JP2001011047A - Phosphodiesterase inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound having a phosphodiesterase IV inhibitory activity and useful for the treatment and prevention of an inflammatory disease, asthma, dermatitis, etc. SOLUTION: This phosphodiesterase inhibitor is a compound of formula I R1 and R2 are each H, a (substituted) 1-8C alkyl, a (substituted) 2-6C alkenyl or the like; R3 is H, a (substituted) 1-7C alkyl or the like; A is a group of formula II [R601 is H, a (substituted) 1-6C alkyl or the like; R602 is H, a (substituted) aryl or the like] or the like; X is C or N}, e.g. 3-(1-cyclopentyl-1H-indazol-6-yl) amino-2-cyclopenten-1-one. The compound of the formula I is obtained in the case that X=C, by alkylating the nitrogen atom of an indole derivative of formula III, reducing the obtained 6-nitroindole derivative catalytically to obtain a 6-aminoindole derivative and performing a dehydrating condensation reaction with a 1,3-dione. In the case of using the above compound as an active ingredient of a medicine, it is preferable to administer 0.01-1,000 mg daily for an adult in oral administration based on the weight of the active ingredient.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel compound having a phosphodiesterase (PDE) IV inhibitory action.

[0002]

BACKGROUND OF THE INVENTION cAMP, an intracellular second messenger, is involved in the relaxation of airway smooth muscle and the regulation of the function of inflammatory cells, and cAMP is degraded by phosphodiesterase (PDE). To be inactive 5'-AMP. If the concentration of cAMP is increased by suppressing the degradation by PDE, a bronchodilator effect and an anti-inflammatory effect are obtained, and it is considered that the compound exhibits a therapeutic effect on inflammatory diseases such as asthma [Eur. Respir. J. , 7,579 (199
4)]. To date, PDEs have been classified into five types of isozymes (PDEI-V), and their distribution varies depending on the tissue [Trends Phar]
m. , Sci. , 12, 19 (1991)]. this is,
This suggests that specific inhibitors for each isozyme of PDE may lead to different elevations of cAMP in various tissues.

[0003] Among the PDE isozymes, type IV (hereinafter sometimes abbreviated as "PDE IV" in the present specification)
Have been reported to suppress the function of inflammatory cells [Thorax, 46, 512 (199).
1)], asthma [J. Pharmacol. Exp.
r. , 266, 306 (1993)], dermatitis [Br.
J. Pharmacol. , 112, 332 (199
4)], inflammatory diseases, multiple sclerosis [Nature
Medicine, 1, 244 (1994)] and rheumatism [Clin. Exp. Immunol. , 10
0, 126 (1995)]. In addition, it is considered that by inhibiting only PDE IV, side effects such as heart observed with non-selective PDE inhibitors such as theophylline can be reduced.

A compound having a specific inhibitory action on PDE IV is rolipram of the following formula (JP-A-50-15).
No. 7360) is known.

Embedded image

[0005] In addition to rolipram, compounds showing specific inhibition of PDE IV are known (US Pat. No. 5,128,128).
358, International Publication WO94 / 10118, International Publication WO94 / 12461, JP-A-7-10186
No. 1, International Publication WO95 / 03794, International Publication WO95 / 08534, etc.). However, these compounds have not been applied clinically to date, and the development of more useful compounds is desired.

[0006] International Publication WO98 / 09961 states that P
The following general formula having an inhibitory effect on DE IV:

Embedded image Are described, but there is no description on the 3-amino-2-cycloalkenone derivative which is the compound of the present invention.

[0007]

Means for Solving the Problems The present inventors have proposed PDEIV.
As a result of searching for a novel compound having an inhibitory action, the compound of the present invention represented by the following general formula (I) showed a strong PD
It has EIV inhibitory activity and is found to be useful for the treatment and / or prevention of various diseases involving PED IV (eg, inflammatory diseases, asthma, dermatitis, etc.), and completes the present invention. Reached.

That is, the present invention provides the following general formula (I):

Embedded image [Wherein, R ¹ and R ² each independently represent a hydrogen atom, a C ₁ -C ₈ alkyl group which may have a substituent, a C ₂ -C ₆ alkenyl which may have a substituent. Group, C ₂ -C ₆ alkynyl group which may have a substituent, C ₃ -C ₇ cycloalkyl group which may have a substituent, aryl group which may have a substituent (Which may have one or more heteroatoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom), a crosslinked polycycloalkyl group, or a condensed polycyclic ring which may have a substituent A formula group (wherein, when X is a nitrogen atom, ^one of the nitrogen atoms to which R ¹ and R ² are bonded represents a nitrogen atom having no substituent); R ³ is a hydrogen atom, a substituent C ₁ to which may have
C ₇ alkyl group, C ₂ -C ₆ which may have a substituent
An alkenyl group, an optionally substituted C ₂ -C ₆ alkynyl group, an optionally substituted C ₃ -C ₇ cycloalkyl group, or an optionally substituted A good aryl group (which may have one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur atoms)
A represents the following general formula:

Embedded image [In the formula (A1), R ¹⁰¹ represents a hydrogen atom, a C _{1 to} C ₅ alkyl group which may have a substituent, a C _{3 to} C ₇ cycloalkyl group which may have a substituent, optionally substituted aryl group (an oxygen atom, a nitrogen atom, and may contain one or more heteroatoms selected from the group consisting of sulfur atom) indicates, R ¹⁰² and R ¹⁰³ Are each independently a hydrogen atom, a C ₁ -C ₆ alkyl group which may have a substituent, a phenyl group which may have a substituent, and a monocyclic aryl which may have a substituent Represents a group (containing one or more hetero atoms selected from the group consisting of oxygen, nitrogen, and sulfur), and a dotted line represents a single bond or a double bond, provided that the dotted line represents a single bond If R
¹⁰⁴ is a hydrogen atom or C ₁ -C ₆ which may have a substituent;
In the formula (A2), R ²⁰¹ represents a hydrogen atom, a C _{1 to} C ₅ alkyl group which may have a substituent,
Represents a C _{3 to} C ₇ cycloalkyl group which may have a substituent, or an acyl group which may have a substituent;
²⁰² is a hydrogen atom, a C ₁ -C ₅ alkyl group which may have a substituent, a halogen atom, the following general formula (A2-II): (R ²⁰⁷ ) (R ²⁰⁸ ) N-CH _2- Wherein R ²⁰⁷ and R ²⁰⁸ each independently represent a C _{1 to} C ₅ alkyl group) or a group represented by the following general formula (A2-I
II):

Embedded image(In the above formula, m represents an integer of 2 to 6, but one CH_TwoBase
Is selected from the group consisting of oxygen, nitrogen, and sulfur
May be substituted by one heteroatom)
Represents a group represented by²⁰³, R²⁰⁴, R²⁰⁵, And R²⁰⁶Haso
Each independently represents a hydrogen atom or an optionally substituted C₁
~ C_FiveAlkyl or a substituent which may have a substituent
A phenyl group;^A2Is-(CH_Two)_n− (N is an integer of 0 to 2
Or a group represented by -N (R²⁰⁹)-(R²⁰⁹Is water
C atom optionally having a hydrogen atom or a substituent₁~ C_FiveArchi
A group represented by the following formula:
³⁰¹Is a hydrogen atom and optionally substituted C₁~ C_Fiveof
Alkyl group, optionally substituted C_Three~ C₇No shiku
Aryl group, aryl group which may have a substituent
(Selected from the group consisting of oxygen, nitrogen, and sulfur atoms
May contain at least one heteroatom
I) or an acyl group which may have a substituent,
R³⁰²Is a hydrogen atom and optionally substituted C₁~ C₆
An alkyl group or an aryl which may have a substituent
Groups (from the group consisting of oxygen, nitrogen, and sulfur
May have at least one selected heteroatom
) And R³⁰³And R³⁰⁴Are independently hydrogen sources
And C which may have a substituent₁~ C_FiveAn alkyl group of
C which may have a substituent_Three~ C₇The cycloalkyl
Group or an aryl group which may have a substituent (an oxygen atom
Selected from the group consisting of oxygen, nitrogen, and sulfur
May contain at least one heteroatom)
In the formula (A4), R⁴⁰¹Is a hydrogen atom; having a substituent
May be C₁~ C_FiveHaving an alkyl group or a substituent of
Good C_Three~ C₇Having a cycloalkyl group or a substituent
Aryl groups (an oxygen atom, a nitrogen atom, and a sulfur atom
At least one heteroatom selected from the group consisting of
May be contained), or may have a substituent.
Represents an acyl group;⁴⁰²Has a hydrogen atom and a substituent
May be C₁~ C₆Having an alkyl group or a substituent
Aryl groups (oxygen, nitrogen, sulfur,
At least one heteroatom selected from the group consisting of atoms
May have a child), and R⁴⁰³And R⁴⁰⁴Is it
Each independently represents a hydrogen atom or an optionally substituted C₁~
C_FiveAlkyl group, C which may have a substituent_Three~ C₇
A cycloalkyl group, or an optionally substituted
Reel group (consisting of oxygen, nitrogen, and sulfur atoms
Containing at least one heteroatom selected from the group
In the formula (A5)⁵⁰¹Is hydrogen field
And C which may have a substituent₁~ C₆An alkyl group of
C which may have a substituent_Three~ C₇The cycloalkyl
Group, an aryl group which may have a substituent (an oxygen atom,
At least one selected from the group consisting of a nitrogen atom and a sulfur atom
And may contain one heteroatom) or
An acyl group which may have a substituent;⁵⁰²Is hydrogen
Atom, C optionally having substituent (s)₁~ C_FiveThe alkyl of
Group, halogen atom, the following general formula (A5-II): (R⁵⁰⁷)
(R⁵⁰⁸) N-CH _Two-(Where R⁵⁰⁷And R⁵⁰⁸Are each
C which may have a substituent independently₁~ C _FiveAlkyl group
Or R⁵⁰⁷And R⁵⁰⁸Is the nitrogen source to which they bind
To form a monocyclic heterocyclic group or a polycyclic heterocyclic group
Or a group represented by the following general formula (A5-III):

Embedded image (In the formula, p represents an integer of 2 to 6, but one CH ₂ group may be substituted with one hetero atom selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom.) Wherein R ⁵⁰³ , R ⁵⁰⁴ , R ⁵⁰⁵ and R ⁵⁰⁶ are each independently a hydrogen atom or a C ₁ -C ₅ which may have a substituent.
X ^A5 represents-[C (R ⁵⁰⁹ ) (R ⁵¹⁰ )] _q- (R ⁵⁰⁹ and R ⁵¹⁰ are each independently a hydrogen atom, A C ₁ -C ₅ alkyl group which may have a group, or a phenyl group which may have a substituent, and q represents an integer of 0 to 2)
Or a group represented by -N (R ⁵¹¹ )-(R ⁵¹¹ represents a hydrogen atom or a C ₁ -C ₅ alkyl group which may have a substituent); In (A6), R ⁶⁰¹ represents a hydrogen atom, a C _{1 to} C ₆ alkyl group which may have a substituent, or an aryl group which may have a substituent (an oxygen atom, a nitrogen atom, and a sulfur atom). 1 selected from the group consisting of atoms
Or more heteroatoms).
⁶⁰² is a hydrogen atom, an aryl group which may have a substituent (may contain one or more hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom);
Or, the following general formula (A6-II): -CO-OR ⁶⁰³ , -CO-NHR ⁶⁰³ , -CO-N (R
^{603) (R 604), -} CS-OR 603, -CS-NHR 603,
-CS-N (R ⁶⁰³ ) (R ⁶⁰⁴ ), and -CO-R ⁶⁰⁵ (wherein R ⁶⁰³ and R ⁶⁰⁴ each independently represent a hydrogen atom or a C ₁ -C ₆ which may have a substituent. An alkyl group, a C ₃ -C ₇ cycloalkyl group which may have a substituent, a C ₂ -C ₆ alkenyl group which may have a substituent, and a C 3 which may have a substituent. _{2 to} C ₆ alkynyl group, aryl group which may have a substituent (may have one or more hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom) Or a heterocyclic group which may have a substituent (may have one or more hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom), or R ⁶⁰³ and R ⁶⁰⁴ together with the nitrogen atom to which they are attached represent a monocyclic or polycyclic heterocyclic group; ⁶⁰⁵ is a C _{1 to} C ₆ alkyl group which may have a substituent, and C ₂ which may have a substituent.
An alkenyl group of ~ C _6, an optionally substituted C ₂ ~
C ₆ alkynyl group, aryl group which may have a substituent (may have one or more hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom)
A) selected from the group consisting of groups represented by (A6-I
X represents a carbon atom or a nitrogen atom], a stereoisomer thereof, a salt thereof, or a water thereof. Or a solvate thereof.

In another aspect, the present invention provides a compound represented by the above formula (I), a stereoisomer thereof, a physiologically acceptable salt thereof, a hydrate thereof or a solvent thereof. There is provided a medicament comprising a Japanese lactide as an active ingredient. The medicament of the present invention is preferably provided in the form of a pharmaceutical composition containing the above-mentioned active ingredient and a pharmaceutical additive, and can be used for the prevention and / or treatment of a disease associated with phosphodiesterase IV. For example, prevention of asthma and / or
Or, it is useful for the treatment and prevention and / or treatment of inflammatory diseases such as dermatitis (eg, atopic dermatitis, contact dermatitis, psoriasis, or urticaria). Further, according to the present invention, a compound represented by the above formula (I), a stereoisomer thereof,
Alternatively, there is provided a phosphodiesterase IV inhibitor comprising a physiologically acceptable salt thereof, or a hydrate or solvate thereof.

From still another viewpoint, the compound represented by the above formula (I), its stereoisomer or its salt, its hydrate or its solvate for the production of the above-mentioned medicament. Use of products; and phosphodiesterase IV
And / or a method for preventing and / or treating a disease (eg, inflammatory disease such as dermatitis, asthma), wherein the compound represented by the above formula (I), its stereoisomer, or its physiological And administering to a mammal, including a human, a therapeutically and / or prophylactically effective amount of a pharmaceutically acceptable salt or a hydrate or solvate thereof.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION As a C ₁ -C ₈ alkyl group represented by R ¹ or R ² , a linear or branched alkyl group can be used. For example, a methyl group, an ethyl group, a propyl group, Isopropyl group, n-butyl group, isobutyl group, s
ec-butyl group, t-butyl group, n-pentyl group, 1,
A 1-dimethylpropyl group, n-hexyl group, 1-methylpentyl group, 1,1-dimethylbutyl group, 2-ethylbutyl group, n-heptyl group, n-octyl group, and the like can be used. Alkyl moiety of other substituents having the alkyl moiety (e.g., alkoxy group) may, if not specifically mentioned, is preferably a straight-chain or branched-chain alkyl group of C ₁ -C ₈ illustrated above. C represented by R ¹ or R ²
Alkyl group of ₁ -C ₈ may have a substituent.

In the present specification, when a specific functional group may have a substituent, the functional group has one or more substituents unless otherwise specified. Means that there are cases. The number of substituents, the types of substituents, and the positions of substitution in the functional group are not particularly limited, and when two or more substituents are present, they may be the same or different. For example, as a substituent present in the functional group, a halogen atom (in the case of "halogen atom" in this specification, any of a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom), a hydroxyl group, an oxo group, Nitro group, cyano group, amino group, monoalkylamino group, dialkylamino group, carboxyl group, alkoxycarbonyl group, alkylcarbonyl group,
An arylcarbonyl group, an aralkyl group, an aryl group (which may contain one or more hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom; for example, a phenyl group, a cumenyl group, a tolyl group , A xylyl group,
Mesityl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, furyl group, thienyl group,
Pyrrolyl group, imidazolyl group, pyridyl group, pyrazolyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group,
A triazolyl group, etc.), and a heterocyclic group which may have a substituent (may contain one or more hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom. Isochromanyl group, chromanyl group, pyrrolidinyl group, pyranyl group, pyrrolinyl group, imidazolidinyl group, imidazolinyl group, pyrazolidinyl group, pyrazolinyl group, piperidyl group, piperazinyl group, morpholinyl group, indolinyl group, isoindolinyl group, quinuclidinyl group, etc. Optionally a fused polycyclic group (which may contain one or more heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; for example, naphthyl, quinolyl, Benzimidazolyl group, benzthiazolyl group, benzoxazolyl group, benzisoxazolyl group, Soquinolyl group, indolizinyl group, indazoyl group, indolyl group, isoindolyl group, naphthyridinyl group, phthalazinyl group, quinazolinyl group, quinoxalinyl group, indanyl group, fluorenyl group, tetrahydronaphthyl group, dibenzocycloheptyl group, azulenyl group, etc., cycloalkyl group (Such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group), a carbamoyl group, and an alkoxy group, but are not limited thereto. Further, the substituents exemplified above may be further substituted with one or more other substituents. Examples of such a group include a haloalkyl group (eg, a trifluoromethyl group), a haloalkylcarboxyl group (eg, a trifluoroacetyl group), and a haloaryl group (eg, a fluorophenyl group, a chlorophenyl group, etc.). .

When the C ₁ -C ₈ alkyl group represented by R ¹ or R ² has a substituent, specific examples include a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, Methylcyclopropylmethyl group, 1-phenylcyclopropylmethyl group,
1-methylcyclobutylmethyl group, 1-methylcyclopentylmethyl group, 1-methylcyclohexylmethyl group,
2-indanylmethyl group, 2-nitroethyl group, 2-cyanoethyl group, 2-methoxyethyl group, 2- (dibenzylamino) ethyl group, 2-anilinoethyl group, benzyl group, 4-bromobenzyl group, 4-nitro Benzyl group, piperonyl group, phenethyl group, 4-fluorophenethyl group, 3-phenylpropyl group, 4-phenylbutyl group,
5-phenylpentyl group, 2-pyridylmethyl group, 3-
Pyridylmethyl group, 4-pyridylmethyl group, furylmethyl group, thiazolylmethyl group, 2-quinolylmethyl group, 1
-Naphthylmethyl group, 2-naphthylmethyl group, 2- (morpholino) ethyl group, 2- (4-methylpiperazinyl)
Ethyl group, 2- (1-piperidinyl) ethyl group, 2-
(1-naphthyl) ethyl group, 2- (2-pyridyl) ethyl group, 2- (benzyloxy) ethyl group, 2- (phenethyloxy) ethyl group, 3- (methoxy) propyl group,
Examples thereof include a 4- (methoxy) butyl group, a 2- (cyclopropylmethyloxy) ethyl group, a 2- (cyclopentyloxy) ethyl group, and a 2- (2-indanyl) ethyl group.

The C ₂ -C ₆ alkenyl group represented by R ¹ or R ² includes, for example, vinyl, propenyl, butenyl, methylpropenyl, dimethylvinyl, pentenyl, methylbutenyl, dimethylpropenyl, Ethylpropenyl group, hexenyl group, dimethylbutenyl group,
Examples thereof include a methylpentenyl group. Examples of the C ₂ -C ₆ alkynyl group represented by R ¹ or R ² include:
Ethynyl, propynyl, butynyl, methylpropynyl, pentynyl, methylbutynyl, hexynyl and the like can be mentioned. These C ₂ -C ₆ alkenyl groups and C ₂ -C ₆ alkynyl groups may have a substituent. Specific examples of the C ₂ -C ₆ alkenyl group and the C ₂ -C ₆ alkynyl group having a substituent include a 2-phenylvinyl group, a 2- (3-pyridyl) vinyl group, a propynyl group, and a 3-phenylvinyl group. (3-pyridyl) propynyl group and the like.

Examples of the C ₃ -C ₇ cycloalkyl group represented by R ¹ or R ² include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group. Cycloalkyl group C ₃ -C ₇ indicated by R ¹ or R ² may have a substituent. Examples of the C ₃ -C ₇ cycloalkyl group having a substituent include a 4-phenylcyclohexyl group and a 1-methylcyclopentyl group.

The aryl group represented by R ¹ or R ² is one selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom.
It may contain two or more heteroatoms and may have a substituent. When two or more heteroatoms are contained, they may be the same or different. R ¹ or R ²
Examples of the aryl group represented by, for example, phenyl group, tolyl group, naphthyl group, pyridyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, furyl group, thienyl group, quinolyl group, isoquinolyl group, pyrrolyl group, imidazolyl group , A pyrazolyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, an indolyl group, and the like. Examples of the crosslinked polycycloalkyl group represented by R ¹ or R ² include bicyclo [2.2.
1] heptyl group, bicyclo [2.2.2] octyl group,
Bicyclo [3.2.1] octyl group, adamantyl group and the like can be mentioned. Examples of the condensed polycyclic group represented by R ¹ or R ² include an indanyl group, a tetrahydronaphthyl group and a dibenzocycloheptyl group. Can be mentioned.

R ¹ or R ² is preferably C ₂ -C ₆
Having an alkyl group, a phenyl group, a benzyloxy group, an indanyl group, or a cycloalkyl group as a substituent
Examples thereof include an alkyl group of ₁ to ₅ carbon atoms, a cycloalkyl group of ₄ to ₆ carbon atoms, a bicyclo [2.2.1] heptyl group, and an indanyl group, and more preferably a cyclopentyl group, a cyclohexyl group, An indanyl group, or 2-
(2-Indanyl) ethyl group and the like can be mentioned.

As the C ₁ -C ₇ alkyl group represented by R ³ , a linear or branched alkyl group can be used. Examples of the C ₁ -C ₇ alkyl group represented by R ³ include a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group,
t-butyl group, n-pentyl group, 1,1-dimethylpropyl group, n-hexyl group, 1-methylpentyl group, 1,
A 1-dimethylbutyl group, a 2-ethylbutyl group, an n-heptyl group, or the like can be used, and these may have a substituent. Examples of the case where the C ₁ -C ₇ alkyl group represented by R ³ has a substituent include, for example, a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, a 1-methylcyclopropylmethyl group A 1-phenylcyclopropylmethyl group,
1-methylcyclobutylmethyl group, 1-methylcyclopentylmethyl group, 1-methylcyclohexylmethyl group,
2-indanylmethyl group, 2-nitroethyl group, 2-cyanoethyl group, 2-methoxyethyl group, 2- (dibenzylamino) ethyl group, 2-anilinoethyl group, benzyl group, 4-bromobenzyl group, 4-nitro Benzyl group, piperonyl group, phenethyl group, 4-fluorophenethyl group, 3-phenylpropyl group, 4-phenylbutyl group,
5-phenylpentyl group, 2-pyridylmethyl group, 3-
Pyridylmethyl group, 4-pyridylmethyl group, furylmethyl group, thiazolylmethyl group, 2-quinolylmethyl group, 1
-Naphthylmethyl group, 2-naphthylmethyl group, 2- (morpholino) ethyl group, 2- (4-methylpiperazinyl)
Ethyl group, 2- (1-piperidinyl) ethyl group, 2-
(1-naphthyl) ethyl group, 2- (2-pyridyl) ethyl group, 2- (benzyloxy) ethyl group, 2- (phenethyloxy) ethyl group, 3- (methoxy) propyl group,
Examples thereof include a 4- (methoxy) butyl group, a 2- (cyclopropylmethyloxy) ethyl group, a 2- (cyclopentyloxy) ethyl group, and a 2- (2-indanyl) ethyl group.

Examples of the C ₂ -C ₆ alkenyl group represented by R ³ include a vinyl group, a propenyl group, a butenyl group, a methylpropenyl group, a dimethylvinyl group, a pentenyl group,
Methylbutenyl group, dimethyl propenyl group, an ethyl propenyl group, hexenyl group, dimethylbutenyl group, may be mentioned, methyl pentenyl group, C ₂ ~ indicated R ³
Examples of the C ₆ alkynyl group include an ethynyl group, a propynyl group, a butynyl group, a methylpropynyl group, a pentynyl group, a methylbutynyl group, and a hexynyl group. These C ₂ -C ₆ alkenyl groups and C
The alkynyl group of _{2 to} C ₆ may have a substituent. R
C ₂ -C ₆ showing ³ alkenyl group or R ³ of C ₂ -C ₆ indicated
When the alkynyl group has a substituent, specific examples thereof include a 2-phenylvinyl group, a 2- (3-pyridyl) vinyl group, a propynyl group, and a 3- (3-pyridyl) propynyl group. it can. C ₃ or more represented by R ³
Examples of the cycloalkyl group C _7, for example, there may be mentioned a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group,
These may have a substituent. C ₃ -C represented by R ³
Specific examples when the cycloalkyl group ₇ has a substituent include a 4-phenylcyclohexyl group and a 1-methylcyclopentyl group.

The aryl group represented by R ³ may contain one or more hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom, and may have a substituent. Good. When two or more heteroatoms are contained, they may be the same or different. Examples of the aryl group represented by R ³ include a phenyl group, a tolyl group, a naphthyl group, a pyridyl group, a thiazolyl group, an isothiazolyl group, an oxazolyl group, an isoxazolyl group, a furyl group, a thienyl group, a quinolyl group, an isoquinolyl group, a pyrrolyl group, Examples thereof include an imidazolyl group, a pyrazolyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, and an indolyl group. R ³ is preferably a hydrogen atom, C ₁ -C
₃ , an alkyl group, a phenyl group, or a pyridyl group, and more preferably, a hydrogen atom, a methyl group, an ethyl group, or a phenyl group.

The C ₁ -C ₅ alkyl group represented by R ¹⁰¹ may be linear or branched, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl. Group, t-butyl group, n-pentyl group and the like. Alkyl C ₁ -C ₅ where R ^{10 1} is shown may have a substituent, preferably, an oxygen atom, a nitrogen atom, and one or more heteroatoms selected from the group consisting of sulfur atoms Aryl groups that may be contained (for example, phenyl group, pyridyl group, thiazolyl group,
Furyl, thienyl, naphthyl, quinolyl, etc.)
As a substituent. C ₁ having a substituent
Examples of -C ₅ alkyl group, e.g., benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl group, 5-phenyl pentyl group, pyridylmethyl group, furylmethyl group, thiazolylmethyl group, 1- Examples include a naphthylmethyl group and a 4-quinolylmethyl group. Examples of the cycloalkyl group C ₃ -C ₇ where R ¹⁰¹ represents, for example, cyclopropyl group, cyclobutyl group,
Examples thereof include a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group. The aryl group represented by R ¹⁰¹ may contain one or more hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom.
Examples of the aryl group R ¹⁰¹ represents, for example, a phenyl group, a pyridyl group, a thiazolyl group, a furyl group, a thienyl group, a naphthyl group, and a quinolyl group. R ¹⁰¹ preferably includes a hydrogen atom, a C ₁ -C ₃ alkyl group, an aryl group, and a C ₁ -C ₂ alkyl group having an aryl group as a substituent, and more preferably a hydrogen atom, Examples include a methyl group, an ethyl group, a phenyl group, and a benzyl group.

The C ₁ -C ₆ alkyl groups represented by R ¹⁰² and R ¹⁰³ may be linear or branched, and include, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, Examples thereof include a t-butyl group, a pentyl group, and a hexyl group. The phenyl group represented by R ¹⁰² and R ¹⁰³ may have a substituent. The phenyl group represented by R ¹⁰² and R ^{1 03,} and examples thereof include a phenyl group, a 4-methylphenyl group, a 4-chlorophenyl group and. As the aryl group represented by R ¹⁰² and R ¹⁰³ , a monocyclic aryl group containing at least one hetero atom selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom can be used. Examples thereof include a pyridyl group, a thiazolyl group, a thienyl group, and a furyl group. R ¹⁰² and R ¹⁰³ preferably include a hydrogen atom, a methyl group, an ethyl group, a phenyl group, or a pyridyl group, and more preferably R ¹⁰³ is a hydrogen atom. A dotted line in the formula (A1) indicates a single bond or a double bond. However, when the dotted line is a single bond, R ¹⁰⁴ represents a hydrogen atom or an alkyl group of C ₁ -C ₆ (e.g., methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group). Preferably, the dotted line indicates a double bond.

The C ₁ -C ₅ alkyl group represented by R ²⁰¹ may be linear or branched, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl. Group, t-butyl group, n-pentyl group and the like. Alkyl C ₁ -C ₅ where R ^{20 1} is shown may have a substituent. C ₁ indicated by R ²⁰¹
Alkyl group -C _5, for example, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, a carboxyl group,
Cycloalkyl group, haloalkyl group, carbamoyl group,
An alkoxy group, an alkylcarbonyl group, an aryl group (which may contain one or more hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom), and the like; Good. C _1- having a substituent
As the alkyl group of C _5, and examples thereof include a benzyl group, phenethyl group, 3-phenylpropyl, 4-phenylbutyl group, 5-phenyl pentyl group, pyridylmethyl group, furylmethyl group, and thiazolylmethyl group .

Examples of the C ₃ -C ₇ cycloalkyl group represented by R ²⁰¹ include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group, and the acyl group represented by R ²⁰¹ Examples thereof include a formyl group, an acetyl group, a propionyl group, a benzoyl group and the like. R ²⁰¹
As is preferably a hydrogen atom, an alkyl group of C ₁ -C _3, an acyl group, or an aryl group (an oxygen atom, a nitrogen atom,
And a C ₁ -C ₂ alkyl group which may have one or more hetero atoms selected from the group consisting of Represents a hydrogen atom, a methyl group, a 4-pyridylmethyl group, a benzyl group, an acetyl group, or the like.

The C ₁ -C ₅ alkyl group represented by R ²⁰² may be linear or branched, for example, methyl, ethyl, propyl, isopropyl, butyl, sec.
-Butyl group, t-butyl group, pentyl group and the like. The C ₁ -C ₅ alkyl group represented by R ²⁰² may have a substituent. Examples of the substituent of the C ₁ -C ₅ alkyl group include a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, a carboxyl group, a cycloalkyl group, a haloalkyl group, a carbamoyl group, an alkoxy group,
Examples thereof include an alkylcarbonyl group and an aryl group (which may contain one or more hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom).

In the general formula (A2-II), R ²⁰⁷ and R
^The C ₁ -C ₅ alkyl group represented by ²⁰⁸ may be linear or branched, and may be, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group, a t-butyl group.
-Butyl group, pentyl group and the like. Specific examples of the group represented by the general formula (A2-II) include, for example, 1-azetidinemethyl group, 1-pyrrolidinemethyl group, 1-piperidinemethyl group, 1-homopiperidinemethyl group, 1-piperazine Examples include a methyl group and a morpholinomethyl group. R ²⁰² is preferably a hydrogen atom, a halogen atom, a C ₁ -C ₃ alkyl group,
Examples include a dimethylaminomethyl group, a morpholinomethyl group, and a benzyl group.

C represented by R ²⁰³ , R ²⁰⁴ , R ²⁰⁵ , and R ²⁰⁶
The alkyl group of ₁ to ₅ may be linear or branched, and examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group, a t-butyl group and a pentyl group. be able to. R ²⁰³ , R
^The C ₁ -C ₅ alkyl group or the phenyl group represented by ²⁰⁴ , R ²⁰⁵ and R ²⁰⁶ may have a substituent. Examples of the substituent include a halogen atom, hydroxyl group, nitro group, cyano group, amino group, carboxyl group, alkyl group, cycloalkyl group, haloalkyl group, carbamoyl group, alkoxy group, alkylcarbonyl group, aryl group (oxygen atom,
(It may contain one or more hetero atoms selected from the group consisting of a nitrogen atom and a sulfur atom.) R ²⁰³ , R ²⁰⁴ , R ²⁰⁵ and R ²⁰⁶ preferably include a hydrogen atom or a methyl group.

In -N (R ²⁰⁹ )-represented by X ^A2 , R ²⁰⁹
The C ₁ -C ₅ alkyl group represented by may be linear or branched, for example, a methyl group, an ethyl group, a propyl group,
Examples thereof include an isopropyl group, a butyl group, a sec-butyl group, a t-butyl group, and a pentyl group. R ²⁰⁹
The C ₁ -C ₅ alkyl group represented by may have a substituent. Examples of the substituent include a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, a carboxyl group, a cycloalkyl group, a haloalkyl group, a carbamoyl group, an alkoxy group, an alkylcarbonyl group, and an aryl group (an oxygen atom, a nitrogen atom, and 1 selected from the group consisting of sulfur atoms
Or more heteroatoms). Specific examples of the alkyl group having a substituent include, for example, a benzyl group, a phenethyl group, a 3-phenylpropyl group, a 4-phenylbutyl group, a 5-phenylpentyl group, a pyridylmethyl group, a furylmethyl group, and a thiazolylmethyl group. Can be mentioned. As X ^A2 ,
Preferably, - (CH _{2) n} - where n is at 0 or 1 or -N (R ^209), - the R ²⁰⁹ is a hydrogen atom, C ₁ -C ₃ alkyl group, or when a benzyl group Can be mentioned.

R³⁰¹C indicated by₁~ C_FiveAlkyl group is linear
Or a branched chain, such as a methyl group or an ethyl group.
Group, n-propyl group, isopropyl group, n-butyl
Group, sec-butyl group, t-butyl group, n-pentyl group
And the like. R ³⁰¹C indicated by₁~ C_Fiveof
The alkyl group may have a substituent. As a substituent
Is, for example, a halogen atom, a hydroxyl group, a nitro group, a cyano
Group, amino group, carbonyl group, aryl group (oxygen atom,
At least one selected from the group consisting of a nitrogen atom and a sulfur atom
Both may contain one heteroatom. For example,
Phenyl, tolyl, naphthyl, pyridyl, thia
Zolyl, furyl, thienyl, etc.) or alkoxy
Examples include a cicarbonyl group and the like. Substituent
Having C₁~ C_FiveSpecific examples of the alkyl group of
For example, an ethoxycarbonylmethyl group, a benzyl group,
Lomobenzyl group, phenethyl group, 3-phenylpropyl
Group, 4-phenylbutyl group, 5-phenylpentyl group,
Pyridylmethyl group, furylmethyl group, thiazolylmethyl
Group, 2-quinolylmethyl group, 1-naphthylmethyl group, 2
-Naphthylmethyl group and the like.

Examples of the C ₃ -C ₇ cycloalkyl group represented by R ³⁰¹ include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group. C ₃ -C where R ³⁰¹ represents
The cycloalkyl group of ₇ may have a substituent. R
^The aryl group represented by ³⁰¹ may contain at least one hetero atom selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom. Examples of the aryl group represented by R ³⁰¹ include a phenyl group, a tolyl group, a naphthyl group,
Examples include a pyridyl group, a thiazolyl group, a furyl group, and a thienyl group. The aryl group may have a substituent. Examples of the acyl group represented by R ³⁰¹ include a formyl group, an acetyl group, a propionyl group, a benzoyl group, a 2-naphthoyl group, a 3-furoyl group, a 2-thenoyl group, a nicotinoyl group, and an isonicotinoyl group.

R ³⁰¹ is preferably a hydrogen atom, C ₁
Alkyl group -C _4, having an oxygen atom, a nitrogen atom, and at least one which may contain a hetero atom aryl group or an ethoxycarbonyl group selected from the group consisting of a sulfur atom as a substituent, a halogen Examples thereof include a C _{1 to} C ₃ alkyl group which may have an atom as a substituent, or an acetyl group, and more preferably a hydrogen atom,
Examples include a methyl group, an ethyl group, a benzyl group, a 2-pyridylmethyl group, and a 4-pyridylmethyl group.

The C ₁ -C ₆ alkyl group represented by R ³⁰² may be linear or branched, for example, methyl, ethyl, propyl, isopropyl, butyl, sec.
-Butyl group, t-butyl group, pentyl group, hexyl group and the like. Alkyl C ₁ -C ₆ where R ^{30 2} is shown may have a substituent. Examples of the aryl group represented by R ³⁰² include a phenyl group, a pyridyl group, a thiazolyl group, a thienyl group, and a furyl group. As the aryl group having a substituent, for example,
Examples thereof include a 4-methylphenyl group and a 4-chlorophenyl group. Preferably, R ³⁰² is a hydrogen atom, a C ₁ -C ₃ alkyl group, or a phenyl group.

The C ₁ -C ₆ alkyl groups represented by R ³⁰³ and R ³⁰⁴ may be linear or branched, and include, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl. , T-butyl group, pentyl group, hexyl group and the like. The C ₁ -C ₆ alkyl groups represented by R ³⁰³ and R ³⁰⁴ may have a substituent. Examples of the substituent include a halogen atom, a hydroxyl group,
Cyano group, amino group, carboxyl group, cycloalkyl group, haloalkyl group, carbamoyl group, alkoxy group,
An alkylcarbonyl group or an aryl group (at least one selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom)
May contain one or more heteroatoms). The aryl group represented by R ³⁰³ and R ³⁰⁴ may have a substituent. Examples of the aryl group include a phenyl group, a tolyl group, a naphthyl group, a pyridyl group, a thiazolyl group, a thienyl group, and a furyl group.
These may have, for example, a halogen atom, a hydroxyl group, a cyano group, an amino group, a carboxyl group, an alkyl group, a cycloalkyl group, a haloalkyl group, a carbamoyl group, an alkoxy group, an alkylcarbonyl group, or the like as a substituent. Examples of the aryl group having a substituent include a 4-methylphenyl group and a 4-chlorophenyl group. R ³⁰³ and R ³⁰⁴ preferably include a hydrogen atom.

R⁴⁰¹C indicated by₁~ C_FiveAlkyl group is linear
Or a branched chain, such as a methyl group or an ethyl group.
Group, n-propyl group, isopropyl group, n-butyl
Group, sec-butyl group, t-butyl group, n-pentyl group
And the like. R ⁴⁰¹C indicated by₁~ C_Fiveof
The alkyl group may have a substituent. As a substituent
Is, for example, a halogen atom, a hydroxyl group, a nitro group, a cyano
Group, amino group, carbonyl group, aryl group (oxygen atom,
At least one selected from the group consisting of a nitrogen atom and a sulfur atom
Both may contain one heteroatom. For example,
Phenyl, tolyl, naphthyl, pyridyl, thia
Zolyl, furyl, thienyl, etc.) or alkoxy
A cicarbonyl group and the like can be mentioned. Has a substituent
C₁~ C_FiveSpecific examples of the alkyl group of, for example,
Ethoxycarbonylmethyl group, benzyl group, 4-bromo
Benzyl group, phenethyl group, 3-phenylpropyl group,
4-phenylbutyl group, 5-phenylpentyl group, pyri
A zirmethyl group, a furylmethyl group, a thiazolylmethyl group,
2-quinolylmethyl group, 1-naphthylmethyl group, 2-na
Examples include a futylmethyl group.

Examples of the C ₃ -C ₇ cycloalkyl group represented by R ⁴⁰¹ include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group. C ₃ -C indicated by R ⁴⁰¹
The cycloalkyl group of ₇ may have a substituent. R
^The aryl group represented by ⁴⁰¹ may contain at least one hetero atom selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom. Examples of the aryl group represented by R ⁴⁰¹ include a phenyl group, a tolyl group, a naphthyl group,
Examples include a pyridyl group, a thiazolyl group, a furyl group, and a thienyl group. The aryl group represented by R ⁴⁰¹ may have a substituent. Examples of the acyl group represented by R ⁴⁰¹ include a formyl group, an acetyl group, a propionyl group, a benzoyl group, a 2-naphthoyl group, a 3-furoyl group, a 2-thenoyl group, a nicotinoyl group, and an isonicotinoyl group.

R ⁴⁰¹ is preferably a hydrogen atom, C ₁
Alkyl group -C _4, having an oxygen atom, a nitrogen atom, and at least one optionally contain heteroatoms aryl or an ethoxycarbonyl group selected from the group consisting of a sulfur atom as a substituent, a halogen atom an alkyl group optionally C ₁ -C ₃ as a substituent, or an acetyl group can be exemplified, more preferably a hydrogen atom, a methyl group, an ethyl group, a benzyl group, 2-pyridylmethyl group Or a 4-pyridylmethyl group.

The C ₁ -C ₆ alkyl group represented by R ⁴⁰² may be linear or branched, for example, methyl, ethyl, propyl, isopropyl, butyl, sec.
-Butyl group, t-butyl group, pentyl group, hexyl group and the like. Alkyl C ₁ -C ₆ where R ^{40 2} is shown may have a substituent. Examples of the aryl group represented by R ⁴⁰² include a phenyl group, a pyridyl group, a thiazolyl group, a thienyl group, and a furyl group. As the aryl group having a substituent, for example,
Examples thereof include a 4-methylphenyl group and a 4-chlorophenyl group. R ⁴⁰² preferably includes a hydrogen atom, a C ₁ -C ₃ alkyl group, or a phenyl group.

The C ₁ -C ₆ alkyl groups represented by R ⁴⁰³ and R ⁴⁰⁴ may be linear or branched, and include, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and the like. , T-butyl group, pentyl group, hexyl group and the like. The C ₁ -C ₆ alkyl groups represented by R ⁴⁰³ and R ⁴⁰⁴ may have a substituent. Examples of the substituent include a halogen atom, a hydroxyl group,
Cyano group, amino group, carboxyl group, cycloalkyl group, haloalkyl group, carbamoyl group, alkoxy group,
An alkylcarbonyl group or an aryl group (at least one selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom)
May contain one or more heteroatoms). The aryl group represented by R ⁴⁰³ and R ⁴⁰⁴ may have a substituent. Examples of the aryl group include a phenyl group, a tolyl group, a naphthyl group, a pyridyl group, a thiazolyl group, a thienyl group, and a furyl group.
These may have a halogen atom, a hydroxyl group, a cyano group, an amino group, a carboxyl group, an alkyl group, a cycloalkyl group, a haloalkyl group, a carbamoyl group, an alkoxy group, an alkylcarbonyl group, or the like as a substituent.
Examples of the aryl group having a substituent include a 4-methylphenyl group and a 4-chlorophenyl group. As R ⁴⁰³ and R ⁴⁰⁴ , preferably a hydrogen atom,
Examples include a methyl group or a phenyl group.

The C ₁ -C ₆ alkyl group represented by R ⁵⁰¹ may be linear or branched, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec- Butyl, t-butyl, n-pentyl, 1,1-dimethylpropyl, n-hexyl, 1-methylpentyl, 1,1-dimethylbutyl, 2-ethylbutyl and the like. . R
^The C ₁ -C ₆ alkyl group represented by ⁵⁰¹ may have a substituent. As a substituent, for example, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, a carboxyl group,
Cycloalkyl group, haloalkyl group, carbamoyl group,
Examples thereof include an alkoxy group, an alkylcarbonyl group, and an aryl group (which may contain one or more hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom). Specific examples when the C ₁ -C ₆ alkyl group represented by R ⁵⁰¹ has a substituent include, for example, cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, 1-methylcyclopropylmethyl Group, 1-phenylcyclopropylmethyl group, 1-methylcyclobutylmethyl group, 1-methylcyclopentylmethyl group, 1-methylcyclohexylmethyl group, 2-indanylmethyl group, 2-nitroethyl group, 2-cyanoethyl group, 2 -Methoxyethyl group, 2
-(Dibenzylamino) ethyl group, 2-anilinoethyl group, benzyl group, 4-bromobenzyl group, 4-nitrobenzyl group, piperonyl group, phenethyl group, 4-fluorophenethyl group, 3-phenylpropyl group, 4-phenyl Butyl group, 5-phenylpentyl group, 2-pyridylmethyl group, 3-pyridylmethyl group, 4-pyridylmethyl group,
Furylmethyl group, thiazolylmethyl group, 2-quinolylmethyl group, 1-naphthylmethyl group, 2-naphthylmethyl group, 2- (morpholino) ethyl group, 2- (4-methylpiperazinyl) ethyl group, 2- (1- Piperidinyl) ethyl group, 2- (1-naphthyl) ethyl group, 2- (2-pyridyl) ethyl group, 2- (benzyloxy) ethyl group,
-(Phenethyloxy) ethyl group, 3- (methoxy) propyl group, 4- (methoxy) butyl group, 2- (cyclopropylmethyloxy) ethyl group, 2- (cyclopentyloxy) ethyl group, 2- (2-indanyl) ) Ethyl group and the like.

Examples of the C ₃ -C ₇ cycloalkyl group represented by R ⁵⁰¹ include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group. C ₃ -C where R ⁵⁰¹ represents
The cycloalkyl group of ₇ may have a substituent. Specific examples having a substituent include, for example, a 4-phenylcyclohexyl group, a 1-methylcyclopentyl group, and the like. The aryl group represented by R ⁵⁰¹ is
It may contain one or more hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom, and may have a substituent. Examples of the aryl group represented by R ⁵⁰¹ include a phenyl group, a tolyl group, a naphthyl group,
Pyridyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, furyl group, thienyl group, quinolyl group, isoquinolyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, indolyl group, etc. be able to. The aryl group represented by R ⁵⁰¹ may have a substituent.

The acyl group represented by R ⁵⁰¹ includes, for example,
Formyl group, acetyl group, propionyl group, butyryl group, valeryl group, acrylo group, aliphatic alkanoyl group such as propioloyl group, benzoyl group, toluoyl group,
Naphthoyl group, nicotinoyl group, isonicotinoyl group,
Aroyl groups such as a thenoyl group, a furoyl group and a cinnamoyl group can be mentioned. The acyl group represented by R ⁵⁰¹ may have a substituent. R ⁵⁰¹ is preferably a hydrogen atom, a C ₁ -C ₅ alkyl group, a C ₃ -C ₇ cycloalkyl group, or one or more selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom. C ₁ -C ₂ having an aryl group which may contain a hetero atom as a substituent
Can be mentioned, more preferably,
Hydrogen atom, methyl group, propyl group, pentyl group, cyclopentyl group, 2-pyridylmethyl group, 3-pyridylmethyl group, 4-pyridylmethyl group, benzyl group, 2-quinolylmethyl group, 1-naphthylmethyl group, 2-naphthyl Examples thereof include a methyl group and an acetyl group.

As the C ₁ -C ₅ alkyl group represented by R ⁵⁰² , a linear or branched alkyl group can be used. Examples of the C ₁ -C ₅ alkyl group represented by R ⁵⁰² include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group, a t-butyl group, and a pentyl group. C ₁ -C where R ⁵⁰² represents
The alkyl group of ₅ may have a substituent. As a substituent, for example, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, a carboxyl group, a cycloalkyl group, a haloalkyl group, a carbamoyl group, an alkoxy group,
Examples thereof include an alkylcarbonyl group and an aryl group (which may contain one or more hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom).

Formula (A5-II) represented by R ⁵⁰² : (R ⁵⁰⁷ ) (R
⁵⁰⁸⁾ N-CH ₂ - In the group represented by, R ⁵⁰⁷ and R
^The C ₁ -C ₅ alkyl group represented by ⁵⁰⁸ may be either linear or branched, and includes, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group, and a t-butyl group.
-Butyl group, pentyl group and the like. R
^The C ₁ -C ₅ alkyl groups represented by ⁵⁰⁷ and R ⁵⁰⁸ may have a substituent. Examples of the monocyclic heterocyclic group or polycyclic heterocyclic group formed by R ⁵⁰⁷ and R ⁵⁰⁸ together with the nitrogen atom to which they are bonded include, for example, a pyrrolyl group, an imidazolyl group, a pyrrolidinyl group, a pyranyl group, a pyrrolinyl group Group, imidazolidinyl group, imidazolinyl group, pyrazolidinyl group, pyrazolinyl group, piperidyl group, piperazinyl group,
Examples include morpholinyl group, indolinyl group, isoindolinyl group, indolizinyl group, indazoyl group, indolyl group, isoindolyl group, benzimidazolyl group, naphthyridinyl group, phthalazinyl group, quinazolinyl group, and quinoxalinyl group. Specific examples of the group represented by the general formula (A5-III) include, for example, a diethylaminomethyl group, a diethylaminomethyl group, a dibenzylaminomethyl group, a benzylmethylaminomethyl group, a 1-azetidinemethyl group, Examples include a pyrrolidinemethyl group, a 1-piperidinemethyl group, a 1-homopiperidinemethyl group, a 1-piperazinemethyl group, a morpholinylmethyl group, and the like. R ⁵⁰² is preferably a hydrogen atom, a halogen atom, a C ₁ -C ₃ alkyl group, a dimethylaminomethyl group,
Examples include a morpholinomethyl group and a benzyl group.

C ₁ represented by R ⁵⁰³ , R ⁵⁰⁴ , R ⁵⁰⁵ and R ⁵⁰⁶
Alkyl group -C ₅ may be linear or branched, for example, a methyl group, an ethyl group, n- propyl group, an isopropyl group, n- butyl group, isobutyl group, sec-
Examples thereof include a butyl group, a t-butyl group, an n-pentyl group, and a 1,1-dimethylpropyl group. R ⁵⁰³ ,
R ^{5 04,} R ^505, and alkyl group or a phenyl group C ₁ -C ₅ indicated by R ⁵⁰⁶ may have a substituent. Examples of the substituent include a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, a carboxyl group, an alkyl group, a cycloalkyl group, a haloalkyl group, a carbamoyl group, an alkoxy group, an alkylcarbonyl group, an aryl group (an oxygen atom, 1 selected from the group consisting of a nitrogen atom and a sulfur atom
Or more heteroatoms). Specific examples of the C ₁ -C ₅ alkyl group having a substituent include, for example, a 2-nitroethyl group,
Cyanoethyl group, 2-methoxyethyl group, 2- (dibenzylamino) ethyl group, 2-anilinoethyl group, benzyl group, 4-bromobenzyl group, 4-nitrobenzyl group,
Piperonyl group, phenethyl group, 3-phenylpropyl group, 4-phenylbutyl group, 5-phenylpentyl group,
2-pyridylmethyl group, 3-pyridylmethyl group, 4-pyridylmethyl group, furylmethyl group, thiazolylmethyl group, 2-quinolylmethyl group, 1-naphthylmethyl group, 2
-Naphthylmethyl group, 2- (morpholino) ethyl group, 2
-(4-methylpiperazinyl) ethyl group, 2- (1-piperidinyl) ethyl group and the like. Specific examples of the phenyl group having a substituent include a 4-methylphenyl group and a 4-chlorophenyl group. R
^503, as preferably R ^{5 04,} R ⁵⁰⁵ and R ^506, include a hydrogen atom or a methyl group.

In the group represented ^by- [C (R ⁵⁰⁹ ) (R ⁵¹⁰ )] _q represented by Y, the C ₁ -C ₅ alkyl group represented by R ⁵⁰⁹ or R ⁵¹⁰ may be any of linear or branched. For example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group,
n-butyl group, isobutyl group, sec-butyl group, t-
Examples thereof include a butyl group, an n-pentyl group, and a 1,1-dimethylpropyl group. C represented by ^R509 or ^R510
₁ alkyl or phenyl -C ₅ may have a substituent. Examples of the substituent include a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, a carboxyl group, a cycloalkyl group, a haloalkyl group, a carbamoyl group, an alkoxy group, an alkylcarbonyl group, and an aryl group (an oxygen atom, a nitrogen atom, And one or more heteroatoms selected from the group consisting of sulfur atoms and sulfur atoms).

[0046] Y represents -N (R ⁵¹¹⁾ - In the group represented by the alkyl group of C ₁ -C ₅ indicated by R ⁵¹¹ may be linear or branched, for example, a methyl group, an ethyl group ,
Examples thereof include a propyl group, an isopropyl group, a butyl group, a sec-butyl group, a t-butyl group, and a pentyl group. The C ₁ -C ₅ alkyl group represented by R ⁵¹¹ may have a substituent. Examples of the substituent include a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, a carboxyl group, a cycloalkyl group, a haloalkyl group, a carbamoyl group, an alkoxy group, an alkylcarbonyl group, and an aryl group (an oxygen atom, a nitrogen atom, and And may contain one or more heteroatoms selected from the group consisting of sulfur atoms). C _{1 to} C ₅ represented by R ⁵¹¹
As a specific example when the alkyl group has a substituent,
Examples include a benzyl group, a phenethyl group, a 3-phenylpropyl group, a 4-phenylbutyl group, a 5-phenylpentyl group, a pyridylmethyl group, a furylmethyl group, and a thiazolylmethyl group. As Y, preferably
-[C (R ⁵⁰⁹ ) (R ⁵¹⁰ )] _q- a group in which q is 0 or 1 (when q is 1, R ⁵⁰⁹ and R ⁵¹⁰ are preferably each independently a hydrogen atom or A methyl group),
Alternatively, a group represented by —N (R ⁵¹¹ ) — in which R ⁵¹¹ is a hydrogen atom, a C ₁ -C ₃ alkyl group, or a benzyl group can be used.

The C ₁ -C ₆ alkyl group represented by R ⁶⁰¹ may be linear or branched, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl. Group, t-butyl group, n-pentyl group, n-hexyl group and the like. R ⁶⁰¹
The aryl group represented by may have a substituent. R ⁶⁰¹
Examples of the aryl group represented by
-Methylphenyl group, 4-chlorophenyl group, pyridyl group, thiazolyl group, thienyl group, furyl group and the like. R ⁶⁰¹ preferably includes a hydrogen atom, a C ₁ -C ₃ alkyl group, a phenyl group, and a pyridyl group, and more preferably a hydrogen atom, a methyl group, an ethyl group, or a phenyl group. it can.

The aryl group represented by R ⁶⁰² may contain one or more hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom. Examples of the aryl group represented by R ⁶⁰² include a phenyl group, a 2-nitrophenyl group, a 2-bromophenyl group, a tolyl group, a naphthyl group, a pyridyl group, a thiazolyl group, an oxazolyl group, a furyl group, a thienyl group, an indolyl group, Examples thereof include a benzothiazolyl group and a benzooxazolyl group.

The C ₁ -C ₅ alkyl groups represented by R ⁶⁰³ and R ⁶⁰⁴ may be linear or branched, and include, for example, methyl, ethyl, n-propyl, isopropyl, n-
Examples thereof include a butyl group, an isobutyl group, a sec-butyl group, a t-butyl group, an n-pentyl group, and a 1,1-dimethylpropyl group. C ₁ to R ⁶⁰³ and R ⁶⁰⁴ indicate
The C ₅ alkyl group may have a substituent. As the substituent, for example, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, a carbonyl group, an aryl group (1 selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom)
It may contain more than one heteroatom. For example, phenyl, tolyl, naphthyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, furyl, thienyl, quinolyl, isoquinolyl, pyrrolyl, imidazolyl, pyrazolyl, pyrazinyl, A pyrimidinyl group, a pyridazinyl group, etc.), an optionally substituted heterocyclic group (an oxygen atom,
It may contain one or more hetero atoms selected from the group consisting of a nitrogen atom and a sulfur atom. For example, a pyrrolidinyl group, a pyrrolinyl group, an imidazolidinyl group, an imidazolinyl group, a pyrazolidinyl group, a pyrazolinyl group, a piperidyl group, a piperazinyl group, a morpholinyl group, or the like may be included. Specific examples of the C ₁ -C ₅ alkyl group having a substituent include, for example, a 2-nitroethyl group,
2-cyanoethyl group, 2-methoxyethyl group, 2- (dibenzylamino) ethyl group, 2-anilinoethyl group, benzyl group, 4-bromobenzyl group, 4-nitrobenzyl group, piperonyl group, phenethyl group, 3-phenylpropy Group, 4-phenylbutyl group, 5-phenylpentyl group, 2-pyridylmethyl group, 3-pyridylmethyl group,
-Pyridylmethyl group, furylmethyl group, thiazolylmethyl group, 2-quinolylmethyl group, 1-naphthylmethyl group,
2-naphthylmethyl group, 2- (morpholino) ethyl group,
2- (4-methylpiperazinyl) ethyl group, 2- (1-
Piperidinyl) ethyl group and the like.

R⁶⁰³And R⁶⁰⁴C indicated by_Three~ C₇Cycloa
Alkyl group, C_Two~ C₆An alkenyl group of C_Two~ C₆Archi
The nyl group may have a substituent. R⁶⁰³And R⁶⁰⁴But
C shown _Three~ C₇Examples of the cycloalkyl group include
Chloropropyl group, cyclobutyl group, cyclopentyl group,
Examples include cyclohexyl and cycloheptyl groups
Can be. R⁶⁰³And R⁶⁰⁴C indicated by_Two~ C₆The alkenyl of
Examples of the group include a vinyl group, a propenyl group,
Group, methylpropenyl group, dimethylvinyl group, pente
Nil, methylbutenyl, dimethylpropenyl,
Tylpropenyl group, hexenyl group, dimethylbutenyl
Group, methylpentenyl group and the like. R
⁶⁰³And R⁶⁰⁴C indicated by_Two~ C₆As the alkynyl group of
For example, ethynyl, propynyl, butynyl, methyl
Lupropynyl, pentynyl, methylbutynyl, f
Xinyl groups and the like can be mentioned. R⁶⁰³And R⁶⁰⁴
C indicated by_Two~ C₆An alkenyl group or C_Two~ C₆Alkini
Examples of the substituent of the hydroxyl group include a halogen atom,
Group, nitro group, cyano group, amino group, carbonyl group,
Loalkyl group, carbamoyl group, alkoxycarbonyl
Groups, aryl groups (oxygen, nitrogen, and sulfur
Containing one or more heteroatoms selected from the group consisting of
May be. For example, phenyl group, tolyl group, naphthyl
Group, pyridyl group, thiazolyl group, isothiazolyl group,
Xazolyl group, isoxazolyl group, furyl group, thienyl
Group, quinolyl group, isoquinolyl group, pyrrolyl group, imi
Dazolyl group, pyrazolyl group, pyrazinyl group, pyrimidini
And pyridazinyl groups).
You. C having a substituent_Two~ C₆An alkenyl group and C_Two~
C₆Specific examples of the alkynyl group include, for example, 2-phenyl
Phenyl vinyl group, 2- (3-pyridyl) vinyl group, pro
And a 3- (3-pyridyl) propynyl group.
I can do it.

The aryl group represented by R ⁶⁰³ and R ⁶⁰⁴ may contain one or more hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom. Examples of the aryl group represented by R ⁶⁰³ and R ⁶⁰⁴ include, for example, phenyl group, tolyl group, naphthyl group, pyridyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, furyl group, thienyl group, quinolyl group, isoquinolyl group, Pyrrolyl group, imidazolyl group, pyrazolyl group,
Examples include a pyrazinyl group, a pyrimidinyl group, and a pyridazinyl group. The heterocyclic group represented by R ⁶⁰³ and R ⁶⁰⁴ may contain one or more hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom.
Examples of the heterocyclic group represented by R ⁶⁰³ and R ⁶⁰⁴ include a pyrrolidinyl group, a pyrrolinyl group, an imidazolidinyl group, an imidazolinyl group, a pyrazolidinyl group, a pyrazolinyl group, a piperidyl group, a piperazinyl group, and a morpholinyl group. Examples of the monocyclic or polycyclic heterocyclic ring formed by R ⁶⁰³ and R ⁶⁰⁴ and a nitrogen atom include, for example,
Examples include pyrrole, indole, imidazole, benzimidazole, morpholine, piperidine, piperazine, or pyrrolidine.

Each of R ⁶⁰³ and R ⁶⁰⁴ preferably has at least one hetero atom selected from the group consisting of a hydrogen atom, a C ₁ -C ₄ alkyl group, an oxygen atom, a nitrogen atom and a sulfur atom. an aryl group which may have an alkyl group of C ₁ -C ₃ having as a substituent, which may have a substituent C ₂
-C ₄ alkenyl group, C ₂ -C optionally having substituent (s)
₄ alkynyl groups, which may have a substituent, and are selected from the group consisting of oxygen, nitrogen, and sulfur atoms
Examples include a heterocyclic group which may have at least two hetero atoms, and more preferably a hydrogen atom, a methyl group, an ethyl group, a phenyl group, a 2- (3-pyridyl) vinyl group, and a 3- ( 3-pyridyl) propynyl group, benzyl group, phenethyl group, 2-furylmethyl group, 1-naphthylmethyl group, 2-naphthylmethyl group, 2-pyridylmethyl group, 3-pyridylmethyl group, 4-pyridylmethyl group, 2
-Quinolylmethyl group, 1-benzylpiperidyl group, 2-
Examples thereof include a (4-methyl-5-thiazolyl) ethyl group and a (1-methyl-2-indolyl) methyl group.

The C ₁ -C ₅ alkyl group represented by R ⁶⁰⁵ may be linear or branched, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, t-butyl group,
Examples thereof include an n-pentyl group and a 1,1-dimethylpropyl group. The C ₁ -C ₅ alkyl group represented by R ⁶⁰⁵ may have a substituent. Examples of the substituent include a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, a carbonyl group, a haloalkyl group, a carbamoyl group, an alkoxy group, an alkylcarbonyl group, an alkoxycarbonyl group, a cycloalkyl group (for example, a cyclopropyl group , A cyclobutyl group, a cyclopentyl group, a cyclohexyl group, etc.) and an aryl group (at least one hetero atom selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom. For example, a phenyl group, Tolyl, naphthyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, furyl, thienyl, quinolyl, isoquinolyl, pyrrolyl, imidazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl Etc.) Door can be. Specific examples of the C ₁ -C ₅ alkyl group represented by R ⁶⁰⁵ include a t-butyl group and a cyclohexylmethyl group.

Examples of the C ₂ -C ₆ alkenyl group represented by R ⁶⁰⁵ include a vinyl group, a propenyl group, a butenyl group,
Methyl propenyl group, dimethylvinyl group, pentenyl group, methylbutenyl group, dimethyl propenyl group, an ethyl propenyl group, hexenyl group, dimethylbutenyl group, may be mentioned, methyl pentenyl group, a C ₂ -C ₆ indicated R ⁶⁰⁵ Examples of the alkynyl group include an ethynyl group, a propynyl group, a butynyl group, a methylpropynyl group,
Examples include a pentynyl group, a methylbutynyl group, and a hexynyl group. These C ₂ -C ₆ alkenyl group and C ₂ -C ₆ alkynyl group include, for example, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, a carbonyl group, a haloalkyl group, a carbamoyl group, An alkoxy group, an alkylcarbonyl group, an alkoxycarbonyl group, an aryl group (which may contain one or more heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur atoms; for example, phenyl group, tolyl Group, naphthyl group, pyridyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, furyl group, thienyl group, quinolyl group, isoquinolyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, etc. ) May be included. Specific examples of the substituted C ₂ -C ₆ alkenyl group and the C ₂ -C ₆ alkynyl group include a 2- (3-pyridyl) vinyl group, a propynyl group,
And-(3-pyridyl) propynyl group.

The aryl group represented by R ⁶⁰⁵ may contain one or more hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom. Examples of the aryl group represented by R ⁶⁰⁵ include a phenyl group, an indolyl group,
Examples thereof include a pyridyl group, a 2-naphthyl group, a 2-furyl group, and a 2-thienyl group. R ⁶⁰⁵ is preferably a C ₁ -C ₄ alkyl group, an oxygen atom, a nitrogen atom,
And a C ₁ -C ₃ alkyl group having an aryl group optionally having one or more hetero atoms selected from the group consisting of
Alkenyl group ₂ -C _4, which may have a substituent C ₂
To C ₄ alkynyl groups, and aryl groups which may have a substituent and may have one or more hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom And more preferably a t-butyl group, a cyclohexylmethyl group, a 2- (3-pyridyl) vinyl group, a 3- (3-pyridyl) propynyl group, a 1-indolyl group, and a 3-pyridyl group. Can be.

Preferred examples of the compound of the present invention represented by the formula (I) include the following compounds.
The scope of the present invention is not limited to these compounds. (1) a compound of the above formula (I) wherein X is a nitrogen atom; (2) a compound of the above formula (I) wherein X is a carbon atom; (3) R ¹ and R ² are each independently a hydrogen atom; _{4 to} C ₆
An alkyl group, a C ₄ -C ₇ cycloalkyl group, a C ₆ -C ₈
Selected from the group consisting of a bicycloalkyl group, a 3-tetrahydrofuryl group, an indanyl group, or a phenyl group, a naphthyl group, an indanyl group, and a C ₃ -C ₇ cycloalkyl group which may have a substituent. C ₁ having a group
(4) R ¹ and R ² each independently represent a hydrogen atom, a butyl group, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a cyclopropylmethyl group, which is a C ₅ alkyl group; , Cyclobutylmethyl group, cyclopentylmethyl group, (1-phenylcyclopropyl) methyl group, benzyl group, phenethyl group, 2-
(1-naphthyl) ethyl group, 2- (2-indanyl) ethyl group, rel (1R, 2R, 4S) bicyclo [2.
2.1] The compound of the above (1) to (3), which is a hepta-2-yl group, a 3-tetrahydrofuryl group, or a 2-indanyl group;

(5) The compound according to any one of the above (1) to (3), wherein R ³ is a hydrogen atom, a methyl group, or an ethyl group; (6) R ¹⁰¹ is a hydrogen atom, C ₁ -C ₃ alkyl C ₁ -C ₂ having a group, an aryl group, or an aryl group as a substituent
Wherein R ¹⁰² and R ¹⁰³ are each independently a hydrogen atom, a methyl group, an ethyl group, a phenyl group, or a pyridyl group; (7) R ²⁰¹ is a hydrogen atom, a methyl group, a 4-pyridylmethyl group, a benzyl group, or an acetyl group, and R ²⁰² is a hydrogen atom, a halogen atom, a methyl group, an ethyl group, a dimethylaminomethyl group, a morpholinomethyl group, or a benzyl group. A compound of any of the above (1) to (5), wherein m is 0 or 1, and R ²⁰⁹ is a hydrogen atom, a C ₁ -C ₃ alkyl group or a benzyl group; (8) R ³⁰¹ May have a hydrogen atom, a C ₁ -C ₄ alkyl group, a halogen atom as a substituent, an oxygen atom,
A C having, as a substituent, an aryl group or an ethoxycarbonyl group optionally containing at least one hetero atom selected from the group consisting of a nitrogen atom and a sulfur atom;
Alkyl group of ₁ -C _3, or an acetyl group, R ³⁰² is a hydrogen atom, an alkyl group, or a phenyl group C ₁ -C _3, to R ³⁰³ and R ³⁰⁴ is (1) not a hydrogen atom Any compound of (5);

(9) R ⁴⁰¹ may have a hydrogen atom, a C ₁ -C ₄ alkyl group or a halogen atom as a substituent, and is selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom. A C ₁ -C ₃ alkyl group or an acetyl group having, as a substituent, an aryl group or an ethoxycarbonyl group which may contain at least one heteroatom, and R ⁴⁰² is a hydrogen atom, C ₁ -C ₃ A compound of any of the above (1) to (5), wherein R ⁴⁰³ and R ⁴⁰⁴ are hydrogen atoms; and (10) R ⁵⁰¹ has a hydrogen atom or a substituent. C ₁ -C ₆ alkyl group, C ₃ optionally having substituent (s)
Cycloalkyl group -C _7, may have a substituent group, is an oxygen atom, a nitrogen atom, and one or more aryl group which may have a hetero atom selected from the group consisting of sulfur atoms (11) ^R501 is a hydrogen atom, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a 2-pyridylmethyl group, a 3-pyridylmethyl group, A compound according to any one of the above (1) to (5), which is a 4-pyridylmethyl group, a benzyl group, a 1-naphthylmethyl group, a 2-naphthylmethyl group, a 2-quinolylmethyl group, a cyclopentyl group, or an acetyl group;

[0059] (12) R ⁵⁰² is a hydrogen atom, a halogen atom, a methyl group, an ethyl group, a dimethylaminomethyl group, morpholinomethyl group, or a benzyl group, R ^503, R
^504, R ^{50 5,} and R ⁵⁰⁶ are each independently a hydrogen atom or a methyl group, p is 0 or 1, R ⁵⁰⁹ and R ⁵¹⁰
Are each independently a hydrogen atom or a methyl group,
Or the compound of any of the above (10) or (11), wherein R ⁵⁰⁹ is a hydrogen atom and R ⁵¹⁰ is a C ₁ -C ₃ alkyl group or a benzyl group; (13)-[C (R ⁵⁰⁹ ) (R ^510)] _q - _q in the group represented by is 0 or 1, or R ⁵⁰⁹ and R ⁵¹⁰ are each independently hydrogen atom or a methyl group, or -N (R
⁵¹¹ )-In the group represented ^by- , R ⁵¹¹ is a hydrogen atom, C ₁ -C
₃ alkyl group, or any compound of a benzyl group from the (10) (12); ( 14) R 503, R 504, R 505, and the R ⁵⁰⁶ are each independently hydrogen atom or a methyl group (10) to (1)
Any of the compounds of 3); and

[0060] (15) R ⁶⁰¹ is a hydrogen atom, an alkyl group of C ₁ -C _4, a phenyl group, or a pyridyl group, R ⁶⁰²
Is a 2-benzoxazolyl group, or the above general formula (A6-I
I) [R ^{60 3} and R ⁶⁰⁴ are each independently a hydrogen atom, a methyl group, an ethyl group, a phenyl group, a benzyl group, phenethyl group, 2-pyridylmethyl group, 3-pyridylmethyl group, 4
-Pyridylmethyl group, 2-furylmethyl group, 2-thienylmethyl group, 2-quinolylmethyl group, 1-naphthylmethyl group, 2-naphthylmethyl group, 2- (4-methyl-5-
(Thiazolyl) ethyl group, (1-methyl-2-indolyl) methyl group, cyclopropylmethyl group, cyclopentylmethyl group, cyclohexyl group, 2- (morpholinyl)
Ethyl group, N-benzylpiperidyl group, or 3- (3-
Pyridyl) propynyl group],
R ⁶⁰⁵ is a t-butyl group, a cyclohexylmethyl group, 2-
(3-pyridyl) vinyl group, phenyl group, pyridyl group,
Or the compound according to any one of the above (1) to (5), which is an indolyl group.

The compound represented by the above formula (I) has an asymmetric carbon atom, and exists in stereoisomers such as optical isomers and diastereoisomers. Moreover, when it has an alkenyl group as a substituent, a geometric isomer also exists. Pure isomers, arbitrary mixtures of isomers, racemates and the like are all included in the scope of the present invention. Further, the compound represented by the above general formula (I) can exist in the form of a salt. As the salt, a physiologically acceptable salt is preferable. As the salt, for example, hydrochloride, hydrobromide, hydroiodide, inorganic acid salts such as phosphate, and oxalate, maleate, fumarate, lactate, malate, Organic acid salts such as citrate, tartrate, benzoate, methanesulfonate, p-toluenesulfonate and the like can be mentioned. Amino acid salts such as glycine salts can also be used. The compound represented by the above general formula (I) or a salt thereof may exist as a hydrate or a solvate, and these substances are also included in the scope of the present invention. The type of the solvent forming the solvate is not particularly limited, but examples include methanol, ethanol, isopropanol, butanol, acetone, ethyl acetate, chloroform and the like.

The method for producing the compound represented by the above general formula (I) is not particularly limited.
/ 58901 and can be produced according to the method described in US Pat. A method for producing a compound having (A1) to (A6) as the substituent A is described in JP-A-10-5955.
0, JP-A-10-72415, JP-A-10-72415
-120665, International Publication WO98 / 0453
4, Japanese Patent Application No. 9-366196 and Japanese Patent Application No. 11-366196.
-59696, so that those skilled in the art
By reference to these publications, the desired substituent A
Can be easily produced. Hereinafter, as an example of the method for producing the compound of the present invention, a method for producing a compound having a substituent A5 will be specifically described. It can be said that any of the compounds encompassed by the above general formula (I) can be produced by appropriately selecting the reaction reagents, reaction conditions, and the like, and further by appropriately modifying or altering as necessary. It will be easily understood by traders.

(A) Method for producing a compound of the above general formula (I) wherein X is a carbon atom

Embedded image (In the scheme, R ¹ , R ² , R ³ , R ⁵⁰¹ , R ⁵⁰² , R ⁵⁰³ ,
R ⁵⁰⁴ , R ⁵⁰⁵ , R ⁵⁰⁶ and X ^A5 are as defined above.

Step 1: Nitrogen source of indole derivative (V)
Alkylation of the 6-nitroindole derivative (VII
I) is synthesized. Alkylation methods include bases (eg,
Halo in the presence of potassium carbonate, sodium hydride, etc.)
Alkyl Genide (R¹-Z) (VI) (wherein Z is halogen
Indicates an atom. ) And alcohol derivatives
(R ¹-OH) (VII) by the Mitsunobu reaction, etc.
No. The compound obtained by this reaction is a known compound.
Method (eg, crystallization, recrystallization, chromatography
Etc.).

Step 2: 6-nitroindole derivative (VI
II) under a stream of hydrogen (pressure in the range of about 1-10 atm) or with a hydrogen-supplying reagent (ammonium formate, sodium formate, potassium formate, lithium formate, formic acid, etc.)
d / C, PtO _2, etc.), and 6-aminoindole derivative (IX) can be synthesized. The solvent for this reaction may be any solvent as long as it does not hinder the reaction. For example, ethanol, methanol, water and the like are preferable. The compound obtained by this reaction can be purified by a known method (for example, crystallization, recrystallization, chromatography, etc.).

Step 3: 6-aminoindole derivative (I
Compound (XI) can be synthesized by dehydrating and condensing X) with 1,3-diones (X). The reaction is
No solvent or a solvent that does not inhibit the reaction (for example, aliphatic hydrocarbons such as pentane and hexane; halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride; aromatic hydrocarbons such as benzene and toluene; diethyl ether; Ethers such as tetrahydrofuran and dioxane,
Dimethylformamide, etc.).
The reaction temperature is not particularly limited, but may be usually between room temperature and the boiling point of the reaction solvent. In some cases, a condensing agent (for example, anhydrous potassium carbonate, anhydrous sodium carbonate, p-
Toluene sulfonic acid, calcium chloride, acetic acid). Aromatic hydrocarbons (benzene,
When using toluene or the like, the reaction may be carried out while azeotropically separating generated water. The compound obtained by this reaction can be purified by a known method (for example, crystallization, recrystallization, chromatography, etc.).

(B) Production method when X of the compound of the above general formula (I) is a nitrogen atom

Embedded image (In the scheme, R ¹ , R ² , R ³ , R ⁵⁰¹ , R ⁵⁰² , R ⁵⁰³ ,
R ⁵⁰⁴ , R ⁵⁰⁵ , R ⁵⁰⁶ and X ^A5 are as defined above.

Step 4: The compound (XV) and the compound (XVI) can be synthesized by alkylating the nitrogen atom of the 6-nitroindazole derivative (XII). The alkylation can be carried out in the same manner as in Step 1 described above. The alkyl halide (R
R in the formulas of Z) (XIII) and the alcohol derivative (ROH) (XIV) has the same meaning as R ¹ or R ² described above.

Step 5: 1-alkyl-6-nitro-1H
The -indazole derivative (XV) and the 2-alkyl-6-nitro-2H-indazole derivative (XVI) were converted to the corresponding 1-alkyl-6 by the same method as in Step 2.
-Amino-1H-indazole derivative (XVII) and 2-
Alkyl-6-amino-2H-indazole derivative (XV
III) can be converted.

Step 6: In the same manner as in step 3, 1-
Alkyl-6-amino-1H-indazole derivative (XV
II) and a 2-alkyl-6-amino-2H-indazole derivative (XVIII) are reacted with a dione (X) to synthesize the corresponding compound (XIX) and compound (XX), respectively.

(C) In the compound of the above general formula (I), R ⁵⁰¹ is a compound other than a hydrogen atom and R ⁵⁰² is a halogen atom or the following general formula (II): (R ⁵⁰⁷ ) (R ⁵⁰⁸ ) N—CH ₂ — For producing a compound which is

Embedded image (In the scheme, R ¹ , R ² , R ³ , R ⁵⁰¹ , R ⁵⁰² , R ⁵⁰³ ,
R ⁵⁰⁴ , R ⁵⁰⁵ , R ⁵⁰⁶ , R ⁵⁰⁷ , R ⁵⁰⁸ , and X ^A5 are as defined above.

Step 7: Compound (XXI) is reacted with an alkyl halide (R ⁵⁰¹ -Z) in the presence of a base such as sodium hydride.
Compound (XXIII) can be obtained by reacting (XXII) (wherein Z represents a halogen atom).

Step 8: According to the production method described in JP-A-49-85050, R ⁵⁰² of compound (XXIII) is formed in a reaction system from a compound having a hydrogen atom, amines (XXIV) and formaldehyde. Compound (XXV) can be synthesized by reacting with amino alcohol. The obtained compound can be purified by a known method (for example, crystallization, recrystallization, chromatography and the like).

Step 9: The compound (XXVI) in which W is a halogen atom can be synthesized by reacting the compound in which R ⁵⁰² of compound (XXIII) is a hydrogen atom with a halogenating agent. As the halogenating agent, N-chlorosuccinimide, N-
Bromosuccinimide and N-iodosuccinimide can be used. The solvent may be any as long as it does not hinder the reaction, but for example, ethanol, methanol, water and the like are preferable. The compound obtained by this reaction can be obtained by a known method (for example, crystallization, recrystallization,
Chromatography). The desired compound can be synthesized even if the order of Step 7 and Step 8 and Step 7 and Step 9 are changed.

The starting compounds used in the above scheme are commercially available or can be easily synthesized by those skilled in the art by known methods or a combination thereof.
The diones (X) in the above scheme can also be produced by using known methods (JP-A-59-25392, JP-A-61-57583, U.S. Pat. No. 3,671,589). In addition, for the nitro compound, the following known method [Chemical Abstracts,
65, 2245 (1966)]. The synthetic intermediate obtained in each step may be used in the next step without purification. By protecting one or more functional groups of a compound or a product used as a raw material, an intended product may be efficiently obtained. Methods for introducing and removing protecting groups commonly used in organic synthetic chemistry are described, for example, in Protective Groups in Organic Synthesis, by TWGreene, John Wiley & Sons.・ Incorporated (John Wiley & Sons, In
c.) (1981), and those skilled in the art can select an appropriate protecting group.

The compound represented by the formula (I) has an inhibitory effect on phosphodiesterase IV and is useful as an active ingredient of a medicament for treating and / or preventing various diseases in which phosphodiesterase IV is involved. Examples of diseases involving phosphodiesterase IV include inflammatory diseases such as dermatitis (atopic dermatitis, contact dermatitis, psoriasis, and urticaria), and autoimmune diseases such as asthma, multiple sclerosis and rheumatism. And the like. As the active ingredient of the medicament of the present invention, compounds represented by the above formula (I), stereoisomers thereof (optically active isomers, diastereoisomers and the like), and physiologically acceptable salts thereof, and A substance selected from the group consisting of hydrates and solvates thereof can be used. The above-mentioned substance may be administered as a medicament as it is, but usually, it is desirable to produce and administer a pharmaceutical composition using a pharmaceutically acceptable pharmaceutical additive together with the above-mentioned substance.

The form of the pharmaceutical composition is not particularly limited.
It can be appropriately determined according to the physicochemical properties of the substance as the active ingredient, the administration route, the administration schedule and the like. Pharmaceutical compositions suitable for oral administration include, for example, granules, powders, tablets, pills, hard capsules, soft capsules, syrups,
Emulsions, suspensions, solutions and the like can be used. Pharmaceutical compositions suitable for parenteral administration include, for example, injections (for intravenous administration, intramuscular administration, subcutaneous administration, etc.), drops, inhalants, aerosols, ear drops, nasal drops, eye drops,
Suppositories, ointments, creams, transdermal absorbents, transmucosal absorbents, tapes for transdermal administration, patches and the like can be mentioned. An injection or infusion provided in a powder form such as a lyophilized form may be dissolved in use before use. However,
The form of the medicament of the present invention is not limited to the form of the above-mentioned pharmaceutical composition.

The type of the pharmaceutical additive is not particularly limited, and an organic or inorganic, or solid or liquid pharmaceutical additive can be used. The pharmaceutical additive suitable for the production of a desired drug is a pharmaceutical composition. Those skilled in the art can appropriately select them according to the form of the product. For example, in the case of a pharmaceutical composition for oral administration,
Excipients such as lactose, glucose, erythritol, corn starch, and sucrose; disintegrants such as carboxymethylcellulose calcium and hydroxypropylcellulose; lubricants such as calcium stearate, magnesium stearate, talc, polyethylene glycol, and hardened oil;
Wetting agents such as hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polyvinyl alcohol, gelatin, gum arabic, and other surfactants and flavoring agents can be used as necessary. In the case of a parenteral pharmaceutical composition,
Water, ethanol, glycerin, propylene glycol,
Using a diluent such as polyethylene glycol, agar, or tragacanth, a solubilizing agent, a buffer, a preservative, a flavor, a coloring agent, and the like can be used as necessary. The method for preparing the pharmaceutical composition may be a conventional method.

The dose of the medicament of the present invention, when used by oral administration, is generally 0.1 to a day for an adult.
The amount is from 0.01 to 1000 mg (weight of the active ingredient), preferably from 0.01 to 100 mg (weight of the active ingredient). The above dosages may be administered once daily or at appropriate intervals for a day.
It may be administered in three to three doses, or may be administered every few days. When used as an injection, it is preferable to continuously or intermittently administer a single dose of 0.001 to 100 mg (weight of the active ingredient) to an adult. When used as an external preparation, the active ingredient concentration is 0.1% for adults.
The base containing about 01 to 1.0% by weight may be applied to the affected area once to several times a day. The dosages exemplified above are preferably increased or decreased as appropriate according to the type of disease, age and condition of the patient, presence or absence of co-administered drugs, and the like.

[0080]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to Examples, Reference Examples, and Test Examples, but the scope of the present invention is not limited to the following Examples, Reference Examples, and Test Examples. . Reference Example 1 Synthesis of 1-cyclopentyl-6-nitro-1H-indazole and 2-cyclopentyl-6-nitro-2H-indazole Sodium hydride (60%) (1.3%) under a stream of argon.
35 g of an anhydrous N, N-dimethylformamide solution in which 6-nitroindazole (5.00 g, 30.6 mM) was dissolved at 15 ° C. was added to 15 mL of an anhydrous N, N-dimethylformamide solution in which 5 g, 33.71 mM) was suspended. After that, the mixture was stirred at room temperature for 30 minutes. Then, bromocyclopentane (5.94 g, 39.84 mM) was added, and the mixture was added at room temperature for 2 hours.
Stir for 4 hours. The reaction solution was diluted with 200 mL of ethyl acetate, and water (5 times with 70 mL) and saturated saline (1 times with 70 mL).
) And dried over anhydrous sodium sulfate. The extract was filtered, and the filtrate was concentrated under reduced pressure to obtain a brown oil. This oil was purified by flash chromatography (SiO ₂ , 1
4-20% ethyl acetate / hexane).
Cyclopentyl-6-nitro-1H-indazole (2.87 g, 40.5%, less polar isomer), 2-cyclopentyl-6-nitro-2H-indazole
(3.41 g, 48.2%, highly polar isomer) was obtained.

1-cyclopentyl-6-nitro-1H-
Indazole ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.7
4-1.87 (2H, m), 1.96-2.06 (2
H, m), 2.15 to 2.29 (4H, m), 5.09
(1H, quintet, J = 7.08 Hz), 7.8
7. (1H, dd, J = 8.79, 0.73 Hz);
00 (1H, dd, J = 8.79, 1.95 Hz),
8.11 (1H, s), 8.45 (1H, m) 2-cyclopentyl-6-nitro-2H-indazole ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.7
6-1.87 (2H, m), 1.95-2.06 (2
H, m), 2.17-2.26 (2H, m), 2.30
-2.39 (2H, m), 5.01 (1H, quint
et, J = 7.32 Hz), 7.74 (1H, dd, J)
= 9.28, 0.73 Hz), 7.89 (1H, dd,
J = 9.28, 1.95 Hz), 8.08 (1H, d,
J = 7.32 Hz), 8.72 (1H, dd, J = 1.
95, 0.98 Hz)

Reference Example 2 Synthesis of 1-cyclohexylmethyl-6-nitroindole Sodium hydride (60%) (0.2%) under a stream of argon.
7 g, 6.78 mM) in 6 mL of a solution of 6-nitroindole (0.50 g, 3.08 mM) dissolved in 1.5 mL of anhydrous N, N-dimethylformamide solution at 0 ° C.
After adding 35 mL of N-dimethylformamide solution, the mixture was stirred at room temperature for 30 minutes. Then, bromomethylcyclohexane (0.47 g, 3.39 mM) was added, and the mixture was added at room temperature for 24 hours.
Stirred for hours. Dilute the reaction with 20 mL of ethyl acetate,
The extract was washed with water (5 times with 7 mL) and saturated saline (1 time with 7 mL), and dried over anhydrous sodium sulfate. The extract was filtered, and the filtrate was concentrated under reduced pressure to obtain a brown oil. This oil was purified by flash chromatography (SiO ₂ , 11-2).
5% ethyl acetate / hexane) and 1-cyclohexylmethyl-6-nitroindole (0.44 g,
41.6%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.0
0 to 1.06 (2H, m), 1.14 to 1.26 (3
H, m), 1.52-1.74 (5H, m), 1.84
−1.89 (1H, m), 4.02 (2H, d, J =
7.32 Hz), 7.34 (1H, d, J = 2.93H)
z), 7.65 (1H, d, J = 8.79 Hz), 8.
00 (1H, dd, J = 8.79, 1.71 Hz),
8.32 (1H, d, J = 1.71 Hz)

Reference Example 3 Synthesis of 6-amino-1-cyclopentyl-1H-indazole 1-cyclopentyl-6-nitro-1H-indazole (0.55 g, 2.38 mM) in dry methanol (6 m
L) 10% Pd / C (55 mg) and ammonium formate (0.67 g, 10.70 mM) were added to the solution, and the mixture was stirred at room temperature for 3 hours. Transfer the reaction solution to porous diatomaceous earth (trade name:
After filtration under reduced pressure, methylene chloride (15 mL) and water (5 mL) were added to the obtained residue, the mixture was shaken, and the organic layer was dried over anhydrous sodium sulfate. The organic solution is filtered, the filtrate is concentrated under reduced pressure,
A crude product (0.46 g, 97.1%) was obtained as a pale orange oil. The obtained product has sufficient purity and can be used for the next step without purification. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.6
6-1.77 (2H, m), 1.91-2.01 (2
H, m), 2.08-2.19 (4H, m), 3.83
(2H, brs), 4.81 (1H, quintet,
J = 7.32 Hz), 6.56 (1H, dd, J = 8.
55, 1.95 Hz), 6.60 (1H, m), 7.4
7. (1H, dd, J = 8.55, 0.49 Hz);
81 (1H, s)

In the same manner as in Reference Example 3, the following Reference Examples 4-5
Was obtained. Reference Example 4 Synthesis of 6-amino-2-cyclopentyl-2H-indazole Raw material compound; 2-cyclopentyl-6-nitro-2H-
Indazole Properties and yield of the title compound: pale orange crystal (yield: 100
%) ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.6
9-1.80 (2H, m), 1.88-1.98 (2
H, m), 2.10-2.19 (2H, m), 2.21
-2.30 (2H, m), 3.72 (2H, brs),
4.84 (1H, quintet, J = 7.32H
z), 6.58 (1H, dd, J = 8.79, 1.95)
Hz), 6.83 (1H, m), 7.44 (1H, d)
d, J = 8.79, 0.73 Hz), 7.80 (1H,
s)

Reference Example 5 Synthesis of 6-amino-1-cyclohexylmethylindole Starting compound: 1-cyclohexylmethyl-6-nitroindole Properties and yield of the title compound: dark brown oil (yield: 10
0%) ¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.9
3-1.02 (2H, m), 1.13-1.25 (3
H, m), 1.58-1.71 (5H, m), 1.77
-1.86 (1H, m), 3.63 (2H, br),
3.81 (2H, d, J = 7.08 Hz), 6.34
(1H, d, J = 3.17 Hz), 6.55 (1H, d
d, J = 8.30, 1.71 Hz), 6.62 (1H,
d, J = 1.71 Hz), 6.86 (1H, d, J =
3.17 Hz), 7.39 (1H, d, J = 8.30H)
z)

Example 1 3- (1-cyclopentyl-1H-indazole-6-
Synthesis of yl) amino-2-cyclopenten-1-one 6-amino-1-cyclopentyl-1H-indazole (0.46 g, 2.31 mM), 1,3-cyclopentanedione (97%) (0.23 g, 1.36 mM) and p-toluenesulfonic acid (50 mg) were dissolved in dry benzene (10 mL), and refluxed for 3 hours while removing generated water. The reaction was cooled to room temperature and allowed to stand overnight. The precipitated crystals were collected by suction filtration and dried by a vacuum pump to give the title compound as pale yellow crystals (0.59 g, 91.
2%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.7
3-1.81 (2H, m), 1.95-2.03 (2
H, m), 2.14 to 2.19 (4H, m), 2.51
−2.54 (2H, m), 2.81-2.84 (2H,
m), 4.89 (1H, quintet, J = 7.32)
Hz), 5.76 (1H, s), 6.81 (1H, br)
s), 6.87 (1H, dd, J = 8.55, 1.71)
Hz), 7.28 (1H, br), 7.68 (1H, br)
d, J = 8.55 Hz), 7.96 (1H, s)

The following Example 2-3 was carried out in the same manner as in Example 1.
Was obtained. <Example 2> 3- (2-cyclopentyl-2H-indazole-6-
Synthesis of yl) amino-2-cyclopenten-1-one Starting compound: 6-amino-2-cyclopentyl-2H-
Indazole Properties and yield of the title compound: pale orange crystal (yield: 100
%) ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.7
4-1.81 (2H, m), 1.92-2.02 (2
H, m), 2.13-2.22 (2H, m), 2.27
-2.35 (2H, m), 2.48-2.51 (2H,
m), 2.80-2.84 (2H, m), 4.93 (1
H, quintet, J = 7.32 Hz), 5.66
(1H, s), 6.93 (1H, dd, J = 8.79,
1.71 Hz), 6.94 (1H, brs), 7.45
(1H, br), 7.63 (1H, d, J = 8.79H)
z), 7.96 (1H, s)

Example 3 Synthesis of 3- (1-cyclohexylmethylindol-6-yl) amino-2-cyclopenten-1-one Starting compound: 6-amino-1-cyclohexylmethylindole Properties and yield of the title compound Rate: light brown crystal (yield: 65.
5%) ¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.9
4-1.03 (2H, m), 1.14 to 1.21 (3
H, m), 1.57-1.72 (5H, m) 1.77-
1.84 (1H, m), 2.48-2.51 (2H,
m), 2.77-2.80 (2H, m), 3.89 (2
H, d, J = 7.08 Hz), 5.59 (1H, s),
6.47 (1H, d, J = 3.17 Hz), 6.74
(1H, br), 6.87 (1H, dd, J = 8.3)
0, 1.71 Hz), 7.08 (1H, d, J = 3.1)
7Hz), 7.16 (1H, brs), 7.57 (1
(H, d, J = 8.30 Hz)

Example 4 Preparation of Tablet 30 g of 3- (1-cyclopentyl-1H-indazol-6-yl) amino-2-cyclopenten-1-one, lactose 253 g, corn starch 63 g, low-substituted hydroxypropylcellulose 40 g and calcium stearate (4 g) were mixed and compressed by a conventional method to produce tablets so that each tablet contained 10 mg of the compound.

Example 5 Production of Capsules 30 g of 3- (1-cyclopentyl-1H-indazol-6-yl) amino-2-cyclopenten-1-one, lactose 260 g, corn starch 66 g and calcium stearate 4 g were prepared. After mixing, gelatin capsules were filled in the usual way, and each capsule
A capsule was prepared to contain mg.

Example 6 Production of Inhalant 3- (1-cyclopentyl-1H-indazole-6-
Il) Amino-2-cyclopenten-1-one was thoroughly pulverized, and 0.15 g of a particle diameter of 1 to 5 μm was mixed with 60 g of lactose (325 mesh, manufactured by DM Buoy). Capsules were filled by the method and inhalants were prepared such that each capsule contained 50 μg of the compound. Inhalation is performed by loading a capsule into a powder inhalation container.

<Example 7> Preparation of ointment 3- (1-cyclopentyl-1H-indazole-6-
Yl) amino-2-cyclopenten-1-one 100 m
g, olive oil 20 g and white vaseline 79.9 g were mixed under aseptic conditions to produce an ointment.

<Test Example 1> Separation of phosphodiesterase (PDE) and measurement of PDE inhibitory activity In order to examine the PDE inhibitory activity and selectivity of a compound,
Four types of PDE isozymes of type III, type III, type IV and type V were prepared [Trends Pharmacol.
Sci. , 12, 19-27 (1992)]. Type I PD
E used was purchased from Sigma. Also III
Type IV, type IV and type V PDE isozymes were partially purified from platelets (types III and V) or neutrophils (type IV) collected from rats. Each enzyme source was 20 mM bistris, ED
TA (ethylenediaminetetraacetic acid) 2 mM, PMSF (phenylmethylsulfonyl fluoride) 0.1 mM,
2-mercaptoethanol 5 mM, pepstatin 0.0
Buffer containing 0.01 mM and 0.01 mM leupeptin (p
H6.5) and homogenized at 30,000 × G.
The centrifuged supernatant obtained by centrifugation for 0 minutes was applied to an ion exchange column (trade name: Q Sepharose Fast Flow, manufactured by Pharmacia) and eluted with 0 to 1 M sodium acetate. Partially purified isozymes were identified by examining the effect of each known selective inhibitor.

A test substance was dissolved in DMSO (dimethyl sulfoxide), and 50 mM containing 5 mM magnesium chloride was added.
Added in mM Tris-HCl buffer. The above-mentioned PDE isozyme and ³ H-cAMP (for type III and type IV PDE) or ³ H-cGMP (type I and type V PDE) were added to this reaction solution.
Was added as a substrate and reacted at 30 ° C. for 30 minutes. The reaction was stopped by immersing the reaction solution in a boiling solution at 100 ° C. for 5 minutes. Nucleotides generated by PDE is decomposed into ³ H- adenosine or ³ H- guanosine 5'-nucleotidase, substrate and reaction products of unreacted ion exchange column (trade name: QAE Sephadex, manufactured by Pharmacia) through separated. Eluted ³
The radioactivity of H-nucleoside was measured with a liquid scintillation counter. The inhibitory activity of each test substance is represented by an IC ₅₀ value (M), and the inhibitory activity against type IV is 10 μM to 10 μM.
Values in the nM range are shown. In addition, type I and II of each test substance
The inhibitory activity against type I and V was less than 1/10 of the inhibitory activity against type IV.

<Test Example 2> Inhibition of mouse TPA-induced pinna edema Five-week-old ICR male mice were used in groups of 7 to 8 mice. 2 μg of TPA (phorbor 1)
20 μl of an acetone solution containing 2-mirristate (SIGMA) was applied to both surfaces of the right auricle of the mouse to induce a reaction. 0.1 mg of the test substance was dissolved in 20 μl of a tetrahydrofuran-methanol mixed solution (mixing ratio 1: 1), and this solution (20 μl) was applied to the right auricle immediately after TPA application. Six hours after the application of TPA, the mice were sacrificed, and the right auricle was punched with a 6 mm diameter punch, and the weight was measured. When the edema inhibition rate of the test substance was determined by setting the edema rate of the solvent control group to 100%, the edema inhibition action was observed.

<Test Example 3> Antigen-induced airway contraction inhibitory action (anti-asthmatic action) Ovalbumin (OA) was added to male Hartley guinea pigs.
Was intramuscularly administered and sensitized 4 days later. Twenty-five to twenty-nine days after the first sensitization, tracheal cannulas were inserted into pentobarbital-anesthetized guinea pigs to perform artificial respiration. Konzet-Roessl
The airway resistance was monitored by the er method, and OA 0.2 mg /
The increase in airway resistance caused by intravenous administration of kg was examined.
The test substance was dissolved in polyethylene glycol 400 and administered intravenously 10 minutes before the administration of the antigen, and the effect of the compound of the present invention was examined.

<Test Example 4> Acute toxicity The compound of the present invention was suspended in a physiological saline solution containing 0.5% carboxymethylcellulose-sodium, and administered intraperitoneally to ddy male mice. 30m
No test substance showed any death at a dose of g / kg.

[0098]

The compound of the present invention represented by the formula (I) has an excellent PDE IV inhibitory activity, and is effective for inflammatory diseases such as asthma and dermatitis, and for autoimmunity such as multiple sclerosis and rheumatism. It is useful as an active ingredient of a medicament for treating and / or preventing a disease or the like.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme court ゛ (Reference) A61K 31/415 604 A61K 31/415 604 31/50 601 31/50 601 31/535 601 31/535 601 C07D 231/56 C07D 231/56 Z // C07D 403/04 403/04 413/04 413/04 (72) Inventor Kenshiro Yamana 1-46 Kitabukurocho, Omiya City, Saitama Prefecture Niken Chemical Co., Ltd. 72) Inventor ▲ Takahama ▼ Akane 1-346 Kitabukuro-cho, Omiya-shi, Saitama F-term (reference) 4C063 AA01 BB01 CC22 CC28 CC54 DD06 DD11 DD22 EE01 4C086 BC13 BC37 GA08 GA09 MA04 NA14 ZA59 ZB11 ZC20 4C204 BB01 CB03 DB01 DB02 EB02 FB06 GB32

Claims (13)

[Claims] 1. The following general formula (I):[Wherein, R¹And R^TwoAre each independently a hydrogen atom, a substituent
C which may have₁~ C₈Having an alkyl group and a substituent
C that may be_Two~ C₆Having an alkenyl group and a substituent
May be C_Two~ C₆Having an alkynyl group and a substituent
May be C_Three~ C₇Having a cycloalkyl group and a substituent
Aryl groups (an oxygen atom, a nitrogen atom,
At least one heteroatom selected from the group consisting of yellow atoms
May have), a cross-linked polycycloalkyl group, or
Represents a condensed polycyclic group which may have a substituent (only
And when X is a nitrogen atom, R¹And R^TwoIs combined
One of the atoms represents a nitrogen atom having no substituent
R)^ThreeIs a hydrogen atom and optionally substituted C₁~
C₇Alkyl group, C which may have a substituent_Two~ C₆
An alkenyl group, optionally substituted C_Two~ C₆of
Alkynyl group, optionally substituted C_Three~ C₇No
Cycloalkyl group or aryl which may have a substituent
(A group consisting of oxygen, nitrogen and sulfur atoms
May have one or more heteroatoms selected from
A represents the following general formula:[In the formula (A1), R¹⁰¹Has a hydrogen atom and a substituent
May be C₁~ C_FiveHaving an alkyl group or a substituent of
Good C_Three~ C₇Having a cycloalkyl group or a substituent
Aryl groups (oxygen, nitrogen, and sulfur
Containing one or more heteroatoms selected from the group consisting of
R)¹⁰²And R¹⁰³Are independent
A hydrogen atom or an optionally substituted C₁~ C₆Al
Kill group, phenyl group which may have a substituent, substituent
A monocyclic aryl group (oxygen atom, nitrogen
One or more atoms selected from the group consisting of
Containing a heteroatom), and the dotted line represents a single bond or a double bond.
A heavy bond, provided that the dotted line indicates a single bond,
¹⁰⁴Is a hydrogen atom or C which may have a substituent₁~ C₆
In the formula (A2), R represents²⁰¹Is hydrogen field
And C which may have a substituent₁~ C_FiveAn alkyl group of
C which may have a substituent_Three~ C₇The cycloalkyl
A group or an acyl group which may have a substituent;
²⁰²Is a hydrogen atom and optionally substituted C₁~ C_Fiveof
Alkyl group, halogen atom, the following general formula (A2-II): (R²⁰⁷) (R²⁰⁸) N-CH_Two-Where R²⁰⁷And R²⁰⁸Are each independently C₁~ C_FiveNo
Or a group represented by the following general formula (A2-I
II):(In the above formula, m represents an integer of 2 to 6, but one CH_TwoBase
Is selected from the group consisting of oxygen, nitrogen, and sulfur
May be substituted by one heteroatom)
Represents a group represented by²⁰³, R²⁰⁴, R²⁰⁵, And R²⁰⁶Haso
Each independently represents a hydrogen atom or an optionally substituted C₁
~ C_FiveAlkyl or a substituent which may have a substituent
A phenyl group;^A2Is-(CH_Two)_n− (N is an integer of 0 to 2
Or a group represented by -N (R²⁰⁹)-(R²⁰⁹Is water
C atom optionally having a hydrogen atom or a substituent₁~ C_FiveArchi
A group represented by the following formula:
³⁰¹Is a hydrogen atom and optionally substituted C₁~ C_Fiveof
Alkyl group, optionally substituted C_Three~ C₇No shiku
Aryl group, aryl group which may have a substituent
(Selected from the group consisting of oxygen, nitrogen, and sulfur atoms
May contain at least one heteroatom
I) or an acyl group which may have a substituent,
R³⁰²Is a hydrogen atom and optionally substituted C₁~ C₆
An alkyl group or an aryl which may have a substituent
Groups (from the group consisting of oxygen, nitrogen, and sulfur
May have at least one selected heteroatom
) And R³⁰³And R³⁰⁴Are independently hydrogen sources
And C which may have a substituent₁~ C_FiveAn alkyl group of
C which may have a substituent_Three~ C₇The cycloalkyl
Group or an aryl group which may have a substituent (an oxygen atom
Selected from the group consisting of oxygen, nitrogen, and sulfur
May contain at least one heteroatom)
In the formula (A4), R⁴⁰¹Is a hydrogen atom; having a substituent
May be C₁~ C_FiveHaving an alkyl group or a substituent of
Good C_Three~ C₇Having a cycloalkyl group or a substituent
Aryl groups (an oxygen atom, a nitrogen atom, and a sulfur atom
At least one heteroatom selected from the group consisting of
May be contained), or may have a substituent.
Represents an acyl group;⁴⁰²Has a hydrogen atom and a substituent
May be C₁~ C₆Having an alkyl group or a substituent
Aryl groups (oxygen, nitrogen, sulfur,
At least one heteroatom selected from the group consisting of atoms
May have a child), and R⁴⁰³And R⁴⁰⁴Is it
Each independently represents a hydrogen atom or an optionally substituted C₁~
C_FiveAlkyl group, C which may have a substituent_Three~ C₇
A cycloalkyl group, or an optionally substituted
Reel group (consisting of oxygen, nitrogen, and sulfur atoms
Containing at least one heteroatom selected from the group
In the formula (A5)⁵⁰¹Is hydrogen field
And C which may have a substituent₁~ C₆An alkyl group of
C which may have a substituent_Three~ C₇The cycloalkyl
Group, an aryl group which may have a substituent (an oxygen atom,
At least one selected from the group consisting of a nitrogen atom and a sulfur atom
And may contain one heteroatom) or
An acyl group which may have a substituent;⁵⁰²Is hydrogen
Atom, C optionally having substituent (s)₁~ C_FiveThe alkyl of
Group, halogen atom, the following general formula (A5-II): (R⁵⁰⁷)
(R⁵⁰⁸) N-CH _Two-(Where R⁵⁰⁷And R⁵⁰⁸Are each
C which may have a substituent independently₁~ C _FiveAlkyl group
Or R⁵⁰⁷And R⁵⁰⁸Is the nitrogen source to which they bind
To form a monocyclic heterocyclic group or a polycyclic heterocyclic group
Or a group represented by the following general formula (A5-III):(Wherein p represents an integer of 2 to 6, but one CH_TwoThe group is an acid
Selected from the group consisting of elementary atoms, nitrogen atoms, and sulfur atoms
Which may be substituted with one heteroatom)
A group represented by⁵⁰³, R⁵⁰⁴, R⁵⁰⁵, And R⁵⁰⁶Each
Each independently represents a hydrogen atom or an optionally substituted C₁~ C_Five
Or an optionally substituted phenyl group
X represents a group^A5Is-[C (R⁵⁰⁹) (R⁵¹⁰)]_q− (R⁵⁰⁹Passing
And R⁵¹⁰Each independently has a hydrogen atom and a substituent
May be C₁~ C_FiveHaving an alkyl group or a substituent
Represents a phenyl group, and q represents an integer of 0 to 2)
Or a group represented by -N (R⁵¹¹)-(R⁵¹¹Is a hydrogen atom or
Is an optionally substituted C₁~ C_FiveRepresents an alkyl group of
Wherein R represents a group represented by the formula:⁶⁰¹Is hydrogen
Atom, C optionally having substituent (s)₁~ C₆The alkyl of
Group or an aryl group which may have a substituent (an oxygen atom
1 selected from the group consisting of a hydrogen atom, a nitrogen atom, and a sulfur atom
Or more heteroatoms).
⁶⁰²Is a hydrogen atom or an aryl group which may have a substituent
(Selected from the group consisting of oxygen, nitrogen, and sulfur atoms
May contain one or more heteroatoms).
Or, the following general formula (A6-II): -CO-OR⁶⁰³, -CO-NHR⁶⁰³, -CO-N (R
⁶⁰³) (R⁶⁰⁴), -CS-OR⁶⁰³, -CS-NHR⁶⁰³,
-CS-N (R⁶⁰³) (R⁶⁰⁴), And -CO-R⁶⁰⁵ (Where R⁶⁰³And R⁶⁰⁴Are each independently a hydrogen atom,
C optionally having a substituent₁~ C₆Alkyl group and substituent
C which may have_Three~ C₇Cycloalkyl group, substitution
C optionally having a group_Two~ C₆Alkenyl group, substituent
C which may have_Two~ C₆Alkynyl group, substituent
Aryl groups (oxygen, nitrogen,
One or more hetero atoms selected from the group consisting of
May have a substituent) or a substituent.
Heterocyclic groups (including oxygen, nitrogen, and sulfur atoms)
Having one or more heteroatoms selected from the group
Good) or R⁶⁰³And R⁶⁰⁴They combine
Monocyclic heterocyclic group or polycyclic ring
A heterocyclic group of the formula⁶⁰⁵May have a substituent
C₁~ C₆Alkyl group, C which may have a substituent_Two
~ C₆An alkenyl group, optionally substituted C_Two~
C₆Alkynyl group, aryl which may have a substituent
(A group consisting of oxygen, nitrogen and sulfur atoms
May have one or more heteroatoms selected from
A) selected from the group consisting of groups represented by (A6-I
I) represents a group selected from the group consisting of
X represents a carbon atom or a nitrogen atom].
Compounds, their stereoisomers, or their salts, or
Hydrates or solvates thereof. 2. R ¹ and R ² each independently represent a hydrogen atom,
Butyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, (1-phenylcyclopropyl) methyl, benzyl, phenethyl,
2- (1-naphthyl) ethyl group, 2- (2-indanyl) ethyl group, rel (1R, 2R, 4S) bicyclo [2.2.1] hept-2-yl group, 3-tetrahydrofuryl group, or The compound according to claim 1, which is a 2-indanyl group, a stereoisomer thereof, or a salt thereof, or a hydrate or a solvate thereof. 3. The compound according to claim 1, wherein R ³ is a hydrogen atom, a methyl group, or an ethyl group, a stereoisomer thereof, a salt thereof, a hydrate thereof, or a solvate thereof. object. 4. R ¹⁰¹ is a hydrogen atom, a C ₁ -C ₃ alkyl group, an aryl group, or a C ₁ -C ₂ alkyl group having an aryl group as a substituent, and R ¹⁰² and R ¹⁰³ are each independently A hydrogen atom, a methyl group, an ethyl group, a phenyl group,
4. The compound according to any one of claims 1 to 3, which is a pyridyl group, a stereoisomer thereof, a salt thereof, a hydrate thereof, or a solvate thereof. 5. ^R201 is a hydrogen atom, a methyl group, a 4-pyridylmethyl group, a benzyl group, or an acetyl group;
²⁰² is a hydrogen atom, a halogen atom, a methyl group, an ethyl group,
4. A dimethylaminomethyl group, a morpholinomethyl group, or a benzyl group, m is 0 or 1, and R ²⁰⁹ is a hydrogen atom, a C ₁ -C ₃ alkyl group, or a benzyl group. Item 4. The compound according to item 1, a stereoisomer thereof, or a salt thereof, or a hydrate or solvate thereof. 6. R ³⁰¹ may have a hydrogen atom, a C ₁ -C ₄ alkyl group or a halogen atom as a substituent, and at least one selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom. A C ₁ -C ₃ alkyl group having an aryl group or an ethoxycarbonyl group which may contain one hetero atom as a substituent, or an acetyl group;
2. The method according to claim ₁ , wherein R ³⁰² is a hydrogen atom, a C ₁ -C ₃ alkyl group or a phenyl group, and R ³⁰³ and R ³⁰⁴ are hydrogen atoms.
4. The compound according to any one of claims 1 to 3, a stereoisomer thereof, or a salt thereof, or a hydrate or solvate thereof. 7. R ⁴⁰¹ is a hydrogen atom, a C ₁ -C ₄ alkyl group, or an aryl group which may have a halogen atom as a substituent (selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom). C ₄ containing at least one heteroatom selected from oxygen, nitrogen, and sulfur.
C ₁ to C ₆ having a C ₆ to C ₆ cycloalkyl group as a substituent
₃ alkyl group, ethoxycarbonylmethyl group or a benzoyl group, R ⁴⁰² is a hydrogen atom, an alkyl group of C ₁ -C _4, a phenyl group, a thiazolyl group, an Chuniru group or pyridyl group, R ⁴⁰³ and R ⁴⁰⁴ 4. A compound according to claim 1, which is a hydrogen atom, a methyl group or a phenyl group.
Or a stereoisomer thereof, a salt thereof, or a hydrate or solvate thereof. 8. ^R501 is a hydrogen atom, methyl group, ethyl group, propyl group, butyl group, pentyl group, 2-pyridylmethyl group, 3-pyridylmethyl group, 4-pyridylmethyl group, benzyl group, 1-naphthyl Methyl group, 2-naphthylmethyl group, 2-quinolylmethyl group, cyclopentyl group,
Or an acetyl group, R ⁵⁰² is a hydrogen atom, a halogen atom, a methyl group, an ethyl group, a dimethylaminomethyl group, morpholinomethyl group, or a benzyl group, R ^503, R
⁵⁰⁴ , R ⁵⁰⁵ and R ⁵⁰⁶ are each independently a hydrogen atom or a methyl group, p is 0 or 1, R ⁵⁰⁹ and R ⁵¹⁰
Are each independently a hydrogen atom or a methyl group,
Or R ⁵⁰⁹ is a hydrogen atom, any one of R ^{5 10} no claim 1 is C ₁ -C ₃ alkyl group or a benzyl group 3 1
Or a stereoisomer thereof, a salt thereof, or a hydrate or solvate thereof. 9. R ⁶⁰¹ is a hydrogen atom, a C ₁ -C ₄ alkyl group, a phenyl group or a pyridyl group, and R ⁶⁰² is a hydrogen atom, a 2-benzoxazolyl group, or a compound represented by the general formula (A6
-II) wherein R ⁶⁰³ and R ⁶⁰⁴ each independently represent a hydrogen atom, a methyl group, an ethyl group, a phenyl group, a benzyl group, a phenethyl group, a 2-pyridylmethyl group, a 3-pyridylmethyl group,
4-pyridylmethyl group, 2-furylmethyl group, 2-thienylmethyl group, 2-quinolylmethyl group, 1-naphthylmethyl group, 2-naphthylmethyl group, 2- (4-methyl-5
-Thiazolyl) ethyl group, (1-methyl-2-indolyl) methyl group, cyclopropylmethyl group, cyclopentylmethyl group, cyclohexyl group, 2- (morpholinyl)
Ethyl group, N-benzylpiperidyl group, or 3- (3-
Pyridyl) propynyl group],
R ⁶⁰⁵ is a t-butyl group, a cyclohexylmethyl group, 2-
(3-pyridyl) vinyl group, phenyl group, pyridyl group,
Or an indolyl group.
Or a stereoisomer thereof, a salt thereof, or a hydrate or solvate thereof. 10. The compound according to any one of claims 1 to 9, a stereoisomer thereof, a physiologically acceptable salt thereof, or a hydrate or a solvate thereof is effectively used. Pharmaceutical containing as an ingredient. 11. The medicament according to claim 10, which is used for prevention and / or treatment of an inflammatory disease or asthma. 12. The medicament according to claim 10, which is used for prevention and / or treatment of a disease associated with phosphodiesterase IV. 13. A compound according to any one of claims 1 to 9, a stereoisomer thereof, or a physiologically acceptable salt thereof, or a hydrate or solvate thereof. Phosphodiesterase IV inhibitors.