JP2005089334A - 8-hydroxyadenine compound - Google Patents

Abstract

例えば、

で表される８−ヒドロキシアデニン化合物、それらの互変異性体、またはそれらの薬学上許容される塩。
【選択図】 なし
Disclosed is a topical drug for use in the treatment or prevention of viral diseases, cancer or allergic diseases.
Equation (1):

For example,

Or a tautomer thereof, or a pharmaceutically acceptable salt thereof.
[Selection figure] None

Description

    The present invention relates to a novel adenine compound useful as a therapeutic / preventive agent for viral diseases or allergic diseases.

Interferon is an endogenous protein that plays an important role in the immune system of mammals, and not only plays a part in the non-specific defense mechanism of the living body but is also greatly involved in the specific defense mechanism. Actually, interferon is used in clinical practice as a therapeutic agent for viral diseases such as hepatitis B and C. Low molecular weight organic compounds (interferon inducers) that induce interferon biosynthesis are being developed as next-generation interferon agents, and are imidazoquinoline derivatives (see Patent Document 1) and adenine derivatives (Patent Document 2 and Patent Documents). For example, imiquimod, which is an imidazoquinoline derivative, is used in clinical practice as an external antiviral agent for genital warts.
By the way, T cells that play a central role in the immune response in vivo are classified into two types, Th1 cells and Th2 cells, but interleukin-4 secreted by Th2 cells in the body of allergic disease patients. Cytokines such as (IL-4) and interleukin-5 (IL-5) are secreted excessively, and compounds that suppress the immune response of Th2 cells can be expected to be therapeutic agents for allergic diseases.
The imidazoquinoline derivatives and adenine derivatives are known to exhibit interleukin-4 (IL-4) and interleukin-5 (IL-5) production inhibitory activity as well as interferon-inducing activity. It is known to be effective in allergic diseases in models.
However, when these derivatives are used as antiallergic agents, there is a concern that systemic adverse effects based on interferon-inducing activity may become a problem.
US Patent Application No. 4689338 International Publication No. 98/01448 Pamphlet WO99 / 28321 pamphlet

  The problem to be solved by the present invention is to provide a locally administered drug characterized by suppressing systemic side reactions based on interferon-inducing activity. That is, when locally administered, a novel 8-hydroxyadenine compound characterized in that it is rapidly metabolized and changed to a low activity substance, and systemic pharmacological activity is reduced, comprising this as an active ingredient, It is to provide a drug for local administration used for treatment or prevention of viral diseases, cancer or allergic diseases.

    The present inventors are effective in treating diseases such as asthma, and when used externally as a spray or the like, they exhibit a strong effect at the administration site and show immune systemic diseases such as allergic diseases that do not show systemic side reactions. As a result of intensive studies to obtain an agent or a preventive agent, the 8-hydroxyadenine compound of the present invention was found. That is, the compound of the present invention is effective as a therapeutic or prophylactic agent for viral diseases, cancers, allergic diseases and the like with reduced systemic pharmacological activity. The present invention has been completed based on the above findings.

That is, the present invention
[1] Formula (1):

［式中、
環Ａは、ベンゼン環または５〜６員の単環性の芳香族複素環を表し、
ｍは、０または１を表し、
ｎは、０〜２の整数を表し、
Ｒは、ハロゲン原子、置換もしくは無置換のアルキル基、置換もしくは無置換のアルコキシ基、または置換もしくは無置換のアミノ基を表し、
ｎが２を表す場合、Ｒは同一もしくは異なっていてもよく、
Ｘ^１は酸素原子、硫黄原子、ＮＲ^１（Ｒ^１は水素原子またはアルキル基を表す。）、または単結合を表し、
Ｙ^１及びＹ^２は、独立して、単結合またはアルキレンを表し、
Ｚはアルキレンを表し、
Ｑ^１は、水素原子、水酸基、アルコキシ基、ハロアルキル基、ハロアルコキシ基または以下の置換基群から選択される任意の置換基を表し、
Ｑ^２は、以下の置換基群から選択される任意の置換基を表し、
Ｑ^１及びＱ^２の少なくとも一つは、−ＰＯ(ＯＲ^２)(ＯＲ^３)を表す。
置換基群：−ＰＯ(ＯＲ^２)(ＯＲ^３)；−ＣＯＯＲ^４；−ＣＯＳＲ^４；−ＣＯＮＲ^５Ｒ^６（式中、Ｒ^２及びＲ^３は独立して、置換もしくは無置換のアルキル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のアルケニル基、または置換もしくは無置換のアルキニル基を表すか、あるいはＲ^２及びＲ^３が結合して隣接する−ＯＰ(＝Ｏ)Ｏ−と共に、５〜８員環を形成していてもよく、Ｒ^４は、置換もしくは無置換のアルキル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のアルケニル基、または置換もしくは無置換のアルキニル基を表し、Ｒ^５及びＲ^６は独立して、水素原子、置換もしくは無置換のアルキル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のアルケニル基、または置換もしくは無置換のアルキニル基を表すか、あるいはＲ^５及びＲ^６が結合して、隣接する窒素原子と共に置換もしくは無置換の５〜７員の含窒素複素環を形成していてもよい。）]
で表される８−ヒドロキシアデニン化合物、またはそれらの薬学上許容される塩。
［２］式（１）において、Ｑ^１が、−ＰＯ(ＯＲ^２)(ＯＲ^３)を表す、［１］に記載の８−ヒドロキシアデニン化合物、またはそれらの薬学上許容される塩、
［３］ 式（１）において、ｍが１を表し、Ｑ^２が、−ＰＯ(ＯＲ^２)(ＯＲ^３)を表す、［１］に記載の８−ヒドロキシアデニン化合物、またはそれらの薬学上許容される塩、
［４］ 式（１）において、Ｘ^１が、単結合を表す、［１］〜［３］のいずれかに記載の８−ヒドロキシアデニン化合物、またはそれらの薬学上許容される塩、
［５］ 式（１）において、Ｚがメチレンを表し、環Ａがベンゼン環を表す、［１］〜［４］のいずれかに記載の８−ヒドロキシアデニン化合物、またはそれらの薬学上許容される塩、
［６］ ［１］〜［５］のいずれかに記載の８−ヒドロキシアデニン化合物、またはその薬学上許容される塩を有効成分として含有する医薬、
［７］ ［１］〜［５］のいずれかに記載の８−ヒドロキシアデニン化合物、またはその薬学上許容される塩を有効成分として含有する医薬組成物、
［８］ ［１］〜［５］のいずれかに記載の８−ヒドロキシアデニン化合物、またはその薬学上許容される塩を有効成分として含有する免疫調節剤、
［９］ ［１］〜［５］のいずれかに記載の８−ヒドロキシアデニン化合物、またはその薬学上許容される塩を有効成分として含有するウイルス性疾患治療剤または予防剤、
［１０］ ［１］〜［５］のいずれかに記載の８−ヒドロキシアデニン化合物、またはその薬学上許容される塩を有効成分として含有するアレルギー性疾患治療剤または予防剤、
［１１］ ［１］〜［５］のいずれかに記載の８−ヒドロキシアデニン化合物、またはその薬学上許容される塩を有効成分として含有する癌疾患治療剤または予防剤、
［１２］ ［１］〜［５］のいずれかに記載の８−ヒドロキシアデニン化合物、またはその薬学上許容される塩を有効成分として含有する局所投与用薬剤、
に関するものである。

[Where:
Ring A represents a benzene ring or a 5- to 6-membered monocyclic aromatic heterocycle,
m represents 0 or 1;
n represents an integer of 0 to 2,
R represents a halogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, or a substituted or unsubstituted amino group;
when n represents 2, R may be the same or different;
X ¹ represents an oxygen atom, a sulfur atom, NR ¹ (R ¹ represents a hydrogen atom or an alkyl group), or a single bond,
Y ¹ and Y ² independently represent a single bond or alkylene,
Z represents alkylene,
Q ¹ represents a hydrogen atom, a hydroxyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group or an arbitrary substituent selected from the following substituent group:
Q ² represents an arbitrary substituent selected from the following substituent group,
At least one of Q ¹ and Q ² represents —PO (OR ² ) (OR ³ ).
Substituent ^{Group: -PO (OR 2) (OR} 3); - COOR 4; -COSR 4; -CONR 5 R 6 ( wherein, ^{R 2} and ^{R 3} are independently substituted or unsubstituted alkyl group, Represents a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkynyl group, or R ² and R ³ are bonded together with the adjacent —OP (═O) O— , R ⁴ may be a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkynyl. R ⁵ and R ⁶ independently represent a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkenyl group, and Represents a substituted or unsubstituted alkynyl group, or R ⁵ and R ⁶ may combine together to form a substituted or unsubstituted 5- to 7-membered nitrogen-containing heterocyclic ring together with the adjacent nitrogen atom. )]
The 8-hydroxyadenine compound represented by these, or those pharmaceutically acceptable salts.
[2] An 8-hydroxyadenine compound or a pharmaceutically acceptable salt thereof according to [1], wherein in formula (1), Q ¹ represents —PO (OR ² ) (OR ³ ),
[3] The 8-hydroxyadenine compound according to [1], wherein m represents 1 and Q ² represents —PO (OR ² ) (OR ³ ) in formula (1), or a pharmaceutically acceptable salt thereof Salt,
[4] The 8-hydroxyadenine compound according to any one of [1] to [3], or a pharmaceutically acceptable salt thereof, wherein, in the formula (1), X ¹ represents a single bond,
[5] The 8-hydroxyadenine compound according to any one of [1] to [4], or a pharmaceutically acceptable salt thereof, wherein in formula (1), Z represents methylene and ring A represents a benzene ring. salt,
[6] A pharmaceutical comprising the 8-hydroxyadenine compound according to any one of [1] to [5], or a pharmaceutically acceptable salt thereof as an active ingredient,
[7] A pharmaceutical composition comprising the 8-hydroxyadenine compound according to any one of [1] to [5], or a pharmaceutically acceptable salt thereof as an active ingredient,
[8] An immunomodulator comprising the 8-hydroxyadenine compound according to any one of [1] to [5], or a pharmaceutically acceptable salt thereof as an active ingredient,
[9] A therapeutic or prophylactic agent for a viral disease containing the 8-hydroxyadenine compound according to any one of [1] to [5], or a pharmaceutically acceptable salt thereof as an active ingredient,
[10] A therapeutic or prophylactic agent for allergic diseases comprising the 8-hydroxyadenine compound according to any one of [1] to [5] or a pharmaceutically acceptable salt thereof as an active ingredient,
[11] A therapeutic or prophylactic agent for cancer diseases comprising the 8-hydroxyadenine compound according to any one of [1] to [5], or a pharmaceutically acceptable salt thereof as an active ingredient,
[12] A drug for topical administration containing the 8-hydroxyadenine compound according to any one of [1] to [5], or a pharmaceutically acceptable salt thereof as an active ingredient,
It is about.

  The present invention provides an adenine compound that is excellent as a drug for local administration, characterized by having a medicinal effect at the administration site and not showing systemic pharmacological action. This has made it possible to treat or prevent allergic diseases such as asthma and atopic dermatitis, and viral diseases such as herpes.

Hereinafter, embodiments of the present invention will be described in detail.
“Halogen atom” includes fluorine, chlorine, bromine or iodine. Preferably, fluorine or chlorine is used.

    Examples of the “alkyl group” include a linear or branched alkyl group having 1 to 10 carbon atoms. Specifically, methyl group, ethyl group, propyl group, 1-methylethyl group, butyl group, 2-methylpropyl group, 1-methylpropyl group, 1,1-dimethylethyl group, pentyl group, 3-methylbutyl group 2-methylbutyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 1,1-dimethylpropyl group, hexyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 1 -Methylpentyl group, 3,3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, heptyl group, 1-methylhexyl group, 1-ethylpentyl Group, octyl group, 1-methylheptyl group, 2-ethylhexyl group, nonyl group, decyl group and the like. Preferably, a C1-C6 alkyl group is mentioned, More preferably, a C1-C4 alkyl group is mentioned.

  Examples of the “cycloalkyl group” include a 3- to 8-membered monocyclic cycloalkyl group. Specific examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cycloheptyl group, and a cyclooctyl group.

    Examples of the “alkenyl group” include a C 2-8 linear or branched alkenyl group having 1 to 3 double bonds. Specifically, ethenyl group, 1-propenyl group, 2-propenyl group, 1-methylethenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 2-methyl-2-propenyl group, 1-pentenyl Group, 2-pentenyl group, 4-pentenyl group, 3-methyl-2-butenyl group, 1-hexenyl group, 2-hexenyl group, 1-octenyl group and the like. Preferably, an alkenyl group having 2 to 4 carbon atoms is used.

    Examples of the “alkynyl group” include a linear or branched alkynyl group having 2 to 8 carbon atoms having 1 or 2 triple bonds. Specifically, ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-methyl 2-propynyl group, 1-pentynyl group, 2-pentynyl group , 3-pentynyl group, 5-pentynyl group, 1-methyl-3-butynyl group, 1-hexynyl group, 2-hexynyl group and the like. Preferably, a C2-C4 alkynyl group is mentioned.

    Examples of the “alkoxy group” include linear or branched alkoxy groups having 1 to 10 carbon atoms. Specifically, methoxy group, ethoxy group, propoxy group, 1-methylethoxy group, butoxy group, 2-methylpropoxy group, 1-methylpropoxy group, 1,1-dimethylethoxy group, pentoxy group, 3-methylbutoxy Group, 2-methylbutoxy group, 2,2-dimethylpropoxy group, 1-ethylpropoxy group, 1,1-dimethylpropoxy group, hexyloxy group, 4-methylpentyloxy group, 3-methylpentyloxy group, 2- Methylpentyloxy group, 1-methylpentyloxy group, 3,3-dimethylbutoxy group, 2,2-dimethylbutoxy group, 1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group, heptyloxy group, 1- Methylhexyloxy group, 1-ethylpentyloxy group, octyloxy group, 1-methylheptyloxy group, 2-ethyl Hexyloxy group, nonyloxy or decyloxy group and the like. Preferably, a C1-C6 alkoxy group is mentioned, More preferably, a C1-C4 alkoxy group is mentioned.

Examples of the “haloalkyl group” include an alkyl group substituted with 1 to 5 identical or different halogen atoms. Specific examples include a trifluoromethyl group, 2,2,2-trifluoroethyl group, 2,2-difluoroethyl group, or pentafluoroethyl group.
The “haloalkoxy group” includes an alkoxy group substituted with 1 to 5 identical or different halogen atoms. Specific examples include a trifluoromethoxy group, 2,2,2-trifluoroethoxy group, 2,2-difluoroethoxy group, or pentafluoroethoxy group.

  Examples of “alkylene” include linear or branched alkylene having 1 to 6 carbon atoms. Specifically, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, 1-methylmethylene, 1-ethylmethylene, 1-propylmethylene, 1-methylethylene, 2-methylethylene, 1-methyltrimethylene , 2-methyltrimethylene, 2-methyltetramethylene, 3-methylpentamethylene and the like.

In the present specification, the substituted amino group represents a substituted or unsubstituted alkylamino group or a substituted or unsubstituted dialkylamino group, or two substituents of the substituted amino group are bonded to each other to form an adjacent nitrogen. A 5- to 7-membered nitrogen-containing heterocyclic ring may be formed together with the atom. Specific examples include a methylamino group, an ethylamino group, a dimethylamino group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, or a morpholinyl group.
Examples of the alkyl in the “alkylamino group” and “dialkylamino group” include the same alkyl groups as those described above.
Examples of the substituent when the alkylamino group or dialkylamino group is substituted include a halogen atom, a hydroxyl group, and an alkoxy group, and 1 to 3 identical or different substituents may be bonded. Specific examples of the substituent include fluorine, chlorine, methoxy group, ethoxy group, and propoxy group.

  In the present specification, the “5- to 7-membered nitrogen-containing heterocycle” is 1 to 2 selected from 1 to 2 nitrogen atoms, 0 or 1 oxygen atom and 0 or 1 sulfur atom. 5- to 7-membered saturated nitrogen-containing heterocycles containing the above heteroatoms. Specific examples include pyrrolidine, piperidine, piperazine, morpholine and the like.

  The “5- to 6-membered monocyclic aromatic heterocycle” in ring A is 1 to 2 selected from 0 to 2 nitrogen atoms, 0 to 1 oxygen atoms, and 0 to 1 sulfur atoms. 5-6 membered monocyclic aromatic heterocycles containing 3 heteroatoms. Specific examples include a pyrrole ring, a furan ring, a thiophene ring, a pyrazole ring, an imidazole ring, an oxazole ring, a thiazole ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, and a triazine ring. Preferably, a pyridine ring, a furan ring, a thiophene ring, etc. are mentioned.

Examples of the substituent in the case where the alkyl group or alkoxy group in R is substituted include a halogen atom, a hydroxyl group, and an alkoxy group, and the same or different, preferably 1 to 3, preferably 1 to 3 substituents. May be substituted. Specific examples include fluorine, chlorine, methoxy group, ethoxy group, and propoxy group.
Preferred examples of R include fluorine, chlorine, methyl group, ethyl group, methoxy group, ethoxy group, trifluoromethyl group, trifluoromethoxy group, and dimethylamino group.

“Alkylene” in Y ¹ is preferably alkylene having 1 to 4 carbon atoms, and specific examples include methylene, methylmethylene, dimethylmethylene, ethylene, 1-methylethylene, 2-methylethylene, and trimethylene.

“Alkylene” in Y ² is preferably alkylene having 1 to 4 carbon atoms, and specific examples include methylene, methylmethylene, dimethylmethylene, ethylene, 1-methylethylene, and 2-methylethylene.

  “Alkylene” in Z is preferably alkylene having 1 to 3 carbon atoms, and specific examples include methylene, methylmethylene, ethylene and the like.

The “alkoxy group” in Q ¹ is preferably a linear or branched alkoxy group having 1 to 4 carbon atoms, and specific examples include a methoxy group, an ethoxy group, and a propoxy group.

Q ¹ or Q ² is the following substituent group:
^{-PO (OR 2) (OR 3} ); - COOR 4; -COSR 4; and -CONR ⁵ R ^{6; (wherein, R 2, R 3, R} 4 and ^{R 5} are as defined above.)
When the alkyl group, cycloalkyl group, alkenyl group or alkynyl group in R ² , R ³ , R ⁴ and R ⁵ is substituted, the substituent may be a halogen atom, a hydroxyl group A substituted or unsubstituted alkoxy group, a substituted or unsubstituted amino group, a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted aromatic heterocyclic group. Preferably, it may be substituted with 1 to 3 substituents.
Examples of the substituent in the substituted alkoxy group include a halogen atom, a hydroxyl group, and an alkoxy group. Specifically, fluorine, chlorine, a methoxy group, an ethoxy group, or the like can be given.
Preferred examples of the substituted or unsubstituted amino group include a methylamino group, an ethylamino group, a dimethylamino group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, and a thiomorpholinyl group.

  Examples of the aromatic carbocyclic group include a phenyl group, a 1-naphthyl group, and a 2-naphthyl group.

The aromatic heterocyclic group is a 5- to 10-membered monocyclic group containing 1 to 4 heteroatoms selected from 0 to 4 nitrogen atoms, 0 to 1 oxygen atoms, and 0 to 1 sulfur atoms. Or a bicyclic aromatic heterocyclic group is mentioned. Specifically, pyrrolyl group, furyl group, thienyl group, pyrazolyl group, isoxazolyl group, isothiazolyl group, imidazolyl group, oxazolyl group, thiazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, indolyl group, benzofuranyl group, Benzothiophenyl group, indazolyl group, benzisoxazolyl group, benzisothiazolyl group, benzimidazolyl group, benzoxazolyl group, benzothiazolyl group, quinolyl group, isoquinolyl group, phthalazinyl group, quinazolinyl, quinoxalinyl group, etc. It is done. Here, the bonding position in the aromatic heterocyclic group is not particularly limited, and may be bonded on any nitrogen atom or carbon atom.
Preferred examples of the aromatic heterocyclic group include a 2-pyridyl group, a 3-pyridyl group, and a 4-pyridyl group.
Examples of the substituent when the substituted aromatic carbocyclic group or the substituted aromatic heterocyclic group is substituted include a halogen atom, a hydroxyl group, and an alkoxy group. Specifically, fluorine, chlorine, a methoxy group, an ethoxy group, or the like can be given.

When R ² and R ³ are combined to form a 5- to 8-membered ring with the adjacent —OP (═O) O—, it is represented by the following formula (5).

（式中、ｑは１〜３の整数を表す。）
Ｒ^５及びＲ^６が結合して、隣接する窒素原子と共に形成する５〜７員の含窒素複素環としては、１〜２の窒素原子、０〜１の酸素原子、及び０〜１の硫黄原子から選択される１〜３のヘテロ原子を含む、置換もしくは無置換の５〜７員の単環性の飽和含窒素複素環が挙げられる。具体的には、ピロリジニル基、ピペリジニル基、ピペラジニル基、ヘキサメチレンイミノ基、ホモピペラジニル基、モルホリニル基、またはチオモルホリニル基等が挙げられる。
前記飽和含窒素複素環が置換されている場合の置換基としては、ハロゲン原子、水酸基、アルキル基またはアルコキシ基等が挙げられる。具体的には、フッ素、塩素、メチル基、エチル基、メトキシ基、またはエトキシ基等が挙げられる。

(In the formula, q represents an integer of 1 to 3.)
The ^5- to 7-membered nitrogen-containing heterocyclic ring formed by combining R ⁵ and R ⁶ together with the adjacent nitrogen atom includes 1 to 2 nitrogen atoms, 0 to 1 oxygen atoms, and 0 to 1 sulfur atoms. And a substituted or unsubstituted 5- to 7-membered monocyclic saturated nitrogen-containing heterocycle containing 1 to 3 heteroatoms selected from Specific examples include a pyrrolidinyl group, piperidinyl group, piperazinyl group, hexamethyleneimino group, homopiperazinyl group, morpholinyl group, or thiomorpholinyl group.
Examples of the substituent when the saturated nitrogen-containing heterocycle is substituted include a halogen atom, a hydroxyl group, an alkyl group, and an alkoxy group. Specific examples include fluorine, chlorine, methyl group, ethyl group, methoxy group, and ethoxy group.

The adenine compound of the present invention is a concept including all tautomers, geometric isomers, and stereoisomers depending on the type of substituent, and may be a mixture thereof.
That is, when one or more asymmetric carbon atoms are present in the compound of formula (1), diastereomers and optical isomers exist, but mixtures or isolated ones of these diastereomers and optical isomers exist. Are also included in the present invention.
In addition, the adenine compound represented by the formula (1) and its tautomer are chemically equivalent, and the adenine compound of the present invention includes the tautomer. The tautomer is specifically represented by the formula (1 ′):

［式中、環Ａ、ｍ、ｎ、Ｒ、Ｘ^１、Ｙ^１、Ｙ^２、Ｚ、Ｑ^１、及びＱ^２は前記と同義である。］
で表されるオキソ体である。

[Wherein, ring A, m, n, R, X ¹ , Y ¹ , Y ² , Z, Q ¹ , and Q ² are as defined above]. ]
It is an oxo form represented by.

  Pharmaceutically acceptable salts include acid addition salts and base addition salts. For example, acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, phosphate, citrate, oxalate, acetate, formate Organic acid salts such as propionate, benzoate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, paratoluenesulfonate, etc. Inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt, organic base salts such as triethylammonium salt, triethanolammonium salt, pyridinium salt, diisopropylammonium salt, and the like, and arginine, Examples thereof include amino acid salts such as basic or acidic amino acids such as aspartic acid and glutamic acid. Further, the compound represented by the formula (1) may be a hydrate or a solvate such as an ethanol solvate.

  The compound represented by the formula (1) can be produced by the following method. The starting material compounds not described below can be produced according to the following method, or according to a known method or a method analogous thereto.

Manufacturing method 1

(式中、Ｑ^３はＱ^１、ホスホン酸基、カルボキシ基または水酸基を表し、Ｑ^４はＱ^２、ホスホン酸基、カルボキシ基または水酸基を表し、Ｌは脱離基を表し、環Ａ、ｍ、ｎ、Ｒ、Ｘ^１、Ｙ^１、Ｙ^２、Ｚ、Ｑ^１、及びＱ^２は前記と同義である。)
化合物(II)は、化合物(I)と化合物(X)とを塩基存在下、反応させることにより得ることができる。
塩基としては例えば、炭酸ナトリウムもしくは炭酸カリウム等のアルカリ金属炭酸塩、炭酸カルシウム等のアルカリ土類金属炭酸塩、水酸化ナトリウムもしくは水酸化カリウム等の金属水酸化物、水素化ナトリウム等の金属水素化物、またはt-ブトキシカリウム等の金属アルコキシド等を用いることができる。溶媒としては例えば、四塩化炭素、クロロホルムもしくは塩化メチレン等のハロゲン化炭化水素系溶媒、ジエチルエーテル、テトラヒドロフランもしくは１，４−ジオキサン等のエーテル系溶媒、またはジメチルホルムアミド、ジメチルスルホキシドもしくはアセトニトリル等の非プロトン性溶媒等を用いることができる。反応温度は例えば、約０℃から溶媒の沸点付近までの範囲から選択される。
化合物(IV)は、化合物(II)と化合物(XI)とを反応させることにより得ることができる。
Ｘ¹がＮＲ^１の場合は、塩基存在下または非存在下に反応させる。塩基としては例えば、炭酸ナトリウムもしくは炭酸カリウム等のアルカリ金属炭酸塩、炭酸カルシウム等のアルカリ土類金属炭酸塩、水酸化ナトリウムもしくは水酸化カリウム等の金属水酸化物、またはトリエチルアミン、ジイソプロピルエチルアミンもしくは4-ジメチルアミノピリジン等の有機塩基等を用いることができる。溶媒としては例えば、テトラヒドロフラン、１，４−ジオキサンもしくはジグライム等のエーテル系溶媒、プロパノールもしくはブタノールなどのアルコール系溶媒、またはジメチルホルムアミド等の非プロトン性溶媒等を用いることができ、あるいは無溶媒で行ってもよい。反応温度は例えば、約50℃から200℃までの範囲から選択される。
Ｘ¹が酸素原子または硫黄原子の場合は、塩基存在下に反応させる。塩基としては例えば、ナトリウムもしくはカリウム等のアルカリ金属、または水素化ナトリウム等のアルカリ金属水素化物等を用いることができる。溶媒としては例えば、テトラヒドロフラン、１，４−ジオキサンもしくはジグライム等のエーテル系溶媒、またはジメチルホルムアミドもしくはジメチルスルホキシド等の非プロトン性溶媒等を用いることができ、あるいは無溶媒で行ってもよい。反応温度は例えば、約50℃から200℃までの範囲から選択される。
なお、化合物(I)から化合物(IV)を製造する工程において、上記と同様の方法を用いて化合物(III)を合成し、化合物(II)の合成と同様の方法を用いて化合物(III)と化合物（X）とを反応させることにより化合物(IV)を得ることもできる。
また、化合物(IV)は下記に示した方法により得ることもできる。

(Wherein Q ³ represents Q ¹ , a phosphonic acid group, a carboxy group or a hydroxyl group, Q ⁴ represents Q ² , a phosphonic acid group, a carboxy group or a hydroxyl group, L represents a leaving group, and ring A, m , N, R, X ¹ , Y ¹ , Y ² , Z, Q ¹ , and Q ² are as defined above.)
Compound (II) can be obtained by reacting compound (I) with compound (X) in the presence of a base.
Examples of the base include alkali metal carbonates such as sodium carbonate and potassium carbonate, alkaline earth metal carbonates such as calcium carbonate, metal hydroxides such as sodium hydroxide and potassium hydroxide, and metal hydrides such as sodium hydride. Or a metal alkoxide such as t-butoxy potassium can be used. Examples of the solvent include halogenated hydrocarbon solvents such as carbon tetrachloride, chloroform and methylene chloride, ether solvents such as diethyl ether, tetrahydrofuran and 1,4-dioxane, or aprotic compounds such as dimethylformamide, dimethyl sulfoxide and acetonitrile. Can be used. The reaction temperature is selected, for example, from a range from about 0 ° C. to around the boiling point of the solvent.
Compound (IV) can be obtained by reacting compound (II) with compound (XI).
When X ¹ is NR ¹ , the reaction is carried out in the presence or absence of a base. Examples of the base include alkali metal carbonates such as sodium carbonate and potassium carbonate, alkaline earth metal carbonates such as calcium carbonate, metal hydroxides such as sodium hydroxide and potassium hydroxide, or triethylamine, diisopropylethylamine or 4- An organic base such as dimethylaminopyridine can be used. As the solvent, for example, an ether solvent such as tetrahydrofuran, 1,4-dioxane or diglyme, an alcohol solvent such as propanol or butanol, or an aprotic solvent such as dimethylformamide, or the like can be used. May be. The reaction temperature is selected, for example, from the range of about 50 ° C to 200 ° C.
When X ¹ is an oxygen atom or a sulfur atom, the reaction is carried out in the presence of a base. As the base, for example, an alkali metal such as sodium or potassium, or an alkali metal hydride such as sodium hydride can be used. As the solvent, for example, an ether solvent such as tetrahydrofuran, 1,4-dioxane or diglyme, an aprotic solvent such as dimethylformamide or dimethyl sulfoxide, or the like may be used, or the solvent may be used without a solvent. The reaction temperature is selected, for example, from the range of about 50 ° C to 200 ° C.
In the step of producing compound (IV) from compound (I), compound (III) is synthesized using the same method as described above, and compound (III) is synthesized using the same method as the synthesis of compound (II). Compound (IV) can also be obtained by reacting a compound with (X).
Compound (IV) can also be obtained by the method shown below.

すなわち、化合物(VIII)は、化合物(II)の合成と同様の方法を用いて化合物(XII)と化合物(X)とを反応させることにより得ることができる。
化合物(XIV)は、化合物(XIII)と化合物(XVII)とを塩基存在下、反応させることにより得ることができる。
塩基としては例えば、ナトリウムメトキシドもしくはナトリウムエトキシド等の金属アルコキシド等を用いることができる。溶媒としては例えば、ジエチルエーテルもしくはテトラヒドロフラン等のエーテル系溶媒、ジメチルホルムアミドもしくはアセトニトリル等の非プロトン性溶媒、またはメタノールもしくはエタノール等のアルコール系溶媒等を用いることができる。反応温度は例えば、室温から溶媒の沸点付近までの範囲から選択される。
化合物(XV)は、化合物(XIV)をクロロ化することにより得ることができる。
クロロ化剤としては例えば、塩化チオニル、またはオキシ塩化リン等を用いることができ、反応において例えば、ジメチルアニリン等の塩基を加えてもよい。溶媒としては例えば、四塩化炭素、塩化メチレンもしくはジクロロエタン等のハロゲン化炭化水素系溶媒、ジエチルエーテルもしくはテトラヒドロフラン等のエーテル系溶媒、またはアセトニトリル等の非プロトン性溶媒等を用いることができる。反応温度は例えば、約０℃から溶媒の沸点付近までの範囲から選択される。
化合物(IV)は、化合物(XV)をアンモニアと反応させることにより得ることができる。
溶媒としては例えば、テトラヒドロフラン、１，４−ジオキサンもしくはジグライム等のエーテル系溶媒、プロパノールもしくはブタノールなどのアルコール系溶媒、ジメチルホルムアミド等の非プロトン性溶媒、または水等を用いることができ、あるいは無溶媒で行ってもよい。反応温度は例えば、約50℃から200℃までの範囲から選択される。
化合物(V)は、化合物(IV)をブロモ化することにより得ることができる。
ブロモ化剤としては例えば、臭素、臭化水素酸ペルブロミド、またはN-ブロモサクシミド等を用いることができ、反応において例えば、酢酸ナトリウム等の反応助剤を加えてもよい。溶媒としては例えば、四塩化炭素、塩化メチレンもしくはジクロロエタン等のハロゲン化炭化水素系溶媒、ジエチルエーテル等のエーテル系溶媒、酢酸、または二硫化炭素等を用いることができる。反応温度は例えば、約０℃から溶媒の沸点付近までの範囲から選択される。
化合物(VI)は、化合物(V)とナトリウムメトキシド等の金属アルコキシド等を反応させることにより得ることができる。
溶媒としては例えば、ジエチルエーテル、テトラヒドロフランもしくは１，４−ジオキサン等のエーテル系溶媒、ジメチルホルムアミド等の非プロトン性溶媒、または用いられる金属アルコキシドに対応するメタノール等のアルコール系溶媒等を用いることができる。反応温度は例えば、室温から溶媒の沸点付近までの範囲から選択される。
化合物(VII)は、化合物（VI）あるいは化合物(V)を酸性条件下で処理することにより得ることができる。
酸としては例えば、塩酸、臭化水素酸もしくは硫酸等の無機酸、またはトリフルオロ酢酸等の有機酸等を用いることができる。溶媒としては例えば、水、または、水と有機溶媒との混合溶媒を用いることができる。前記有機溶媒としては、ジエチルエーテルもしくはテトラヒドロフラン等のエーテル系溶媒、ジメチルホルムアミドもしくはアセトニトリル等の非プロトン性溶媒、またはメタノールもしくはエタノール等のアルコール系溶媒等が挙げられる。反応温度は例えば、室温から溶媒の沸点付近までの範囲から選択される。
また、化合物(I)から化合物(VII)を製造する工程において、前述と同様の方法を用いて、順に化合物(VIII)、化合物(IX)を合成し、化合物(VII)を得ることもできる。

That is, compound (VIII) can be obtained by reacting compound (XII) with compound (X) using the same method as the synthesis of compound (II).
Compound (XIV) can be obtained by reacting compound (XIII) and compound (XVII) in the presence of a base.
As the base, for example, metal alkoxide such as sodium methoxide or sodium ethoxide can be used. As the solvent, for example, an ether solvent such as diethyl ether or tetrahydrofuran, an aprotic solvent such as dimethylformamide or acetonitrile, or an alcohol solvent such as methanol or ethanol can be used. The reaction temperature is selected, for example, from a range from room temperature to around the boiling point of the solvent.
Compound (XV) can be obtained by chlorinating compound (XIV).
As the chlorinating agent, for example, thionyl chloride or phosphorus oxychloride can be used. For example, a base such as dimethylaniline may be added in the reaction. As the solvent, for example, a halogenated hydrocarbon solvent such as carbon tetrachloride, methylene chloride or dichloroethane, an ether solvent such as diethyl ether or tetrahydrofuran, or an aprotic solvent such as acetonitrile can be used. The reaction temperature is selected, for example, from a range from about 0 ° C. to around the boiling point of the solvent.
Compound (IV) can be obtained by reacting compound (XV) with ammonia.
As the solvent, for example, an ether solvent such as tetrahydrofuran, 1,4-dioxane or diglyme, an alcohol solvent such as propanol or butanol, an aprotic solvent such as dimethylformamide, water or the like can be used. You may go on. The reaction temperature is selected, for example, from the range of about 50 ° C to 200 ° C.
Compound (V) can be obtained by brominating compound (IV).
As the brominating agent, for example, bromine, perbromide hydrobromide, N-bromosuccinimide, or the like can be used. For example, a reaction aid such as sodium acetate may be added in the reaction. As the solvent, for example, a halogenated hydrocarbon solvent such as carbon tetrachloride, methylene chloride, or dichloroethane, an ether solvent such as diethyl ether, acetic acid, carbon disulfide, or the like can be used. The reaction temperature is selected, for example, from a range from about 0 ° C. to around the boiling point of the solvent.
Compound (VI) can be obtained by reacting compound (V) with a metal alkoxide such as sodium methoxide.
As the solvent, for example, an ether solvent such as diethyl ether, tetrahydrofuran or 1,4-dioxane, an aprotic solvent such as dimethylformamide, or an alcohol solvent such as methanol corresponding to the metal alkoxide used can be used. . The reaction temperature is selected, for example, from a range from room temperature to around the boiling point of the solvent.
Compound (VII) can be obtained by treating compound (VI) or compound (V) under acidic conditions.
As the acid, for example, an inorganic acid such as hydrochloric acid, hydrobromic acid or sulfuric acid, or an organic acid such as trifluoroacetic acid can be used. As the solvent, for example, water or a mixed solvent of water and an organic solvent can be used. Examples of the organic solvent include ether solvents such as diethyl ether or tetrahydrofuran, aprotic solvents such as dimethylformamide or acetonitrile, alcohol solvents such as methanol or ethanol, and the like. The reaction temperature is selected, for example, from a range from room temperature to around the boiling point of the solvent.
Further, in the step of producing compound (VII) from compound (I), compound (VIII) and compound (IX) can be synthesized in sequence using the same method as described above to obtain compound (VII).

Manufacturing method 2

(式中、Ｑ^３はＱ^１、ホスホン酸基、カルボキシ基または水酸基を表し、Ｑ^４はＱ^２、ホスホン酸基、カルボキシ基または水酸基を表し、Ｘ^２はアミノ基、水酸基、またはメルカプト基を表し、Ｌは脱離基を表し、環Ａ、ｍ、ｎ、Ｒ、Ｘ^１、Ｙ^１、Ｙ^２、Ｚ、Ｑ^１、及びＱ^２は前記と同義である。)
化合物(XIX)は、化合物(XVIII)と化合物(XXII)とを塩基存在下、反応させることにより得ることができる。
塩基としては例えば、炭酸ナトリウムもしくは炭酸カリウム等のアルカリ金属炭酸塩、炭酸カルシウム等のアルカリ土類金属炭酸塩、水酸化ナトリウムもしくは水酸化カリウム等の金属水酸化物、トリエチルアミン、ジイソプロピルエチルアミン、ピリジンもしくは4-ジメチルアミノピリジン等の有機塩基、またはナトリウムメトキシド等の金属アルコキシド等を用いることができる。溶媒としては例えば、塩化メチレン等のハロゲン化炭化水素系溶媒、ジエチルエーテル、テトラヒドロフランもしくは１，４−ジオキサン等のエーテル系溶媒、メタノールもしくはエタノール等のアルコール系溶媒、またはジメチルホルムアミド、ジメチルスルホキシドもしくはアセトニトリル等の非プロトン性溶媒等を用いることができる。反応温度は例えば、約０℃から溶媒の沸点付近までの範囲から選択される。
化合物(XX)は、化合物(XIX)と化合物(XXIII)とを塩基存在下または非存在下、反応させることにより得ることができる。
塩基としては例えば、炭酸ナトリウムもしくは炭酸カリウム等のアルカリ金属炭酸塩、炭酸カルシウム等のアルカリ土類金属炭酸塩、水酸化ナトリウムもしくは水酸化カリウム等の金属水酸化物等の無機塩基、トリエチルアミン、ジイソプロピルエチルアミン、ピリジンもしくは4-ジメチルアミノピリジン等の有機塩基、またはナトリウムメトキシド等の金属アルコキシド等を用いることができる。溶媒としては例えば、テトラヒドロフラン、１，４−ジオキサンもしくはジグライム等のエーテル系溶媒、メタノールもしくはエタノール等のアルコール系溶媒、またはトルエン、ジメチルホルムアミドもしくはジメチルスルホキシド等の非プロトン性溶媒等を用いることができ、あるいは無溶媒で行ってもよい。反応温度は例えば、室温から溶媒の沸点付近までの範囲から選択される。
なお、化合物(XIX)から化合物(XX)を製造する工程において、化合物(XXI)を合成し、化合物(XX)を得ることもできる。
Ｘ^２がアミノ基の場合、化合物(XXI)は、化合物(XIX)とグアニジンとを塩基存在下または非存在下、反応させることにより得ることができる。
塩基としては例えば、炭酸ナトリウムもしくは炭酸カリウム等のアルカリ金属炭酸塩、炭酸カルシウム等のアルカリ土類金属炭酸塩、水酸化ナトリウムもしくは水酸化カリウム等の金属水酸化物、トリエチルアミン、ジイソプロピルエチルアミン、ピリジンもしくは4-ジメチルアミノピリジン等の有機塩基、またはナトリウムメトキシド等の金属アルコキシド等を用いることができる。溶媒としては例えば、テトラヒドロフラン、１，４−ジオキサンもしくはジグライム等のエーテル系溶媒、メタノールもしくはエタノール等のアルコール系溶媒、またはトルエン、ジメチルホルムアミドもしくはジメチルスルホキシド等の非プロトン性溶媒等を用いることができ、あるいは無溶媒で行ってもよい。反応温度は例えば、室温から溶媒の沸点付近までの範囲から選択される。
Ｘ^２が水酸基の場合、化合物(XXI)は、化合物(XIX)と尿素とを塩基存在下または非存在下、反応させることにより得ることができる。塩基としては例えば、炭酸ナトリウムもしくは炭酸カリウム等のアルカリ金属炭酸塩、炭酸カルシウム等のアルカリ土類金属炭酸塩、水酸化ナトリウムもしくは水酸化カリウム等の金属水酸化物、トリエチルアミン、ジイソプロピルエチルアミン、ピリジンもしくは4-ジメチルアミノピリジン等の有機塩基、またはナトリウムメトキシド等の金属アルコキシド等を用いることができる。溶媒としては例えば、テトラヒドロフラン、１，４−ジオキサンもしくはジグライム等のエーテル系溶媒、メタノールもしくはエタノール等のアルコール系溶媒、または、トルエン、ジメチルホルムアミドもしくはジメチルスルホキシド等の非プロトン性溶媒等を用いることができ、あるいは無溶媒で行ってもよい。反応温度は例えば、室温から溶媒の沸点付近までの範囲から選択される。
Ｘ^２がメルカプト基の場合、化合物(XXI)は、化合物(XIX)とベンゾイルイソチオシアネートを塩基存在下または非存在下反応させてチオウレアとし、次いで環化反応を行うことにより得ることができる。
化合物(XIX)とベンゾイルイソチオシアネートとの縮合反応では、塩基としては例えば、炭酸ナトリウムもしくは炭酸カリウム等のアルカリ金属炭酸塩、炭酸カルシウム等のアルカリ土類金属炭酸塩、またはトリエチルアミン、ジイソプロピルエチルアミン、ピリジンもしくは4-ジメチルアミノピリジン等の有機塩基等を用いることができる。溶媒としては例えば、塩化メチレン等のハロゲン化炭化水素系溶媒、テトラヒドロフランもしくは１，４−ジオキサン等のエーテル系溶媒、またはジメチルホルムアミドもしくはジメチルスルホキシド等の非プロトン性溶媒等を用いることができる。反応温度は例えば、約0℃から溶媒の沸点付近までの範囲から選択される。
上記で得られるチオウレアを環化反応に供することによりピリミジン骨格を構築できる。すなわち、環化反応では、塩基としては例えば、水酸化ナトリウムもしくは水酸化カリウム等のアルカリ金属水酸化物、またはナトリウムメトキシドもしくはt-ブトキシカリウム等の金属アルコキシド等を用いることができる。溶媒としては例えば、テトラヒドロフラン等のエーテル系溶媒、エタノールもしくは２−プロパノール等のアルコール系溶媒、またはジメチルホルムアミドもしくはジメチルスルホキシド等の非プロトン系溶媒等を用いることができる。反応温度は例えば、約室温から溶媒の沸点付近までの範囲から選択される。
化合物(XX)は、化合物(XXI)と化合物(XVIV)とを塩基存在下、反応させることにより得ることができる。
塩基としては例えば、炭酸水素ナトリウム等のアルカリ金属炭酸水素塩、炭酸ナトリウムもしくは炭酸カリウム等のアルカリ金属炭酸塩、炭酸カルシウム等のアルカリ土類金属炭酸塩、水酸化ナトリウムもしくは水酸化カリウム等の金属水酸化物、水素化ナトリウム等の金属水素化物、トリエチルアミン、ジイソプロピルエチルアミン、ピリジン、もしくは4-ジメチルアミノピリジン等の有機塩基、またはt-ブトキシカリウム等の金属アルコキシド等を用いることができる。溶媒としては例えば、四塩化炭素、クロロホルムもしくは塩化メチレン等のハロゲン化炭化水素系溶媒、ジエチルエーテル、テトラヒドロフランもしくは１，４−ジオキサン等のエーテル系溶媒、またはジメチルホルムアミド、ジメチルスルホキシドもしくはアセトニトリル等の非プロトン性溶媒等を用いることができる。反応温度は例えば、約０℃から溶媒の沸点付近までの範囲から選択される。

(Wherein Q ³ represents Q ¹ , a phosphonic acid group, a carboxy group or a hydroxyl group, Q ⁴ represents Q ² , a phosphonic acid group, a carboxy group or a hydroxyl group, and X ² represents an amino group, a hydroxyl group or a mercapto group. L represents a leaving group, and ring A, m, n, R, X ¹ , Y ¹ , Y ² , Z, Q ¹ , and Q ² are as defined above.)
Compound (XIX) can be obtained by reacting compound (XVIII) with compound (XXII) in the presence of a base.
Examples of the base include alkali metal carbonates such as sodium carbonate and potassium carbonate, alkaline earth metal carbonates such as calcium carbonate, metal hydroxides such as sodium hydroxide and potassium hydroxide, triethylamine, diisopropylethylamine, pyridine or 4 An organic base such as dimethylaminopyridine or a metal alkoxide such as sodium methoxide can be used. Examples of the solvent include halogenated hydrocarbon solvents such as methylene chloride, ether solvents such as diethyl ether, tetrahydrofuran or 1,4-dioxane, alcohol solvents such as methanol or ethanol, or dimethylformamide, dimethyl sulfoxide or acetonitrile. These aprotic solvents can be used. The reaction temperature is selected, for example, from a range from about 0 ° C. to around the boiling point of the solvent.
Compound (XX) can be obtained by reacting compound (XIX) and compound (XXIII) in the presence or absence of a base.
Examples of the base include alkali metal carbonates such as sodium carbonate and potassium carbonate, alkaline earth metal carbonates such as calcium carbonate, inorganic bases such as metal hydroxides such as sodium hydroxide and potassium hydroxide, triethylamine, diisopropylethylamine An organic base such as pyridine or 4-dimethylaminopyridine, a metal alkoxide such as sodium methoxide, or the like can be used. As the solvent, for example, an ether solvent such as tetrahydrofuran, 1,4-dioxane or diglyme, an alcohol solvent such as methanol or ethanol, or an aprotic solvent such as toluene, dimethylformamide or dimethyl sulfoxide can be used. Or you may carry out without a solvent. The reaction temperature is selected, for example, from a range from room temperature to around the boiling point of the solvent.
In the step of producing compound (XX) from compound (XIX), compound (XXI) can also be synthesized to obtain compound (XX).
When X ² is an amino group, compound (XXI) can be obtained by reacting compound (XIX) with guanidine in the presence or absence of a base.
Examples of the base include alkali metal carbonates such as sodium carbonate and potassium carbonate, alkaline earth metal carbonates such as calcium carbonate, metal hydroxides such as sodium hydroxide and potassium hydroxide, triethylamine, diisopropylethylamine, pyridine or 4 An organic base such as dimethylaminopyridine or a metal alkoxide such as sodium methoxide can be used. As the solvent, for example, an ether solvent such as tetrahydrofuran, 1,4-dioxane or diglyme, an alcohol solvent such as methanol or ethanol, or an aprotic solvent such as toluene, dimethylformamide or dimethyl sulfoxide can be used. Or you may carry out without a solvent. The reaction temperature is selected, for example, from a range from room temperature to around the boiling point of the solvent.
When X ² is a hydroxyl group, compound (XXI) can be obtained by reacting compound (XIX) with urea in the presence or absence of a base. Examples of the base include alkali metal carbonates such as sodium carbonate and potassium carbonate, alkaline earth metal carbonates such as calcium carbonate, metal hydroxides such as sodium hydroxide and potassium hydroxide, triethylamine, diisopropylethylamine, pyridine or 4 An organic base such as dimethylaminopyridine or a metal alkoxide such as sodium methoxide can be used. As the solvent, for example, an ether solvent such as tetrahydrofuran, 1,4-dioxane or diglyme, an alcohol solvent such as methanol or ethanol, or an aprotic solvent such as toluene, dimethylformamide or dimethyl sulfoxide can be used. Alternatively, it may be carried out without a solvent. The reaction temperature is selected, for example, from a range from room temperature to around the boiling point of the solvent.
When X ² is a mercapto group, compound (XXI) can be obtained by reacting compound (XIX) with benzoyl isothiocyanate in the presence or absence of a base to give thiourea and then performing a cyclization reaction.
In the condensation reaction of compound (XIX) and benzoyl isothiocyanate, examples of the base include alkali metal carbonates such as sodium carbonate and potassium carbonate, alkaline earth metal carbonates such as calcium carbonate, or triethylamine, diisopropylethylamine, pyridine or An organic base such as 4-dimethylaminopyridine can be used. As the solvent, for example, a halogenated hydrocarbon solvent such as methylene chloride, an ether solvent such as tetrahydrofuran or 1,4-dioxane, an aprotic solvent such as dimethylformamide or dimethyl sulfoxide, or the like can be used. The reaction temperature is selected, for example, from a range from about 0 ° C. to around the boiling point of the solvent.
A pyrimidine skeleton can be constructed by subjecting the thiourea obtained above to a cyclization reaction. That is, in the cyclization reaction, for example, an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, or a metal alkoxide such as sodium methoxide or t-butoxy potassium can be used as the base. As the solvent, for example, an ether solvent such as tetrahydrofuran, an alcohol solvent such as ethanol or 2-propanol, or an aprotic solvent such as dimethylformamide or dimethyl sulfoxide can be used. The reaction temperature is selected, for example, from a range from about room temperature to around the boiling point of the solvent.
Compound (XX) can be obtained by reacting compound (XXI) and compound (XVIV) in the presence of a base.
Examples of the base include alkali metal hydrogen carbonates such as sodium hydrogen carbonate, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkaline earth metal carbonates such as calcium carbonate, and metal water such as sodium hydroxide and potassium hydroxide. An oxide, a metal hydride such as sodium hydride, an organic base such as triethylamine, diisopropylethylamine, pyridine, or 4-dimethylaminopyridine, or a metal alkoxide such as t-butoxy potassium can be used. Examples of the solvent include halogenated hydrocarbon solvents such as carbon tetrachloride, chloroform and methylene chloride, ether solvents such as diethyl ether, tetrahydrofuran and 1,4-dioxane, or aprotic compounds such as dimethylformamide, dimethyl sulfoxide and acetonitrile. Can be used. The reaction temperature is selected, for example, from a range from about 0 ° C. to around the boiling point of the solvent.

Manufacturing method 3
In the above formula (II) to formula (XXIV), when Q ³ or Q ⁴ is a phosphonic acid group, a carboxy group, or a hydroxyl group, Q ¹ or Q ^{2 is} respectively determined according to a method known to those skilled in the art or a method analogous thereto. Can be converted to The method is described in, for example, “Comprehensive Organic Transformation, RC Laroque, (VCH Publishers, Inc, 1989)”. This will be specifically described below.
(1) ^{If Q 1} or ^{Q 2} is represented by ^{-PO (OR 2) (OR 3} ),
A phosphonic acid ester can be obtained by reacting phosphonic acid, which is an intermediate for producing the compound of the present invention, with R ² X or R ³ X (X represents a halogen atom) in the presence of a base. As the base, for example, a metal hydroxide such as sodium hydroxide or potassium hydroxide, an organic base such as triethylamine, diisopropylethylamine, pyridine, or 4-dimethylaminopyridine can be used. As the solvent, for example, a halogenated hydrocarbon solvent such as methylene chloride, an ether solvent such as diethyl ether or tetrahydrofuran, or an aprotic solvent such as dimethylformamide or dimethyl sulfoxide can be used. The reaction temperature is selected, for example, from a range from about 0 ° C. to around the boiling point of the solvent.
In addition, a phosphonic acid ester can be obtained by halogenating a hydroxyl group that is an intermediate for producing the compound of the present invention and then reacting with HPO (OR ² ) (OR ³ ) in the presence of a base. As the halogenating agent, for example, thionyl chloride, thionyl bromide, phosphorus oxychloride or the like can be used. Examples of the solvent include halogenated hydrocarbon solvents such as carbon tetrachloride, chloroform and methylene chloride, ether solvents such as diethyl ether, tetrahydrofuran and 1,4-dioxane, or aprotic solvents such as toluene and xylene. Can be used. The reaction temperature is selected, for example, from a range from about 0 ° C. to around the boiling point of the solvent. In the reaction with HPO (OR ² ) (OR ³ ), as the base, for example, a metal hydride such as sodium hydride or a metal alkoxide such as t-butoxy potassium can be used. As the solvent, for example, an ether solvent such as diethyl ether, tetrahydrofuran or 1,4-dioxane, or an aprotic solvent such as dimethylformamide, dimethyl sulfoxide or acetonitrile can be used. The reaction temperature is selected, for example, from a range from about 0 ° C. to around the boiling point of the solvent.
When R ² and R ³ are combined to form a 5- to 8-membered ring with the adjacent —OP (═O) O—, for example, phosphonic acid, which is a production intermediate of the compound of the present invention, and X (CH ₂ ) Cyclic phosphonic acid ester can be obtained by reacting _n X (X represents a halogen atom. N represents 2 to 5) in the presence of a base. As the base, for example, a metal hydroxide such as sodium hydroxide or potassium hydroxide, an organic base such as triethylamine, diisopropylethylamine, pyridine, or 4-dimethylaminopyridine can be used. As the solvent, for example, a halogenated hydrocarbon solvent such as methylene chloride, an ether solvent such as diethyl ether or tetrahydrofuran, or an aprotic solvent such as dimethylformamide or dimethyl sulfoxide can be used. The reaction temperature is selected, for example, from a range from about 0 ° C. to around the boiling point of the solvent.
Moreover, after halogenating the hydroxyl group of the production intermediate in which Q ³ is a hydroxyl group, a phosphonic acid ester can be obtained by reacting with HPO (OR ² ) (OR ³ ) in the presence of a base. As the halogenating agent, for example, thionyl chloride, thionyl bromide, phosphorus oxychloride or the like can be used. Examples of the solvent include halogenated hydrocarbon solvents such as carbon tetrachloride, chloroform and methylene chloride, ether solvents such as diethyl ether, tetrahydrofuran and 1,4-dioxane, or aprotic solvents such as toluene and xylene. Can be used. The reaction temperature is selected, for example, from a range from about 0 ° C. to around the boiling point of the solvent. In the reaction with HPO (OR ² ) (OR ³ ), as the base, for example, a metal hydride such as sodium hydride or a metal alkoxide such as t-butoxy potassium can be used. As the solvent, for example, an ether solvent such as diethyl ether, tetrahydrofuran or 1,4-dioxane, or an aprotic solvent such as dimethylformamide, dimethyl sulfoxide or acetonitrile can be used. The reaction temperature is selected, for example, from a range from about 0 ° C. to around the boiling point of the solvent.

(2) ^{When Q 1} or ^{Q 2} is represented by -COOR ^4,
Esters can be obtained by dehydration condensation of carboxylic acid, which is an intermediate for producing the compound of the present invention, and R ⁴ OH in the presence of an acid catalyst. Examples of the acid include inorganic acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid, Lewis acids such as methanesulfonic acid, p-toluenesulfonic acid, and boron fluoride etherate. The reaction temperature is selected from the range from room temperature to the vicinity of the boiling point of R ⁴ OH, for example.
Further, the carboxylic acid is a production intermediate of the compound of the present invention after the acid halide, the presence or absence of a base, to give the ester by reacting R 4 ^OH. As the halogenating agent, for example, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, or phosphorus trichloride can be used. Examples of the solvent include halogenated hydrocarbon solvents such as carbon tetrachloride, chloroform and methylene chloride, ether solvents such as diethyl ether, tetrahydrofuran and 1,4-dioxane, or aprotic solvents such as toluene and xylene. Can be used. The reaction temperature is selected, for example, from a range from about 0 ° C. to around the boiling point of the solvent. In the reaction with R ⁴ OH, as the base, for example, an organic base such as triethylamine, diisopropylethylamine, pyridine, or 4-dimethylaminopyridine can be used. As the solvent, for example, a halogenated hydrocarbon solvent such as methylene chloride, an ether solvent such as diethyl ether or tetrahydrofuran, or an aprotic solvent such as dimethylformamide or dimethyl sulfoxide can be used. The reaction temperature is selected, for example, from a range from about 0 ° C. to around the boiling point of the solvent.

(3) ^{When Q 1} or ^{Q 2} is represented by -COSR ^4,
A thioester can be obtained by dehydrating condensation of a carboxylic acid, which is a production intermediate of the compound of the present invention, with R ⁴ SH using a condensing agent. As the condensing agent, for example, carbodiimides such as dicyclohexylcarbodiimide can be used. As the solvent, for example, a halogenated hydrocarbon solvent such as methylene chloride, an ether solvent such as diethyl ether or tetrahydrofuran, an aprotic solvent such as dimethylformamide, or the like can be used. The reaction temperature is selected, for example, from a range from about room temperature to around the boiling point of the solvent.
Further, the carboxylic acid is a production intermediate of the compound of the present invention after the acid halide in the presence of a base can be obtained thioester by reacting R 4 ^SH. In the reaction with R ⁴ SH, examples of the base include alkali metal carbonates such as sodium carbonate and potassium carbonate, alkaline earth metal carbonates such as calcium carbonate, triethylamine, diisopropylethylamine, pyridine, and 4-dimethylaminopyridine. Or an organic base thereof can be used. As the solvent, for example, a halogenated hydrocarbon solvent such as methylene chloride, an ether solvent such as diethyl ether or tetrahydrofuran, or an aprotic solvent such as dimethylformamide or dimethyl sulfoxide can be used. The reaction temperature is selected, for example, from a range from about 0 ° C. to around the boiling point of the solvent.

(4) When Q ¹ or Q ² is represented by —CONR ⁵ R ⁶ ,
An amide can be obtained by dehydrating and condensing a carboxylic acid, which is a production intermediate of the compound of the present invention, and R ⁵ R ⁶ NH in the presence or absence of an active esterification reagent using a condensing agent. As the condensing agent, for example, carbodiimides such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride or dicyclohexylcarbodiimide can be used. As the active esterification reagent, for example, N-hydroxybenzotriazole, N-hydroxysuccinimide, or the like can be used. As the solvent, for example, a halogenated hydrocarbon solvent such as chloroform or methylene chloride, an ether solvent such as diethyl ether or tetrahydrofuran, or an aprotic solvent such as dimethylformamide or dimethyl sulfoxide can be used. The reaction temperature is selected, for example, from a range from about 0 ° C. to around the boiling point of the solvent.
Further, the carboxylic acid is a production intermediate of the compound of the present invention after the acid halide in the presence of a base, gives the amide by reacting ^R 5 R 6 ^NH. In the reaction with R ⁵ R ⁶ NH, examples of the base include alkali metal carbonates such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates such as calcium carbonate, triethylamine, diisopropylethylamine, pyridine, or 4-dimethylamino. An organic base such as pyridine can be used. As the solvent, for example, a halogenated hydrocarbon solvent such as methylene chloride, an ether solvent such as diethyl ether or tetrahydrofuran, or an aprotic solvent such as dimethylformamide or dimethyl sulfoxide can be used. The reaction temperature is selected, for example, from a range from about 0 ° C. to around the boiling point of the solvent.
In addition, each manufacturing process described in the manufacturing method 3 may use any compound in the manufacturing method 1 or 2 as a raw material as long as there is no hindrance to the reaction performed after this manufacturing process. The reaction may be carried out in any step in the reaction formula.

When the 8-hydroxyadenine compound of the present invention, an intermediate thereof, or a raw material compound thereof has a functional group, an appropriate process, that is, each of the production methods shown in Production Methods 1 or 2 is performed as necessary. At an intermediate stage or the like, a substituent introduction reaction, a functional group conversion reaction, or the like can be performed according to a conventional method of those skilled in the art. These are described in “Experimental Chemistry Course (Chemical Society of Japan, Maruzen)” or “Comprehensive Organic Transformation, RC Laroque, (VCH Publishers, Inc, 1989)”. A method or the like can be used. For example, functional group conversion reactions include acylation or sulfonylation reaction using acid halide, sulfonyl halide, etc., reaction with alkylating agent such as alkyl halide, hydrolysis reaction, Friedel-Crafts reaction And carbon-carbon bond forming reaction such as Wittig reaction, oxidation or reduction reaction, and the like.
In addition, when the compound of the present invention or an intermediate thereof has a functional group such as an amino group, a carboxy group, a hydroxyl group, or an oxo group, a protection or deprotection technique can be used as necessary. Suitable protecting groups, protecting methods, and deprotecting methods are described in detail in “Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc .; 1990)” and the like.

  The compound of the formula (1) of the present invention or an intermediate for producing the compound can be purified by methods known to those skilled in the art. For example, it can be purified by column chromatography (for example, silica gel column chromatography or ion exchange column chromatography) or recrystallization. Examples of the recrystallization solvent include alcohol solvents such as methanol, ethanol or 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, aromatic hydrocarbon solvents such as benzene or toluene, acetone A ketone solvent such as hexane, a hydrocarbon solvent such as hexane, an aprotic solvent such as dimethylformamide or acetonitrile, water, or a mixed solvent thereof can be used. As other purification methods, the methods described in Experimental Chemistry Course (edited by the Chemical Society of Japan, Maruzen) Vol. 1 etc. can be used.

In the compound of the formula (1) of the present invention, when there is one or more asymmetric points, by using a raw material having the asymmetric point or introducing the asymmetry at an intermediate stage according to a usual method Can be manufactured. For example, in the case of an optical isomer, it can be obtained by using an optically active raw material or performing optical resolution at an appropriate stage of the production process. As an optical resolution method, for example, a compound of the formula (1) or an intermediate thereof in an inert solvent (for example, an alcohol solvent such as methanol, ethanol or 2-propanol, an ether solvent such as diethyl ether, an ester such as ethyl acetate) System solvents, hydrocarbon solvents such as toluene, aprotic solvents such as acetonitrile, and mixed solvents thereof), optically active acids (for example, monocarboxylic acids such as mandelic acid, N-benzyloxyalanine, or lactic acid) , Tartaric acid, dicarboxylic acid such as o-diisopropylidene tartaric acid or malic acid, or sulfonic acid such as camphor sulfonic acid or bromocamphor sulfonic acid).
When the compound of formula (1) or an intermediate thereof has an acidic functional group such as a carboxy group, an optically active amine (for example, an organic amine such as α-phenethylamine, quinine, quinidine, cinchonidine, cinchonine, strychnine) and a salt are used. It can also be performed by forming.

  The temperature at which the salt is formed is selected from the range from room temperature to the boiling point of the solvent. In order to improve the optical purity, it is desirable to raise the temperature once to near the boiling point of the solvent. When the precipitated salt is collected by filtration, the yield can be improved by cooling as necessary. The amount of the optically active acid or amine used is in the range of about 0.5 to about 2.0 equivalents, preferably in the range of about 1 equivalent, relative to the substrate. Crystals in an inert solvent as necessary (for example, alcohol solvents such as methanol, ethanol, 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, hydrocarbon solvents such as toluene, acetonitrile, etc. And a high-purity optically active salt can be obtained. Further, if necessary, the optically resolved salt can be treated with an acid or base by a conventional method to obtain a free form.

The 8-hydroxyadenine compound of the present invention, a tautomer thereof, or a pharmaceutically acceptable salt thereof exhibits interferon-inducing activity and / or IL-4 and IL-5 production inhibitory activity, and is a viral disease. It is effective as a therapeutic or prophylactic agent for allergic diseases and skin diseases. In addition, the 8-hydroxyadenine compound of the present invention, their tautomers, or pharmaceutically acceptable salts thereof show a medicinal effect in the administered tissue when locally administered, but are substantially controlled by enzymes in vivo. It is converted into another compound (degradation product) with reduced efficacy, and is useful as a drug for local administration characterized by not exhibiting systemic pharmacological activity. Here, the drug effect represents the pharmacological activity of the compound, and specifically includes interferon-inducing activity, IL-4 production inhibitory activity, and / or IL-5 production inhibitory activity.
Preferably, the degradation product is 10 times, more preferably 100 times, and even more preferably 1000 times less effective than the parent compound.

The pharmacological activity can be measured by any evaluation test known to those skilled in the art, and preferably by an in vitro evaluation test. As a specific measurement method, a method described in Method in ENZYMOLOGY (Academic Press) or the like, a method using a commercially available ELISA kit (for example, AN'ALYSA (Immunoassay System) or the like), or the Examples in the present specification. Examples of the method are described.
For example, interferon-inducing activity can be measured by a bioassay using rat splenocytes, and the amount of interferon produced (IU / ml) at the same concentration can be compared between the parent compound (the compound of the present invention) and its degradation product. . It is also possible to compare the drug concentration of the parent compound showing a certain ability to produce interferon and its degradation product.

  Examples of the pharmacological activity include in vivo action based on interferon-inducing activity. Examples of the in vivo action include immunostimulatory action and influenza-like symptoms. The immunostimulatory action includes inducing cytotoxic activity such as natural killer (NK) cells, and the influenza-like symptom includes fever and the like. Fever represents an increase in body temperature in mammals, for example, in humans, it represents an increase in body temperature beyond normal heat.

  There are no particular limitations on the method of topical administration, but when administered to the nasal cavity, alveoli or airways, it is administered by aeration or inhalation, and when administered to the skin, administration by application to the skin, In the case of ophthalmic administration, examples include administration by eye drops. Preferably, an administration method by aeration or inhalation is mentioned.

When the compound of the present specification is locally administered, it is degraded in human blood or animal blood to become a degradation product, for example, in an in vitro evaluation test, due to a half-life in serum or liver S9. Can also be confirmed. Test methods for determining the half-life of the compounds of the present invention in in vitro evaluation tests are known.
The compound of the present invention is metabolized in liver S9 in an in vitro evaluation test, and its half-life is preferably within 60 minutes, more preferably within 30 minutes, and even more preferably within 10 minutes. The compound of the present invention is metabolized in serum, and its half-life is preferably within 60 minutes, more preferably within 30 minutes, and even more preferably within 10 minutes.

The “decomposed product” is a phosphonic acid produced by hydrolysis of a phosphonate ester bond, ester bond, thioester bond, or amide bond contained in a substituent in Q ¹ and / or Q ² in formula (1). Represents a compound having a group or a carboxy group.

The method for measuring the half-life in liver S9 of the compound of the present invention is as follows. That is, the compound of the present invention is added to the liver S9 solution and incubated at 37 ± 0.5 ° C. for 5 minutes to 2 hours. The elimination rate constant is determined by quantifying the amount of the compound of the present invention remaining in the liver S9 solution at regular intervals by HPLC (high performance liquid chromatography) or the like, and the half-life is calculated. Specifically, the method described in the Example is mentioned.
Here, liver S9 refers to a mixture of the supernatant fraction obtained by homogenizing a mammalian liver in an aqueous solution such as physiological saline, sucrose solution, KCl solution, etc., and then centrifuging at 9000 × g. Here, the aqueous solution is usually used in an amount of 2 to 4 times that of the liver. Examples of mammals include humans, dogs, rabbits, guinea pigs, mice, and rats. The liver S9 can be appropriately diluted with a buffer solution or the like.

The method for measuring the serum half-life of the compound of the present invention is as follows. That is, the compound of the present invention is added to a serum solution and incubated at 37 ± 0.5 ° C. for 5 minutes to 2 hours. The elimination rate constant is determined by quantifying the amount of the compound of the present invention remaining in the serum solution at regular intervals by HPLC (high performance liquid chromatography) or the like, and the half-life is calculated.
Here, serum refers to a supernatant fraction obtained by removing blood cells and blood coagulation factors from blood by centrifugation or the like, and can be used by appropriately diluting with a buffer solution or the like.

The compound of the present invention may be formulated in any preparation as long as it is a preparation used for topical administration. The preparation can be prepared by using a conventionally known technique and can contain an acceptable normal carrier, excipient, binder, stabilizer, buffer, solubilizer, isotonic agent and the like.
Examples of preparations for topical administration include ointments, lotions, creams, gels, tapes, transdermal patch preparations, poultices, sprays, aerosols, or liquids for spraying cartridges for inhalers or aerators. / Suspensions, eye drops, nasal drops, external powders and the like are included.
Ointments, creams and gels usually contain 0.01 to 10 w / w% of a compound of the present invention, with the addition of thickeners and / or gelling agents and / or solvents suitable for aqueous or oily bases. Also good. For example, the base includes water and / or oils such as liquid paraffin or vegetable oils such as peanut oil or castor oil, or solvents such as polyethylene glycol. Thickeners and gelling agents include soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycol, wool fat, beeswax, carboxypolymethylene and cellulose derivatives and / or glyceryl monostearate and / or nonionic emulsifiers. Can be mentioned.
Lotions usually contain 0.01-10 w / w% of a compound of the invention and may be formulated with an aqueous or oily base and will generally contain emulsifiers, stabilizers, dispersants, suspending agents, or thickening agents. May be included.
Topical powders usually contain 0.01-10 w / w% of a compound of the invention and may be formed with a suitable powder base such as talc, lactose, or starch.
Infusions may be formulated with an aqueous or non-aqueous base and may contain dispersing agents, solubilizers, suspending agents or preservatives.
The spray may be formulated as an aqueous solution or suspension, for example using a suitable liquefied propellant, or as an aerosol delivered from a pressurized pack such as a metered dose inhaler.
Aerosols suitable for inhalation may be either suspensions or solutions, generally suitable propellants such as compounds of the invention and fluorocarbons or hydrogen-containing chlorofluorocarbons or mixtures thereof, in particular hydrofluoroalkanes, in particular 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane or mixtures thereof. The aerosol may optionally contain further formulation excipients well known in the art such as surfactants such as oleic acid or lecithin and cosolvents such as ethanol.
For example, gelatin capsules or cartridges for use in inhalers or ventilators may be formulated containing a powder mixture for inhalation of the compounds used in the present invention and a suitable powder base such as lactose or starch. . Each capsule or cartridge usually contains 20 μg to 10 mg of a compound of the invention. Alternatively, the compounds used in the present invention may be provided without an excipient such as lactose.
In the medicament for topical administration of the invention, the proportion of the active compound used in the present invention is generally 0.001 to 10% by weight, preferably 0.005 to 1%, depending on the form of the preparation to be produced. Moreover, the ratio used in the powder for inhalation or ventilation is in the range of 0.1 to 5%.
Aerosols preferably include 20 μg to 2000 μg, preferably about 20 μg to 500 μg, of the compound used in the present invention in each metered dose or “blow amount” of the aerosol. Administration may be once daily or several times daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or 3 doses each time.

  The pharmaceutical composition of the present invention may be used in combination with other therapeutically effective agents. For example, when used as an anti-asthma drug, it can be used in combination with a β 2 -adrenergic receptor agonist, antihistamine or antiallergic, particularly β 2 -adrenergic receptor agonist. The individual compounds of such combinations may be administered either sequentially or simultaneously, individually or in combination, with pharmaceutical formulations.

  Although the compound of this invention is illustrated in the following Table 1-Table 17, this invention is not limited to this.

以下に実施例及び参考例を挙げて本発明を詳細に説明するが、本発明はもとよりこれに限定されるものではない。

EXAMPLES The present invention will be described in detail below with reference to examples and reference examples, but the present invention is not limited to these examples.

Synthesis of 9-Benzyl-2-dimethoxyphosphorylmethyl-8-hydroxyadenine

氷浴下、亜リン酸ジメチル（Dimethyl phosphite） 800 mg (7.27 mmol)のDMF 15 ml溶液に水素化ナトリウム144 mg (6.00 mmol)を加え、室温で1時間攪拌した後、参考例8で得られた9-ベンジル-2-クロロメチル-8-ヒドロキシアデニン（9-Benzyl-2-chloromethyl-8-hydroxyadenine） 105 mg (0.36 mmol)を加え、室温で12時間撹拌した。溶媒を留去し、残渣を水にあけ濃塩酸で中和した後、クロロホルム抽出、有機層を無水硫酸マグネシウムで乾燥後濃縮し、残渣をカラムクロマトグラフィー（SiO₂ 20g、溶出溶媒 : CHCl₃/MeOH=50/1〜15/1）で精製、メタノールで洗浄し、54 mg (0.15 mmol)の白色固体として標記化合物を得た。
¹H NMR (DMSO-d₆) δ10.22 (1H, brs), 7.29 (5H, m), 6.50 (2H, s), 4.90 (2H, s), 3.61 (3H, s), 3.58 (3H, s), 3.25 (2H, d, J = 18.4 Hz).

Obtained in Reference Example 8 after adding sodium hydride 144 mg (6.00 mmol) to DMF 15 ml solution of dimethyl phosphite 800 mg (7.27 mmol) in an ice bath and stirring at room temperature for 1 hour. 9-Benzyl-2-chloromethyl-8-hydroxyadenine (105 mg, 0.36 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The solvent was distilled off, the residue was poured into water, neutralized with concentrated hydrochloric acid, extracted with chloroform, the organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to column chromatography (SiO ₂ 20 g, elution solvent: CHCl ₃ / Purification with MeOH = 50 / 1-15 / 1) and washing with methanol gave the title compound as a white solid, 54 mg (0.15 mmol).
¹ H NMR (DMSO-d ₆ ) δ 10.22 (1H, brs), 7.29 (5H, m), 6.50 (2H, s), 4.90 (2H, s), 3.61 (3H, s), 3.58 (3H, s), 3.25 (2H, d, J = 18.4 Hz).

Synthesis of 9-Benzyl-2-diethoxyphosphorylmethyl-8-hydroxyadenine

実施例1と同様の方法で標記化合物を得た。
¹H NMR (DMSO-d₆) δ10.26 (1H, brs), 7.29 (5H, m), 6.49 (2H, s), 4.90 (2H, s), 3.95 (4H, m), 3.22 (2H, d, J = 21.6 Hz) , 3.25 (6H, t, J = 7.0 Hz).

The title compound was obtained in the same manner as in Example 1.
¹ H NMR (DMSO-d ₆ ) δ 10.26 (1H, brs), 7.29 (5H, m), 6.49 (2H, s), 4.90 (2H, s), 3.95 (4H, m), 3.22 (2H, d, J = 21.6 Hz), 3.25 (6H, t, J = 7.0 Hz).

Synthesis of 9-Benzyl-2-dibenzyloxyphosphorylmethyl-8-hydroxyadenine

実施例1と同様の方法で標記化合物を得た。
¹H NMR (DMSO-d₆) δ10.24 (1H, brs), 7.31 (10H, m), 7.24 (5H, m), 6.50 (2H, s), 4.99 (4H, m), 4.85 (2H, s), 3.40 (2H, d, J = 21.6 Hz).

The title compound was obtained in the same manner as in Example 1.
¹ H NMR (DMSO-d ₆ ) δ 10.24 (1H, brs), 7.31 (10H, m), 7.24 (5H, m), 6.50 (2H, s), 4.99 (4H, m), 4.85 (2H, s), 3.40 (2H, d, J = 21.6 Hz).

Synthesis of 2-Butoxy-9- [3- (dimethoxyphosphorylmethyl) benzyl] -8-hydroxyadenine

実施例1と同様の方法で標記化合物を得た。
¹H NMR (DMSO-d₆) δ10.04 (1H, brs), 7.20 (4H, m), 6.47 (2H, brs), 4.83 (2H, s), 4.13 (2H, t, J = 6.6 Hz), 3.56 (3H, s), 3.53 (3H, s), 3.22 (2H, d, J = 21.6 Hz), 1.62 (2H, 5, J = 6.6 Hz), 1.36 (2H, 6, J = 7.2 Hz), 0.90 (3H, t, J = 7.3 Hz).

The title compound was obtained in the same manner as in Example 1.
¹ H NMR (DMSO-d ₆ ) δ10.04 (1H, brs), 7.20 (4H, m), 6.47 (2H, brs), 4.83 (2H, s), 4.13 (2H, t, J = 6.6 Hz) , 3.56 (3H, s), 3.53 (3H, s), 3.22 (2H, d, J = 21.6 Hz), 1.62 (2H, 5, J = 6.6 Hz), 1.36 (2H, 6, J = 7.2 Hz) , 0.90 (3H, t, J = 7.3 Hz).

Synthesis of 2-Butoxy-9- [3- (dibenzyloxyphosphorylmethyl) benzyl] -8-hydroxyadenine

実施例1と同様の方法で標記化合物を得た。
¹H NMR (DMSO-d₆) δ10.05 (1H, brs), 7.31 (14H, m), 6.47 (2H, brs), 4.90 (2H, s), 4.88 (2H, s), 4.81 (2H, s), 4.10 (2H, t, J = 6.6 Hz), 3.31 (2H, m), 1.57 (2H, 5, J = 6.7 Hz), 1.33 (2H, 6, J = 7.3 Hz), 0.87 (3H, t, J = 7.4 Hz).

The title compound was obtained in the same manner as in Example 1.
¹ H NMR (DMSO-d ₆ ) δ10.05 (1H, brs), 7.31 (14H, m), 6.47 (2H, brs), 4.90 (2H, s), 4.88 (2H, s), 4.81 (2H, s), 4.10 (2H, t, J = 6.6 Hz), 3.31 (2H, m), 1.57 (2H, 5, J = 6.7 Hz), 1.33 (2H, 6, J = 7.3 Hz), 0.87 (3H, t, J = 7.4 Hz).

Interferon induction in rat spleen cells (in vitro)
Remove spleen from SD rat (male; 8-10 weeks old), prepare 1 × 10 ⁷ cells / ml spleen cell suspension using bloodless MEM medium, and add to each well of 24-well microplate. 0.5 ml was dispensed. Then add 0.5 ml of test compound diluted in the same medium (containing 0.2% DMSO) to each well and incubate at 37 ° C for 24 hours in a 5% CO ₂ incubator. Aseptic filtration was performed to obtain a culture supernatant. The interferon titer in the culture supernatant was quantified by a bioassay described in JA Armstrong, Methods in Enzymology 78, 381-7. That is, 1 × 10 ⁴ cells / 50 μl of mouse fibroblast L929 was cultured in a 96-well culture plate for 24 hours, 50 μl of diluted culture supernatant was added, and further cultured for 24 hours. Subsequently, 100 μl of vesicular stomatitis virus was added, and the cytopathic effect 44 hours after virus infection was confirmed by neutral red staining. The quantification was performed by extracting the dye with a 50% ethanol / PBS aqueous solution and measuring the absorption at 540 nm. Table 18 shows the interferon-inducing activity (minimum effective concentration) of each compound.

Metabolic stability test using rat liver S9 Reaction using rat liver S9 was performed on a 96-well plate using a screening robot manufactured by Tecan. S9 solution is prepared by adding 20 ml of 250 mM Kpi (ph 7.4) and 20 ml of deionized water to 10 ml of rat liver S9, and cofactor solution is prepared by dissolving 220 mg of NADPH in 40.5 ml of deionized water (Final 6 mM). The IS (Internal Standard) solution was prepared by adding 300 μl of IS solution (1 mM DMSO solution) to 30 ml of acetonitrile (diluted 100 times). Dissolve the test compound (1 mM DMSO solution) in a 37 ° C incubator and dispense 35 μL each into a 96-well plate (24 samples / plate), then plates (sample plate, 96-well plate for dilution, reaction and recovery) Each well well plate and solid phase extraction plate) and reagents (S9 solution, Cofactor solution, IS (Internal Standard) solution, Stop solution, elution acetonitrile) are set in a predetermined position in the robot booth and reacted. (Concentration of test compound 1 μM). After incubation at 37 ° C with shaking, solid-phase extraction (at the same time adding an internal standard for analysis), 50 μL of each well was added to the collected 200 μL / well sample, and FALCON Deep well Dispense 100 μL / well into two plates, conduct LC / MS analysis, draw chromatograms of the test substance and internal standard, determine the peak area, and then perform stability (residual rate after reaction) using the internal standard method. ) Was calculated. The results are shown in Table 19.

Formulation example of formulation In 1 g of aerosol,
Compound of Example 1: 0.641 mg (0.06%)
Ethanol: 26.816 mg (2.68%)
1,1,1,2-Tetrafluoroethane: 972.543 mg (97.25%)
An aerosol solution containing the above components is prepared.

Formulation example of formulation In 1 g of aerosol,
Compound of Example 4: 0.641 mg (0.06%)
Ethanol: 26.816 mg (2.68%)
1,1,1,2-Tetrafluoroethane: 972.543 mg (97.25%)
An aerosol solution containing the above components is prepared.

Comparative Example 1: Synthesis of 9-Benzyl-8-hydroxy-2-phosphonomethyladenine

実施例3で得られた9-ベンジル-2-ジベンジルホスホノメチル-8-ヒドロキシアデニン（9-Benzyl-2-dibenzylphosphonomethyl-8-hydroxyadenine）61 mg (0.12 mmol)と20% Pd(OH)₂/C 0.12 gのメタノール 20 ml懸濁液を、水素雰囲気下室温で7時間攪拌した。触媒を濾去後濃縮し、21 mg（0.063 mmol）の白色固体として標記化合物を得た。
¹H NMR (CD₃OD) δ7.26 (5H, m), 5.06 (2H, s), 3.11 (2H, d, J = 20.1 Hz).

61 mg (0.12 mmol) of 9-Benzyl-2-dibenzylphosphonomethyl-8-hydroxyadenine obtained in Example 3 and 20% Pd (OH) ₂ A suspension of / C 0.12 g in methanol 20 ml was stirred at room temperature under a hydrogen atmosphere for 7 hours. The catalyst was filtered off and concentrated to give the title compound as a white solid (21 mg, 0.063 mmol).
¹ H NMR (CD ₃ OD) δ7.26 (5H, m), 5.06 (2H, s), 3.11 (2H, d, J = 20.1 Hz).

Comparative Example 2: Synthesis of 2-butoxy-8-hydroxy-9- [3- (phosphonomethyl) benzyl] adenine (2-Butoxy-8-hydroxy-9- [3- (phosphonomethyl) benzy] adenine)

比較例1と同様の方法で標記化合物を得た。
¹H NMR (CD₃OD) δ7.10 (4H, m), 4.54 (2H, s), 4.18 (2H, t, J = 6.6 Hz), 2.84 (2H, d, J = 20.8 Hz), 1.58 (2H, 5, J = 6.5 Hz), 1.34 (2H, 6, J = 7.6 Hz), 0.83 (3H, t, J = 7.4 Hz).

The title compound was obtained in the same manner as in Comparative Example 1.
¹ H NMR (CD ₃ OD) δ7.10 (4H, m), 4.54 (2H, s), 4.18 (2H, t, J = 6.6 Hz), 2.84 (2H, d, J = 20.8 Hz), 1.58 ( 2H, 5, J = 6.5 Hz), 1.34 (2H, 6, J = 7.6 Hz), 0.83 (3H, t, J = 7.4 Hz).

Reference Example 1: Synthesis of 2-Butoxyadenine

ナトリウム 13.56 g (590 mmol)をn-ブタノール 480 mlに溶解させ、2-クロロアデニン（2-Chloroadenine） 4.0 g (23.59 mmol)を加え、140℃で19時間撹拌した。放冷後、水 400 mlを加え、有機層を分離、濃縮した。残渣に水400 ml加え、濃塩酸で中和した後、析出固体を濾取、エタノールで洗浄し、3.72 g (17.97 mmol)の白色固体として標記化合物を得た。収率 76%。
¹H NMR (DMSO-d₆) δ12.53 (1H, brs), 7.88 (1H, s), 7.06 (2H, brs), 4.16 (2H, t, J = 6.6 Hz), 1.63 (2H, 5, J = 6.6 Hz), 1.40 (2H, 6, J = 7.4 Hz), 0.92 (3H, t, J = 7.4 Hz).

13.56 g (590 mmol) of sodium was dissolved in 480 ml of n-butanol, 4.0 g (23.59 mmol) of 2-chloroadenine was added, and the mixture was stirred at 140 ° C. for 19 hours. After allowing to cool, 400 ml of water was added, and the organic layer was separated and concentrated. After adding 400 ml of water to the residue and neutralizing with concentrated hydrochloric acid, the precipitated solid was collected by filtration and washed with ethanol to obtain the title compound as 3.72 g (17.97 mmol) of a white solid. Yield 76%.
¹ H NMR (DMSO-d ₆ ) δ12.53 (1H, brs), 7.88 (1H, s), 7.06 (2H, brs), 4.16 (2H, t, J = 6.6 Hz), 1.63 (2H, 5, J = 6.6 Hz), 1.40 (2H, 6, J = 7.4 Hz), 0.92 (3H, t, J = 7.4 Hz).

Reference Example 2: Synthesis of 2-butoxy-9- (3-methoxycarbonylbenzyl) adenine

参考例１で得られた2-ブトキシアデニン（2-Butoxyadenine） 0.66 g (3.19 mmol)、炭酸カリウム 0.80 g (5.79 mmol)のDMF 40 ml懸濁液に、3-メトキシカルボニルベンジルブロミド（3-Methoxycarbonylbenzylbromide）1.99 g (10.78 mmol)を加え、室温で18時間撹拌した。溶媒を留去後、残渣を水にあけジクロロメタン抽出、有機層を無水硫酸マグネシウムで乾燥後濃縮した。残渣をカラムクロマトグラフィー（SiO₂ 20g、溶出溶媒 : CHCl₃/MeOH=300/1〜50/1）で精製し、0.50 g (1.41 mmol)の白色固体として標記化合物を得た。収率44%。¹H NMR (DMSO-d₆) δ8.07 (1H, s), 7.96 (1H, s), 7.86 (1H, d, J = 7.5 Hz), 7.61 (1H, d, J = 7.7 Hz), 7.49 (1H, t, J = 7.5 Hz), 7.20 (2H, brs), 5.33 (2H, s), 4.19 (2H, t, J = 6.6 Hz), 3.82 (3H, s), 1.63 (2H, 5, J = 7.0 Hz), 1.36 (2H, 6, J = 7.5 Hz), 0.89 (3H, t, J = 7.3 Hz).

To a suspension of 0.66 g (3.19 mmol) of 2-butoxyadenine and 0.80 g (5.79 mmol) of potassium carbonate obtained in Reference Example 1 in a 40 ml suspension of DMF, 3-methoxycarbonylbenzylbromide (3-Methoxycarbonylbenzylbromide) ) 1.99 g (10.78 mmol) was added and stirred at room temperature for 18 hours. After the solvent was distilled off, the residue was poured into water and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (SiO ₂ 20 g, elution solvent: CHCl ₃ / MeOH = 300/1 to 50/1) to obtain 0.50 g (1.41 mmol) of the title compound as a white solid. Yield 44%. ¹ H NMR (DMSO-d ₆ ) δ8.07 (1H, s), 7.96 (1H, s), 7.86 (1H, d, J = 7.5 Hz), 7.61 (1H, d, J = 7.7 Hz), 7.49 (1H, t, J = 7.5 Hz), 7.20 (2H, brs), 5.33 (2H, s), 4.19 (2H, t, J = 6.6 Hz), 3.82 (3H, s), 1.63 (2H, 5, J = 7.0 Hz), 1.36 (2H, 6, J = 7.5 Hz), 0.89 (3H, t, J = 7.3 Hz).

Reference Example 3: Synthesis of 8-Bromo-2-Butoxy-9- (3-methoxycarbonylbenzyl) adenine

参考例2で得られた2-ブトキシ-9-(3-メトキシカルボニルベンジル)アデニン（2-Butoxy-9-(3-methoxycarbonylbenzyl)adenine ）0.41 g (1.54 mmol)、酢酸ナトリウム 1.14 g (13.90 mmol)の酢酸50 ml溶解液に、臭素 0.1 ml (7.7 mmol)を加え、室温で5時間撹拌した。溶媒を留去後、残渣を水にあけジクロロメタン抽出、有機層を飽和重曹水、飽和亜硫酸水素ナトリウム水溶液、飽和食塩水の順に洗った後、無水硫酸マグネシウムで乾燥後濃縮し、0.45 g (1.04 mmol)の黄色油状物として標記化合物を得た。収率90%。
¹H NMR (DMSO-d₆) δ7.89 (2H, m), 7.51 (2H, m), 7.45 (2H, brs), 5.33 (2H, s), 4.21 (2H, t, J = 6.6 Hz), 3.83 (3H, s), 1.64 (2H, 5, J = 7.8 Hz), 1.38 (2H, 6, J = 7.6 Hz), 0.90 (3H, t, J = 7.3 Hz).

2-Butoxy-9- (3-methoxycarbonylbenzyl) adenine obtained in Reference Example 2 0.41 g (1.54 mmol), sodium acetate 1.14 g (13.90 mmol) Bromine (0.1 ml, 7.7 mmol) was added to 50 ml of acetic acid dissolved solution, and the mixture was stirred at room temperature for 5 hours. After distilling off the solvent, the residue was poured into water and extracted with dichloromethane. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate, saturated aqueous sodium hydrogen sulfite and saturated brine, then dried over anhydrous magnesium sulfate and concentrated, 0.45 g (1.04 mmol The title compound was obtained as a yellow oil. Yield 90%.
¹ H NMR (DMSO-d ₆ ) δ 7.89 (2H, m), 7.51 (2H, m), 7.45 (2H, brs), 5.33 (2H, s), 4.21 (2H, t, J = 6.6 Hz) , 3.83 (3H, s), 1.64 (2H, 5, J = 7.8 Hz), 1.38 (2H, 6, J = 7.6 Hz), 0.90 (3H, t, J = 7.3 Hz).

Reference Example 4: Synthesis of 2-butoxy-9- (3-carboxybenzyl) -8-methoxyadenine

Na 0.49 g (21.30 mmol)をメタノール 50 mlに溶解させ、参考例3で得られた8-ブロモ-2-ブトキシ-9-（3-メトキシカルボニルベンジル）アデニン（8-Bromo-2-Butoxy-9-(3-methoxycarbonylbenzyl)adenine） 0.22 g (0.51 mmol)を加え、30 時間加熱還流した。放冷後、濃塩酸で中和、濃縮した。残渣を水にあけ析出固体を濾取、メタノールで洗浄し、0.13 g (0.35 mmol)の白色固体として標記化合物を得た。収率69%。

Na 0.49 g (21.30 mmol) was dissolved in 50 ml of methanol, and 8-bromo-2-butoxy-9- (3-methoxycarbonylbenzyl) adenine (8-Bromo-2-Butoxy-9) obtained in Reference Example 3 was obtained. -(3-methoxycarbonylbenzyl) adenine) 0.22 g (0.51 mmol) was added, and the mixture was heated to reflux for 30 hours. After standing to cool, the mixture was neutralized with concentrated hydrochloric acid and concentrated. The residue was poured into water and the precipitated solid was collected by filtration and washed with methanol to give the title compound as a white solid of 0.13 g (0.35 mmol). Yield 69%.

Reference Example 5: Synthesis of 2-Butoxy-8-hydroxy-9- (3-methoxycarbonylbenzyl) adenine

参考例4で得られた2-ブトキシ-9-（3-カルボキシベンジル）-8-メトキシアデニン（2-Butoxy-9-(3-carboxybenzyl)-8-methoxyadenine）0.60 g (1.61 mmol)のメタノール20 ml溶液に、硫酸1 mlを加え、1時間加熱還流した。飽和重曹水で中和し、析出固体を濾取、メタノールで洗浄し、0.48 g (1.29 mmol)の白色固体として標記化合物を得た。収率80%。
¹H NMR (DMSO-d₆) δ10.02 (1H, brs), 7.93 (1H, s), 7.87 (1H, d, J = 7.3 Hz), 7.59 (1H, d, J = 7.6 Hz), 7.49 (1H, t, J = 7.6 Hz), 6.48 (2H, brs), 4.93 (2H, s), 4.14 (2H, t, J = 6.5 Hz), 3.84 (3H, s), 1.63 (2H, 5, J = 7.0 Hz), 1.36 (2H, 6, J = 7.0 Hz), 0.90 (3H, t, J = 7.3 Hz).

2-Butoxy-9- (3-carboxybenzyl) -8-methoxyadenine obtained in Reference Example 4 0.60 g (1.61 mmol) of methanol 20 1 ml of sulfuric acid was added to the ml solution, and the mixture was heated to reflux for 1 hour. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate, and the precipitated solid was collected by filtration and washed with methanol to give 0.48 g (1.29 mmol) of the title compound as a white solid. Yield 80%.
¹ H NMR (DMSO-d ₆ ) δ10.02 (1H, brs), 7.93 (1H, s), 7.87 (1H, d, J = 7.3 Hz), 7.59 (1H, d, J = 7.6 Hz), 7.49 (1H, t, J = 7.6 Hz), 6.48 (2H, brs), 4.93 (2H, s), 4.14 (2H, t, J = 6.5 Hz), 3.84 (3H, s), 1.63 (2H, 5, J = 7.0 Hz), 1.36 (2H, 6, J = 7.0 Hz), 0.90 (3H, t, J = 7.3 Hz).

Reference Example 6: Synthesis of 2-Butoxy-8-hydroxy-9- (3-hydroxymethylbenzyl) adenine

氷浴下、水素化リチウムアルミニウム129 mg (3.40 mmol)のTHF 40 ml懸濁液に、参考例5で得られた2-ブトキシ-8-ヒドロキシ-9-(3-メトキシカルボニルベンジル)アデニン（2-Butoxy-8-hydroxy-9-(3-methoxycarbonylbenzyl)adenine）207 mg (0.56 mmol)のTHF 20 ml溶液を滴下し、室温で７時間撹拌した。氷浴下、水0.13 ml、5%水酸化ナトリウム水溶液0.39 ml、水0.39 mlの順に滴下した後、反応液を濾過、濾液を濃縮し、残渣をカラムクロマトグラフィー（SiO₂ 20g、溶出溶媒 : CHCl₃/MeOH=30/1）で精製し、172 mg (0.50 mmol)の白色固体として標記化合物を得た。収率89%。
¹H NMR (DMSO-d₆) δ9.94 (1H, s), 7.93 (2H, m), 7.87 (1H, s), 7.59 (1H, t, J = 7.6 Hz), 6.44 (2H, brs), 5.17 (1H, t, J = 5.7 Hz), 4.84 (2H, s), 4.44 (2H, d, J = 5.7 Hz), 4.14 (2H, t, J = 6.6 Hz), 1.62 (2H, 5, J = 6.6 Hz), 1.38 (2H, 6, J = 7.4 Hz), 0.90 (3H, t, J = 7.3 Hz).

In an ice bath, a suspension of lithium aluminum hydride 129 mg (3.40 mmol) in THF 40 ml suspension was charged with 2-butoxy-8-hydroxy-9- (3-methoxycarbonylbenzyl) adenine (2 A solution of -Butoxy-8-hydroxy-9- (3-methoxycarbonylbenzyl) adenine) in 207 mg (0.56 mmol) in THF was added dropwise and stirred at room temperature for 7 hours. In an ice bath, water (0.13 ml), 5% aqueous sodium hydroxide solution (0.39 ml) and water (0.39 ml) were added dropwise in this order, the reaction solution was filtered, the filtrate was concentrated, and the residue was subjected to column chromatography (SiO ₂ 20 g, elution solvent: CHCl ₃ / MeOH = 30/1) to give 172 mg (0.50 mmol) of the title compound as a white solid. Yield 89%.
¹ H NMR (DMSO-d ₆ ) δ9.94 (1H, s), 7.93 (2H, m), 7.87 (1H, s), 7.59 (1H, t, J = 7.6 Hz), 6.44 (2H, brs) , 5.17 (1H, t, J = 5.7 Hz), 4.84 (2H, s), 4.44 (2H, d, J = 5.7 Hz), 4.14 (2H, t, J = 6.6 Hz), 1.62 (2H, 5, J = 6.6 Hz), 1.38 (2H, 6, J = 7.4 Hz), 0.90 (3H, t, J = 7.3 Hz).

Reference Example 7: Synthesis of 2-butoxy-9- (3-chloromethylbenzyl) -8-hydroxyadenine

参考例6で得られた2-ブトキシ-8-ヒドロキシ-9-(3-ヒドロキシメチルベンジル)アデニン（2-Butoxy-8-hydroxy-9-(3-hydroxymethylbenzyl)adenine）118 mg (0.34 mmol)のクロロホルム20 ml溶液に、塩化チオニル0.4 mlを加え、8時間加熱還流した。溶媒を留去し、残渣を飽和重曹水にあけ、ジクロロメタン抽出、有機層を無水硫酸マグネシウムで乾燥後濃縮し、残渣をメタノール/エーテル（1/10）で洗浄し、112 mg (0.31 mmol)の桃色固体として標記化合物を得た。収率91%。
¹H NMR (DMSO-d₆) δ9.69 (1H, s), 7.93 (3H, m), 7.87 (1H, m), 6.46 (2H, brs), 4.86 (2H, s), 4.73 (2H, s), 4.14 (2H, t, J = 6.6 Hz), 1.62 (2H, 5, J = 6.6 Hz), 1.37 (2H, 6, J = 7.3 Hz), 0.90 (3H, t, J = 7.4 Hz).

2-Butoxy-8-hydroxy-9- (3-hydroxymethylbenzyl) adenine 118 mg (0.34 mmol) obtained in Reference Example 6 To a 20 ml solution of chloroform, 0.4 ml of thionyl chloride was added and heated to reflux for 8 hours. The solvent was distilled off, the residue was poured into saturated aqueous sodium bicarbonate, extracted with dichloromethane, the organic layer was dried over anhydrous magnesium sulfate and concentrated, and the residue was washed with methanol / ether (1/10) to give 112 mg (0.31 mmol). The title compound was obtained as a pink solid. Yield 91%.
¹ H NMR (DMSO-d ₆ ) δ9.69 (1H, s), 7.93 (3H, m), 7.87 (1H, m), 6.46 (2H, brs), 4.86 (2H, s), 4.73 (2H, s), 4.14 (2H, t, J = 6.6 Hz), 1.62 (2H, 5, J = 6.6 Hz), 1.37 (2H, 6, J = 7.3 Hz), 0.90 (3H, t, J = 7.4 Hz) .

Reference Example 8: Synthesis of 9-Benzyl-2-chloromethyl-8-hydroxyadenine

9-ベンジル-8-ヒドロキシ-2-ヒドロキシメチルアデニン（9-Benzyl-2-8-hydroxy-2-hydroxymethyladenine）4.52 g (16.7 mmol)に塩化チオニル100 mlを加え、1時間加熱還流した。溶媒を留去し、残渣を水にあけ、析出固体を濾取、クロロホルムで洗浄し、3.99 g (13.8 mmol)の白色固体として標記化合物を得た。収率83%。
¹H NMR (DMSO-d₆) δ10.35 (1H, brs), 7.29 (5H, m), 6.63 (2H, s), 4.93 (2H, s), 4.50 (2H, s).

To 4.52 g (16.7 mmol) of 9-benzyl-8-hydroxy-2-hydroxymethyladenine (9-Benzyl-2-8-hydroxy-2-hydroxymethyladenine) was added 100 ml of thionyl chloride, and the mixture was heated to reflux for 1 hour. The solvent was distilled off, the residue was poured into water, the precipitated solid was collected by filtration and washed with chloroform to give the title compound as 3.99 g (13.8 mmol) of a white solid. Yield 83%.
¹ H NMR (DMSO-d ₆ ) δ 10.35 (1H, brs), 7.29 (5H, m), 6.63 (2H, s), 4.93 (2H, s), 4.50 (2H, s).

Claims (12)

Formula (1):

[Where:
Ring A represents a benzene ring or a 5- to 6-membered monocyclic aromatic heterocycle,
m represents 0 or 1;
n represents an integer of 0 to 2,
R represents a halogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, or a substituted or unsubstituted amino group;
when n represents 2, R may be the same or different;
X ¹ represents an oxygen atom, a sulfur atom, NR ¹ (R ¹ represents a hydrogen atom or an alkyl group), or a single bond,
Y ¹ and Y ² independently represent a single bond or alkylene,
Z represents alkylene,
Q ¹ represents a hydrogen atom, a hydroxyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group or an arbitrary substituent selected from the following substituent group:
Q ² represents an arbitrary substituent selected from the following substituent group,
At least one of Q ¹ and Q ² represents —PO (OR ² ) (OR ³ ).
Substituent ^{Group: -PO (OR 2) (OR} 3); - COOR 4; -COSR 4; -CONR 5 R 6 ( wherein, ^{R 2} and ^{R 3} are independently substituted or unsubstituted alkyl group, Represents a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkynyl group, or R ² and R ³ are bonded together with the adjacent —OP (═O) O— , R ⁴ may be a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkynyl. R ⁵ and R ⁶ independently represent a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkenyl group, and Represents a substituted or unsubstituted alkynyl group, or R ⁵ and R ⁶ may combine together to form a substituted or unsubstituted 5- to 7-membered nitrogen-containing heterocyclic ring together with the adjacent nitrogen atom. )]
The 8-hydroxyadenine compound represented by these, or those pharmaceutically acceptable salts. Salts in the formula (1), ^{Q 1} is representative of a ^{-PO (OR 2) (OR 3} ), which is pharmaceutically acceptable for 8-hydroxy adenine compound, or their Claim 1. In the formula (1), m represents 1, salt ^{Q 2} is representative of a ^{-PO (OR 2) (OR 3} ), which is pharmaceutically acceptable for 8-hydroxy adenine compound, or their Claim 1 . The 8-hydroxyadenine compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein in the formula (1), X ¹ represents a single bond.   The 8-hydroxyadenine compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein in formula (1), Z represents methylene and ring A represents a benzene ring.   The pharmaceutical which contains the 8-hydroxy adenine compound in any one of Claims 1-5, or its pharmaceutically acceptable salt as an active ingredient.   A pharmaceutical composition comprising the 8-hydroxyadenine compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof as an active ingredient.   An immunomodulator comprising the 8-hydroxyadenine compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof as an active ingredient.   A therapeutic or prophylactic agent for a viral disease comprising the 8-hydroxyadenine compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof as an active ingredient.   A therapeutic or prophylactic agent for allergic diseases comprising the 8-hydroxyadenine compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof as an active ingredient.   A therapeutic or prophylactic agent for cancer diseases comprising the 8-hydroxyadenine compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof as an active ingredient. A drug for topical administration comprising the 8-hydroxyadenine compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof as an active ingredient.