JP4827197B2 - Influenza preventive - Google Patents

Description

  The present invention relates to a preventive agent for influenza comprising, as an active ingredient, a pharmacologically acceptable ester derivative of a compound having sialidase inhibitory activity.

  Influenza is an epidemic acute respiratory infection caused by infection with an influenza A or B virus. Its clinical features are characterized by symptoms such as sudden high fever and general malaise, headache, muscle pain, and joint pain, in addition to symptoms of upper respiratory tract inflammation, accompanied by a severe sensation that can force a bed of several days. Influenza repeats its epidemic every winter and is concentrated in a short period of time, resulting in a large number of millions of patients. In addition, when the elderly over 65, infants, pregnant women, and high-risk groups with various underlying diseases are affected by influenza, the risk of complications of pneumonia, hospitalization, and death is several hundred times higher than that of healthy adults. Therefore, influenza is recognized as an important disease that has a great social and economic impact from the magnitude of the patient's health damage and the scale of the epidemic.

  Influenza vaccines are conventionally used as a method for preventing influenza. However, even if the vaccine strain is different from the epidemic strain, or even if the strains match, the ability to induce defense against the body is insufficient, and the preventive effect is not always satisfactory. In addition, side effects such as redness, swelling, pain, fever, headache, chills, and malaise may occur in the vaccine recipient. In addition, there is a possibility of urticaria, rash, numbness of the oral cavity, anaphylactic shock, etc. in people who are allergic to eggs, and gelatin allergy to gelatin contained as a stabilizer in vaccines has been reported. Other side effects such as Guillain-Barre syndrome, acute encephalopathy, convulsions and purpura are also reported.

  In addition, prophylactic administration of drugs known as influenza treatment agents such as amantadine, zanamivir, and oseltamivir is also being studied, but in the respiratory tract (including lung, respiratory tract, nasal cavity and oral tissues) which are the main infection sites Since a sufficient concentration for preventing virus infection cannot be maintained, a satisfactory preventive effect has not been obtained.

  As a result of intensive investigations over many years on drugs for preventing influenza, the inventors have found that pharmacologically acceptable ester derivatives of compounds having sialidase inhibitory activity can be administered to the recipient's respiratory tract to produce sialidase inhibitory activity. Compared to the case where the compound itself having the same is administered in the same manner, the compound having sialidase inhibitory activity can be retained in the recipient's respiratory tissue at a high concentration for a long time, so it is extremely effective as a preventive agent for influenza. As a result, the present invention was completed.

The present invention is the following influenza preventive and preventive method.
(1) An influenza preventive agent comprising a pharmacologically acceptable ester derivative of a compound having sialidase inhibitory activity as an active ingredient and administered to a recipient's respiratory organ.
(2) In (1), by administering a pharmacologically acceptable ester derivative of a compound having sialidase inhibitory activity to the recipient's respiratory tract, the compound having sialidase inhibitory activity is retained in the recipient's respiratory tissue. Influenza preventive agent characterized by that.
(3) In any one item selected from (1) and (2), the compound having sialidase inhibitory activity is a 2-deoxy-2,3-didehydro-N-acetylneuraminic acid derivative, a cyclohexenecarboxylic acid derivative, a cyclohexane An influenza preventive agent which is a pentanecarboxylic acid derivative or a pyrrolidine-2-carboxylic acid derivative.
(4) In any one item selected from (1) and (2), the compound having sialidase inhibitory activity is represented by the general formula:

[Wherein, X represents a halogen atom, a hydroxyl group or an alkoxy group having 1 to 4 carbon atoms. ],
General formula

[Wherein, R ^b1 represents an amino or guanidino group, and R ^b2 represents an alkyl group having 1 to 12 carbon atoms. ],
General formula

[Wherein, R ^c1 represents a hydrogen atom or a hydroxyl group, R ^c2 represents an alkyl group having 1 to 8 carbon atoms, and R ^c3 represents an amino or guanidino group. ],
Or general formula

[Wherein, R ^d1 represents an alkenyl group having 2 to 5 carbon atoms, R ^d2 and R ^d3 represent an alkyl group having 1 to 6 carbon atoms, and R ^d4 represents an alkyl group having 1 to 3 carbon atoms. Show. ]
An influenza preventive agent, which is a compound represented by:
(5) In any one item selected from (1) to (4), the pharmacologically acceptable ester derivative has an alkanoyl ester having 6 to 20 carbon atoms or sialidase inhibitory activity at the hydroxyl group of the compound having sialidase inhibitory activity. The influenza preventive agent which is a C8 thru | or C20 alkyl ester in the carboxyl group of the compound which has.
(6) A method for preventing influenza, comprising administering a pharmacologically acceptable ester derivative of a compound having sialidase inhibitory activity to a recipient's respiratory organ.
(7) In (6), by administering a pharmacologically acceptable ester derivative of a compound having sialidase inhibitory activity to the recipient's respiratory tract, the compound having sialidase inhibitory activity is retained in the recipient's respiratory tissue. A method for preventing influenza.

In the above,
The “compound having sialidase inhibitory activity” refers to a compound having an action of inhibiting the function of sialidase (this enzyme is also called neuraminidase), which is an enzyme essential for the growth of influenza virus. 2-deoxy-2,3-didehydro-N-acetylneuraminic acid derivatives described in JP-A-507068, JP-A-10-330373, PCT International Publication WO97 / 06157, WO98 / 11083 and the like; PCT Cyclohexenecarboxylic acid derivatives described in International Publication WO96 / 26933 etc .; Cyclopentanecarboxylic acid derivatives described in PCT International Publication WO96 / 33781, WO97 / 47194 etc .; PCT International Publication WO99 / 54299 Pyro described in etc. 2-carboxylic acid derivatives. Of these, compounds represented by the general formula (Ia), (Ib), (Ic) or (Id) are preferable.

In the compound represented by the general formula (Ia),
Examples of the “halogen atom” in the definition of X include a fluorine, chlorine, bromine or iodine atom, preferably a fluorine or chlorine atom, and most preferably a fluorine atom.

  The “C 1-4 alkoxy group” in the definition of X is, for example, one having 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy or t-butoxy group. A linear or branched alkoxy group can be mentioned, and a methoxy or ethoxy group is preferable, and a methoxy group is most preferable.

The compound represented by the general formula (Ia) is preferably the following compound (Ia-1) or (Ia-2).
(Ia-1) A compound in which X is an alkoxy group having 1 to 4 carbon atoms.
(Ia-2) A compound wherein X is a methoxy group.

In the compound represented by the general formula (Ib),
In the definition of R ^b1, an amino group is preferable.

In the definition of R ^b2 , examples of the “alkyl group having 1 to 12 carbon atoms” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl. 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5- Methylhexyl, 1-propylbutyl, 4,4-dimethylpentyl, octyl, 1 Methylheptyl, 2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 6-methylheptyl, 1-propylpentyl, 2-ethylhexyl, 5,5-dimethylhexyl, nonyl, 3-methyloctyl 4-methyloctyl, 5-methyloctyl, 6-methyloctyl, 1-propylhexyl, 2-ethylheptyl, 6,6-dimethylheptyl, decyl, 1-methylnonyl, 3-methylnonyl, 8-methylnonyl, 3-ethyl Examples include octyl, 3,7-dimethyloctyl, 7,7-dimethyloctyl, undecyl, 4,8-dimethylnonyl, and dodecyl groups, with 1-ethylpropyl group being preferred.

A compound represented by the general formula (Ib) is preferably the following compound (Ib-1) or (Ib-2).
(Ib-1) A compound wherein R ^b1 is an amino group and R ^b2 is a 1-ethylpropyl group.
(Ib-2) A compound wherein R ^b1 is a guanidino group and R ^b2 is a 1-ethylpropyl group.

In the compound represented by the general formula (Ic),
In the definition of R ^c1, a hydroxyl group is preferable.

In the definition of R ^c2 , examples of the “alkyl group having 1 to 8 carbon atoms” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl. 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5- Methylhexyl, 1-propylbutyl, 4,4-dimethylpentyl, octyl, 1- Linear such as tilheptyl, 2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 6-methylheptyl, 1-propylpentyl, 2-ethylhexyl, 5,5-dimethylhexyl group or A branched alkyl group or a saturated cyclic alkyl group having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl can be exemplified, and a 1-ethylpropyl group is preferred. .

In the definition of R ^c3, a guanidino group is preferable.

The compound represented by the general formula (Ic) is preferably a compound (Ic-1) in which R ^c1 is a hydroxyl group, R ^c2 is a 1-ethylpropyl group, and R ^c3 is a guanidino group.

In the compound represented by the general formula (Id),
Examples of the “alkenyl group having 2 to 5 carbon atoms” in the definition of R ^d1 include vinyl, 1-propenyl, isobutenyl, isopropenyl, 1-methyl-1-propenyl, 1,3-dimethyl-1-propenyl, 1 -Butenyl, 2-methyl-1-butenyl, 2-butenyl, 1-ethyl-1-propenyl group can be mentioned, and cis-1-propenyl, trans-1-propenyl, isobutenyl and vinyl groups are preferable. More preferred are cis-1-propenyl and vinyl, and most preferred is cis-1-propenyl.

Examples of the “alkyl group having 1 to 6 carbon atoms” in the definition of R ^d2 and R ^d3 include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl. , Neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1- Examples thereof include linear or branched alkyl groups such as dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl and 2-ethylbutyl groups, preferably methyl. , An ethyl or propyl group.

^Examples of the “alkyl group having 1 to 3 carbon atoms” in the definition of R ^d4 include methyl, ethyl, propyl, and isopropyl groups, and most preferably a methyl group.

In the compound represented by the general formula (Id), R ^d1 is preferably a cis-1-propenyl group, R ^d2 is a methyl group, R ^d3 is a propyl group, and R ^d4 is a methyl group. It is a certain compound (Id-1). In the compound (Id-1), a compound in which the configuration of the carbon atom to which R ^d2 and R ^d3 are bonded is S configuration is known as ABT-675.

  “Pharmaceutically acceptable ester derivative” means that the hydroxyl group or carboxyl group of the compound is cleaved by a chemical or biological method such as hydrolysis in the human or animal body to produce a compound having sialidase inhibitory activity. This refers to protected ester derivatives (so-called “ester type prodrugs”). Whether such ester derivatives are used is determined by oral, nasal, nasal, pulmonary, intravenous injection, etc. in laboratory animals such as rats and mice. And then the body fluid of the animal is examined, and the compound having sialidase inhibitory activity can be detected.

  Examples of such pharmacologically acceptable ester derivatives include ester derivatives in which a hydroxyl group is modified with an aliphatic or aromatic acyl group and ester derivatives in which a carboxyl group is protected.

  Examples of the aliphatic acyl group include acetyl, propionyl, butanoyl, 2-methylpropionyl, 2,2-dimethylpropionyl (pivaloyl), pentanoyl, isopentanoyl, 2-methylbutanoyl, neopentanoyl, hexanoyl, isohexa Noyl, 4-methylpentanoyl, 3-methylpentanoyl, 2-methylpentanoyl, 3,3-dimethylbutanoyl, 2,2-dimethylbutanoyl, 2,3-dimethylbutanoyl, 2-ethylbutanoyl, Heptanoyl, 2-methylhexanoyl, 3-methylhexanoyl, 4-methylhexanoyl, 5-methylhexanoyl, 4,4-dimethylpentanoyl, octanoyl, 2-methylheptanoyl, 3-methylheptanoyl, 4- Methylheptanoyl, 5-methylheptanoyl, 6-methylheptanoyl, 2-ethylhexanoyl, 5,5-dimethylhexanoyl, nonanoyl, 3-methyloctanoyl, 4-methyloctanoyl, 5-methyloctanoyl, 6-methyloctanoyl, 2-ethylhepta Noyl, 6,6-dimethylheptanoyl, decanoyl, 3-methylnonanoyl, 8-methylnonanoyl, 3-ethyloctanoyl, 3,7-dimethyloctanoyl, 7,7-dimethyloctanoyl, undecanoyl, 4,8-dimethylnonano Yl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, 3,7,11-trimethyldodecanoyl, hexadecanoyl, 4,8,12-trimethyltridecanoyl, 1-methylpentadecanoyl, 14-methylpenta Decanoyl, 13,13-dimethylte Alkanoyl groups having 2 to 20 carbon atoms such as radecanoyl, heptadecanoyl, 15-methylhexadecanoyl, octadecanoyl, 1-methylheptadecanoyl, nonadecanoyl or icosanoyl group; methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxy Carbonyl, butyloxycarbonyl, isobutyloxycarbonyl, s-butyloxycarbonyl, t-butyloxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, heptyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl , Dodecyloxycarbonyl, tridecyloxycarbonyl, tetradecyloxycarbonyl, pentadecyloxy Carbonyl, hexadecyl oxycarbonyl, mention may be made of heptadecyloxy carbonyl, octadecyloxycarbonyl or nonadecyl number 2 to 20 alkoxycarbonyl group having a carbon such as oxycarbonyl group. The alkyl part of these aliphatic acyl groups may have a 3- to 7-membered cyclic structure and a double or triple bond.

  Examples of the aromatic acyl group include arylcarbonyl groups having 7 to 11 carbon atoms such as benzoyl, α-naphthoyl and β-naphthoyl; 2-phenylacetyl, 3-phenylpropionyl, 4-phenylbutyryl, 5- 8 to 20 carbon atoms such as phenylpentanoyl, 6-phenylhexanoyl, 7-phenylheptanoyl, 8-phenyloctanoyl, 9-phenylnonanoyl, 10-phenyldecanoyl, 10-naphthyldecanoyl groups An aralkylcarbonyl group can be mentioned. The aryl part of these aromatic acyl groups may be substituted with an alkyl group having 1 to 4 carbon atoms, a halogen atom, or an alkoxy group having 1 to 4 carbon atoms.

  Examples of the ester residue of the ester derivative in which the carboxyl group is protected include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, and 1-ethylpropyl. Hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2- Dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1- Propylbutyl, 4,4-dimethylpentyl, octyl, 1-methyl Tilheptyl, 2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 6-methylheptyl, 1-propylpentyl, 2-ethylhexyl, 5,5-dimethylhexyl, nonyl, 3-methyloctyl, 4-methyloctyl, 5-methyloctyl, 6-methyloctyl, 1-propylhexyl, 2-ethylheptyl, 6,6-dimethylheptyl, decyl, 1-methylnonyl, 3-methylnonyl, 8-methylnonyl, 3-ethyloctyl 3,7-dimethyloctyl, 7,7-dimethyloctyl, undecyl, 4,8-dimethylnonyl, dodecyl, tridecyl, tetradecyl, pentadecyl, 3,7,11-trimethyldodecyl, hexadecyl, 4,8,12-trimethyl Tridecyl, 1-methylpentadecyl, An alkyl group having 1 to 20 carbon atoms such as 4-methylpentadecyl, 13,13-dimethyltetradecyl, heptadecyl, 15-methylhexadecyl, octadecyl, 1-methylheptadecyl, nonadecyl or an eicosyl group; Alkenyl group having 2 to 20 carbon atoms having 1 or 2 double bonds in the group; alkynyl group having 2 to 20 carbon atoms having 1 or 2 triple bonds in the above alkyl group; benzyl, phenethyl An aralkyl group having 7 to 20 carbon atoms such as 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, 8-phenyloctyl, 10-phenyldecyl or 10-naphthyldecyl; Oxymethyl, propionyloxymethyl, butyryloxymethyl Pentanoyloxymethyl, hexanoyloxymethyl, octanoyloxymethyl, decanoyloxymethyl, dodecanoyloxymethyl, tetradecanoyloxymethyl, hexadecanoyloxymethyl, octadecanoyloxymethyl, 1- (acetyloxy) ethyl 1- (propionyloxy) ethyl, 1- (butyryloxy) ethyl, 1- (pentanoyloxy) ethyl, 1- (hexanoyloxy) ethyl, 1- (octanoyloxy) ethyl, 1- (decanoyloxy) 1- (2 carbon atoms) such as ethyl, 1- (dodecanoyloxy) ethyl, 1- (tetradecanoyloxy) ethyl, 1- (hexadecanoyloxy) ethyl, 1- (octadecanoyloxy) ethyl group To 20 alkanoyloxy) 1 to 3 carbon atoms Alkyl group; methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propyloxycarbonyloxymethyl, isopropyloxycarbonyloxymethyl, butyloxycarbonyloxymethyl, isobutyloxycarbonyloxymethyl, s-butyloxycarbonyloxymethyl, t-butyloxycarbonyl Oxymethyl, pentyloxycarbonyloxymethyl, 2-pentyloxycarbonyloxymethyl, 3-pentyloxycarbonyloxymethyl, isopentyloxycarbonyloxymethyl, neopentyloxycarbonyloxymethyl, cyclopentyloxycarbonyloxymethyl, hexyloxycarbonyloxymethyl , 2-hexyloxycarbonyloxymethyl, 3-hexyloxycarbo Ruoxymethyl, isohexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, heptyloxycarbonyloxymethyl, octyloxycarbonyloxymethyl, decyloxycarbonyloxymethyl, dodecyloxycarbonyloxymethyl, tetradecyloxycarbonyloxymethyl, hexadecyloxycarbonyl Oxymethyl, octadecyloxycarbonyloxymethyl, 1- (methoxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) ethyl, 1- (propyloxycarbonyloxy) ethyl, 1- (isopropyloxycarbonyloxy) ethyl, 1- ( Butyloxycarbonyloxy) ethyl, 1- (isobutyloxycarbonyloxy) ethyl, 1- (s-butyloxy) Cicarbonyloxy) ethyl, 1- (t-butyloxycarbonyloxy) ethyl, 1- (pentyloxycarbonyloxy) ethyl, 1- (2-pentyloxycarbonyloxy) ethyl, 1- (3-pentyloxycarbonyloxy) Ethyl, 1- (isopentyloxycarbonyloxy) ethyl, 1- (neopentyloxycarbonyloxy) ethyl, 1- (cyclopentyloxycarbonyloxy) ethyl, 1- (hexyloxycarbonyloxy) ethyl, 1- (2-hexyl) Oxycarbonyloxy) ethyl, 1- (3-hexyloxycarbonyloxy) ethyl, 1- (isohexyloxycarbonyloxy) ethyl, 1- (cyclohexyloxycarbonyloxy) ethyl, 1- (heptyloxycarbonyloxy) ethyl 1- (octyloxycarbonyloxy) ethyl, 1- (decyloxycarbonyloxy) ethyl, 1- (dodecyloxycarbonyloxy) ethyl, 1- (tetradecyloxycarbonyloxy) ethyl, 1- (hexadecyloxycarbonyloxy) And 1- (alkoxycarbonyloxy having 1 to 20 carbon atoms) alkyl groups having 1 to 3 carbon atoms such as ethyl and 1- (octadecyloxycarbonyloxy) ethyl groups.

  The ester at the hydroxyl group is preferably an alkanoyl group having 6 to 20 carbon atoms, and among the esters at the carboxyl group, an alkyl group having 8 to 20 carbon atoms is preferred.

  “To be administered to the recipient's respiratory system” means that a pharmacologically acceptable ester derivative of a compound having a sialidase inhibitory action is administered to the recipient's respiratory system by, for example, nasal, nasal, transpulmonary or buccal administration. Reaching a tissue (tissues such as nasal cavity, respiratory tract, lungs, oral cavity).

  A pharmacologically acceptable ester derivative of a compound having sialidase inhibitory activity that has reached the respiratory tissue of the recipient is rapidly degraded by a chemical or biological method such as hydrolysis to form a compound having sialidase inhibitory activity. Converted.

  "Restoring a compound having sialidase inhibitory activity in the recipient's respiratory tissue" means respiration of the recipient when a pharmacologically acceptable ester derivative of the compound having sialidase inhibitory activity is administered to the recipient's respiratory organ. It means that the concentration of the compound having sialidase inhibitory activity in the organ tissue is maintained at a higher concentration for a long time compared to the concentration when the compound having sialidase inhibitory activity itself is administered in the same manner.

  When the compound having sialidase inhibitory activity is represented by the general formula (Ia), the pharmacologically acceptable ester derivative is preferably represented by the general formula (IIa).

  General formula

[Wherein, R ¹ and R ² are the same or different and each represents a hydrogen atom or an alkanoyl group having 2 to 20 carbon atoms, and X ¹ represents a halogen atom, a hydroxyl group, an alkoxy group having 1 to 4 carbon atoms or a carbon atom. R ² represents an alkanoyloxy group having 2 to 20 carbon atoms, and R ³ represents a hydrogen atom or an alkyl group having 1 to 20 carbon atoms. However, when R ¹ and R ² are hydrogen atoms and X ¹ is a halogen atom, a hydroxyl group or an alkoxy group having 1 to 4 carbon atoms, R ³ represents an alkyl group having 8 to 20 carbon atoms. ]
In the compound represented by the general formula (IIa),
The alkanoyl part of the “alkanoyl group having 2 to 20 carbon atoms” in the definition of R ¹ and R ² and the “alkanoyloxy group having 2 to 20 carbon atoms” in the definition of X ¹ And a straight-chain or branched alkanoyl group having 2 to 20 carbon atoms, preferably an alkanoyl group having 6 to 20 carbon atoms, and more preferably an alkanoyl group having 6 to 18 carbon atoms. More preferably a hexanoyl, octanoyl, decanoyl, dodecanoyl, tetradecanoyl, hexadecanoyl or octadecanoyl group.

The “halogen atom” and the “C 1-4 alkoxy group” in the definition of X ¹ are the same as those in the definition of X described above.

The “alkyl group having 1 to 20 carbon atoms” in the definition of R ³ is a linear or branched alkyl group having 1 to 20 carbon atoms as in the definition of the ester in the carboxyl group described above.

The “alkyl group having 1 to 20 carbon atoms” of the above R ³ is preferable when R ¹ and R ² are hydrogen atoms and X is a halogen atom, a hydroxyl group or an alkoxy group having 1 to 4 carbon atoms. Is an alkyl group having 8 to 20 carbon atoms, more preferably an alkyl group having 10 to 20 carbon atoms, and still more preferably a decyl, dodecyl, tetradecyl, hexadecyl or octadecyl group.

When R ¹ or R ² is an alkanoyl group having 6 to 20 carbon atoms, R ³ is preferably a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and more preferably a hydrogen atom. .

A compound represented by the general formula (IIa) is preferably the following compound (IIa-A) or (IIa-B).
(IIa-A) R ¹ is an alkanoyl group having 6 to 20 carbon atoms, R ² is a hydrogen atom, X ¹ is a halogen atom, a hydroxyl group or an alkoxy group having 1 to 4 carbon atoms, and R ³ In which is a hydrogen atom.
(IIa-B) R ¹ and R ² are hydrogen atoms, X ¹ is a halogen atom, a hydroxyl group or an alkoxy group having 1 to 4 carbon atoms, and R ³ is an alkyl group having 8 to 20 carbon atoms. Compound.

Of the compounds (IIa-A), the following compounds (IIa-A-1) to (IIa-A-6) are more preferred.
(IIa-A-1) A compound in which R ¹ is an alkanoyl group having 6 to 18 carbon atoms in the above compound (IIa-A).
(IIa-A-2) The compound of (IIa-A) above, wherein R ¹ is a hexanoyl, octanoyl, decanoyl, dodecanoyl, tetradecanoyl, hexadecanoyl or octadecanoyl group.
(IIa-A-3) The compound of (IIa-A) above, wherein X ¹ is an alkoxy group having 1 to 4 carbon atoms.
(IIa-A-4) A compound in which X ¹ is a methoxy group in the above compound (IIa-A).
(IIa-A-5) A compound in which R ¹ is an alkanoyl group having 6 to 18 carbon atoms and X ¹ is an alkoxy group having 1 to 4 carbon atoms in the above compound (IIa-A).
(IIa-A-6) In the compound of (IIa-A) above, R ¹ is a hexanoyl, octanoyl, decanoyl, dodecanoyl, tetradecanoyl, hexadecanoyl or octadecanoyl group, and X ¹ is a methoxy group A compound.

Of the compounds (IIa-B), the following compounds (IIa-B-1) to (IIa-B-6) are more preferred.
(IIa-B-1) The compound of (IIa-B) above, wherein R ³ is an alkyl group having 10 to 20 carbon atoms.
(IIa-B-2) The compound of (IIa-B) above, wherein R ³ is a decyl, dodecyl, tetradecyl, hexadecyl or octadecyl group.
(IIa-B-3) The compound of (IIa-B), wherein X ¹ is an alkoxy group having 1 to 4 carbon atoms.
(IIa-B-4) The compound of (IIa-B) above, wherein X ¹ is a methoxy group.
(IIa-B-5) The compound of (IIa-B) above, wherein R ³ is an alkyl group having 10 to 20 carbon atoms and X is an alkoxy group having 1 to 4 carbon atoms.
(IIa-B-6) The compound of (IIa-B) above, wherein R ³ is a decyl, dodecyl, tetradecyl, hexadecyl or octadecyl group and X ¹ is a methoxy group.

  When the compound having sialidase inhibitory activity is represented by the general formula (Ib), the pharmacologically acceptable ester derivative is preferably represented by the general formula (IIb).

  General formula

[Wherein, R ^b1 represents an amino or guanidino group, R ^b2 represents an alkyl group having 1 to 12 carbon atoms, and R ⁴ represents an alkyl group having 8 to 20 carbon atoms. ]
R ^b1 and R ^b2 are preferably the same as those in the aforementioned compound (Ib).

The alkyl group having 8 to 20 carbon atoms of R ⁴ is the same as that in R ³ of the aforementioned compound (IIa), preferably an alkyl group having 10 to 20 carbon atoms, more preferably decyl. , Dodecyl, tetradecyl, hexadecyl or octadecyl groups.

  When the compound having sialidase inhibitory activity is represented by the general formula (Ic), the pharmacologically acceptable ester derivative is preferably represented by the general formula (IIc).

  General formula

[Wherein, R ^c1 represents a hydrogen atom or a hydroxyl group, R ^c2 represents an alkyl group having 1 to 8 carbon atoms, R ^c3 represents an amino or guanidino group, and R ⁵ represents an alkyl having 8 to 20 carbon atoms. Indicates a group. ]
R ^c1 , R ^c2 and R ^c3 are preferably the same as those in the aforementioned compound (Ic).

The alkyl group having 8 to 20 carbon atoms of R ⁵ is the same as that in R ³ of the aforementioned compound (IIa), preferably an alkyl group having 10 to 20 carbon atoms, more preferably decyl. , Dodecyl, tetradecyl, hexadecyl or octadecyl groups.

  When the compound having sialidase inhibitory activity is represented by the general formula (Id), the pharmacologically acceptable ester derivative is preferably represented by the general formula (IId).

  General formula

[Wherein, R ^d1 represents an alkenyl group having 2 to 5 carbon atoms, R ^d2 and R ^d3 represent an alkyl group having 1 to 6 carbon atoms, and R ^d4 represents an alkyl group having 1 to 3 carbon atoms. R ⁶ represents an alkyl group having 8 to 20 carbon atoms. ]
R ^d1 , R ^d2 , R ^d3 and R ^d4 are preferably the same as those in the aforementioned compound (Id).

The alkyl group having 8 to 20 carbon atoms of R ⁶ is the same as that in R ³ of the aforementioned compound (IIa), preferably an alkyl group having 10 to 20 carbon atoms, more preferably decyl. , Dodecyl, tetradecyl, hexadecyl or octadecyl groups.

The compounds represented by the general formulas (IIa), (IIb), (IIc) and (IId) have an amino group or a guanidino group in the molecule, and the compounds represented by the general formula (IIa) are R ³ Since it has a carboxyl group when is a hydrogen atom, it can form a pharmacologically acceptable salt by binding with an acid or base that does not exhibit pharmacological toxicity.

  Examples of the “pharmacologically acceptable salt” include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide; nitrate, perchlorate, Inorganic acid salts such as sulfate and phosphate; Alkane sulfonate such as methane sulfonate, ethane sulfonate and trifluoromethane sulfonate; benzene sulfonate and p-toluene sulfonate Aryl sulfonates; organic acid salts such as acetate, trifluoroacetate, citrate, tartrate, oxalate, maleate; glycine, lysine, arginine, ornithine, glutamate, asparagine Amino acid salts such as acid salts; alkali metal salts such as lithium salts, sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; Metal salts such as minium salt, iron salt, zinc salt, copper salt, nickel salt, cobalt salt; ammonium salt, t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, ethylenediamine salt, guanidine salt, diethylamine Salt, triethylamine salt, dicyclohexylamine salt, procaine salt, ethanolamine salt, diethanolamine salt, piperazine salt, organic amine salt such as tetramethylammonium salt, and the like, preferably lithium salt, sodium salt Alkali metal salts such as potassium salts; organic acid salts such as acetates and trifluoroacetates; or inorganic acid salts such as hydrochlorides and sulfates.

  The compounds represented by the general formulas (IIa), (IIb), (IIc) and (IId) are combined with water or a solvent by being left in the atmosphere or mixed with water or an organic solvent to form a hydrate Or a solvate may be formed.

  These pharmacologically acceptable salts, hydrates and solvates are also included in the active ingredients of the preventive agent of the present invention.

  A pharmacologically acceptable ester derivative of a compound having sialidase inhibitory activity is administered to the recipient's respiratory tract, so that the sialidase inhibitory activity of the compound having sialidase inhibitory activity is compared to that administered in the same manner. Can be retained in the recipient's respiratory tissue at a high concentration over a long period of time, and is therefore extremely effective as an influenza preventive agent.

  Compounds represented by general formulas (Ia), (Ib), (Ic) and (Id) and compounds represented by general formulas (IIa), (IIb), (IIc) and (IId) or pharmacologically acceptable thereof The salts to be used are JP-T-5-507068, JP-A-10-330373, PCT International Publication WO97 / 06157, WO98 / 11083; PCT International Publication WO96 / 26933; PCT International Publication WO96. / 33781, WO97 / 47194; PCT International Publication No. WO99 / 54299, etc. or a method analogous thereto.

  When an ester derivative of a compound having sialidase inhibitory activity is used as a preventive agent for influenza, it is mixed with itself or appropriate pharmacologically acceptable excipients, diluents, tablets, capsules, It can be administered by granules, powders, syrups, ointments, solutions, suspensions, aerosols, troches and the like.

  These formulations include excipients (eg, sugars such as lactose, sucrose, glucose, mannitol, sorbit; starch derivatives such as corn starch, potato starch, α-starch, dextrin, carboxymethyl starch; crystalline cellulose, Low substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, cellulose derivatives such as internally cross-linked sodium carboxymethylcellulose; gum arabic; dextran; pullulan; light anhydrous silicic acid, synthetic aluminum silicate, magnesium magnesium aluminometasilicate Silicates such as; phosphates such as calcium phosphate; carbonates such as calcium carbonate; sulfates such as calcium sulfate), binders (eg For example, the above excipients; gelatin; polyvinyl pyrrolidone; tuna gorgol etc.), disintegrants (eg, the above excipients; chemically modified such as croscarmellose sodium, sodium carboxymethyl starch, cross-linked polyvinyl pyrrolidone, Starch or cellulose derivatives, etc.), lubricants (eg, talc; stearic acid; stearic acid metal salts such as calcium stearate and magnesium stearate; colloidal silica; bee gum; waxes such as beeswax and gallows; boric acid; glycol Carboxylic acids such as fumaric acid and adipic acid; sodium carboxylic acid salts such as sodium benzoate; sulfates such as sodium sulfate; leucine; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic anhydride , Silicic acids such as silicic acid hydrate; starch derivatives in the above-mentioned excipients, stabilizers (for example, parahydroxybenzoic acid esters such as methylparaben and propylparaben; chlorobutanol, benzyl alcohol, phenylethyl alcohol) Alcohols such as: benzalkonium chloride; phenols such as phenol and cresol; thimerosal; acetic anhydride; sorbic acid, etc.], flavoring agents (eg, commonly used sweeteners, acidulants, flavors, etc.), It is produced by a known method using additives such as a suspending agent (for example, polysorbate 80, sodium carboxymethyl cellulose), a diluent, a solvent for preparation (for example, water, ethanol, glycerin, etc.).

  The influenza preventive agent of the present invention can be administered orally or parenterally, but the recipient's respiratory tissue (oral cavity, nasal cavity) in which an ester derivative of a compound having sialidase inhibitory activity is the main infection route of influenza virus. It is preferable to administer by an administration method that can be delivered to the respiratory tract, lung tissue), for example, nasal, nasal, transpulmonary, buccal administration or the like. In general, the compounds may be administered in the form of a solution or suspension or as a dry powder. Solutions and suspensions are aqueous, for example, water alone (eg, sterile or pyrogen-free water), or water and physiologically acceptable co-solvents (eg, ethanol, propylene glycol, polyethylene glycol, eg PEG 400) in general. Such solutions or suspensions may contain other excipients such as preservatives (eg benzalkonium chloride), solubilizers / surfactants such as polysorbates (eg Tween 80, Span 80, benzalkco chloride). Nium), a buffer, an isotonicity adjusting agent (for example, sodium chloride), an absorption enhancer and a thickener. The suspension may further contain a suspending agent (for example, microcrystalline cellulose, sodium carboxymethyl cellulose). Solutions or suspensions are applied directly to the nasal cavity or oral cavity by conventional means, for example with a dropper, pipette or spray. The formulation may be provided in a single dose or multiple dose form. In the latter case, it is desirable to provide a dose metering means. In the case of a dropper or pipette, this can be done by the patient administering an appropriate predetermined volume of solution or suspension. In the case of a nebulizer, this can be done, for example, by means of a metered atomizing spray pump. For administration to the respiratory tract or lungs, the compound is contained in a pressurized pack with a suitable propellant such as chlorofluorocarbon (CFC), eg dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, carbon dioxide or other suitable gas. This can be done with a shaped aerosol formulation. The aerosol may also conveniently contain a surfactant such as lecithin. The dose of the drug can be controlled by providing a metering valve. Alternatively, the compound is provided in the form of a dry powder, eg, a powder mixture in which the compound is mixed with a suitable powder base such as lactose, starch, starch derivatives (eg, hydroxypropylmethylcellulose), and polyvinylpyrrolidine (PVP). Also good. Conveniently the powder carrier will form a gel in the nasal cavity. The powder composition may be provided in unit dosage forms such as capsules or cartridges made of gelatin, or blister packs from which powders may be administered by inhaler. In formulations for administration to the respiratory tract or lung, including intranasal formulations, the particle size of the compound is generally small, for example, 5 microns or less. Such a particle size is obtained by methods known in the art such as by micronization. When desired, formulations may be used that provide a sustained release of the active ingredient.

  Ester derivatives of compounds having sialidase inhibitory activity can also be used in combination with other therapeutic agents, for example anti-influenza drugs such as amantadine, rimantadine, ribavirin. The individual components of such combinations can be administered sequentially or simultaneously in the form of separate or combined pharmaceutical formulations. When the compounds of the invention are used with a second therapeutic agent that is active against the same virus, the dosage of each compound may be the same or different from the dosage used when each compound is used alone.

  Administration of the influenza preventive agent of the present invention can be carried out 1 to 7 times a week while increasing or decreasing as needed, starting in the influenza epidemic season. In other words, when fashion is imminent, places where people live together, or places where an unspecified number of people gather, such as nurseries, kindergartens, schools, companies, hospitals, nursing homes, movie theaters, libraries, concert venues If you live, work, or go to a sports spectator hall, you can increase the frequency of administration or administer in advance. Increasing the frequency of administration is, for example, administration once a day, and pre-administration is administration before or after behavior that may cause infection before the onset of influenza. .

  The amount used varies depending on the type of prophylactic agent used, the degree of influenza epidemic, the weight, age, etc. of the person to be administered, but for example, when using Compound (II), the lower limit is 0. It is desirable to administer 1 mg (preferably 1 mg) and an upper limit of 1000 mg (preferably 500 mg) to adults 1 to 7 times per week.

  The virus infection preventing effect of the influenza preventive agent of the present invention can be evaluated by the following method.

  For example, administration of the active ingredient of the present invention in the form of a solution, suspension or powder, such as nasal, nasal, pulmonary, inhalation, etc. to the respiratory organs of vertebrates such as humans, mice, rats, ferrets, pigs and birds The appropriate amount is administered according to the method. Immediately after that, the influenza virus is infected by inhalation or dripping into the nose once at an appropriate time one month later. After that, influenza symptoms such as fever, headache, general malaise, joint pain, muscle pain, cough, sputum and other respiratory symptoms, throat swabs, nasal discharge, lung lavage fluid, etc. It can be observed or measured to know the preventive effect of the influenza preventive agent of the present invention.

  Alternatively, the human respiratory tract by oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including intramuscular, subcutaneous and intravenous) or inhalation in humans in areas where influenza is endemic Create a group to administer the appropriate amount to (including passing through the nose). On the other hand, a group without administration of the compound of the present invention is created. After a certain period of time, the proportion of both groups infected with influenza and developing their symptoms can be statistically verified to know the preventive effect of the influenza preventive agent of the present invention.

  When the preventive effect is verified using a mouse, an appropriate amount of the active ingredient of the present invention dissolved in physiological saline is dropped into the nasal cavity for intranasal administration, and an appropriate time one month after that Infection with influenza virus in the same way. After the infection, the preventive effect can be known by removing the mouse lung and measuring the amount of virus in the lung. When the influenza virus used causes a lethal infection in mice, the preventive effect can be known by observing the life and death of the mice.

  Note that the method for evaluating the preventive effect is not limited to that described here.

The production examples, formulation examples and test examples are shown below to explain the present invention in more detail.
(Production Example 1)
5-Acetamido-4-guanidino-9-O-octanoyl-2,3,4,5-tetradeoxy-7-O-methyl-D-glycero-D-galacto-non-2-enopyrazonic acid hydrate crystals

(1) Compound of Example 35 (i) of JP-A-10-330373, 5-acetamido-4- (N, N′-bis-t-butyroxycarbonyl) guanidino-9-O-octanoyl-2 3,4,5-tetradeoxy-7-O-methyl-D-glycero-D-galacto-non-2-enopyranosonic acid diphenylmethyl (3.46 g, 4.1 mmol) was added to methylene chloride (27 ml), trifluoroacetic acid (14 ml) and stirred at room temperature overnight. The reaction solution was concentrated to dryness under reduced pressure, and then azeotropically dried three times with toluene (5 ml). The resulting oil was dissolved in ethyl acetate (10 ml). On the other hand, this solution was poured into saturated sodium bicarbonate water (50 ml), and 20% aqueous sodium carbonate solution was added to adjust the pH to 8.5. The mixture was stirred at room temperature for 3 hours, adjusted to pH 5.0 with hydrochloric acid (3 ml), and stirred at room temperature for 1 hour. Further, after stirring for 1 hour under ice cooling, the crystals were suction filtered and dried in vacuum at an external temperature of 50 ° C. for 10 hours. The product was left in the air for 1 day to give the title object compound as crystals. (0.97g, 51%)
Infrared absorption spectrum (KBr) νmax cm ^-1 : 3412, 2929, 2856, 1676, 1401, 1320, 1285, 1205, 1137, 722.
¹ H nuclear magnetic resonance spectrum (400 MHz, CD3OD) δ ppm: 5.88 (1H, d, J = 2.5 Hz), 4.45 (3H, m), 4.27 (1H, dd, J = 10.0 Hz, 10.0 Hz), 4.15 (1H , m), 3.47 (2H, m), 3.42 (3H, s), 2.37 (2H, t, J = 7.4 Hz), 2.10 (3H, s), 1.31 (2H, m), 1.20-1.40 (8H, m), 0.85-0.95 (3H, m).
¹³ C nuclear magnetic resonance spectrum (100 MHz, CD ₃ OD) δ ppm: 176.5, 173.7, 164.7, 158.9, 146.7, 108.7, 80.1, 78.0, 69.3, 66.8, 61.4, 52.4, 35.1, 32.8, 30.2, 30.1, 26.0, 23.7 , 22.8, 14.4.
(2) The title compound was also obtained by the following method.

Example 35 (ii) of JP-A-10-330373, 5-acetamido-4-guanidino-9-O-octanoyl-2,3,4,5-tetradeoxy-7-O-methyl-D- Glycero-D-galacto-non-2-enopyrazonic acid trifluoroacetate (3.0 g, 5.1 mmol) was subjected to reverse phase column chromatography (Nacalai Tesque Cosmosil 75C18PREP, 100 g) and methanol-water (0 : 1, 1: 1,2: 1) and increasing the methanol content. The fraction containing the desired product was concentrated under reduced pressure, and the precipitated crystals were suction filtered and dried under reduced pressure. The product was left in the air for 1 day to give the title object compound as crystals (1.2 g, 49%). The physical property data of the obtained compound was completely consistent with that obtained in the above (1).
(Production Example 2)
(3R, 4R, 5S) -4-Acetamide-5-amino-3- (1-ethylpropoxy) -1-cyclohexene-1-carboxylic acid tetradecane

(1) ethyl (3R, 4R, 5S) -4-acetamido-5-Nt-butoxycarbonylamino-3- (1-ethylpropoxy) -1-cyclohexene-1-carboxylate (3R, 4R, 5S) Ethyl-4-acetamido-5-amino-3- (1-ethylpropoxy) -1-cyclohexene-1-carboxylate (GS4104) (compound described in WO 96/26933) (600 mg, 1.92 mmol) , Dissolved in dimethylformamide (3 mL), di-t-butyl dicarbonate (440 mg, 2.02 mmol) was added under a nitrogen atmosphere, and triethylamine (294 μL, 2.11 mmol) was added under ice-cooling. Stir for hours.

  Ethyl acetate (30 mL) was added to the reaction solution, and saturated aqueous ammonium chloride (10 mL) was further added to separate the layers. The obtained organic phase was separated, washed with saturated brine (10 mL) and then with tap water (10 mL × 2), dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure to remove the title compound (800 mg, yield). 99%) was obtained as a white amorphous.

Infrared absorption spectrum (CHCl ₃ ) νmax: 3692, 3607, 3434, 2981, 2938, 2878, 1811, 1750, 1705, 1602, 1511, 1505, 1458, 1393, 1369, 1321 cm ^-1 ;
¹ H nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δppm: 0.88 (3H, t, J = 7.3 Hz), 0.90 (3H, t, J = 7.3 Hz), 1.29 (3H, t, J = 7.3 Hz) , 1.42 (9H, s), 1.46-1.56 (4H, m), 1.98 (3H, s), 2.25-2.33 (1H, m), 2.75 (1H, dd, J = 17.6, 5.9 Hz), 3.33-3.38 (1H, m), 3.76-3.84 (1H, m), 3.94-3.97 (1H, m), 4.04-4.11 (1H, m), 4.17-4.25 (2H, m), 5.10 (1H, d, J = 9.8 Hz), 5.76 (1H, d, J = 9.8 Hz), 6.79 (1H, s);
Mass spectrum (FAB) m / e: 413 ([M + H] ⁺ ).
(2) (3R, 4R, 5S) -4-Acetamide-5-Nt-butoxycarbonylamino-3- (1-ethylpropoxy) -1-cyclohexene-1-carboxylic acid potassium salt Production Example 2 (1) (3R, 4R, 5S) -4-Acetamide-5-Nt-butoxycarbonylamino-3- (1-ethylpropoxy) -1-cyclohexene-1-carboxylate (790 mg, 1.92 mmol) prepared in Was dissolved in methanol (5 mL), aqueous potassium hydroxide solution (6N, 0.5 mL, 3 mmol) was added, and the mixture was stirred at 40 ° C. for 1 hr.

  The solvent was distilled off under reduced pressure to obtain the crude title compound. This was used in the following reaction.

¹ H nuclear magnetic resonance spectrum (400 MHz, D ₂ O) δ ppm: 0.71 (3H, t, J = 7.3 Hz), 0.77 (3H, t, J = 7.3 Hz), 1.30 (9H, s), 1.26-1.37 (2H, m), 1.38-1.48 (2H, m), 1.89 (3H, s), 2.10-2.18 (1H, m), 2.75 (1H, dd, J = 17.6, 4.9 Hz), 3.37-3.42 (1H , m), 3.55-3.62 (1H, m), 3.63-3.70 (1H, m), 4.10-4.15 (1H, m), 6.29 (1H, s).
(3) (3R, 4R, 5S) -4-Acetamide-5-Nt-butoxycarbonylamino-3- (1-ethylpropoxy) -1-cyclohexene-1-carboxylic acid tetradecane In Production Example 2 (2) Prepared (3R, 4R, 5S) -4-acetamido-5-Nt-butoxycarbonylamino-3- (1-ethylpropoxy) -1-cyclohexene-1-carboxylic acid potassium salt (400 mg, 0.946 mmol) Was dissolved in dimethylformamide (3 mL), 1-bromotetradecane (1.12 mL, 3.70 mmol) was added, and the mixture was stirred at 50 ° C. for 3 hr.

  The solvent was distilled off under reduced pressure to obtain the crude title compound.

  The obtained crude title target compound was purified using silica gel column chromatography (hexane: ethyl acetate, 4: 1-2: 1, v / v) to give the title target compound (430 mg, yield 78%) as white. Obtained as an oil.

Infrared absorption spectrum (CHCl ₃ ) νmax: 3434, 2963, 2928, 2872, 2855, 1705, 1525, 1511, 1503, 1465, 1438, 1393, 1368, 1322 cm ^-1 ;
¹ H nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δppm: 0.88 (3H, t, J = 7.3 Hz), 0.90 (3H, t, J = 7.3 Hz), 1.25-1.38 (25H, m), 1.42 ( 9H, s), 1.46-1.56 (4H, m), 1.60-1.68 (2H, m), 1.98 (3H, s), 2.25-2.33 (1H, m), 2.75 (1H, dd, J = 17.6, 5.9 Hz), 3.33-3.38 (1H, m), 3.76-3.84 (1H, m), 3.94-3.97 (1H, m), 4.04-4.11 (1H, m), 4.17-4.25 (2H, m), 5.10 ( 1H, d, J = 9.8 Hz), 5.76 (1H, d, J = 9.8 Hz), 6.79 (1H, s);
Mass spectrum (FAB) m / e: 581 ([M + H] ⁺ );
High resolution mass spectrometry (FAB) Calcd for C ₃₃ H ₆₁ O ₆ N ₂ : 581.4530; found 581.4526 ([M + H] ⁺ ).
(4) (3R, 4R, 5S) -4-Acetamide-5-amino-3- (1-ethylpropoxy) -1-cyclohexene-1-carboxylic acid tetradecanetrifluoroacetate Prepared in Preparation Example 2 (3) (3R, 4R, 5S) -4-Acetamide-5-Nt-butoxycarbonylamino-3- (1-ethylpropoxy) -1-cyclohexene-1-carboxylic acid tetradecane (430 mg, 0.740 mmol) was dissolved in methylene chloride. (6 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 2 hr.

  The solvent was distilled off under reduced pressure to obtain the crude title compound.

  The resulting crude title compound was purified using reverse phase chromatography (cosmosyl, water: methanol, 1: 0-1-1: 1-1: 8, v / v) to give the title compound (376 mg, yield). 85%) was obtained as a white amorphous.

Infrared absorption spectrum (KBr) νmax: 3279, 3060, 2960, 2926, 2874, 2854, 2094, 1715, 1667, 1554, 1466, 1434, 1375, 1349, 1331, 1301 cm ^-1 ;
¹ H nuclear magnetic resonance spectrum (400 MHz, CD ₃ OD) δppm: 0.89 (3H, t, J = 7.3 Hz), 0.93 (3H, t, J = 7.3 Hz), 1.24-1.43 (25H, m), 1.46 -1.60 (4H, m), 1.64-1.72 (2H, m), 2.03 (3H, s), 2.40-2.48 (1H, m), 2.92 (1H, dd, J = 17.6, 5.9 Hz), 3.40-3.46 (1H, m), 3.48-3.55 (1H, m), 3.96 (1H, dd, J = 11.7, 8.8 Hz), 4.13-4.25 (3H, m), 6.85 (1H, s);
Mass spectrum (FAB) m / e: 481 ([M + H] ⁺ );
High Resolution Mass Spectrometry (FAB) Calcd for C ₂₈ H ₅₃ O ₄ N ₂ : 481.4006; found 481.3990 ([M + H] ⁺ ).

(Production Example 3)
(3R, 4R, 5S) -4-Acetamide-5-amino-3- (1-ethylpropoxy) -1-cyclohexene-1-carboxylic acid octadecane

(1) (3R, 4R, 5S) -4-Acetamide-5-Nt-butoxycarbonylamino-3- (1-ethylpropoxy) -1-cyclohexene-1-carboxylic acid octadecane In Production Example 2 (2) Prepared (3R, 4R, 5S) -4-acetamido-5-Nt-butoxycarbonylamino-3- (1-ethylpropoxy) -1-cyclohexene-1-carboxylic acid potassium salt (400 mg, 0.946 mmol) Was dissolved in dimethylformamide (3 mL), 1-bromooctadecane (1.26 mL, 3.70 mmol) was added, and the mixture was stirred at 50 ° C. for 3 hr.

  The solvent was distilled off under reduced pressure to obtain the crude title compound.

  The resulting crude title target compound was purified using silica gel column chromatography (hexane: ethyl acetate, 4: 1-2: 1, v / v) to give the title target compound (335 mg, yield 55%) as white. Obtained as an oil.

Infrared absorption spectrum (CHCl ₃ ) νmax: 3691, 3607, 3434, 2961, 2927, 2855, 1705, 1602, 1511, 1505, 1465, 1438, 1393, 1368, 1322 cm ^-1 ;
¹ H nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ0.88 (3H, t, J = 7.3 Hz), 0.90 (3H, t, J = 7.3 Hz), 1.25-1.38 (33H, m), 1.42 ( 9H, s), 1.46-1.56 (4H, m), 1.60-1.68 (2H, m), 1.98 (3H, s), 2.25-2.33 (1H, m), 2.74 (1H, dd, J = 17.6, 5.9 Hz), 3.32-3.37 (1H, m), 3.75-3.83 (1H, m), 3.93-3.97 (1H, m), 4.04-4.11 (1H, m), 4.10-4.18 (2H, m), 5.04 ( 1H, d, J = 8.8 Hz), 5.69 (1H, d, J = 8.8 Hz), 6.79 (1H, s);
Mass spectrometry spectrum (FAB) m / e: 637 ([M + H] ⁺ );
High Resolution Mass Spectrometry (FAB) Calcd for C ₃₇ H ₆₉ O ₆ N ₂ : 637.5155; found 637.5154 ([M + H] ⁺ ).
(2) (3R, 4R, 5S) -4-Acetamide-5-amino-3- (1-ethylpropoxy) -1-cyclohexene-1-carboxylic acid octadecane trifluoroacetate salt Prepared in Preparation Example 3 (1) (3R, 4R, 5S) -4-Acetamide-5-Nt-butoxycarbonylamino-3- (1-ethylpropoxy) -1-cyclohexene-1-carboxylate octadecane (330 mg, 0.518 mmol) was dissolved in methylene chloride. (6 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 2 hr.

  The solvent was distilled off under reduced pressure to obtain the crude title compound.

  The resulting crude title compound was purified using reverse phase chromatography (cosmosyl, water: methanol, 1: 0-1-1: 1: 10, v / v) to give the title compound (246 mg, yield). 73%) was obtained as a white amorphous.

Infrared absorption spectrum (KBr) νmax: 3278, 3055, 2959, 2925, 2854, 1715, 1668, 1556, 1466, 1434, 1375, 1350, 1331, 1301 cm ^-1 ;
¹ H nuclear magnetic resonance spectrum (400 MHz, CD ₃ OD) δppm: 0.89 (3H, t, J = 7.3 Hz), 0.93 (3H, t, J = 7.3 Hz), 1.24-1.43 (33H, m), 1.46 -1.60 (4H, m), 1.64-1.72 (2H, m), 2.03 (3H, s), 2.39-2.48 (1H, m), 2.92 (1H, dd, J = 17.6, 5.2 Hz), 3.40-3.46 (1H, m), 3.48-3.55 (1H, m), 3.96 (1H, dd, J = 11.7, 8.8 Hz), 4.12-4.25 (3H, m), 6.85 (1H, s);
Mass spectrometry spectrum (FAB) m / e 537 ([M + H] ⁺ );
High resolution mass spectrometry (FAB) Calcd for C ₃₂ H ₆₁ O ₄ N ₂ : 537.4632; found 537.4625 ([M + H] ⁺ ).
(Formulation example 1) Solution 1
Compound of Production Example 1 is 10% (W / W), benzalkonium chloride is 0.04% (W / W), phenethyl alcohol is 0.40% (W / W), and purified water is 89.56% ( Adjust the solution so that (W / W).
(Formulation Example 2) Solution 2
Compound of Production Example 1 is 10% (W / W), benzalkonium chloride is 0.04% (W / W), polyethylene glycol 400 is 10% (W / W), propylene glycol is 30% (W / W) ), Adjust the liquid so that the purified water is 39.96% (W / W).
(Formulation example 3) Powder A powder is adjusted so that the compound of manufacture example 1 may be 40% (W / W), and lactose will be 60% (W / W).
(Formulation example 4) Aerosol agent The compound of Production Example 1 is 10% (W / W), lecithin is 0.5% (W / W), Freon 11 is 34.5% (W / W), Freon 12 is 55 Adjust the aerosol so that it becomes% (W / W).
(Test Example 1)
Influenza prophylaxis with 5-acetamido-4-guanidino-9-O-octanoyl-2,3,4,5-tetradeoxy-7-methoxy-D-glycero-D-galacto-non-2-enopyrazonic acid (compound A) Effect 5-6 week old Balb / C mice (female) were placed in an anesthetic bottle filled with chloroform / ether (1: 1) and anesthetized. To an anesthetized mouse, 50 μL of a compound A (ester derivative) solution dissolved in physiological saline was added dropwise into the nasal cavity so that the dose was 0.3 μmol / kg. Mice similarly anesthetized 10 days, 7 days, 5 days, 3 days or 4 hours after the administration were infected with influenza virus A / PR / 8/34 strain (1,500 plaque formation units). The mice were observed for life and death until 20 days after infection.

  FIG. 1 shows the results. The horizontal axis indicates the number of days after infection, and the vertical axis indicates the survival rate. The black squares show the survival plots of mice not administered with the compound of the present invention, the black triangles are 10 days ago, the black circles are 7 days ago, the white triangles are 5 days ago, the white squares are 3 days ago, and the white circles are 4 hours before The survival rate plot of the mouse | mouth which administered the compound A is shown.

As a result, the total number of non-administered mice died by 6 days after infection, whereas the total number of 10-day pre-administered mice and 7-day pre-administered mice required 8 days and 11 days, respectively. Mice that were administered 5 days, 3 days, and 4 hours before were still alive at the 20th day after infection, and the survival rates at that time were 50%, 83%, and 100%, respectively. These results demonstrate that Compound A (ester derivative at the hydroxyl group) has an excellent effect in prophylactic administration.
(Test Example 2)
5-acetamide-4-guanidino-9-O-octanoyl-2, 3, 4, 5-tetradeoxy-7-methoxy-D-glycero-D-galacto-non-2-enopyrazonic acid (compound A) was administered Sustained concentration of 5-acetamide-4-guanidino-2,3,4,5-tetradeoxy-7-methoxy-D-glycero-D-galacto-non-2-enopyrazonic acid (compound B) in mouse lung tissue Effect 5-6 week old Balb / C mice (female) were placed in an anesthetic bottle filled with chloroform / ether (1: 1) and anesthetized. To anesthetized mice, ¹⁴ C-labeled compound A (ester derivative) dissolved in physiological saline is 0.3 μmol / kg and 1 μmol / kg, or ¹⁴ C-labeled compound B (active substance) is 4 μmol / kg. Each was administered dropwise to the nasal cavity. After administration, the lung tissue and upper respiratory tract of the mouse were removed, and the concentrations of Compound A and Compound B were measured for up to 72 hours using a liquid scintillation counter and thin layer chromatography. The chemical structural formulas of Compound A and Compound B are as follows, and Compound A is an ester derivative at the 9-position hydroxyl group of Compound B having sialidase inhibitory activity.

  2 and 3 show the results, with the horizontal axis indicating the time after administration and the vertical axis indicating the compound concentration. In FIG. 2, black squares are administered with Compound A (ester derivative) at 0.3 μmol / kg, black triangles are administered with Compound A (ester derivative) at 1 μmol / kg, and white circles are administered with Compound B (active substance) at 4 μmol / kg. The concentration transition of the compound B (active substance) detected in the lung tissue after is shown. In FIG. 3, white squares indicate compound A (ester derivative) 0.3 μmol / kg, white triangles indicate compound A (ester derivative) 1 μmol / kg, compound A (ester) detected in lung tissue after administration. The concentration transition of the derivative) is shown.

As a result, when Compound B (active substance: compound having sialidase activity) itself was administered, Compound B quickly disappeared from the lung tissue. In contrast, when compound A (ester derivative) is administered, compound A (ester derivative) is rapidly converted to compound B (active substance), and the concentration of compound B (active substance) in the lung tissue is prolonged. Lasted.
(Test Example 3)
Influenza preventive effect 5-6 week old Balb / C mice (female) were placed in an anesthetic bottle filled with chloroform / ether (1: 1) and anesthetized. To an anesthetized mouse, 50 μL of a test compound solution (compounds A to J) dissolved in physiological saline was dropped into the nasal cavity so that the dose was 1.0 μmol / kg. Seven days after the administration, the similarly anesthetized mice were infected with influenza virus A / PR / 8/34 strain (500 plaque formation units). The mice were observed for life and death until 20 days after infection.

  As a result, all the mice to which compounds B, G, and J (active form) were administered died on the 11th, 13th, and 8th days, respectively. In addition, all mice that received Compound I (ethyl ester) died on the 9th day. In contrast, mice administered compounds A, C, D, E, F and H (long chain ester derivatives) were 63%, 25%, 75%, 50%, 20 days after infection, respectively. 50%, 50% of mice survived. These results demonstrate that long chain ester derivatives at the carboxyl group show excellent effects in prophylactic administration.

FIG. 1 shows 5-acetamido-4-guanidino-9-O-octanoyl-2,3,4,5-tetradeoxy-7-methoxy-D-glycero-D-galacto-non-2-enopyrazonic acid (compound A) This shows the influenza preventive effect in mice.

The horizontal axis indicates the number of days after influenza virus infection, and the vertical axis indicates the survival rate. The black squares show the survival plots of mice not treated with Compound A (ester derivatives). The black triangles are 10 days before infection, the black circles are 7 days before, the white triangles are 5 days ago, the white squares are 3 days ago, and the white circles are 4 hours ago. Shows the survival plots of the mice administered with compound A (ester derivative).
FIG. 2 shows 5-acetamido-4-guanidino-9-O-octanoyl-2,3,4,5-tetradeoxy-7-methoxy-D-glycero-D-galacto-non-2-enopyrazonic acid (compound A) Of 5-acetamide-4-guanidino-2,3,4,5-tetradeoxy-7-methoxy-D-glycero-D-galacto-non-2-enopyrazonic acid (compound B) in the lung tissue of mice administered This shows the continuous effect of concentration.

The horizontal axis represents the time after administration, and the vertical axis represents the compound concentration. Black squares indicate compound A (ester derivative) 0.3 μmol / kg, black triangles indicate compound A (ester derivative) 1 μmol / kg, white circles indicate compound B (active substance) 4 μmol / kg lung tissue after administration The concentration transition of the compound B (active substance) in it is shown.
FIG. 3 shows 5-acetamido-4-guanidino-9-O-octanoyl-2,3,4,5-tetradeoxy-7-methoxy-D-glycero-D-galacto-non-2-enopyrazonic acid (compound A) 2 shows the change in the concentration of Compound A in the lung tissue of mice administered with sucrose.

  The horizontal axis represents the time after administration, and the vertical axis represents the compound concentration. White squares indicate compound A (ester derivative) 0.3 μmol / kg, white triangles indicate compound A (ester derivative) 1 μmol / kg, and change in concentration of compound A (ester derivative) in lung tissue after administration .

Claims (5)

Contains a pharmacologically acceptable ester derivative of a compound having sialidase inhibitory activity as an active ingredient, and receives the compound having sialidase inhibitory activity by administering the pharmacologically acceptable ester derivative to the respiratory tract of the recipient. Influenza preventive agent characterized in that it is retained in the respiratory tissue of a person, wherein the pharmacologically acceptable ester derivative has the general formula

[Wherein R ¹ represents an alkanoyl group having 6 to 18 carbon atoms, R ² represents a hydrogen atom, X ¹ represents a hydroxyl group or an alkoxy group having 1 to 4 carbon atoms, and R ³ represents a hydrogen atom. Or
R ¹ and R ² represent a hydrogen atom, X ¹ represents a hydroxyl group or an alkoxy group having 1 to 4 carbon atoms, and R ³ represents an alkyl group having 10 to 20 carbon atoms. However, when R ¹ represents an alkanoyl group having 6 to 18 carbon atoms, the octanoyl group is excluded as R ¹ . ] Or general formula

[Wherein, R ^b1 represents an amino group, R ^b2 represents a 1-ethylpropyl group, and R ⁴ represents an alkyl group having 8 to 20 carbon atoms. ]
An influenza preventive agent, which is a compound represented by: In Claim 1, a pharmacologically acceptable ester derivative is represented by general formula (IIa), and in general formula (IIa), R ¹ is a tetradecanoyl group, R ² is a hydrogen atom, and X ¹ is Influenza preventive agent which is a methoxy group and R ³ is a hydrogen atom. In Claim 1, a pharmacologically acceptable ester derivative is represented by the general formula (IIa), and in the general formula (IIa), R ¹ and R ² are hydrogen atoms, X ¹ is a methoxy group, and R ^An influenza preventive agent, wherein ³ is a tetradecyl group or an octadecyl group. In Claim 1, the pharmacologically acceptable ester derivative is represented by the general formula (IIa), and in the general formula (IIa), R ¹ and R ² are hydrogen atoms, X ¹ is a hydroxyl group, and R ³ Influenza preventive agent wherein is tetradecyl group or octadecyl group. The influenza preventive agent according to claim 1, wherein the pharmacologically acceptable ester derivative is represented by the general formula (IIb), and in the general formula (IIb), R ⁴ is an octadecyl group.