JP2006077004A - Compound having anti-HCV action and pharmaceutical composition containing the same - Google Patents

Abstract

〔式中、Ｒ¹、Ｒ²、及びＲ³は、同一又は異なって、水素原子など；Ｚは、炭素数１〜４の直鎖もしくは分岐鎖状のアルキル基など；Ａは、水素原子を表わすか、あるいはヒドロキシ基で置換されていてもよい炭素数５の直鎖もしくは分岐鎖状のアルケニル基；Ｂは、水素原子など；Ｃは、ヒドロキシ基で置換されていてもよい炭素数７の直鎖もしくは分岐鎖状のアルキル基など；結合Ｑは、一重結合または二重結合を表す〕で示される化合物もしくはそのプロドラッグ、または製薬上許容されうるそれらの塩。
【選択図】 なしPROBLEM TO BE SOLVED: To provide a compound useful for the prevention and treatment of viral infections, particularly liver diseases caused by infection with HCV, and a pharmaceutical composition comprising these compounds, since they have high hepatitis C virus (HCV) replication inhibitory activity To do.
SOLUTION:

[Wherein R ¹ , R ² , and R ³ are the same or different and are a hydrogen atom, etc .; Z is a linear or branched alkyl group having 1 to 4 carbon atoms, etc .; A is a hydrogen atom; A linear or branched alkenyl group having 5 carbon atoms which may be substituted by a hydroxy group; B is a hydrogen atom or the like; C is a carbon atom having 7 carbons which may be substituted by a hydroxy group A straight chain or branched alkyl group and the like; the bond Q represents a single bond or a double bond] or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
[Selection figure] None

Description

  The present invention relates to compounds useful for the prevention and treatment of viral infections, particularly liver diseases caused by infection with HCV, and pharmaceutical compositions containing these compounds, since they have high replication inhibitory activity against hepatitis C virus (HCV). .

  It is estimated that there are 1 to 200 million people infected with HCV worldwide and more than 2 million people in Japan. About 50% of these patients transition to chronic hepatitis, of which about 20% develop cirrhosis and liver cancer more than 30 years after infection. About 90% of liver cancer is said to be caused by hepatitis C. In Japan, more than 20,000 patients die from liver cancer associated with HCV infection every year.

  HCV was discovered in 1989 as a major causative virus for non-A non-B hepatitis after blood transfusion. HCV is an RNA virus having an envelope, and its genome consists of single-stranded (+) RNA, and is classified into the genus Hepacivirus of the Flaviviridae family.

  HCV avoids the immune system of the host due to an unclear cause, so persistent infection is often established even when infected with an adult with an advanced immune system, which progresses to chronic hepatitis, cirrhosis, and liver cancer. It is also known that even after excision, there are many patients whose liver cancer recurs due to inflammation that continues in the non-cancerous part.

  Therefore, establishment of an effective treatment method for hepatitis C is desired. In particular, apart from symptomatic treatment that suppresses inflammation with an anti-inflammatory agent, development of a drug that reduces or eradicate HCV in the affected liver is strong. It is desired.

  Currently, interferon therapy is known as the only effective treatment for HCV exclusion. However, about 1/3 of all patients have effective interferon. In particular, the response rate of interferon against HCV genotype 1b is very low. Therefore, development of an anti-HCV drug that can replace or be used in combination with interferon is strongly desired.

  In recent years, ribavirin (1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide) has been marketed as a therapeutic agent for hepatitis C in combination with interferon. It is still low and further novel hepatitis C therapeutics are desired. In addition, although attempts have been made to eliminate viruses by enhancing the immunity of patients such as interferon agonists and interleukin-12 agonists, no effective drug has been found yet.

  Since the HCV gene was cloned, molecular biological analysis of viral gene mechanisms and functions, protein functions of each virus, etc. has rapidly progressed, but virus replication, persistent infection, and pathogenicity in host cells. Such mechanisms have not been fully elucidated, and at present, a reliable HCV infection experimental system using cultured cells has not been established. Therefore, in the past, alternative virus assays using other closely related viruses had to be used in evaluating anti-HCV drugs.

  However, in recent years, it has become possible to observe HCV replication in vitro using a non-structural region portion of HCV, so that anti-HCV drugs can be easily evaluated by a replicon assay method (non- Patent Document 1). The mechanism of HCV RNA replication in this system is thought to be identical to the replication of the full-length HCV RNA genome infected with hepatocytes. Thus, this system can be referred to as a cell-based assay system useful for identifying compounds that inhibit HCV replication.

更に本願発明者らは、該化合物およびその誘導体を全合成する方法を開発し、その方法により得られた各種誘導体が同様に優れたＨＣＶ複製阻害活性を有することを見出した（特許文献３）。
特願２００３−３４０５６号明細書 国際公開第９８／５６７５５号パンフレット 特願２００３−２７２４２０号明細書 ブイ・ローマンなど著、サイエンス（Science）、１９９９年、第２８５巻、第１１０−１１３頁 The inventors of the present application isolated the following compound from Fusarium sp. Strain F1476 (hereinafter referred to as “F1476 strain”) belonging to filamentous fungi, and found that the compound has high HCV replication inhibitory activity. (Patent Document 1). The compound is also disclosed in International Publication No. WO 98/56755 (Patent Document 2), and is known to have antifungal activity and immune reaction inhibitory action.

Furthermore, the present inventors have developed a method for fully synthesizing the compound and its derivatives, and found that various derivatives obtained by the method have excellent HCV replication inhibitory activity (Patent Document 3).
Japanese Patent Application No. 2003-34056 International Publication No. 98/56755 Pamphlet Japanese Patent Application No. 2003-272420 Specification Buoy Lohmann et al., Science, 1999, 285, 110-113

  As a result of intensive studies, the present inventor has found that the “F1476 strain” produces a new group of natural compounds not described in the above document, and further, the compound group has a very strong anti-HCV replicon. The present invention has been completed by finding that it has an activity and further suppresses the amplification of HCV, has minimal in vitro cytotoxicity, and is extremely useful as an anti-HCV preventive / therapeutic agent. .

  An object of the present invention is to provide compounds useful for the prevention and treatment of viral infections, particularly liver diseases caused by HCV infection, and pharmaceutical compositions containing these compounds, since they have high HCV replication inhibitory activity. To do.

The present invention
Formula (I):

[Wherein R ¹ , R ² , and R ³ are the same or different and are mono- or di-substituted with a hydrogen atom, a hydroxy group, an amino group (a linear or branched alkyl group having 1 to 4 carbon atoms). -OZ, a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkenyl group having 2 to 4 carbon atoms, or a linear chain having 2 to 4 carbon atoms Or a branched alkynyl group;
Z represents a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkenyl group having 2 to 4 carbon atoms, or a linear or branched alkynyl group having 2 to 4 carbon atoms. Represents a group;
A represents a hydrogen atom or a hydroxy group (the hydrogen atom of the hydroxy group is a linear or branched alkyl group having 1 to 4 carbon atoms or a linear or branched alkenyl group having 2 to 4 carbon atoms). A linear or branched alkenyl group having 5 carbon atoms which may be further substituted with a group, or an optionally substituted linear or branched alkynyl group having 2 to 4 carbon atoms;
B is a hydrogen atom, a halogen atom, -N (R ⁴ ) (R ⁵ ), = N-OR ⁶ , = N-OH, a hydroxy group (the hydrogen atom of the hydroxy group is a straight chain having 1 to 4 carbon atoms or (Optionally substituted with a branched alkyl group, a linear or branched alkenyl group having 2 to 4 carbon atoms, or a linear or branched alkynyl group having 2 to 4 carbon atoms) or oxo R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, or a linear or branched chain group having 2 to 6 carbon atoms. Represents an alkenyl group or a linear or branched alkynyl group having 2 to 6 carbon atoms, or R ⁴ and R ⁵ together represent a 3 to 8 membered ring, and R ⁶ represents 1 to 8 linear or branched alkyl groups (straight or branched chain having 1 to 4 carbon atoms) An optionally substituted mono- or di-substituted amino group).
C is a linear or branched alkyl group having 7 carbon atoms which may be substituted with a hydroxy group, a linear or branched alkenyl group having 7 carbon atoms which may be substituted with a hydroxy group, or Represents a linear or branched alkynyl group having 7 carbon atoms which may be substituted with a hydroxy group (the hydrogen atom of each hydroxy group is a linear or branched alkyl group having 1 to 4 carbon atoms, carbon And may be further substituted with a linear or branched alkenyl group having 2 to 4 carbon atoms, or a linear or branched alkynyl group having 2 to 4 carbon atoms);
Bond Q represents a single bond or a double bond;
However, when A represents a hydrogen atom or an alkenyl group that is not substituted with a hydroxy group, is C a straight-chain or branched alkenyl group having 7 carbon atoms that may be substituted with a hydroxy group? Or a 2-hydroxy-n-heptyl group]
Or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

  The present invention further relates to a pharmaceutical composition comprising a compound of the above formula (I) or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

  The compound of the formula (I) of the present invention or a prodrug thereof, or a pharmaceutically acceptable salt thereof has a very strong anti-HCV replicon activity, and further has an inhibitory effect on the amplification of HCV, and further has an in vitro cytotoxicity. Since it is minor, it is effective for the treatment and prevention of viral infections, particularly HCV infections such as hepatitis C.

  In the present specification, the linear or branched alkyl group means a hydrocarbon group having a predetermined carbon number. Examples of the linear or branched alkyl group having 1 to 4 carbon atoms include methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl and t-butyl. Examples of the linear or branched alkyl group having 5 carbon atoms include n-pentyl, t-pentyl, isopentyl, neopentyl and the like. Examples of the linear or branched alkyl group having 6 carbon atoms include n-hexyl, isohexyl, neohexane-1-yl and the like. Examples of the linear or branched alkyl group having 7 carbon atoms include n-heptyl, 5-methylhexyl, 4,4-dimethyl-pentyl, 1,1-dimethyl-pentyl and the like. Examples of the linear or branched alkyl group having 8 carbon atoms include n-octyl and isooctyl.

  The straight chain or branched alkenyl group means a hydrocarbon group having a predetermined number of carbon atoms and having at least one double bond. Examples of the linear or branched alkenyl group having 2 to 4 carbon atoms include vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-methyl-1-propenyl, 1-methyl-1-propenyl and the like. be able to. Examples of the linear or branched alkenyl group having 5 carbon atoms include 1-pentenyl and 3-methyl-2-butenyl. Examples of the linear or branched alkenyl group having 2 to 6 carbon atoms include 1-hexenyl, 2-hexen-1-yl, 3-hexen-1-yl and the like in addition to the above alkenyl groups. . Examples of the straight-chain or branched alkenyl group having 7 carbon atoms include 1-hepten-1-yl and 2-hepten-1-yl.

  Further, the linear or branched alkynyl group means a hydrocarbon group having a predetermined number of carbon atoms and having at least one triple bond. Examples of the linear or branched alkynyl group having 2 to 4 carbon atoms include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl and the like. Examples of the linear or branched alkynyl group having 2 to 6 carbon atoms include 1-pentyn-1-yl, 2-pentyn-1-yl, 1-hexyn-1-yl, 2 -Hexin-1-yl, 3-hexyn-1-yl, etc. can be mentioned. Examples of the linear or branched alkynyl group having 7 carbon atoms include 1-heptin-1-ynyl, 2-heptin-1-ynyl, and 3-heptin-1-ynyl.

The prodrugs described herein are chemicals that can be converted into a compound of formula (I) or a pharmaceutically acceptable salt thereof under physiological conditions or by solvolysis after being formulated as a pharmaceutical. Means a derivative of a compound of formula (I), with modifications. Prodrugs may be inactive when administered to a patient, but are present converted to a compound of formula (I) that is active in vivo. Examples of the prodrug include, for example, C _1-6 alkyl esterification, C _6-10 aryl esterification, C _1-6 alkyloxy C _1-6 alkyl esterification (following formula), C _1-6 alkoxymethyl esterification include the compounds subjected to such hydroxy -C _1-6 alkyl esterification (the following formulas).

  The pharmaceutically acceptable salts described in the present specification are not particularly limited as long as they are pharmacologically acceptable. For example, salts with mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid; acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzene Examples thereof include salts with organic acids such as sulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid and camphorsulfonic acid; salts with alkali metals or alkaline earth metals such as sodium, potassium and calcium.

  In addition, the term treatment described in the present specification refers to the disappearance or reduction of HCV, suppression of further spread of HCV, and symptoms caused by infection with HCV by administering the pharmaceutical composition of the present invention to a subject. Means to reduce. Symptoms caused by HCV infection include hepatitis C, cirrhosis, liver fibrosis, liver cancer and the like.

The compounds of the present invention are described in detail below.
The compound of the formula (I) of the present invention is represented by the formula shown above, and in this formula (I), R ¹ , R ² , and R ³ are the same or different and represent a hydrogen atom, hydroxy Group, amino group (which may be mono- or di-substituted by a linear or branched alkyl group having 1 to 4 carbon atoms), -OZ, a linear or branched alkyl group having 1 to 4 carbon atoms Represents a linear or branched alkenyl group having 2 to 4 carbon atoms, or a linear or branched alkynyl group having 2 to 4 carbon atoms, where Z is a linear or branched chain alkynyl group having 1 to 4 carbon atoms or A branched alkyl group, a linear or branched alkenyl group having 2 to 4 carbon atoms, or a linear or branched alkynyl group having 2 to 4 carbon atoms is represented. The R ^1, R ^2, and R ^3, hydroxy or -OZ group is preferred, a hydroxy group are particularly preferred. Specific examples of the —OZ group include methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, s-butyloxy, t-butyloxy, vinyloxy, 1-propen-1-yloxy, Examples include allyloxy, 1-buten-1-yloxy, ethynyloxy, 1-propyn-1-yloxy, 1-butyn-1-yloxy and the like.

  In the compound of the formula (I) of the present invention, A represents a hydrogen atom, or a hydroxy group (the hydrogen atom of the hydroxy group is a linear or branched alkyl group having 1 to 4 carbon atoms, carbon number And may be further substituted with 2 to 4 linear or branched alkenyl group or 2 to 4 linear or branched alkynyl group). A linear or branched alkenyl group is represented. A is preferably a 3-methyl-2-buten-1-yl group or a 4-hydroxy-3-methyl-2-buten-1-yl group.

In the compound of the formula (I) of the present invention, B is a hydrogen atom, a halogen atom, —N (R ⁴ ) (R ⁵ ), ═N—OR ⁶ , ═N—OH, a hydroxy group (hydrogen of a hydroxy group) The atom is a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkenyl group having 2 to 4 carbon atoms, or a linear or branched alkynyl group having 2 to 4 carbon atoms. Or an oxo group, wherein R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, carbon Represents a linear or branched alkenyl group having 2 to 6 carbon atoms, or a linear or branched alkynyl group having 2 to 6 carbon atoms, or R ⁴ and R ⁵ together represent 3 to 8 members. Represents a ring, and R ⁶ represents a linear or branched alkyl having 1 to 8 carbon atoms. Represents a ru group (which may be substituted with an amino group which may be mono- or di-substituted with a linear or branched alkyl group having 1 to 4 carbon atoms). The 3- to 8-membered ring represented by R ⁴ and R ^{5 taken} together is at least one hetero ring selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to the nitrogen atom to which R ⁴ and R ⁵ are bonded. Represents a 3- to 8-membered monocyclic or bicyclic saturated or unsaturated carbocyclic ring which may contain atoms as ring atoms, and examples of such rings include rings such as piperidine, piperazine and morpholine. Can do.

In the compound of the formula (I) of the present invention, C is a C7 linear or branched alkyl group which may be substituted with a hydroxy group, or a carbon number which may be substituted with a hydroxy group. A linear or branched alkenyl group or a linear or branched alkynyl group having 7 carbon atoms which may be substituted with a hydroxy group, wherein the hydrogen atom of each hydroxy group has 1 to 4 carbon atoms. A linear or branched alkyl group, a linear or branched alkenyl group having 2 to 4 carbon atoms, or a linear or branched alkynyl group having 2 to 4 carbon atoms. Good. C is preferably a 1-heptenyl group, a 2-hepten-1-yl group, an n-heptyl group, a 1-hydroxy-2-hepten-1-yl group, or a 2-hydroxy-n-heptyl group.
In the compound of the formula (I) of the present invention, the bond Q represents a single bond or a double bond. Preferably, the bond Q is a double bond.

  Preferred compounds of formula (I) of the present invention include the following compounds.

Among the preferred compounds of formula (I) above, R ¹ , R ² , and R ³ are each a hydroxy group or —OZ group, where Z is as described in formula (I) A compound or a prodrug thereof, or a pharmaceutically acceptable salt thereof can be mentioned. Furthermore, the following compounds or their prodrugs, or pharmaceutically acceptable salts thereof, wherein R ¹ , R ² and R ³ are each a hydroxy group, can be particularly preferably mentioned.

  The compound of the formula (I) of the present invention belongs to a filamentous fungus and can produce the above compounds 1 to 7, for example, Fusarium sp. F1476 strain (hereinafter referred to as “F1476 strain”). Can be obtained by culturing and modifying the isolated compound as necessary. The physiological properties of the F1476 strain are as follows:

The growth temperature range is 10 to 30 ° C, preferably 20 to 30 ° C.
The growth possible pH range is 3 to 11, preferably 5 to 7.
The F1476 strain is designated as Fusarium sp. F 1476 and has been deposited with the Patent Organism Depositary, National Institute of Advanced Industrial Science and Technology as of April 4, 2003 under the deposit number FERM BP-8290.

  In the present invention, in addition to the F1476 strain described above, natural or artificial mutants of the F1476 strain, or other bacterial species belonging to filamentous fungi such as Fusarium, etc., which have the same productivity as the F1476 strain. The microorganism which has can be used.

  In the present invention, a culture can be obtained by inoculating the F1476 strain on a nutrient source-containing medium and culturing it. Among the nutrient sources, examples of the carbon source include glucose, fructose, saccharose, starch, dextrin, glycerin, molasses, starch syrup, fats and oils, and organic acids.

  Among the above nutrient sources, examples of nitrogen sources include soy flour, cottonseed flour, corn steep liquor, casein, peptone, yeast extract, meat extract, germ, urea, amino acids, ammonium salts and other organic nitrogen compounds, inorganic nitrogen A compound etc. can be mentioned.

Among the above nutrient sources, examples of the salts include inorganic salts such as sodium salts, potassium salts, calcium salts, magnesium salts, and phosphates. These may be used alone or in appropriate combination.
The above nutrient sources can be used alone or in appropriate combination.

  In the above nutrient source-containing medium, if necessary, heavy metal salts such as iron salt, copper salt, zinc salt and cobalt salt; vitamins such as biotin and vitamin B1; An organic substance, an inorganic substance, or the like can be added as appropriate.

  In addition to the nutrient source, an antifoaming agent such as silicone oil and polyalkylene glycol ether, a surfactant, and the like can be added to the nutrient source-containing medium as necessary.

  When culturing the strain producing the compound of the present invention in the above nutrient source-containing medium, culture such as solid culture and liquid culture, which is generally used for producing physiologically active substances by culturing microorganisms The method can be adopted.

  By the above-described culture method, the compound of the present invention is accumulated in the culture. In the present invention, the compounds accumulated in the culture can be separated from the culture by a known method and further purified as necessary.

  The separation can be performed by extracting the whole culture with a non-hydrophilic organic solvent such as ethyl acetate, butyl acetate, chloroform, butanol, methyl isobutyl ketone. In addition, the culture can be separated into a culture solution and cells by filtration or centrifugation, and then separated from each of the culture solution and cells.

  In order to separate the compound of the present invention from the separated culture broth, a method of extracting with the non-hydrophilic organic solvent can be employed, or the culture broth is brought into contact with an adsorptive carrier to It is also possible to employ a method in which the compound is adsorbed on a carrier and then eluted with a solvent.

  Examples of the carrier include activated carbon, powdered cellulose, and adsorptive resin. The solvent can be used singly or in combination of two or more depending on the type and nature of the carrier, for example, an aqueous solution of a water-soluble organic solvent such as hydrous acetone or hydrous alcohol, etc. The thing etc. can be mentioned.

  In order to separate the compound of the present invention from the separated cells, a method of extracting with a hydrophilic organic solvent such as acetone can be employed.

  In the present invention, the crude extract of the compound of the present invention thus separated from the culture can be subjected to a further purification step as necessary.

  The above purification can be performed by a method usually used for separation and purification of a fat-soluble physiologically active substance. Examples of such a method include a column using a carrier such as silica gel, activated alumina, activated carbon, and adsorbent resin. Examples thereof include a chromatography method and a high performance liquid chromatography method. When the column chromatography method using silica gel as a carrier is employed, examples of the elution solvent include chloroform, ethyl acetate, methanol, acetone, water and the like, and these can be used in combination of two or more. .

  When employing the high performance liquid chromatography method, examples of the carrier include chemically bonded silica gel bonded with an octadecyl group, octyl group, phenyl group, etc .; a polystyrene-based porous polymer gel, and the like as a mobile phase. For example, a water-containing aqueous solution of a water-soluble organic solvent such as water-containing methanol or water-containing acetonitrile can be used.

The compound of this invention can be manufactured by culture | cultivating the strain which produces the compounds 1-7 as mentioned above, and isolating said compounds 1-7 from a culture after that. Furthermore, various derivatives can be obtained using the above-described isolated compounds as starting materials and the methods described below.
Manufacturing method 1
The isolated compound is hydrogenated in a solvent such as methanol, ethanol, ethyl acetate or tetrahydrofuran in the presence of a catalyst such as palladium palladium, palladium hydroxide or Raney nickel at room temperature or under heating conditions to obtain a dihydro form. (A compound in which Q is a single bond or a compound in which a double bond of another carbon chain is dihydrolated) can be obtained.
Manufacturing method 2
The isolated compound is mixed with sodium borohydride, sodium trimethoxyborohydride, sodium cyanoborohydride, lithium borohydride, diethylaluminum sodium hydride, hydrogen in a solvent such as methanol, ethanol, propanol or tetrahydrofuran. An alcohol form (such as a compound in which B is a hydroxy group) can be obtained by reduction at room temperature or under cooling conditions in the presence of a reducing agent such as aluminum lithium iodide.
Manufacturing method 3
Dealkenylation by treating the isolated compound in a solvent such as methanol, dioxane, tetrahydrofuran or water in the presence of hydrochloric acid, sulfuric acid, methanesulfonic acid, trifluoroacetic acid or the like at room temperature or under cooling conditions. A body (such as a compound in which A is hydrogen) can be obtained. Furthermore, this dealkenylated compound is hydrogenated in a solvent such as methanol, ethanol, ethyl acetate, tetrahydrofuran in the presence of a catalyst such as palladium carbon, palladium hydroxide, Raney nickel, platinum oxide, at room temperature or under heating conditions. By doing so, a dihydro form (such as a compound in which Q is a single bond and A is hydrogen) can be obtained.
Manufacturing method 4
The above dealkenylated compound is reacted with an alkyl halide in the presence of a base such as sodium hydroxide, potassium hydroxide, calcium carbonate, potassium carbonate, in a solvent such as dimethylformamide (DMF), tetrahydrofuran at room temperature or under heating conditions. Treatment with an alkyl, alkenyl or alkynylating agent such as an allyl halide, alkynyl halide, etc. to give the desired tetraalkyl, tetraalkynyl or tetraalkenylated compound (a compound wherein A is alkyl, alkenyl or alkynyl, and / or Z Is a compound in which is alkyl, alkynyl or alkenyl.
In addition, the isolated compound may be reacted with alkyl, alkynyl in the presence of a base such as sodium hydroxide, potassium hydroxide, calcium carbonate, potassium carbonate in a solvent such as methanol, dioxane, tetrahydrofuran, water, at room temperature or under heating conditions. Alternatively, an alkyl, alkynyl or alkenylated compound (such as a compound in which A is alkyl, alkynyl or alkenyl) can be synthesized by treating with an alkenylating agent.
Manufacturing method 5
In the presence of a base such as diisopropylethylamine or triethylamine in a solvent such as dimethylformamide (DMF) or tetrahydrofuran, the isolated compound and various amines are mixed with dicyclohexylcarbodiimide (DCC) or water-soluble carbodiimide hydrochloride (WSC / HCl). ) And 1-hydroxybenzotriazole (HOBt) and the like to obtain a corresponding triamide (R ¹ = R ² = R ³ = amino group, etc.) at room temperature or under heating conditions. be able to.

Manufacturing method 6
By hydrogenating the isolated compound in a solvent such as methanol, ethanol, ethyl acetate or tetrahydrofuran in the presence of a catalyst such as palladium carbon, palladium hydroxide, Raney nickel or platinum oxide at room temperature or under heating conditions. Tetrahydro forms (such as compounds in which Q is a single bond) can be obtained.
Manufacturing method 7
By reacting the isolated compound with various alcohols (Z-OH) having the desired group Z with a condensing agent such as dicyclohexylcarbodiimide (DCC) in a solvent such as tetrahydrofuran, DMF and dichloromethane at room temperature or Corresponding triesters (such as compounds where R ¹ = R ² = R ³ = OZ) can be obtained under heating conditions. Alternatively, the isolated compound is treated with an amide dihydro form trimethylsilyldiazomethane (TMSCHN ₂ ) or the like in a mixed solvent such as methanol and dichloromethane to obtain a trimethyl ester form (R ¹ = R ² = R ³ = OCH ₃ ). A compound can be obtained.
Manufacturing method 8
By treating the trimethyl ester obtained in Production Method 7 with a hydrazine derivative such as 4-toluenesulfonyl hydrazide in a solvent such as methanol, ethanol and butanol, the corresponding hydrazide is obtained at room temperature or under heating conditions. The hydrazide is treated with a reducing agent such as catecholborane, and then dehydrated in the presence of a base such as lithium hydroxide, sodium hydroxide, or potassium hydroxide in a solvent such as ethanol, methanol, and water at room temperature or under heating conditions. A keto form (compound in which B is hydrogen) can be obtained.
Manufacturing method 9
By treating the isolated compound and hydroxylamine or various O-substituted hydroxylamines in the presence of pyridine, triethylamine, diisopropylethylamine or the like at room temperature or under heating conditions, the corresponding oxime ether and oxime compound (B = N-OR ⁶ and ═N—OH, etc.) can be obtained. R ⁶ represents a linear or branched alkyl group having 1 to 8 carbon atoms (an amino group optionally mono- or disubstituted with a linear or branched alkyl group having 1 to 4 carbon atoms). It may be substituted with
Manufacturing method 10
The isolated compound is treated with N, N-diethylaminosulfur trifluoride (DAST) or the like in a solvent such as tetrahydrofuran, dichloromethane or chloroform to give a halide (such as a compound in which B is a halogen such as fluorine). Can be obtained.
Manufacturing method 11
Sodium cyanoborohydride or sodium triacetoxyborohydride such as sodium cyanoborohydride or sodium triacetoxyborohydride in a solvent such as ethanol, methanol and tetrahydrofuran under neutral or weakly acidic conditions at room temperature or under heating conditions By treating with a reducing agent, a reductive amination can be carried out to obtain a corresponding amine compound (such as a compound having B = —N (R ⁴ ) (R ⁵ )). R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkenyl group having 2 to 6 carbon atoms, or It represents a straight or branched alkynyl group having 2 to 6 carbon atoms, or R ⁴ and R ⁵ together represent a 3 to 8 membered ring.
Said manufacturing method can be implemented in combination suitably according to the target compound of the formula (I).

  The thus obtained compound of the formula (I) of the present invention can be used as a pharmaceutical composition as it is, as a prodrug thereof, or as a pharmaceutically acceptable salt. The amount of the active ingredient compound contained in the pharmaceutical composition is not particularly limited and is appropriately selected over a wide range, and is, for example, 0.1 to 99.5% by weight, preferably 0.5 to 90% by weight.

The compound of formula (I) of the present invention or a prodrug thereof, or a pharmaceutically acceptable salt thereof is prepared according to a conventional method by using an excipient, a binder, a disintegrant, a lubricant, a flavoring agent, a solubilizing agent. Formulation into a dosage form suitable for oral administration, intra-tissue administration, topical administration, rectal administration, etc., using known adjuvants that can be generally used in the pharmaceutical formulation technical field such as suspensions, coatings, etc. can do. In addition to the above-mentioned auxiliary agents, coloring agents, preservatives, fragrances, flavoring agents, sweetening agents, and other auxiliary agents as well as other pharmaceuticals may be included as necessary.
Examples of dosage forms suitable for oral administration include tablets, dragees, pills, capsules, drops, sublinguals, powders, powders, liquids for drinking, and other dosage forms. Furthermore, the tablet can be made into a tablet coated with a normal coating, for example, a sugar-coated tablet, a gelatin-encapsulated tablet, an enteric tablet, a film-coated tablet, a double tablet, or a multilayer tablet as necessary. When preparing into the form of a tablet, a conventionally well-known thing can be widely used as a support | carrier in this field | area. Such carriers include, for example, excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid; water, ethanol, propanol, simple syrup, glucose solution, starch Liquid, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders; dried starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, lauryl Disintegrators such as sodium sulfate, monostearate monoglyceride, starch, lactose; disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil; absorption accelerators such as quaternary ammonium salts and sodium lauryl sulfate; Phosphorus, moisturizing agents such as starch; starch, lactose, kaolin, bentonite, adsorbents such as colloidal silicic acid; purified talc, stearates, boric acid powder, such as lubricants such as polyethylene glycol can be exemplified.
In preparing the pill form, a wide variety of carriers conventionally known in this field can be used. Examples of such carriers include excipients such as glucose, lactose, cocoa butter, starch, hydrogenated vegetable oil, kaolin and talc; binders such as gum arabic powder, tragacanth powder, gelatin and ethanol; disintegrants such as laminaran agar Etc. can be exemplified.
These preparations for oral administration can be administered in solid, powder or liquid dosage units.

Examples of dosage forms suitable for intra-tissue administration include injections.
When prepared as an injection, it can be in the form of a solution, emulsion, suspension or the like. They are preferably sterilized and isotonic with blood. In preparing in the form of these solutions, emulsions and suspensions, those conventionally used in this field as diluents can be used. As such a diluent, for example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like can be used. A sufficient amount of sodium chloride, glucose, or glycerin to prepare an isotonic solution, and usual solubilizers, buffers, pH adjusters, soothing agents, and the like can also be blended. These solutions, emulsions and suspensions can be used to dilute a certain amount of a compound of formula (I) of the present invention or a prodrug thereof, or a pharmaceutically acceptable salt thereof as an aqueous or oily non-toxic dilution as described above. It can be prepared by dissolving or suspending in an agent, adding an isotonic agent, if necessary, and sterilizing. These injections can be administered subcutaneously, intramuscularly or intravenously.
Examples of dosage forms suitable for topical administration include topical preparations such as topical solutions, creams, powders, pastes, gels and ointments. These include a certain amount of a compound of formula (I) of the present invention or a prodrug thereof, or a pharmaceutically acceptable salt thereof, a fragrance, a colorant, a filler, a surfactant, It can be prepared by combining with one or more of a humectant, emollient, gelling agent, carrier, preservative, stabilizer and the like.
Suppositories can be mentioned as dosage forms suitable for rectal administration. In preparing a suppository, a variety of conventionally known base materials in this field can be used. Examples of such a substrate include low-melting-point substrates such as higher esters such as myristic palmitate, higher alcohols, polyethylene glycol, cocoa butter, gelatin, semi-synthetic glycerides, and mixtures thereof. Suppositories can be prepared by mixing the compound of the formula (I) of the present invention or a prodrug thereof, or a pharmaceutically acceptable salt thereof into a base as described above and molding.

  The pharmaceutical composition is preferably administered in dosage unit form, and is administered orally, intra-tissue (subcutaneous, intramuscular, intravenous, etc.), topical (transdermal etc.) or rectally. can do. Of course, the pharmaceutical composition is administered in a dosage form suitable for these administration methods.

  When the compound of the present invention or a prodrug thereof, or a pharmaceutically acceptable salt thereof is administered as a medicine, the dose as an antiviral agent depends on the patient's condition such as age and weight, administration route, nature and degree of disease. In general, for an adult human, the amount of active ingredient is in the range of 1 to 2000 mg per day. Depending on the patient's condition and the like, a dose below or above the above range can be administered. When administering a large amount, it is desirable to divide the dose into several times a day.

EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.
Example 1
A platinum loop from a slant culture of Fusarium sp. Strain F1476 was added to 100 ml of liquid medium (glucose 2%, glycerol 1.5%, potato starch 1%, polypeptone 0.25%, yeast extract 0.35%, carbonic acid. 0.5% calcium, 0.3% sodium chloride, 0.005% zinc sulfate heptahydrate, 0.0005% copper sulfate pentahydrate, 0.0005% manganese chloride tetrahydrate, 1% toast soya Inoculate 400 umbilical Erlenmeyer flasks with a volume of 500 ml and culture with shaking at 25 ° C. for 3 days (shaking at 220 rpm) to obtain a seed culture solution. 16 ml of this seed culture with a 500 ml navel containing solid medium (50 g of brown rice, 18 ml of SF1 solution (yeast extract 0.2%, sodium tartrate 0.1%, potassium dihydrogen phosphate 0.1%)) 400 Erlenmeyer flasks were inoculated and subjected to static culture at 27 ° C. for 10 days. 40 L of methanol was added to the culture cultured in this way, infiltrated overnight, allowed to stand, and then filtered. 20 L of methanol was added to the precipitate, and the mixture was allowed to stand overnight and filtered. The methanol extracts thus obtained were combined and concentrated, suspended in 3 L of water, adjusted to pH 6.3 with an aqueous sodium hydroxide solution, and extracted with 3 L of ethyl acetate. The aqueous layer was adjusted to pH 2.2 with hydrochloric acid and extracted with 3 L of ethyl acetate. The aqueous layer was extracted again with 2 L of ethyl acetate, combined with the first extract, and concentrated to dryness. This extract was dissolved in 500 ml of ethyl acetate, 500 ml of water was added, and the pH was adjusted to 10 with an aqueous sodium hydroxide solution, followed by partitioning. 300 ml of water was added to the ethyl acetate layer, and the pH was adjusted to 10 with an aqueous sodium hydroxide solution, followed by partitioning. The aqueous layers obtained by these partitioning operations were combined, adjusted to pH 2.1 with hydrochloric acid, and extracted sequentially with 500 ml and 350 ml of ethyl acetate. The ethyl acetate extract (850 ml) thus obtained was dried over anhydrous sodium sulfate and then concentrated to dryness to obtain 11.4 g of a crude extract.

  This was dissolved in a 50% acetonitrile aqueous solution, and fractions containing Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 7, and Compound 6 were obtained by ODS open column chromatography under Condition 1 shown below. . These were concentrated to dryness, dissolved in methanol, and fractionated ODS high performance liquid chromatography was repeated under the conditions 2 shown below, whereby fractions containing Compound 1 and Compound 2 (Fraction 1, 9.9 mg), Compound 4 And a fraction containing compound 5 (fraction 2, 5 mg), a fraction containing compound 3 (fraction 3, 0.7 mg), a fraction containing compound 7 (fraction 4, 10 mg), and a fraction containing compound 6 (fraction) 5, 5 mg) was obtained. Fraction 1 was subjected to preparative CN high performance liquid chromatography under the conditions 3 shown below to obtain a fraction containing compound 1 (fraction 1-1) and a fraction containing compound 2 (fraction 1-2). Fractions 1-1, 1-2 and 3 were concentrated under reduced pressure to give 2.0 mg of compound 1, 4.2 mg of compound 2 and 0.7 mg of compound 3 as colorless tar substances, respectively.

Condition 1: Condition for ODS open column chromatography Column: 250 g of ODS packing material (Preparative C18, 125A Bulk Packing Material, manufactured by Waters Co., Ltd.) on a glass column having an inner diameter of 5.5 cm and a length of 50 cm, and a packing height of 24 cm It filled so that it might become. It was equilibrated by passing acetonitrile containing 0.01% trifluoroacetic acid, wetting the filler, and passing 50% acetonitrile water containing 0.01% trifluoroacetic acid. did.
Sample addition and elution: 11.4 g of sample was dissolved in 100 ml of 50% acetonitrile water and added to the top of the column. Next, 50%, 60%, 70%, and 80% acetonitrile water added with 0.01% trifluoroacetic acid was added in an amount of 2 L each to elute the compound.

Condition 2: Conditioning equipment for preparative ODS high performance liquid chromatography: CCPP-D, MCPD-3600 system (Tosoh)
Column: CAPCELL PAK C18 (UG80, 20 mm x 250 mm) (manufactured by Shiseido)
Mobile phase: Solvent gradient elution with water containing 0.01% trifluoroacetic acid and acetonitrile containing 0.01% trifluoroacetic acid (15% acetonitrile to 98% acetonitrile, stepwise)

Condition 3: Preparative CN high performance liquid chromatography condition equipment: 306, 811C, 806 system (Gilson)
Column: CAPCELL PAK CN (SG120, 20 mm x 250 mm) (manufactured by Shiseido)
Mobile phase: 40% acetonitrile water with 0.1% formic acid (isocratic elution)

分子量 ６７５
ESI（LC/MSポジティブモード）６７６（M＋H⁺）
ESI（LC/MSネガティブモード）６７４（M−H^-)
¹H-NMR (メタノールd-4中)の化学シフト値d
0.89(3H, t, J=7Hz)、1.25-1.40(12H, m)、1.50(2H, m)、1.73(3H, s)、1.77(3H, s)、1.95-2.20(4H, m)、2.56(1H, d, J=16.5Hz)、2.85(1H, d, J=16.5Hz)、2.93(1H, dd, J=14, 9Hz)、3.14(1H, dd, J=14, 4.5Hz)、3.19(1H, d, J=8Hz)、3.38(1H, m)、4.17(1H,dd,J=6,9Hz)、4.48(2H, d, J=6Hz)、4.62(1H, dd, J=9, 4.5Hz)、5.34(1H, m)、5.42(1H, m)、5.54(3H, m)、6.78(2H, d, J=9Hz)、7.10(2H, d, J=9Hz) Physicochemical properties of Compound 1

Molecular weight 675
ESI (LC / MS positive mode) 676 (M + H ⁺ )
ESI (LC / MS negative mode) 674 (M−H ⁻ )
Chemical shift value d of ¹ H-NMR (in methanol d-4)
0.89 (3H, t, J = 7Hz), 1.25-1.40 (12H, m), 1.50 (2H, m), 1.73 (3H, s), 1.77 (3H, s), 1.95-2.20 (4H, m), 2.56 (1H, d, J = 16.5Hz), 2.85 (1H, d, J = 16.5Hz), 2.93 (1H, dd, J = 14, 9Hz), 3.14 (1H, dd, J = 14, 4.5Hz) 3.19 (1H, d, J = 8Hz), 3.38 (1H, m), 4.17 (1H, dd, J = 6, 9Hz), 4.48 (2H, d, J = 6Hz), 4.62 (1H, dd, J = 9, 4.5Hz), 5.34 (1H, m), 5.42 (1H, m), 5.54 (3H, m), 6.78 (2H, d, J = 9Hz), 7.10 (2H, d, J = 9Hz)

分子量 ６７５
ESI（LC/MSポジティブモード）６７６（M＋H⁺）
ESI（LC/MSネガティブモード）６７４（M−H^-）
¹H-NMR (メタノールd-4中)の化学シフト値d
0.89(3H, t, J=7Hz)、1.20-1.40(14H, m)、1.53(4H, m)、1.73(3H, s)、1.98(2H, m)、2.41(4H, m)、2.57(1H, d, J=16.5Hz)、2.83(1H, d, J=16.5Hz)、2.91(1H, dd, J=14, 9Hz)、3.15(1H, dd, J=14, 4.5Hz)、3.19(1H, d, J=8Hz)、3.99(2H,s)、4.57(2H, d, J=6Hz)、4.62(1H, dd, J=9, 4.5Hz)、5.53(2H, m)、5.70(1H, m)、6.80(2H, d, J=9Hz)、7.11(2H, d, J=9Hz) Physicochemical properties of Compound 2

Molecular weight 675
ESI (LC / MS positive mode) 676 (M + H ⁺ )
ESI (LC / MS negative mode) 674 (M−H ⁻ )
Chemical shift value d of ¹ H-NMR (in methanol d-4)
0.89 (3H, t, J = 7Hz), 1.20-1.40 (14H, m), 1.53 (4H, m), 1.73 (3H, s), 1.98 (2H, m), 2.41 (4H, m), 2.57 ( 1H, d, J = 16.5Hz), 2.83 (1H, d, J = 16.5Hz), 2.91 (1H, dd, J = 14, 9Hz), 3.15 (1H, dd, J = 14, 4.5Hz), 3.19 (1H, d, J = 8Hz), 3.99 (2H, s), 4.57 (2H, d, J = 6Hz), 4.62 (1H, dd, J = 9, 4.5Hz), 5.53 (2H, m), 5.70 (1H, m), 6.80 (2H, d, J = 9Hz), 7.11 (2H, d, J = 9Hz)

分子量 ６５７
ESI（LC/MSポジティブモード）６５８（M＋H⁺）
ESI（LC/MSネガティブモード）６５６（M−H^-）
¹H-NMR (メタノールd-4中)の化学シフト値d
0.90(3H, t, J=7Hz)、1.25-1.35(10H, m)、1.48(2H, m)、1.55(2H, m)、1.73(3H, s)、1.77(3H, s)、1.97(2H, m)、2.23(2H, m)、2.57(2H, t, J=8Hz)、2.57(1H, d, J=16.5Hz)、2.85(1H, d, J=16.5Hz)、2.92(1H, dd, J=14, 9Hz)、3.14(1H, dd, J=14, 4.5Hz)、3.19(1H, d, J=8Hz)、4.47(2H, d, J=6Hz)、4.62(1H, dd, J=9, 4.5Hz)、5.43(1H, m)、5.52(2H, m)、6.10(1H, d, J=16Hz)6.78(2H, d, J=9Hz)、6.92(1H, dt, J=16, 7.5Hz)、 7.11(2H, d, J=9Hz) Physicochemical properties of Compound 3

Molecular weight 657
ESI (LC / MS positive mode) 658 (M + H ⁺ )
ESI (LC / MS negative mode) 656 (M−H ⁻ )
Chemical shift value d of ¹ H-NMR (in methanol d-4)
0.90 (3H, t, J = 7Hz), 1.25-1.35 (10H, m), 1.48 (2H, m), 1.55 (2H, m), 1.73 (3H, s), 1.77 (3H, s), 1.97 ( 2H, m), 2.23 (2H, m), 2.57 (2H, t, J = 8Hz), 2.57 (1H, d, J = 16.5Hz), 2.85 (1H, d, J = 16.5Hz), 2.92 (1H , dd, J = 14, 9Hz), 3.14 (1H, dd, J = 14, 4.5Hz), 3.19 (1H, d, J = 8Hz), 4.47 (2H, d, J = 6Hz), 4.62 (1H, dd, J = 9, 4.5Hz), 5.43 (1H, m), 5.52 (2H, m), 6.10 (1H, d, J = 16Hz) 6.78 (2H, d, J = 9Hz), 6.92 (1H, dt , J = 16, 7.5Hz), 7.11 (2H, d, J = 9Hz)

Example 2
The fraction obtained in Example 1 (Fraction 2, 5 mg) was further subjected to preparative Phenyl high performance liquid chromatography under the condition 4 shown below to give a fraction containing Compound 4 (Fraction 2-1) and Compound 5. A fraction containing fraction (fraction 2-2) was obtained. Fractions 2-1 and 2-2 were concentrated in vacuo to give 1.1 mg of compound 4 and 0.6 mg of compound 5 as colorless tars, respectively.

Condition 4: Preparative Phenyl high performance liquid chromatography condition equipment: 306, 811C, 806 system (Gilson)
Column: YMC PAK Ph (120A, 20 mm x 250 mm) (manufactured by YMC)
Mobile phase: 48% acetonitrile water with 0.1% formic acid (isocratic elution)

分子量 ６７５
ESI（LC/MSポジティブモード）６７６（M＋H⁺）
ESI（LC/MSネガティブモード）６７４（M−H^-）
¹H-NMR (メタノールd-4中)の化学シフト値d
0.89(3H, t, J=7Hz)、1.20-1.40(14H, m)、1.53(4H, m)、1.83(3H, s)、1.96(2H, m)、2.42(4H, m)、2.57(1H, d, J=16.5Hz)、2.89(1H, d, J=16.5Hz)、2.91(1H, dd, J=14, 9Hz)、3.15(1H, dd, J=14, 4.5Hz)、3.20(1H, d, J=8Hz)、4.13(2H, s)、4.50(2H, d, J=6Hz)、4.63(1H, dd, J=9, 4.5Hz)、5.50(1H, m)、5.52(2H, m)、6.78(2H, d, J=9Hz)、7.10(2H, d, J=9Hz) Physicochemical properties of Compound 4

Molecular weight 675
ESI (LC / MS positive mode) 676 (M + H ⁺ )
ESI (LC / MS negative mode) 674 (M−H ⁻ )
Chemical shift value d of ¹ H-NMR (in methanol d-4)
0.89 (3H, t, J = 7Hz), 1.20-1.40 (14H, m), 1.53 (4H, m), 1.83 (3H, s), 1.96 (2H, m), 2.42 (4H, m), 2.57 ( 1H, d, J = 16.5Hz), 2.89 (1H, d, J = 16.5Hz), 2.91 (1H, dd, J = 14, 9Hz), 3.15 (1H, dd, J = 14, 4.5Hz), 3.20 (1H, d, J = 8Hz), 4.13 (2H, s), 4.50 (2H, d, J = 6Hz), 4.63 (1H, dd, J = 9, 4.5Hz), 5.50 (1H, m), 5.52 (2H, m), 6.78 (2H, d, J = 9Hz), 7.10 (2H, d, J = 9Hz)

分子量 ６７５
ESI（LC/MSポジティブモード）６７６（M＋H⁺）
ESI（LC/MSネガティブモード）６７４（M−H^-）
¹H-NMR (メタノールd-4中)の化学シフト値d
0.89(3H, t, J=7Hz)、1.20-1.35(12H, m)、1.42(4H, m)、1.52(2H, m)、1.73(3H, s)、1.77(3H, s)、1.96(2H, m)、2.40-2.50(4H, m)、2.57(1H, d, J=16.5Hz)、2.80(1H, d, J=16.5Hz)、2.91(1H, dd, J=14, 9Hz)、3.15(1H, dd, J=14, 4.5Hz)、3.20(1H, d, J=8Hz)、4.00(1H, s)、4.47(2H, d, J=6Hz)、4.63(1H, dd, J=9, 4.5Hz)、5.43(1H, m)、5.52(2H, m)、6.78(2H, d, J=9Hz)、7.10(2H, d, J=9Hz) Physicochemical properties of Compound 5

Molecular weight 675
ESI (LC / MS positive mode) 676 (M + H ⁺ )
ESI (LC / MS negative mode) 674 (M−H ⁻ )
Chemical shift value d of ¹ H-NMR (in methanol d-4)
0.89 (3H, t, J = 7Hz), 1.20-1.35 (12H, m), 1.42 (4H, m), 1.52 (2H, m), 1.73 (3H, s), 1.77 (3H, s), 1.96 ( 2H, m), 2.40-2.50 (4H, m), 2.57 (1H, d, J = 16.5Hz), 2.80 (1H, d, J = 16.5Hz), 2.91 (1H, dd, J = 14, 9Hz) 3.15 (1H, dd, J = 14, 4.5Hz), 3.20 (1H, d, J = 8Hz), 4.00 (1H, s), 4.47 (2H, d, J = 6Hz), 4.63 (1H, dd, J = 9, 4.5Hz), 5.43 (1H, m), 5.52 (2H, m), 6.78 (2H, d, J = 9Hz), 7.10 (2H, d, J = 9Hz)

Example 3
From the fraction 4 by subjecting the fractions obtained in Example 1 (fractions 4, 10 mg and fractions 5, 5 mg) to preparative ODS high performance liquid chromatography (neutral), respectively, under the conditions 5 shown below, respectively. Obtained a fraction (fraction 4-1) containing compound 7 and a fraction containing compound 6 (fraction 5-1) from fraction 5. Fractions 4-1 and 5-1 were concentrated in vacuo to give 1 mg of compound 7 and 1 mg of compound 6 as colorless tars, respectively.
Condition 5: Preparative ODS high performance liquid chromatography (neutral) condition equipment: 306, 811C, 806 system (Gilson)
Column: Mightysil RP18 GP (5μm, 20mm x 50mm) (manufactured by Kanto Chemical)
Mobile phase: Solvent gradient elution with 3 parts of water containing water, acetonitrile and 100 mM ammonium acetate (15% acetonitrile to 80% acetonitrile, final ammonium acetate concentration 10 mM)

分子量 ６５９
ESI（LC/MSポジティブモード）６６０（M＋H⁺）
ESI（LC/MSネガティブモード）６５８（M−H^-）
¹H-NMR (メタノールd-4中)の化学シフト値d
0.89(3H, t, J=7Hz)、1.20-1.40(14H, m)、1.72(3H, s)、1.77(3H, s)、1.98(2H, m)、2.04(2H, m)、2.19(2H, m)、2.51(1H, d, J=16.5Hz)、2.79(1H, d, J=16.5Hz)、2.97(1H, dd, J=14, 9Hz)、3.11(1H, dd, J=14, 4.5Hz)、3.18(1H, m)、3.52(1H, m)、4.46(2H, d, J=6Hz)、4.50(1H, dd, J=9, 4.5Hz)、5.43(3H, m)、5.57(2H, m)、6.78(2H, d, J=9Hz)、7.10(2H, d, J=9Hz) Physicochemical properties of Compound 6

Molecular weight 659
ESI (LC / MS positive mode) 660 (M + H ⁺ )
ESI (LC / MS negative mode) 658 (M−H ⁻ )
Chemical shift value d of ¹ H-NMR (in methanol d-4)
0.89 (3H, t, J = 7Hz), 1.20-1.40 (14H, m), 1.72 (3H, s), 1.77 (3H, s), 1.98 (2H, m), 2.04 (2H, m), 2.19 ( 2H, m), 2.51 (1H, d, J = 16.5Hz), 2.79 (1H, d, J = 16.5Hz), 2.97 (1H, dd, J = 14, 9Hz), 3.11 (1H, dd, J = 14, 4.5Hz), 3.18 (1H, m), 3.52 (1H, m), 4.46 (2H, d, J = 6Hz), 4.50 (1H, dd, J = 9, 4.5Hz), 5.43 (3H, m ), 5.57 (2H, m), 6.78 (2H, d, J = 9Hz), 7.10 (2H, d, J = 9Hz)

分子量 ６５９
ESI（LC/MSポジティブモード）６６０（M＋H⁺）
ESI（LC/MSネガティブモード）６５８（M−H^-）
¹H-NMR (メタノールd-4中)の化学シフト値d
0.89(3H, t, J=7Hz)、1.20-1.40(16H, m)、1.73(3H, s)、1.77(3H, s)、1.98(4H, m)、2.52(1H, d, J=16.5Hz)、2.79(1H, d, J=16.5Hz)、2.96(1H, dd, J=14, 9Hz)、3.11(1H, dd, J=14, 4.5Hz)、3.18(1H, m)、4.35(1H、m)、4.46(2H, d, J=6Hz)、4.51(1H, dd, J=9, 4.5Hz)、5.29(1H、m)、5.43(2H, m)、5.57(2H, m)、6.78(2H, d, J=9Hz)、7.13(2H, d, J=9Hz) Physicochemical properties of Compound 7

Molecular weight 659
ESI (LC / MS positive mode) 660 (M + H ⁺ )
ESI (LC / MS negative mode) 658 (M−H ⁻ )
Chemical shift value d of ¹ H-NMR (in methanol d-4)
0.89 (3H, t, J = 7Hz), 1.20-1.40 (16H, m), 1.73 (3H, s), 1.77 (3H, s), 1.98 (4H, m), 2.52 (1H, d, J = 16.5 Hz), 2.79 (1H, d, J = 16.5Hz), 2.96 (1H, dd, J = 14, 9Hz), 3.11 (1H, dd, J = 14, 4.5Hz), 3.18 (1H, m), 4.35 (1H, m), 4.46 (2H, d, J = 6Hz), 4.51 (1H, dd, J = 9, 4.5Hz), 5.29 (1H, m), 5.43 (2H, m), 5.57 (2H, m ), 6.78 (2H, d, J = 9Hz), 7.13 (2H, d, J = 9Hz)

Test example 1
Replicon assay In order to quantify the copy number of HCV-RNA, a HCV-RNA in which a firefly-derived luciferase gene was introduced as a reporter gene was constructed. According to the method of Krieger et al. (J. Virol. 75: 4614), the luciferase gene was introduced in the form of fusing with the neomycin resistance gene directly under the IRES (Internal Ribosome Entry Site) of the HCV gene. After synthesizing the RNA in vitro, it was introduced into Huh7 cells by electroporation and isolated as a G418 resistant clone. Firefly luciferase HCV replicon cells (3-1) were suspended in Dulbecco's MEM (Gibco cat. No. 10569-010) containing 5% fetal calf serum (Hyclone cat. No. SH30071.03), and 5000 cells were plated in a 96-well plate. Cells / well were seeded and cultured overnight at 37 ° C. with 5% CO ₂ . After about 20 hours, 10 μl of diluted test compound was added per well and further cultured for 3 days. Two assay plates were prepared, one was a white plate and the other was a clear plate. After completion of the culture, the white plate was used for Steady-Glo Luciferase Assay System (Promega cat. No. E2520). That is, 100 μl of reagent was added per well, mixed with a pipette 3 to 4 times, allowed to stand for 5 minutes, and luminescence was measured with 1450 MicroBeta TRILUX (WALLAC). The IC ₅₀ (50% inhibitory concentration) of the drug was calculated by subtracting the value with no cell added from all the values as the background, and setting the value with no test compound added to 0% inhibition.

Test example 2
Cytotoxicity test Cell counting kit-8 (Dojindo catalog No. CK04) was used for the measurement of cytotoxicity. That is, 10 μl of Cell counting kit-8 was added to the clear plate and incubated at 37 ° C. for 30-60 minutes. Absorbance was measured with a 96-well plate reader at a wavelength of 450 nm and a control wavelength of 630 nm. The value of no added cells was subtracted from all the values as a background, and the value of no added drug was taken as 0% inhibition to calculate the CC ₅₀ (50% cell inhibitory concentration) of the drug.
The results of Test Examples 1 and 2 are shown below.

Claims (8)

Formula (I):

[Wherein R ¹ , R ² , and R ³ are the same or different and are mono- or di-substituted with a hydrogen atom, a hydroxy group, an amino group (a linear or branched alkyl group having 1 to 4 carbon atoms). -OZ, a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkenyl group having 2 to 4 carbon atoms, or a linear chain having 2 to 4 carbon atoms Or a branched alkynyl group;
Z represents a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkenyl group having 2 to 4 carbon atoms, or a linear or branched alkynyl group having 2 to 4 carbon atoms. Represents a group;
A represents a hydrogen atom or a hydroxy group (the hydrogen atom of the hydroxy group is a linear or branched alkyl group having 1 to 4 carbon atoms or a linear or branched alkenyl group having 2 to 4 carbon atoms). A linear or branched alkenyl group having 5 carbon atoms which may be further substituted with a group, or an optionally substituted linear or branched alkynyl group having 2 to 4 carbon atoms;
B is a hydrogen atom, a halogen atom, -N (R ⁴ ) (R ⁵ ), = N-OR ⁶ , = N-OH, a hydroxy group (the hydrogen atom of the hydroxy group is a straight chain having 1 to 4 carbon atoms or (Optionally substituted with a branched alkyl group, a linear or branched alkenyl group having 2 to 4 carbon atoms, or a linear or branched alkynyl group having 2 to 4 carbon atoms) or oxo R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, or a linear or branched chain group having 2 to 6 carbon atoms. Represents an alkenyl group or a linear or branched alkynyl group having 2 to 6 carbon atoms, or R ⁴ and R ⁵ together represent a 3 to 8 membered ring, and R ⁶ represents 1 to 8 linear or branched alkyl groups (straight or branched chain having 1 to 4 carbon atoms) An optionally substituted mono- or di-substituted amino group).
C is a linear or branched alkyl group having 7 carbon atoms which may be substituted with a hydroxy group, a linear or branched alkenyl group having 7 carbon atoms which may be substituted with a hydroxy group, or Represents a linear or branched alkynyl group having 7 carbon atoms which may be substituted with a hydroxy group (the hydrogen atom of each hydroxy group is a linear or branched alkyl group having 1 to 4 carbon atoms, carbon And may be further substituted with a linear or branched alkenyl group having 2 to 4 carbon atoms, or a linear or branched alkynyl group having 2 to 4 carbon atoms);
Bond Q represents a single bond or a double bond;
However, when A represents a hydrogen atom or an alkenyl group that is not substituted with a hydroxy group, is C a straight-chain or branched alkenyl group having 7 carbon atoms that may be substituted with a hydroxy group? Or a 2-hydroxy-n-heptyl group]
Or a prodrug thereof, or a pharmaceutically acceptable salt thereof. The following compounds:

[Wherein R ¹ , R ² and R ³ are as defined in formula (I) of claim 1]
The compound according to claim 1 or a prodrug thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: R ¹ , R ² , and R ³ are each a hydroxy group or an —OZ group, wherein Z is as defined in formula (I) of claim 1 or a pro thereof. Drugs, or pharmaceutically acceptable salts thereof. The compound according to claim 2 or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , and R ³ are each a hydroxy group.   A pharmaceutical composition comprising the compound according to any one of claims 1 to 4 or a prodrug thereof, or a pharmaceutically acceptable salt thereof.   The pharmaceutical composition according to claim 5 for preventing or treating a viral infection.   The pharmaceutical composition according to claim 6, wherein the viral infection is an HCV infection.   The pharmaceutical composition according to claim 7, wherein the HCV infection is hepatitis C.