JP2009179589A - Antiviral agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an antiviral agent effective for influenza or the like. <P>SOLUTION: The antiviral agent contains a pyrrole derivative represented by formula (I) (wherein, R<SP>A</SP>, R<SP>B</SP>, R<SP>C</SP>and R<SP>D</SP>are the same or different and each a hydrogen atom, an alkyl group, an aryl group or the like; X is a hydrogen atom, a substituted alkyl group or the like; or each of X and R<SP>A</SP>, R<SP>A</SP>and R<SP>B</SP>, and R<SP>C</SP>and R<SP>D</SP>may form a ring by bonding to each other). <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to an antiviral agent comprising a pyrrole derivative.

  Influenza viruses are divided into three types, A, B, and C, based on the difference in antigenicity of the nucleoprotein complex in the virus particle. Of these, types A and B show the epidemic spread. There are glycoproteins called hemagglutinin (HA) and neuraminidase (NA) on the surface of the type A virus particle, and HA and NA have several subtypes. Since these have various combinations and are widely distributed in other host animals such as pigs and birds in addition to humans, influenza A viruses are regarded as zoonotic diseases.

  HA and NA on the surface of the virus range from continuous antigen mutations that change slight antigenicity every year to discontinuous antigen mutations that suddenly change to another subtype (the appearance of so-called “new” influenza), Viruses survive by easily repeating various mutations. Especially because people don't have antibodies against “new”, it becomes a pandemic. In recent years, the avian influenza A / H5N1 was isolated from humans for the first time in Hong Kong and attracted worldwide attention as the possibility of the emergence of “new” influenza viruses. Furthermore, this type of influenza A / H5N1 has been confirmed to cause human infection and death, and is wary of a pandemic of human-to-human infection and death from new influenza in various countries around the world.

  Specific therapy for influenza virus includes administration of an antiviral agent. Amantadine (1-aminoadamantane), an anti-influenza A drug, acts on the M2 protein on the surface of the A virus to prevent entry of influenza virus into cells and exerts an antiviral effect. It is ineffective against influenza B. In addition, Zanamivir, a sialic acid derivative that inhibits the release of virus that has been infected and propagated intracellularly by inhibiting the action of NA of influenza virus and exerts antiviral action, is known. (For example, refer nonpatent literature 1). Zanamivir is administered by inhalation as a powder, but oseltamivir (also known as Tamiflu), a prodrug with NA inhibitory activity, is also known as an oral drug. A syrup is also considered as a dosage form. Both zanamivir and oseltamivir act on both A and B types, but the presence of resistant viruses has also been reported.

  As a preventive method against influenza, the current influenza HA vaccine is one of useful means. Influenza vaccines can reduce symptoms such as high fever and reduce hospitalization and death due to complications. In particular, elderly people over 65 years old and people with underlying diseases (respiratory diseases such as bronchial asthma, cardiovascular diseases such as heart failure, diabetes, renal failure, etc.) are prone to severe flu, so prevention by vaccination is recommended . Research and development of new vaccines such as the number of administrations, administration methods (nasal administration, etc.), devised adjuvants, live vaccines, artificial membrane vaccines, etc. are being promoted as improvements to better vaccines. However, since a pandemic of a new influenza is expected, vaccine production is not possible at a stage where no new influenza has been discovered, and there is a concern that it will not be able to cope with the pandemic.

  Conventionally, Distamycin is known as an antitumor antibiotic having an N-methylpyrrole skeleton.

  It is known that derivatives having an N-methylpyrrole ring, which is a basic skeleton of distamycin represented by the following formula, have antiviral activity (see, for example, Patent Documents 1, 2, and 3).

  As a pyrrole derivative related to the present invention, for example, a compound represented by the following formula is known as a silver halide color photosensitive material, but is not known as an antiviral agent (for example, Patent Documents 4 and 5). reference).

(In the formula, EWG represents an electron-withdrawing group, R ₁ and R ₂ represent a hydrogen atom and a substituent, X represents a hydrogen atom and a leaving group, and Y represents a hydrogen atom, a hydroxyl group, and a sulfonamide group)

  Further, a compound in which a nitrogen-containing 5- to 6-membered heterocyclic ring is condensed to a pyrrole ring represented by the following formula is known as a silver halide color photosensitive material, but is not known as an antiviral agent (for example, a patent) References 6, 7 and 8).

(Wherein R ₁ and R ₂ represent a hydrogen atom and a substituent, X represents a hydrogen atom and a leaving group, and Z represents a nitrogen-containing 5- to 6-membered heterocyclic ring)

JP-A-6-92933 JP-A-6-184098 JP 2001-181279 A JP-A-4-188137 JP-A-4-190347 Japanese Patent Laid-Open No. 6-118587 JP-A-5-232648 JP 2000-310842 A J. Virol., 74, 11108-11114 (2000)

Both the sialic acid derivatives zanamivir and oseltamivir are known to have resistant viruses, and there is a need for a safer anti-influenza drug having a basic skeleton other than the sialic acid derivative that is the basic skeleton of NA inhibitors. Yes.
An object of the present invention is to provide an excellent antiviral agent containing a pyrrole derivative.

  The present inventors have found that a pyrrole derivative having no N-methylpyrrole ring has antiviral activity, and has completed the present invention.

That is, the present invention
(1) Formula (I)

{Where,
R ^A , R ^B , R ^C and R ^D are the same or different and each represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, Substituted or unsubstituted alicyclic heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted aralkyl group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic alkyl group, OR ¹ (formula R ¹ is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted alicyclic heterocyclic group, substituted Or an unsubstituted aryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted aromatic heterocyclic group, or a substituent Or an unsubstituted aromatic heterocyclic alkyl group), ^NR 2 ^{R 3} (wherein, ^{R 2} and ^{R 3,} identical or different, or the same meaning as the ^{R 1,} or ^{R 2} and ^{R 3} together And represents a substituted or unsubstituted nitrogen-containing heterocyclic group), S (O) mR ⁴ (wherein, m represents 0, 1 or 2 and R ⁴ has the same meaning as R ¹ ). , COR ⁵ (wherein R ⁵ has the same meaning as R ¹ ), COOR ⁶ (wherein R ⁶ has the same meaning as R ¹ ), OCOR ⁷ (wherein R ⁷ is the same as above) RNR ¹ and CONR ⁸ R ⁹ (wherein R ⁸ and R ⁹ are the same or different and have the same meanings as R ² and R ³ , respectively), NR ¹⁰ COR ¹¹ (wherein R 1 ¹⁰ and ^{R 11} are identical or different and have the same meanings as the ^{R 1), NR} 12 CO R ^{13 (wherein, R 12} and ^{R 13} are the same or different, wherein ^{R 1} as ^synonymous) in NR ₁₄ SO ^{2 R 15 (wherein, R 14} and ^{R 15} are the same or different, wherein R ^{1 synonymous), NR 16 C (= Q} 1) NR 17 R 18 [ in formula (I), ^{Q 1} represents an oxygen atom, in a sulfur atom, ^{NR 19 (wherein, R 19} is the above ^{R 1} as defined present), represents NCN, a CHNO ₂ or C (CN) ^{_2, R 16} has the same meaning as the ^{R 1, R 17} and ^{R 18} are the same or different, in each have the same meanings as defined above ^{R 2} and ^{R 3 there], NR 20 C (= Q} 2) NR 21 COR 22 ( wherein, ^{Q 2} has the same meaning as the ^{Q 1, R 20,} R ²¹ and ^{R 22} are the same or different, with the ^{R 1 synonymous), NR 23 C (= Q} 3) NR 24 COO ²⁵ (wherein, ^{Q 3} has the same meaning as the ^{Q 1, R 23,} R ²⁴ and ^{R 25} are the same or different, have the same meanings as the _{^{R 1), NR 26 SO 2}} NR 27 R 28 ( In the formula, R ²⁶ has the same meaning as R ¹ , R ²⁷ and R ²⁸ are the same or different and have the same meaning as R ² and R ³ , respectively, SO ₂ NR ²⁹ R ³⁰ (wherein R ²⁹ and R ³⁰ are the same or different and have the same meanings as R ² and R ³ above, respectively, and represent a nitro group, a cyano group or a halogen atom, wherein at least one of R ^{A to} R ^D is Represents a group other than a hydrogen atom,
X is a hydrogen atom, a substituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted alicyclic heterocyclic group, a substituted or unsubstituted aryl group, A substituted or unsubstituted aralkyl group, a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted aromatic heterocyclic alkyl group, OR ³¹ (wherein R ³¹ is as defined above for R ¹ ), NR ³² R ³³ (wherein R ³² and R ³³ are the same or different and have the same meanings as R ² and R ³ ), SO ₂ R ³⁴ (wherein R ³⁴ has the same meaning as R ¹ ), respectively. , ^{COR 35 (wherein, R 35} is the same as defined in the ^{R 1),} COOR ^{36 (wherein, R 36,} said ^{R 1} as synonymous), OCOR ³⁷ (wherein, R ^7, the ^{R 1} as ^{synonymous), CONR} 38 ^{R 39 (wherein, R 38} and ^{R 39} are the same or different and have the same meanings as defined above ^{R 2} and ^{R 3), NR 40 COR 41} ( In the formula, R ⁴⁰ and R ⁴¹ are the same or different and have the same meaning as R ¹ ), NR ⁴² COOR ⁴³ (wherein R ⁴² and R ⁴³ are the same or different and have the same meaning as R ¹⁾ . NR ⁴⁴ SO ₂ R ⁴⁵ , wherein R ⁴⁴ and R ⁴⁵ are the same or different and have the same meaning as R ¹ above,
Or
X and R ^A , R ^A and R ^B or R ^C and R ^D may be combined to form a ring (hereinafter, the ring formed by combining X and R ^A together with Z ^A And a ring formed by R ^A and R ^B together is Z ^B and a ring formed by R ^C and R ^D together is Z ^C )}
And an antiviral agent comprising a pharmacologically acceptable salt thereof.

The present invention also provides:
(2) X is a hydrogen atom, and the following formula (Ia)

(Wherein, R ^A , R ^B , R ^C and R ^D have the same meanings as described above)
An antiviral agent comprising the pyrrole derivative according to (1) or a pharmacologically acceptable salt thereof, characterized by being represented by:
(3) R ^A is a substituted or unsubstituted phenyl group, amino group, CONHR ^9a (wherein R ^9a represents a substituted or unsubstituted alkyl group) or NHC (═S) NHCOOR ^25a (wherein R ^25a Represents a substituted or unsubstituted alkyl group), and ^RD is a hydrogen atom, and contains the pyrrole derivative or the pharmacologically acceptable salt thereof according to the above (2), Antiviral agents,
(4) R ^B and R ^C are the same or different and are a hydrogen atom, a substituted or unsubstituted phenyl group, SO ₂ R ^4b (wherein R ^4b represents a substituted or unsubstituted phenyl group), COOR ^6a ( In the formula, R ^6a represents a substituted or unsubstituted alkyl group), CONR ^8b R ^9b (wherein R ^8b and R ^9b are the same or different and represent a hydrogen atom or a substituted or unsubstituted alkyl group) or An antiviral agent comprising the pyrrole derivative according to any one of the above (2) or (3) or a pharmacologically acceptable salt thereof, which is a cyano group,
(5) The pyrrole according to (2) above, wherein R ^A is an m-nitrophenyl group, R ^B is a 2-ethylhexyloxycarbonyl group, R ^C is a carbamoyl group, and R ^D is a hydrogen atom. An antiviral agent comprising a derivative or a pharmacologically acceptable salt thereof,
(6) R ^A and R ^C are substituted or unsubstituted phenyl groups, R ^B is a cyano group, and R ^D is a hydroxy group, or a pyrrole derivative according to (2) or a pharmacological thereof An antiviral agent containing an acceptable salt,
(7) Z ^A is Ya substituted or unsubstituted nitrogen-containing heterocyclic in the is characterized in that (1), wherein the pyrrole derivative or antiviral agent comprising their pharmacologically acceptable salts ,
(8) A substituted or unsubstituted nitrogen-containing heterocycle is represented by the following formula (II)

^Wherein, Z 1, ^{Z 2} and ^{Z 3} are the same or different, ^-CR E = (wherein, ^{R E} has the same meaning as defined above ^{R A,} a plurality of ^{R E} are simultaneously present in the formula R ^E may be the same or different), —CR ^F R ^G — (wherein R ^F and R ^G are the same or different and have the same meaning as the above R ^A , When R ^F and / or R ^G are present simultaneously, R ^F and R ^G may be the same or different from each other), —C (= Q ⁴ ) — (wherein Q ⁴ is the same as Q ¹ and When a plurality of Q ⁴ are present simultaneously in the formula, Q ⁴ may be the same or different), —N═, —NR ³¹ — (wherein R ³¹ is the same as R ¹ above) are synonymous, when a plurality of R ³¹ in the formula are present simultaneously, R ³¹ may be the same or different Represents -O- or -S-]
An antiviral agent comprising the pyrrole derivative according to the above (7) or a pharmacologically acceptable salt thereof, wherein the pyrrole derivative is a 5-membered ring represented by:
(9) A substituted or unsubstituted nitrogen-containing 5-membered heterocyclic ring represented by the formula (II) is represented by the following formula (IIa)

(Wherein R ^E and R ³¹ are as defined above)
An antiviral agent comprising the pyrrole derivative or the pharmacologically acceptable salt thereof according to (8) above,
(10) An antiviral agent comprising the pyrrole derivative according to (9) or a pharmacologically acceptable salt thereof, wherein R ³¹ is a hydrogen atom,
(11) R ^B represents COR ^5b (wherein R ^5b represents a substituted or unsubstituted alkyl group) or COOR ^6b (wherein R ^6b represents a substituted or unsubstituted cycloalkyl group), and R ^C represents The pyrrole derivative according to any one of the above (9) or (10), wherein ^RD is a hydrogen atom, and R ^E is a substituted or unsubstituted phenyl group, or a pharmacologically acceptable group thereof An antiviral agent containing a salt,
(12) A substituted or unsubstituted nitrogen-containing heterocyclic ring is represented by the following formula (III)

[In the formula, Z ⁴ , Z ⁵ , Z ⁶ and Z ⁷ are the same or different, and —CR ^H = (wherein R ^H has the same meaning as the above R ^A , and a plurality of R ^H When present at the same time, R ^H may be the same or different), —CR ^I R ^J — (wherein R ^I and R ^J are the same or different and have the same meaning as the above R ^A , In the case where a plurality of R ^I and / or R ^J are simultaneously present, R ^I and R ^J may be the same or different from each other), -C (= Q ⁵ )-(wherein Q ⁵ is Q ¹ is the same as Q ^1, and when a plurality of Q ⁵ are simultaneously present in the formula, Q ⁵ may be the same or different), —N═, —NR ³² — (wherein R ³² represents the aforementioned has the same meaning as R ^1, when a plurality of ^{R 32} in the formula are present ^{simultaneously, R 32} is identical or different May also be), - O-or an -S-]
An antiviral agent comprising the pyrrole derivative according to the above (7) or a pharmacologically acceptable salt thereof, wherein the pyrrole derivative is a six-membered ring represented by:
(13) A substituted or unsubstituted nitrogen-containing 6-membered heterocycle represented by the formula (III) is represented by the formula (IIIa)

(In the formula, Z ^5a represents —CH═ or —N═, and R ^H and R ³² have the same meanings as described above).
An antiviral agent comprising the pyrrole derivative according to the above (12) or a pharmacologically acceptable salt thereof,
(14) An antiviral agent comprising the pyrrole derivative or the pharmaceutically acceptable salt thereof according to (13), wherein R ³² is a hydrogen atom,
(15) Z ^5a represents —CH═, R ^B represents a substituted or unsubstituted phenyl group, SO ₂ R ^4b (wherein R ^4b is as defined above), CONR ^8b R ^9b (where R ^8b And R ^9b are as defined above) or a cyano group, R ^C is a substituted or unsubstituted phenyl group or cyano group, R ^D is a hydrogen atom, R ^H is an amino group or NHCOOR ^13a (where R ^13a represents a substituted or unsubstituted alkyl group), and contains the pyrrole derivative according to any one of the above (13) or (14) or a pharmacologically acceptable salt thereof. Antiviral agents,
(16) R ^B is a p-toluenesulfonyl group, R ^C is a phenyl group, and R ^H is an ethoxycarbonylamino group, or a pharmacologically acceptable pyrrole derivative thereof according to (15), An antiviral agent containing a salt,
(17) Z ^5a is -N =, R ^B is COOR ^6b (wherein R ^6b is as defined above), R ^C and R ^H are the same or different, and a substituted or unsubstituted phenyl group ^RD is a hydrogen atom, an antiviral agent comprising the pyrrole derivative according to any one of the above (13) or (14) or a pharmacologically acceptable salt thereof,
(18) Z ^B is a substituted or unsubstituted aromatic hydrocarbon ring, a substituted or unsubstituted alicyclic hydrocarbon ring, a substituted or unsubstituted aromatic heterocyclic ring or a substituted or unsubstituted alicyclic heterocyclic ring. An antiviral agent comprising the pyrrole derivative or the pharmacologically acceptable salt thereof described in (1) above,
(19) The pyrrole derivative or the pharmacologically acceptable salt thereof according to the above (18), wherein the substituted or unsubstituted aromatic hydrocarbon ring is a substituted or unsubstituted benzene ring. An antiviral agent,
(20) The above (19), wherein X is a hydrogen atom, substituted alkyl, substituted or unsubstituted phenyl group or NHR ^33a (wherein R ^33a represents a substituted or unsubstituted phenyl group) An antiviral agent comprising a pyrrole derivative or a pharmacologically acceptable salt thereof,
(21) The pyrrole derivative or the drug thereof according to (20), wherein the substituent of the substituted alkyl is SO ₂ R ^4b (wherein R ^4b is as defined above) or a cyano group An antiviral agent containing a physically acceptable salt,
(22) The above (19) to (21), wherein the substituent of the substituted benzene ring is OR ^1a (wherein R ^1a represents a hydrogen atom or a substituted or unsubstituted alkyl group) or a nitro group. ) An antiviral agent comprising the pyrrole derivative or a pharmacologically acceptable salt thereof,
(23) Z ^C is a substituted or unsubstituted aromatic hydrocarbon ring, a substituted or unsubstituted alicyclic hydrocarbon ring, that is substituted or unsubstituted aromatic heterocyclic ring or a substituted or unsubstituted alicyclic heterocyclic An antiviral agent comprising the pyrrole derivative according to any one of the above (1) or (18) to (22) or a pharmacologically acceptable salt thereof,
(24) The antiviral comprising the pyrrole derivative or the pharmacologically acceptable salt thereof according to (23), wherein the substituted or unsubstituted alicyclic hydrocarbon ring is a cyclohexane ring Agents,
(25) The pyrrole derivative or the pharmacology thereof according to the above (24), wherein the substituent of the substituted cyclohexane ring is OCOR ^37a (wherein R ^37a represents a substituted or unsubstituted phenyl group) The present invention relates to an antiviral agent containing a chemically acceptable salt.

  The pyrrole derivative of the present invention has excellent antiviral activity and can be used as an antiviral agent against various viruses.

  The definition of each group in the present invention is as follows.

  The alkyl group is, for example, linear or branched alkyl having 1 to 20 carbon atoms, specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl. Hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl and the like.

  Examples of the cycloalkyl group include cycloalkyl having 3 to 8 carbon atoms, specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, 1-cyclohexenyl and the like.

  The alkenyl group is, for example, linear or branched alkenyl having 2 to 10 carbon atoms, specifically vinyl, 1-propenyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, 2-pentenyl, 2-hexenyl and the like can be mentioned.

  The alkynyl group is, for example, linear or branched alkynyl having 2 to 10 carbon atoms, specifically, ethynyl, 1-propynyl, 2-propynyl, isopropynyl, 2-butynyl, 2-pentynyl, 2-pentene- 4-inyl, 2-hexynyl and the like can be mentioned.

  Examples of the aryl group include aryl having 6 to 14 carbon atoms, specifically, phenyl, naphthyl, anthryl, phenanthryl and the like.

  The aralkyl group has the same aryl portion as the aryl group, and the alkyl portion has the same meaning as the alkyl group. For example, aralkyl having 7 to 15 carbon atoms, specifically benzyl, phenethyl, phenylpropyl, benzhydryl, Examples include trityl and naphthylmethyl.

  The aromatic heterocyclic group is the same or different and consists of a 5- or 6-membered aromatic heterocyclic group containing at least one or more hetero atoms such as nitrogen, oxygen, sulfur and the like, It may be a monocyclic or a polycyclic fused aromatic heterocyclic group in which a plurality of the monocyclic heterocyclic groups are condensed with an aryl group, for example, a bicyclic or tricyclic heterocyclic group. Specific examples of the monocyclic aromatic heterocyclic group include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl and the like. And polycyclic condensed aromatic heterocyclic groups include benzofuryl, benzothienyl, indolyl, carbazolyl, quinolyl, isoquinolyl, acridinyl, naphthyridinyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, indazolyl, quinoxalinyl, quinazolinyl Cinnolinyl, phthalazinyl, purinyl, pteridinyl, thiantenyl, phenoxatinyl, phenoxazinyl, phenothiazinyl, phenazinyl, etc. It can gel.

  The aromatic heterocyclic alkyl group has the same aromatic heterocyclic moiety as the aromatic heterocyclic group, and the alkyl moiety has the same meaning as the alkyl group, for example, an aromatic group containing at least one hetero atom. Heterocyclic alkyl, specifically pyridylmethyl, pyridylethyl, furanylmethyl, thienylmethyl and the like can be mentioned.

  The alicyclic heterocyclic group is the same or different and contains at least one hetero atom such as nitrogen, oxygen, sulfur and the like, and may be a saturated or partially unsaturated bond. An alicyclic heterocyclic group, which may be monocyclic or a polycyclic fused alicyclic heterocyclic group in which the monocyclic heterocyclic group is condensed with an aryl group or an aromatic heterocyclic group. Good. Specific examples of monocyclic alicyclic heterocyclic groups include aziridinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, dihydrothiazolyl, tetrahydrofuranyl, 1,3-dioxolanyl, thiolanyl, piperidino, piperidyl, piperazinyl , Morpholino, morpholinyl, thiomorpholinyl, pyranyl, oxathianyl, oxadiazinyl, thiadiazinyl, dithiazinyl, azepinyl, dihydroazosinyl and the like. Specific examples of the polycyclic fused alicyclic heterocyclic groups include , Isochromanyl, quinuclidinyl and the like.

  The nitrogen-containing heterocyclic group is a heterocyclic group containing at least one nitrogen atom as a hetero atom among the alicyclic heterocyclic group or aromatic heterocyclic group, specifically, aziridinyl, pyrrolidinyl, Examples include piperidino, homopiperidinyl, piperazinyl, homopiperazinyl, morpholino, thiomorpholinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, indolyl, indazolyl, benzimidazolyl, benzotriazolyl and the like.

  The halogen atom means each atom of fluorine, chlorine, bromine and iodine.

Z ^A is a substituted or unsubstituted nitrogen-containing heterocyclic ring, preferably a 5- to 6-membered nitrogen-containing heterocyclic ring, and the nitrogen-containing 5-membered heterocyclic ring is represented by the following formula (II) Is more preferable.

^Wherein, Z 1, ^{Z 2} and ^{Z 3} are the same or different, ^-CR E = (wherein, ^{R E} has the same meaning as defined above ^{R A,} a plurality of ^{R E} are simultaneously present in the formula R ^E may be the same or different), —CR ^F R ^G — (wherein R ^F and R ^G are the same or different and have the same meaning as the above R ^A , When R ^F and / or R ^G are present simultaneously, R ^F and R ^G may be the same or different from each other), —C (= Q ⁴ ) — (wherein Q ⁴ is the same as Q ¹ and When a plurality of Q ⁴ are present simultaneously in the formula, Q ⁴ may be the same or different), —N═, —NR ³¹ — (wherein R ³¹ is the same as R ¹ above) are synonymous, when a plurality of R ³¹ in the formula are present simultaneously, R ³¹ may be the same or different Represents -O- or -S-]

  Moreover, as a nitrogen-containing 6-membered heterocyclic ring, what is represented by following formula (III) is more preferable.

[In the formula, Z ⁴ , Z ⁵ , Z ⁶ and Z ⁷ are the same or different, and —CR ^H = (wherein R ^H has the same meaning as the above R ^A , and a plurality of R ^H When present at the same time, R ^H may be the same or different), —CR ^I R ^J — (wherein R ^I and R ^J are the same or different and have the same meaning as the above R ^A , In the case where a plurality of R ^I and / or R ^J are simultaneously present, R ^I and R ^J may be the same or different from each other), -C (= Q ⁵ )-(wherein Q ⁵ is Q ¹ is the same as Q ^1, and when a plurality of Q ⁵ are simultaneously present in the formula, Q ⁵ may be the same or different), —N═, —NR ³² — (wherein R ³² represents the aforementioned has the same meaning as R ^1, when a plurality of ^{R 32} in the formula are present ^{simultaneously, R 32} is identical or different May also be), - O-or an -S-]

Z ^B and Z ^C are the same or different and each represents a substituted or unsubstituted aromatic hydrocarbon ring, a substituted or unsubstituted alicyclic hydrocarbon ring, a substituted or unsubstituted aromatic heterocyclic ring, or a substituted or unsubstituted alicyclic heterocyclic ring. Represents a ring or the like. Here, examples of the aromatic hydrocarbon ring include, for example, an aromatic hydrocarbon ring corresponding to the aryl group having 6 to 14 carbon atoms, such as benzene, naphthalene, and anthracene. Examples of the alicyclic hydrocarbon ring include alicyclic hydrocarbon rings corresponding to the cycloalkyl group having 5 to 8 carbon atoms, and specific examples include cyclopentane, cyclohexane, cyclooctane, and the like. The aromatic heterocyclic ring is, for example, a 5- to 6-membered aromatic heterocyclic ring corresponding to the aromatic heterocyclic group, specifically, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, thiadiazole, isothiazole, Examples include imidazole, pyrazole, triazole, pyridine, pyrazine, pyrimidine, and pyridazine. The alicyclic heterocycle is, for example, a 5- to 8-membered alicyclic heterocycle corresponding to the alicyclic heterocyclic group, specifically, pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, dihydrothiazole. , Tetrahydrofuran, dioxolane, thiolane, piperidine, piperazine, morpholine, thiomorpholine, pyran, oxathiane, oxadiazine, thiadiazine, dithiazine, azepine and the like.

Alkyl group, cycloalkyl group, alkenyl group, alkynyl group, aryl group, aralkyl group, aromatic heterocyclic group, aromatic heterocyclic alkyl group, alicyclic heterocyclic group, nitrogen-containing heterocyclic group, aromatic hydrocarbon ring The substituents in the alicyclic hydrocarbon ring, aromatic heterocycle and alicyclic heterocycle include alkyl group, cycloalkyl group, alkenyl group, alkynyl group, aryl group, aralkyl group, aromatic heterocyclic group, aromatic Group heterocyclic alkyl group, alicyclic heterocyclic group, O (CH ₂ CH ₂ O) nR ^a (wherein n represents 0, 1 or 2), NR ^b R ^c , S (O) pR ^d (Wherein p represents 0, 1 or 2), COR ^e , COOR ^f , OCOR ^g , CONR ^h R ⁱ , NR ^j COR ^k , NR ¹ COOR ^m , NR ⁿ SO ₂ R ^o , NR ^p C (= ^{Q a)} NR ^{q r} (wherein, ^{Q a} represents an oxygen atom, a sulfur ^atom, NR s, NCN, the CHNO ₂ or _{C (CN) 2), NR} s C (= Q b) NR t COR u ( wherein, ^{Q b} Is synonymous with Q ^a ), NR ^v C (= Q ^c ) NR ^w COOR ^x (where Q ^c is synonymous with Q ^a ), NR ^y SO ₂ NR ^z R ^aa , SO ₂ NR ^ab R ^ac , a nitro group, a cyano group, a halogen atom and the like are appropriately selected. Here, R ^{a to} R ^ac are the same or different and each represents a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, an aralkyl group, an aromatic heterocyclic group, an aromatic heterocyclic alkyl group, or R ^b and R ^c , R ^h and R ⁱ , R ^q and R ^r , R ^z and R ^aa and R ^ab and R ^ac together represent a nitrogen-containing heterocyclic group May be formed.

  The alkyl group, cycloalkyl group, alkenyl group, alkynyl group, aryl group, aralkyl group, aromatic heterocyclic group, aromatic heterocyclic alkyl group and alicyclic heterocyclic group are as defined above.

  In addition, an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, an aralkyl group, an aromatic heterocyclic group, an aromatic heterocyclic alkyl group, an alicyclic heterocyclic group and the like as a substituent are further substituted. The substituent may be the same as those described above.

  The number of substitution of these substituents may be the same or different and may be up to the number of hydrogen atoms present in each group, but is preferably 1 to 10, more preferably 1 to 5.

  The antiviral agent of the present invention is a compound represented by the formula (I) [hereinafter referred to as compound (I). The same applies to the compounds of other formula numbers]. However, in the compound (I), X is a hydrogen atom, and a compound represented by the following formula (Ia) is preferable.

(Wherein, R ^A , R ^B , R ^C and R ^D have the same meanings as described above)
Further, in compound (Ia), R ^A is a substituted or unsubstituted phenyl group, amino group, CONHR ^9a (wherein R ^9a represents a substituted or unsubstituted alkyl group) or NHC (═S) NHCOOR ^25a ( In the formula, R ^25a represents a substituted or unsubstituted alkyl group, and R ^B and R ^C are the same or different and represent a hydrogen atom, a substituted or unsubstituted phenyl group, SO ₂ R ^4b (wherein R ₂ ^4b represents a substituted or unsubstituted phenyl group), COOR ^6a (wherein R ^6a represents a substituted or unsubstituted alkyl group), CONR ^8b R ^9b (wherein R ^8b and R ^9b are the same or ^A compound that is a hydrogen atom or a substituted or unsubstituted alkyl group) or a cyano group, and R ^D is a hydrogen atom, and R ^A and R The ^C is a substituted or unsubstituted phenyl group, a R ^B is a cyano group, a compound R ^D is a hydroxy group is more preferred. Specific examples of compound (Ia) are shown in Table 1.

Further, in the compound (I), Z ^A is a substituted or unsubstituted nitrogen-containing 5-membered heterocyclic ring, a compound represented by the following formula (Ib) are preferred.

(In the formula, R ^B , R ^C , R ^D , Z ^C , Z ¹ , Z ² and Z ³ are as defined above.)

  Furthermore, in the compound represented by the formula (Ib), the compound represented by the following formula (Iba) is more preferable.

(Wherein R ^B , R ^C , R ^D , R ^E and R ³¹ are as defined above)
In particular, in the compound (Iba), a compound in which R ^D and R ³¹ are hydrogen atoms is preferable. Furthermore, R ^D and R ³¹ are hydrogen atoms, and R ^B is COR ⁵ (wherein R ⁵ is the same as defined above). A compound in which R ⁶ is synonymous) or COOR ⁶ (wherein R ⁶ is as defined above), R ^C is a cyano group, and R ^E is a substituted phenyl group is preferable.
Specific examples of compound (Iba) are shown in Table 2.

Further, in the compound (I), Z ^A is a substituted or unsubstituted nitrogen-containing 6-membered heterocyclic ring, a compound represented by the following formula (Ic) are preferred.

（式中、Ｒ^Ｂ、Ｒ^Ｃ、Ｒ^Ｄ、Ｚ^Ｃ、Ｚ^４、Ｚ^５、Ｚ^６およびＺ^７は、前記と同義である）
さらに、式（Ｉｃ）で表される化合物において、下記式（Ｉｃａ）で表される化合物がより好ましい。

(Wherein R ^B , R ^C , R ^D , Z ^C , Z ⁴ , Z ⁵ , Z ⁶ and Z ⁷ are as defined above).
Furthermore, in the compound represented by the formula (Ic), a compound represented by the following formula (Ica) is more preferable.

(Wherein R ^B , R ^C , R ^D , R ^H , R ³² and Z ^5a are as defined above)
In particular, in the compound (Ica), a compound in which Z ^5a represents —CH═ or —N═ and R ³² is a hydrogen atom is preferred, and further, Z ^5a is —CH═ and R ³² represents a hydrogen atom. If, ^{R B} is a substituted or unsubstituted phenyl _group, SO ^{2 R 4b (wherein, R 4b} are the same as defined ^above), in ^CONR 8b ^{R 9b (wherein, R 8b} and ^{R 9b} is a as defined above Or a cyano group, R ^C is a substituted or unsubstituted phenyl group or cyano group, R ^D is a hydrogen atom, R ^H is an amino group or NHCOOR ^13a (wherein R ^13a is a substituted or unsubstituted alkyl group) And a compound in which R ^B is a p-toluenesulfonyl group, R ^C is a phenyl group, and R ^H is an ethoxycarbonylamino group. . Further, when Z ^5a is —N═ and R ³² is a hydrogen atom, R ^B is COOR ^6b (wherein R ^6b is as defined above), and R ^C and R ^H are the same or different. In addition, a substituted or unsubstituted phenyl group, and a compound in which ^RD is a hydrogen atom are more preferable.

  Specific examples of the compound (Ica) are shown in Table 3.

In the compound (I), a compound represented by the following formula (Id), in which Z ^B is a substituted or unsubstituted benzene ring, is preferable.

(Wherein, R ^K has the same meaning as R ^A , p represents 0 or an integer of 1 to 4, and X, R ^C and R ^D have the same meanings as described above).

In particular, in the compound (Id), a compound in which X is a hydrogen atom, a substituted alkyl, a substituted or unsubstituted phenyl group or NHR ^33a (wherein R ^33a represents a substituted or unsubstituted phenyl group) is more preferred, In particular, a compound in which the substituent of the substituted alkyl is SO ₂ R ^4b (wherein R ^4b is as defined above) or a cyano group is preferable. The substituent of the benzene ring is more preferably a compound in which OR ^1a (wherein R ^1a represents a hydrogen atom or a substituted or unsubstituted alkyl group) or a nitro group.
Specific examples of compound (Id) are shown in Table 4.

In the compound (I), Z ^C is preferably a substituted or unsubstituted cyclohexane ring, and Z ^B is a substituted or unsubstituted benzene ring, and Z ^C is a substituted or unsubstituted cyclohexane ring. A certain compound represented by the following formula (Ie) is more preferable.

(In the formula, R ^L has the same meaning as R ^A , q represents 0 or an integer of 1 to 4, and X, R ^K and p have the same meanings as described above).

In particular, in the compound (Ie), X is a hydrogen atom, the substituent of the benzene ring is OR ^1a (wherein R ^1a is as defined above) or the nitro group, and the substituent of the cyclohexane ring is OCOR ^37a ( In the formula, R ^37a is preferably a substituted or unsubstituted phenyl group.
Specific examples of compound (Ie) are shown in Table 5.

  Examples of the pharmacologically acceptable salt of compound (I) include acid addition salts, metal salts, ammonium salts, organic amine addition salts and the like, and acid addition salts include hydrochloric acid, hydrobromic acid, sulfuric acid, Nitric acid, phosphoric acid, boric acid and other inorganic acid salts, and organic acids such as formic acid, acetic acid, propionic acid, fumaric acid, malonic acid, succinic acid, maleic acid, tartaric acid, benzoic acid and other carboxylic acids, methanesulfone Examples include acids, sulfonic acids such as p-toluenesulfonic acid, and amino acids such as glutamic acid and aspartic acid. As the metal salt, each alkali metal salt such as lithium, sodium, potassium, etc., each alkaline earth metal salt such as magnesium, calcium, etc., each metal salt such as aluminum, zinc, etc., as the ammonium salt, ammonium, tetramethylammonium, etc. Examples of the organic amine salt include salts of triethylamine, piperidine, morpholine, toluidine and the like.

  The compound (I) used as the antiviral agent of the present invention can be produced according to the method described in the above-mentioned patent document or the like, and can also be obtained as a commercial product.

  For example, the compound (Ia) can be prepared by the method described in Patent Documents 4 and 5 above, or JP-A 2000-63353, JP-A 2000-327681, JP-A 2000-330245, JP-A 2000-122250. No. 2000-122251, JP-A-10-316654, WO2003020684 and the like, or the like.

  Compounds (Ib) and (Ic) can be prepared by the methods described in Patent Documents 6 to 8, or JP-A-7-330771, JP-A-2000-44564, JP-A-2000-327681, and JP-A-2000. -330245, JP-A-2001-181526, JP-A-2001-213882 and the like, or the like.

  Compounds (Id) and (Ie) may be used in JP-A-55-40401, JP-A-5-230020, Tetrahedron, 1999, 55, 6243-6260 or Chem. Rev., 1969, 69, 227- It can be obtained according to the methods described in No. 250 or the like.

  Although there are compounds (I) in which various isomers may exist, the present invention can use all possible isomers and mixtures thereof as antiviral agents.

  When it is desired to obtain a salt of compound (I), if compound (I) is obtained in the form of a salt, it can be purified as it is, and if it is obtained in a free form, it can be dissolved in an appropriate organic solvent. Alternatively, it may be suspended and an acid or base is added to form a salt by a conventional method.

  Compound (I) and pharmacologically acceptable salts thereof may exist in the form of adducts with water or various solvents, and these adducts should also be used as the antiviral agent of the present invention. Can do.

  The compound (I) or a pharmacologically acceptable salt thereof can be administered alone as it is, but it is usually desirable to prepare various pharmaceutical preparations. It can be produced by a conventional method of pharmaceutics by mixing with one or two or more types of carriers that are acceptable.

  Examples of the administration route include oral administration, inhalation administration, and parenteral administration such as intravenous administration.

  Examples of the dosage form include tablets, inhalants, injections, etc. The tablets are mixed with various additives such as lactose, starch, magnesium stearate, hydroxypropyl cellulose, polyvinyl alcohol, surfactant, glycerin and the like. The inhalant may be produced according to a conventional method by adding, for example, lactose. An injection may be produced according to a conventional method by adding water, physiological saline, vegetable oil, solubilizer, preservative and the like.

  The effective amount and frequency of administration of compound (I) or a pharmacologically acceptable salt thereof vary depending on the administration form, patient age, body weight, symptoms, etc., but usually 0.001 mg to 5 g per adult, preferably Is administered in a dose of 0.1 mg to 1 g, more preferably 1 to 500 mg, once a day or several times a day.

  EXAMPLES Hereinafter, although an Example demonstrates this invention more concretely, the technical scope of this invention is not limited to these illustrations.

Antiviral activity measurement test

(Materials and equipment)
Canine renal epithelioma tumor MDCK was purchased from RIKEN BioResource Center (RCB). Medium MEM powder was purchased from Sigma and prepared by dissolving it. DMSO, glycerol, SDS, paraformaldehyde (PFA) manufactured by Nacalai Corporation were used. Penicillin-streptomycin (PS), L-glutamine solution, Phosphate buffer saline (PBS), and 0.25% Trypsin solution were purchased from Invitrogen. Fetal bovine serum (FBS) was purchased from Hi-Uloan. MTS powder was purchased from Promega and dissolved in a final concentration of 5 mg / ml. The 96-well microplate, culture dish, and 1.5 ml tube were all manufactured by Greiner. The plate reader for measuring the absorbance was measured using an Envision made by PerkinElmer. Of the control drugs (control drugs) in the influenza experiment, amantadine was purchased from Sigma. Zanamivir was purchased from Roche and used after purification.

(Cell culture)
In the following contents, unless otherwise indicated, the solution added to the cultured cells was preliminarily kept at 37 ° C. In normal subculture, a solution in which 1/100 amount of PS, L-glutamine and 5% FBS were added to each liquid medium was used. MDCK cells were cultured in MEM medium. From the first generation before each experimental use, the influence of antibiotics on the experimental results was eliminated by culturing in a medium excluding PS. The cells were cultured under the conditions of 37 ° C / 5% CO ₂ .

(Virus preparation)
Influenza A virus: A / PR / 8/34 (H1N1 type) seed virus was diluted with PBS to 0.1 HAU / ml, and this was inoculated into 200 μl of 11-day-old chicken eggs. Culturing was carried out for 48 hours at 0 ° C. The urine fluid was collected and centrifuged at 3000 rpm for 10 minutes at 4 ° C. The supernatant was further centrifuged at 4 ° C. and 8000 rpm for 3 hours, and the precipitate was dissolved in PBS. Glycerol was added to a final concentration of 25%, and the mixture was further centrifuged at 38000 rpm at 4 ° C. for 2 hours. The precipitate was dissolved in PBS, centrifuged at 15,000 rpm for 1 hour at 4 ° C., and the precipitate dissolved in 1 ml with PBS was used as the “virus stock solution”. Since the HAU activity was 224, diluted to about 5000 HAU / ml (150,000 times the stock solution) was used in the MTS experiment.

(MTS assay)
Cells were seeded into 96-well microplates at 5.0 × 10 ³ cells / well. MDCK cells were cultured in MEM + 5% FBS. The medium used after this was a “dilution medium solution” to which 0.1% Trypsin + 5 μM EDTA was further added.
All drugs including the control drug were diluted with a dilution medium so as to be 10 μM (DMSO content 0.1%). After 24 hours from the introduction of 5.0 × 10 ³ cells / well, the medium was removed after confirming that the cells had adhered. Immediately 100 μl / well of various drugs diluted with a dilution medium were added. Two hours after the addition of various drugs, 100 μl / well of virus solution (final drug concentration 5 μM) was added. This was cultured for 48 hours at 37 ° C./5% CO ₂ . After removing the virus / drug mixture, the cells were washed twice with PBS solution. In this way, cells that have been killed by virus entry can be removed. A medium having a normal composition of 100 μl / well was added, 20 μl / well of MTS solution was further added, and the mixture was reacted at 37 ° C. for 1 hour. MTS increases the degree of coloration from light yellow to red in proportion to the number of living cells. Therefore, by measuring the red absorbance, it is possible to calculate the ratio of viable cells that have escaped virus entry. Absorbance at 490 nm was measured on a plate reader Envision. The ratio of the number of viable cells in each drug at 5 μM was applied to the following formula and evaluated as antiviral activity.

cell survival (%) = [(AbVT−AbVC) / (AbCC−AbVC)] × 100
AbVT: Absorbance in cells cultured in virus / drug mixture
AbVC: Absorbance in cells cultured only with virus solution
AbCC: Absorbance test results for cells cultured under normal conditions not containing both virus and drug are shown in Table 6.

  Tablets are prepared by a conventional method using a composition consisting of 10 mg of compound (1), 70 mg of lactose, 15 mg of starch, 4 mg of polyvinyl alcohol and 1 mg of magnesium stearate (total 200 mg).

  According to a conventional method, distilled water for injection is added to a composition comprising 70 mg of compound (8), 50 mg of purified soybean oil, 10 mg of egg yolk lecithin and 25 mg of glycerin so that the total volume becomes 100 mL, and after filling into a vial, heat sterilized and injected. Prepare the agent.

[Production Example 1]
Synthesis of 4- (aminocarbonyl) -2- (3-nitrophenyl) -1H-pyrrole-3-carboxylic acid 2-ethylhexyl [Compound (1)] The compound was synthesized according to the following reaction scheme (A).

(1) Synthesis of Compound (A-2) 2.6 ml (0.036 mol) of thionyl chloride was added to a benzene solution (250 ml) of 6.9 g (0.030 mol) of Compound (A-1) at room temperature, and the mixture was heated to 60 ° C. Stir for 2 hours after heating. Benzene and thionyl chloride were distilled off, and the residue was dissolved in chloroform (180 ml). Under ice-cooling, 28% aqueous ammonia solution (100 ml) was added and stirred for 1 hour. Thereafter, the reaction was stopped by adding a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The extract was filtered and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography to obtain 1.8 g of compound (A-2) (yield 26%).

(2) Synthesis of Compound (A-5) 10 g (0.056 mol) of Compound (A-3), 5.4 g (0.062 mol) of formaldehyde solution (35%), 11 g (0.060 mol) of Compound (A-4) ), Formic acid (15 ml), and H ₂ O (60 ml) were mixed and stirred at 80-90 ° C. for 6 hours. After diluting with chloroform, it was poured into water, and the organic layer was collected and the solvent was distilled off to obtain 17 g (yield 91%) of compound (A-5).

(3) Synthesis of Compound (1) 1.4 g (0.060 mol) of Compound (A-2) was dissolved in a mixed solution of acetonitrile (50 ml) and carbon tetrachloride (6 ml), and 20 g (0.078 mol) of triphenylphosphine was dissolved. And stirred at room temperature overnight. Thereafter, 6.7 g (0.020 mol) of compound (A-5), 4.2 g (0.10 mol) of lithium chloride and 14 ml (0.1 mol) of triethylamine were added, and the mixture was stirred overnight, followed by addition of saturated aqueous sodium bicarbonate to react. Stopped. The mixture was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The extract was filtered and the residue obtained by evaporating the solvent was purified by silica gel column chromatography to obtain 3.8 g (yield 16%) of the target compound (1). The purity and structure of compound (1) were confirmed by LC-MS and NMR.
¹ H NMR (CDCl ₃ ) d: 0.65 (3H, t, J = 7.6 Hz), 0.79-1.19 (12H, m), 3.97-4.02 (2H, m), 5.64 (1H, br s), 7.62 (1H , t, J = 8.0 Hz), 7.71-7.77 (2H, m), 8.28 (1H, d, J = 8.4 Hz), 8.32 (1H, s), 9.67 (1H, br s), 9.88 (1H, br s); LS-MS (ESI, +) m / z388 [M + H] ⁺ , t _R = 12.93 min

[Production Example 2]
Synthesis of ethyl {8-[(4-methylphenyl) sulfonyl] -4-oxo-7-phenyl-1,4-dihydropyrrolo [1,2-a] pyrimidin-2-yl} carbamate [compound (8)] Synthesis was performed according to the following reaction scheme (B).

(1) Synthesis of compound (B-3) Under ice-cooling, 3.1 g (0.018 mol) of hydrochloride of compound (B-1) was dissolved in ethanol (50 ml), and 4.8 ml (0.035 mol) of triethylamine and 4.3 g (0.018 mol) of compound (B-2) was slowly added. Thereafter, the temperature was returned to room temperature, and the precipitated solid was dissolved by adding ethanol (400 ml), 2.4 ml (0.018 mol) of triethylamine was added, and the mixture was stirred at 50 ° C. overnight. Thereafter, the reaction was stopped by adding a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, washed with saturated brine, and then dried over magnesium sulfate. The extract was filtered, the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography to obtain 2.6 g (yield 47%) of compound (B-3).

(2) Synthesis of Compound (B-5) 26 g (0.11 mmol) of Compound (B-4) and 19 ml (0.14 mol) of Triethylamine were added to 28 g (0.091 mol) of Compound (B-3) in acetonitrile solution (180 ml). Then, 15 ml (0.27 mol) of acetic acid was added, and the mixture was heated to 60 ° C. and stirred for 9 hours. Thereafter, the reaction was stopped by adding a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, washed with saturated brine, and then dried over magnesium sulfate. The extract was filtered, the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography to obtain 14 g (yield 40%) of compound (B-5).

(3) Synthesis of Compound (8) Tetrahydrofuran (10 ml) was added to 0.13 g (3.3 mmol) of sodium hydride to form a suspension, and 1.2 g (3.3 mmol) of Compound (B-5) was cooled with ice. ) Was added and stirred at room temperature for 2 hours, and then 340 ml (3.9 mmol) of ethyl chloroformate was added and stirred overnight at room temperature. Thereafter, the reaction was stopped by adding a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, washed with saturated brine, and then dried over magnesium sulfate. The extract was filtered and the residue obtained by evaporating the solvent was purified by silica gel column chromatography to obtain 0.086 g (yield 59%) of the target compound (8). Compound (8) was confirmed for purity and structure by LC-MS and NMR.
¹ H NMR (CDCl ₃ ) d: 1.34 (3H, t, J = 7.2 Hz), 2.31 (3H, s), 4.38 (2H, q, J = 7.2 Hz), 5.33 (1H, s), 7.03 (2H , d, J = 7.6 Hz), 7.30-7.41 (8H, m), 7.78 (1H, br s); LS-MS (ESI, +) m / z 452 [M + H] ⁺ , t _R = 12.69 min

Claims (25)

Formula (I)

{Where,
R ^A , R ^B , R ^C and R ^D are the same or different and each represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, Substituted or unsubstituted alicyclic heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted aralkyl group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic alkyl group, OR ¹ (formula R ¹ is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted alicyclic heterocyclic group, substituted Or an unsubstituted aryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted aromatic heterocyclic group, or a substituent Or an unsubstituted aromatic heterocyclic alkyl group), ^NR 2 ^{R 3} (wherein, ^{R 2} and ^{R 3,} identical or different, or the same meaning as the ^{R 1,} or ^{R 2} and ^{R 3} together And represents a substituted or unsubstituted nitrogen-containing heterocyclic group), S (O) mR ⁴ (wherein, m represents 0, 1 or 2 and R ⁴ has the same meaning as R ¹ ). , COR ⁵ (wherein R ⁵ has the same meaning as R ¹ ), COOR ⁶ (wherein R ⁶ has the same meaning as R ¹ ), OCOR ⁷ (wherein R ⁷ is the same as above) RNR ¹ and CONR ⁸ R ⁹ (wherein R ⁸ and R ⁹ are the same or different and have the same meanings as R ² and R ³ , respectively), NR ¹⁰ COR ¹¹ (wherein R 1 ¹⁰ and ^{R 11} are identical or different and have the same meanings as the ^{R 1), NR} 12 CO R ^{13 (wherein, R 12} and ^{R 13} are the same or different, wherein ^{R 1} as ^synonymous) in NR ₁₄ SO ^{2 R 15 (wherein, R 14} and ^{R 15} are the same or different, wherein R ^{1 synonymous), NR 16 C (= Q} 1) NR 17 R 18 [ in formula (I), ^{Q 1} represents an oxygen atom, in a sulfur atom, ^{NR 19 (wherein, R 19} is the above ^{R 1} as defined present), represents NCN, a CHNO ₂ or C (CN) ^{_2, R 16} has the same meaning as the ^{R 1, R 17} and ^{R 18} are the same or different, in each have the same meanings as defined above ^{R 2} and ^{R 3 there], NR 20 C (= Q} 2) NR 21 COR 22 ( wherein, ^{Q 2} has the same meaning as the ^{Q 1, R 20,} R ²¹ and ^{R 22} are the same or different, with the ^{R 1 synonymous), NR 23 C (= Q} 3) NR 24 COO ²⁵ (wherein, ^{Q 3} has the same meaning as the ^{Q 1, R 23,} R ²⁴ and ^{R 25} are the same or different, have the same meanings as the _{^{R 1), NR 26 SO 2}} NR 27 R 28 ( In the formula, R ²⁶ has the same meaning as R ¹ , R ²⁷ and R ²⁸ are the same or different and have the same meaning as R ² and R ³ , respectively, SO ₂ NR ²⁹ R ³⁰ (wherein R ²⁹ and R ³⁰ are the same or different and have the same meanings as R ² and R ³ above, respectively, and represent a nitro group, a cyano group or a halogen atom, wherein at least one of R ^{A to} R ^D is Represents a group other than a hydrogen atom,
X is a hydrogen atom, a substituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted alicyclic heterocyclic group, a substituted or unsubstituted aryl group, A substituted or unsubstituted aralkyl group, a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted aromatic heterocyclic alkyl group, OR ³¹ (wherein R ³¹ is as defined above for R ¹ ), NR ³² R ³³ (wherein R ³² and R ³³ are the same or different and have the same meanings as R ² and R ³ ), SO ₂ R ³⁴ (wherein R ³⁴ has the same meaning as R ¹ ), respectively. , ^{COR 35 (wherein, R 35} is the same as defined in the ^{R 1),} COOR ^{36 (wherein, R 36,} said ^{R 1} as synonymous), OCOR ³⁷ (wherein, R ^7, the ^{R 1} as ^{synonymous), CONR} 38 ^{R 39 (wherein, R 38} and ^{R 39} are the same or different and have the same meanings as defined above ^{R 2} and ^{R 3), NR 40 COR 41} ( In the formula, R ⁴⁰ and R ⁴¹ are the same or different and have the same meaning as R ¹ ), NR ⁴² COOR ⁴³ (wherein R ⁴² and R ⁴³ are the same or different and have the same meaning as R ¹⁾ . NR ⁴⁴ SO ₂ R ⁴⁵ , wherein R ⁴⁴ and R ⁴⁵ are the same or different and have the same meaning as R ¹ above,
Or
X and R ^A , R ^A and R ^B or R ^C and R ^D may be combined to form a ring (hereinafter, the ring formed by combining X and R ^A together with Z ^A And a ring formed by R ^A and R ^B together is Z ^B and a ring formed by R ^C and R ^D together is Z ^C )}
The antiviral agent containing the pyrrole derivative represented by these, or those pharmacologically acceptable salts. X is a hydrogen atom, and is represented by the following formula (Ia)

(Wherein, R ^A , R ^B , R ^C and R ^D have the same meanings as described above)
An antiviral agent comprising the pyrrole derivative according to claim 1 or a pharmaceutically acceptable salt thereof. R ^A is a substituted or unsubstituted phenyl group, amino group, CONHR ^9a (wherein R ^9a represents a substituted or unsubstituted alkyl group) or NHC (═S) NHCOOR ^25a (wherein R ^25a is a substituted group) Or an unsubstituted alkyl group), and ^RD is a hydrogen atom. The antiviral agent comprising the pyrrole derivative or a pharmaceutically acceptable salt thereof according to claim 2. R ^B and R ^C are the same or different and are a hydrogen atom, a substituted or unsubstituted phenyl group, SO ₂ R ^4b (wherein R ^4b represents a substituted or unsubstituted phenyl group), COOR ^6a (wherein R ^6a represents a substituted or unsubstituted alkyl group), CONR ^8b R ^9b (wherein R ^8b and R ^9b are the same or different and represent a hydrogen atom or a substituted or unsubstituted alkyl group) or a cyano group An antiviral agent comprising the pyrrole derivative according to any one of claims 2 and 3, or a pharmacologically acceptable salt thereof. 3. A pyrrole derivative or a pyrrole derivative thereof according to claim 2, wherein R ^A is an m-nitrophenyl group, R ^B is a 2-ethylhexyloxycarbonyl group, R ^C is a carbamoyl group, and R ^D is a hydrogen atom. An antiviral agent comprising a pharmacologically acceptable salt. 3. A pyrrole derivative or a pharmacologically acceptable product thereof according to claim 2, wherein R ^A and R ^C are substituted or unsubstituted phenyl groups, R ^B is a cyano group, and R ^D is a hydroxy group. An antiviral agent comprising a salt. Z ^A is an anti-viral agent comprising the claims 1 pyrrole derivative or a pharmaceutically acceptable salt thereof a pharmacologically wherein the substituted or unsubstituted nitrogen-containing heterocyclic ring. A substituted or unsubstituted nitrogen-containing heterocyclic ring is represented by the following formula (II)

^Wherein, Z 1, ^{Z 2} and ^{Z 3} are the same or different, ^-CR E = (wherein, ^{R E} has the same meaning as defined above ^{R A,} a plurality of ^{R E} are simultaneously present in the formula R ^E may be the same or different), —CR ^F R ^G — (wherein R ^F and R ^G are the same or different and have the same meaning as the above R ^A , When R ^F and / or R ^G are present simultaneously, R ^F and R ^G may be the same or different from each other), —C (= Q ⁴ ) — (wherein Q ⁴ is the same as Q ¹ and When a plurality of Q ⁴ are present simultaneously in the formula, Q ⁴ may be the same or different), —N═, —NR ³¹ — (wherein R ³¹ is the same as R ¹ above) are synonymous, when a plurality of R ³¹ in the formula are present simultaneously, R ³¹ may be the same or different Represents -O- or -S-]
An antiviral agent comprising the pyrrole derivative or a pharmacologically acceptable salt thereof according to claim 7, wherein the pyrrole derivative is a five-membered ring represented by the formula: A substituted or unsubstituted nitrogen-containing 5-membered heterocyclic ring represented by the formula (II) is represented by the following formula (IIa)

(Wherein R ^E and R ³¹ are as defined above)
An antiviral agent comprising the pyrrole derivative according to claim 8 or a pharmacologically acceptable salt thereof. The antiviral agent comprising a pyrrole derivative or a pharmaceutically acceptable salt thereof according to claim 9, wherein R ³¹ is a hydrogen atom. R ^B represents COR ^5b (wherein R ^5b represents a substituted or unsubstituted alkyl group) or COOR ^6b (wherein R ^6b represents a substituted or unsubstituted cycloalkyl group), and R ^C represents a cyano group. The pyrrole derivative or the pharmaceutically acceptable salt thereof according to claim 9 or 10, wherein R ^D is a hydrogen atom, and R ^E is a substituted or unsubstituted phenyl group. Antiviral agent. A substituted or unsubstituted nitrogen-containing heterocyclic ring is represented by the following formula (III)

[In the formula, Z ⁴ , Z ⁵ , Z ⁶ and Z ⁷ are the same or different, and —CR ^H = (wherein R ^H has the same meaning as the above R ^A , and a plurality of R ^H When present at the same time, R ^H may be the same or different), —CR ^I R ^J — (wherein R ^I and R ^J are the same or different and have the same meaning as the above R ^A , In the case where a plurality of R ^I and / or R ^J are simultaneously present, R ^I and R ^J may be the same or different from each other), -C (= Q ⁵ )-(wherein Q ⁵ is Q ¹ is the same as Q ^1, and when a plurality of Q ⁵ are simultaneously present in the formula, Q ⁵ may be the same or different), —N═, —NR ³² — (wherein R ³² represents the aforementioned has the same meaning as R ^1, when a plurality of ^{R 32} in the formula are present ^{simultaneously, R 32} is identical or different May also be), - O-or an -S-]
An antiviral agent comprising the pyrrole derivative or a pharmacologically acceptable salt thereof according to claim 7, wherein the pyrrole derivative is a six-membered ring represented by the formula: A substituted or unsubstituted nitrogen-containing 6-membered heterocycle represented by the formula (III) is represented by the formula (IIIa)

(In the formula, Z ^5a represents —CH═ or —N═, and R ^H and R ³² have the same meanings as described above).
An antiviral agent comprising the pyrrole derivative according to claim 12 or a pharmacologically acceptable salt thereof. The antiviral agent comprising the pyrrole derivative or the pharmaceutically acceptable salt thereof according to claim 13, wherein R ³² is a hydrogen atom. Z ^5a is —CH═, R ^B is a substituted or unsubstituted phenyl group, SO ₂ R ^4b (wherein R ^4b is as defined above), CONR ^8b R ^9b (wherein R ^8b and R ^9b Is as defined above) or a cyano group, R ^C is a substituted or unsubstituted phenyl group or cyano group, R ^D is a hydrogen atom, R ^H is an amino group or NHCOOR ^13a (wherein R ^13a is The antiviral agent comprising the pyrrole derivative or the pharmaceutically acceptable salt thereof according to any one of claims 13 and 14, wherein the antiviral agent is a substituted or unsubstituted alkyl group. The pyrrole derivative or pharmacologically acceptable salt thereof according to claim 15, wherein R ^B is a p-toluenesulfonyl group, R ^C is a phenyl group, and R ^H is an ethoxycarbonylamino group. An antiviral agent comprising. Z ^5a is —N═, R ^B is COOR ^6b (wherein R ^6b is as defined above), R ^C and R ^H are the same or different, and a substituted or unsubstituted phenyl group is R ^The antiviral agent comprising the pyrrole derivative according to any one of claims 13 and 14, or a pharmaceutically acceptable salt thereof, wherein ^D is a hydrogen atom. Z ^B is a substituted or unsubstituted aromatic hydrocarbon ring, a substituted or unsubstituted alicyclic hydrocarbon ring, a substituted or unsubstituted aromatic heterocyclic ring or a substituted or unsubstituted alicyclic heterocyclic ring An antiviral agent comprising the pyrrole derivative according to claim 1 or a pharmacologically acceptable salt thereof. 19. The antiviral agent comprising a pyrrole derivative or a pharmaceutically acceptable salt thereof according to claim 18, wherein the substituted or unsubstituted aromatic hydrocarbon ring is a substituted or unsubstituted benzene ring. . The pyrrole derivative according to claim 19, wherein X is a hydrogen atom, a substituted alkyl, a substituted or unsubstituted phenyl group, or NHR ^33a (wherein R ^33a represents a substituted or unsubstituted phenyl group). An antiviral agent comprising a pharmacologically acceptable salt thereof. The pyrrole derivative according to claim 20, or a pharmacologically acceptable group thereof, wherein the substituent of the substituted alkyl is SO ₂ R ^4b (wherein R ^4b has the same meaning as described above) or a cyano group. An antiviral agent comprising a salt obtained. The substituent of the substituted benzene ring is OR ^1a (wherein R ^1a represents a hydrogen atom or a substituted or unsubstituted alkyl group) or a nitro group, according to any one of claims 19 to 21. An antiviral agent comprising a pyrrole derivative or a pharmacologically acceptable salt thereof. Z ^C is a substituted or unsubstituted aromatic hydrocarbon ring, a substituted or unsubstituted alicyclic hydrocarbon ring, a substituted or unsubstituted aromatic heterocyclic ring or a substituted or unsubstituted alicyclic heterocyclic ring An antiviral agent comprising the pyrrole derivative according to any one of claims 1 or 18 to 22 or a pharmacologically acceptable salt thereof. 24. The antiviral agent comprising the pyrrole derivative or a pharmaceutically acceptable salt thereof according to claim 23, wherein the substituted or unsubstituted alicyclic hydrocarbon ring is a cyclohexane ring. The pyrrole derivative according to claim 24, or a pharmacologically acceptable group thereof, wherein the substituent of the substituted cyclohexane ring is OCOR ^37a (wherein R ^37a represents a substituted or unsubstituted phenyl group). An antiviral agent comprising a salt.