JPH11193282A - Heterocyclic compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide the subject new compound exhibiting remarkable interferon biosynthesis inducing activity in vivo and useful as an active component of an antiviral agent, anticancer agent and agent for treating immune diseases. SOLUTION: This compound is a heterocyclic compound of formula I (X is SO or SO2 ; X<1> and X<2> are each N atom or the like; R<1> is amino, an alkylamino or the like; R<2> is an alkyl, an alkenyl or the like; R<3> is H, an alkyl, an alkanoyl or the like; Y<1> is H, hydroxyl group, alkyl or the like; Y<2> is H, hydroxyl group, alkyl or the like) or its pharmacologically permissible salt, e.g. 6-amino-9-benzyl-2-(n-butylsulfinyl)-8-purinol. The compound of formula I can be produced by reacting a compound of formula II with a compound of formula; NHR<4> R<5> (R<4> and R<5> are each H, an alkyl- or the like), reacting the product with a compound of formula III (Y is I atom or the like), reacting the obtained compound of formula IV with a compound of formula; R<2> SH, reacting the product with bromine and then with an alcohol and finally treating the product with an acid.

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. Since the technology for mass production of interferon was established, natural interferon was readily available from cultured cells, and large quantities of recombinant interferon could be produced from E. coli transfected with the interferon gene. Much research has been accumulated using interferons. Specifically, with respect to interferon, various biological effects such as antiviral effect, cytostatic effect and immunomodulatory effect have been confirmed, and in the clinical setting, therapeutic agents for viral diseases such as hepatitis B and C, Alternatively, it has already been put to practical use as a therapeutic agent for cancer and immune diseases. 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]

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 and a therapeutic agent for an immunological disease containing the compound as an active ingredient. is there.

[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 (Tmoane Necrosis Factor α) are also induced simultaneously (Testerman,
TL, et al .: J. Leukocyte Biol., 1995, 58, 36.
Five).

[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.

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

Embedded image (Wherein, -X- is -SO- or -SO ₂ - represents, X ¹
And X ² both represent a nitrogen atom, or X ¹ is a nitrogen atom and X
² or X ¹ represents CH is X ² in CH represents a nitrogen atom, R ¹ represents an amino group, an alkylamino group, a substituted alkyl amino group, a dialkylamino group or an alicyclic heterocyclic group, R ² Represents 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, a substituted aralkyl group, a heterocyclic group or a substituted heterocyclic group;
³ represents a hydrogen atom, an alkyl group, a substituted alkyl group, an alkanoyl group, a substituted alkanoyl group, aroyl group, substituted aroyl group, an alkoxycarbonyl group, a substituted alkoxycarbonyl group, a benzyloxycarbonyl group or a substituted benzyloxycarbonyl 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,
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 cyano group represents, Y ² is a hydrogen atom, a hydroxyl group, an alkyl group, a substituted alkyl group, an alkoxy group, substituted alkoxy group, an alkanoyl group, a substituted alkanoyl group, aroyl group, substituted aroyl group, carboxyl group, alkoxycarbonyl group, substituted alkoxycarbonyl group, Represents 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. ) Or a pharmaceutically acceptable salt thereof.

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

Embedded image (Wherein, -X- is -SO- or -SO ₂ - represents, R ²
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 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,
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.

More specifically, the present invention relates to (c) wherein R ² is 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, 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, Y ² is a hydrogen atom, an alkoxy group,
The present invention relates to the heterocyclic compound according to (a) or (b), which is a substituted alkoxy group, a halogen atom or a nitro group, or a pharmaceutically acceptable salt thereof.

More specifically, the present invention relates to (d) -X-
Is -SO-, or a pharmaceutically acceptable salt thereof according to (a), (b) or (c).

Further, the present invention provides (e) (a), (b),
The present invention relates to a pharmaceutical composition containing the compound described in (c) or (d) as an active ingredient or an interferon inducer containing (f) a compound described in (a), (b), (c) or (d) as an active ingredient.

Specifically, the present invention provides (g) (a)
(B) an antiviral agent containing the compound described in (c) or (d) as an active ingredient; and (h) an anticancer agent containing the compound described in (a), (b), (c) or (d) as an active ingredient. Or (i) a therapeutic agent for an immunological disease, comprising the compound described in (a), (b), (c) or (d) as an active ingredient.

Preferred compounds in the present invention include (j) the heterocyclic compound described in (a) or (d) wherein R ³ is a hydrogen atom, or a pharmaceutically acceptable salt thereof. Preferred compounds in the present invention include (k) R ³ is a hydrogen atom, X ¹ is a nitrogen atom,
The heterocyclic compound according to (a) or (d), wherein X ² is a nitrogen atom, or a pharmaceutically acceptable salt thereof.
Preferred compounds in the present invention include (l) R ³
Is a hydrogen atom, X ¹ is a nitrogen atom, and X ² is CH, or a pharmaceutically acceptable salt thereof according to (a) or (d). Preferred compounds in the present invention include (m) the heterocyclic compound according to (a) or (d), wherein R ³ is a hydrogen atom, X ¹ is CH, and X ² is a nitrogen atom, or a pharmaceutically acceptable salt thereof. Acceptable salts are included.

Preferred compounds in the present invention include (n) the heterocyclic compound or a pharmaceutically acceptable salt thereof according to (a) or (d), wherein R ¹ is an amino group and R ³ is a hydrogen atom. Is mentioned. Preferred compounds in the present invention include (o) R ¹ is an amino group and R ³
Is a hydrogen atom, X ¹ is a nitrogen atom, and X ² is a nitrogen atom. (A) or (d), or a pharmaceutically acceptable salt thereof. Preferred compounds in the present invention include (p) R ¹ is an amino group, R ³ is a hydrogen atom, X ¹ is a nitrogen atom, and X
The heterocyclic compound according to (a) or (d), wherein ² is CH, or a pharmaceutically acceptable salt thereof. Preferred compounds in the present invention include (q) R ¹ is an amino group, R ³ is a hydrogen atom, X ¹ is CH,
The heterocyclic compound according to (a) or (d), wherein X ² is a nitrogen atom, or a pharmaceutically acceptable salt thereof.

In a preferred group of compounds according to the present invention, (r) R ² is an alkyl group, a substituted alkyl group, an aralkyl group or a substituted aralkyl group (a) or (d).
Or a pharmaceutically acceptable salt thereof. In the present invention, preferred examples of the compound group include (s) the heterocyclic compound according to (a) or (d), wherein R ² is an alkyl group, a substituted alkyl group, an aralkyl group or a substituted aralkyl group, and R ³ is a hydrogen atom. And pharmaceutically acceptable salts thereof. Preferred compounds in the present invention include (t) R ² is an alkyl group, a substituted alkyl group, an aralkyl group or a substituted aralkyl group, R ³ is a hydrogen atom, X ¹ is a nitrogen atom, and X
The heterocyclic compound according to (a) or (d), wherein ² is a nitrogen atom, or a pharmaceutically acceptable salt thereof. Preferred compounds in the present invention include (u) R ² is an alkyl group, a substituted alkyl group, an aralkyl group or a substituted aralkyl group, R ³ is a hydrogen atom, X ¹ is a nitrogen atom, and X ² is CH (A) or (d), or a pharmaceutically acceptable salt thereof. Preferred compounds in the present invention include (v) R ² is an alkyl group, a substituted alkyl group, an aralkyl group or a substituted aralkyl group, R ³ is a hydrogen atom, X ¹ is CH, and X ² is a nitrogen atom (A) or (d), or a pharmaceutically acceptable salt thereof.

Preferred compounds in the present invention include (w) R ¹ is an amino group, R ² is an alkyl group, a substituted alkyl group, an aralkyl group or a substituted aralkyl group, and R ³ is a hydrogen atom (a ) Or (d), or a pharmaceutically acceptable salt thereof. In the present invention, a preferable compound group includes (x)
R ¹ is an amino group, R ² is an alkyl group, a substituted alkyl group, an aralkyl group or a substituted aralkyl group, R ³
Is a hydrogen atom, X ¹ is a nitrogen atom, and X ² is a nitrogen atom. (A) or (d), or a pharmaceutically acceptable salt thereof. Preferred compounds in the present invention include (y) R ¹ is an amino group, R ² is an alkyl group, a substituted alkyl group, an aralkyl group or a substituted aralkyl group, R ³ is a hydrogen atom, and X ¹ is a nitrogen atom. The heterocyclic compound or a pharmaceutically acceptable salt thereof according to (a) or (d), wherein X is CH and X ² is CH. Preferred compounds in the present invention include (z) R ¹ is an amino group, R ² is an alkyl group, a substituted alkyl group, an aralkyl group or a substituted aralkyl group, R ³ is a hydrogen atom, and X ¹ is CH And
The heterocyclic compound according to (a) or (d), wherein X ² is a nitrogen atom, or a pharmaceutically acceptable salt thereof.

Further, the heterocyclic compound of the present invention may contain cytokines (eg, IL-4 (interleukin 4), IL-5 (interleukin 5), and IL-) on the type 2 helper T cell (hereinafter abbreviated as Th2) side. 10 (interleukin 10), IL-
The present inventors have found that the production or regulation of 13 (interleukin 13) or the like is suppressed or regulated. Th2 is regarded as an important regulatory cell for allergic reactions because it produces many cytokines involved in allergic reactions. For example, IL-4 induces B cells to produce IgE antibodies and also induces gene expression of VCAM-1, a key molecule that functions when eosinophils adhere to vascular endothelial cells and infiltrate tissues. I do. Recently, IL-4 has attracted attention as a differentiation and growth factor of Th2 itself. For example, IL-5 induces differentiation, proliferation, migration and activation of eosinophils, and becomes an inducer of an allergic inflammatory response. Therefore, Th2 is IgE
It is a central cell that controls two allergic reactions, an immediate reaction involving antibodies and mast cells, and a late reaction involving eosinophils. That is, it can be said that an allergic disease is a state in which Th2 is pathologically hyperactive. In fact, it promotes the production of Th2 type cytokines such as IL-4 and IL-5 in the respiratory tract and skin, which are allergic disease lesions, or Th.
2 has been confirmed, and T
Control or regulation of h2 activation has been noted as important (clinician (1994) 20: 40-46). In autoimmune diseases in which antibody production or humoral immunity such as systemic lupus erythematosus is abnormally enhanced, Th2 is also said to be in a pathologically hyperfunctional state (Medical Immunol).
ogy (1988) 15: 401). Therefore, returning or approaching normal by suppressing or modulating the pathologically hyper-functional state of Th2 is required for allergic diseases (eg, asthma (atopic asthma,
Non-atopic asthma), allergic dermatitis, allergic rhinitis, atopic dermatitis, etc.), systemic lupus erythematosus, and acquired immunodeficiency syndrome (AIDS).

The present invention further provides an inhibitor of Th2 pathological hyperactivity, which comprises as an active ingredient the heterocyclic compound described in (aa), (a), (b) or (d) or a pharmaceutically acceptable salt thereof. It relates to a regulator.

The present invention more specifically relates to (ab)
The present invention relates to an inhibitor or regulator of interleukin 4 and / or interleukin 5 production, which comprises the heterocyclic compound described in (a), (b) or (d) or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention further provides (ac) (a)
(B) or allergic disease due to pathological hyperactivity of Th2, or systemic lupus erythematosus or acquired immunodeficiency syndrome (AIDS), comprising the heterocyclic compound or a pharmaceutically acceptable salt thereof according to (d) as an active ingredient. It relates to a therapeutic or prophylactic agent.

The present invention more specifically relates to (ad)
Asthma, allergic dermatitis, allergic rhinitis or atopic illness due to pathological hyperactivity of Th2 containing the heterocyclic compound described in (a), (b) or (d) or a pharmaceutically acceptable salt thereof as an active ingredient. The present invention relates to an agent for treating or preventing allergic diseases of dermatitis.

[0021]

BEST MODE FOR CARRYING OUT THE INVENTION The compound represented by the formula (1) of the present invention is represented by the following formulas (3), (4), (5), (6), (7) and ( 8).

Embedded image

Embedded image

Embedded image (Wherein, R ¹ represents an amino group, an alkylamino group, a substituted alkylamino group, a dialkylamino group or an alicyclic heterocyclic group, and R ² represents an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an 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, and R ³ represents a hydrogen atom, an alkyl group, a substituted alkyl group, an alkanoyl group, a substituted alkanoyl group, an aroyl group, a substituted aroyl group, an alkoxycarbonyl group, a substituted alkoxycarbonyl group. Represents a benzyloxycarbonyl group or a substituted benzyloxycarbonyl group, Y ¹ is a hydrogen atom,
Hydroxyl group, alkyl group, substituted alkyl group, alkoxy group,
Substituted alkoxy, alkanoyl, substituted alkanoyl, aroyl, substituted aroyl, carboxy, alkoxycarbonyl, substituted alkoxycarbonyl, amino, alkylamino, dialkylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl Represents a group, a halogen atom, a 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. Group, alkoxycarbonyl group, substituted alkoxycarbonyl group, amino group, alkylamino group, dialkylamino group, carbamoyl group, alkylcarbamoyl group, dialkylcarbamoyl group, halogen atom, nitro group or cyano It represents a group. )

When R ³ is a hydrogen atom, the following formulas (9), (10), (11) and (1)
2), an equilibrium mixture with the tautomers represented by the formulas (13) and (14).

Embedded image

Embedded image

Embedded image (Wherein, R ¹ represents an amino group, an alkylamino group, a substituted alkylamino group, a dialkylamino group or an alicyclic heterocyclic group, and R ² represents an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an 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, 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, a substituted alkanoyl group, an aroyl group, a substituted aroyl group Represents 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, and Y ² represents 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, dialkylamino group, carbamoyl group, alkylcarbamoyl group, dialkylcarbamoyl group, halogen atom, nitro group or cyano group Represent. )

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

The alkylamino group for R ¹ is, for example, a linear or branched alkyl group having 1 to 6 carbon atoms (eg, methyl, ethyl, propyl, butyl, pentyl, hexyl, etc.). A cycloalkyl group having 3 to 7 carbon atoms (e.g., cyclopropyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, etc.), and a cycloalkyl alkyl group having 4 to 10 carbon atoms (e.g., , A cyclopropylmethyl group,
Cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl and the like. ) And the like. Specifically, for example, methylamino group, ethylamino group, propylamino group, butylamino group, pentylamino group, hexylamino group, cyclopropylamino group, cyclopentylamino group, cyclohexylamino group, cycloheptylamino group, cyclopropyl Examples thereof include a methylamino group, a cyclopentylmethylamino group, a cyclohexylmethylamino, and a 2-cyclohexylethylamino group.

As the substituted alkylamino group for R ^1, an alkyl group substituted with a substituent (for example, one having 1 carbon atom)
To 6 linear or branched alkyl groups (for example, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, etc.) and a cycloalkyl group having 3 to 7 carbon atoms (for example, , A cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, etc.), a cycloalkylalkyl group having 4 to 10 carbon atoms (eg, a cyclopropylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, a cyclohexylethyl) And the like.). )) And the like. 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 the like, and specifically, a pyrrolidinyl group , A piperidyl group, a piperazinyl group, a tetrahydroazepinyl group, a morpholinyl group, etc.).

As the dialkylamino group for R ¹ , the same or different linear or branched alkyl groups having 1 to 6 carbon atoms (for example, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group) 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, those containing at least one nitrogen atom as a hetero atom and the nitrogen atom being directly bonded to the heterocyclic ring of the mother nucleus. And alicyclic heterocyclic groups containing 1-2 nitrogen atoms and 0-1 oxygen atoms. 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.

Examples of the alkyl group for R ² include:
A linear or branched alkyl group having 1 to 10 carbon atoms (for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 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 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 1 to 6 carbon atoms (eg, a methyl group, an ethyl group, a propyl group, a 1-methylethyl group, a butyl group, a 1-methylpropyl group, -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 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.

As the substituted alkyl group for R ^{2, a} linear or branched alkyl group having 1 to 10 carbon atoms and substituted with one or the same or different substituents (eg, 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.).

The alkenyl group for R ² is, 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 R ² is a straight-chain or branched alkenyl group having 2 to 10 carbon atoms which is substituted by one or more substituents (eg, 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 R ² includes, for example, a linear or branched alkynyl group having 2 to 10 carbon atoms, and specific examples thereof include a 2-propynyl group, a 2-butynyl group and a 2-pentynyl group. Group, 4-methyl-2-pentynyl group, 4-methyl-2-hexynyl group, 4-methyl-
And a 2-heptynyl group.

As the substituted alkynyl group for R ² ,
A straight-chain or branched alkynyl group having 2 to 10 carbon atoms and substituted by 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 R ^2, 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 R ^2, 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 R ² 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 R ² is, for example, the number of carbon atoms substituted by a monocyclic or condensed aryl group having 6 to 10 carbon atoms substituted by one or the same or different 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.

As the heterocyclic group for R ^2, a monocyclic saturated group containing at least one hetero atom, containing 0 to 3 nitrogen atoms and 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 R ² includes 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.

As the alkyl group for R ^3, for example,
Examples thereof include a linear or branched alkyl group having 1 to 6 carbon atoms, and specifically, a methyl group, an ethyl group, a propyl group, a 1-methylethyl group, a butyl group, a 1-methylpropyl group, -Methylpropyl group, 1,1-dimethylethyl group, pentyl group, 1-methylbutyl group, 2-methylbutyl group, 3-methylbutyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2 -Dimethylpropyl group and the like.

The substituted alkyl group for R ³ 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 (for example, 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, 1,2-dimethylpropyl group, 2,2-dimethylpropyl 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) 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.). An alkanoyloxy group having 1 to 6 carbon atoms (for example, a formyloxy group, an acetyloxy group, a propanoyloxy group, a butanoyloxy group, a pentanoyloxy group, a hexanoyloxy group and the like); To 11 aroyl groups (e.g., benzoyl group, p-toluoyl group, naphthoyl group, etc.), carboxy An alkoxycarbonyl group having 2 to 7 carbon atoms (for example, methoxycarbonyl group, 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) Specific examples 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 C1 to C6 Examples include an amino group substituted with an alkyl group, specifically, a dimethylamino group, a diethylamino group, an ethylmethylamino group, and the like, and a halogen atom (eg, fluorine, chlorine, bromine, and the like). )).

Examples of the alkanoyl group for R ³ include 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. .

The substituted alkanoyl group for R ³ is an alkanoyl group having 1 to 6 carbon atoms substituted by one or a plurality of the same or different substituents (for example, formyl, acetyl, propanoyl, butanoyl) Pentanoyl group, hexanoyl 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.)
A dialkylamino group (for example, an amino group substituted by 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; And a halogen atom (for example, fluorine, chlorine, bromine, etc.).

As the aroyl group for R ^3, for example,
An aroyl group having 7 to 11 carbon atoms is mentioned, and specifically,
Examples include a benzoyl group and a naphthoyl group.

As the substituted aroyl group for R ^3, for example, those having 7 to 7 carbon atoms substituted by one or more substituents
11 aroyl groups (for example, benzoyl group, naphthoyl 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. And a 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. Specific examples include a dimethylamino group, a diethylamino group, and an ethylmethyl group. An amino group, etc.), a halogen atom (for example, fluorine, chlorine, bromine, etc.).

Examples of the alkoxycarbonyl group for R ³ 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 R ^3, an alkoxycarbonyl group having 2 to 7 carbon atoms substituted with one or a plurality of the same or different substituents (for example, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxy group) A carbonyl 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, etc.), a carboxy group,
Examples thereof include an alkoxycarbonyl group having 2 to 7 carbon atoms (for example, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, and the like), a halogen atom (for example, fluorine, chlorine, and bromine). .

Examples of the substituted benzyloxycarbonyl group for R ³ include a benzyloxycarbonyl group substituted with one or a plurality of the same or different substituents. 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, etc.), a carboxy group,
Examples thereof include an alkoxycarbonyl group having 2 to 7 carbon atoms (for example, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, and the like), a halogen atom (for example, fluorine, chlorine, and bromine). .

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).

Examples of the alkoxy group for Y ¹ and Y ² include 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,
Examples include a methoxy group, an ethoxy group, and a propoxy 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).

Examples of the alkanoyl group for Y ¹ and Y ² include alkanoyl groups 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).

Examples of the aroyl group for Y ¹ and Y ² include an aroyl group having 7 to 11 carbon atoms, and specific examples include a benzoyl group and a naphthoyl group.

As the substituted aroyl group for Y ¹ and Y ^2, for example, an aroyl group having 7 to 11 carbon atoms substituted by 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, which is 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).

The alkylamino group for Y ¹ and Y ² includes, for example, 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. 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 groups used without particular definition in the present specification are described in detail below. Examples of the alkyl group include a linear or branched alkyl group having 1 to 6 carbon atoms (specifically, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, and the like). A cycloalkyl group having 3 to 7 carbon atoms (for example, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, etc.);
A cycloalkylalkyl group having 4 to 10 carbon atoms (for example,
Examples include a cyclopropylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, and a cyclohexylethyl group. ) And the like.

The alkyl group in the alkylamino group and the dialkylamino group includes, for example, a linear or branched alkyl group having 1 to 6 carbon atoms. Specifically, a methyl group, an ethyl group, a propyl group, Examples thereof include a butyl group, a pentyl group, and a hexyl group.

Examples of the substituted alkylamino group include the above-mentioned alkyl groups substituted with a substituent. Examples of the substituent include an alicyclic heterocyclic group (for example, a nitrogen atom having 1 to 2 nitrogen atoms).
And an alicyclic heterocyclic group containing 0 to 1 oxygen atom, specifically, a pyrrolidinyl group, a piperidyl group, a piperazinyl group, a tetrahydroazepinyl group, a morpholinyl group and the like. ) And the like.

The alicyclic heterocyclic group includes, for example, those containing at least one nitrogen atom as a heteroatom. For example, one or two nitrogen atoms and 0 to 0 oxygen atoms.
And alicyclic heterocyclic groups containing one. More specifically, a pyrrolidinyl group, a piperidyl group, a piperazinyl group, a tetrahydroazepin-1-yl group, a morpholinyl group 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 compounds specifically included in the present invention include, for example, the following compounds. In the table, H represents a hydrogen atom. amino is an amino group, methyl is a methyl group, e
thyl is ethyl, propyl is propyl, butyl is butyl, pentyl is pentyl, hexyl is hexyl, heptyl is heptyl, methylethyl is methylethyl, and methylpropyl is methylpropyl. , Dimethyl
ethyl is a dimethylethyl group, methylbutyl is a methylbutyl group, dimethylpropyl is a dimethylpropyl group, meth
ylpentyl is methylpentyl, dimethylbutyl is dimethylbutyl, ethylbutyl is ethylbutyl, and trimethy
lpropyl is a trimethylpropyl group, cyclopropyl is a cyclopropyl group, cyclopentyl is a cyclopentyl group, c
yclohexyl is a cyclohexyl group, cycloheptyl is a cycloheptyl group, cyclopropylmethyl is a cyclopropylmethyl group, cyclopentylmethyl is a cyclopentylmethyl group, cyclohexylmethyl is a cyclohexylmethyl group,
cycloheptylmethyl is a cycloheptylmethyl group,
propylethyl is a cyclopropylethyl group, cyclopentyl
ethyl is cyclopentylethyl group, cyclohexylethyl is cyclohexylethyl group, cycloheptylethyl is cycloheptylethyl group, cyclopropylpropyl is cyclopropylpropyl group, cyclopentylpropyl is cyclopentylpropyl group, cyclohexylpropyl is cyclohexylpropyl group, cycloheptylpropyl is cycloheptylpropyl Group, cyclopropylbutyl is cyclopropylbutyl group, cyclopentylbutyl is cyclopentylbutyl group, cy
clohexylbutyl is a cyclohexylbutyl group
ylbutyl is a cycloheptylbutyl group, cyclopropylpent
yl is a cyclopropylpentyl group, cyclopentylpentyl
Is cyclopentylpentyl, cyclohexylpentyl is cyclohexylpentyl, cycloheptylpentyl is cycloheptylpentyl, methoxyhexyl is methoxyhexyl, methoxypentyl is methoxypentyl, met
hoxybutyl is methoxybutyl, methoxypropyl is methoxypropyl, methoxyethyl is methoxyethyl, fluorohexyl is fluorohexyl, fluoropenty
l is a fluoropentyl group, fluorobutyl is a fluorobutyl group, fluoropropyl is a fluoropropyl group, fluoro
ethyl is a fluoroethyl group, chlorohexyl is a chlorohexyl group, chloropentyl is a chloropentyl group, chloro
butyl is chlorobutyl, chloropropyl is chloropropyl, chloroethyl is chloroethyl, hydroxyhe
xyl is a hydroxyhexyl group, hydroxypentyl is a hydroxypentyl group, hydroxybutyl is a hydroxybutyl group, hydroxypropyl is a hydroxypropyl group,
ethyl is hydroxyethyl group, carboxyhexyl is carboxyhexyl group, carboxypentyl is carboxypentyl group, carboxybutyl is carboxybutyl group, carbox
ypropyl is carboxypropyl group, carboxyethyl is carboxyethyl group, methoxycarbonylhexyl is methoxycarbonylhexyl group, methoxycarbonylpentyl is methoxycarbonylpentyl group, methoxycarbonylbutyl
Is a methoxycarbonyl butyl group,
pyl represents a methoxycarbonylpropyl group,
ylethyl is a methoxycarbonylethyl group, carbamoylhe
xyl is carbamoylhexyl, carbamoylpentyl is carbamoylpentyl, carbamoylbutyl is carbamoylbutyl, carbamoylpropyl is carbamoylpropyl, carbamoylethyl is carbamoylethyl, di
methylcarbamoylhexyl is a dimethylcarbamoylhexyl group, dimethylcarbamoylpentyl is a dimethylcarbamoylpentyl group, dimethylcarbamoylbutyl is a dimethylcarbamoylbutyl group, dimethylcarbamoylpropyl is a dimethylcarbamoylpropyl group, dimethylcarbamoyle
thyl is a dimethylcarbamoylethyl group, methylcarbam
oylhexyl is a methylcarbamoylhexyl group, methylca
rbamoylpentyl is a methylcarbamoylpentyl group, met
hylcarbamoylbutyl is a methylcarbamoylbutyl group, m
ethylcarbamoylpropyl is methylcarbamoylpropyl, methylcarbamoylethyl is methylcarbamoylethyl, ethylcarbamoylhexyl is ethylcarbamoylhexyl, ethylcarbamoylpentyl is ethylcarbamoylpentyl, ethylcarbamoylbutyl is ethylcarbamoylbutyl, ethylcarbamoylpropyl is ethylcarbamoylpropyl, ethylcarbamoylpropyl is ethylcarbamoylpropyl. Ethylcarbamoylethyl group, diethylcarbamoylhexyl, diethylcarbamoylhexyl group, diethylcarbamoylpentyl group
yl is a diethylcarbamoylpentyl group, diethylcarba
moylbutyl is a diethylcarbamoylbutyl group,
carbamoylpropyl is diethylcarbamoylpropyl, diethylcarbamoylethyl is diethylcarbamoylethyl, trifluorohexyl is trifluorohexyl, trifluoropentyl is trifluoropentyl, tri
fluorobutyl replaces the trifluorobutyl group with trifluoroprop
yl is a trifluoropropyl group, trifluoroethyl is a trifluoroethyl group, aminohexyl is an aminohexyl group, aminopentyl is an aminopentyl group, aminobutyl is an aminobutyl group, aminopropyl is an aminopropyl group, and aminoethyl is an aminoethyl group. , Methylaminohexyl
Is methylaminohexyl, methylaminopentyl is methylaminopentyl, methylaminobutyl is methylaminobutyl, methylaminopropyl is methylaminopropyl, methylaminoethyl is methylaminoethyl, dimethylaminohexyl is dimethylaminohexyl, dimethylaminopentyl is dimethyl Aminopentyl group, dimethylaminobutyl is dimethylaminobutyl group,
dimethylaminopropyl is a dimethylaminopropyl group, d
imethylaminoethyl is a dimethylaminoethyl group, acety
laminohexyl is an acetylaminohexyl group
nopentyl is an acetylaminopentyl group,
utyl is an acetylaminobutyl group
Is acetylaminopropyl, acetylaminoethyl is acetylaminoethyl, benzoylaminohexyl is benzoylaminohexyl, benzoylaminopentyl is benzoylaminopentyl, benzoylaminobutyl is benzoylaminobutyl, benzoylaminopropyl is benzoylaminopropyl, and benzoylaminoethyl is benzoyl. Aminoethyl, ethoxypentyl, ethoxypentyl, ethoxybutyl, ethoxybutyl, ethoxypropy
l is ethoxypropyl group, ethoxyethyl is ethoxyethyl group, propoxypropyl is propoxypropyl group, pro
poxyethyl is propoxyethyl group, benzyl is benzyl group, phenylethyl is phenylethyl group, fluorobenzy
l is a fluorobenzyl group, difluorobenzyl is a difluorobenzyl group, chrolobenzyl is a chlorobenzyl group,
dichrolobenzyl is a dichlorobenzyl group, methoxybenzy
l is methoxybenzyl group, dimethoxybenzyl is dimethoxybenzyl group, trimethoxybenzyl is trimethoxybenzyl group, hydroxybenzyl is hydroxybenzyl group, d
ihydroxybenzyl is a dihydroxybenzyl group, methylbe
nzyl is methylbenzyl, aminobenzyl is aminobenzyl, dimethylaminobenzyl is dimethylaminobenzyl, carbamoylbenzyl is carbamoylbenzyl, dimethylcarbamoylbenzyl is dimethylcarbamoylbenzyl, methylcarbamoylbenzyl is methylcarbamoylbenzyl, and cyanobenzyl is cyanobenzyl. Phenoxybenzyl is a phenoxybenzyl group, carboxy
benzyl is a carboxybenzyl group, methoxycarbonylben
zyl is a methoxycarbonylbenzyl group, acetylbenzyl
Is acetylbenzyl, benzoylbenzyl is benzoylbenzyl, phenyl is phenyl, fluorophenyl is fluorophenyl, difluorophenyl is difluorophenyl, chlorophenyl is chlorophenyl, dichlo
rophenyl is a dichlorophenyl group, methoxyphenyl is a mexitophenyl group, dimethoxyphenyl is a dimethoxyphenyl group, trimethoxyphenyl is a trimethoxyphenyl group, hydroxyphenyl is a hydroxyphenyl group, dihyd
roxyphenyl is a dihydroxyphenyl group, methylphenyl
Is a methylphenyl group, aminophenyl is an aminophenyl group, dimethylaminophenyl is a dimethylaminophenyl group, methylphenyl is a methylphenyl group, cyanopheny
l is cyanophenyl, phenoxyphenyl is phenoxyphenyl, carbanoylphenyl is carbamoylphenyl, methycarbamoylphenyl is methylcarbamoylphenyl, dimethylcarbamoylphenyl is dimethylcarbamoylphenyl, carboxyphenyl is carboxyphenyl, and methoxycarbonylphenyl is methoxycarbonylphenyl. , Acetylphenyl is an acetylphenyl group, benzoylphenyl is a benzoylphenyl group, (4-fluo
rophenyl) ethyl is a (4-fluorophenyl) ethyl group, and (4-chlorophenyl) ethyl is (4-chlorophenyl)
Ethyl, (4-methoxyphenyl) ethyl is (4-methoxyphenyl) ethyl, chloro is chlorine, fluoro is fluorine, bromo is bromine, nitro is nitro, and methoxy is methoxy. , Acetyl represents an acetyl group, b
enzoyl is a benzoyl group, cyano is a cyano group, carbamo
yl is a carbamoyl group, dimethylcarbamoyl is a dimethylcarbamoyl group, methylcarbamoyl is a methylcarbamoyl group, methoxycarbonyl is methoxycarbonyl, d
imethylamino is a dimethylamino group, methylamino is a methylamino group, trifluoromethyl is a trifluoromethyl group, fluoromethyl is a fluoromethyl group, hydroxy is a hydroxy group (hydroxyl group), fluorobenzoyl is a fluorobenzoyl group, and methylbenzoyl is a methylbenzoyl group. , Chloroacetyl, chloroacetyl group, ethoxycarbon
yl is ethoxycarbonyl group, carboxy is carboxy group, chloromethoxy is chloromethoxy group, ethylamino is ethylamino group, propylamino is propylamino group, piperazinyl is piperazinyl group, pyrrolidinyl is pyrrolidinyl group, and pyrrololidinylmethylamino is pyrrolidinyl A methylamino group and ethoxycarbonyl represent an ethoxycarbonyl group. In Y ¹ and Y ² , for example, 2-chlo
The term ro means that a chlorine atom is substituted at the 2-position of the benzene ring.

Table 1

[Table 1]

[Table 2]

[Table 3]

[Table 4]

[Table 5]

[Table 6]

[Table 7]

[Table 8]

[Table 9]

[Table 10]

[Table 11]

[Table 12]

[Table 13]

[Table 14]

[Table 15]

[Table 16]

[Table 17]

[Table 18]

[Table 19]

[Table 20]

[0070]

[Table 21]

[Table 22]

[Table 23]

[Table 24]

[Table 25]

[Table 26]

[Table 27]

[Table 28]

[Table 29]

[Table 30]

[Table 31]

[Table 32]

[Table 33]

[Table 34]

[Table 35]

[Table 36]

[Table 37]

[Table 38]

[Table 39]

[Table 40]

[0071]

[Table 41]

[Table 42]

[Table 43]

[Table 44]

[Table 45]

[Table 46]

[Table 47]

[Table 48]

[Table 49]

[Table 50]

[Table 51]

[Table 52]

[Table 53]

[Table 54]

[Table 55]

[Table 56]

[Table 57]

[Table 58]

[Table 59]

[Table 60]

[0072]

[Table 61]

[Table 62]

[Table 63]

[Table 64]

[Table 65]

[Table 66]

[Table 67]

[Table 68]

[Table 69]

[Table 70]

[Table 71]

[Table 72]

[Table 73]

[Table 74]

[Table 75]

[Table 76]

[Table 77]

[Table 78]

[Table 79]

[Table 80]

[0073]

[Table 81]

[Table 82]

[Table 83]

[Table 84]

[Table 85]

[Table 86]

[Table 87]

[Table 88]

[Table 89]

[Table 90]

[Table 91]

[Table 92]

[Table 93]

[Table 94]

[Table 95]

[Table 96]

[Table 97]

[Table 98]

[Table 99]

[Table 100]

[0074]

[Table 101]

[Table 102]

[Table 103]

[Table 104]

[Table 105]

[Table 106]

Table 2

[Table 107]

[Table 108]

[Table 109]

[Table 110]

[Table 111]

[Table 112]

[Table 113]

[Table 114]

[Table 115]

[Table 116]

[Table 117]

[Table 118]

[Table 119]

[Table 120]

[0076]

[Table 121]

[Table 122]

[Table 123]

[Table 124]

[Table 125]

[Table 126]

[Table 127]

Table 3

[Table 128]

[Table 129]

[Table 130]

[Table 131]

[Table 132]

[Table 133]

[Table 134]

[Table 135]

[Table 136]

[Table 137]

[Table 138]

[Table 139]

[Table 140]

[0078]

[Table 141]

[Table 142]

[Table 143]

[Table 144]

[Table 145]

[Table 146]

[Table 147]

[Table 148]

Table 4

[Table 149]

[Table 150]

[Table 151]

[Table 152]

[Table 153]

[Table 154]

[Table 155]

[Table 156]

[Table 157]

[Table 158]

[Table 159]

[Table 160]

[0080]

[Table 161]

[Table 162]

[Table 163]

[Table 164]

[Table 165]

[Table 166]

[Table 167]

[Table 168]

[Table 169]

Table 5

[Table 170]

[Table 171]

[Table 172]

[Table 173]

[Table 174]

[Table 175]

[Table 176]

[Table 177]

[Table 178]

[Table 179]

[Table 180]

[0082]

[Table 181]

[Table 182]

[Table 183]

[Table 184]

[Table 185]

[Table 186]

[Table 187]

[Table 188]

[Table 189]

[Table 190]

Table 6

[Table 191]

[Table 192]

[Table 193]

[Table 194]

[Table 195]

[Table 196]

[Table 197]

[Table 198]

[Table 199]

[Table 200]

[0084]

[Table 201]

[Table 202]

[Table 203]

[Table 204]

[Table 205]

[Table 206]

[Table 207]

[Table 208]

[Table 209]

[Table 210]

[Table 211]

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 described above. Y represents a leaving group such as a halogen atom such as an iodine atom and a bromine atom. R ⁴ and R ⁵ represents a hydrogen atom, an alkyl group or a substituted alkyl group, and R ⁴ and R ⁵ may form an alicyclic heterocyclic group together with a nitrogen atom, and when R ⁴ and R ⁵ are hydrogen atoms, R ⁴ or R ⁵ includes an amino-protecting group because R ⁴ or R ⁵ can be protected with an amino-protecting group in an intermediate step, R ⁶ represents an alkyl group, and M represents an alkali metal cation. The compound (16) can be obtained by reacting the compound (15) with NHR ⁴ R ⁵ in an aqueous solution or an organic solvent. As the amount of NHR ⁴ R ⁵ , compound (15)
To about 1: 1 mole to a large excess. Examples of the organic solvent include alcohol solvents such as methanol, ethanol, propanol and butanol,
Examples include ether solvents such as tetrahydrofuran, 1,4-dioxane, and diglyme; and aprotic solvents such as dimethylformamide, dimethyl sulfoxide, acetonitrile, and hexamethylphosphorous triamide (((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 (18) can be obtained by reacting compound (16) with compound (17) in the presence of a base in an organic solvent. The amount of the compound (17) can be about an equimolar to a several-fold molar amount of the compound (16). 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 (17). Examples of the organic solvent include carbon tetrachloride,
Halogenated hydrocarbon solvents such as chloroform and methylene chloride, diethyl ether, tetrahydrofuran, 1,4
Ether solvents such as dioxane; aprotic solvents such as dimethylformamide, dimethylsulfoxide, acetonitrile, and hexamethylphosphorustriamide. The reaction temperature is selected, for example, from the range of about 0 ° C. to around the boiling point of the solvent.

Compound (19) is obtained by combining compound (18) with R ²
It can be obtained by reacting SH or R ² SM in an organic solvent. The amount of R ² SH or R ² SM can be used in an amount of about 1-fold molar to several-fold molar with respect to compound (18). When R ² SH is used as a reagent, 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, and alkalis such as sodium hydride and potassium hydride. metal hydride, methyl lithium, butyl lithium, organic metal salts such as lithium diisopropylamide. Examples of the amount of the base, about equi-magnification molar amount with respect to R ² SH is preferred. 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. Alternatively, an alcohol compound used as a reagent (for example, methanol, ethanol, propanol, butanol, etc.) may be mentioned. The reaction temperature is selected, for example, from the range of about room temperature to around the boiling point of the solvent.

Compound (20) can be obtained by reacting compound (19) with bromine (Br ₂ ) in an organic solvent. In the reaction, for example, a reaction aid such as sodium acetate may be added. The amount of bromine can be used in the amount of 1-fold mole to several-fold mole with respect to compound (19), but is preferably in the range of 1-fold mole to about 1.5-fold mole. Examples of the organic solvent include halogenated hydrocarbon solvents such as carbon tetrachloride, methylene chloride and dichloroethane, ether solvents such as diethyl ether, acetic acid, and carbon disulfide. 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 obtained by combining compound (20) with R ⁶
It can be obtained by reacting OH with an organic solvent in the presence of a base. Examples of the base 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 of the base is preferably about equimolar to about 2 molar times with respect to compound (20). Examples of the organic solvent include ether solvents such as diethyl ether, tetrahydrofuran, and 1,4-dioxane, and aprotic solvents such as dimethylformamide, acetonitrile, and hexamethylphosphoric triamide. Alternatively, R ⁶ OH used as a reagent
(For example, methanol, ethanol, propanol, butanol and the like can be mentioned.). The reaction temperature is selected, for example, from the range of about room temperature to around the boiling point of the solvent.

Compound (22) can be obtained by treating compound (21) with an acid in water or a mixed solvent of water and an organic solvent. Examples of the acid include an inorganic acid such as hydrochloric acid and hydrobromic acid, and an organic acid such as trifluoroacetic acid. As the organic solvent, for example, ether solvents such as diethyl ether and tetrahydrofuran, dimethylformamide, aprotic solvents such as acetonitrile,
Examples thereof include 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.

Production method 2

Embedded image (Wherein, R ² , R ³ , X ¹ , X ² , Y ¹ and Y ² represent the same meaning as described above. R ⁴ and R ⁵ represent a hydrogen atom, an alkyl group, a substituted alkyl group, or R ⁴ and R ⁵ together represent an alicyclic heterocyclic group.)

Compound (22) can be obtained by treating compound (20) with an acid in water or a mixed solvent of water and an organic solvent. Examples of the acid include an inorganic acid such as hydrochloric acid and hydrobromic acid. Examples of the organic solvent include an aprotic solvent such as dimethyl sulfoxide, an alcoholic solvent 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.

Production method 3

Embedded image (Wherein, R ² , X ¹ , X ² , Y ¹ and Y ² have the same meanings as described above. Y represents a leaving group such as a halogen atom such as an iodine atom or a bromine atom. 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. R ⁶
Represents an alkyl group. Boc represents a t-butoxycarbonyl group. ) The amino group of compound (23) 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, compound (24) can be obtained by converting compound (23) to water or an organic solvent or a mixture thereof with di-t-butyl dicarbonate in the presence of a base. It can be obtained by reacting in a 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 (2
5) can be obtained by reacting compound (24) 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 (26) is obtained by converting compound (25) to R ²
It can be obtained by reacting SH with an organic solvent in the presence 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. etc,
Tertiary amines such as triethylamine; pyridines such as pyridine and 4-dimethylaminopyridine;
Examples of the organic solvent include halogenated hydrocarbon solvents such as methylene chloride, aprotic solvents such as dimethylformamide and dimethylsulfoxide, and ether solvents such as diethyl ether and tetrahydrofuran.
The reaction temperature is selected, for example, from the range of about room temperature to around the boiling point of the solvent.

Compound (27) can be obtained by treating compound (26) with an acid in water or 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 (28) can be obtained by reacting compound (27) with compound (17) 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 (29) can be obtained by nitrating compound (28). 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 (30) can be obtained by reducing compound (29) 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 (31) is obtained by converting compound (30) 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.

Compound (32) can be obtained by reacting compound (31) with bromine (Br ₂ ) in an organic solvent. In the reaction, for example, a reaction aid such as sodium acetate may be added. As the organic solvent, for example,
Examples include halogenated hydrocarbon solvents such as carbon tetrachloride, methylene chloride, and dichloroethane, ether solvents such as diethyl ether, acetic acid, and carbon disulfide. The reaction temperature is selected, for example, from the range of about 0 ° C. to around the boiling point of the solvent.

Compound (33) is obtained by combining compound (32) with R ⁶
It can be obtained by reacting OH in an organic solvent in the presence of a base. As the base, for example, sodium,
Alkali metals such as potassium, sodium hydride, alkali metal hydrides such as potassium hydride, methyl lithium,
Organic metal salts such as butyllithium and lithium diisopropylamide are exemplified. Examples of the organic solvent include ether solvents such as diethyl ether and tetrahydrofuran, and aprotic solvents such as dimethylformamide and acetonitrile. Alternatively, R ⁶ OH used as a reagent (for example, methanol, ethanol, propanol, butanol, etc. may be mentioned). The reaction temperature is selected, for example, from the range of about room temperature to around the boiling point of the solvent.

Compound (34) can be obtained by treating compound (33) with an acid in water or a mixed solvent of water and an organic solvent. Examples of the acid include an inorganic acid such as hydrochloric acid and hydrobromic acid, and an organic acid such as trifluoroacetic acid. As the organic solvent, for example, ether solvents such as diethyl ether and tetrahydrofuran, dimethylformamide, aprotic solvents such as acetonitrile,
Examples thereof include 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. Manufacturing method 4

Embedded image (Wherein R ² , Y ¹ and Y ² represent the same meaning as described above.
Y represents a leaving group such as a halogen atom such as an iodine atom and a bromine atom. ph represents a phenyl group. The compound (37) can be obtained by reacting the compound (36) with the compound (35) in an organic solvent. The reaction can be performed in the presence or absence of a base. Examples of the base include an inorganic base such as an alkali metal carbonate such as potassium carbonate, a tertiary amine such as triethylamine and diisopropylethylamine, and an organic base such as pyridines such as 4-dimethylaminopyridine and pyridine. Examples of the organic solvent include halogenated hydrocarbon solvents such as methylene chloride, ether solvents such as diethyl ether, tetrahydrofuran, and 1,4-dioxane, and aprotic solvents such as dimethylformamide, dimethyl sulfoxide, and acetonitrile. . The reaction temperature is selected, for example, from the range of about 0 ° C. to around the boiling point of the solvent.

Compound (38) can be obtained by reacting compound (37) in water, an organic solvent or a mixed solvent thereof. The reaction can be performed in the presence or absence of a base. Examples of the base include inorganic bases such as alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal alkoxides such as sodium methoxide; alkali metal carbonates such as potassium carbonate; and tertiary bases such as triethylamine and diisopropylethylamine. Organic bases such as amines, pyridines such as 4-dimethylaminopyridine and pyridine are exemplified. Examples of the organic solvent include halogenated hydrocarbon solvents such as methylene chloride, ether solvents such as tetrahydrofuran and 1,4-dioxane, aprotic solvents such as dimethylformamide and acetonitrile, methanol, ethanol, 2-ethanol, and the like.
Alcohol solvents such as propanol and the like can be mentioned. The reaction temperature is selected, for example, from a range around the boiling point of the solvent.

Compound (39) can be obtained by reacting compound (38) in an organic solvent in the presence of a dehydrating agent. Examples of the dehydrating agent include diphosphorus pentoxide, dicyclohexylcarbodiimide and the like. Examples of the organic solvent include halogenated hydrocarbon solvents such as methylene chloride, and aprotic solvents such as dimethylformamide and dimethylsulfoxide. The reaction temperature is selected, for example, from the range of about room temperature to around the boiling point of the solvent.

Compound (40) can be obtained by reacting compound (39) with benzoyl isothiocyanate in an organic solvent. The reaction can be performed in the presence or absence of a base. Examples of the base include alkali metal carbonates such as potassium carbonate; tertiary amines such as triethylamine and diisopropylethylamine;
And 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 and dimethyl sulfoxide. The reaction temperature is selected, for example, from the range of about 0 ° C. to around the boiling point of the solvent.

Compound (41) can be obtained by reacting compound (40) in the presence of a base in water, an organic solvent or a mixed solvent thereof. Examples of the organic solvent include alcohol solvents such as methanol, ethanol and 2-propanol, and aprotic solvents such as dimethylformamide and dimethylsulfoxide. Examples of the base include alkali metal hydroxides such as sodium hydroxide, inorganic bases such as ammonia, tertiary amines such as triethylamine, and organic bases such as pyridines such as 4-dimethylaminopyridine and pyridine. The reaction temperature is selected, for example, from the range of about room temperature to around the boiling point of the solvent.

Compound (42) is obtained by converting compound (41) to R ²
It can be obtained by reacting Y with a base in the presence of a base in an organic solvent. Examples of the base include alkali metal bicarbonates such as sodium bicarbonate, alkali metal carbonates such as potassium carbonate, tertiary amines such as triethylamine and diisopropylethylamine, and pyridines such as pyridine and dimethylaminopyridine. 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.

Production method 5

Embedded image (Wherein R ² , Y ¹ and Y ² represent the same meaning as described above.
R ⁶ represents an alkyl group. Y represents a leaving group such as a halogen atom such as a chlorine atom, a bromine atom and an iodine atom. )

Compound (44) is obtained by combining compound (43) with R ²
It can be obtained by reacting Y in an organic solvent in the presence of a base. As the base, for example, sodium carbonate,
Alkali metal carbonates such as potassium carbonate, alkali metal bicarbonates such as sodium bicarbonate, triethylamine,
Tertiary amines such as diisopropylethylamine; pyridines such as pyridine and 4-dimethylaminopyridine; 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 and dimethyl sulfoxide. The reaction temperature is selected, for example, from the range of about 0 ° C. to around the boiling point of the solvent.

Compound (45) can be obtained by reacting compound (44) with compound (17) in an organic solvent in the presence of a base. 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 0 ° C. to around the boiling point of the solvent.

Compound (46) can be obtained by reacting compound (45) with bromine (Br ₂ ) in an organic solvent. In the reaction, for example, a reaction aid such as sodium acetate may be added. Examples of the organic solvent include halogenated hydrocarbon solvents such as carbon tetrachloride, methylene chloride and dichloroethane, ether solvents such as diethyl ether, acetic acid, and carbon disulfide. The reaction temperature is selected, for example, from the range of about 0 ° C. to around the boiling point of the solvent.

Compound (47) is obtained by combining compound (46) with R ⁶
It can be obtained by reacting OH (for example, an alcohol compound such as methanol) in an organic solvent in the presence of a base. Examples of the base 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. Examples of the organic solvent include ether solvents such as diethyl ether and tetrahydrofuran, and aprotic solvents such as dimethylformamide and acetonitrile. Alternatively, an alcohol compound used as a reagent (eg, methanol, ethanol, propanol, butanol, etc.) may be mentioned. The reaction temperature is selected, for example, from the range from room temperature to around the boiling point of the solvent.

Compound (48) can be obtained by treating compound (47) with an acid in water or a mixed solvent of water and an organic solvent. Examples of the acid include an inorganic acid such as hydrochloric acid and hydrobromic acid, and an organic acid such as trifluoroacetic acid. As the organic solvent, for example, ether solvents such as diethyl ether and tetrahydrofuran, dimethylformamide, aprotic solvents such as acetonitrile,
Examples thereof include 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.

Production method 6

Embedded image (Wherein, R ¹ , R ² , R ³ , X ¹ , X ² , Y ¹ and Y ² represent the same meaning as described above. Y represents elimination of a halogen atom such as a chlorine atom, a bromine atom and an iodine atom. Represents a group.) Compound (50) can be obtained by reacting compound (49) with R ³ Y in an organic solvent in the presence of a base. Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal hydrides such as sodium hydride and potassium hydride, methyllithium and butyl. Organic metal salts such as lithium and lithium diisopropylamide; tertiary amines such as triethylamine and diisopropylethylamine; and pyridines such as dimethylaminopyridine and pyridine. Examples of the organic solvent include halogenated hydrocarbon solvents such as methylene chloride and dichloroethane, ether solvents such as diethyl ether and tetrahydrofuran, and aprotic solvents such as acetonitrile, dimethylformamide, and dimethyl sulfoxide. The reaction temperature is, for example, about -78 ° C.
To the vicinity of the boiling point of the solvent.

Compound (51) can be obtained by reacting compound (49) with an oxidizing agent in an organic solvent. Examples of the oxidizing agent include organic peracids such as perbenzoic acid and m-chloroperbenzoic acid. Examples of the organic solvent include halogenated hydrocarbons such as methylene chloride and chloroform. The reaction temperature is selected from the range of about 0 ° C. to about room temperature.

Compound (52) can be obtained by reacting compound (50) with an oxidizing agent in an organic solvent. Examples of the oxidizing agent include organic peracids such as perbenzoic acid and m-chloroperbenzoic acid. Examples of the organic solvent include halogenated hydrocarbons such as methylene chloride and chloroform. The reaction temperature is selected from the range of about 0 ° C. to about room temperature.

Compound (52) is obtained by combining compound (51) with R ³
It can be obtained by reacting Y with an organic solvent in the presence of a base. Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal hydrides such as sodium hydride and potassium hydride, methyllithium and butyl. Organic metal salts such as lithium and lithium diisopropylamide; tertiary amines such as triethylamine and diisopropylethylamine; and pyridines such as dimethylaminopyridine and pyridine. Examples of the organic solvent include halogenated hydrocarbon solvents such as methylene chloride and dichloroethane, ether solvents such as diethyl ether and tetrahydrofuran, and aprotic solvents such as acetonitrile, dimethylformamide, and dimethyl sulfoxide. The reaction temperature is selected, for example, from the range of about −78 ° C. to around the boiling point of the solvent.

Production method 7

Embedded image (Wherein, R ¹ , R ² , R ³ , X ¹ , X ² , Y ¹ and Y ² represent the same meaning as described above. Y represents elimination of a halogen atom such as a chlorine atom, a bromine atom and an iodine atom. Represents a group.)

Compound (53) can be obtained by reacting compound (49) with an oxidizing agent in an acid solvent such as sulfuric acid or acetic acid. Examples of the oxidizing agent include peracids such as aqueous hydrogen peroxide. The reaction temperature is selected from the range of about room temperature to about 70 ° C.

Compound (54) is obtained by combining compound (53) with R ³
It can be obtained by reacting Y with an organic solvent in the presence of a base. Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal hydrides such as sodium hydride and potassium hydride, methyllithium and butyl. Organic metal salts such as lithium and lithium diisopropylamide; tertiary amines such as triethylamine and diisopropylethylamine; and pyridines such as dimethylaminopyridine and pyridine. Examples of the organic solvent include halogenated hydrocarbon solvents such as methylene chloride and dichloroethane, ether solvents such as diethyl ether and tetrahydrofuran, and aprotic solvents such as acetonitrile, dimethylformamide, and dimethyl sulfoxide. The reaction temperature is selected, for example, from the range of about −78 ° C. to around the boiling point of the solvent.

Compound (54) can be obtained by reacting compound (50) with an oxidizing agent in an acid solvent such as sulfuric acid or acetic acid. Examples of the oxidizing agent include peracids such as aqueous hydrogen peroxide. The reaction temperature is selected from the range of about room temperature to about 70 ° C.

When R ¹ requires protection in the above reaction, the reaction is carried out as follows. Manufacturing method 8

Embedded image (Wherein, R ² , R ³ , X ¹ , X ² , Y ¹ and Y ² have the same meanings as described above. R represents a hydrogen atom, an alkyl group, a substituted alkyl group or a saturated heterocyclic ring. Represents a protecting group such as an acetyl group, a chloroacetyl group, a dichloroacetyl group, a trichloroacetyl group, a trifluoroacetyl group, etc. Y represents a leaving group such as a halogen atom such as a chlorine atom, a bromine atom and an iodine atom. (56) can be obtained by reacting compound (55) with a corresponding acid, acid anhydride or the like. Examples of the acid include acetic acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid and the like. Examples of the acid anhydride include acetic anhydride, chloroacetic anhydride, dichloroacetic anhydride, trichloroacetic anhydride, trifluoroacetic anhydride and the like. The reaction with an acid can be carried out in an organic solvent in the presence of a condensing agent. Examples of the condensing agent include dicyclohexylcarbodiimide and the like. Further, for example, a reaction aid such as 4-dimethylaminopyridine may be added to the reaction. 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 dimethylformamide, and alcohol solvents such as methanol, ethanol, and 2-propanol. No. The reaction temperature is selected from the range of about 0 ° C. to about room temperature. The reaction with an acid anhydride can be performed in an organic solvent in the presence of a base. Examples of the base include tertiary amines such as triethylamine, and pyridines such as pyridine and 4-dimethylaminopyridine. 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 dimethylformamide, methanol, ethanol, and the like.
-Alcoholic solvents such as propanol.
Further, water may be added to these organic solvents. Preferably, water or an alcoholic solvent such as methanol or ethanol or a mixed solvent thereof is used. The reaction temperature is selected from a range from about 0 ° C to about 100 ° C.

Compound (57) is obtained by combining compound (56) with R ³
It can be obtained by reacting Y with an organic solvent in the presence of a base. Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal hydrides such as sodium hydride and potassium hydride, methyllithium and butyl. Lithium, organic metal salts such as lithium diisopropylamide, triethylamine,
Tertiary amines such as diisopropylethylamine; pyridines such as dimethylaminopyridine and pyridine; Examples of the organic solvent include halogenated hydrocarbon solvents such as methylene chloride and dichloroethane, ether solvents such as diethyl ether and tetrahydrofuran, and aprotic solvents such as acetonitrile, dimethylformamide, and dimethyl sulfoxide. The reaction temperature is about-
It is selected from a range from 78 ° C. to around the boiling point of the solvent.

Compound (58) can be obtained by deprotecting compound (57) in water or an organic solvent or a mixed solvent thereof in the presence of a base. Examples of the organic solvent include alcohol solvents such as methanol, ethanol, and 2-propanol. Examples of the base include inorganic bases such as alkali metal hydroxides such as potassium hydroxide and sodium hydroxide, and alkali metal carbonates such as sodium carbonate and potassium carbonate. The reaction temperature is selected, for example, from the range of about 0 ° C. to around the boiling point of the solvent.

The compound (1) of the present invention or an intermediate for producing the same 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 frequency of administration vary depending on the disease to be treated, the condition of the patient, age, body weight, sex, etc., and the dosage form and formulation. However, when administered orally, the active ingredient is usually about 1 to 1 per day for an adult. A dose in the range of 500 mg, preferably in the range of about 5-200 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 300 mg, preferably in a range of about 1 to about 100 mg, in one or several divided doses. The interferon-inducing agent of the present invention can be specifically used as a therapeutic or prophylactic agent such as an antiviral agent, an anticancer agent, or an immunological disease therapeutic agent. The administration method includes the above-mentioned oral or parenteral administration method.

[0129]

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

Reference Example 1 6-amino-2-chloropurine

Embedded image 0.5 g (2.7 mmol) of 2,6-dichloropurine
Was dissolved in a 30% ammonia-methanol solution and heated to 100 ° C. in an autoclave for 12 hours. The solution was concentrated to give the 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

Embedded image 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 was added 0.17 ml (1.4 mmol) of benzyl bromide, and the mixture was stirred at room temperature for 4 hours. The suspension 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, filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (5% -methanol / chloroform) and recrystallized from ethanol to give the title compound in 20%.
0 mg was obtained (58%). Melting point: 216-218 ° C UVλ _max (EtOH): 265.7nm ¹ H-NMR (DMSO-d ₆ ) δ: 8.26 (1H, s), 7.81 (2H, brs), 7.3
1 (5H, m), 5.34 (2H, s).

Reference Example 3 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. A saline solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure of the filtrate.
The residue was purified by silica gel column chromatography (1% -methanol / chloroform) to give 64 mg of the title compound (6
1%). 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).

Reference Example 4 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. A saline solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and the solvent in the filtrate was distilled off. The residue was purified by silica gel column chromatography (1% -methanol / chloroform) to give 90 mg of the title compound (82 mg).
%). 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 (3
(H, t, J = 7.3Hz).

Reference Example 5 6-amino-9-benzyl-2- (n-propylthio) propyl
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. A saline solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (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
H, m), 1.03 (3H, t, J = 7.3Hz).

Reference Example 6 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. A saline solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate, filtered, and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (1% -methanol / chloroform) to obtain 112 mg of the title compound (61%). 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).

Reference Example 7 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 n-butylthiolate in 30 ml of DMF were heated and stirred at 100 ° C. for 4.5 hours. A saline solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (0.5%-
Methanol / chloroform) to give 194 m of the title compound.
g (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 (2
H, m), 1.48 (2H, m), 0.93 (3H, t, J = 7.6Hz).

Reference Example 8 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. A saline solution was added to the reaction solution, extracted with chloroform, the organic layer was dried over magnesium sulfate and filtered, and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (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 (d, 2H, J = 6.9Hz), 2.00 (1
H, m), 1.04 (6H, d, J = 6.6Hz).

Reference Example 9 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. A saline solution was added to the reaction solution, extracted with chloroform, the organic layer was dried over magnesium sulfate, and filtered.
The solvent of the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (1% methanol / chloroform).
85 mg of the title compound were obtained (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), 1.4
2 (3H, d, J = 6.9Hz), 1.03 (3H, t, J = 7.6Hz).

Reference Example 10 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. Brine was added to the reaction solution, extracted with ethyl acetate, the organic layer was dried over magnesium sulfate, and filtered,
The solvent of the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (1% methanol / chloroform).
102 mg (81%) of the title compound were obtained. 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
(H, m), 1.33-1.46 (4H, m), 0.89 (3H, t, J = 7.3Hz).

Reference Example 11 6-amino-9-benzyl-2- (3-methylbutyl)
Thioprine

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. A saline solution was added to the reaction solution, extracted with chloroform, the organic layer was dried over magnesium sulfate, filtered, and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (1% -methanol /
Chloroform) to give 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 (3
H, m), 0.94 (6H, d, J = 6.6Hz).

Reference Example 12 6-amino-9-benzyl-2- (2-methylbutyl)
Thioprine

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. A saline solution was added to the reaction solution, extracted with chloroform, the organic layer was dried over magnesium sulfate, filtered, and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (1% -methanol /
Chloroform) to give 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 (1
H, q, J = 7.6Hz), 1.78 (1H, m), 1.55 (1H, m), 1.28 (1
H, m), 1.02 (3H, d, J = 11.9Hz), 0.92 (3H, t, J = 11.8
Hz).

Reference Example 13 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. Brine was added to the reaction solution, extracted with ethyl acetate, the organic layer was dried over magnesium sulfate, and filtered,
The solvent of the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (1% methanol / chloroform).
112 mg (86%) of the title compound were obtained. ¹ H-NMR (CDCl ₃ ) δ: 7.65 (1H, s), 7.33 (5H, m), 5.86 (2H,
br s), 5.28 (2H, m), 3.75-3.87 (1H, m), 2.11-2.17 (2
H, m), 1.25-1.67 (8H, m).

Reference Example 14 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. A saline solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (0.5% -methanol / chloroform) to obtain 228 mg of the title compound (8
9%). ¹ H-NMR (CDCl ₃ ) δ: 7.65 to 7.70 (3H, m), 7.41 to 7.45 (3H,
m), 7.28-7.33 (3H, m), 7.15-7.20 (2H, m), 5.54 (2H, b
rs), 5.09 (2H, s).

Reference Example 15 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. A saline solution was added to the reaction solution, extracted with chloroform, the organic layer was dried over magnesium sulfate, filtered, and the solvent in the filtrate was distilled off under reduced pressure. The residue is purified by silica gel column chromatography (1% methanol / chloroform).
This gave 124 mg (93%) of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 7.62 (1 H, s), 7.55 (2 H, d, J = 8.2 H
z), 7.15-7.31 (7H, m), 5.61 (2H, br s), 5.10 (2H, s),
2.40 (3H, s).

Reference Example 16 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 ℃. A saline solution was added to the reaction solution, extracted with chloroform, the organic layer was dried over magnesium sulfate, filtered, and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (0.5% -methanol / chloroform) to obtain 244 mg of the title compound (83%). _{^{1 H-NMR (CDCl 3)}} δ: 8.17 (1H, s), 7.52-7.92 (7H, m), 7.0
6-7.30 (5H, m), 5.63 (2H, br s), 5.04 (2H, s).

Reference Example 17 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. Brine was added to the reaction solution, extracted with ethyl acetate, the organic layer was dried over magnesium sulfate, and filtered,
The solvent of the filtrate was distilled off under reduced pressure. The residue is purified by silica gel column chromatography (0.5% -methanol / chloroform).
This gave 97 mg (73%) of the title compound. 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).

Reference Example 18 6-amino-9-benzyl-8-bromo-2-methylthio
Oplin

Embedded image 6-amino-9-benzyl-2-methylthiopurine 10
A solution of 0 mg (0.37 mmol) and 0.5 ml of bromine in 100 ml of methylene chloride was stirred at room temperature for 3 hours. An aqueous solution of sodium thiosulfate was added to the reaction solution, the organic layer was separated, the organic layer was dried over magnesium sulfate, filtered, and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (0.5% -methanol / chloroform),
10 mg of the title compound were obtained (8%). ¹ H-NMR (CDCl ₃ ) δ: 7.34 (5H, m), 5.64 (2H, br s), 5.33
(2H, s), 2.57 (3H, s).

Reference Example 19 6-amino-9-benzyl-8-bromo-2-ethylthio
Oplin

Embedded image 6-amino-9-benzyl-2-ethylthiopurine 21
A solution of 4 mg (0.75 mmol) and 0.5 ml of bromine in 100 ml of methylene chloride was stirred at room temperature for 7 hours. An aqueous solution of sodium thiosulfate was added to the reaction solution, the organic layer was separated, the organic layer was dried over magnesium sulfate, filtered, and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (1% -methanol / chloroform) to obtain 43 mg of the title compound (16%). ¹ H-NMR (CDCl ₃ ) δ: 7.32 (5H, m), 5.82 (2H, br s), 5.32
(2H, s), 3.16 (2H, q, J = 7.3Hz), 1.39 (3H, t, J = 7.3H
z).

Reference Example 20 6-amino-9-benzyl-8-bromo-2- (n-propyl
Ropircio) pudding

Embedded image 6-amino-9-benzyl-2- (n-propylthio)
Purine 290mg (0.97mmol) and bromine 0.7m
l of methylene chloride in 160 ml was stirred for 4.5 hours at room temperature. An aqueous solution of sodium thiosulfate was added to the reaction solution,
Separate the organic layer, dry the organic layer over magnesium sulfate,
After filtration, the solvent of the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (1% -methanol / chloroform) to obtain 58 mg of the title compound (16%). ¹ H-NMR (CDCl ₃ ) δ: 7.35 (5H, m), 5.70 (2H, br s), 5.32
(2H, s), 3.13 (2H, t, J = 7.6Hz), 1.76 (2H, m), 1.04 (3
(H, t, J = 7.6Hz).

Reference Example 21 6-amino-9-benzyl-8-bromo-2- (iso-
Propylthio) purine

Embedded image 60 mg (0.20 mmol) of 6-amino-9-benzyl-2- (iso-propylthio) purine and 0.4 of bromine
An 85 ml solution of methylene chloride in 85 ml was stirred for 2 hours at room temperature. An aqueous solution of sodium thiosulfate was added to the reaction solution, the organic layer was separated, the organic layer was dried over magnesium sulfate, filtered, and the solvent in the filtrate was distilled off under reduced pressure. The residue is purified by silica gel column chromatography (1% methanol / chloroform).
This gave 20 mg of the title compound (26%). ¹ H-NMR (CDCl ₃ ) δ: 7.34 (5H, m), 5.72 (2H, br s), 5.32
(2H, s), 3.96 (1H, m), 1.42 (6H, d, J = 7.0Hz).

Reference Example 22 6-amino-9-benzyl-8-bromo-2- (n-butyl
Tilthio) purine

Embedded image 163 mg (0.52 mmol) of 6-amino-9-benzyl-2- (n-butylthio) purine and 0.6 ml of bromine
Was stirred at room temperature for 4.5 hours. An aqueous solution of sodium thiosulfate was added to the reaction solution, the organic layer was separated, the organic layer was dried over magnesium sulfate, filtered, and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (1% -methanol / chloroform) to obtain 35 mg of the title compound (17%). ¹ H-NMR (CDCl ₃ ) δ: 7.34 (5H, m), 5.81 (2H, br s), 5.32
(2H, s), 3.15 (2H, t, J = 7.3Hz), 1.72 (2H, m), 1.45 (2
H, m), 0.92 (3H, t, J = 7.6Hz).

Reference Example 23 6-amino-9-benzyl-8-bromo-2- (iso-
Butylthio) purine

Embedded image 6-amino-9-benzyl-2- (iso-butylthio)
Purine 60mg (0.19mmol) and bromine 0.4ml
Was stirred at room temperature for 2 hours. An aqueous solution of sodium thiosulfate was added to the reaction solution, the organic layer was separated, the organic layer was dried over magnesium sulfate, filtered, and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) to give the title compound in 2 parts.
0 mg was obtained (27%). ¹ H-NMR (CDCl ₃ ) δ: 7.34 (5H, m), 5.59 (2H, br s), 5.32
(2H, s), 3.07 (2H, t, J = 6.6Hz), 1.96 (1H, m), 1.04 (6
(H, d, J = 6.6Hz).

Reference Example 24 6-amino-9-benzyl-8-bromo-2- (sec-
Butylthio) purine

Embedded image 6-amino-9-benzyl-2- (sec-butylthio)
Purine 60mg (0.19mmol) and bromine 0.4ml
Was stirred at room temperature for 2 hours. An aqueous solution of sodium thiosulfate was added to the reaction solution, the organic layer was separated, the organic layer was dried over magnesium sulfate, filtered, and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) to give the title compound (5).
3 mg was obtained (71%). ¹ H-NMR (CDCl ₃ ) δ: 7.34 (5H, m), 5.45 (2H, br s), 5.32
(2H, s), 3.83 (1H, m), 1.63 (2H, m), 1.42 (3H, d, J =
7.0Hz), 1.03 (3H, t, J = 7.3Hz).

Reference Example 25 6-amino-9-benzyl-8-bromo-2- (n-pe
Nthylthio) purine

Embedded image 260 mg (0.79 mmol) of 6-amino-9-benzyl-2- (n-pentylthio) purine and 0.5 ml of bromine
Was stirred at room temperature for 7 hours. An aqueous solution of sodium thiosulfate was added to the reaction solution, the organic layer was separated, the organic layer was dried over magnesium sulfate, filtered, and the solvent in the filtrate was distilled off under reduced pressure. The residue is purified by silica gel column chromatography (1% methanol / chloroform).
This gave 49 mg (15%) of the title compound. _{^{1 H-NMR (CDCl 3)}} δ: 7.33 (5H, m), 5.95 (2H, br s), 5.31
(2H, s), 3.14 (2H, t, J = 7.3Hz), 1.74 (2H, m), 1.27-
1.47 (4H, m), 0.88 (3H, t, J = 7.3Hz).

Reference Example 26 6-amino-9-benzyl-8-bromo-2- (3-meth
Butylbutylthio) purine

Embedded image 260 mg (0.79 mmol) of 6-amino-9-benzyl-2- (3-methylbutylthio) purine and 0.1 mg of bromine.
A solution of 5 ml of 100 ml of methylene chloride was stirred for 7 hours at room temperature. An aqueous solution of sodium thiosulfate was added to the reaction solution,
Separate the organic layer, dry the organic layer over magnesium sulfate,
After filtration, the solvent of the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (1% -methanol / chloroform) to obtain 49 mg of the title compound (15%). ¹ H-NMR (CDCl ₃ ) δ: 7.33 (5H, m), 5.52 (2H, br s), 5.30
(2H, s), 3.15 (2H, t, J = 7.9Hz), 1.61-1.76 (3H, m),
0.92 (6H, t, J = 6.2Hz).

Reference Example 27 6-amino-9-benzyl-8-bromo-2- (2-meth
Butylbutylthio) purine

Embedded image 60 mg (0.18 mmol) of 6-amino-9-benzyl-2- (2-methylbutylthio) purine and 0.4 of bromine
A solution of 90 ml of methylene chloride in 90 ml was stirred for 7 hours at room temperature. An aqueous solution of sodium thiosulfate was added to the reaction solution, the organic layer was separated, the organic layer was dried over magnesium sulfate, filtered, and the solvent in the filtrate was distilled off under reduced pressure. The residue is purified by silica gel column chromatography (1% methanol / chloroform).
This gave 39 mg (53%) of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 7.33 (5H, m), 5.44 (2H, br s), 5.32
(2H, s), 3.24 (1H, q, J = 7.9Hz), 2.98 (1H, q, J = 7.3H
z), 1.75 (1H, m), 1.52 (1H, m), 1.28 (1H, m), 1.01 (3
H, d, J = 6.6Hz), 0.91 (3H, t, J = 7.3Hz).

Reference Example 28 6-Amino-9-benzyl-8-bromo-2-cyclohexane
Xylthiopurine

Embedded image 178 mg (0.52 mmol) of 6-amino-9-benzyl-2-cyclohexylthiopurine and 0.4 ml of bromine
Was stirred at room temperature for 7 hours. An aqueous solution of sodium thiosulfate was added to the reaction solution, the organic layer was separated, the organic layer was dried over magnesium sulfate, filtered, and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (0.5% -methanol / chloroform) to obtain 86 mg of the title compound (40%). ¹ H-NMR (CDCl ₃ ) δ: 7.30-7.45 (5H, m), 5.69 (2H, br s),
5.31 (2H, s), 3.80 (1H, m), 2.10 (2H, m), 1.25-1.78 (8
H, m).

Reference Example 29 6-amino-9-benzyl-8-bromo-2-phenyl
Thioprine

Embedded image 6-amino-9-benzyl-2-phenylthiopurine 9
A solution of 5 mg (0.28 mmol) and 0.4 ml of bromine in 150 ml of methylene chloride was stirred at room temperature for 4.5 hours.
An aqueous solution of sodium thiosulfate was added to the reaction solution, the organic layer was separated, the organic layer was dried over magnesium sulfate, filtered, and the solvent in the filtrate was distilled off under reduced pressure. The residue is purified by silica gel column chromatography (0.5% -methanol / chloroform).
This gave 25 mg (22%) of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 7.65 to 7.68 (2H, m), 7.42-7.44 (3H,
m), 7.20-7.28 (5H, m), 5.49 (2H, br s), 5.09 (2H, s).

Reference Example 30 6-amino-9-benzyl-8-bromo-2- (p-to
Rilthio) pudding

Embedded image A solution of 86 mg (0.37 mmol) of 6-amino-9-benzyl-2- (p-tolylthio) purine and 0.4 ml of bromine in 120 ml of methylene chloride was stirred at room temperature for 4 hours. An aqueous solution of sodium thiosulfate was added to the reaction solution, the organic layer was separated, the organic layer was dried over magnesium sulfate, filtered, and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (0.5% -methanol / chloroform) to obtain 20 mg of the title compound (19%). ¹ H-NMR (CDCl ₃ ) δ: 7.55 (2H, d, J = 7.9 Hz), 7.20-7.28 (7
H, m), 5.40 (2H, br s), 5.10 (2H, s), 2.41 (3H, s).

Reference Example 31 6-amino-9-benzyl-8-bromo-2- (2-na
Futylthio) pudding

Embedded image 6-amino-9-benzyl-2- (2-naphthylthio)
221 mg (0.58 mmol) of pudding and 0.4 m of bromine
l of methylene chloride in 160 ml was stirred for 5.5 hours at room temperature. An aqueous solution of sodium thiosulfate was added to the reaction solution,
Separate the organic layer, dry the organic layer over magnesium sulfate,
After filtration, the solvent of the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (0.5% -methanol / chloroform) to obtain 118 mg of the title compound (44%). ¹ H-NMR (CDCl ₃ ) δ: 8.42 (1 H, d, J = 8.3 Hz), 7.80-7.87 (3
H, m), 7.52-7.66 (2H, m), 7.04-7.21 (6H, m), 5.56 (2
H, br s), 5.00 (2H, s).

Reference Example 32 6-amino-9-benzyl-2-benzylthio-8-bu
Lomo pudding

Embedded image 6-amino-9-benzyl-2-benzylthiopurine 1
A solution of 76 mg (0.51 mmol) and 1 ml of bromine in 160 ml of methylene chloride was stirred at room temperature for 4 hours. An aqueous solution of sodium thiosulfate was added to the reaction solution, and the organic layer was separated.
The organic layer was dried over magnesium sulfate, filtered, and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (0.5% -methanol / chloroform) to obtain 19 mg of the title compound (9%). ¹ H-NMR (CDCl ₃ ) δ: 7.21-7.39 (10H, m), 5.50 (2H, br s),
5.33 (2H, s), 4.41 (2H, m).

Reference Example 33 6-amino-9-benzyl-2-methylthio-8-puri
Nord

Embedded image 10 mg (0.026 mmol) of 6-amino-9-benzyl-8-bromo-2-methylthiopurine in concentrated hydrochloric acid 10
The ml solution was heated to reflux for 4 hours. The reaction solution was basified with 28% aqueous ammonia, and the precipitate was collected by filtration, washed with water, and dried to give 8 mg of the title compound (96%). ¹ H-NMR (DMSO-d ₆ ) δ: 9.60 (1 H, br s), 7.31 (5 H, m), 6.5
3 (2H, br s), 4.88 (2H, s), 2.42 (3H, s).

Reference Example 34 6-amino-9-benzyl-2-ethylthio-8-puri
Nord

Embedded image 25 mg (0.069 mmol) of 6-amino-9-benzyl-8-bromo-2-ethylthiopurine in concentrated hydrochloric acid 25
The ml solution was heated to reflux for 4 hours. The reaction solution was made basic with 28% aqueous ammonia, and the precipitate was collected by filtration, washed with water, and dried to give 6 mg of the title compound (29%). ¹ H-NMR (DMSO-d ₆ ) δ: 10.09 (1H, br s), 7.31 (5H, m), 6.
51 (2H, br s), 4.88 (2H, s), 2.97 (2H, q, J = 7.3Hz),
1.25 (3H, t, J = 7.3Hz).

Reference Example 35 6-amino-9-benzyl-2- (n-propylthio)
-8-purinol

Embedded image A solution of 33 mg (0.087 mmol) of 6-amino-9-benzyl-8-bromo-2- (n-propylthio) purine in 35 ml of concentrated hydrochloric acid was heated under reflux for 2 hours. The reaction solution was made basic with 28% aqueous ammonia, and the precipitate was collected by filtration.
Wash with water and dry to give 24 mg of the title compound (87
%). ¹ H-NMR (DMSO-d ₆ ) δ: 10.19 (1H, br s), 7.31 (5H, m), 6.
55 (2H, br s), 4.87 (2H, s), 2.98 (2H, t, J = 6.9Hz),
1.61 (2H, m), 0.94 (3H, t, J = 7.2Hz).

Reference Example 36 6-amino-9-benzyl-2- (iso-propylthio)
E) -8-Prinol

Embedded image 6-amino-9-benzyl-8-bromo-2- (iso-
15 mg (0.040 mmol) of propylthio) purine
Was heated and refluxed for 2 hours. The reaction solution was basified with 28% aqueous ammonia, and the precipitate was collected by filtration, washed with water, and dried to obtain 10 mg of the title compound (79).
%). ^{1 H-NMR (DMSO-d} 6) δ: 10.09 (1H, s), 7.32 (5H, m), 6.50
(2H, br s), 4.87 (2H, s), 3.78 (1H, m), 1.30 (6H, d,
J = 6.9Hz).

Reference Example 37 6-amino-9-benzyl-2- (n-butylthio)-
8-Prinol

Embedded image A solution of 23 mg (0.059 mmol) of 6-amino-9-benzyl-8-bromo-2- (n-butylthio) purine in 10 ml of concentrated hydrochloric acid was heated under reflux for 5 hours. Reaction solution 2
The mixture was made basic with 8% aqueous ammonia, and the precipitate was collected by filtration, washed with water, and dried to give 14 mg of the title compound (99%). ¹ H-NMR (DMSO-d ₆ ) δ: 10.05 (1 H, br s), 7.30 (5 H, m), 6.
50 (2H, br s), 4.88 (2H, s), 3.00 (2H, t, J = 7.0Hz),
1.58 (2H, m), 1.35 (2H, m), 0.86 (3H, t, J = 7.2Hz).

Reference Example 38 6-amino-9-benzyl-2- (iso-butylthio)
-8-purinol

Embedded image 6-amino-9-benzyl-8-bromo-2- (iso-
A solution of 21 mg (0.053 mmol) of butylthio) purine in 20 ml of concentrated hydrochloric acid was heated under reflux for 5 hours. The reaction solution was made basic with 28% aqueous ammonia, and the precipitate was collected by filtration, washed with water, and dried to give 16 mg of the title compound (91%). ¹ H-NMR (DMSO-d ₆ ) δ: 10.10 (1 H, s), 7.26-7.35 (5 H, m),
6.51 (2H, br s), 4.87 (2H, s), 2.93 (2H, d, J = 6.6H
z), 1.83 (1H, m), 0.93 (6H, d, J = 6.6Hz).

Reference Example 39 6-amino-9-benzyl-2- (sec-butylthio)
-8-purinol

Embedded image 6-amino-9-benzyl-8-bromo-2- (sec-
A solution of 39 mg (0.092 mmol) of butylthio) purine in 20 ml of concentrated hydrochloric acid was heated under reflux for 2 hours. The reaction solution was made basic with 28% aqueous ammonia, and the precipitate was collected by filtration, washed with water, and dried to give 12 mg of the title compound (40%). ¹ H-NMR (DMSO-d ₆ ) δ: 10.09 (1 H, br s), 7.24-7.35 (5 H,
m), 6.50 (2H, br s), 4.87 (2H, s), 3.65 (1H, m), 1.61
(2H, m), 1.28 (3H, d, J = 7.0Hz), 0.93 (3H, t, J = 7.3
Hz).

Reference Example 40 6-amino-9-benzyl-2- (n-pentylthio)
-8-purinol

Embedded image A solution of 39 mg (0.096 mmol) of 6-amino-9-benzyl-8-bromo-2- (n-pentylthio) purine in 35 ml of concentrated hydrochloric acid was heated under reflux for 2.5 hours. The reaction solution was basified with 28% aqueous ammonia, and the precipitate was collected by filtration, washed with water, and dried to give 30 mg of the title compound (91).
%). ¹ H-NMR (DMSO-d ₆ ) δ: 10.05 (1 H, br s), 7.30 (5 H, m), 6.
50 (2H, br s), 4.88 (2H, s), 2.99 (2H, t, J = 7.3Hz),
1.59 (2H, m), 1.30 (4H, m), 0.84 (3H, t, J = 7.3Hz).

Reference Example 41 6-amino-9-benzyl-2- (3-methylbutylthio)
E) -8-Prinol

Embedded image 6-amino-9-benzyl-8-bromo-2- (3-methylbutylthio) purine 11 mg (0.027 mmol
A solution of l) in 20 ml of concentrated hydrochloric acid was heated under reflux for 3 hours. The reaction solution was basified with 28% aqueous ammonia, and the precipitate was collected by filtration, washed with water, and dried to obtain 7 mg of the title compound (75%).
%). ¹ H-NMR (DMSO-d ₆ ) δ: 10.10 (1 H, br s), 7.30 (5 H, m), 6.
50 (2H, br s), 4.88 (2H, s), 3.00 (2H, t, J = 7.6Hz),
1.63 (1H, m), 1.51 (2H, m), 0.86 (6H, t, J = 6.2Hz).

Reference Example 42 6-amino-9-benzyl-2- (2-methylbutylthio)
E) -8-Prinol

Embedded image 6-amino-9-benzyl-8-bromo-2- (2-methylbutylthio) purine 29 mg (0.071 mmol
A solution of l) in 20 ml of concentrated hydrochloric acid was heated under reflux for 3 hours. The reaction solution was basified with 28% aqueous ammonia, and the precipitate was collected by filtration, washed with water, and dried to give 6 mg of the title compound (25
%). ¹ H-NMR (DMSO-d ₆ ) δ: 10.08 (1H, s), 7.30 (5H, m), 6.50
(2H, br s), 4.88 (2H, s), 3.08 (1H, q, J = 6.6Hz), 2.
86 (1H, m), 1.62 (1H, m), 1.43 (1H, m), 1.15 (1H, m),
0.91 (3H, d, J = 6.6Hz), 0.86 (3H, t, J = 6.2Hz).

Reference Example 43 6-amino-9-benzyl-2-cyclohexylthio-
8-Prinol

Embedded image A solution of 20 mg (0.048 mmol) of 6-amino-9-benzyl-8-bromo-2-cyclohexylthiopurine in 10 ml of concentrated hydrochloric acid was heated under reflux for 6 hours. Reaction solution 2
The mixture was made basic with 8% aqueous ammonia, and the precipitate was collected by filtration, washed with water, and dried to obtain 12 mg of the title compound (70%). ¹ H-NMR (DMSO-d ₆ ) δ: 10.09 (1H, br s), 7.31 (5H, m), 6.
49 (2H, br s), 4.87 (2H, s), 3.62 (1H, m), 2.00 (2H,
m), 1.68 (2H, m), 1.62-1.56 (1H, m), 1.35 (5H, m).

Reference Example 44 6-amino-9-benzyl-2-phenylthio-8-propyl
Linole

Embedded image 31 mg (0.075 mmol) of 6-amino-9-benzyl-8-bromo-2-phenylthiopurine in concentrated hydrochloric acid 2
The 0 ml solution was heated to reflux for 12 hours. 28% reaction solution
The mixture was made basic with ammonia water, and the precipitate was collected by filtration, washed with water,
Drying afforded 11 mg of the title compound (42%). ^{1 H-NMR (DMSO-d} 6) δ: 9.50 (1H, br s), 7.55 (2H, m), 7.4
6 (3H, m), 7.28 (3H, m), 7.13 (2H, m), 6.55 (2H, br s),
4.67 (2H, s).

Reference Example 45 6-amino-9-benzyl-2- (p-tolylthio)-
8-Prinol

Embedded image A solution of 15 mg (0.035 mmol) of 6-amino-9-benzyl-8-bromo-2- (p-tolylthio) purine in 20 ml of concentrated hydrochloric acid was heated under reflux for 7.5 hours. The reaction solution was made basic with 28% aqueous ammonia, and the precipitate was collected by filtration.
Wash with water and dry to give 5 mg of the title compound (39%). ¹ H-NMR (DMSO-d ₆ ) δ: 7.44 (2H, d, J = 7.9 Hz), 7.27 (5H,
m), 7.13 (2H, m), 6.51 (2H, br s), 4.67 (2H, s), 2.35
(3H, s).

Reference Example 46 6-amino-9-benzyl-2- (2-naphthylthio)
-8-purinol

Embedded image 20 mg of concentrated hydrochloric acid containing 33 mg (0.043 mmol) of 6-amino-9-benzyl-8-bromo-2- (2-naphthylthio) purine and dimethylsulfoxide (DMSO) 7
The mixture was heated to reflux for 6 hours. 28% reaction solution
The mixture was made basic with aqueous ammonia, and the precipitate was collected by filtration and washed with water. The crude was purified by thin layer chromatography to give 6 mg (35%) of the title compound. ¹ H-NMR (DMSO-d ₆ ) δ: 10.14 (1 H, br s), 8.30 (1 H, d, J =
8.6Hz), 7.98-8.07 (2H, m), 7.67-7.77 (3H, m), 7.12-7.
20 (3H, m), 6.69 (2H, d, J = 6.9Hz), 6.59 (2H, br s),
4.58 (2H, s).

Reference Example 47 6-amino-9-benzyl-2-benzylthio-8-propyl
Linole

Embedded image 18 mg (0.042 mmol) of 6-amino-9-benzyl-2-benzylthio-8-bromopurine in concentrated hydrochloric acid 1
The 0 ml solution was heated to reflux for 9 hours. The reaction solution was basified with 28% aqueous ammonia, and the precipitate was collected by filtration, washed with water, and dried to obtain 8 mg of the title compound (52%). ¹ H-NMR (DMSO-d ₆ ) δ: 10.12 (1 H, br s), 7.19-7.34 (10 H,
m), 6.58 (2H, br s), 4.91 (2H, s), 4.29 (2H, s).

Example 1 6-amino-9-benzyl-2- (n-butylsulfini
) -8-purinol

Embedded image 6-amino-9-benzyl-2- (n-butylthio) -8
-26 mg of m-chloroperbenzoic acid in a 25 ml solution of purinol 50 mg (0.152 mmol) in methylene chloride
(0.152 mmol) was added and stirred at room temperature for 1 hour. After evaporating the solvent of the reaction solution under reduced pressure, the residue was suspended in diethyl ether, and the solid was collected by filtration. The obtained solid was purified by silica gel column chromatography (5% methanol / chloroform) to obtain 18 mg of the title compound (34%). ¹ H-NMR (DMSO-d ₆ ) δ: 10.52 (1H, br s), 7.29 (5H, m),
6.96 (2H, s), 4.95 (2H, s), 3.02-2.84 (2H, m), 1.63-1.
55 (1H, m), 1.38-1.25 (3H, m), 0.83 (3H, t, J = 7.1H
z).

Example 2 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
3) Test compound Each test compound was accurately weighed in an amount of about 1 mg, and was added to DMSO.
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 spleen cells 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. further,
The cells were suspended in 5 ml of 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 treated with trypsin, a medium was immediately added, and a cell suspension was prepared by pipetting (4 × 10 4). 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.
One by one was added. In addition, 50 μl of the medium alone was added to the uninfected cell control group and the virus infection control group. 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 7. It was revealed that the compound of the present invention has an interferon biosynthesis inducing activity.

[Table 212]

Example 3 Effect on Cytokine Production from Mouse Lymph Node Cells <Experimental Method> 1. Animals BALB / c mice were purchased from Charles River Japan (Yokohama), and 8-week-old females were used. 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) to be used at 50 μM. 3. Drug 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 typical Th2-type cytokines, and interferon γ (I
FN-γ) is quantified.

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 coat 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) was diluted 500-fold with PBS (-) containing 0.1% BSA (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, 100ml /
well). Incubate at 37 ° C. for 1 hour, rinse the plate, and use PNPP substrate (p-nitrophenyl phosphate disodium, Nacalai Tesque) (1 mg / ml, 10 mg / ml).
(0 ml / well). For measurement, use a microplate reader (MTP-120 Microplatereader, Corona Ele
ctric) (wavelength 415 nm). For the determination of IFN-γ, 1
Rat anti-mouse IFN-γ antibody (Pharmingen, S
an Diego, CA, Code No. 18181D, 0.5 mg / ml), and a biotin-labeled rat anti-mouse IFN-γ antibody (Pharmi
ngen, Code No. 18112D, 0.5 mg / ml) in the same manner. Recombinant mouse IFN-
Use γ (Pharmingen, Code No. 19301U). For the quantification of IL-5, a rat anti-mouse IL-5 antibody (Phar
mingen, SanDiego, CA, Code No. 18051D, 0.5mg / ml),
Biotin-labeled rat anti-mouse IL-5 antibody (Pharmingen, Code No. 18062D, 0.5 mg / ml) is used in the same manner as the secondary antibody. To prepare a calibration curve, recombinant mouse IL-5 (Pharmingen, Code No. 19241W) is used.
The experiment is performed by triplicate, and the average value is obtained.

[0181]

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.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/52 AED A61K 31/52 AED C07D 471/04 107 C07D 471/04 107A (72) Inventor Hajime Kawakami Hajime Konohana, Osaka-shi, Osaka 3-1-98, Kasuganaka, Ward, Sumitomo Pharmaceutical Co., Ltd.

Claims (9)

[Claims] 1. A compound of the general formula (1) (Wherein, -X- is -SO- or -SO ₂ - represents either X ¹ and X ² represent together a nitrogen atom, X ¹ is or X ¹ X ² nitrogen atoms represent CH is CH And X ² represents a nitrogen atom; R ¹ represents an amino group, an alkylamino group, a substituted alkylamino group, a dialkylamino group or an alicyclic heterocyclic group; R ² represents an alkyl group, a substituted alkyl group, an alkenyl group, R ³ represents a hydrogen atom, an alkyl group, a substituted alkyl group, an alkanoyl group, a substituted alkenyl group, an alkynyl group, a substituted alkynyl group, an aryl group, a substituted aryl group, an aralkyl group, a substituted aralkyl group, a heterocyclic group or a substituted heterocyclic group; Group, substituted alkanoyl group, aroyl group, substituted aroyl group, alkoxycarbonyl group, substituted alkoxycarbonyl group, benzyloxycarbonyl group or substituted benzyloxycarbo group Y ¹ 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, or a substituted alkoxy group A carbonyl 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; and Y ² represents a hydrogen atom, a hydroxyl group, an alkyl group, or a substituted alkyl group. , Alkoxy, substituted alkoxy, alkanoyl, substituted alkanoyl, aroyl, substituted aroyl, carboxy, alkoxycarbonyl, substituted alkoxycarbonyl, amino, alkylamino, dialkylamino, carbamoyl, · The carbamoyl group, a dialkylcarbamoyl group, a halogen atom, a heterocyclic compound or a pharmaceutically acceptable salt thereof represented by a nitro group or a cyano group.). 2. A compound of the general formula (2) (Wherein, -X- is -SO- or -SO ₂ - represents, R ² is 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, Aralkyl group, substituted aralkyl group, represents 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, Y represents 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; ² is a hydrogen atom, a hydroxyl group, an alkyl group, a substituted alkyl group, A Coxy 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, dialkylamino group, carbamoyl group, alkylcarbamoyl group , A dialkylcarbamoyl group, a halogen atom, a nitro group or a cyano group.) Or a pharmaceutically acceptable salt thereof. 3. R ² is 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, a substituted aralkyl group, a heterocyclic group or a substituted heterocyclic ring. And 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 a nitro group. Or a pharmaceutically acceptable salt thereof. 4. The heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein -X- is -SO-. 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 anticancer agent comprising the heterocyclic compound according to claim 1, 2, 3 or 4 or a pharmaceutically acceptable salt thereof as an active ingredient. 9. An agent for treating an immune disease, comprising the heterocyclic compound according to claim 1, 2, 3 or 4 or a pharmaceutically acceptable salt thereof as an active ingredient.