WO1999042106A1 - Anti-hcmv agent - Google Patents

Abstract

An anticytomegalovirus agent comprising, as an active component, a quinolone-carboxylic acid derivative such as a compound represented by general formula (Ia), wherein X represents a hydrogen atom or a halogen atom, Y represents a hydrogen atom, a halogen atom, an alkyl group or the like, Z represents an optionally protected carboxylic group, Q represents a nitrogen atom, a C-H group, a C-CF3 group, a C-OCF2H group or the like, R1 represents a hydrogen atom, an alkyl group or the like, and R represents a piperazino group which is substituted with an aromatic group.

Description

Technical Field of the Invention The present invention relates to 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. Compositions for the treatment or prevention of viral infections (especially HCMV infection), anti-herpesvirus agents containing them as active ingredients (especially anti-HCMV agents), herpes Use of them for the manufacture of a medicament for the treatment or prophylaxis of Russ infections (especially HC MV infections), or administration of a pharmacologically effective amount of them to warm-blooded animals. The present invention relates to a method for treating or preventing lupus infection (particularly HCMV infection). Background Art The human cytomegalovirus (HCMV) is a virus that is indigenous to humans and that lurks in various organs and often reactivates to cause opportunistic infections. Are known. The pathogenicity of HC MV is usually weak and infectious, but immunocompromised, for example, after organ transplantation on immunosuppressive therapy, cancer on radiation and chemotherapy, and more. It is also the first factor in opportunistic infections in AIDS patients and is known to cause severe symptoms.

As a treatment for HCMV infection, Ganciclovir — Nets are commercially available. However, all of these drugs have strong side effects and the emergence of resistant viruses after long-term use. Therefore, there is a need for even better therapeutic drugs. 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. Was completed. DISCLOSURE OF THE INVENTION The quinolone carboxylic acid derivative which is an active ingredient of the present invention is represented by the following general formula (Ia), (b) or (Ic).

 R

N H (I b)

R

In the above formula (Ia), (Ib) 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. A mono- or di-aralkyl-substituted amino group substituted with 1 to 2 aralkyl groups having 1 to 2 carbon atoms having 7 to 14 carbon atoms;

Z represents an optionally protected carboxy group or 5 —tetra 'zolyl group;

Q is a nitrogen atom or formula (d)

[In the formula (d), 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. Represents an alkenylene group,

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 A cycloalkyl having 3 to 6 cycloalkyls having 2 to 5 carbon atoms, a formula (e)

(In the formula (e), R ^Θ 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 monocyclic group or a heteroaromatic condensed ring group obtained by condensing a heteroaromatic monocyclic ring with a benzene ring]; an alkenyl group having 2 to 5 carbon atoms which may be substituted by halogen; 2 to 4 alkynyl groups; amino group; 1 to 2 alkyl groups having 1 to 4 carbon atoms Wakashi clause dialkyl location Substituted amino S; a cycloalkyl group having 3 to 6 carbon atoms which may be substituted with halogen; an alkoxy group having 1 to 4 carbon atoms; or a carbon which may be substituted by R ° described below. 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,

R ¹ and R ² of equation (d) in Q join together to form equation (f)

 [In the formula (f), 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. Or the formula (g)

(g)

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 N one (h)

./QcH n

[In the formulas (h) and (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 group or an alkoxy group having from 1 to 4 carbon atoms; n represents 1 or 2; m represents 0 or 1; n ′ represents 1 or 2; Or 4]. That is, the compounds represented by the general formulas (Ia), (Ib) or (Ic) include the general formulas (Ia-1) (lb-1), (Ic) — 1), (la

2) The following compounds represented by (〖b_2) and (Ic-2)

Replacement form (Rule 26)

Replacement paper (Kaikai IJ26) (In each formula, X, Y, Z, W , Q, T, R 1 and R ³ to R ⁸ and m, n, n '及Pi n "are as defined above) are included.

 Further, among the compounds represented by the general formulas (Ia), (Ib) or (Ic), preferred compounds include (Ia-3), (Ib-3), and (Ib-3). Ic-1 3), (Ia_4), (lb-4), (Ic-4), (Ia-5).

The following compounds represented by (Ib—5), (Ic—5), (la—6) and (la—7)

ZZ.00 / 66df / X3d 901/66 OM

01

901h / 66 Ο (In each formula, A, X, Y, Z, W, R, T and R ¹ have the same meanings as described above, and —OR ¹² is substituted with halogen (particularly fluorine). 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). Alkyl group

(Especially, a trifluoromethyl group), and A ′ represents an alkyl group having 1 to 4 carbon atoms which may be substituted with a hydrogen atom or a halogen (especially, fluorine). In the present invention, the compounds represented by the general formulas (la-3), (lb-3), (Ic-3), (Ia-4) or (Ia-6) are preferable. Preferably, in the general formula (Ia-3), (Ia-4) or the general formula (Ia-6) wherein A 'is an alkyl group having 1 to 4 carbon atoms substituted by fluorine. And more preferably a compound represented by the general formula (Ia-3) or (Ia-4). Compounds represented by the general formula (Ia) or (Ib) wherein R ¹ is a hydrogen atom include tautomers (IIa) and (IIb) as shown below. Although present, the active ingredients of the present invention also include these tautomers.

(I a) Ri = H (II a)

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.

In the above general formulas (Ia), (Ib) and (Ic), 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. It is substituted with Jibenshirua Mi Bruno, di (phenyl Echiru) A Mi Bruno Ararukiru Do having 7 to 1 4 carbon will Yo groups; that of mono aralkylsubstituted A Mi substituted with Ararukiru amino group And preferably a hydrogen atom, a fluorine atom, an amino group, a methyl group or an ethyl group, and more preferably a hydrogen atom. It is. Examples of the protecting group of the carboxy group of “optionally protected carboxy group” for Z in the above general formulas (Ia) and (Ic) include methyl, ethyl, propyl, and isopropyl. 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-—morpholinoethyl, 2-piperidinoethyl, 2 -— (4— 5- to 6-membered heterosaturated monocyclic group-substituted alkyl group containing 1-2 heteroatoms selected from N, O and S, such as methylpyridino) ethyl group; (5-methyl) — 2 — Oxo 1, 3 _ dioxolen 1 4 — yl) Methyl group or (5 '1 phenyl 1 2 _ oxo 1 1, 3 — dioxolen 1 4 — yl) Groups such as groups that can be easily deprotected in a living body and converted into carboxy groups are exemplified. In the general formulas (Ia) and (Ic), Z is preferably a carboxy group which may be protected, and more preferably a carboxy group. When Q in the general formulas (Ia), (Ib) and (Ic) is represented by the formula (d), the halogen atom of R ² is fluorine, chlorine, bromine or iodine. And an atom, preferably a fluorine or chlorine atom. When Q in the general formulas (Ia), (Ib) and (Ic) is represented by the formula (d), the alkyl having 1 to 4 carbon atoms which may be substituted by halogen of R ^2. 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.

When Q in the above general formulas (Ia), (lb) and (Ic) is represented by the formula (d), the alkoxy group having 1 to 4 carbon atoms which may be substituted by a halogen of R ^2. These include 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 And 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.

When Q in the general formulas (Ia), (Ib) and (Ic) is represented by the formula (d), 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. In formula (Ib), W is preferably a sulfur atom, and in formula (Ic), T is methylene or ethylidene.

[One CH (CH3) ―], ethylene, trimethylene, propylene, An alkylene group having 1 to 4 carbon atoms which may be substituted by an alkyl having 1 to 4 carbon atoms such as a tramethylene group; one CH = CH-, one C

(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. In the general formulas (Ia) and (Ib), as the “C1 to C4 alkyl group” of the optionally substituted C1 to C4 alkyl group for R ¹ , 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. In general formulas (Ia) and (Ib), 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. In the general formulas (Ia) and (Ib), 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. And ethoxy, propoxy, isopropoxy, butoxy groups, etc., preferably methoxy or ethoxy groups, and more preferably methoxy groups. In the general formulas (Ia) and (Ib), the cycloalkyl having 3 to 6 carbon atoms which is a substituent of the substituted alkyl group having 1 to 4 carbon atoms of R ^1. Examples of the alkyl group include cyclopropyl pinole, cyclopentinole, cyclopentinole, and cyclohexyl groups, and preferably a cyclopropyl group. In the general formulas (Ia) and (Ib), 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 , is preferably Examples thereof include a toxic, propionyloxy and butyloxy group, and an acetoxy group is preferred. R ^{1 in} the general formulas (Ia) and (Ib), which is a substituent of a substituted alkyl group having 1 to 4 carbon atoms, R ⁹ and R ¹⁰ in the formula (e) each having 1 to 4 carbon atoms. 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. . In the general formulas (Ia) and (Ib), 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. In addition, together with the nitrogen atom to which they are bonded, and optionally, 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. In the formulas (Ia) and (Ib), R ^{1 is} a substituent of a substituted alkyl group having 1 to 4 carbon atoms, and the formula (e) is preferably an amino. And a methylamino group, a dimethylamino group, a piperidino group or a morpholino group, and more preferably a dimethylamino group. R ^{1 in} the above general formulas (Ia) and (Ib), which is a substituent of an alkyl group having 1 to 4 carbon atoms and which may be substituted by R ¹ to be described later. 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 . In the general formulas (Ia) and (Ib), 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. Examples of the “heteroaromatic 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. And a 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 For example, 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-propynole, 3—Funole-butynole, 3—Funole-butynole, 3—Funole-butynole, 4 1 to 4 carbon atoms substituted with a fluorine atom such as a fluorobutyl group Alkyl groups; alkoxy groups having 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy groups; methylthio, ethylthio, propylthio Alkylthio groups having 1 to 4 carbon atoms, such as isopropylthio and butylthio groups; amino groups; methylaminoethylamino, propylamino, isopropylamino, butylamino, isobutylamino A monoalkyl-substituted amino group substituted with an alkyl group having 1 to 4 carbon atoms such as a s-, s-butylamino, and a t-butylamino group; dimethylamino, getylamino, dipropylamino Dialkyl substituted amino substituted with an alkyl group having 1 to 4 carbon atoms, such as pyramino, dibutylamino, dibutylamino, diisobutylamino, and ethyl (methyl) amino. And preferably a fluorine, chlorine atom; a methyl group; a methoxy group. In the general formulas (Ia) and (Ib), 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-dimethylaminoethyl, 2-morpholinoethyl, 2-piperidinoethyl; 2—Metokishetil; Huéninole Chinole, 1—Feninore Chinole, 2—Fue Ninoré Chinole, Naphtinoremetinore, 2—Funole Lo Feñore Metinole, 3—Funole Lo Feñenolemeleno Fehermetyl, 2,4-difluoropheninolemethyl, 34-di Ruoro Feni Zoleme Chinole, 2, 6 —Diphnoleolo Fe Ninoreme Chinole 2 —Mechinore Fe Enole Metinole, 3 —Mechinore Fe Enoleme Chinole, 4-Metinole Fuenore Metinole, 2 —Chlolet (B) Mouth feninoleme chinore, 4 croin heninoleme chinore, 2 — methoxy pheninoleme chinole, 3 — methoxypheninele methinolle, 4 — methoxyphenineleme chinole, 2 — chenilmetyl, 2 _ Furylmethyl, 2-pyridylmethyl or 2-pyrimidinylmethyl group,

 More preferably, 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;

 More preferably, it is a methyl, ethyl, 2-hydroxyl or 2-fluoroethyl group.

Most preferably, it is a methyl, ethyl or 2-fluoroethyl group (especially a methyl group). In the general formulas (Ia) and (Ib), R ¹ is substituted with halogen. Examples of 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. In the general formulas (Ia) and (Ib), 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. In the general formulas (Ia) and (Ib), the cycloalkyl group having 3 to 6 carbon atoms which may be substituted with a halogen of R ¹ includes propinole, cyclopentinole and cyclopentinole. Sic Lopentinole, Sic Lo Hexinole, 2- Fenoleolo Siculo Pro Pinore, 2—Krolo Scro Pro Pinore, 2—Promo Siro Pro Pinore, 2, 2—Diphnoreolo Siculo Pro Pinore, 2—Kuro , 2—Funolecyclocyclobutynole, 2—Funolelocyclopentyl, 2—Fluorocyclohexyl group and the like, preferably cyclopropyl, cyclobutyl, cyclopentyl or 2-fluorocyclopropyl. And more preferably a cyclopropyl group. In the general formulas (Ia) and (Ib), 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.

In the general formulas (Ia) and (Ib), 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”. Aryl group '' and a 5- or 6-membered heteroaromatic monocyclic group containing 1 or 2 heteroatoms selected from N, O and S which may be substituted by R ⁰ , or a heteroaromatic monocyclic group thereof. 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. , Preferably phenyl, naphthyl, 2-thiazolyl, 2-oxazolinol, 2-pyridyl, 3-pyridyl Jil, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5_pyrimidyl, 2-benzoxazolyl or 2-benzothiazolyl group, and more preferably, H Phenyl or 2-pyridyl group. In the general formulas (la) and (Ib), 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. In the general formulas (Ia) and (Ib), R ^{1 is} a substituent of an alkyl group having 1 to 4 carbon atoms and is substituted with R ^0. And the same as those for the RO of the heteroaromatic ring group which may be mentioned, and preferred are a fluorine atom, a chlorine atom and a methyl group. 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. 2—force norebokishechinole, fnoreleolo methinolle, 2—fnorolelo echinolle, 2 — Krolo ェ echnole, 3 — H ノ nore, Lo プ ロ P ピ pinore, 3 — Kuroguchi Prop レ le, Gibno レ löro M ch 、 l, Trif ォ l ロ o M チ ch ノ nore, 2,2,2 — Trifno レ オ le ロ o ェ l; Chill; 2—acetoxityl, 2—acetoxypropyl, 3—acetoxypropyl, 2—aminoethyl, 2—methylaminoethyl, 2—dimethyl Aminoethyl, 2—Morpholinoethyl, 2—Piperidinoethyl; 2—Metokishechinole; Fennirme Chinole, 1 1 Feininoletinolle, 2—Fue Ninoretochinole, Na Fuchinoreme Chinolle, 2—Funoleno mouthエ レ 3 3, 3 フ フ — No , 2, 6 — Dichnoroleno Feni Noreme Chinole, 2 — Mechinore Feni Noreme Chinole, 3 — Mechinorefe Ni Noreme Chinoré, 4-Mechinorefu Eni Noreme Chile, 2—Kuro mouth fenenoreme chinore, 3—Kuro mouth fuinenoreme chinore, 4—Kuro mouth fuinenoreme chinore, 2—Methoxy fueno-noreme chinore, 3—Methoxy phenynoreme chinore, 4—Metoxime Chinore; 2—Cheninoleme Chinore 2—Frylmethyl, 2—Pyridylmethyl, 2—Pyrimidininoleme Chinole; Amino; Metylamino, Ethilamino, Dimethyamino, Methoxy, Ethoxy, Propoxy; cyclopro pinole, cyclopentinole, cyclopentyl, 2—fluorocyclopentole; fueinole, 1—naphtinole, 2—naphtinole, 2—funeole, feninole, 3—funeole , 4-Funole Oro Feninore, 2—Kuro mouth Feninole, 3—Kuro mouth Feninole, 4 Black mouth feninole, 2, 4-diphnoleolo fenore, 3, 4 diphnoleolo fenore, 2, 6-diphnoleolo feninole, 2-methinolefeninole, 3-methylthiophene, 4-methyfenenole 2 — thiazolinole, 2 — oxazolyl, 2 — pyridyl, 3 _ pyridyl, 4 — pyridyl, 2 — pyrimidinyl. 4 monopyrimidinyl, 5 — pyrimidininole, 2 — Benzoxazolinole, 2-benzothiazolyl; Bull, 2—Propaninole, 3,3—Dimethinole-1—Propaninole, 3,3—Dichloro1-2—Propaninole; Etchinisole, 2-— A propynyl group,

More preferably, a hydrogen atom; methyl, ethyl, propyl, isopropyl; 2—hydroxechinole; canoleboximetinole; 2—phnoleoletinole, 2—chloroechinole, 2,2,2—trifnole Leorochinole; 2—acetoxityl; phenylmethyl, 2—phenylethyl; 2—pyridylmethyl; 2—dimethylinoethyl, 2-morpholinoethyl; amino; methinorea; methoxy; methoxy; Lo-Pro Pinore, Siculo Petit, Sic-Pentorinore, 2—Funole Rosicuro-Pro-Pinole; Fue Ninore, 2—Funole, Fue Ninore, 3—Funole 2,4-Difluoropheel; Bier, 2-Progenol; 2-Propininole , More preferably, they are a hydrogen atom, methyl, ethyl, 2 — hydroxethyl 2 — fluoroethyl, cyclopropyl or methylamino group, most preferably a hydrogen atom, methyl, ethyl, 2_fluoroethyl or Is a cyclic propyl group. In the general formulas (Ia) and (lb), when R ¹ and R ² together form the bond represented by the formula (f), the “halogen” of A in the formula (f) Examples of the atom, hydroxy group or alkyl group having 1 to 4 carbon atoms which may be substituted with an alkoxy group having 1 to 4 carbon atoms "include methyl, ethyl, propyl, and isopropyl. And 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 or hydroxymethyl group. In the above general formulas (Ia) and (Ib), when R ¹ and R ² together form a bond represented by the formula (f), A is represented by the formula (f). Preferably, it is a hydrogen atom, methyl, fluoromethyl or hydroxymethyl group. In the general formulas (Ia) and (lb), when R ¹ and R ² are linked to form a bond represented by the formula (ί), G in the formula (ί) is defined as G. Preferably, it 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) Examples include methyl, ethyl, propyl, isopropyl, butyl, etc., and preferably a methyl or ethyl group, and G ^{1 in the} formula (f) is preferably Is an oxygen atom or a sulfur atom, and is more preferably an oxygen atom. Wherein in the general formula (I a) and (I b), when the bond with R ¹ and R ² are represented by the formula (I) together are formed, is ρ in formula (I), Preferably, it is 1. On the aryl group and the heteroaromatic group represented by R ³ and R ^e in the formulas (h) and ('i) of R in the general formulas (Ia), (Ib) and (Ic) The substituent 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. The same as the above, preferably a fluorine, chlorine atom; methyl, ethyl; trifluoromethyl; methoxy, ethoxy; methylthio, ethylthio group, and more preferably, Fluorine, chlorine atom; methyl; trifluoromethyl; methoxy; methylthio groups. Formula (I a), and (I b) and (I c) in the formula (h) and (i) in R ³ and R ^e having 6 to 1 0 in § Li Lumpur group carbon of the R Examples include phenyl, 1-naphthyl, 2-naphthyl and the like, and preferably a phenyl group. Examples of the 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 — pyridinole, 2 — Pirimigel, 2 —Benzothiazolinol or 2 —Benzoxazo Ri Le group Der, preferably in the al, 2 - thiazol le, 2 - pyrimidone Jininore, 2 - Benzooki no doubt Li Le group - pyridinium Jinore, 2 - base Nzochiazori le or 2. 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. A phenyl group which may be substituted with a methoxy group or a trifluoromethyl group, or a heteroaromatic ring group which may be substituted with RO. More preferably, R is a group represented by the formula (h ) And 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. A 5- or 6-membered heteroaromatic ring group containing 1 or 2 nitrogen atoms, and most preferably, R is the formula (h), and R ³ in the formula (h) is Nitrogen, chlorine, methoxy or trifluor A phenyl group which may be substituted with a methyl group, and a pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, benzothiazolyl, benzoisothiazolyl or benzozoxazolyl group which may be substituted with R ^0. . More specifically, as R ³ and R ⁶ in the formulas (h) and (i) of R in the general formulas (Ia), (Ib) and (Ic), 2-pyridyl; 2-pyrimidinyl; 4-pyrimidinyl; 4-pyrimigel; dimethoxy-1 2-pyrimidinyl; 2-thiazolyl; 2-benzoxazolyl; 2; benzothiazolinole; 3—benzoisothiazolyl; 2—, 3— or 4-—fluorine, chlorine. Methoxy, nitro, trifluoromethyl, amino or dimethylami Phenyl substituted by phenyl; 2-pyridyl substituted by methoxy, amino or nitro; 2-pyrimidinyl substituted by chlorine, methyl or ethyl; chloro-substituted by methyl or ethyl 4 — Pirimi gel; chlorine, methyl 2 main butoxy-substituted - Benzookisazo Li Le; chlorine, methyl or main butoxy 2 _ base Nzookisazo Li Le group substituted is preferred der is,

 More preferably, phenyl; 2-seven. Lysyl; 2—pyrazul; 2—pyrimidinyl; 4—pyrimidinyl; 2—thiazolyl; 2—benzoxosazolyl; 2—benzothiazolyl; 2—, 3—or fluorine at the 4- or 4-position Phenyl substituted by chlorine, methoxy, nitro, trifluoromethyl, amino or dimethylamino; 2-pyridyl substituted by methoxy or nitro; substituted by chlorine, methyl or ethyl 2-pyrimigel; 4-pyrimidyl substituted with chlorine, methyl or ethyl; 2-benzothiazolyl substituted with methoxy; 2-benzoxazolyl group substituted with methoxy.

More preferably, the nozzle is 2 二, the mouth is 2 ク, the 3 — is the mouth, 2 Le, 4—Funoleolo feninole, 2—Methoxyfino enole, 3—Trifneolelo mesylphenyl; 2—Pyridyl; 2—Pirimi gel, 5—Furilo—2—Pyrimido genore 2-thiazolinole; 2-benzothiazolinole; 2-benzoxazolyl; 6-methoxybenzothiazoly; 6-methoxybenzoxazolyl group;

Most preferably, phenyl, 2 — black mouth, 3 — black mouth, 4 — funoreo mouth, 2 — methoxy2, 3 — trifonore 2-methylpyrrolidinol; 2-thiazolyl; 2-benzothiazolyl; 2-benzoxazolyl. Formula (I a), and (I b) and (I c) R ⁴ in the formula of R (h) and (i) in, R ⁵ and having 1 to 4 carbon Al killed groups of carbon atoms of R ⁷ Examples thereof include alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropylbutyl, isobutyl, s-butyl and t-butyl groups. , Methyl, ethyl, propyl or isopropyl group, and particularly preferably a methyl or ethyl group. Formula (I a), (I b ) and is set to R ^4, R ⁵及Pi R ⁷ in the formula of R (h) and (i) in (I c), a hydrogen atom, main Ji Le, An ethyl, propyl or isopropyl group is preferred, and a hydrogen atom, a methyl or ethyl group (particularly a hydrogen atom) is more preferred. As the alkyl group having 1 to 4 carbon atoms of R ⁸ in the formula (i) of R in the general formulas (Ia), (Ib) and (Ic), methyl, ethyl and propyl And alkyl groups such as isopropyl, butyl, isobutyl and t-butyl, and preferably methyl, ethyl, propyl and the like. And isopropyl group, more 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. As R ⁸ in the formula (i) of R in the general formulas (Ia), (Ib) and (Ic), a hydrogen atom, a hydroxyl group, methyl, ethyl, propyl, isopropyl, A methoxy, ethoxy or propoxy group is preferred, more preferably a hydrogen atom, a hydroxyl group, methyl, ethyl, methoxy or ethoxy group (particularly a hydrogen atom). In R in the general formulas (Ia), (Ib) and (Ic), in the formula (h), 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 — Benzothiazolinol) Piperazine 1 1 — Inole 4 — (2 benzobenzoxazo (Ril) Piper gin-1 1-inole, 4 — (6-Methoxy 1-Benzoxazolyl) Piperazine 1-in-ole, 4-

(6-methoxy-1-benzothiazolyl) piperazine-1 -yl or 4- (2-pyridyl) piperazine-1 -yl group, more preferably Is 4-(phenyl) piperazine 1-yl, 4-(2-black phenyl) piper 1-yl, 4-1 (3-black phenyl- 1) Piperazine-1 1-inole, 4- 1 (2-methoxyphenyl) Piperine 1- 1-inole 41- (3—Trifnorolelo-metinolefer) Piperazine 1- 1-inole , 4-1 (4-phenolic phenyl) pyridine 1-1, 4-1 (2-pyrimidinyl), 4-(2-thiazolyl) Piperazin-1-yl, 4- (2-benzothiazolinole) piperazine-1-yl or 4- (2-benzoxazolyl) piper When the above-mentioned general formula (Ia), (Ib) or (Ic) which is a phenyl-1-yl group has a carboxy group in the molecule, those carboxy groups are protected by a protecting group. 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. 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. You. Among the compounds of the formula (Ia), (Ib) or (Ic) which are the active ingredients of the present invention, preferred are:

1) a compound wherein X is a fluorine atom,

 2) compounds wherein Y is a hydrogen atom, a fluorine atom, an ano group, a methyl group or an ethyl group,

 3) compounds wherein Y is a hydrogen atom,

 4) a compound wherein Z is a carboxy group which may be protected,

5) a compound wherein Q is the formula (d), and R ^{2 in} the formula (d) is a difluoromethoxy, trifluoromethoxy or trifluoromethyl group;

 6) compounds wherein W is a sulfur atom,

7) T is E Chile den, _ CH = CH - or one C (CH ₃₎ = CH - compound is a group,

 8) compounds wherein T is an ethylidene group,

9) 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 — funorelolo feninore, 2,4 — diphnore orolo Feel; Bier, 2-propenyl; or a compound that is 2-probuyl,

10) a compound wherein R ¹ is a hydrogen atom, methyl, ethyl, cyclopropyl, 2-fluoroethyl or methylamino group,

1 1) a compound wherein R ¹ is a hydrogen atom, a methyl group, an ethyl group, a 2-fluoroethyl group or a cyclopropyl group;

 1 2) R-force, 4-(Fuel) Pirazine 1-1, 4-1 (2-Kurofue-Nore) Pirazine 1-1, 4-(3-Crop (Feninole) Piperazine-1 1-yl, 4- 1 (2-Methoxyphenyl) Piperazine-1 1-yl, 4 — (3—Trifluoro methinolephenyl) Piperazine 1 1— Dinole, 4 — (4-Fno Leolo Fenore) Pirazine 1 1

(2-pyridyl) piperazine 1-yl, 4- 1 (2-pyridinyl) piperazine 1-yl, 4-(5-fluo 2-pyrimidyl) piperazine 1 — yl, 4 — (2 — thiazolyl) piperazine 1 — yl 4 — (2 benzothiazolyl) piperazine 1 1, 4 — (2 — benzoxazolinol) piperazine 1-yl, 4 -— (6-Methoxy-1-2-benzothiazolyl) piperazine-1-1-yl or 4 -— (6-Methoxy-2-2-benzoxazolyl) -piperazine-1-1-yl Compound,

1 3) 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 —

(2-pyrimigel) piperazine 1-yl, 4-1 (2-thiazolyl) piperazine 1-1, 4-(2-benzothiazolyl) piperazin-1-inole or 4 _ ( 2-benzoxazolyl) piperazine- 1-yl group.

 Further, compounds comprising two or more combinations of the above 1) to 13) are also suitable.

The compounds represented by the above general formula (Ia), (lb) or (Ic) which are the active ingredients of the present invention can be exemplified in the following table.

R ³ R ³

Phenyl 2-oxazolyl

 -Fluorophenyl 2-thiazolyl

 3-〃 2-〃 Midazolinore

 4-〃2-pyridyl

 2-chlorophenyl 6-methoxy-1-pyridyl

 3- "3-Nitroguchi 2-Pyridyl

 4- "3-amino-1-pyridyl

 2-methoxyphenyl 3-methylamino-1-pyridyl

 3-"3-ethylamino 2-pyridyl

 4- "3-fluoro-2-pyridyl

 2-diphenyl 3-pyridyl

 3- "4-"

 4- "2-benzoxazolyl

 2-Aminophenyl 5-chloro-2-benzoxazolyl

3-"2-benzothiazolyl

 4- "5-methyl-2-benzothiazolyl

2-dimethylaminophenyl 2-benzimidazolyl

 3- ". 2-pyrimidinyl

 4- "5-chloro-1-pyrimidinyl

 2-trifluoromethylphenyl 4-methoxy-2-pyrimidinyl

 3- "4.6-Dimethoxy-1-pyrimidinyl

4-»4-pyrimidinyl

 2. 4-difluorophenyl 5-chloro-1-6-methyl-1-pyrimidinino

6-Methoxy-2-benzoxazolyl 3-pyridazinyl

 6-Chloro-1-pyridazinyl

 5-methoxy-l-benzoxazolyl 2-birazinyl

 6-methoxy 2-benzothiazolyl 3-benzoisoxazolyl

 5-Methoxy-2-benzothiazolyl 3-benzoisothiazolyl

Replacement form (Rule 26) 36

R

Phenyl 2-oxazolyl

 'Fluorophenyl 2-thiazolyl

 2-Midazolyl

 2-pyridyl

 'Chlorophenyl 6-methoxy-2-pyridyl

 , 3-Nitro-2-pyridyl

 3-Amino-2-pyridyl

 -Methoxyxyphenyl 3-methylamino-1-pyridyl

 -3-ethylamino 2-pyridyl

 -3-Fluoro. One 2-Pyridyl

 -Nitrofeninole 3-pyridyl

 Four- 〃

 2-benzoxazolyl

 -Aminophenyl 5-chloro- 2-benzoxazolyl-"2-benzothiazolyl ·

 -"5-Methyl-1-benzothiazolyl

 -Dimethylaminophenyl 2-benzimidazolyl

 -"2-pyrimidinyl

 -"5- .Chloro-1-pyrimidinyl

 -Trifluoromethylphenyl 4-methoxy-1-pyrimidinyl

 -"4,6-Dimethoxy 2-pyrimidinyl-" 4-Pyrimidinyl

 .4-Difluorophenyl 5-chloro- 6-methyl-4-pyridinyl-methoxy-2-benzoxazolyl 3-pyridazinyl

-Methoxy-2-benzoxazolyl 6-chloro-3-pyridazinyl

 2-virazinyl

-Methoxy-2-benzothiazolyl 3-lyl

-Methoxy-1-2-benzothiazolyl 3-lyl

Replacement paper (

R ^;

F-nil 2-oxazolyl

 'Fluorophenyl 2-thiazolyl

 -"2-imidazolyl

 — "2-pyridyl

 -Kuguchi phenyl 6-methoxy 2-pyridyl

 -"3-Nitro-2-pyridyl

 -"3-amino-1 2-pyridyl

 -Metoxif Xnil 3-methylamino

 〃 One-pyridyl

 3-ethylamino-2-pyridyl

 〃

 3-fluoro-2-pyridyl

 Nitrophenyl 3-pyridyl

 Four- "

 〃 2-benzoxazolyl

 Aminophenyl 5-chloro □ -2-Benzoxazolyl- "2-benzothiazolyl

 4- "5-methyl-2-benzothiazolyl

2-dimethylaminophenyl 2-benzomidazolyl

 3- "2-pyrimidinyl

 4- "5-chloro-2-pyrimidinyl

 2-trifluoromethylphenyl 4-methoxy 2-pyrimidinyl

 3- "4,6-dimethoxy-2-pyrimidinyl 4« "4-pyrimidinyl

 2. 4-Difluorophenyl '5-chloro-6-methyl-1-pyrimidinyl-methoxy-2-pentoxoxazolyl 3-pyridazinyl

 -6-Chloro-3-pyridazinyl methoxy-2-benzoxyl oxazolyl 2-birazinyl

 -Methoxy-2-benzothiazolyl 3- -methoxy-2-benzothiazolyl 3-

Replacement form (Rule 26) 38

IT

Phenyl 2-oxazolyl

2-fluorofuninyl 2-thiazolyl

3- 2-imidazolyl

4- 2-pyridyl

2-chlorophenyl 6-methoxy 2-pyridyl

3- 3-Nitro-2-pyridyl

4- 6- "

2-methoxyphenyl 3-amino-2-pyridyl

3- 3-methylamino-2-pyridyl

4- 3-ethylamino-2-pyridyl

2-ethoxyphenyl 3-fluoro-2-pyridyl

2-nitrophenyl 3-pyridyl

3- no /

4- 2-benzoxazolyl

2-aminophenyl 5-chloro-2-benzoxazolyl 3- 〃2-benzothiazolyl

4-〃5-methyl-1-benzothiazolyl 2-dimethylaminophenyl 2-benzimidazolyl

 3-2-pyrimidinyl

4- ₅ -Black mouth — ₂ _ pyrimidinyl

 2-Trifluoromethylphenyl 4-methoxy 2-pyrimidinyl

 3,4,6-Dimethoxy-1-pyrimidinyl 4-"4-pyrimidinyl

 2,, 4-difluorophenyl 6-ethyl-4-pyrimidinyl

 2-Methylphenyl 6-chloro-1-pyrimidinyl

 3--1-chloro-6-methyl-1-pyrimidinyl 3-hydroxyphenyl 3-pyridazinyl

 6- -Methoxy-oxazolyl 6-glolor 3-pyridazinyl

 2-benzo

 2-virazinyl

 5--Methoxy--2-benzoxazolyl

 3-benzoisoxazolyl

 6-Methoxy—2-Penzothiazolyl

 3-benzothiazolyl

 5-Methoxy-1-benzothiazolyl

Replacement form (Rule 26) OH

R ³ R ³

Noeno? i-oki

 -Fluorophenyl 2-thiazolyl

 -"2-imidazolyl

 -〃 2-pyridyl

 -Chlorophenyl 6-methoxy 2-pyridyl

 -〃 3-Nitro-2-pyridyl

 -"3-Amino 2-pyridyl

 -Methoxyphenyl • 3-Methylamino-1-pyridyl

 -"3-ethylamino-1-pyridyl

 -"3-Fluoro-2-pyridyl

 2-ditropenyl 3-pyridyl

 3- ". 4- 〃

 4- "2-benzoxazolyl

 2-aminophenyl 5-chloro- 2-benzoxazolyl

3-〃2-benzothiazolyl

 4-〃5-methyl-2-benzothiazolyl

2-dimethylaminophenyl 2-benzomidazolyl

 3- "2-pyrimidinyl

 4- "5-chloro-2-pyrimidinyl

 2-trifluoromethylphenyl 4-methoxy 2-pyrimidinyl

 3-"4,6-Dimethoxy-1-birimidinyl

4-〃 4-pyrimidinyl

 2, 4-difluorophenyl 5-chloro-6-methyl-1-pyrimidine

 3-pyridazinyl

 6-methoxy-2-benzoxyl

 6-Chloro-1-pyridazinyl

 5-methoxy-2-benzoylxazolyl 2-birazinyl

 6-methoxy-2-benzothiazolyl 3-benzizoxazolyl

 5-methoxy-2-benzothiazolyl 3-benzoisothiazolyl

Replacement form (Rule 26)

F: dinyl 2-oxazolyl

 -Fluorophenyl '2-thiazolyl

 -2-Yimyu 'Zolil

 -2-pyridyl

2-chlorophenyl 6-methoxy-2-pyridyl

 -3-Nitro 2-Viridyl

 -3-amino-1 2-pyridyl

 -Methoxyxnil 3-methylamino-2-pyridyl

 -〃

 3-ethylamino-2-pyridyl

 -3-fluoro-2-pyridyl

 -Nitroguchi 3-pyridyl

 - Four- "

 -2-Ben.zoxazolyl

 Aminophenyl 5-glo 2-benzoxazolyl-2-benzothiazolyl

 -5-methyl-2-benzothiazolyl-dimethylaminophenyl 2-benzoimidazolyl

3- 2-pyrimidinyl

 -5-chloro-2- 1-pyrimidinyl

2-trifluoromethylphenyl 4-methoxy-1-pyrimidinyl.3,4-, 6-dimethoxy-2-pyrimidinyl

2. 4-Difluorophenyl 5-chloro-6-methyl-4-pyrimidinyl 4-methylphenyl 3-pyridazinyl

4-hydroxyphenyl 6-chloro-3-pyridazinyl

6-methoxy-2-benzoxazolyl 2-birazinyl

 5-Methoxy-2-oxazolyl 3-benzoyl

6-methoxy-2-benzothiazolyl 3-benzoisothiazolyl

5-methoxy-2-benzothiazolyl

Replacement paper (Kaikai IJ26)

R ¹ R ³ Methyl methoxy 3-chlorophenyl-fluorophenyl 4-nitrophenyl

2. 4-Difluorophenyl 4-diethylminophenyl methyl diphenyl / dimethoxy a-methoxy-2-methylphenyl

 2-methoxy-2-

Four-

 ? -Hydroxyphenyl

フ ル オ ロ Fluorophenyl pyridyl

 9-pyrimidinyl, noprosomethoxy methoxyphenyl

 2-Pyrimidinyl 1- (7: i) 2-

2,4-difluorophenyl 2--trifluorophenyl cyclobutyl 2--pyrimidinyl

 Cyclohexisole "

 Methoxy

 2, a-sh!

 Ethyl ethoxy '2 -Methoxy ethoxy

Η difluorome toxic

 2-hydroxyxetil

 2-ace tokishetil

 Carboxymethyl

 2-dimethylaminoethyl

 2-morpholinoethyl

 2-pyridylmethyl 〃

 Methylamino

 2-hydroxyxethyl 2-pyrimidinyl methylamino

 vinyl

 2-propenyl

 Ethur

 2-propynyl

 Cyclopropyl methyl

 2. 4-difluorophenyl

Replacement form (Rule 26)

R ^l R ² R ³

Benzyl difluromethoxy-2-benzothiazolyl

Methyl / No Nono

 Nono Nono 6-Chloro-2-benzothiazolyl Nono "6-Methoxy-2-benzothiazolyl

2-hydroxyethyl nono 2-benzothiazolyl

 2-Methoxyethyl nono 2-pyrimidinyl

 H 1) 2 —Benzothiazolyl

Cyclobutene pill difluoromethyl 2-pyrimidinyl

Methylamino difluoromethoxy 2-benzoxazolyl

Replacement form (Rule 26) 43

Replacement form (Rule 26)

R n R 'R ¹ Ethyl methoxy 2-pyridyl

 2-Fluoroethyl H H Cyclopropyl

Ethyl 2-pyrimidyl

 2-Fluoroethyl

Cyclopropyl

Ethyl methyl

 2-Fluoroethyl

Cycloprovir

Ethyl 2-pyridyl

 2-Fluoroethyl

Shikuguchi Pro Building

Ethil difluorome toxic

 2-Fluoro mouth H

Cyclopropyl

Ethisole 2-pyrimidinyl

 2-Fluoroethyl

Cyclopropyl

Etil

 Methyl

 2-Fluoroethyl

Sigloprovir

Ethyl 2-pyridyl

 2-Fluoroethyl

Cyclopropyl

Methyl 2-pyrimidinyl methylethyl

Cloth propyl

Methyl trifluoromethyl non 2-benzophenone

Replacement form (Rule 26)

COOH

R ¹

Cyclopropyl H 2-methoxyphenyl

Etil

 2-fluorophenyl 3-methoxyphenyl

4-fluorophenyl 4-trifluoromethylphenyl 2. 4-difluorophenyl 3-aminophenyl

Cyclopropyl 2-pyridyl

Etil

 2-Fluoroecinole

4-fluorophenyl

Cyclopropyl F 2-methoxyphenyl methyl 2-fluorophenyl 2-methoxyphenyl

 2-Fluoroethyl

 〃

 2-pyridyl

Proportion

4-Fujileo-phenyl 4-methoxy

2. 4-difluorophenyl 4-aminophenyl

Methyl C I 3-fluorophenyl

 4-fluorophenyl 2-nitrophenyl

2, 4-difluorophenyl 2-dimethylaminophenyl methyl Br r 4-fluorophenyl

 Methyl 2-chlorophenyl

 4-fluorophenyl 3-nitrophenyl

2. 4-difluorophenyl 3-dimethylamino.nilethylfluoromethyl 2-pyrimidinyl

Cyclopropyl H

t-butyl

 2. 4-difluorophenyl

2-Fluoroethyl F

2-hydroxyxetil

Ethil C I

 〃

 Methyl

 Io C3 Hand 1

Replacement form (Rule 26)

R ^;

Feninole 2-oxazolyl

 2-fluorophenyl 2-thiazolyl

 3- "2-imidazolyl

 ~ "2-pyridyl

 2-chlorophenyl 6-methoxy-2-pyridyl

 3- "3-nitro-1-pyridyl

 4- "4-amino-1-pyridyl

 2-methoxyphenyl 3-methylamino-2-pyridyl

 3- "3-ethylamino

 A.- "One 2-pyridyl

 3-fluoro-2-pyridyl

 2-Nittophenyl 3-pyridyl

3 "4-"

 4- "2-benzoxazolyl

 2-aminophenyl 5-chloro-1-benzobenzoxazolyl

3- "2-benzothiazolyl

λ-"

 5-methyl-2-benzothiazolyl

 2-dimethylaminophenyl 2-benzimidazolyl

 3- "2-pyrimidinyl

 4- "5-chloro-1-pyrimidinyl

 2-trifluoromethylphenyl 4-methoxy 2-pyrimidinyl

 3- "4,6-dimethyloxy 2-pyrimidinyl-4-pyrimidinyl

 2,4-difluorophenyl 5-chloro □-6-methyl-4-pyrimidinyl

 3-pyridazinyl

 6-chloro-3-pyridazinyl

 2-virazinyl

Replacement paper (Kaikai IJ26)

XY n R ³ R ⁴

C £ H 12-Dichlorophenyl Η.

 3,4-amino 1-naphthyl

 2- »

 F H 2 2-pyridyl

 2-pyrimidinyl

 1 2-pyridyl methyl

2-pyrimidinyl

Replacement form (Rule 26)

Replacement form (Rule 26)

Replacement form (Rule 26) COOH

R 'R ³ Cyclopropyl 2-pyridyl

 Ethil 〃

 2-Fluoroethyl

 4-Fluorophininyl 2-methoxyphenylinethyl チ ル

 2-pyrimidinyl

2.4-difluorophenyl 〃

Replacement form (Rule 26)

Replacement paper (26) H

Replacement form (Rule 26)

Replacement form (Rule 26) 54

Replacement paper O 99/42106

 55

R ³

Phenyl 2-xoxazolyl

 2-fluorophene 2-thiazolyl

 3-Nono 2—Imidazolyl

 4-2-pyridyl

 2 Black mouth phenyl 6—Toki 1—Piri

 3 3 1 J

 4 one no no no no

 2-Methoxyphenyl 4-nono

 3-• Nono 2 One Benzoki i Hatazo U 1

 4--11 r-r n _ m — ヽ, no, no / J ""?

2-Ethoxyphenyl 2-benzothiazolyl

 2-Trifluoromethylphenyl 5-methyl-2-benzothiazolyl

 3--Nono 2 Benzoimiguzoril

 4--Nono 2-pyrimidinyl

 2,4-difluorophenyl 5-chloro-2-birimidinyl

 2-Methylphenyl 4-methoxy-2-pyrimidinyl

 3--n 4.6 -dimethoxy-2-pyrimidinyl

2--Methylthiophenyl 4-birimidinyl

 3--Nono 6-ethyl-4-pyrimidinyl

 4--) 1 6—Black mouth— 4—Birimidinyl

 2--Ethylthiophenyl

3--No / 3-Viridazinil

 4--"6-chloro-3-pyridazinyl

 2-virazinyl

 3-'Benzoisoxazolyl 3-benzoisothiazolyl

 S-methoxy-2-benzothiazolyl 6-methoxy-2-benzoxazolyl;

5-methoxy-2-benzothiazolyl 5-methoxy-2-benzoxazolyl 2106

 56

R3

Tsu no jiano 1 shire 0 "—

 つ ノ j j 5 α \ ~ * 1 し * * · · · · — 午 — 午

 _ Zono

 ^ One, seven

 · £ / Renozore

 2 ー ス

d—Nono d—No J u—2—t «Liso J

 4—Nono i—Ju Sol

 "Yannoere 4— / no

d—No-no-one-no-V

 O-mouth o- one-way; 3-r V

 Ζ— Γ "Yannnore—Henosona

 「“ No no no no! No — S 1 ^^^^^^^^^^^^^^^^^^^^^^^^^^

 — ΪΙ 一, ，, f f-^ Z ノ 1

 4-"2-Bilimidinyl

 2; 4-difluorophenyl 5-chloro-2-pyrimidinyl

 .2-Methylphenyl 4-methoxy-2-birimidinyl

 3— “4,6-dimethoxy-2-pyrimidyl

2-Methylthiophenyl 4-Bilimidinyl

 3— ”6—ethyl-4 monopyrimidinyl

 4— 〃 6—black α—4-birimidinyl

 2-Ethylthiophenyl 5-chloro-1-6-methyl-4-pyrimidinyl

3-"3-pyridazinyl

 4 -1, ι 6-Chloro 3-biridazinyl

 6-methoxy-2 zonoxazolyl 2-birazinyl

 5-methoxy-2-nzoxazolyl

 & Methoxy-2-benzothiazolyl 3-Penzoisothiazolyl

5-methoxy-1-benzothiazolyl

R *

 Propylphenyl Isopropylphenyl

 n 2—Black U phenyl Gas 2—Black mouth phenyl Nono 3—3 “n 4—1” Nono nn 2—Fluorophenyl II 2—Full-year Rophenyl Nono 3— “Nono 3—)) n 4—” Nono 4— Nono

 n 2-Methoxyphenyl / 2-methoxyphenyl

II 3— »3—})

 Nono Α 一 Nono 4— Nono

 2-1 Trifluoro group 2-1 R Trifluoro group 3-'Methylphenyl / 3-'

 n 2—Pyridyl / 2—Py.

 "4-") 1 4 1 n

 2-Bilimidinyl II 2-Pyrimidinyl

 4—Nono 4—No Factory

 2-methylthiophenenyl, 2-methylthiophenenyl

3— I) 3-"

 〃 4-"

 2-ethylthiophenyl nono 2-ethylthiophenyl n 3-"3—))

 II 4—n mo 4 1 1)

 3—Amino 2—Pyrimidini J

Broville

R 'R ¹ R ³

Funarefe: Isobutyl phenyl

 "2-Chlorophenyl 2-Chloro-Xnil

 3 3

 4 Nonoga 4 JJ Puno 2 —Fluorophenyl Puno 2 monofluorophenyl it 3 Nono Nono 3))

 4 ga 4 »nono-2-methoxyphenyl Xnil 2-methoxyphenyl

 3 1) 3) 1

4 Nono 4 / No

1) 2 ―, Trifluo α JJ 2 Trifluro

)) 3 Methylphenyl 3 'Methylphenyl Xnyl Nono 4 G 4

 Nono 2-Pyridyl 2-Pyridyl Nono 3 n Mo 3 Nono

 NONO 4 JJ GA 4 NONO

 "2-pyrimidinyl 1) 2-birimidinyl n 4 η II 4 nono n 2-methylthiophene Xnil" 2-methylthiophene; nil

II 3 η 3 JJ

 JJ 4 Nono JJ A JJ

 )) 2-diethylthiophenyl nono 2-ethylthiophenyl

JJ 3 "3 n

ι> 4 no / 4 no

Γν R

Ku 1 elephant ^ ^ Hue: Nil Isobrovir Noenyl

 Nono 2-chloro phenyl Nono 2-chlorophenyl

〃 3-'Nono' Nono Nono

〃 4-II Nono 4 1)

 11 2—Fluorophenyl II 2 —Full-year rophenyl

II 3— 1) 3 Nono

 1 4-Nono 4 mo

 11 2-Methoxyphenyl / 2-methoxyphenyl

11 3— II Nono 3 Nono

〃 4-Nono 4 Nono

 »2-· Trifloorono / 2

II 3-'Methylphenyl) 1 3' Melphenyl nono 41.)> 4

 1! 2—Pyridylile 11 2—Birigil

 11 3— No / No / 3 Nono

 Nono 4 1 1) No / 4))

 1) 2-Pyrimidinyl 11 2 -Pyrimidinyl nono 41) 1 4 1)

 Nono 2-methylthiophenil 2-methylthiophenyl

〃 3— NONO 3 NONO NONO 4 1 NONO NO 4

 Nono 2-ethylthiophenyl Nono-2-ethylthiophenyl Nono 3-1) Nono 3

 II 4 I. U no / 4

 3-amino 2-pyrimidinyl

Broville

Replacement form (Rule 26) COOH

CF ₃ R '

R ¹ R3 乂 1 1 ^ 匕 2 2- 匕 tmxn phenyl

 〃 2-black phenyl gas 2-black alpha phenyl

 3- »Non 3-', BU / 4-» 4-η

〃 2-Fluorophenyl / 2-fluoro α-Xnil

 3— "Moth 3-II

 / No 4-1) nono 4- "Ga 2-methoxyf; t-yl nono 2-methoxyfuron nono 3-" / 3-a

 // 4-u 4 »G 2-Viridyl Nono 21-Jill

 3-»3-»

 , ノ 4-ga 41

 Nono 2—Birimidinyl Nono 2 Birimidinyl

 JJ 4-Ga 41

 JJ 2-Methyl off A-le. »2-Methylthiophenyl nono 3-" JJ 3-u

// 4- »Nono 4-) 'Mo 2-Echiruchi A- A-' D 2-Λ Chiruchiofue 2-Le Nono 3-" JJ3- Μ Nono 4- / '4- η

 Three

R 3 R R—Fluoroethyl

 2-—αα-phenyl ΧΛ ϊ · Trifluoroethyl

 3- 'II 2-Chloro-2-yl

4-a-2-trifluorec

 2-Fo α-X X J J 2-Chloroethyl 41-Fluoro α-phenyl

3-u

 4- u 2-chloro α-ethyl 2-methoxyph; t-nil

2-Methoxyphenyl 2-trifluoro α-U

 3—u-clo-ethyl 2—viridyl

 4-»1Λ 2-Trifluorethyl u

 2-trifluoromethylphenyl 2-chloro α-ethyl 2-birimidyl

3-M 2.2 2-Trifluoroethyl 4-u

 2-pyridyl

 3- »

 Four- "

 2-pyrimidinyl

 4-, η

 3-Methylthiol

 3-u

 4-U

 2—Technical tilt-off

 3—moth

■ 4— u

R 'R3 R Methyl 9.- -Viridylile methyl 2--Pyrimini J

2> -meth i i ⁵ "no two 2) re nono nono 2--ゥ α π funi j-nonoethyl 0-t nonogarbi 1] sago., Nono nono 2'-methoxyphenylene

 2 · -Ku mouth phenyl "Isobrovir 2 · -Pyridyl nono Nono 2 · —Pyrimidinyl»

)> 2-Methoxyphenyl nono

JJ 2 Chlorophenyl nono Cyclobutene building 2 Pyridylile nono

 2 Birimidinyl nono

2-methoxyphenyl nono

1) 2-cloth phenyl

2—Fluoroethyl 2 Pyridyl h

 2 Birimidinyl son

2-methoxyphenyl nono

2 Chloroph: tnil nono

R ³ chill 2--pyridyl

 Nono 2

 Nono Δ-Methoxyoxophenyl

 Nono Δ-

 Δ-Methoxyphenyl

〃-Chlorophenyl isopropyl 2--pyridyl

 2--pyrimidinyl

2-methoxyphenyl

2-Chlorophenyl. SiC pProvir 2-pyridyl

 〃 2- -Pirimigel

 2—Methoxyphenyl nono 2-chloro phenyl

2—Full-year Roetil 2 Pyridyl

 2 Pyrimidinyl

2-Methoxyf Xnil

2 Black phenyl

R R Provir 3 Benzoisoxazolyl

 (3) Benzoisothiazolyl

 6—Methoxy 2—Penzoxazolyl

5—Methoxy 2—Benzoxazolyl

6—Methoxy 2—Penzothiazolyl

5—Methoxy 2—Penzothiazolyl

 2 Benzothiazolyl

 2-Benzoxazolyl izopropir 3 Benzoisoxazolyl

 3-Penzoisothiazolyl

 6—Methoxy 2—Penzoxazolyl

5—Methoxy 1—Benzoxazolyl

6-Methoxy 2-benzothiazolyl 5-Methoxy 2-benzothiazolyl

 2-benzothiazolyl

2-benzoxazolyl

R R 'Butyl 3-benzoisoxazolyl

 3-Penzoisothiazolyl

 6-methoxy-2-pentoxoxazolyl

5-Methoxy-1- 2-benzoxazolyl

6-Methoxy-2-benzothiazolyl

5-Methoxy-2-benzothiazolyl

 2 Penzothiazolyl

 (2) Penzoxazolyl isobutyl (3) Benzoisoxazolyl

 3—Benzoisothiazolyl

 6-Methoxy-2-benzoxazolyl 5-methoxy-2-benzoxazolyl

6-methoxy-2-benzothiazolyl 5-methoxy-2-benzothiazolyl

 2-Penzothiazolyl

2-Penzoxazolyl

R R Hydrogen atom 3-Penzoisoxazolyl

 3 Benzoisothiazolyl

 6-methoxy-2-pentoxoxazolyl

5-Methoxy 2-Penzoxazolyl

6—Methoxy 2—Venzothiazolyl

5-Methoxy 2 benzothiazolyl

 2 Benzothiazolyl

 2 Benzoxazolyl cyclobutyl 3 Penzoisoxazolyl

 3-benzothiazolyl

 6-Methoxy-2-benzoxazolyl 5-Methoxy-2-penzoxazolyl 6-Methoxy .2-Benzothiazolyl

5-Methoxy-1 2-benzothiazolyl

 2-Penzothiazolyl

2-benzoxazolyl

R R Cyclopentyl 3-benzoisoxazolyl

 3 Benzoisothiazolyl

 6-Methoxy-1- 2-benzoxazolyl

5-Methoxy-2-benzozoxazolyl

6-Methoxy-2-pentazothiazolyl 5-Methoxy-1-pentazothiazolyl

 2-benzothiazolyl

 2-Penzoxazolyl methylamino 3 Benzoisoxazolyl

 3 Benzoisothiazolyl

 6-methoxy-2-benzoxazolyl

5-methoxy-2-pentoxoxazolyl

6-methoxy-2-benzothiazolyl 5-methoxy-2-benzothiazolyl

 2 Benzothiazolyl

2-benzoxazolyl

R 'R

2-fluoroethyl 3-benzoisoxazolyl

 3-benzothiazolyl

 6-methoxy "2-benzoxazolyl

5-Methoxy-1- 2-benzoxazolyl

6-Methoxy-2-benzothiazolyl

5-Methoxy-2-benzothiazolyl

 2-Penzothiazolyl

 2 Benzoxazolyl — hydroxyethyl 3 Penzoisoxazolyl

 3 Benzoisothiazolyl

 6-Methoxy-2-pentozoxazolyl 5'-Methoxy-2-pentozoxazolyl 6-Methoxy-2-pentazothiazolyl

5-Methoxy-2-pentazothiazolyl

 2-Penzothiazolyl

2-benzoxazolyl COOH

CF ₃ R '

R R R Methyl 3-Penzoisoxazolyl methyl

 3-benzoisothiazolyl methyl 6-methoxy-2-benzobenzoazolyl methyl

5—Methoxy 2—Penzoxazolyl methyl

6—Methoxy-2-benzothiazolyl methyl 5—Methoxy-1 2—Penzothiazolyl methyl

 2-Benzoisoxazolyl methylethyl 3-Benzoisoxazolyl methyl

 3-Benzisothiazolyl methyl 6-Methoxy 2-benzoxazolyl methyl

5—Methoxy 2—Penzoxazolyl methyl

6—Methoxy 2—Penzothiazolyl methyl 5—Methoxy-1-2-benzothiazolyl methyl

 2-benzothiazolyl methyl

2-Penzoxazolyl methyl COOH

CF ₃ R ¹

R-Methyl 3-benzoisoxazolyl

 3-benzoisothiazolyl

 6-Methoxy-2-benzoxazolyl 5-methoxy-2-benzoxazolyl 6-methoxy-1-2-benzothiazolyl

5-Methoxy-2-benzothiazolyl

 2 Benzothiazolyl

 2-Besisoxazolyl ethyl 3-Benzisoxazolyl

 3-diazoisothiazolyl

 6-methoxy-2-benzoxazolyl

5-Methoxy-1-benzobenzoazolyl 6-methoxy-2-benzothiazolyl 5-methoxy-2-benzothiazolyl

 2-Penzothiazolyl

2-benzoxazolyl COOH

0-CHP _{2 H}

R ³

Phenyl 2-oxazolyl

 -Fluorophenyl 2-thiazolyl

 -2-imidazolyl

 -2-pyridyl

 -Black mouth _nil 6-methoxy-2-pyridyl

 -3-nitro-1-pyridyl

 -〃

 6- "

 -Methoxy phenyl 3-amino-1-pyridyl

 -3-methylamino-1-pyridyl

 -3-ethylamino 2-pyridyl

 -Ethoxyphenyl 3-fluoro-2-pyridyl

 -Nitrophenyl 3-pyridyl

 - Four- "

 -2-benzoxazolyl

 -Aminof Xnyl 5-chloro-1-benzobenzoxazolyl

 2-benzothiazolyl

 5-Methyl-1-benzothiazolyl dimethylaminophenyl 2-benzimidazolyl

3 2-Pyrimidinyl

 5-chloro-2-pyrimidinyl

2 Trifluoromethylphenyl 4-methoxy 2-pyrimidinyl

3 4, 6-Dimethoxy 2-pyrimidinyl 4 4-Pyrimidinyl

2 4-Difluorophenyl 6-ethyl 4-pyrimidinyl

2 methylph Xnyl 6-chloro-4-pyrimidinyl

Three

 5-methyl-6-methyl-4-pyrimidinyl 3-hydroxyphenyl 3-pyrigdinyl

 Methoxy-2-benzoylxazolyl 6-glolor 3-pyridazinyl

 2-virazinyl

 Metokiji 2-benzozoxilazolyl

 3-Benso'sisoxazolyl methoxy 2-Benzothiazolyl

 3-benzothiazolyl

 Methoxy-2-benzothiazolyl

Replacement form (Rule 26) COOH

Suitable compounds represented by the general formula (Ia), (Ib) or (Ic), which are the active ingredients of the present invention, include:

 6 — Fluoro-8 — difluoromethoxy 7 — [4- (2—pyrimidinyl) piperazine—1—yl] 1-4—Hydroxyquinoline—3—potassium

 1-Cyclopropyl-6-Fluoro-8-Tri-Fnorolero methine-7-1 [4-(3-Mouth phenol)-1-Inole]-1, 4-1 Doro 4-oxoquinoline 3-carboxylic acid.,

 1 1 Methyl 1 6 — Phenoleolo 8 — Tri Fenoleolo Metinole 7 — [4 — (2—Black mouth Feninole) Pirazine 1 1 — Inole]-1,4 — 4 1-oxoquinoline-1 3—Rubonic acid or

 1-Cyclo Pro Pinole 6-Funoreo 1 8-Tri Funoleolo Metinole 7

-[-(3-Trifluorophenyl) piperazine-1 -yl]-1,4,4-Hydroxy-4-oxoquinoline 3-Potassium. The compound represented by the above general formula (Ia), (Ib) or (Ic), which is an active ingredient of the present invention, is disclosed in EP 572,259 (Japanese Unexamined Patent Publication No. Hei 6-11). No. 6241) and / or the method described in W096 / 02512 (Japanese Patent Application Laid-Open No. 8-187375) and modifications thereof. It is manufactured by a method. The route of administration when the anti-HCMV agent of the present invention is used as a medicament is an oral route or a parenteral route. 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). Hereinafter, the present invention will be described in more detail with reference to Examples, but the scope of the present invention is not limited thereto. BEST MODE FOR CARRYING OUT THE INVENTION The anti-HCMV activity and cytotoxicity of a quinoline carboxylic acid derivative as an active ingredient of the present invention were measured as follows.

(Test Example 1) Antiviral activity

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.

(Test Example 2) Cytotoxicity

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 Ρ 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 μl, and cultured at 37 ° C. for 5 days in the presence of 5% carbon dioxide. After completion of the culture, 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.

Compound 2 Compound 1

 Compound 5

Compound 8 Compound 7 78

Compound 9 Compound 10

Compound 1 Compound 1 2

Compound 1 3 Compound 1 4

Compound 1 5 (Table 1) Test compounds IC 5 O and 5 O

 (g X m 1) (g / m 1) Compound 1 0.3 6 2 5

 Compound 20.2

 Compound 30.36

 Compound 4 0.2 3

 Compound 50 0.332

 Compound 6 0.5 5 6

 Compound 7 0.2 8 3

 Compound 80 .6 16

 Compound 90 0.18

 Compound 1 0 0 .0 7 0

 Compound 1 1 0 .0 9 0 8 9986528 Compound 5733

 1 2 0. 1 6

 Compound 1.30.3

 Compound 1 4 0.58

Compound 150.55

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 μg / m 1 or less. In particular, 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.

(Reference example 1)

 6 — Fluoro-8 — difluoromethoxy 7 — [4 — (2 — pyrimidinyl) piperazine-1 1 -yl] — 4-Hydroxyquinolinine 3 — Power Synthesis of rubonic acid (compound 1)

 (a) 1-Benzinole 6, 7-Diphnoreo mouth 1 8-Diphnoreolomethoxine 1, 4-Dihydro 4-Oxoquinoline 1 3-Potassium 15.0 g (0.03 9 mol) and 1— (2—pyrimidinyl) pidazine (164 g, 0.10 mol) were dissolved in 200 ml of pyridine, and the mixture was dissolved at 105 ° C. Heated for hours. After evaporating the solvent under reduced pressure, water was added, the precipitated solid was collected by filtration, washed with water, dried, and dried with 1-benzyl-16-fluoro-8-difluoromethoxy7— [4— (2— 19.1 g of pyridinyl) pyrazine-1—yl] —1,4 dihydro-4-oxoquino ”lin-13—carboxylic acid was obtained as a slightly yellow powder.

(b) 1-Benzinole 6-Phenoleolo 8-Diphnorelomethoxy 7-[412-Pyrimidinyl) piperazine 1-1]-1,4 Zhidro 4-1-oxoquinoline 1-3-g-Rubonic acid 19.1 g (0.036 monole), octa-no-nole 9.5 g (0.073 monole), 1-ethyl-mono-3- (3-dimethylaminopropyl) ) 14.0 g (0.073 mol) of carposimid hydrochloride and 6.7 g (0.055 mol) of 4-dimethylaminopyridine were added to 500 ml of methylene chloride, and the mixture was added at room temperature. Stirred for 8 days. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (eluent; chromatographic form: methanol == 9: 1 mixture). 1 1-Penzinole 6 —Hunoleo mouth 1 8 —Diphnorelomethoxy 7 — [4— (2—Pyrimidel) Pirazine 1 1 1] 1 1,4—Dihydro 1 4—Oxoquinoline 1 3 — 19.6 g of octinoleestenolate was obtained as a white powder.

(c) 1-Benzinole 6-Fluoro-8-Difluoromethoxy 7-1 [4-(2-Pyrimidel) piperazine 1 1-yl]-1, 4-Dihydro-4 Li down one 3 -. carboxylic acid O-lipped Honoré ester 1 0 0 g to ethanolate Lumpur 5 0 0 m 1 solution (. 0 0 1 6 Monore), 5% Nono ⁰ Raj © beam force one carbon 1 0. 0 g was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 7 hours. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent; chromatographic form: methanol: 28% aqueous ammonia = 40: 9). 1), 6-Fluoro-8-difluoromethoxy-1 7- [4- (2-Pyrimidinyl) piperazine-1 1-yl] 14-Hydroxyquinoline-1 27 g of octyl carboxylate were obtained as a pale yellow powder.

(d) 6-Fluoro-8-difluoromethoxy 7-[4-(2-Pyrimidinyl) piperazine-1-yl]-4-Hydroxyquinoline-1-3-Octyl ester of rurubonic acid 2.92 g (5.0 mmol) was added to a mixed solution of 10 ml of acetic acid, 6 ml of water, and 1 ml of concentrated sulfuric acid, and the mixture was heated under reflux for 2 hours. After cooling, water was added, and the precipitated solid was collected by filtration. Then, silica gel column chromatography (eluent; eluent; black form: methanol: 28% ammonia water = 40: 9: 1) Mixture), and 6 — phenolol 8 — difluoromethoxy 1 7 — [4- (2 — pyrimigel) piperazine 1 1 1] 1 4 — hydroxyquinoline 1 3 — carvone 1.3 _g of the acid were obtained as a white powder.

 Melting point: 270 to 272 ° C

MS spectrum (CI): m / e 43 6 (M + 1) (Reference example 2)

 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.

(Reference example 3)

 Compounds 8, 9, 12, 14, and 15 were described in Examples and Reference Examples of JP-A-6-116241 and JP-A-8-183775. It was synthesized according to the method. Table 2 shows the properties and melting points of these compounds.

(Table 2) Compound properties Melting point C) Compound 8 pale yellow powder 26 2-2 6 4

 Compound 9 pale yellow powder 2 8 2.5-2 8 4.5 Compound 1 2 yellow powder 2 6 8-2 7 0

 Compound 1 4 pale yellow powder> 3 0 0

Compound 15 Orange powder 2 80 .5-2 8 3 INDUSTRIAL APPLICABILITY 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).

Claims

General Claims — /,

 I (I b) or (I c)

 a

In the above formula (1a), (lb) 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 with 1 to 2 alkyl groups having 1 to 4 carbon atoms. Amino group or 1 to 2 carbon atoms 7 to 1 With four aralkyl groups ^{: represents a} substituted mono- or diaralkyl-substituted amino group;

Z represents an optionally protected carboxy group or 5 —tetrazolyl group;

 Q is a nitrogen atom or formula (d)

C-R:

 (d)

[In the formula (d), R ² is a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms which may be substituted with a halogen, or a carbon number which may be substituted with a halogen. Represents 1 to 4 alkoxy groups].

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 an alkyl having 1 to 4 carbon atoms or an alkenyl group having 2 to 4 carbon atoms which may be substituted with an alkyl having 1 to 4 carbon atoms. Represents a len group,

R ¹ is a hydrogen atom; a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms [substituents of the alkyl group are hydroxy, carboxy, halogen, carbon alkoxy having 1 to 4 carbon atoms, and carbon atom having 3 to 4 carbon atoms. 6 cycloalkyls, alkanoyloxys having 2 to 5 carbon atoms, formula (e) 1.

 N ヽ (e)

R ^{, e} (In the formula (e), R ⁹ and R ¹⁰ each represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, or R ⁹ and R ¹⁰ are combined to form a bond. Together with a nitrogen atom to form a 3- to 7-membered saturated monocyclic ring containing a heteroatom selected from N, O and S, as the case may be, or a group represented by RO An optionally substituted aryl group having 6 to 10 carbon atoms, a 5- to 6-membered heteroaromatic monocyclic group containing 1 to 2 heteroatoms selected from N, O and S, or A heteroaromatic condensed ring group obtained by condensing a heteroaromatic monocyclic ring with a benzene ring]; an alkenyl group having 2 to 5 carbon atoms which may be substituted by halogen; and 2 to 4 carbon atoms An alkynyl group; an amino group; a mono- or mono-alkyl group substituted with 1 to 2 carbon atoms having 1 to 4 alkyl groups Is a dialkyl-substituted amino group; a cycloalkyl group having 3 to 6 carbon atoms which may be substituted with a halogen; an alkoxy group having 1 to 4 carbon atoms; or a group substituted by R ° described below. A 5- to 6-membered heterocyclic monocyclic group containing 1 to 2 heteroatoms selected from N, O, and S, or a heteroaromatic monocyclic ring thereof. And a benzene ring fused to a heteroaromatic fused ring group,

R ¹ and R ² of equation (d) in Q join together to form equation (f)

[In the formula (ί), Α represents a hydrogen atom or a halogen, a hydroxy or an alkyl group having 1 to 4 carbon atoms which may be substituted by an alkoxy having 1 to 4 carbon atoms, and G represents Nitrogen atom or formula (g)

(g)

G ¹ represents a methylene group, a carbonyl group, an oxygen atom, a sulfur atom, or a — (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].

R is the formula (h) or the formula (i)

[In the formulas (h) and (i), R ³ and R ⁶ are R o (R ° is halogen, nitro, hydroxy, alkyl having 1 to 4 carbon atoms, or fluorine.) Substituted with 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, amino, and 1 to 2 alkyl groups having 1 to 2 carbon atoms Represents a group selected from mono- or dialkyl-substituted amino), an aryl group having 6 to 10 carbon atoms which may be substituted or a heteroatom selected from N, O and S. A 5- to 6-membered heteroaromatic monocyclic group containing 1 to 2 or a heteroaromatic condensed ring group obtained by condensing these heteroaromatic monocycles with a benzene ring; R ⁴ , R ⁵ and R ⁷ each represent a hydrogen atom or represents a number from 1 to 4 alkyl group having a carbon; R ⁸ is a hydrogen atom, a hydroxyl group, having 1 to 4 alkyl carbon Or it represents a number 1 乃 optimum 4 alkoxy group having a carbon; n represents 1 or 2;. M is replaced with 0 or 1 paper (Rule 26) N 'represents 1 or 2; n "represents 1, 2, 3 or 4]), a pharmaceutically acceptable salt thereof or a pharmacologically acceptable salt or ester thereof. An anti-human cytomegalovirus agent containing as an active ingredient.

2. In Claim 1, a quinoline carboxylic acid compound in which X in (Ia), (Ib) and (Ic) is a fluorine atom, a pharmacologically acceptable salt or an ester thereof is effective. The anti-site cytomegalovirus according to claim 1, which is contained as a component.

3. In Claims 1 and 2, γ in the formula (Ia), (Ib) or (Ic) is a hydrogen atom, a fluorine atom, an amino group, a methyl group or an ethyl group, 3. The anti-histosite megalo wineless agent according to claim 1, comprising a quinolone carboxylic acid compound, a pharmacologically acceptable salt thereof, or an ester thereof as an active ingredient.

4. The quinolone carboxylic acid compound according to claim 1 or 2, wherein γ in the formula (Ia), (lb) or 'Ic' is a hydrogen atom, which is pharmacologically acceptable. 3. The anti-human cytomegalovirus agent according to claim 1, which comprises a salt or an ester thereof as an active ingredient.

5. A quinoline carboxylic acid compound according to claims 1 to 4, wherein Z in the formula (Ia) or (Ic) is an optionally protected carboxy group, or a pharmaceutically acceptable salt thereof. 5. The anti-human cytomegalovirus agent according to claim 1, which comprises an ester as an active ingredient.

6. In claims 1 to 5, the formula (Ia), (Ib) or (Ic) A quinoline carboxylic acid compound, wherein Q in the formula (d) is a compound of the formula (d), and R ^{2 in} the formula (d) is a difluoromethoxy, trifluoromethoxy or trifluoromethyl group; 6. The anti-human cytomegalovirus agent according to claim 1, comprising a pharmacologically acceptable salt or an ester thereof as an active ingredient.

7. The method according to claim 1, wherein W of the formula (Ib) is a sulfur atom, and the quinolone carboxylic acid compound, a pharmaceutically acceptable salt or an ester thereof is contained as an active ingredient. The anti-site cytomegalo wineless agent according to claim 1, wherein

8. The quinolocarbonate compound according to claim 1, wherein T in the formula (I c) is an ethylidene, one CH = CH— or one C (CH 3) = CH— group. The anti-human cytomegalovirus agent according to any one of claims 1 to 6, comprising a pharmacologically acceptable salt or an ester thereof as an active ingredient.

9. The method according to claim 1, wherein T in the formula (Ic) is an ethylidene group, wherein the quinolone carboxylic acid compound, a pharmaceutically acceptable salt or an ester thereof is contained as an active ingredient. The anti-human site megalovirus agent according to claim 1.

10. The method according to claim ¹ , wherein R ¹ in the formula (Ia) or (Ib) is a hydrogen atom; methyl, ethyl, propyl, isopropyl; 2-hydroxyshetinole; carboxymethinele; 2 — Henoreolochinole, 2 — Kroroethyl, 2,2,2 — Trifluoloethyl, 2 — Acetokishetil; Feninoremetinole, 2 — Fuelenlechinole, 2 — Pyridinolemethyl; Ruaminoethyl, 2 — morpholinoethyl; amino; methylamino; methoxy; cyclopropyl, cyclopropinole, cyclopentyl, 2—funoleolo cyclopropinole; feninole, 2—funoleolo Pheninole, 3 — phenolic mouth, 4 — phenolic, 2, 4 — diphnoline, bininole, 2-propinyl, or 2-propyninole 8. The anti-histomegalovirus agent according to claim 1, which comprises a quinolone rubonic acid compound, a pharmacologically acceptable salt thereof, or an ester thereof as an active ingredient.

11. The method according to claim ¹ , wherein R ¹ of the formula (Ia) or the formula (Ib) is a hydrogen atom, methyl, ethyl, cyclopropyl, 2-fluoroethyl or methylamino group. A quinolone carboxylic acid compound, a pharmacologically acceptable salt or an ester thereof is contained as an active ingredient.

8. The anti-human cytomegalovirus agent according to any one of 1 to 7.

1 2. The quinolo according to claims 1 to 7, wherein R ¹ in the formula (Ia) or (Ib) is a hydrogen atom, a methyl group, an ethyl group, a 2-fluoroethyl group or a cyclopropyl group. The anti-human cytomegalovirus agent according to any one of claims 1 to 7, comprising a carboxyl'acid compound, a pharmacologically acceptable salt thereof, or an ester thereof as an active ingredient.

13. In Claims 1 through 12, the formula (Ia), (Ib) or (Ic) is represented by the formula (Ia), (Ib) or (Ic). (L-Feninole) Pirazine 1 1 1 Innole, 4 1 '(3 — Black mouth Feninole) Pirazine 1 1-Inole, 4 — (2-Methoxyfuel) Pirazine 1 1-Innole, 4 1- (3-trino-norelomethyl-phenyl) piperazine 1-dinole, 4— (4-fluorophenyl) piperazine-1-inole, 4- (2-pyridyl) pyrazine 1-1, 4-1 (2-pyrimigenole) piperazine 1-1, 4-(5-fluoro-2-pyrimidinyl) Piperazine 1 1-inole, 4 — (2—thiazolinole) Piperazine 1 1-inole. 4 1 (2—benzothiazolyl) Piperazine 1 1-yl, 4 — (2—benzozoxazolyl) Perazine-111, 4- (6-methoxy-2-benzothiazolinole) piperazine-1-1 or 4- (6-methoxy1-2-benzoxazolyl) pirazin-1-yl 13. The anti-cytomegalovirus agent according to claim 1, which comprises, as an active ingredient, a quinoline carboxylic acid compound, a pharmacologically acceptable salt thereof, or an ester thereof.

14. In Claims 1 to 12, the formula (Ia), (Ib) or (Ic) has a length of 41 (phenyl) piperazine, 4 — (2— 1-yl, 4- (3—black mouth) 1-yl, 4— (2—Methoxyfir) 1 1, 4 1 (3 — trifluoromethylphenyl) piperazine 1 — dinole, 4 — (4 — fluorophenyl) piperazine 1 1 ′

(2-pyrimidinyl) piperazine 1 '-yl, 4-(2-thiazolyl) piperazine 1-1 -yl, 4-(2-benzothiazolyl) piperazin-1 -yl or 41. Claim 1 containing a quinolone carboxylic acid compound, a pharmacologically acceptable salt or an ester thereof as an active ingredient, which is a 1- (2-benzobenzozolyl) pidazine-1 1-yl group. To 12 anti-human cytomegalovirus agents.

15.6—Fluoro-8—Difluoromethoxy 7— [4-1 (2—Pyrimidinyl) pyrazine-1 1-yl] 1-4-Hydroxyquinolin-1 3—Carboxylic acid, its pharmaceutically acceptable nature Effective salt or its ester The anti-human cytomegalovirus agent according to claim 1, which is contained in

1 6 1 — Cycloprop pinole 6 — Phenorero 8 — Trif noreolomeno 7 1 — 4 — (3 — 3) The anti-histomegalo according to claim 1, wherein the antihydrocytomegalo contains 4-dioxoquinoline-1-3-potassolenoic acid, a pharmacologically acceptable salt thereof, or an ester thereof as an active ingredient. Virus agent.

1 7 .1 — Metinole 1 6 — Funoleolo 8 — Tri-Fenole 1 7 — [4 — (2 — Black Mouth Feninole) Pirazine 1 1 1, 4 page 2. The anti-human cytomegalovirus agent according to claim 1, comprising a hydro- _4- oxoquinoline- ₃ -carboxylic acid, a pharmaceutically acceptable salt thereof, or an ester thereof as an active ingredient.

1 8.1-Cyclopropyl 1 6-Fluoro-8-Trifnoroleromethyl 7-[4-(3-Trifluorophenyl) piperazine '1-1] 1, 4-Dihi The anti-human cytomegalovirus agent according to claim 1, which comprises draw 4 —oxoquinolin-1 3 —carboxylic acid, a pharmaceutically acceptable salt thereof, or an ester thereof as an active ingredient.