 -pyridazur, 2 -benzozoxazolyl, 2 -benzothiazolyl, 2 -benzoimidazolyl, 3- Benzoi soxazolinol and 3-benzoisothiazolyl groups are preferred, preferably 2 — thiazolyl, 4-pyrimidyl, 2 — pyrazul, 3 — benzoysothiazolyl, 2 — pyr
  • R 3 and R 6 in the formulas (h) and (i) of R in the general formulas (I a), (I b) and (I c) represent a phenyl group which may be substituted by R 0 As well as R.
  • a heteroaromatic group which may be substituted with, is more preferable, and R is preferably a formula (h), and R 3 in the formula (h) is a fluorine atom or a chlorine atom.
  • R is a group represented by the formula (h )
  • R 3 in the formula (h) may be substituted with a phenyl group which may be substituted with a fluorine atom, a chlorine atom, a methoxy group or a trifluoromethyl group, and RO.
  • the nozzle is 2 ⁇
  • the mouth is 2 ⁇
  • the 3 — is the mouth
  • Methyl, ethyl, propyl or isopropyl group and particularly preferably a methyl or ethyl group.
  • the alkoxy group having 1 to 4 carbon atoms of R 8 in the formula (i) of R in the general formulas (Ia.), (Ib) and (Ic) may be methoxyethoxy, Alkoxy groups such as boxy, isopropoxy and butoxy groups can be mentioned, preferably methoxy, ethoxy or propoxy groups.
  • n is preferably 1 and in the formula (i), the sum of n and n " Is preferably 3, 4 or 5, particularly preferably 3 or 4, and m is preferably 0.
  • the above general formula (Ia), (Ia) R in I b) and (I c) is preferably 4 — (pheninole) piperazine 1-inole, 4 — (4 — hunoleolofe-nore) piperazine 1 — , 4 — (3 — tri-funoleolomethinolefenil) piperazine 1 — yl, 4 — (2 — black mouth feninole) piperazine 1 — dinole, 4 — (3 — Black mouth 1) Pirazine 1 — Innole, 4 — (2 — Methoxypir) Pirazine 1 1 — Ill, 4 — (2 — Thiazolyl Pipera Gin one 1 one I le, 4 i (2 - Pi Li Mi Jiniru) Pipera Gin-1 1-yl, 4 — (5 — Fluoro 2 — pyrimidinyl) Piperazin 1 1 — Inole, 4 — (2 — Benzothi
  • the protective group may be the same as that described above for the “optionally protected carboxy group”.
  • the compound represented by the above general formula (Ia), (Ib) or (Ic), which is the active ingredient of the present invention, can be a pharmacologically acceptable salt, if necessary.
  • Such salts include acid addition salts of mineral acids such as hydrochloride, hydrobromide, hydroiodide, sulphate, phosphate; methansulphonate , Eta Acid sulfonate, benzenesulfonate, p-toluenesulfonate oxalate, maleate, fumarate, tartrate, citrate acid addition salts of organic acids Or a metal salt of rubonic acid, such as a sodium salt, a calcium salt, a calcium salt, a magnesium salt, a manganese salt, an iron salt, or an aluminum salt.
  • mineral acids such as hydrochloride, hydrobromide, hydroiodide, sulphate, phosphate; methansulphonate , Eta Acid sulfonate, benzenesulfonate, p-toluenesulfonate oxalate, maleate, fumarate, tartrate, citrate acid addition salts of organic acids
  • the compound (Ia), (Ib) or (Ic) or a pharmacologically acceptable salt or ester thereof, which is an active ingredient of the present invention can also exist as a hydrate.
  • Y is a hydrogen atom, a fluorine atom, an ano group, a methyl group or an ethyl group
  • T is E Chile den
  • R 1 is a hydrogen atom; Mechinole, Etinole, Propinore, Isopropinole; 2—Hydroxishetinole; Canoleboximetinole; 2—Funoleoletinole, 2—Chlorotineole, 2,2,2 — Trifluoroethyl; 2 — Acetoxy Ethynole; pheninoleme chinole; 2—phenylenoletinole; 2—pyridinolemethyl; 2—dimethylaminoethyl; 2—morpholinoethyl; aminino; methinoreamino; methoxy; cyclopropyl; Cyclobutyl, cyclopent chinole, 2 — fuzoreolo cyclopropinore; fuenore, 2 — funoreolo fenore, 3 — funoreo mouth fuenore, 4 — funore
  • R 1 is a hydrogen atom, methyl, ethyl, cyclopropyl, 2-fluoroethyl or methylamino group
  • R 1 is a hydrogen atom, a methyl group, an ethyl group, a 2-fluoroethyl group or a cyclopropyl group;
  • R is 4 — (Fer) 1-Pyrazine, 4 — (2 — Chloro 2) Pyrazine 1 1 ⁇ 1, 4 — (3 — C (2) Mouth fermentation) Pirazine 1-1-1, 4- (2—Methoxyfir) Pirazine 1--1-, 4- (3— Trif-noreo Lo-Mechinore-Feninore ) Pirazine 1 — I Nore, 4 I (4—Hunoreolo Feni Nore) Pirazine I 1—I Nore, 4 —
  • n 2 Black U phenyl Gas 2—Black mouth phenyl Nono 3—3 “n 4—1”
  • Nono nn 2 Feluorophenyl II 2—Full-year Rophenyl Nono 3— “Nono 3—))
  • n 4— Nono 4—
  • Nono 4— Nono
  • Suitable compounds represented by the general formula (Ia), (Ib) or (Ic), which are the active ingredients of the present invention, include:
  • the dosage form is, for example, tablets, capsules, granules
  • the preparation may be an oral preparation such as a powder, a syrup, or the like, or a parenteral preparation such as an intravenous injection, an intramuscular injection, a suppository, etc., and can be prepared by a usual preparation technique.
  • the dose of the anti-HCMV agent of the present invention depends on the activity, symptoms, and age of each drug. It can vary greatly depending on various conditions such as body weight, but is usually 0.1 mg (preferably 5 mg) per day and l OOO mg (preferably 500 mg).
  • 0.1 mg preferably 5 mg
  • l OOO mg preferably 500 mg
  • the present invention will be described in more detail with reference to Examples, but the scope of the present invention is not limited thereto.
  • the antiviral activity of quinolones was measured by general plaque reduction according to the method reported by Tims et al. (J. Antimicrobial and Chemotherapy 8 vol. 62-75, 1989). Determined by law. That is, human embryonic fibroblasts (MRC- 5) H CMV strain in the single 'layer culture (AD 1 6 9) 1 0 0 plaque forming units (piu) / 1 0 5 cells were infected, compound (drug ), And cultured at 37 ° C for 8 days. The culture after infection was layered cell layer in Eagle's MEM culture locations containing 0.5% agar (which was added 2% fetal calf serum), it was fixed in 1 0 days after infection, stained with methylene blue did. A drug concentration-dependent curve of the rate of plaque formation reduction compared to the drug-untreated control was constructed, and the 50 % inhibitory concentration (IC50) was determined.
  • the cytotoxicity of compounds is determined by the method of R. Pauwe 1 et al. (J. Virolog ical Methods, Vol. 20, pp. 309-321, 1988) using MT-4 cells. That is, 1 0% fetal bovine serum added R ⁇ M l - 1 6 4 0 medium (hereinafter, referred to as serum medium) were suspended in earthenware pots by the MT- 4 cells becomes 4 x 1 0 5 or Z m 1, serum The compound, which had been serially diluted in advance with the medium, was added to each well of a 96-well plate for tissue culture at 100 ⁇ l, and cultured at 37 ° C. for 5 days in the presence of 5% carbon dioxide.
  • the number of viable cells was measured using MMT (3— (4,5-dimethylthiothiazol-2-yl) -1,2,5—diphenyltetrazolamide), and the viable cells without compound were added. When the number is 100%, the number of viable cells with the compound added. /. Ask for 50 ° /. The compound concentration (CC 50 ) at which the cells survived was determined. Table 1 shows the test results of the following compounds 1 to 15 among the compounds which are the active ingredients of the present invention. Compounds 1 to 15 were synthesized by the methods described in Reference Examples.
  • the compound as the active ingredient of the present invention exhibited excellent anti-HMCV activity and low cytotoxicity.
  • Compounds 1 to 15 exhibited excellent anti-HCMV activity with an IC 50 value of 0.61 ⁇ g / m 1 or less.
  • Compound 1 to 4 are safety factor (a value obtained by dividing the cytotoxicity CC 5 0 value in anti-HCMV activity IC 5 0 value) 2 0 or a highly safe compound to cells. (Test Example 3)
  • the compound as the active ingredient of the present invention showed a high oral absorption rate when orally administered to rats.
  • Compounds 2, 3, 4, 10, 10 and 13 are disclosed as Examples 5, 20, 7, 6, 4, and 1 in JP-A-8-187375, respectively. The compound was synthesized in the same manner.
  • Compounds 5, 6, and 7 are compounds disclosed as Examples 30, 23, and 1, respectively, in JP-A-6-116241, and were synthesized in the same manner.
  • the quinolone carboxylic acid compounds (Ia), (Ib) and (Ic), which are the active ingredients of the present invention, have excellent anti-viral virus activity (particularly anti-HCMV activity). And low toxicity. Also has good oral absorption. Therefore, the present invention is useful as an anti-herpes virus agent (especially an anti-HCMV agent) and is useful for preventing or treating herpes virus infection (especially HCMV infection).

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Abstract

L'invention porte sur un agent anti-cytomégalovirus comportant comme principe actif un dérivé de l'acide quinolone-carboxylique tel qu'un composé de formule (Ia) dans laquelle: Y représente un atome d'hydrogène ou d'halogène, Y représente un atome d'hydrogène ou d'halogène, un groupe alkyle ou analogue, Z représente un groupe carboxylique facultativement protégé, Q représente un atome d'azote, un groupe C-H, un groupe C-CF3, un groupe C-OCF2H, R1 représente un atome d'hydrogène, un groupe alkyle ou analogue, et R représente un groupe pipérazino substitué par un groupe aromatique.
PCT/JP1999/000728 1998-02-19 1999-02-18 Agent anti-hcmv WO1999042106A1 (fr)

Priority Applications (1)

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AU25476/99A AU2547699A (en) 1998-02-19 1999-02-18 Anti-hcmv agent

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JP3711998 1998-02-19
JP10/37119 1998-02-19

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WO1999042106A1 true WO1999042106A1 (fr) 1999-08-26

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05255089A (ja) * 1991-12-18 1993-10-05 Sanwa Kagaku Kenkyusho Co Ltd 抗ウイルス剤
JPH0616673A (ja) * 1992-04-02 1994-01-25 Bayer Ag ７−オキソ−７Ｈ−ピリド［１，２，３−ｄｅ［１，４ベンゾキサジン−６−カルボン酸類およびエステル類
JPH06116241A (ja) * 1992-05-27 1994-04-26 Ube Ind Ltd アリール基又は複素芳香環基置換アミノキノロン誘導体及びエイズ治療剤
JPH06271570A (ja) * 1993-02-09 1994-09-27 Bayer Ag キノロンカルボン酸およびナフチリドンカルボン酸の新規な誘導体
JPH0899957A (ja) * 1994-09-30 1996-04-16 Toyama Chem Co Ltd 新規なキノロンまたはナフチリドン化合物もしくはそれらの塩、それらからなる抗ヘルペスウイルス剤
JPH09249568A (ja) * 1996-01-12 1997-09-22 Sankyo Co Ltd トリフルオロメチルキノリンカルボン酸誘導体を含有する医薬組成物
JPH09323932A (ja) * 1996-01-31 1997-12-16 Sankyo Co Ltd エイズ治療剤又は予防剤

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05255089A (ja) * 1991-12-18 1993-10-05 Sanwa Kagaku Kenkyusho Co Ltd 抗ウイルス剤
JPH0616673A (ja) * 1992-04-02 1994-01-25 Bayer Ag ７−オキソ−７Ｈ−ピリド［１，２，３−ｄｅ［１，４ベンゾキサジン−６−カルボン酸類およびエステル類
JPH06116241A (ja) * 1992-05-27 1994-04-26 Ube Ind Ltd アリール基又は複素芳香環基置換アミノキノロン誘導体及びエイズ治療剤
JPH06271570A (ja) * 1993-02-09 1994-09-27 Bayer Ag キノロンカルボン酸およびナフチリドンカルボン酸の新規な誘導体
JPH0899957A (ja) * 1994-09-30 1996-04-16 Toyama Chem Co Ltd 新規なキノロンまたはナフチリドン化合物もしくはそれらの塩、それらからなる抗ヘルペスウイルス剤
JPH09249568A (ja) * 1996-01-12 1997-09-22 Sankyo Co Ltd トリフルオロメチルキノリンカルボン酸誘導体を含有する医薬組成物
JPH09323932A (ja) * 1996-01-31 1997-12-16 Sankyo Co Ltd エイズ治療剤又は予防剤

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WITVROUW M. et al., "Broad-Spectrum Antiviral Activity and Mechanism of Antiviral Action of the Fluoroquinolone Derivative K-12", ANTIVIRAL CHEMISTRY & CHEMOTHERAPY, 9(5), (1998), pages 403-411. *

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