JPH11180981A - Heterocyclic derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new heterocyclic compound capable of expressing a remarkable interferon biosynthesis-inducing activity and useful as an antiviral agent, an anticancer agent or an immune disease medicine. SOLUTION: A compound of formula I X<1> and X<2> are each N, or one of X<1> and X<2> is N and the other is CH; R<1> is amino, a (substituted) alkylamino, a dialkylamino or an alicyclic heterocyclic group; R<2> is a group of the formula: O-X<3> (X<3> is H, a (substituted) alkyl or the like), a group of the formula: S-X<3> or R<1> except dialkylamino groups; Y<1> and Y<2> are each H, OH, a (substituted) alkyl, a halogen or the like} or its salt. For example, 2,6-diamino-9-benzylpurine. The compound of formula I is obtained, for example, by reacting a compound of formula II [R<3> and R<4> are each H, a (substituted) alkyl or the like] with a compound of formula III (Y is a releasing group such as a halogen) and subsequently reacting the obtained compound of formula IV with a compound of the formula: R<2> H.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel heterocyclic compound having an activity of inducing interferon biosynthesis.
The heterocyclic compound of the present invention induces the biosynthesis of endogenous interferon in a living body, and is specifically useful as a drug such as an antiviral agent, an anticancer agent or a therapeutic agent for an immune disease.

[0002]

2. Description of the Related Art In recent years, endogenous interferon plays a central role in biological defense mechanisms against viral and microbial infections in vivo, and also plays an important role in antitumor and immune regulation. Is being revealed. With the establishment of mass production technology for interferon, natural interferon was readily available from cultured cells, and the production of recombinant interferon from E. coli transfected with the interferon gene became possible in large quantities. Many research results have been accumulated using. Specifically, for interferon, antiviral action,
Various biological effects such as cytostatic and immunomodulatory effects have been confirmed, and clinical use has already been commercialized as a therapeutic agent for viral diseases such as hepatitis B and C, or a therapeutic agent for cancer and immunological diseases. It has been done. It has also been suggested that interferon has an effect of suppressing carcinogenesis in hepatitis B and C. By the way, interferon is heavily used especially for many of the above diseases because there is no other effective treatment method.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel low molecular weight compound having an activity of inducing interferon biosynthesis, and an antiviral agent, an anticancer agent, a therapeutic agent for an immune disease and the like containing the compound as an active ingredient. It is in.

[0004]

As substances that induce the biosynthesis of interferon, various animal viruses, microorganisms such as bacteria and protozoa and their extracts, mitogens, specific antigens, and immunostimulants are known. . For example, various natural double-stranded RNAs and synthetic double-stranded RNAs such as poly I: C,
It is known that anionic polymer compounds such as polyacrylic acid and chlorite oxyamylose have an interferon-inducing action. On the other hand, among low molecular weight compounds, fluorenones, pyrimidine derivatives, anthraquinones, acridine compounds and the like having interferon-inducing activity have been found (Stringfrllow, D. et al.
A .: Methods in Enzymology, 1981, 78, 262). However, when these compounds are used in clinical trials, these compounds have not been successfully developed due to unexpectedly low interferon inducibility and strong side effects or reduced interferon inducibility due to repeated administration. In addition, imidazoquinolines are also known as low-molecular interferon inducers, but these compounds have low interferon-selective inducing ability, and include IL-6 (interleukin 6), TN
It is known that cytokines such as F-α (Tumor necrosis factor α) are also induced simultaneously (Te
sterman, TL, et al .: J. Leukocyte Biol., 1995,
58,365).

[0005] From such a background, the present inventors have conducted intensive studies to develop a low molecular weight interferon biosynthesis inducer, and as a result, have found that the heterocyclic compound of the present invention has a remarkable interferon biosynthesis induction activity. The present invention has been completed. Indeed, the present inventors have found that the heterocyclic compound of the present invention is a type 2 helper T cell (hereinafter abbreviated as Th2) -side cytokine (for example, IL-4 (interleukin 4), IL-5 (interleukin 5)). , IL-10 (interleukin 10), IL-13 (interleukin 13), etc.)
Have also been found to have the effect of suppressing or regulating the production of.

That is, the present invention relates to (a) general formula (1)

Embedded image (Wherein X ¹ and X ² both represent a nitrogen atom, X ¹ is a nitrogen atom and X ² represents CH, or X ¹ is CH and X ² represents a nitrogen atom, R ¹ is an amino group, Alkylamino group,
Represents a substituted alkylamino group, a dialkylamino group or an alicyclic heterocyclic group, wherein R ² is a group represented by OX ³ , SX
^{3 represents} an amino group, an alkylamino group, a substituted alkylamino group or an alicyclic heterocyclic group, and X ³ represents a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group,
Substituted alkenyl group, alkynyl group, substituted alkynyl group,
Represents an aryl group, a substituted aryl group, an aralkyl group, a substituted aralkyl group, a heterocyclic group or a substituted heterocyclic group, and Y ¹ is a hydrogen atom, a hydroxyl group, an alkyl group, a substituted alkyl group, an alkoxy group, a substituted alkoxy group, an alkanoyl group, Substituted alkanoyl group, aroyl group, substituted aroyl group, carboxy group, alkoxycarbonyl group, substituted alkoxycarbonyl group, amino group, alkylamino group, dialkylamino group, carbamoyl group, alkylcarbamoyl group, dialkylcarbamoyl group, halogen atom, nitro group Or a cyano group, and Y ² represents a hydrogen atom, a hydroxyl group, an alkyl group, a substituted alkyl group, an alkoxy group, a substituted alkoxy group, an alkanoyl group, a substituted alkanoyl group, an aroyl group, a substituted aroyl group, a carboxy group, an alkoxycarbonyl group, Alkoxyka Rubonyl group, amino group, alkylamino group, dialkylamino group, carbamoyl group,
Alkylcarbamoyl group, dialkylcarbamoyl group,
Represents a halogen atom, a nitro group or a cyano group. ) Or a pharmaceutically acceptable salt thereof.

Specifically, the present invention relates to (b) the general formula (2)

Embedded image (Wherein, R ² represents a group represented by O-X ^3, a group represented by S-X ^3, an amino group, an alkylamino group, a substituted alkyl amino group or an alicyclic heterocyclic group, X ³ is hydrogen It represents atom, an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group, substituted alkynyl group, an aryl group, a substituted aryl group, an aralkyl group, a substituted aralkyl group, a heterocyclic group or substituted heterocyclic group, Y ¹ Is a hydrogen atom, a hydroxyl group, an alkyl group, a substituted alkyl group, an alkoxy group, a substituted alkoxy group, an alkanoyl group, a substituted alkanoyl group, an aroyl group, a substituted aroyl group, a carboxy group,
An alkoxycarbonyl group, a substituted alkoxycarbonyl group, an amino group, an alkylamino group, a dialkylamino group, a carbamoyl group, an alkylcarbamoyl group, a dialkylcarbamoyl group, a halogen atom, a nitro group or a cyano group, Y ² is a hydrogen atom, a hydroxyl group, Alkyl group,
Substituted alkyl group, alkoxy group, substituted alkoxy group, alkanoyl group, substituted alkanoyl group, aroyl group, substituted aroyl group, carboxy group, alkoxycarbonyl group,
Represents a substituted alkoxycarbonyl group, amino group, alkylamino group, dialkylamino group, carbamoyl group, alkylcarbamoyl group, dialkylcarbamoyl group, halogen atom, nitro group or cyano group. ) Or a pharmaceutically acceptable salt thereof,

(C) R ² is a group represented by OX ³ ,
A group or an amino group represented by X ^3, X ³ is a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group, substituted alkynyl group, an aryl group, a substituted aryl group, an aralkyl group, a substituted An aralkyl group, a heterocyclic group or a substituted heterocyclic group, Y ¹ is a hydrogen atom, an alkoxy group, a substituted alkoxy group, a halogen atom or a nitro group, and Y ² is a hydrogen atom, an alkoxy group, a substituted alkoxy group, a halogen atom Or the heterocyclic compound or a pharmaceutically acceptable salt thereof according to the above (a) or (b), which is a nitro group,

(D) R ² is a group represented by OX ³ ,
A group or an amino group represented by X ^3, X ³ is an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group, an aralkyl group, a substituted aralkyl group, said heterocyclic group or substituted heterocyclic group (a) And the heterocyclic compound or a pharmaceutically acceptable salt thereof according to (b),

(E) a pharmaceutical composition comprising, as an active ingredient, the compound according to (a), (b), (c) or (d);
(F) an interferon inducer comprising the compound according to (a), (b), (c) or (d) as an active ingredient;

(G) an antiviral agent comprising the compound of (a), (b), (c) or (d) as an active ingredient;
(H) an anticancer agent comprising the compound described in (a), (b), (c) or (d) as an active ingredient; and (i) the above (a), (b), (c) or (d) And a therapeutic agent for an immunological disease comprising the compound described in (1) as an active ingredient.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION As a preferred embodiment of the compound of the present invention, (j) the heterocyclic compound according to the above (a), wherein R ¹ is an amino group, X ¹ is a nitrogen atom, and X ² is a nitrogen atom. Or pharmaceutically acceptable salts thereof.

In a more preferred embodiment of the compound of the present invention, (n) R ¹ is an amino group, X ¹ is a nitrogen atom,
² is a nitrogen atom, R ² is a group represented by OX ³ ,
The heterocyclic compound described in the above (a), which is a group represented by X ³ or an amino group, or a pharmaceutically acceptable salt thereof is mentioned.

The invention compound (1), if X ³ in R ³ is a hydrogen atom, each of the following formula (3),
It is an equilibrium mixture with the tautomers represented by (4), (5) and (6).

Embedded image

Embedded image

Embedded image

Embedded image (Wherein X ¹ and X ² both represent a nitrogen atom, X ¹ is a nitrogen atom and X ² represents CH, or X ¹ is CH and X ² represents a nitrogen atom, R ¹ is an amino group, Alkylamino group,
Represents a substituted alkylamino group, a dialkylamino group or an alicyclic heterocyclic group, Y ¹ is a hydrogen atom, a hydroxyl group, an alkyl group, a substituted alkyl group, an alkoxy group, a substituted alkoxy group, an alkanoyl group, a substituted alkanoyl group, an aroyl group, Substituted aroyl group, carboxy group, alkoxycarbonyl group, substituted alkoxycarbonyl group, amino group, alkylamino group, dialkylamino group, carbamoyl group,
Alkylcarbamoyl group, dialkylcarbamoyl group,
Represents a halogen atom, a nitro group or a cyano group, Y ² is a hydrogen atom, a hydroxyl group, an alkyl group, a substituted alkyl group, an alkoxy group, a substituted alkoxy group, an alkanoyl group, a substituted alkanoyl group, an aroyl group, a substituted aroyl group, a carboxy group, Represents an alkoxycarbonyl group, a substituted alkoxycarbonyl group, an amino group, an alkylamino group, a dialkylamino group, a carbamoyl group, an alkylcarbamoyl group, a dialkylcarbamoyl group, a halogen atom, a nitro group or a cyano group. )

In the compound (1) of the present invention, R ¹ , R ² ,
The groups represented by X ³ , Y ¹ and Y ² will be specifically described below.

The alkylamino group for R ¹ is an alkyl group (for example, a linear or branched alkyl group having 1 to 6 carbon atoms (for example, a methyl group, an ethyl group, a propyl group,
Examples thereof include a butyl group, a pentyl group, and a hexyl group. ), A C3-C7 cycloalkyl group (for example, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, etc.), a C4-C4 group.
And 10 cycloalkylalkyl groups (for example, cyclopropylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, cyclohexylethyl group, etc.). ) Is an amino group substituted with

The substituted alkylamino group for R ¹ is
An alkylamino group substituted with a substituent. Examples of the substituent include an alicyclic heterocyclic group (for example, an alicyclic heterocyclic group containing 1 to 2 nitrogen atoms and 0 to 1 oxygen atom). And a ring group, and specifically, a pyrrolidinyl group, a piperidyl group, a piperazinyl group, a tetrahydroazepinyl group, a morpholinyl group, and the like.

As the dialkylamino group for R ¹ , the same or different linear or branched alkyl groups having 1 to 6 carbon atoms (eg, methyl, ethyl, propyl, butyl, pentyl, hexyl) And the like.) And the like. Specific examples include a dimethylamino group, a diethylamino group, an ethylmethylamino group, a dipropylamino group, and the like.

The alicyclic heterocyclic group for R ¹ includes, for example, at least one nitrogen atom as a hetero atom,
Examples thereof include those in which the nitrogen atom is directly bonded to a heterocyclic ring of a mother nucleus, and specifically, an alicyclic heterocyclic group containing 1 to 2 nitrogen atoms and 0 to 1 oxygen atom. Is mentioned. More specifically, 1-pyrrolidinyl group, 1-piperidyl group, 1-piperazinyl group, tetrahydroazepine-
Examples thereof include a 1-yl group and a 4-morpholinyl group.

The alkylamino group for R ² is, for example, a linear or branched alkyl group having 1 to 6 carbon atoms (for example, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group and the like). And the like). Specific examples include a methylamino group, an ethylamino group, a propylamino group, a butylamino group, a pentylamino group, and a hexylamino group. As the substituted alkylamino group for R ^2, an alkyl group substituted with a substituent (for example, one having 1 carbon atom)
And amino groups substituted with straight-chain or branched alkyl groups (for example, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group and the like). Specific examples of the substituent include a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms (for example, methoxy group, ethoxy group, propoxy group and the like), and an alkanoyl group having 1 to 6 carbon atoms (for example, formyl) Group, acetyl group, propanoyl group, butanoyl group, pentanoyl group, hexanoyl group, etc.), carboxy group, alkoxycarbonyl group having 2 to 7 carbon atoms (for example,
Examples include a methoxycarbonyl group and an ethoxycarbonyl group. ), An amino group, an alkylamino group (for example, an amino group substituted with an alkyl group having 1 to 6 carbon atoms, etc., and specifically, a methylamino group, an ethylamino group,
Examples thereof include a propylamino group and a butylamino group. ), A dialkylamino group (for example, an amino group substituted with the same or different two alkyl groups having 1 to 6 carbon atoms), and specifically, a dimethylamino group, a diethylamino group, and an ethylmethylamino group And the like.), A carbamoyl group, and an alkylcarbamoyl group (for example, a carbamoyl group substituted with an alkyl group having 1 to 6 carbon atoms, specifically, a methylcarbamoyl group, an ethylcarbamoyl group, and a propylcarbamoyl group). ,
And a butylcarbamoyl group. ), A dialkylcarbamoyl group (for example, having the same or different carbon number 1)
And a carbamoyl group substituted with an alkyl group of No. 6 to 6, specifically, a dimethylcarbamoyl group, a diethylcarbamoyl group, an ethylmethylcarbamoyl group and the like. ), Halogen atoms (eg, fluorine, chlorine, bromine, etc.). Examples of the alicyclic heterocyclic group for R ² include those having at least one nitrogen atom as a hetero atom, and the nitrogen atom is directly bonded to the heterocyclic ring of the mother nucleus. An alicyclic heterocyclic group containing 1 to 2 atoms and 0 to 1 oxygen atom is exemplified. More specifically, a 1-pyrrolidinyl group, a 1-piperidyl group, a 1-piperazinyl group, a tetrahydroazepin-1-yl group, a 4-morpholinyl group and the like can be mentioned. As the alkyl group for X ^3, for example, a linear or branched alkyl group having 1 to 10 carbon atoms (eg, a methyl group, an ethyl group, a propyl group, a 1-methylethyl group, a butyl group, a 1-methylpropyl group) , 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-
Examples include a dimethylpropyl group and a 2,2-dimethylpropyl group. ), A C3-C7 cycloalkyl group (for example, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, etc.), a C4-C10 cycloalkylalkyl group (for example, cyclopropylmethyl) A cyclopentylmethyl group, a cyclohexylmethyl group, a cyclohexylethyl group, etc.). Preferred are, for example, a linear or branched alkyl group having 2 to 6 carbon atoms (for example, ethyl group, propyl group, 1-methylethyl group, butyl group, 1-methylpropyl group, 2-methylpropyl Group, 1,1-dimethylethyl group, pentyl group, 1-
Examples thereof include a methylbutyl group, a 2-methylbutyl group, a 3-methylbutyl group, a 1,1-dimethylpropyl group, a 1,2-dimethylpropyl group, and a 2,2-dimethylpropyl group. ), A C5-C7 cycloalkyl group (for example, a cyclopentyl group, a cyclohexyl group, etc.), a C5-C8 cycloalkylalkyl group (for example, a cyclohexylmethyl group, etc.) and the like. No.

As the substituted alkyl group for X ^3, a straight-chain or branched alkyl group having 1 to 10 carbon atoms and substituted by one or a plurality of the same or different substituents (for example, methyl group, ethyl group Group, propyl group, 1-methylethyl group, butyl group, 1-methylpropyl group, 2-methylpropyl group, 1,1-dimethylethyl group, pentyl group, 1-methylbutyl group, 2-methylbutyl group, 3-methylbutyl Group, 1,1-dimethylpropyl group, 1,2-
Examples include a dimethylpropyl group and a 2,2-dimethylpropyl group. ), A cycloalkyl group having 3 to 7 carbon atoms (for example, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group and the like), a cycloalkylalkyl group having 4 to 10 carbon atoms (for example, a cyclopropylmethyl group, a cyclopentyl) A methyl group, a cyclohexylmethyl group, a cyclohexylethyl group, etc.). Specific examples of the substituent include a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms (for example, a methoxy group, an ethoxy group, a propoxy group and the like), and a 1 to carbon atom.
6 alkanoyl groups (for example, formyl group, acetyl group, propanoyl group, butanoyl group, pentanoyl group,
Hexanoyl group and the like. ), An aroyl group having 7 to 11 carbon atoms (for example, a benzoyl group, a p-toluoyl group, a naphthoyl group, etc.), a carboxy group,
An alkoxycarbonyl group having 2 to 7 carbon atoms (for example, a methoxycarbonyl group, an ethoxycarbonyl group, etc.), an amino group, an alkylamino group (for example, an amino group substituted with an alkyl group having 1 to 6 carbon atoms, etc.) And specific examples include a methylamino group, an ethylamino group, a propylamino group, and a butylamino group.)
Dialkylamino group (for example, an amino group substituted with the same or different two alkyl groups having 1 to 6 carbon atoms, and the like; specifically, a dimethylamino group, a diethylamino group, an ethylmethylamino group, and the like; Carbamoyl group, alkylcarbamoyl group (for example, a carbamoyl group substituted with an alkyl group having 1 to 6 carbon atoms, specifically, a methylcarbamoyl group, an ethylcarbamoyl group, a propylcarbamoyl group, and a butyl group). And a dialkylcarbamoyl group (for example, a carbamoyl group substituted with the same or different alkyl group having 1 to 6 carbon atoms, specifically, a dimethylcarbamoyl group, a diethylcarbamoyl group, An ethylmethylcarbamoyl group, etc.),
An alkanoylamino group having 1 to 6 carbon atoms (for example, formylamino group, acetylamino group, propanoylamino group,
Butanoylamino, pentanoylamino, hexanoylamino and the like. ), An aroylamino group having 7 to 11 carbon atoms (e.g., benzoylamino group, p-toluoylamino group, naphthoylamino group, etc.), and a halogen atom (e.g., fluorine, chlorine, bromine, etc.). ), An alicyclic heterocyclic group (for example, a heterocyclic group containing 1 to 2 nitrogen atoms and 0 to 1 oxygen atom, etc., and specifically, a pyrrolidinyl group, a piperidyl group, a piperazinyl group, a morpholinyl group) And the like.).

As the alkenyl group for X ^3, for example, a linear or branched alkenyl group having 2 to 10 carbon atoms (for example, 2-propenyl group, 2-butenyl group,
-Methyl-2-propenyl group, 2-pentenyl group, 3-
Examples include a methyl-2-butenyl group and a 3-methyl-2-hexenyl group. ), A C5-C8 cycloalkenyl group (for example, a cyclo-2-hexenyl group, etc.), a C6-C10 cycloalkenylalkyl group (for example, a cyclo-1-hexenylmethyl group, etc.). )).

The substituted alkenyl group for X ³ is a linear or branched alkenyl group having 2 to 10 carbon atoms and substituted with one or more substituents (for example, 2-propenyl group, 2-propenyl group, A butenyl group, a 2-methyl-2-propenyl group, a 2-pentenyl group, a 3-methyl-2-butenyl group, a 3-methyl-2-hexenyl group and the like; a C5-C8 cycloalkenyl group ( For example, a cyclo-2-hexenyl group and the like can be mentioned.), And carbon number 6
And 10 to 10 cycloalkenylalkyl groups (for example, a cyclo-1-hexenylmethyl group and the like). Specific examples of the substituent include a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms (for example, a methoxy group, an ethoxy group, a propoxy group and the like), and an alkanoyl group having 1 to 6 carbon atoms (for example, formyl) Groups, acetyl groups, propanoyl groups, butanoyl groups, pentanoyl groups, hexanoyl groups, etc.), and aroyl groups having 7 to 11 carbon atoms (e.g., benzoyl groups, p-toluoyl groups, naphthoyl groups, etc.). , Carboxy group, carbon number 2
To 7 alkoxycarbonyl groups (for example, methoxycarbonyl group, ethoxycarbonyl group and the like);
Amino group, alkylamino group (for example, an amino group substituted with an alkyl group having 1 to 6 carbon atoms and the like, and specifically, a methylamino group, an ethylamino group, a propylamino group, a butylamino group, and the like. And a dialkylamino group (for example, two same or different two carbon atoms having 1 to 1 carbon atoms).
And an amino group substituted with an alkyl group of No. 6, specifically, a dimethylamino group, a diethylamino group, an ethylmethylamino group and the like. ), A halogen atom (for example, fluorine, chlorine, bromine, etc.), an alicyclic heterocyclic group (for example, a heterocyclic group containing 1-2 nitrogen atoms and 0-1 oxygen atoms). ,In particular,
Examples include a pyrrolidinyl group, a piperidyl group, a piperazinyl group, and a morpholinyl group. ) And the like.

The alkynyl group for X ³ includes, for example, a straight-chain or branched alkynyl group having 3 to 10 carbon atoms. Group, 4-methyl-2-pentynyl group, 4-methyl-2-hexynyl group, 4-methyl-
And a 2-heptynyl group.

As the substituted alkynyl group for X ³ ,
A straight-chain or branched alkynyl group having 3 to 10 carbon atoms which is substituted with one or the same or different substituents (specifically, a 2-propynyl group, a 2-butynyl group,
2-pentynyl group, 4-methyl-2-pentynyl group, 4
-Methyl-2-hexynyl group, 4-methyl-2-heptynyl group and the like. ). Specific examples of the substituent include a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms (for example, a methoxy group, an ethoxy group, a propoxy group and the like), and an alkanoyl group having 1 to 6 carbon atoms (for example, formyl) Groups, an acetyl group, a propanoyl group, a butanoyl group, a pentanoyl group, a hexanoyl group, etc.), an aroyl group having 7 to 11 carbon atoms (eg, a benzoyl group, a p-toluoyl group, a naphthoyl group, etc.). A carboxy group, an alkoxycarbonyl group having 2 to 7 carbon atoms (e.g., methoxycarbonyl group, ethoxycarbonyl group, etc.), an amino group, an alkylamino group (e.g., substituted with an alkyl group having 1 to 6 carbon atoms). And specifically include a methylamino group, an ethylamino group, a propylamino group, and a butylamino group. Mentioned are.), Dialkylamino group (e.g.,
Examples thereof include an amino group substituted with the same or different two alkyl groups having 1 to 6 carbon atoms, such as a dimethylamino group, a diethylamino group, and an ethylmethylamino group. ), Halogen atoms (eg, fluorine,
Chlorine, bromine and the like. ), An alicyclic heterocyclic group (for example, a heterocyclic group containing 1 to 2 nitrogen atoms and 0 to 1 oxygen atoms, etc., and specifically, a pyrrolidinyl group, a piperidyl group, a piperazinyl group, a morpholinyl group, and the like) And the like.) And the like.

As the aryl group for X ^3, for example,
Examples thereof include a monocyclic or condensed aryl group having 6 to 10 carbon atoms, and specific examples include a phenyl group and a naphthyl group.

As the substituted aryl group for X ^3, for example, a monocyclic or condensed aryl group having 6 to 10 carbon atoms and substituted by one or the same or different plural substituents (specifically, A phenyl group, a naphthyl group, etc.). Examples of the substituent include a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms (for example, a methoxy group, an ethoxy group, a propoxy group and the like), and an alkanoyl group having 1 to 6 carbon atoms (for example, formyl group, acetyl) Group, propanoyl group, butanoyl group, pentanoyl group, hexanoyl group, etc.), and having 7 to 7 carbon atoms.
11 aroyl group (for example, benzoyl group, p-toluoyl group, naphthoyl group, etc.), carboxy group, alkoxycarbonyl group having 2 to 11 carbon atoms (for example, methoxycarbonyl group, ethoxycarbonyl group, benzyloxycarbonyl) Groups, etc.), an amino group, an alkylamino group (for example, an amino group substituted with an alkyl group having 1 to 6 carbon atoms, and specifically, a methylamino group, an ethylamino group, a propylamino group , A butylamino group, etc.), a dialkylamino group (for example, an amino group substituted with the same or different two alkyl groups having 1 to 6 carbon atoms, specifically, a dimethylamino group, A diethylamino group, an ethylmethylamino group, etc.), a carbamoyl group, an alkylcarbamoyl group ( A carbamoyl group substituted with an alkyl group having 1 to 6 carbon atoms include eg to specifically,
Examples include a methylcarbamoyl group, an ethylcarbamoyl group, a propylcarbamoyl group, and a butylcarbamoyl group. ), A dialkylcarbamoyl group (for example, a carbamoyl group substituted with two identical or different alkyl groups having 1 to 6 carbon atoms, specifically, a dimethylcarbamoyl group, a diethylcarbamoyl group, an ethylmethylcarbamoyl group, etc.) ), A halogen atom (for example, fluorine, chlorine, bromine and the like), a nitro group, a cyano group and the like.

The aralkyl group for X ³ is, for example, an alkyl group having 1 to 6 carbon atoms, which is substituted by a monocyclic or condensed aryl group having 6 to 10 carbon atoms. And a phenethyl group.

The substituted aralkyl group represented by X ³ is, for example, the number of carbon atoms substituted by a monocyclic or condensed aryl group having 6 to 10 carbon atoms substituted with one or the same or different plural substituents. 1 to 6 alkyl groups. As the substituent, for example, a hydroxyl group, a carbon number of 1 to 6
(E.g., methoxy, ethoxy, propoxy, etc.), alkanoyl having 1 to 6 carbon atoms (e.g., formyl, acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, etc.) ), An aroyl group having 7 to 11 carbon atoms (e.g., a benzoyl group, a p-toluoyl group, a naphthoyl group, etc.), a carboxy group, and a 2-1 carbon atom.
1 alkoxycarbonyl group (for example, methoxycarbonyl group, ethoxycarbonyl group, benzyloxycarbonyl group, etc.), amino group, alkylamino group (for example, amino group substituted with alkyl group having 1 to 6 carbon atoms) And specifically include a methylamino group, an ethylamino group, a propylamino group, a butylamino group, and the like. A dialkylamino group (for example, two identical or different alkyl groups having 1 to 6 carbon atoms) And a carbamoyl group and an alkylcarbamoyl group (for example, an alkyl group having 1 to 6 carbon atoms), such as a dimethylamino group, a diethylamino group, and an ethylmethylamino group. A carbamoyl group substituted with, for example, a methylcarbamoyl group or an ethylcarbamoyl group. Yl group, propylcarbamoyl group,
And a butylcarbamoyl group. ), A dialkylcarbamoyl group (for example, a carbamoyl group substituted with two identical or different alkyl groups having 1 to 6 carbon atoms, specifically, a dimethylcarbamoyl group, a diethylcarbamoyl group, an ethylmethylcarbamoyl group, etc.) ), A halogen atom (for example, fluorine, chlorine, bromine and the like), a nitro group, a cyano group and the like.

The heterocyclic group represented by X ³ includes a monocyclic saturated group containing at least one hetero atom, containing 0 to 3 nitrogen atoms and containing 0 to 1 oxygen atom or containing 0 to 1 sulfur atom. Represents a heterocyclic group or a monocyclic or condensed unsaturated heterocyclic group. Here, the monocyclic saturated heterocyclic group means, for example, a saturated heterocyclic group forming a 5- or 6-membered ring such as a tetrahydrofuranyl group, a pyrrolidinyl group, a morpholinyl group, a piperidyl group, a piperazinyl group, and a pyrazolidinyl group. The monocyclic unsaturated heterocyclic group is, for example, a furyl group,
Represents an unsaturated heterocyclic group forming a 5- or 6-membered ring such as a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a thiazolyl group, a thienyl group, a pyridyl group, a pyrimidinyl group, and the like. The condensed unsaturated heterocyclic group means, for example, a bicyclic unsaturated heterocyclic group such as an indolyl group, an isoindolyl group, a quinolyl group, a benzothiazolyl group, a chromanyl group, and a benzofuranyl group.

The substituted heterocyclic group represented by X ³ is a heterocyclic group substituted by one or a plurality of the same or different substituents. As the heterocyclic group, a monocyclic saturated heterocyclic group containing at least one heteroatom, containing 0 to 3 nitrogen atoms and containing 0 to 1 oxygen atom or containing 0 to 1 sulfur atom, Alternatively, it represents a monocyclic or condensed unsaturated heterocyclic group. Here, the monocyclic saturated heterocyclic group means, for example, a saturated heterocyclic group forming a 5- or 6-membered ring such as a tetrahydrofuranyl group, a pyrrolidinyl group, a morpholinyl group, a piperidyl group, a piperazinyl group, and a pyrazolidinyl group. A monocyclic unsaturated heterocyclic group is, for example, an unsaturated heterocyclic group forming a five-membered or six-membered ring such as a furyl group, a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a thiazolyl group, a thienyl group, a pyridyl group, and a pyrimidinyl group. Represents a ring group. Examples of the condensed unsaturated heterocyclic group include an indolyl group,
Isoindolyl group, quinolyl group, benzothiazolyl group,
It represents a bicyclic unsaturated heterocyclic group such as a chromanyl group and a benzofuranyl group. Examples of the substituent include a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms (for example, a methoxy group, an ethoxy group, a propoxy group, and the like), and a carbon atom having 1 to 6 carbon atoms.
6 alkanoyl groups (for example, formyl group, acetyl group, propanoyl group, butanoyl group, pentanoyl group,
Hexanoyl group and the like. ), An aroyl group having 7 to 11 carbon atoms (for example, a benzoyl group, a p-toluoyl group, a naphthoyl group, etc.), a carboxy group,
An alkoxycarbonyl group having 2 to 11 carbon atoms (for example, a methoxycarbonyl group, an ethoxycarbonyl group, a benzyloxycarbonyl group, etc.), an amino group, an alkylamino group (for example, substituted with an alkyl group having 1 to 6 carbon atoms) And specifically include a methylamino group, an ethylamino group, a propylamino group, a butylamino group and the like, a dialkylamino group (for example, two identical or different carbon atoms having 1 to 1 carbon atoms). And an amino group substituted with an alkyl group of No. 6, specifically, a dimethylamino group, a diethylamino group, an ethylmethylamino group, etc., and a halogen atom (for example, fluorine, chlorine, bromine, etc.). ), A nitro group, a cyano group and the like.

Examples of the alkyl group for Y ¹ and Y ² include an alkyl group having 1 to 6 carbon atoms. Specifically, specifically, methyl, ethyl, propyl, 1
-Methylethyl group, butyl group, 1-methylpropyl group,
2-methylpropyl group, 1,1-dimethylethyl group, pentyl group, 1-methylbutyl group, 2-methylbutyl group,
3-methylbutyl group, 1,1-dimethylpropyl group,
Examples thereof include a 1,2-dimethylpropyl group and a 2,2-dimethylpropyl group.

As the substituted alkyl group for Y ¹ and Y ^2, for example, an alkyl group having 1 to 6 carbon atoms substituted with one or a plurality of the same or different substituents (for example,
Methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-
Examples thereof include a methylbutyl group, a 2-methylbutyl group, a 3-methylbutyl group, a 1,1-dimethylpropyl group, a 1,2-dimethylpropyl group, and a 2,2-dimethylpropyl group. ). Examples of the substituent include a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms (for example, a methoxy group, an ethoxy group, a propoxy group and the like), a carboxy group, an alkoxycarbonyl group having 2 to 7 carbon atoms (for example, A methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, etc.), a halogen atom (for example, fluorine, chlorine, bromine and the like).

The alkoxy group for Y ¹ and Y ² includes, for example, an alkoxy group having 1 to 6 carbon atoms, and specific examples include a methoxy group, an ethoxy group and a propoxy group.

As the substituted alkoxy group for Y ¹ and Y ^2, an alkoxy group having 1 to 6 carbon atoms substituted with one or a plurality of the same or different substituents (for example, a methoxy group, an ethoxy group, a propoxy group) And the like.). Examples of the substituent include a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms (for example, a methoxy group, an ethoxy group, a propoxy group and the like), a carboxy group, an alkoxycarbonyl group having 2 to 7 carbon atoms (for example, A methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, etc.), a halogen atom (for example, fluorine, chlorine, bromine and the like).

The alkanoyl group for Y ¹ and Y ^{2 includes} an alkanoyl group having 1 to 6 carbon atoms, and specific examples include a formyl group, an acetyl group, a propanoyl group, a butanoyl group, a pentanoyl group, and a hexanoyl group. No.

The substituted alkanoyl group for Y ¹ and Y ² is an alkanoyl group having 1 to 6 carbon atoms which is substituted with one or a plurality of the same or different substituents.
Examples include a formyl group, an acetyl group, a propanoyl group, a butanoyl group, a pentanoyl group, and a hexanoyl group. ). Examples of the substituent include a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms (for example, a methoxy group, an ethoxy group, a propoxy group and the like), a carboxy group, an alkoxycarbonyl group having 2 to 7 carbon atoms (for example, A methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, etc.), a halogen atom (for example, fluorine, chlorine, bromine and the like).

The aroyl group for Y ¹ and Y ² includes, for example, an aroyl group having 7 to 11 carbon atoms, and specific examples include a benzoyl group and a naphthoyl group.

The substituted aroyl group for Y ¹ and Y ² is, for example, an aroyl group having 7 to 11 carbon atoms substituted with one or a plurality of the same or different substituents (for example, benzoyl group, naphthoyl group, etc.). And the like). Examples of the substituent include a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms (for example, methoxy group, ethoxy group, propoxy group, etc.), a carboxy group, an alkoxycarbonyl group having 2 to 7 carbon atoms (for example,
Examples include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group and the like. ), Halogen atoms (eg, fluorine, chlorine, bromine, etc.).

Examples of the alkoxycarbonyl group for Y ¹ and Y ² include an alkoxycarbonyl group having 2 to 7 carbon atoms, and specific examples include a methoxycarbonyl group, an ethoxycarbonyl group, and a propoxycarbonyl group. .

As the substituted alkoxycarbonyl group for Y ¹ and Y ^2, an alkoxycarbonyl group having 2 to 7 carbon atoms substituted by one or a plurality of the same or different substituents (for example, methoxycarbonyl group, ethoxycarbonyl group) Group, propoxycarbonyl group, etc.). Examples of the substituent include a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms (for example, a methoxy group, an ethoxy group, a propoxy group and the like), a carboxy group, an alkoxycarbonyl group having 2 to 7 carbon atoms (for example, A methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, etc.), a halogen atom (for example, fluorine, chlorine, bromine and the like).

Examples of the alkylamino group for Y ¹ and Y ² include an amino group substituted with an alkyl group having 1 to 6 carbon atoms, specifically, a methylamino group, an ethylamino group, a propylamino group, And a butylamino group.

Examples of the dialkylamino group for Y ¹ and Y ² include, for example, amino groups substituted with the same or different alkyl groups having 1 to 6 carbon atoms, and specifically, a dimethylamino group, a diethylamino group, And an ethylmethylamino group.

Examples of the alkylcarbamoyl group for Y ¹ and Y ² include a carbamoyl group substituted with an alkyl group having 1 to 6 carbon atoms. Specific examples include a methylcarbamoyl group, an ethylcarbamoyl group, a propylcarbamoyl group, And a butylcarbamoyl group.

The dialkylcarbamoyl groups for Y ¹ and Y ² include, for example, the same or different C 1 -C 1
And a carbamoyl group substituted with an alkyl group of No. 6, specifically, a dimethylcarbamoyl group, a diethylcarbamoyl group, and an ethylmethylcarbamoyl group.

As the halogen atom for Y ¹ and Y ^2, for example, fluorine, chlorine, bromine and the like can be mentioned.

The compound of the present invention can form a salt with an acid. Preferred acids are pharmaceutically acceptable acids. Specifically, hydrochloric acid, sulfuric acid, inorganic acids such as hydrobromic acid, acetic acid, oxalic acid, citric acid, malic acid,
Organic acids such as tartaric acid, fumaric acid, maleic acid and the like can be mentioned. When the compound has an acidic substituent, it can form a salt with a base. Preferred bases include pharmaceutically acceptable bases. Specific examples include inorganic bases such as alkali metals such as sodium and potassium, and organic bases such as triethylamine and pyridine.

The compound of the present invention can be produced by the following method. In addition, the starting material compounds not described below can be produced according to the following method, or a known method or a method analogous thereto. Manufacturing method 1

Embedded image (Wherein, R ² , X ¹ , X ² , Y ¹ and Y ² represent the same meaning as in the formula (1). Y represents a leaving group such as a halogen atom such as an iodine atom and a bromine atom. ³ and R ⁴ represent a hydrogen atom, an alkyl group or a substituted alkyl group, and R ³ and R ⁴
May form an alicyclic heterocyclic group together with a nitrogen atom. R
^{When 3} and R ⁴ are hydrogen atoms, they can be appropriately protected with an amino group protecting group in an intermediate step, so that R ³ or R ⁴ includes an amino group protecting group. )

The alkyl group for R ³ and R ⁴ includes, for example, a linear or branched alkyl group having 1 to 6 carbon atoms. Specifically, methyl, ethyl, propyl, 1 -Methylethyl group, butyl group, 1-methylpropyl group, 2-methylpropyl group, 1,1-dimethylethyl group and the like.

The substituted alkyl group for R ³ and R ⁴ includes a linear or branched alkyl group having 1 to 6 carbon atoms and substituted by one or a plurality of the same or different substituents. (Examples include a methyl group, an ethyl group, a propyl group, a 1-methylethyl group, a butyl group, a 1-methylpropyl group, a 2-methylpropyl group, and a 1,1-dimethylethyl group.) Specific examples of the substituent include a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms (for example, a methoxy group, an ethoxy group, a propoxy group and the like), a carboxy group, and an alkoxycarbonyl group having 2 to 7 carbon atoms. (For example, a methoxycarbonyl group, an ethoxycarbonyl group, etc.), a halogen atom (for example, fluorine, chlorine, bromine, etc.) are mentioned. The alicyclic heterocyclic group formed by combining R ³ and R ⁴ with a nitrogen atom is, for example, a 5- or 6-membered ring such as a pyrrolidinyl group, a morpholinyl group, a piperidyl group, a piperazinyl group, and a pyrazolidinyl group. Represents a saturated heterocyclic group to be formed. Compound (8) is obtained by combining compound (7) with NHR ³ R ⁴
Is reacted in an aqueous solution or an organic solvent. As the amount of NHR ³ R ⁴ , an approximately equimolar to large excess amount can be used based on compound (7). Examples of the organic solvent include alcohol solvents such as methanol, ethanol, propanol, and butanol; ether solvents such as tetrahydrofuran, 1,4-dioxane, and diglyme; dimethylformamide, dimethyl sulfoxide, acetonitrile, and hexamethylphosphorous triamide ((( Aprotic solvents such as CH ₃ ) ₂ N) ₃ P); The reaction temperature is selected, for example, from the range of about room temperature to around the boiling point of the solvent.

Compound (10) can be obtained by reacting compound (8) with compound (9) in the presence of a base in an organic solvent. The compound (9) can be used in an amount of about equimolar to several times the molar amount of the compound (8). Examples of the base include inorganic bases such as alkali metal carbonates such as sodium carbonate and potassium carbonate; tertiary amines such as triethylamine and diisopropylethylamine; and organic bases such as pyridines such as 4-dimethylaminopyridine and pyridine. The amount of the base is preferably about equimolar amount to the compound (9). Examples of the organic solvent include halogenated hydrocarbon solvents such as carbon tetrachloride, chloroform, and methylene chloride; ether solvents such as diethyl ether, tetrahydrofuran, and 1,4-dioxane; dimethylformamide, dimethyl sulfoxide, acetonitrile, and hexamethylphospho. Aprotic solvents such as rastriamide and the like.
The reaction temperature is selected, for example, from the range of about 0 ° C. to around the boiling point of the solvent.

Compound (11) is obtained by combining compound (10) with R ²
It can be obtained by reacting H in an organic solvent in the presence or absence of a base. The amount of R ² H can be about an equimolar to a several-fold molar amount with respect to compound (10). Examples of the base include alkali metal carbonates such as potassium carbonate, alkali metals such as sodium and potassium, alkali metal hydrides such as sodium hydride and potassium hydride, and organic metal salts such as methyllithium, butyllithium, and lithium diisopropylamide. etc,
Tertiary amines such as triethylamine; pyridines such as pyridine and 4-dimethylaminopyridine;
In particular, when R ² H is an alcohol or thiol compound, it is necessary to carry out the reaction in the presence of a base,
Examples of the base used include alkali metals such as sodium and potassium, alkali metal hydrides such as sodium hydride and potassium hydride, and organic metal salts such as methyllithium, butyllithium, and lithium diisopropylamide. The amount is preferably about equimolar amount to R ² H. Examples of the organic solvent include dimethylformamide, acetonitrile, an aprotic solvent such as hexamethylphosphorous triamide, diethyl ether,
Examples include ether solvents such as tetrahydrofuran, 1,4-dioxane, and diglyme. When R ² H is an alcohol compound (for example, methanol, ethanol, propanol, butanol, etc.), it may be used as a solvent. The reaction temperature is selected, for example, from the range of -78 ° C to around the boiling point of the solvent.

Production method 2

Embedded image (In the formula, R ² , X ¹ , X ² , Y ¹ and Y ² represent the same meaning as in the formula (1). Y represents a leaving group such as a halogen atom such as an iodine atom and a bromine atom. X represents a methanesulfonyloxy group, a halogen atom such as an iodine atom or a bromine atom, p-
It represents a leaving group such as a toluenesulfonyloxy group. Bo
c represents a t-butoxycarbonyl group. ) The amino group of compound (13) can be protected, and a substituent can be introduced in the next step. The protecting group for the amino group can be removed under appropriate conditions. The following is an example.

For example, when the protecting group for the amino group is a t-butoxycarbonyl group, the compound (14) can be obtained by converting the compound (13) with water or an organic solvent or di-t-butyl dicarbonate in the presence of a base. It can be obtained by reacting in a mixed solvent. Examples of the base include inorganic bases such as alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as potassium carbonate, and organic bases such as pyridines such as 4-dimethylaminopyridine and pyridine. Can be Examples of the organic solvent include halogenated hydrocarbon solvents such as methylene chloride, ether solvents such as diethyl ether and tetrahydrofuran, aprotic solvents such as acetonitrile, and alcohol solvents such as methanol and ethanol.
Reaction temperatures are selected from the range of about 0 ° C. to about room temperature.

The leaving group can be introduced by a method known to those skilled in the art. For example, when the leaving group is a methanesulfonyloxy group, it can be introduced by the following method. Compound (1
5) can be obtained by reacting compound (14) with methanesulfonyl chloride in the presence of a base in an organic solvent. As the base, for example, an inorganic base such as an alkali metal carbonate such as potassium carbonate, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine,
Organic bases such as pyridine and the like can be mentioned. Examples of the organic solvent include halogenated hydrocarbon solvents such as methylene chloride, ether solvents such as diethyl ether and tetrahydrofuran, and aprotic solvents such as dimethylformamide. The reaction temperature is selected, for example, from the range of about 0 ° C. to around the boiling point of the solvent.

Compound (16) is obtained by converting compound (15) to R ²
It can be obtained by reacting H in an organic solvent in the presence or absence of a base. Examples of the base include alkali metal carbonates such as potassium carbonate, alkali metals such as sodium and potassium, alkali metal hydrides such as sodium hydride and potassium hydride, and organic metal salts such as methyllithium, butyllithium, and lithium diisopropylamide. And tertiary amines such as triethylamine, and pyridines such as pyridine and 4-dimethylaminopyridine. In particular, when R ² H is an alcohol or a thiol compound, it is necessary to carry out the reaction in the presence of a base. Examples of the base used include alkali metals such as sodium and potassium, sodium hydride, and hydride. Examples include alkali metal hydrides such as potassium, and organic metal salts such as methyllithium, butyllithium, and lithium diisopropylamide. Examples of the organic solvent include aprotic solvents such as dimethylformamide, acetonitrile, and hexamethylphosphorustriamide; and ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and diglyme. When R ² H is an alcohol compound (for example, methanol, ethanol, propanol, butanol, etc.), it may be used as a solvent. The reaction temperature is selected, for example, from the range of -78 ° C to around the boiling point of the solvent.

Compound (17) can be obtained by treating compound (16) with an acid in water, an organic solvent or a mixed solvent thereof. Examples of the acid include an inorganic acid such as hydrochloric acid and hydrobromic acid, and an organic acid such as trifluoroacetic acid. Examples of the organic solvent include halogenated hydrocarbon solvents such as methylene chloride, diethyl ether,
Examples include ether solvents such as tetrahydrofuran and 1,4-dioxane; aprotic solvents such as dimethylformamide and acetonitrile; alcohol solvents such as methanol, ethanol and propanol; and acetic acid. The reaction temperature is selected, for example, from the range of about room temperature to around the boiling point of the solvent.

Compound (18) can be obtained by reacting compound (17) with compound (12) in the presence of a base in an organic solvent. Examples of the base include inorganic bases such as alkali metal carbonates such as sodium carbonate and potassium carbonate; tertiary amines such as triethylamine and diisopropylethylamine; and organic bases such as pyridines such as dimethylaminopyridine and pyridine. Examples of the organic solvent include halogenated hydrocarbon solvents such as methylene chloride, ether solvents such as diethyl ether and tetrahydrofuran, and aprotic solvents such as dimethylformamide, dimethyl sulfoxide, and acetonitrile. The reaction temperature is selected, for example, from the range of about room temperature to around the boiling point of the solvent.

Compound (19) can be obtained by nitrating compound (18). The nitration includes, for example, a method of adding nitric acid in an organic solvent such as acetic acid. The reaction temperature is selected, for example, from the range of about −20 ° C. to around the boiling point of the solvent.

Compound (20) can be obtained by reducing compound (19) in an organic solvent. As the reducing agent, for example, hydrogen, sodium borohydride, lithium aluminum hydride or the like is used. Examples of the organic solvent include alcohol solvents such as methanol and ethanol, ester solvents such as ethyl acetate, and ether solvents such as diethyl ether and tetrahydrofuran. The reaction temperature is selected, for example, from the range of about 0 ° C. to around the boiling point of the solvent.

Compound (21) is prepared by converting compound (20) with formic acid or trimethyl orthoformate in the presence of an acid.
It can be obtained by reacting. Examples of the acid include an inorganic acid such as hydrochloric acid and an organic acid such as p-toluenesulfonic acid and camphorsulfonic acid. The reaction temperature is selected, for example, from the range of about room temperature to around the boiling point of the solvent.

The compound (1) of the present invention or an intermediate for producing it can be purified by a usual method. For example, it can be purified by column chromatography, recrystallization and the like. As the recrystallization solvent, for example, methanol,
Alcoholic solvents such as ethanol and 2-propanol,
Ether solvents such as diethyl ether, ester solvents such as ethyl acetate, aromatic hydrocarbon solvents such as benzene and toluene, ketone solvents such as acetone, hydrocarbon solvents such as hexane, non-solvents such as dimethylformamide and acetonitrile. Proton-based solvents and the like or a mixed solvent thereof are exemplified. In performing the above reaction, if necessary, techniques for protection and deprotection can be used. protection,
(TWGreene and PG
M. Wuts, "Protecting Groups in Organic Synthesis",
1990). When the compound (1) of the present invention has an asymmetric carbon, optical isomers are present, and a mixture of these optical isomers and an isolated isomer are also included in the compound (1) of the present invention.

The compound (1) of the present invention can be administered orally or parenterally as an interferon inducer. When administered orally, it can be administered in commonly used dosage forms such as tablets, capsules, syrups, suspensions and the like. For parenteral administration, for example, solutions such as solutions, emulsions and suspensions are administered as injections, rectally administered in the form of suppositories, transdermally administered from the skin, and sprays. Can be administered. It can also be administered as a depot preparation. Such a dosage form can be produced according to a general method by mixing an active ingredient with a usual carrier, excipient, binder, stabilizer and the like. When used in the form of an injection, a buffer, a solubilizing agent, an isotonic agent and the like can be added. The dose and the number of administrations vary depending on the disease to be treated, the condition of the patient, age, weight, sex, etc., and the administration form and preparation. However, when administered orally, the active ingredient is usually about 1 to 1 per day for an adult. A dose in the range of 1000 mg, preferably in the range of about 10-500 mg, can be administered in one or several doses. When administered as an injection, the active ingredient can be administered in a range of about 0.1 to 500 mg, preferably in a range of about 3 to about 100 mg, in one or several divided doses. The heterocyclic compound of the present invention can be used for treating various diseases as an interferon inducer, and specifically, for example, used as a therapeutic or prophylactic agent such as an antiviral agent, an anticancer agent, or a therapeutic agent for immunological diseases. be able to. Furthermore, since the heterocyclic compound of the present invention suppresses or regulates the production of Th2-side cytokines, the compound of the present invention can also be used as a therapeutic agent for allergic diseases. Specifically, Th2 pathologically hyperactive state is returned to normal by suppressing or regulating the state, and thereby allergic diseases caused by Th2 pathological hyperfunction (eg, asthma (atopic asthma, non-atopic asthma) ), Allergic dermatitis, allergic rhinitis, atopic dermatitis, etc.), systemic lupus erythematosus,
It can be used as a therapeutic or prophylactic agent for acquired immunodeficiency syndrome (AIDS). In this case, the administration method is the same as described above.

[0064]

EXAMPLES Specific examples of the compounds included in the present invention include the following compounds. In addition, these compounds are only illustrations and this invention is not limited to these.

Reference Example 1 0.5 g (2.7 mmol ) of 6-amino-2-chloropurine 2,6-dichloropurine
Was dissolved in a 30% ammonia-methanol solution and heated in an autoclave at 100 ° C. for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a crude title compound. This sample can be used for the next reaction without further purification. ¹ H-NMR (DMSO-d ₆ ) δ: 8.13 (1H, s), 7.66 (2H, br s).

Reference Example 2 6-amino-9-benzyl -2-chloropurine 0.17 ml of benzyl bromide was added to a suspension of 295 mg of 6-amino-2-chloropurine and 0.55 g (4.0 mmol) of potassium carbonate in 10 ml of DMF. (1.4mmo
l) was added and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, brine was added to the residue, and the mixture was extracted with chloroform.
The organic layer was washed with brine, dried over magnesium sulfate,
It was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with 5% methanol / chloroform, and recrystallized from ethanol to obtain 200 mg of the title compound (5
8%). mp 216-218 ° C UVλ _max (EtOH): 265.7 nm ¹ H-NMR (DMSO-d ₆ ) δ: 8.26 (1H, s), 7.81 (2H, br s),
7.31 (5H, m), 5.34 (2H, s).

Example 1 2,6-diamino-9-benzylpurine

Embedded image 5.00 g of 2,6-diaminopurine (33.3 mmol
l) and 6.91 g (50.0 mmol) of potassium carbonate in 250 ml of DMF were added to 8.5 ml of benzyl bromide.
5 g (50.0 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with 5% methanol / chloroform to give the title compound 1.
56 g were obtained (19%). ¹ H-NMR (DMSO-d ₆ ) δ: 7.78 (1H, s), 7.36-7.21 (5H,
m), 6.69 (2H, br s), 5.80 (2H, br s), 5.19 (2H, br s)
s).

Example 2 6-amino-9-benzyl-2-methylaminopurine

Embedded image 6-amino-9-benzyl-2-chloropurine 200m
g (0.77 mmol) and 50 ml of a 40% methylamine-methanol solution were heated in an autoclave at 120 ° C for 20 hours. The reaction solution was concentrated under reduced pressure, 5N aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with chloroform.
The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with 2% methanol / chloroform to obtain 163 mg of the title compound (8).
3%). ¹ H-NMR (DMSO-d ₆ ) δ: 7.78 (1H, s), 7.36-7.26 (5H,
m), 6.68 (2H, br s), 6.20 (1H, q, J = 4.8Hz), 5.19
(2H, s), 2.76 (3H, d, J = 4.8 Hz).

Example 3 6-amino-9-benzyl-2-ethylaminopurine

Embedded image 6-amino-9-benzyl-2-chloropurine 200m
g (0.77 mmol) and 50 ml of ethylamine aqueous solution
Was heated in an autoclave at 120 ° C. for 20 hours. The reaction solution was concentrated under reduced pressure, 5N aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with 2% methanol / chloroform to obtain 147 mg of the title compound (71%). ¹ H-NMR (DMSO-d ₆ ) δ: 7.78 (1H, s), 7.36-7.26 (5H,
m), 6.65 (2H, br s), 6.22 (1H, t, J = 5.7Hz), 5.18
(2H, s), 3.26 (2H, m), 1.09 (3H, t, J = 7.1Hz).

Example 4 6-amino-9-benzyl-2- (n-propylamido
No) Pudding

Embedded image 6-amino-9-benzyl-2-chloropurine 100m
g (0.385 mmol) and n-propylamine 228
50 ml of a methanol solution of mg (3.85 mmol) was heated in an autoclave at 120 ° C. for 10 hours. The reaction solution was concentrated under reduced pressure, 5N aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with 2% methanol / chloroform to obtain 99 mg of the title compound (91%). ¹ H-NMR (DMSO-d ₆ ) δ: 7.78 (1H, s),
7.33-7.26 (5H, m), 6.64
(2H, brs), 6.25 (1H, t,
J = 5.7 Hz), 5.17 (2H, s),
3.18 (2H, m), 1.50 (2H,
m), 0.87 (3H, t, J = 7.5H
z).

Example 5 6-amino-9-benzyl-2- (n-butylamino)
Pudding

Embedded image 6-amino-9-benzyl-2-chloropurine 100m
g (0.385 mmol) and n-butylamine 282 m
g (3.85 mmol) of a methanol solution of 50 ml was heated in an autoclave at 120 ° C. for 10 hours. The reaction solution was concentrated under reduced pressure, 5N aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure.
Perform silica gel column chromatography purification with chloroform,
113 mg of the title compound were obtained (99%). ¹ H-NMR (DMSO-d ₆ ) δ: 7.82 (1H, s), 7.34-7.26 (5H,
m), 6.81 (2H, br s), 6.34 (1H, t, J = 6.2Hz), 5.18
(2H, s), 3.24 (2H, m), 1.49 (2H, m), 1.31 (2H, m),
0.88 (3H, t, J = 7.3Hz).

Example 6 6-amino-9-benzyl-2- (n-pentylamido
No) Pudding

Embedded image 6-amino-9-benzyl-2-chloropurine 100m
g (0.385 mmol) and n-pentylamine 336
mg (3.85 mmol) of n-butanol suspension 10
ml was heated in an autoclave at 100 ° C. for 10 hours.
The reaction solution was concentrated under reduced pressure, 1N aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with 2% methanol / chloroform to obtain 83 mg of the title compound (70%). ¹ H-NMR (DMSO-d ₆ ) δ: 7.79 (1H, s), 7.32-7.26 (5H,
m), 6.62 (2H, br s), 6.21 (1H, t, J = 6.0Hz), 5.17
(2H, s), 3.25-3.18 (2H, m), 1.52-1.47 (2H, m), 1.30-
1.26 (4H, m), 0.86 (3H, t, J = 6.6Hz).

Example 7 6-amino-9-benzyl-2- (iso-propyla
Mino) pudding

Embedded image 6-amino-9-benzyl-2-chloropurine 100m
g (0.385 mmol) and isopropylamine 228
mg (3.85 mmol) of n-butanol suspension 10
ml was heated in an autoclave at 100 ° C. for 10 hours.
The reaction solution was concentrated under reduced pressure, 1N aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with 2% methanol / chloroform to obtain 89 mg of the title compound (82%). ¹ H-NMR (DMSO-d ₆ ) δ: 7.79 (1H, s), 7.36-7.26 (5H,
m), 6.62 (2H, br s), 6.00 (1H, d, J = 8.9Hz), 5.17
(2H, s), 4.10-3.98 (1H, m), 1.11 (6H, d, J = 66Hz).

Example 8 6-amino-9-benzyl-2- (iso-butylamido)
No) Pudding

Embedded image 6-amino-9-benzyl-2-chloropurine 100m
g (0.385 mmol) and 282 m of isobutylamine
g (3.85 mmol) of n-butanol suspension 10 m
was heated in an autoclave at 100 ° C. for 10 hours. The reaction solution was concentrated under reduced pressure, 1N aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with 2% methanol / chloroform to obtain 89 mg of the title compound (78%). ¹ H-NMR (DMSO-d ₆ ) δ: 7.79 (1H, s),
7.33-7.26 (5H, m), 6.62
(2H, brs), 6.28 (1H, t,
J = 6.0 Hz), 5.17 (2H, s),
3.07 (2H, dd, J = 6.0, 6.0
Hz), 1.89-1.79 (1H, m),
0.87 (6H, d, J = 6.8 Hz).

Example 9 6-amino-9-benzyl-2- (sec-butylamido
No) Pudding

Embedded image 6-amino-9-benzyl-2-chloropurine 100m
g (0.385 mmol) and 282 m of 2-butylamine
g (3.85 mmol) of n-butanol suspension 10 m
was heated in an autoclave at 100 ° C. for 10 hours. The reaction solution was concentrated under reduced pressure, 1N aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with 2% methanol / chloroform to obtain 71 mg of the title compound (628%). ¹ H-NMR (DMSO-d ₆ ) δ: 7.78 (1H, s), 7.33-7.26 (5H,
m), 6.60 (2H, br s), 5.97 (1H, d, J = 8.4Hz), 5.17
(2H, s), 3.90-3.85 (1H, m), 1.54-1.38 (2H, m), 1.0
8 (3H, d, J = 6.4Hz), 0.85 (3H, t, J = 7.3Hz).

Example 10 6-amino-9-benzyl-2- (2,2-dimethylprop
Ropylamino) purine

Embedded image 6-amino-9-benzyl-2-chloropurine 100m
g (0.385 mmol) and neopentylamine 336
mg (3.85 mmol) of n-butanol suspension 10
ml was heated in an autoclave at 100 ° C. for 10 hours.
The reaction solution was concentrated under reduced pressure, 1N aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with 2% methanol / chloroform to obtain 88 mg of the title compound (74%). ¹ H-NMR (DMSO-d ₆ ) δ: 7.78 (1H, s), 7.32-7.24 (5H,
m), 6.61 (2H, br s), 6.08 (1H, t, J = 6.2Hz), 5.17
(2H, s), 3.15 (2H, d, J = 6.2Hz), 0.87 (9H, s).

Example 11 6-amino-9-benzyl-2-benzylaminopurine

Embedded image 6-amino-9-benzyl-2-chloropurine 200m
g (0.77 mmol) and 825 mg of benzylamine
10 ml of an n-butanol solution (7.70 mmol) was heated under reflux for 8 hours. The reaction solution was concentrated under reduced pressure, and 5
An aqueous solution of N sodium hydroxide was added, followed by extraction with chloroform. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with 2% methanol / chloroform to obtain 171 mg of the title compound (67%). ¹ H-NMR (DMSO-d ₆ ) δ: 7.80 (1H, s), 7.34-7.15 (10H,
m), 6.86 (1H, t, J = 6.4Hz), 6.69 (2H, br s), 5.15
(2H, s), 4.47 (2H, d, J = 6.4Hz).

Example 12 6-amino-9-benzyl-2-cyclohexylamino
Pudding

Embedded image 6-amino-9-benzyl-2-chloropurine 200m
g (0.77 mmol) and cyclohexylamine 764
mg (7.70 mmol) of n-butanol solution 10 m
was heated to reflux for 60 hours. The reaction solution was concentrated under reduced pressure, 5N aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with 2% methanol / chloroform to give the title compound 115
mg (46%). ¹ H-NMR (DMSO-d ₆ ) δ: 7.79 (1H, s), 7.33-7.26 (5H,
m), 6.60 (2H, br s), 6.00 (1H, d, J = 8.1Hz), 5.16
(2H, s), 3.71 (1H, m), 1.86 (2H, m), 1.72 (2H, m),
1.68 (1H, m), 1.31-1.14 (5H, m).

Example 13 6-amino-2-anilino-9-benzylpurine

Embedded image 6-amino-9-benzyl-2-chloropurine 100m
g (0.385 mmol) and 359 mg of aniline (3.
85 mmol) of n-butanol solution was heated and refluxed for 20 hours. The reaction solution was concentrated under reduced pressure, and 5N
An aqueous sodium hydroxide solution was added, and the mixture was extracted with chloroform. The organic layer is dried over sodium sulfate, and then concentrated under reduced pressure.
The residue was purified by silica gel column chromatography with 2% methanol / chloroform to obtain 108 mg of the title compound (89%). ¹ H-NMR (DMSO-d ₆ ) δ: 8.88 (1H, s), 7.98 (1H, s), 7.
81 (2H, d, J = 7.9Hz), 7.38-7.25 (5H, m), 7.20 (2H,
t, J = 8.3Hz), 6.95 (2H, br s), 6.83 (1H, t, J = 7.3H
z), 5.29 (2H, s).

Example 14 6-amino-9-benzyl-2-dimethylaminopurine

Embedded image 6-amino-9-benzyl-2-chloropurine 100m
g (0.385 mmol) and dimethylamine aqueous solution 30
ml was heated in an autoclave at 120 ° C. for 15 hours.
The reaction solution was concentrated under reduced pressure, 5N aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with 2% methanol / chloroform to obtain 90 mg of the title compound (87%). ¹ H-NMR (DMSO-d ₆ ) δ: 7.82 (1H, s), 7.37-7.25 (5H,
m), 6.73 (2H, br s), 5.19 (2H, s), 3.07 (6H, s).

Example 15 6-amino-9-benzyl-2-benzylmethylamino
Pudding

Embedded image 6-amino-9-benzyl-2-chloropurine 100m
g (0.385 mmol) and benzylmethylamine 46
7 mg (3.85 mmol) of n-butanol solution 30
ml was heated to reflux for 10 hours. The reaction solution was concentrated under reduced pressure,
A 5N aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with 2% methanol / chloroform to give the title compound 97
mg (73%). ¹ H-NMR (DMSO-d ₆ ) δ: 7.85 (1H, s), 7.35-7.19 (10H,
m), 6.78 (2H, br s), 5.18 (2H, s), 4.85 (2H, s),
3.05 (3H, s).

Example 16 6-amino-9-benzyl-2-methoxypurine

Embedded image 6-amino-9-benzyl-2-chloropurine 200m
g (0.77 mmol) and sodium methoxide 208
A solution of mg (3.85 mmol) in 20 ml of methanol was stirred with heating under reflux for 30 hours. The reaction solution was concentrated under reduced pressure,
Water was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with 2% methanol / chloroform to obtain 151 mg of the title compound (77%). ¹ H-NMR (DMSO-d ₆ ) δ: 8.05 (1H, s), 7.37-7.25 (7H,
m), 5.26 (2H, s), 3.81 (3H, s).

Example 17 6-amino-9-benzyl-2-ethoxypurine

Embedded image 6-amino-9-benzyl-2-chloropurine 200m
g (0.77 mmol) and sodium ethoxide 262
A solution of mg (3.85 mmol) in 20 ml of ethanol was stirred with heating under reflux for 20 hours. The reaction solution was concentrated under reduced pressure,
Water was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with 2% methanol / chloroform to obtain 151 mg of the title compound (73%). ¹ H-NMR (DMSO-d ₆ ) δ: 8.04 (1H, s), 7.37-7.21 (7H,
m), 5.25 (2H, s), 4.25 (2H, q, J = 7.1Hz), 1.27 (3
(H, t, J = 7.1Hz).

Example 18 6-amino-9-benzyl-2- (n-propoxy) p
Rin

Embedded image 6-amino-9-benzyl-2-chloropurine 200m
g (0.77 mmol) and 316 mg (3.85 mmol) of sodium n-propoxide in n-propanol 2
The 0 ml solution was stirred for 3 hours under reflux. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with 2% methanol / chloroform to obtain 162 mg of the title compound (74).
%). ¹ H-NMR (DMSO-d ₆ ) δ: 8.04 (1H, s), 7.37-7.21 (7H, m),
5.26 (2H, s), 4.16 (2H, t, J = 6.6Hz), 1.68 (2H, s)
m), 0.95 (3H, t, J = 7.3Hz).

Example 19 6-amino-9-benzyl-2- (n-butoxy) pri
N

Embedded image 6-amino-9-benzyl-2-chloropurine 200m
g (0.77 mmol) and sodium n-butoxide 3
70 mg (3.85 mmol) of n-butanol 20 m
The solution was stirred for 2 hours while heating under reflux. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure.
Purification by silica gel column chromatography with -methanol / chloroform gave 131 mg of the title compound (54
%). ¹ H-NMR (DMSO-d ₆ ) δ: 8.03 (1H, s), 7.37-7.21 (7H,
m), 5.25 (2H, s), 4.20 (2H, t, J = 6.4Hz), 1.65 (2
H, m), 1.39 (2H, m), 0.92 (3H, t, J = 7.3Hz).

Example 20 6-amino-9-benzyl-2- (n-pentoxy) p
Rin

Embedded image 6-amino-9-benzyl-2-chloropurine 150m
g (0.58 mmol) and 318 mg (2.89 mmol) of sodium n-pentoxide in n-pentanol 5
The 0 ml solution was stirred for 5 hours while heating to 130 ° C. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The organic layer is dried over sodium sulfate, and then concentrated under reduced pressure.
The residue was purified by silica gel column chromatography with 2% methanol / chloroform to obtain 103 mg of the title compound (57%). ¹ H-NMR (DMSO-d ₆ ) δ: 8.03 (1H, s), 7.37-7.25 (5H,
m), 7.20 (2H, br s), 5.26 (2H, s), 4.20 (2H, t, J =
6.6Hz), 1.67 (2H, m), 1.33 (4H, m), 0.88 (3H, t, J
= 6.6Hz).

Example 21 6-amino-9-benzyl-2-methylthiopurine

Embedded image 6-amino-9-benzyl-2-chloropurine 100m
g (0.39 mmol) and 270 mg (3.9 mmol) of sodium methylthiolate in 10 ml of DMF were heated and stirred at 110 ° C. for 3.5 hours. The reaction solution was concentrated under reduced pressure, saturated saline was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with 1% methanol / chloroform to obtain 64 mg of the title compound (61%). ¹ H-NMR (CDCl ₃ ) δ: 7.63 (1H, s), 7.34 (5H, m), 5.45
(2H, br s), 5.31 (2H, s), 2.58 (3H, s).

Example 22 6-amino-9-benzyl-2-ethylthiopurine

Embedded image Sodium hydride (60% mineral oil mixture) 300mg
(7.5 mmol) of dimethylformamide (DM
F) 2 ml of ethanethiol (27 m
mol) and 100 mg (0.39 mmol) of 6-amino-9-benzyl-2-chloropurine. The mixture was heated and stirred at 110 ° C. for 3.5 hours. The reaction solution was concentrated under reduced pressure, saturated saline was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with 1% methanol / chloroform to give the title compound (90 mg).
(82%). ¹ H-NMR (CDCl ₃ ) δ: 7.64 (1H, s), 7.33 (5H, m), 5.91
(2H, br s), 5.29 (2H, s), 3.17 (2H, q, J = 7.3Hz),
1.39 (3H, t, J = 7.3Hz).

Example 23 6-amino-9-benzyl-2- (n-propylthio) p
Rin

Embedded image 917 mg of sodium hydride (60% mineral oil mixture) (2
5.0 mmol (55 mmol) of propanethiol and 500 mg (1.9 mmol) of 6-amino-9-benzyl-2-chloropurine.
l) was added sequentially. The mixture was heated and stirred at 110 ° C. for 2.5 hours. The reaction solution was concentrated under reduced pressure, saturated saline was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using 1% methanol / chloroform to obtain 505 mg of the title compound (87%). ¹ H-NMR (CDCl ₃ ) δ: 7.64 (1H, s), 7.32 (5H, m), 6.09
(2H, br s), 5.28 (2H, s), 3.14 (2H, t, J = 7.3Hz),
1.76 (2H, m), 1.03 (3H, t, J = 7.3Hz).

Example 24 6-amino-9-benzyl-2- (iso-propylthio)
E) pudding

Embedded image Sodium hydride (60% mineral oil mixture) 300mg
To a suspension of (7.5 mmol) in 10 ml of DMF was added 1.0 ml (11 mmol) of 2-propanethiol and 160 mg of 6-amino-9-benzyl-2-chloropurine (0.1 mg).
62 mmol) were added sequentially. The mixture was left for 2.5 hours,
The mixture was heated and stirred at 100 ° C. The reaction solution was concentrated under reduced pressure, saturated saline was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure.
-Purification by silica gel column chromatography with methanol / chloroform gave 112 mg of the title compound (61 mg).
%). ¹ H-NMR (CDCl ₃ ) δ: 7.64 (1H, s), 7.32 (5H, m), 5.49
(2H, br s), 5.29 (2H, s), 3.98 (1H, m), 1.43 (6H,
d, J = 6.6Hz).

Example 25 6-amino-9-benzyl-2- (n-butylthio) p
Rin

Embedded image 6-amino-9-benzyl-2-chloropurine 310m
g (1.2 mmol) and 670 mg (6.0 mmol) of sodium thio n-butylthiolate in 30 ml of DMF
The mixture was heated and stirred at 100 ° C. for 4.5 hours. The reaction solution was concentrated under reduced pressure, saturated saline was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with 0.5% methanol / chloroform to give the title compound 1
94 mg were obtained (52%). ¹ H-NMR (CDCl ₃ ) δ: 7.63 (1H, s), 7.35 (5H, m), 5.54
(2H, br s), 5.29 (2H, s), 3.17 (2H, t, J = 7.3Hz),
1.72 (2H, m), 1.48 (2H, m), 0.93 (3H, t, J = 7.6H
z).

Example 26 6-amino-9-benzyl-2- (iso-butylthio)
Pudding

Embedded image Sodium hydride (60% mineral oil mixture) 300mg
(7.5 mmol) in 10 ml of DMF, 1 ml (11 mmol) of isobutanethiol and 6-amino-9
-Benzyl-2-chloropurine 200 mg (0.77 m
mol) were added sequentially. The mixture was heated and stirred at 100 ° C. for 5 hours. The reaction solution was concentrated under reduced pressure, saturated saline was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with 1% methanol / chloroform to obtain 76 mg of the title compound (31%). ¹ H-NMR (CDCl ₃ ) δ: 7.63 (1H, s), 7.32 (5H, m), 5.46
(2H, br s), 5.29 (2H, s), 3.08 (2H, d, J = 6.9Hz),
2.00 (1H, m), 1.04 (6H, d, J = 6.6Hz).

Example 27 6-amino-9-benzyl-2- (sec-butylthio)
Pudding

Embedded image Sodium hydride (60% mineral oil mixture) 300mg
(7.5 mmol) in 1 ml of DMF suspension was mixed with 1 ml (11 mmol) of 2-butanethiol and 6-amino-9.
-Benzyl-2-chloropurine 200 mg (0.77 m
mol) were added sequentially. The mixture was heated and stirred at 100 ° C. for 5 hours. The reaction solution was concentrated under reduced pressure, saturated saline was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with 1% methanol / chloroform to obtain 85 mg of the title compound (35%). ¹ H-NMR (CDCl ₃ ) δ: 7.63 (1H, s), 7.32 (5H, m), 5.46
(2H, br s), 5.29 (2H, s), 3.85 (1H, m), 1.75 (2H,
m), 1.42 (3H, d, J = 6.9Hz), 1.03 (3H, t, J = 7.6H
z).

Example 28 6-amino-9-benzyl-2- (n-pentylthio)
Pudding

Embedded image 277 mg of sodium hydride (60% mineral oil mixture)
(6.9 mmol) in a 10 ml suspension of DMF, 2 ml (16 mmol) of n-pentanethiol and 6-amino-
9-benzyl-2-chloropurine 100 mg (0.39
mmol) were added sequentially. The mixture is kept at 110 ° C. for 4 hours.
And heated and stirred. The reaction solution was concentrated under reduced pressure, saturated saline was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using 1% methanol / chloroform to obtain 102 mg of the title compound (81%). ¹ H-NMR (CDCl ₃ ) δ: 7.64 (1H, s), 7.33 (5H, m), 5.77
(2H, br s), 5.29 (2H, s), 3.16 (2H, t, J = 7.3Hz),
1.75 (2H, m), 1.33-1.46 (4H, m), 0.89 (3H, t, J = 7.
3Hz).

Example 29 6-amino-9-benzyl-2-[(3-methylbutyi
Le) Thio] pudding

Embedded image Sodium hydride (60% mineral oil mixture) 300mg
(7.5 mmol) in a DMF (10 ml) suspension, 3-methylbutanethiol (1 ml, 8.0 mmol) and 6-amino-9-benzyl-2-chloropurine (200 mg).
(0.77 mmol) were added sequentially. 2.5
The mixture was heated and stirred at 100 ° C. for an hour. The reaction solution was concentrated under reduced pressure, saturated saline was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with 1% methanol / chloroform to obtain 120 mg of the title compound (48%). ¹ H-NMR (CDCl ₃ ) δ: 7.63 (1H, s), 7.32 (5H, m), 5.44
(2H, br s), 5.29 (2H, s), 3.17 (2H, t, J = 7.9Hz),
1.64 (3H, m), 0.94 (6H, d, J = 6.6Hz).

Example 30 6-amino-9-benzyl-2-[(2-methylbutyi
Le) Thio] pudding

Embedded image Sodium hydride (60% mineral oil mixture) 300mg
To a suspension of (7.5 mmol) in DMF (10 ml) was added 1 ml (8.0 mmol) of 2-methylbutanethiol and 200 mg of 6-amino-9-benzyl-2-chloropurine.
(0.77 mmol) were added sequentially. The mixed solution is 4.5
The mixture was heated and stirred at 100 ° C. for an hour. The reaction solution was concentrated under reduced pressure, saturated saline was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with 1% methanol / chloroform to obtain 80 mg of the title compound (32%). ¹ H-NMR (CDCl ₃ ) δ: 7.63 (1H, s), 7.32 (5H, m), 5.50
(2H, br s), 5.30 (2H, s), 3.26 (1H, q, J = 5.9Hz),
2.99 (1H, q, J = 7.6Hz), 1.78 (1H, m), 1.55 (1H,
m), 1.28 (1H, m), 1.02 (3H, d, J = 11.9Hz), 0.92 (3
(H, t, J = 11.8Hz).

Example 31 6-amino-9-benzyl-2-cyclohexylthiop
Rin

Embedded image 256mg sodium hydride (60% mineral oil mixture)
(6.4 mmol) in 10 ml of DMF was suspended in 2 ml (16 mmol) of cyclohexanethiol and 6-amino-
9-benzyl-2-chloropurine 100 mg (0.39
mmol) were added sequentially. The mixture was left for 10 hours for 3.5 hours.
Heated at 0 ° C. The reaction solution was concentrated under reduced pressure, saturated saline was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with 1% methanol / chloroform to obtain 112 mg of the title compound (86%). ¹ H-NMR (CDCl ₃ ) δ: 7.65 (1H, s), 7.33 (5H, m), 5.86
(2H, br s), 5.28 (2H, s), 3.75-3.87 (1H, m), 2.11-
2.17 (2H, m), 1.25-1.67 (8H, m).

Example 32 6-Amino-9-benzyl-2-phenylthiopurine

Embedded image 6-amino-9-benzyl-2-chloropurine 200m
g (0.77 mmol) and 2 g (15 mmol) of sodium thiophenolate in 12 ml of DMF are mixed with 7.5 g of the mixture.
The mixture was heated and stirred at 100 ° C. for an hour. The reaction solution was concentrated under reduced pressure, saturated saline was added to the residue, and the mixture was extracted with ethyl acetate.
The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with 0.5% methanol / chloroform to obtain 228 mg of the title compound (89%). ¹ H-NMR (CDCl ₃ ) δ: 7.65 to 7.70 (3H, m), 7.41-7.45 (3H,
m), 7.28-7.33 (3H, m), 7.15-7.20 (2H, m), 5.54 (2H,
br s), 5.09 (2H, s).

Example 33 6-amino-9-benzyl-2- (p-tolylthio) p
Rin

Embedded image Sodium hydride (60% mineral oil mixture) 300mg
1.9 g (15 mmol) of p-toluenethiol and 6-amino-
9-benzyl-2-chloropurine 100 mg (0.39
mmol) were added sequentially. The mixture is kept at 100 ° C. for 3 hours.
And heated and stirred. The reaction solution was concentrated under reduced pressure, saturated saline was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with 1% methanol / chloroform to obtain 124 mg of the title compound (93%). ¹ H-NMR (CDCl ₃ ) δ: 7.62 (1H, s), 7.55 (2H, d, J = 8.2H
z), 7.15-7.31 (7H, m), 5.61 (2H, br s), 5.10 (2H,
s), 2.40 (3H, s).

Example 34 6-amino-9-benzyl-2- (2-naphthylthio)
Pudding

Embedded image 800 mg of sodium hydride (60% mineral oil mixture) (2
0 mmol) in a 20 ml suspension of DMF in a suspension of 3.8 g (24 mmol) of 2-naphthalenthiol and 6-amino-9-.
Benzyl-2-chloropurine 200mg (0.77mm
ol) were added sequentially. The mixture is kept for 10.5 hours at 100
The mixture was heated and stirred at ℃. The reaction solution was concentrated under reduced pressure, saturated saline was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure.
Purification by silica gel column chromatography with methanol / chloroform gave 244 mg of the title compound (83
%). ¹ H-NMR (CDCl ₃ ) δ: 8.17 (1H, s), 7.52-7.92 (7H, m),
7.06-7.30 (5H, m), 5.63 (2H, br s), 5.04 (2H, s).

Example 35 6-amino-9-benzyl-2-benzylthiopurine

Embedded image 410 mg of sodium hydride (60% mineral oil mixture)
Benzyl mercaptan 1.7 ml (14 mmol) and 6-amino-9-
100 mg of benzyl-2-chloropurine (0.39 mm
ol) were added sequentially. The mixture is kept at 100 ° C. for 4.5 hours.
And heated and stirred. The reaction solution was concentrated under reduced pressure, saturated saline was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with 0.5% methanol / chloroform to obtain 97 mg of the title compound (73%). ¹ H-NMR (CDCl ₃ ) δ: 7.64 (1 H, s), 7.22-7.45 (10 H, m),
5.48 (2H, br s), 5.31 (2H, s), 4.43 (2H, s).

Example 36 Interferon Biosynthesis Inducing Activity Experimental method 1) Experimental animals Male (5-8 weeks) male C3H / HeJ mice were used (obtained from CLEA Japan). 2) Reagents MEM (Osaka University Micro-Lab), FCS (GIBCO or filtron), DMSO (Nacalai Tesque) 3) Test compound The test compound is accurately weighed about 1 mg each,
Dissolve in SO to make a 1 or 10 mM solution of the test compound. This solution was further added to a medium (MEM + 10% FC).
The sample was diluted 500 times in S) and used as a sample solution.

4) Preparation of Splenocytes and Culture Supernatant Two or three mice were preliminarily reared for one week, and the spleen was removed. A uniform cell suspension was prepared from the spleen by pipetting in a PBS (-) solution. This cell suspension was centrifuged (1200 rpm, 5 min., 4 ° C.), and the supernatant was removed. 4 ml of ice-cooled 0.2% saline was added to suspend quickly. After 30 seconds, 4 ml of ice-cooled 1.6% saline was added and centrifuged, and the supernatant was removed. 10 ml of a PBS (-) solution was added to suspend, and after centrifugation, the supernatant was removed. Medium (MEM + 10% FCS) 10
The suspension was added and suspended, and the supernatant was removed after centrifugation. Furthermore, the cells were suspended in 5 ml of a medium, and the number of cells was adjusted (trypan blue staining, 2 × 10 ⁶ cells / ml). After injecting the obtained cell preparation into a 24-well plate (0.5 ml / well), 0.5 ml / well of the sample solution was added to each, and incubation was performed (37 ° C., 5% carbon dioxide) for 24 hours. The culture supernatant was filtered (0.22 μm) and stored at −20 ° C. as a bioassay sample.

5) Quantification of Interferon-α in Culture Supernatant L cells (Dainippon Pharmaceutical Co., Ltd.) cultured in a monolayer were trypsinized, a medium was immediately added, and a cell suspension was prepared by pipetting ( 4 × 10 ⁵ cell / ml). 100 μl of the cell solution was injected into all wells of a 96-well plate (manufactured by Sumitomo Bakelite) and incubated for about 6 hours (37 ° C., 5% carbon dioxide). A standard mouse IFN (manufactured by Lee Bio Molec. Res.) Serially diluted in a dilution plate and the above bioassay sample were added to the assay plate at 50 µl.
Add 1 at a time. To the uninfected cell control group and the virus infection control group, 50 μl of the medium alone is added. About 1
After incubation for 8 hours, the culture solution of the assay plate was removed. The diluted bovine vesicular stomatitis virus solution (the virus distributed from the Livestock Hygiene Laboratory was cloned into BHK cells (3.7 × 10 ⁸ PFU / ml),
Was added to all wells except the virus-uninfected control group. 100 μl of medium alone was added to the virus-uninfected control group. After incubation for about 48 hours, the virus solution on the assay plate was removed by suction. 50 μl of a staining solution (neutral red) was added to all wells and incubated for 45 minutes. The stain was removed by suction, and the wells were washed with PBS (-). After removal of the PBS (-), a UV lamp is irradiated for 10 hours to inactivate the virus. 0.1M NaH ₂ PO ₄ and 99.5
100 μl of a 1: 1 mixture of% ethanol was added to each well, and the mixture was stirred for about 5 minutes using a plate mixer. Thereafter, the absorbance at 540 nm was measured with a plate reader.

6) Measurement results The results are shown in Table 1. It was revealed that the compound of the present invention has an interferon biosynthesis inducing activity.

[Table 1]

Example 37 Production of cytokines from mouse lymph node cells
Use <Experimental Method> 1. Animals BALB / c mice were purchased from Charles River Japan (Yokohama), using an 8-week-old female. 2. Medium RPMI1640 medium "Daigo" (Nippon Pharmaceutical, Tokyo) at 56 ℃
Inactivated fetal bovine serum (Fetal Bovine Serum,
Characterized, Code No.A-1115-L, HyCloneLab., Loga
n, Utah) to 10%, 2-mercaptoethanol (Sigma, S
t Louis, MO, Code No. M-6250) at 50 mM. 3. Drug The compound is dissolved in dimethyl sulfoxide (Nacalai Tesque (Kyoto) Code No. 11J) to 100 mM,
Dilute to final concentration with medium. 4. Sensitization and lymph node cell preparation KLH 0.2 mg was added to Freund's complete adjuvant (Difco La
b., Detroit, Michigan, Code No. 3113-60-5) and injected subcutaneously (0.1 ml) in the mouse footpad. Ten days later, popliteal lymph nodes are removed and a cell suspension is prepared. 5. Cytokine production by antigen stimulation KLH (0.1 mg / ml) was added to lymph node cell suspension (5 x 10 ⁶ cells / ml).
ml) and a drug, and cultured at 37 ° C. in the presence of 5% CO ₂ for 4 days (Corning 25850, 0.15 ml / well), and then the cytokine produced in the supernatant is quantified by a specific ELISA method.
Interleukin 4 (IL-4) and interleukin 5 (IL-5) are used as representative Th2-type cytokines, and interferon γ is used as a representative Th1-type cytokine.
(IFN-γ).

6. ELISA Method The quantification of IL-4 is carried out by the following ELISA method. As a primary antibody, a rat anti-mouse IL-4 antibody (Pharmingen, San Di
ego, CA, Code No. 18031D, 0.5 mg / ml) was diluted 250-fold with a carbonate buffer, and a 96-well plate (Falcon 3912, Becton Dickinson and company, Fra, was added at 50 μl / well).
nklin Lakes, NJ) and coated overnight at 4 ° C.
Thereafter, the plate is blocked with PBS (−) containing 3% BSA (200 μl / well). The plate is rinsed, dried and stored at -20 ° C until use. Culture supernatant 5
The cells were sown at 0 μl / well and incubated at room temperature for 4 hours. Recombinant mouse IL-4 (Pha
rmingen, Code No.19231W). After rinsing the plate, a biotin-labeled rat anti-mouse IL-4 antibody (Pharmingen, Code No. 18042D, 0.5 mg / m
l) diluted 500-fold with PBS (-) containing 0.1% BSA is added (100 μl / well), and incubated at room temperature for 1 hour. The bound secondary antibody was streptavidin alkaline phosphatase (Kirkegaard & Perry Lab., Gaither
ersburg, MD, Code No.15-30-00) (0.25mg / ml, 100μl)
/ well). After incubating at 37 ° C. for 1 hour, the plate was rinsed, and PNPP substrate (p-nitrophenyl phosphate disodium, Nacalai Tesque) (1 mg / m 2)
l, 100μl / well) for color development. For measurement, use a microplate reader (MTP-120 Microplatereader, Coro
na Electric) (wavelength 415 nm). For the quantification of IL-5, a rat anti-mouse IL-5 antibody (Pharming
en, SanDiego, CA, Code No. 18051D, 0.5 mg / ml), biotin-labeled rat anti-mouse IL-5 antibody (Phar
mingen, Code No. 18062D, 0.5 mg / ml) in the same manner. Recombinant mouse for preparing calibration curve
Use IL-5 (Pharmingen, Code No. 19241W). The experiment is performed by triplicate, and the average value is obtained.

[0108]

According to the present invention, there is provided an interferon inducer comprising the compound of the present invention as an active ingredient. Since the interferon-inducing agent of the present invention induces or activates the biosynthesis of interferon, it exerts its effects on the biological effects of interferon, namely, various effects such as antiviral effect, cell growth inhibitory effect, and immunomodulatory effect. It is useful as a therapeutic agent based on, for example, a therapeutic agent for viral diseases such as hepatitis B and C, an anticancer agent or a therapeutic agent for immunological diseases.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI C07D 473/18 C07D 473/18 473/24 473/24 (72) Inventor Hajime Kawakami 3-chome, Kasuganaka, Konohana-ku, Osaka-shi, Osaka No. 1 98 Sumitomo Pharmaceutical Co., Ltd.

Claims (9)

[Claims] 1. A compound of the general formula (1) (Wherein X ¹ and X ² both represent a nitrogen atom, X ¹ is a nitrogen atom and X ² represents CH, or X ¹ is CH and X ² represents a nitrogen atom, R ¹ is an amino group, alkylamino group, a substituted alkyl amino group, dialkylamino group or an alicyclic heterocyclic group, R ² is a group represented by O-X ^3, a group represented by S-X ^3, an amino group, an alkylamino group, Represents a substituted alkylamino group or an alicyclic heterocyclic group; X ³ represents a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group, a substituted alkynyl group, an aryl group, a substituted aryl group, an aralkyl group; ,
Represents a substituted aralkyl group, a heterocyclic group or a substituted heterocyclic group; Y ¹ is a hydrogen atom, a hydroxyl group, an alkyl group, a substituted alkyl group, an alkoxy group, a substituted alkoxy group, an alkanoyl group, a substituted alkanoyl group, an aroyl group, a substituted aroyl group , carboxy group, alkoxycarbonyl group, substituted alkoxycarbonyl group, an amino group, an alkylamino group, a dialkylamino group, a carbamoyl group, an alkylcarbamoyl group, a dialkylcarbamoyl group, a halogen atom, a nitro group or a cyano group, Y ² is hydrogen Atom, hydroxyl group, alkyl group, substituted alkyl group, alkoxy group, substituted alkoxy group, alkanoyl group, substituted alkanoyl group, aroyl group, substituted aroyl group, carboxy group, alkoxycarbonyl group, substituted alkoxycarbonyl group, amino group, alkylamino group , Alkylamino group, a carbamoyl group, an alkylcarbamoyl group, a dialkylcarbamoyl group, a halogen atom, a nitro group or a cyano group. Or a pharmaceutically acceptable salt thereof. 2. A compound of the general formula (2) (Wherein, R ² represents a group represented by O-X ^3, a group represented by S-X ^3, an amino group, an alkylamino group, a substituted alkyl amino group or an alicyclic heterocyclic group, X ³ is hydrogen Atom, alkyl group, substituted alkyl group, alkenyl group, substituted alkenyl group, alkynyl group, substituted alkynyl group, aryl group, substituted aryl group, aralkyl group,
Represents a substituted aralkyl group, a heterocyclic group or a substituted heterocyclic group; Y ¹ is a hydrogen atom, a hydroxyl group, an alkyl group, a substituted alkyl group, an alkoxy group, a substituted alkoxy group, an alkanoyl group, a substituted alkanoyl group, an aroyl group, a substituted aroyl group , carboxy group, alkoxycarbonyl group, substituted alkoxycarbonyl group, an amino group, an alkylamino group, a dialkylamino group, a carbamoyl group, an alkylcarbamoyl group, a dialkylcarbamoyl group, a halogen atom, a nitro group or a cyano group, Y ² is hydrogen Atom, hydroxyl group, alkyl group, substituted alkyl group, alkoxy group, substituted alkoxy group, alkanoyl group, substituted alkanoyl group, aroyl group, substituted aroyl group, carboxy group, alkoxycarbonyl group, substituted alkoxycarbonyl group, amino group, alkylamino group , Alkylamino group, a carbamoyl group, an alkylcarbamoyl group, a dialkylcarbamoyl group, a halogen atom, a nitro group or a cyano group. Or a pharmaceutically acceptable salt thereof. Wherein group R ² is represented by O-X ^3, a group or an amino group represented by S-X ^3, X ³ is a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group Alkynyl group, substituted alkynyl group, aryl group, substituted aryl group, aralkyl group, substituted aralkyl group, heterocyclic group or substituted heterocyclic group, wherein Y ¹ is a hydrogen atom, an alkoxy group, a substituted alkoxy group, a halogen atom or a nitro group. Y ² is a hydrogen atom, an alkoxy group,
The heterocyclic compound according to claim 1 or 2, which is a substituted alkoxy group, a halogen atom or a nitro group, or a pharmaceutically acceptable salt thereof. Wherein R ² is a group or an amino group represented a group represented by O-X ^3, in S-X ^3, X ³ is an alkyl group,
The heterocyclic compound according to claim 1 or 2, which is a substituted alkyl group, an aryl group, a substituted aryl group, an aralkyl group, a substituted aralkyl group, a heterocyclic group or a substituted heterocyclic group, or a pharmaceutically acceptable salt thereof. 5. A pharmaceutical composition comprising the compound according to claim 1, 2, 3 or 4 as an active ingredient. 6. An interferon-inducing agent comprising the heterocyclic compound according to claim 1, 2, 3 or 4 or a pharmaceutically acceptable salt thereof as an active ingredient. 7. An antiviral agent comprising the heterocyclic compound according to claim 1, 2, 3 or 4 or a pharmaceutically acceptable salt thereof as an active ingredient. 8. An anti-cancer agent comprising the heterocyclic compound according to claim 1, 2, 3 or 4 or a pharmaceutically acceptable salt thereof as an active ingredient. 9. A therapeutic agent for an immunological disease, comprising the heterocyclic compound according to claim 1, 2, 3 or 4 or a pharmaceutically acceptable salt thereof as an active ingredient.