JPWO2020090967A1 - Expression inhibitor of fibrosis-inducing gene and its use - Google Patents

Abstract

Provided is an expression inhibitor capable of suppressing the expression of a fibrosis-inducing gene. The expression inhibitor of the present invention contains a compound represented by the following formula (I) or a salt thereof. [Chemical 1]

Description

The present invention relates to an agent for suppressing the expression of a fibrosis-inducing gene and its use.

Since a large number of genes are involved in the development of liver cirrhosis, effective preventive and therapeutic methods have not been established. Therefore, symptomatic treatment is performed for liver cirrhosis.

In addition, non-alcoholic fatty liver disease (NAFLD) is known as a form of liver disease leading to liver cirrhosis. In NAFLD, non-alcoholic fatty liver (NAFL) progresses to non-alcoholic steatohepatitis (NASH), eventually leading to cirrhosis. However, there is no effective therapeutic agent at each stage of NAFLD (Non-Patent Document 1).

Soo Ryang Kim et.al., “An Overview of NAFLD / NASH in Japan”, YAKUGAKU ZASSHI, The Pharmaceutical Society of Japan, 2016, vol. 136, No. 4, pages 565-572

Therefore, an object of the present invention is to provide a new drug for non-alcoholic steatohepatitis (NASH).

前記式（Ｉ）中、
Ｒ、Ｒ_０およびＲ_１は、同じでも異なってもよく、独立して水素原子であるか；または
ＲとＲ_０とは、隣接した炭素原子上に存在し、一緒になって、それらが結合しているベンゼン環と合体してナフタレン環を形成してもよく；
Ｒ_２は、水素原子、低級アルキル基、フェニル基、シアノ−フェニル基、トリフルオロメチル−フェニル基、ハロゲン化フェニル基、低級アルコキシ−フェニル基、ヒドロキシ−フェニル基、低級アルキル−フェニル基、フェニル−低級アルキル基、ヒドロキシ−フェニル−低級アルキル基、シアノ−フェニル−低級アルキル基、ピリジル基もしくはチエニル基であるか；または
Ｒ_１とＲ_２とが、一緒になって、低級アルキリデン基もしくはジ−［（低級アルコキシもしくはヒドロキシ）−フェニル］−低級アルキリデン基を表すか；または
Ｒ_１とＲ_２とが、一緒になって、炭素数４〜６の直鎖アルキレン基もしくはオルトフェニレン架橋された炭素数２〜４の直鎖アルキレン基を表し、それらに結合している炭素原子と共に、対応する場合によりベンゾ縮合された５−、６−もしくは７員環を形成してもよく；
Ｗは、１−（1,2,4もしくは1,3,4）−トリアゾリル基または３−ピリジル基であるか；または
Ｗは、１−イミダゾリル基または低級アルキル置換−１−イミダゾリル基であり、その場合には、下記式（Ｉ′）：

で表される基は、式（Ｉ）の−Ｃ≡Ｎ基に関してフェニル環の４位に結合している。In order to achieve the above object, the expression inhibitor of the fibrosis-inducing gene of the present invention (hereinafter, also referred to as "expression inhibitor") is a compound represented by the following formula (I), a salt thereof, or a solvate thereof. Including things:

In the formula (I),
R, R ₀ and R ₁ may be the same or different and are independent hydrogen atoms; or R and R ₀ are on adjacent carbon atoms and together they are bonded together. It may be combined with the benzene ring to form a naphthalene ring;
R ₂ is a hydrogen atom, a lower alkyl group, a phenyl group, a cyano-phenyl group, a trifluoromethyl-phenyl group, a halogenated phenyl group, a lower alkoxy-phenyl group, a hydroxy-phenyl group, a lower alkyl-phenyl group, and a phenyl- Is it a lower alkyl group, a hydroxy-phenyl-lower alkyl group, a cyano-phenyl-lower alkyl group, a pyridyl group or a thienyl group; or R ₁ and R ₂ together to form a lower alkylidene group or di-[ (Lower alkoxy or hydroxy) -Phenyl] -represents a lower alkylidene group; or R ₁ and R ₂ together have a linear alkylene group having 4 to 6 carbon atoms or orthophenylene crosslinked carbon atoms 2 It represents ~ 4 linear alkylene groups and may form a correspondingly benzo-condensed 5-, 6- or 7-membered ring with carbon atoms attached to them;
W is a 1- (1,2,4 or 1,3,4) -triazolyl group or 3-pyridyl group; or W is a 1-imidazolyl group or a lower alkyl-substituted-1-imidazolyl group. In that case, the following equation (I'):

The group represented by is bonded to the 4-position of the phenyl ring with respect to the -C≡N group of the formula (I).

The fibrosis drug of the present invention contains the above-mentioned agent for suppressing the expression of the fibrosis-inducing gene of the present invention.

The non-alcoholic steatohepatitis drug of the present invention (hereinafter, also referred to as “NASH drug”) includes the above-mentioned agent for suppressing the expression of the fibrosis-inducing gene of the present invention.

The fibrosis inhibitor of the present invention (hereinafter, also referred to as “fibrosis inhibitor”) includes the expression inhibitor of the fibrosis-inducing gene of the present invention.

According to the present invention, the expression of the fibrosis-inducing gene can be suppressed by containing the compound of the formula (I), a salt thereof, or a solvate thereof. That is, according to the present invention, since the expression of the fibrosis-inducing gene can be suppressed, for example, fibrosis of living tissues such as liver tissue can be suppressed, and it can be used for the treatment of fibrosis. Moreover, in NASH, fibrosis progresses. Therefore, according to the present invention, a medicine for NASH can be provided.

FIG. 1 is a graph showing the expression of the fibrosis-inducing gene in Example 1. FIG. 2 is a photograph of tissue staining in Example 2, (A) shows a photograph of HE staining, and (B) shows a photograph of Sirius red staining. FIG. 3 is a graph showing the fibrosis index and the amount of hydroxyproline in Example 2. FIG. 4 is a graph showing the concentration of fibrosis markers in serum in Example 2.

前記式（Ｉ）中、
Ｒ、Ｒ_０およびＲ_１は、同じでも異なってもよく、独立して水素原子であるか；または
ＲとＲ_０とは、隣接した炭素原子上に存在し、一緒になって、それらが結合しているベンゼン環と合体してナフタレン環を形成してもよく；
Ｒ_２は、水素原子、低級アルキル基、フェニル基、シアノ−フェニル基、トリフルオロメチル−フェニル基、ハロゲン化フェニル基、低級アルコキシ−フェニル基、ヒドロキシ−フェニル基、低級アルキル−フェニル基、フェニル−低級アルキル基、ヒドロキシ−フェニル−低級アルキル基、シアノ−フェニル−低級アルキル基、ピリジル基もしくはチエニル基であるか；または
Ｒ_１とＲ_２とが、一緒になって、低級アルキリデン基もしくはジ−［（低級アルコキシもしくはヒドロキシ）−フェニル］−低級アルキリデン基を表すか；または
Ｒ_１とＲ_２とが、一緒になって、炭素数４〜６の直鎖アルキレン基もしくはオルトフェニレン架橋された炭素数２〜４の直鎖アルキレン基を表し、それらに結合している炭素原子と共に、対応する場合によりベンゾ縮合された５−、６−もしくは７員環を形成してもよく；
Ｗは、１−（1,2,4もしくは1,3,4）−トリアゾリル基または３−ピリジル基であるか；または
Ｗは、１−イミダゾリル基または低級アルキル置換−１−イミダゾリル基であり、その場合には、下記式（Ｉ′）：

で表される基は、式（Ｉ）の−Ｃ≡Ｎ基に関してフェニル環の４位に結合している。<Inhibitor of expression of fibrosis-inducing gene>
As described above, the agent for suppressing the expression of the fibrosis-inducing gene of the present invention is a compound represented by the following formula (I), a salt thereof, or a solvate thereof (hereinafter, "the compound of the present invention or a salt thereof, etc." Also called).

In the formula (I),
R, R ₀ and R ₁ may be the same or different and are independent hydrogen atoms; or R and R ₀ are on adjacent carbon atoms and together they are bonded together. It may be combined with the benzene ring to form a naphthalene ring;
R ₂ is a hydrogen atom, a lower alkyl group, a phenyl group, a cyano-phenyl group, a trifluoromethyl-phenyl group, a halogenated phenyl group, a lower alkoxy-phenyl group, a hydroxy-phenyl group, a lower alkyl-phenyl group, and a phenyl- Is it a lower alkyl group, a hydroxy-phenyl-lower alkyl group, a cyano-phenyl-lower alkyl group, a pyridyl group or a thienyl group; or R ₁ and R ₂ together to form a lower alkylidene group or di-[ (Lower alkoxy or hydroxy) -Phenyl] -represents a lower alkylidene group; or R ₁ and R ₂ together have a linear alkylene group having 4 to 6 carbon atoms or orthophenylene crosslinked carbon atoms 2 It represents ~ 4 linear alkylene groups and may form a correspondingly benzo-condensed 5-, 6- or 7-membered ring with carbon atoms attached to them;
W is a 1- (1,2,4 or 1,3,4) -triazolyl group or 3-pyridyl group; or W is a 1-imidazolyl group or a lower alkyl-substituted-1-imidazolyl group. In that case, the following equation (I'):

The group represented by is bonded to the 4-position of the phenyl ring with respect to the -C≡N group of the formula (I).

The expression inhibitor of the present invention is characterized by containing a compound represented by the above formula (I) (hereinafter, also referred to as "compound of the present invention"), a salt thereof, or a solvate thereof, and the like. The configuration and conditions of the above are not particularly limited. The compound of the present invention or a salt thereof or the like can suppress the expression of a fibrosis-inducing gene, whereby, for example, the fibrosis of a living tissue can be suppressed. In the following description, unless otherwise specified, the description of the compounds of the present invention can be incorporated into the description of salts of the compounds of the present invention or solvates thereof.

As described above, the expression inhibitor of the present invention can suppress the expression of the fibrosis-inducing gene. In the present invention, "expression suppression" may be, for example, suppression of transcription from the target gene, suppression of the amount of transcript produced from the target gene, suppression of the activity of the transcript, or suppression of the activity of the target gene. The translation from mRNA may be suppressed, the amount of translation product produced from the target gene may be suppressed, or the activity of the translation product may be suppressed. The "expression suppression" may be, for example, suppression of transcription of a functional transcript or suppression of translation of a functional translation product. Examples of the protein include mature proteins or precursor proteins that have not undergone processing or post-translational modification. The suppression of expression can be confirmed, for example, by measuring the amount of the transcript produced, the activity of the transcript, the amount of the translation product produced, or the activity of the translation product.

In the present invention, "expression suppression" means that the expression level of the fibrosis-inducing gene is (significantly) reduced as compared with the absence of the expression-suppressing agent of the present invention (non-administration condition). However, the expression level of the fibrosis-inducing gene may be increased as compared with the start (at the start of administration). In this case, the "expression suppression" can also be referred to as, for example, "maintenance of expression level", "suppression of increase in expression level", or the like.

In the present invention, the fibrosis-inducing gene is, for example, TGF-β (Transforming Growth Factor-β), CTGF (Connective Tissue Growth Factor), α-SMA (α-Smooth Muscle Actin) and YAP1 (Yes-associated Protein 1). ) Etc. Examples of TGF-β include TGF-β1, TGF-β2, TGF-β3, TGF-β4, TGF-β5 and the like, and TGF-β1 or TGF-β2 is preferable.

The compound of the present invention has an asymmetric carbon atom. For this reason, the compounds of the present invention may be present, for example, as a racemate, an enantiomer of its R and S, or a mixture of any proportions of R and S. The compounds of the present invention may have two or more asymmetric centers. In this case, the compounds of the present invention may include diastereomers and mixtures thereof. When the compound of the present invention has a double bond in the molecule, the compound of the present invention may include, for example, the form of geometric isomers of cis and trans isomers.

In the present invention, the term "lower" in an organic group or compound means, for example, one having 7 or less carbon atoms (number of carbon atoms), 4 or less, or 1 or 2 carbon atoms. The lower alkyl group is, for example, an alkyl group containing 1 to 4 carbon atoms, and as a specific example, a methyl group, an ethyl group, a propyl group or a butyl group, preferably a methyl group.

In the cyano-phenyl group, the modification position of the cyano group and the number of substitutions thereof are not particularly limited, and for example, any one of the 2-position, 3-position, 4-position, 5-position, and 6-position of the phenyl ring, 2 One, or three or more.

In the trifluoromethyl-phenyl group, the modification position of the trifluoromethyl group is, for example, any one, two, three, of the 2-position, 3-position, 4-position, 5-position, and 6-position of the phenyl ring. Four or five.

In the halogenated phenyl group (halogen-phenyl group), the modification position of the halogen group is, for example, any one, two, three of the 2-position, 3-position, 4-position, 5-position, and 6-position of the phenyl ring. One, four, or five.

The halogen group is, for example, a chlorine atom, a bromine atom, a fluorine atom, or an iodine atom, preferably a chlorine atom.

In the lower alkoxy-phenyl group, the modification position of the lower alkoxy group is, for example, any one, two, three, four of the 2-position, 3-position, 4-position, 5-position, and 6-position of the phenyl ring. , Or five.

The lower alkoxy group is, for example, an alkoxy group containing 1 to 4 carbon atoms, and specific examples thereof are a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, or a tert-butoxy group. , Preferably a methoxy group or an ethoxy group.

In the hydroxy-phenyl group, the modification position of the hydroxy group is, for example, one, two, three, four, or any one of the 2-position, 3-position, 4-position, 5-position, and 6-position of the phenyl ring. There are five.

In the lower alkyl-phenyl group, the modification position of the lower alkyl group is, for example, any one, two, three, four of the 2-position, 3-position, 4-position, 5-position, and 6-position of the phenyl ring. , Or five.

In the hydroxy-phenyl-lower alkyl group, the modification position of the hydroxy group is, for example, any one, two, three, four of the 2-position, 3-position, 4-position, 5-position, and 6-position of the phenyl ring. One or five.

In the cyanophenyl-lower alkyl group, the modification position of the cyano group is, for example, any one, two, three, four of the 2-position, 3-position, 4-position, 5-position, and 6-position of the phenyl ring. , Or five.

The pyridyl group is a 2-, 3- or 4-pyridyl group, preferably a 3- or 4-pyridyl group, and more preferably a 3-pyridyl group.

The thienyl group is, for example, a 2- or 3-thienyl group, preferably a 2-thienyl group.

The lower alkylidene group is preferably a linear lower alkylidene group, more preferably a methylidene group or an ethylidene group.

The alkylene group having 4 to 6 carbon atoms is preferably a butylene group or a pentylene group.

The straight chain alkylene group having 2 to 4 carbon atoms cross-linked with ortho-phenylene is preferably CH ₂ CH ₂ cross-linked with ortho-phenylene.

In the compound represented by the formula (I), for example, R and R ₀ are hydrogen atoms or lower alkyl groups; or R and R ₀ are combined together with a benzene ring to which they are attached and naphthalene. A ring may be formed.

In the compound represented by the formula (I), the _{substituent-phenyl group (substituted phenyl group) in R 2} is a lower alkyl group, a lower alkoxy group, a hydroxy group, a halogen group, a trifluoromethyl group, or a cyano group. Substituted phenyl groups are preferred.

The compound represented by the formula (I) may be, for example, a compound in which W is a 1-imidazolyl (imidazole) group or a 1-imidazolyl (imidazole) group substituted with a lower alkyl, and W is , 1- (1,2,4 or 1,3,4) -triazolyl group may be used, or W may be a compound having a 3-pyridyl group.

Further, in the compound represented by the above formula (I), R and R ₀ are independently hydrogen atoms; or R and R ₀ are present on adjacent carbon atoms and together. Together with the benzene ring to which they are attached, they form a naphthalene ring; R ₁ is a hydrogen atom; R ₂ is a hydrogen atom, a lower alkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted phenyl group. It is a phenyl-lower alkyl group, a thienyl group, or a pyridyl group; or R ₁ and R ₂ together are a lower alkylidene group or an alkylene group having 4 to 6 carbon atoms; W is 1- (1). , 2,4 or 1,3,4) -triazolyl group or 3-pyridyl group; the substituted phenyl group is a lower alkyl group, a lower alkoxy group, a hydroxy group, a halogen group, a trifluoromethyl group, and a cyano group. It is preferably a phenyl group substituted with 1 substituent selected from.

前記式（II）中、
Ｒ_１′が、水素原子であり；
Ｒ_２′が、水素原子、低級アルキル基、フェニル基、ピリジル基、チエニル基もしくはベンジル基であり；または、
Ｒ_２′が、そのフェニル環上で、それぞれ、シアノ基、低級アルキル基、低級アルコキシ基、ヒドロキシ基、ハロゲン基、もしくはトリフルオロメチル基でモノ置換されたフェニル基、またはシアノ基もしくはヒドロキシ基でモノ置換されたベンジル基であるか；または
Ｒ_１′およびＲ_２′が、一緒になって、低級アルキリデン基またはジ−［（低級アルコキシもしくはヒドロキシ）−フェニル］低級アルキリデン基を表すか；または
Ｒ_１′およびＲ_２′が、一緒になって、炭素数４〜６の直鎖アルキレン基を表し；
Ｒ_３が、水素原子である。As a specific example, the expression inhibitor of the present invention preferably contains, for example, a compound represented by the following formula (II).

In the above formula (II),
R ₁ 'is hydrogen atom;
R ₂ ′ is a hydrogen atom, a lower alkyl group, a phenyl group, a pyridyl group, a thienyl group or a benzyl group; or
R ₂ ′ is a phenyl group mono-substituted with a cyano group, a lower alkyl group, a lower alkoxy group, a hydroxy group, a halogen group, or a trifluoromethyl group, or a cyano group or a hydroxy group, respectively, on the phenyl ring. Is it a mono-substituted benzyl group; or does R ₁ ′ and R ₂ ′ together represent a lower alkylidene group or a di-[(lower alkoxy or hydroxy) -phenyl] lower alkylidene group; or R ₁ ′ and R ₂ ′ together represent a linear alkylene group having 4 to 6 carbon atoms;
R ₃ is a hydrogen atom.

In the compound of formula (II), R ₁ ′ is a hydrogen atom; R ₂ ′ is a hydrogen atom, a lower alkyl group or a pyridyl group; or R ₂ ′ is unsubstituted or on a phenyl ring. A cyano group, a lower alkyl group, a lower alkoxy group, a hydroxy group, or a phenyl group mono-substituted with a halogen group, or a benzyl group mono-substituted with a cyano group or a hydroxy group; R ₃ is a hydrogen atom. More preferably.

In the compound of formula (II), R ₁ ′ is a hydrogen atom; R ₂ ′ is a hydrogen atom, a lower alkyl group, a benzyl group, a phenyl group or a 3- or 4-pyridyl group; or R _{2 ′.} ′ Is a phenyl group mono-substituted with a cyano group, a halogen group, a lower alkoxy group, a lower alkyl group, or a trifluoromethyl group, or a benzyl mono-substituted with a cyano group or a hydroxy group, respectively, on the phenyl ring. It is a group; it is more preferred that _{R 3 is a hydrogen atom.}

In the compound of formula (II), R ₁ ′ and R ₃ are hydrogen atoms; _{most preferably R 2} ′ is a 3-pyridyl group, a p-cyanobenzyl group, or a p-cyanophenyl group. ..

前記式（III）中、
Ｒ_２′は、３−ピリジル基、ｐ−シアノベンジル基もしくはｐ−シアノフェニル基である。As a specific example, the expression inhibitor of the present invention preferably contains, for example, a compound represented by the following formula (III).

In the above formula (III),
R ₂ 'is 3-pyridyl group, a p- cyanobenzyl group or p- cyanophenyl groups.

The expression-suppressing agent of the present invention has, for example, a letrozole (4,4'-(1,2,4-triazol-1-yl-methyl) dibenzonitrile, for example, because it has a high ability to suppress the expression of the fibrosis-inducing gene. , PubChem (CID: 3902)) or salts thereof. Letrozole is a compound represented by the following formula (IV), and in the above formula (III), R ₂ ′ is a p-cyanophenyl group.

Further, in the compound represented by the above formula (I), R and R ₀ are independently hydrogen atoms; or R and R ₀ are present on adjacent carbon atoms and together. Together with the benzene ring to which they are attached, they form a naphthalene ring; R ₁ is a hydrogen atom; R ₂ is a hydrogen atom, a lower alkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted phenyl group. It is a phenyl-lower alkyl group, a thienyl group, or a pyridyl group; or R ₁ and R ₂ together are a lower alkylidene group or an alkylene group having 4 to 6 carbon atoms; W is a 1-imidazolyl group. Alternatively, it is a lower alkyl-substituted-1-imidazolyl group; the substituted phenyl group is substituted with one substituent selected from a lower alkyl group, a lower alkoxy group, a hydroxy group, a halogen group, a trifluoromethyl group, and a cyano group. It is preferably a phenyl group.

前記式（Ｖ）において、
Ｒ_１′が、水素原子であり；
Ｒ_２′が、水素原子、低級アルキル基、フェニル基、ピリジル基、チエニル基、ベンジル基；シアノ基、低級アルキル基、低級アルコキシ基、ヒドロキシ基、ハロゲン基もしくはトリフルオロメチル基でモノ置換されたフェニル基；または、フェニル環上でシアノ基もしくはヒドロキシ基でモノ置換されたベンジル基（それぞれ、シアノ−フェニル−メチル基、ヒドロキシ−フェニル−メチル基）であり；または
Ｒ_１′とＲ_２′とは、一緒になって低級アルキリデン基を形成し；または
Ｒ_１′とＲ_２′とが一緒になって炭素数４〜６の直鎖アルキレン基を表し；
Ｒ_３が、水素原子または低級アルキル基である。As a specific example, the expression inhibitor of the present invention preferably contains, for example, a compound represented by the following formula (V).

In the formula (V)
R ₁ 'is hydrogen atom;
R 2 _'is a hydrogen atom, a lower alkyl group, a phenyl group, a pyridyl group, a thienyl group, a benzyl group; a cyano group, a lower alkyl group, a lower alkoxy group, hydroxy group, which is mono-substituted by halogen or trifluoromethyl group phenyl group; or a mono-substituted benzyl group with a cyano group or a hydroxy group on the phenyl ring (respectively, cyano - phenyl - methyl, hydroxy - phenyl - methyl); and or _'and R _2' R ₁ and Together form a lower alkylidene group; or R ₁ ′ and R ₂ ′ together represent a linear alkylene group having 4 to 6 carbon atoms;
R ₃ is a hydrogen atom or a lower alkyl group.

In the compound represented by the formula (V), R ₁ ′ is a hydrogen atom; R ₂ ′ is a hydrogen atom, a lower alkyl group, a benzyl group, a phenyl group, a 3- or 4-pyridyl group; a cyano group. , A halogen group, a lower alkoxy group, a lower alkyl group, or a phenyl group mono-substituted with a trifluoromethyl group; or a benzyl group mono-substituted with a cyano group on the phenyl ring; R ₃ is at the 4-position or It is preferably a hydrogen atom at the 5-position or a lower alkyl group.

In the compound represented by the formula (V), R ₁ ′ and R ₃ are hydrogen atoms; R ₂ ′ is a hydrogen atom, a lower alkyl group, a benzyl group, a phenyl group, a 3- or 4-pyridyl group. It is preferably a phenyl group mono-substituted with a cyano group, a halogen group, a lower alkoxy group, a lower alkyl group, or a trifluoromethyl group; or a benzyl group mono-substituted with a cyano group on the phenyl ring.

前記式（VI）中、
Ｒ_２′は、３−ピリジル基、ｐ−シアノベンジル基もしくはｐ−シアノフェニル基である。As a specific example, the expression inhibitor of the present invention preferably contains, for example, a compound represented by the following formula (VI).

In the above equation (VI),
R ₂ 'is 3-pyridyl group, a p- cyanobenzyl group or p- cyanophenyl groups.

前記式（VII）中、
Ｒ_１′が、水素原子であり；
Ｒ_２′が、水素原子、低級アルキル基、フェニル基、ピリジル基、チエニル基、もしくはベンジル基であり；または
Ｒ_２′が、そのフェニル環上で、それぞれ、シアノ基、低級アルキル基、低級アルコキシ基、ヒドロキシ基、ハロゲン基もしくはトリフルオロメチル基でモノ置換されたフェニル基、またはシアノ基もしくはヒドロキシ基でモノ置換されたベンジル基であり；または
Ｒ_１′およびＲ_２′が、一緒になって、低級アルキリデン基またはジ−［（低級アルコキシもしくはヒドロキシ）−フェニル］低級アルキリデン基を表すか；または
Ｒ_１′およびＲ_２′が、一緒になって、炭素数４〜６の直鎖アルキレン基を表し；
Ｒ_３が、水素原子である。The expression inhibitor of the present invention preferably contains, for example, a compound represented by the following formula (VII).

In the above formula (VII),
R ₁ 'is hydrogen atom;
R ₂ ′ is a hydrogen atom, a lower alkyl group, a phenyl group, a pyridyl group, a thienyl group, or a benzyl group; or R ₂ ′ is a cyano group, a lower alkyl group, and a lower alkoxy group on the phenyl ring, respectively. A phenyl group mono-substituted with a group, a hydroxy group, a halogen group or a trifluoromethyl group, or a benzyl group mono-substituted with a cyano group or a hydroxy group; or R ₁ ′ and R ₂ ′ together. , lower alkylidene group or a di - [(lower alkoxy or hydroxy) - phenyl] represent a lower alkylidene group; or R _{1 'and} R _2' are taken together, a straight-chain alkylene group having 4-6 carbon atoms Representation;
R ₃ is a hydrogen atom.

In the compound represented by the above formula (VII), R ₁ ′ and R ₃ are hydrogen atoms; R ₂ ′ is a hydrogen atom, a lower alkyl group, or a pyridyl group; or R ₂ ′ is a non-hydrogen atom. A phenyl group mono-substituted with a cyano group, a lower alkyl group, a lower alkoxy group, a hydroxy group, a halogen group, or a trifluoromethyl group, or a cyano group or a hydroxy group, respectively, on the substituted or phenyl ring thereof. More preferably, it is a substituted benzyl group.

In the compound represented by the above formula (VII), R ₁ ′ and R ₃ are hydrogen atoms; R ₂ ′ is a hydrogen atom, a lower alkyl group, a benzyl group, a phenyl group, or 3- or 4-pyridyl. A group; or a _{phenyl group in which R 2} ′ is substituted on its phenyl ring with a cyano group, a halogen group, a lower alkoxy group, a lower alkyl group, or a tolfluoromethyl group, respectively, or a cyano group or hydroxy. More preferably, it is a benzyl group mono-substituted with a group.

In the compound represented by the above formula (VII), R ₁ ′ and R ₃ represent a hydrogen atom; R ₂ ′ represents a 3- or 4-pyridyl group, a p-cyanobenzyl group, or a p-cyanophenyl group. Is most preferable.

The compound of the present invention may be, for example, an isomer. Examples of the isomer include tautomers and stereoisomers. Examples of the tautomer or stereoisomer include all theoretically possible tautomers or stereoisomers. Further, in the present invention, the configuration of each substituent is not particularly limited. The compound of the present invention may be, for example, a solvate such as a hydrate of the compound represented by the formula (I) or a salt thereof. The compound of the present invention is represented by, for example, the formulas (I) to (VII), and specific examples thereof include letrozole. The compound of the present invention may be, for example, a solvate. Hereinafter, the description of the compound of the present invention can be incorporated into the description of the salt of the compound of the present invention or a solvate thereof.

In the present invention, the salt of the compound of the present invention is not particularly limited, and is, for example, a pharmaceutically acceptable salt. The pharmaceutically acceptable salt is not particularly limited, and for example, an alkali metal salt such as a sodium salt and a potassium salt; an alkaline earth metal salt such as a calcium salt and a magnesium salt; an ammonium salt; a trimethylamine salt and a triethylamine salt, Aliphatic amine salts such as dicyclohexylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt; aralkylamine salt such as N, N-dibenzylethylenediamine; heterocycle such as pyridine salt, picolin salt, quinoline salt and isoquinoline salt Aromatic amine salts; quaternary ammonium salts such as tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltributylammonium salt, methyltrioctylammonium salt, tetrabutylammonium salt; arginine salt, lysine salt, aspartic acid Amino acid salts such as salts and glutamates; inorganic acid salts such as hydrochlorides, sulfates, nitrates, phosphates, carbonates, hydrogen carbonates and perchlorates; acetates, propionates, succinates, glycols Acid salt, lactate, maleate, fumarate, tartrate, malate, citrate, ascorbate, hydroxymaleate, pyruvate, phenylacetate, benzoate, 4-aminobenzoate Aliase or aromatic organic salts such as acid salts, anthranilates, 4-hydroxybenzoates, salicylates, 4-aminosalicylates, pamoates, gluconates, nicotinates; methanesulphonic acid Sulfates such as salts, isethionates, ethane sulfonates, benzene sulfonates, halobenzene sulfonates, p-toluene sulfonates, toluene sulfonates, naphthalene sulfonates, sulfanilates, cyclohexyl sulfamates, etc. Salts; etc.

The expression inhibitor of the present invention may be used , for example, in vivo or in vitro . The expression inhibitor of the present invention can be used, for example, as a research reagent or as a pharmaceutical product. In the latter case, the expression-suppressing agent of the present invention can also be said to be a drug or a pharmaceutical composition for suppressing the expression of a fibrosis-inducing gene.

The administration target of the expression inhibitor of the present invention is not particularly limited. When the expression inhibitor of the present invention is used in vivo , the administration target includes, for example, humans or non-human animals other than humans. Examples of the non-human animal include mammals such as mice, rats, rabbits, dogs, sheep, horses, cats, goats, monkeys and guinea pigs, birds and fish. When the expression inhibitor of the present invention is used in vitro , the administration target includes, for example, cells, tissues, organs, etc., and the cells include, for example, cells collected from a living body, cultured cells, and the like. Examples of the tissue or organ include a tissue (living tissue) or organ collected from a living body. Examples of the cells include hepatocytes, iPS cells (induced pluripotent stem cells), stem cells and the like. The hepatocytes mean, for example, cells constituting the liver.

The conditions for using the expression-suppressing agent of the present invention (administration conditions) are not particularly limited, and for example, the administration form, administration time, dose and the like can be appropriately set according to the type of administration target and the like.

The dose of the expression inhibitor of the present invention is not particularly limited. When the expression inhibitor of the present invention is used in vivo, it can be appropriately determined, for example, depending on the type, symptom, age, administration method, etc. of the administration target. As a specific example, when administered to humans, the total daily dose of the compound is, for example, 0.001 to 30 mg / kg, preferably 0.05 to 5 mg / kg, and the daily dose. The number of administrations per administration is, for example, 1 to 5 times, 1 to 3 times, and preferably 1 time. When orally administered to an adult human, the daily dose of the compound is, for example, 2.5 mg, and the number of administrations per day is, for example, once. The content of the compound in the expression inhibitor is not particularly limited, and can be appropriately set according to the above-mentioned daily dose, for example.

The administration form of the expression inhibitor of the present invention is not particularly limited. When the expression inhibitor of the present invention is administered in vivo , it may be administered orally or parenterally. The parenteral administration includes, for example, intravenous injection (intravenous administration), intramuscular injection (intramuscular administration), transdermal administration, subcutaneous administration, intradermal administration, enteral administration, rectal administration, vaginal administration, and nasal administration. Examples include transpulmonary administration, intraperitoneal administration, and local administration.

The dosage form of the expression-suppressing agent of the present invention is not particularly limited, and can be appropriately determined, for example, according to the administration form. Examples of the dosage form include a liquid state and a solid state. As a specific example, the dosage type includes a release-regulated preparation (enteric-soluble preparation, sustained-release preparation, etc.), a capsule, an oral solution (elixyl agent, suspending agent, emulsion, aromatic water agent, limonade agent, etc.), syrup agent. (Pharmaceuticals for syrup, etc.), granules (foam granules, fine granules, etc.), powders, tablets (orally disintegrating tablets, chewable tablets, effervescent tablets, dispersion tablets, solubilizers, coated tablets, etc.), rounds, oral jelly Oral preparations such as agents; oral tablets (gum, sublingual, troche, drop, buccal tablets, adhesive tablets, etc.), oral sprays, oral semi-solids, mouthwashes, etc. Preparations; Injectable preparations such as injections (embedded injections, continuous injections, infusions (drip preparations, etc.), lyophilized injections, powder injections, filled syringes, cartridges, etc.); dialysis agents Bronchial / lung-applied preparations such as (peritoneal dialysis agents, blood dialysis agents); inhalants (inhalation aerosols, inhalation solutions, inhalation powders, etc.); eye administration of eye ointments, eye drops, etc. Preparations for nasal use such as ear drops; Nasal preparations such as nasal drops (nasal drops, nasal powders, etc.); Vaginal suppositories, vaginal tablets and other vaginal products; external liquids (liquor, liniment, lotion, etc.), creams, gels, solids (external powders, etc.), sprays (aerosols, pumps, etc.) Examples thereof include spray agents), patches (tapes, paps, etc.), skin-applying agents such as ointments; and the like. When the expression inhibitor of the present invention is orally administered, the dosage form may be, for example, tablets, coated tablets, pills, fine granules, granules, powders, capsules, liquids, syrups, emulsions, suspensions and the like. Can be given. When the expression inhibitor of the present invention is orally administered, examples of the dosage form include a preparation for injection administration and a preparation for infusion. When the expression inhibitor of the present invention is transdermally administered, examples of the dosage form include external preparations such as patches, coating agents, ointments, creams, and lotions.

The expression-suppressing agent of the present invention may contain, for example, an additive, if necessary, and when the expression-suppressing agent of the present invention is used as a drug or a pharmaceutical composition, the additive is pharmaceutically acceptable. It preferably contains an additive or a pharmaceutically acceptable carrier. The additive is not particularly limited, and is, for example, a base material, an excipient, a colorant, a lubricant, a binder, a disintegrant, a stabilizer, a coating agent, a preservative, a flavoring agent such as a fragrance, and the like. Can be given. In the present invention, the blending amount of the additive is not particularly limited as long as it does not interfere with the function of the compound.

The excipients are, for example, sugar derivatives such as lactose, lactose hydrate, sucrose, glucose, mannitol, sorbitol; starch derivatives such as corn starch, potato starch, α starch, dextrin; cellulose derivatives such as crystalline cellulose; Arabia. Rubber; Dextrin; Organic excipients such as Plulan; Sirate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, magnesium aluminometasilicate; Phosphates such as calcium hydrogen phosphate; Carbonates: Examples thereof include inorganic excipients such as sulfates such as calcium sulfate. Examples of the colorant include yellow iron sesquioxide and the like. Examples of the lubricant include metal stearic acid salts such as stearic acid, calcium stearate, and magnesium stearate; talc; polyethylene glycol; silica; and cured vegetable oil. Examples of the flavoring agent include fragrances such as cocoa powder, mint brain, fragrance powder, mint oil, borneol, and cinnamon powder, sweeteners, and acidulants. Examples of the binder include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, macrogol and the like. Examples of the disintegrant include cellulose derivatives such as carboxymethyl cellulose and carboxymethyl cellulose calcium; chemically modified starches such as carboxymethyl starch, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone and sodium starch glycolate, and chemically modified celluloses. The stabilizers include, for example, paraoxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalconium chloride; phenols such as phenol and cresol; timerosal; dehydroacetic acid. ; Sorbic acid and the like can be mentioned. Examples of the coating agent include hypromellose, macrogol such as macrogol 6000, talc, titanium oxide and the like.

The compounds represented by the formulas (I) to (VII) (for example, letrozole) can be produced by a known method. Can be referenced and incorporated as part of this specification.

According to the expression inhibitor of the present invention, the expression of the fibrosis-inducing gene can be suppressed as described above. As will be described later, the expression inhibitor of the present invention can also be used as a fibrosis inhibitor, a non-alcoholic steatohepatitis drug, or a fibrosis inhibitor in non-alcoholic steatohepatitis and the like.

<Medicine for fibrosis>
As described above, the fibrosis drug of the present invention contains the expression inhibitor of the present invention. The fibrosis drug of the present invention is characterized by containing the expression inhibitor of the present invention, that is, containing the compound represented by the formula (I) or a salt thereof, and other configurations and conditions are , There are no particular restrictions. The fibrosis drug of the present invention can be referred to, for example, the description of the expression inhibitor of the present invention. According to the fibrosis drug of the present invention, as described above, the expression of the fibrosis-inducing gene can be suppressed, so that fibrosis can be treated.

In the fibrosis drug of the present invention, "treatment" may be used to mean any of the treatment, prevention, amelioration, suppression of sign development, and / or stop of sign progression. Therefore, the fibrosis drug of the present invention can also be referred to as, for example, a therapeutic agent, a preventive agent, an ameliorating agent, a progress inhibitory agent, and / or a progress arresting agent for fibrosis. In addition, the fibrosis drug of the present invention should (significantly) suppress fibrosis of living tissues or cells as compared with the absence of the fibrosis drug of the present invention (non-administration condition). Fibrosis may be more advanced than at the start (at the start of administration).

The fibrosis is not particularly limited, and examples thereof include pulmonary fibrosis, myelofibrosis, skin sclerosis, and arteriosclerosis. The fibrosis excludes, for example, liver fibrosis.

The administration conditions of the fibrosis drug of the present invention are not particularly limited, and for example, the administration form, administration time, dose and the like can be appropriately set according to the type of administration target and the like. As the administration target and administration condition of the fibrosis drug of the present invention, for example, the description of the administration target and administration condition of the expression inhibitor of the present invention can be incorporated.

<Pharmaceuticals for NASH>
The medicament for non-alcoholic steatohepatitis (NASH) of the present invention contains the expression inhibitor of the present invention as described above. The medicament for NASH of the present invention is characterized by containing the expression inhibitor of the present invention, that is, containing the compound represented by the formula (I), a salt thereof or a solvate thereof, and other The configuration and conditions are not particularly limited. The drug for NASH of the present invention can be referred to, for example, the description of the expression inhibitor of the present invention. According to the drug for NASH of the present invention, as described above, by suppressing the expression of the fibrosis-inducing gene, the fibrosis of the liver tissue that progresses in NASH can be suppressed, so that NASH can be treated.

In the medicament for NASH of the present invention, "treatment" may be used to mean any of the treatment, prevention, amelioration, suppression of sign development, and / or stop of sign progression of fibrosis. Therefore, the drug for NASH of the present invention can also be referred to as, for example, a therapeutic agent, a preventive agent, an improving agent, a progress inhibitory agent, and / or a progress arresting agent for NASH. The suppression of the progression of the symptom means, for example, the suppression of the progression from non-alcoholic steatohepatitis to liver cirrhosis. In addition, the drug for NASH of the present invention has a progression of NASH such as living tissue (for example, liver) or cells (for example, hepatocytes) as compared with the absence of the NASH drug of the present invention (non-administration condition). Should be (significantly) suppressed, and NASH may be advanced as compared with the start (at the start of administration).

The administration conditions of the drug for NASH of the present invention are not particularly limited, and for example, the administration form, administration time, dose and the like can be appropriately set according to the type of administration target and the like. As the administration target and administration condition of the drug for NASH of the present invention, for example, the description of the administration target and administration condition of the expression inhibitor of the present invention can be incorporated.

<Fibrosis inhibitor>
As described above, the fibrosis inhibitor of the present invention includes the expression inhibitor of the present invention. The fibrosis inhibitor of the present invention is characterized by containing the expression inhibitor of the present invention, that is, containing the compound represented by the formula (I), a salt thereof or a solvate thereof, and the like. The configuration and conditions of the above are not particularly limited. For the fibrosis inhibitor of the present invention, for example, the description of the expression inhibitor of the present invention can be incorporated. As described above, the fibrosis inhibitor of the present invention can suppress the expression of the fibrosis-inducing gene, and thus can suppress fibrosis.

The fibrosis inhibitor of the present invention can be used to suppress fibrosis, more specifically to treat, prevent, improve, suppress the progression of fibrosis, and / or stop the progression of fibrosis. Therefore, the fibrosis inhibitor of the present invention can also be referred to as, for example, a therapeutic agent, a preventive agent, an improving agent, a progress inhibitor and / or a progress arresting agent for fibrosis. According to the fibrosis inhibitor of the present invention, as described above, by suppressing the expression of the fibrosis-inducing gene, the fibrosis of liver tissue that progresses in NASH can be suppressed. Therefore, the fibrosis inhibitor of the present invention can also be referred to as, for example, an inhibitor of fibrosis in non-alcoholic steatohepatitis or an agent for suppressing the progression of non-alcoholic steatohepatitis to liver cirrhosis.

In the present invention, "fibrosis suppression" means that fibrosis of living tissue or cells is (significantly) suppressed as compared with the absence of the fibrosis inhibitor of the present invention (non-administration condition). Fibrosis may be advanced as compared with the start (at the start of administration). In this case, the "inhibition of fibrosis" can also be referred to as, for example, "inhibition of the progress of fibrosis". The fibrosis can be assessed, for example, by directly or indirectly measuring the amount of collagen protein. Examples of the indirect measurement include the measurement of hydroxyproline.

The administration conditions of the fibrosis inhibitor of the present invention are not particularly limited, and for example, the administration form, administration time, dose and the like can be appropriately set according to the type of administration target and the like. As the administration subject and administration condition of the fibrosis inhibitor of the present invention, for example, the description of the administration subject and administration condition of the expression inhibitor of the present invention can be incorporated.

<Method of suppressing expression of fibrosis-inducing gene>
The method for suppressing the expression of a fibrosis-inducing gene of the present invention includes an administration step of administering the agent for suppressing the expression of the fibrosis-inducing gene of the present invention to a subject. The expression-suppressing method of the present invention is characterized by administering the expression-suppressing agent of the present invention, and other steps and conditions are not particularly limited. The above-mentioned description can be incorporated into the expression inhibitor of the present invention. According to the expression suppression method of the present invention, the expression of a fibrosis-inducing gene can be suppressed. The fibrosis-inducing gene can be referred to, for example, the above description.

The expression-suppressing method of the present invention includes, for example, an administration step of administering the expression-suppressing agent, and specifically includes an administration step of administering the expression-suppressing agent to an administration subject. The expression inhibitor may be administered in vitro or in vivo . As the administration subject and administration condition of the expression inhibitor of the present invention, for example, the description of the administration subject and administration condition of the expression inhibitor of the present invention can be incorporated.

<Treatment method for fibrosis>
As described above, the method for treating fibrosis of the present invention includes an administration step of administering the fibrosis drug of the present invention to a subject. The method for treating fibrosis of the present invention is characterized by administering the above-mentioned pharmaceutical agent for fibrosis of the present invention, and other steps and conditions are not particularly limited. As the therapeutic method of the present invention, the description of the expression-suppressing agent of the present invention, the pharmaceutical for fibrosis, and the expression-suppressing method can be incorporated. The fibrosis is not particularly limited, and examples thereof include pulmonary fibrosis, myelofibrosis, skin sclerosis, and arteriosclerosis.

The method for treating fibrosis of the present invention includes, for example, an administration step of administering the fibrosis drug, and specifically includes an administration step of administering the fibrosis drug to an administration subject. The fibrosis drug may be administered in vitro or in vivo . As the administration subject and administration condition of the fibrosis drug of the present invention, for example, the description of the administration subject and administration condition in the expression inhibitor of the present invention can be incorporated.

<NASH treatment method>
As described above, the method for treating non-alcoholic steatohepatitis of the present invention includes an administration step of administering the drug for non-alcoholic steatohepatitis of the present invention to a subject. The method for treating NASH of the present invention is characterized by administering the above-mentioned drug for NASH of the present invention, and other steps and conditions are not particularly limited. As the therapeutic method of the present invention, the description of the expression-suppressing agent of the present invention, the drug for NASH, and the expression-suppressing method can be incorporated.

The method for treating NASH of the present invention includes, for example, an administration step of administering the drug for NASH, and specifically includes an administration step of administering the drug for NASH to an administration subject. The drug for NASH may be administered in vitro or in vivo . As the administration subject and administration condition of the drug for NASH of the present invention, for example, the description of the administration subject and administration condition in the expression inhibitor of the present invention can be incorporated.

<Method of suppressing fibrosis>
The method for suppressing fibrosis of the present invention (hereinafter, also referred to as “method for suppressing fibrosis”) includes, as described above, an administration step of administering the fibrosis inhibitor of the present invention to a subject. The method for suppressing fibrosis of the present invention is characterized by administering the agent for suppressing fibrosis of the present invention, and other steps and conditions are not particularly limited. As the method for suppressing fibrosis of the present invention, the description of the expression inhibitor, the agent for suppressing fibrosis, and the method for suppressing expression of the present invention can be incorporated. According to the method for suppressing fibrosis of the present invention, as described above, by suppressing the expression of the fibrosis-inducing gene, the fibrosis of liver tissue that progresses in NASH can be suppressed. Therefore, the method for suppressing fibrosis of the present invention can also be referred to as, for example, a method for suppressing fibrosis in non-alcoholic steatohepatitis or a method for suppressing progression from non-alcoholic steatohepatitis to liver cirrhosis.

The method for suppressing fibrosis of the present invention includes, for example, an administration step of administering the fibrosis inhibitor, and specifically includes an administration step of administering the fibrosis inhibitor to an administration subject. The fibrosis inhibitor may be administered in vitro or in vivo . In the method for suppressing fibrosis of the present invention, the administration target and administration conditions of the fibrosis inhibitor can be referred to, for example, the description of the administration target and administration conditions of the expression inhibitor of the present invention.

<Use of compound or salt thereof>
The present invention is a compound represented by the above formula (I), a salt thereof or a solvate thereof, or a use thereof for use in suppressing the expression of a fibrosis-inducing gene, and is used for the treatment of fibrosis. The compound represented by the above formula (I), a salt thereof or a solvate thereof, or a use thereof, which is represented by the above formula (I) for use in the treatment of non-alcoholic steatosis. Compounds, salts thereof or solvates thereof, or uses thereof, compounds represented by the above formula (I), salts thereof or solvates thereof, or solvates thereof. It is used. Further, the present invention is the use of a compound represented by the above formula (I), a salt thereof or a solvate thereof for producing an agent for suppressing the expression of a fibrosis-inducing gene, and is a medicament for treating fibrosis. The use of a compound represented by the above formula (I), a salt thereof or a solvate thereof for producing the above formula (I), and for producing a therapeutic drug for non-alcoholic steatosis. Use of a compound represented by the above formula (I), a salt thereof or a solvate thereof, and a compound represented by the above formula (I), a salt thereof or a solvate thereof, for producing an inhibitor of fibrosis. Is. In the present invention, for example, the description of the expression inhibitor, the fibrosis drug, the NASH drug, and the fibrosis suppressant of the present invention can be incorporated.

Next, examples of the present invention will be described. However, the present invention is not limited by the following examples. Commercially available reagents were used based on their protocols unless otherwise indicated.

[Example 1]
It was confirmed that the expression inhibitor of the present invention suppresses the expression of the fibrosis-inducing gene.

(1) Preparation of mice NASH and associated fibrosis were induced by a methionine / choline deficient diet (MCD diet) model. Specifically, 10-week-old wild-type mice (BALB / C, male) are fed with powdered MCD feed (EPS Masshin Co., Ltd .: A02082002B) or control feed (MCS feed, EPS Masshin Co., Ltd .: A02082003B) was given and the animals were bred for 4 weeks. The former was the MCD group and the latter was the negative control group.

(2) Drug administration Next, in half of the mice in the MCD group, letrozole, which is an expression inhibitor of the present invention, was added to half of the mice in the MCD group in an amount equivalent to 0.1 mg / kg per daily feed instead of the MCD feed. MCD feed (MCD + LET) was added so as to be the same, and the mice were bred for 5 weeks to obtain the mice of Examples (MCD + LET). Further, among the mice in the MCD group, the mice bred in the same manner for 5 weeks except that the MCD feed (MCD) was continuously fed were used as NASH model mice (MCD) and used as controls. Then, the mice in the negative control group that continued to receive the control feed (CTL) were similarly bred for 5 weeks to obtain negative control mice (CTL). From the start of the test to the end of the test, the general condition (appearance, breathing and behavior), body weight, and amount of residual feed are measured every other week, and blood is collected before the start of retrosol administration, 2 weeks after the start, and 5 weeks after the start. Then, aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin / total cholesterol (TC), and triglyceride (TG) were measured (measurement was outsourced to Oriental Yeast Industry Co., Ltd.).

(3) Confirmation of expression level of fibrosis-inducing gene Each mouse was sacrificed at 5 weeks and liver tissue was removed. RNA was extracted from the excised liver tissue using an RNA preparation kit (RNeasy Mini kit, manufactured by QIAGEN). Next, for the obtained RNA, cDNA was synthesized using a cDNA preparation kit (QuantiTect® Reverse Transcription Kit, manufactured by QIAGEN). Then, for the obtained cDNA, an RT-PCR reagent (QuantiTect (registered trademark) SYBR (registered trademark) Green PCR kits (QIAGEN)) and a PCR device (Step One Plus (trademark) -01, manufactured by Applied Biosystems) were used. The fibrosis-inducing genes TGF-β1 (Transforming Growth Factor-β1), CTGF (Connective Tissue Growth Factor), α-SMA (α-Smooth Muscle Actin) and YAP1 (Yes-associated Protein 1), and internal The expression level of the standard gene GAPDH mRNA was measured, and the relative expression level with respect to the GAPDH gene expression level was calculated. Furthermore, the relative expression level of each mRNA in the negative control mice slaughtered at 5 weeks was similarly measured, and the average value of the relative expression levels of the mRNA of each gene was used as a calibrator, and the comparative C _t method (ΔΔC _{t) was used.} The relative value of the expression level of each gene was calculated using the method). In the RT-PCR, the following primers (QuantiTect (registered trademark) Primer Assay, manufactured by QIAGEN) were used.
Primer for TGF-β1: Mm_Tgfb1_1_SG (Cat no: QT00145250)
Primer for CTGF: Mm_Ctgf_1_SG (Cat no: QT00096131)
Primer for α-SMA: Mm_Acta2_1_SG (Cat no: QT140119)
Primer for YAP1: Mm_Yap1_1_SG (Cat no: QT01061130)
Primer for GAPDH: Mm_Gapdh_3_SG (Cat no: QT01658692)

The result is shown in FIG. In FIG. 1, (A) shows the result of TGF-β1, (B) shows the result of CTGF, (C) shows the result of α-SMA, and (D) shows the result of YAP1. In FIG. 1, the vertical axis represents the relative value of the expression level of each gene, and the horizontal axis represents the period after the start of letrozole administration. As shown in FIG. 1, the control mouse (MCD) has increased expression of the fibrosis-inducing gene as compared with the negative control mouse (CTL), which causes fibrosis in NASH. all right. In addition, the expression of TGF-β1, CTGF, α-SMA, and YAP1 was significantly suppressed in the mouse (MCD + LET) of the example as compared with the control mouse (MCD) at 5 weeks after the start of letrozole administration. .. From the above, it was found that the expression inhibitor of the present invention can suppress the expression of the fibrosis-inducing gene.

[Example 2]
It was confirmed that the expression inhibitor of the present invention can suppress fibrosis of liver tissue in NASH, that is, can treat NASH.

(1) Measurement of Liver Tissue Each liver tissue derived from the mouse at 5 weeks removed in Example 1 (3) was embedded in paraffin, and the embedded tissue was cut into 10 μm sections. The obtained sections were HE-stained by a conventional method. In addition, the section was stained with Sirius red, and the stained tissue was observed with an upright microscope (Axio Imager 1 microscope, manufactured by Carl Zeiss). Furthermore, for the liver tissue of each mouse, 10 visual fields were observed at a magnification of 10 × 10 times per animal, the average ratio of the stained region of Sirius red in one visual field was measured, and the fibrosis index of each liver tissue was calculated. Then, the amount of hydroxyproline was measured in the liver tissue of each mouse using a hydroxyproline measurement kit (Quickzyme hydroxyproline kit, manufactured by QuickZime Biosciences).

The result of tissue staining is shown in FIG. FIG. 2 is a microscopic photograph of the stained liver tissue, (A) shows a photograph of HE staining, and (B) shows a photograph of Sirius red staining. In FIGS. 2A and 2B, each photograph is the result of a negative control mouse (CTL), a control mouse (MCD), and an example mouse (MCD + LET) from the left.

As shown in FIG. 2, as compared with the negative control mouse (CTL), the control mouse (MCD) has a large number of fibrotic regions in the area surrounded by the arrow, and is particularly typical from the perivascular area. Fibrosis was occurring, and fibrosis of liver tissue was progressing. On the other hand, in the mouse of the example (MCD + LET), fibrosis from around the blood vessel was suppressed as compared with the control mouse (MCD), and the fibrosis of the liver tissue was significantly suppressed.

Next, the results of the fibrosis index and the amount of hydroxyproline are shown in FIG. In FIG. 3, (A) is a graph showing the fibrosis index, and (B) is a graph showing the amount of hydroxyproline. In FIGS. 3A and 3B, the horizontal axis represents the period after the start of letrozole administration, the vertical axis represents the fibrosis index in (A), and the vertical axis represents hydroxy in (B). Indicates the amount of proline.

As shown in FIG. 3 (A), the control mouse (MCD) had advanced fibrosis of liver tissue as compared with the negative control mouse (CTL). On the other hand, the mice of the example (MCD + LET) significantly suppressed the fibrosis of the liver tissue as compared with the control mouse (MCD). Further, as shown in FIG. 3 (B), the amount of hydroxyproline was significantly increased in the control mouse (MCD) as compared with the negative control mouse (CTL), and the amount of collagen in the liver tissue was increased. It was found that there was an increase, that is, fibrosis of liver tissue was progressing. In contrast, the mice of the example (MCD + LET) had a significantly reduced amount of hydroxyproline and a reduced amount of collagen as compared with the control mouse (MCD), that is, liver tissue. It was found that the progression of fibrosis was suppressed.

(2) Measurement of blood markers Blood was collected after breeding each mouse of Example 1 (2) for 5 weeks, and the concentration of two fibrillation markers (Mac-2 Binding Protein (M2BP) and hyaluronic acid) in serum. Was measured. M2BP was measured using an M2BP measurement kit (mouse mac-2 BP assay kit, manufactured by Immuno-Biological Laboratories). Hyaluronic acid was measured using a hyaluronic acid measurement kit (hyaluronan immunoassay kit, manufactured by R & D systems). These results are shown in FIG.

In FIG. 4, (A) shows the result of M2BP, and (B) shows the result of hyaluronic acid. In FIG. 4, the vertical axis indicates the concentration of each serum marker. As shown in FIG. 4, the concentrations of two serum fibrosis markers (Mac-2 Binding Protein (M2BP) and hyaluronic acid) in the control mice (MCD) were higher in the control mice (MCD) than in the negative control mice (CTL). It was confirmed that the amount increased and fibrosis occurred. On the other hand, in the mouse of the example (MCD + LET), the concentration of two fibrosis markers (Mac-2 Binding Protein (M2BP) and hyaluronic acid) in the serum was decreased as compared with the mouse of the control (MCD). It was found that the expression inhibitor of the present invention can suppress fibrosis of liver tissue.

From the above, it was found that the expression inhibitor of the present invention can suppress fibrosis of liver tissue in NASH, that is, can treat NASH.

[Example 3]
It was confirmed that the expression inhibitor of the present invention can suppress the expression of the fibrosis-inducing gene in human hepatocytes in vivo.

(1) Preparation of Chimeric Mouse A PXB (registered trademark) mouse was used to prepare a chimeric mouse having a liver composed of human hepatocytes. Specifically, normal human hepatocytes were transplanted via the spleen into uPA / SCID mice (mouse with severe immunodeficiency liver injury having both uPA transgenic and SCID traits) 2-3 weeks old.

(2) Drug administration To the obtained chimeric mice, letrozole was orally administered at a rate of 200 mg / kg / day for 3 days. The oral administration was carried out in the morning. At 24 hours after the last dose of letrozole, the liver was removed from the chimeric mice and the expression of TGF-β2, CTGF, α-SMA, and YAP1 was measured using the T-LEX® method. Specifically, after preparing Total RNA from the liver, cRNA was prepared from the Total RNA. Then, with respect to the cRNA, the expression level of each gene was measured using a DNA chip. Controls were measured in the same manner except that letrozole was not administered. Then, the relative expression level was calculated with the expression level of each gene in the control as 1. As a result, the expression level of TGF-β2 was 0.87, the expression level of CTGF was 0.16, the expression level of α-SMA was 0.57, and the expression level of YAP-1 was 0.64. It was suppressed. From these results, it was found that the expression inhibitor of the present invention can suppress the expression of the fibrosis-inducing gene in human hepatocytes in vivo.

Although the present invention has been described above with reference to the embodiments and examples, the present invention is not limited to the above embodiments and examples. Various changes that can be understood by those skilled in the art can be made to the structure and details of the present invention within the scope of the present invention.

This application claims priority on the basis of Japanese application Japanese Patent Application No. 2018-205632 filed on October 31, 2018, and incorporates all of its disclosures herein.

前記式（Ｉ）中、
Ｒ、Ｒ_０およびＲ_１は、同じでも異なってもよく、独立して水素原子であるか；または
ＲとＲ_０とは、隣接した炭素原子上に存在し、一緒になって、それらが結合しているベンゼン環と合体してナフタレン環を形成してもよく；
Ｒ_２は、水素原子、低級アルキル基、フェニル基、シアノ−フェニル基、トリフルオロメチル−フェニル基、ハロゲン化フェニル基、低級アルコキシ−フェニル基、ヒドロキシ−フェニル基、低級アルキル−フェニル基、フェニル−低級アルキル基、ヒドロキシ−フェニル−低級アルキル基、シアノ−フェニル−低級アルキル基、ピリジル基もしくはチエニル基であるか；または
Ｒ_１とＲ_２とが、一緒になって、低級アルキリデン基もしくはジ−［（低級アルコキシもしくはヒドロキシ）−フェニル］−低級アルキリデン基を表すか；または
Ｒ_１とＲ_２とが、一緒になって、炭素数４〜６の直鎖アルキレン基もしくはオルトフェニレン架橋された炭素数２〜４の直鎖アルキレン基を表し、それらに結合している炭素原子と共に、対応する場合によりベンゾ縮合された５−、６−もしくは７員環を形成してもよく；
Ｗは、１−（1,2,4もしくは1,3,4）−トリアゾリル基または３−ピリジル基であるか；または
Ｗは、１−イミダゾリル基または低級アルキル置換−１−イミダゾリル基であり、その場合には、下記式（Ｉ′）：

で表される基は、式（Ｉ）の−Ｃ≡Ｎ基に関してフェニル環の４位に結合している。
（付記２）
下記式（II）で表される化合物を含む、付記１記載の発現抑制剤：

前記式（II）中、
Ｒ_１′が、水素原子であり；
Ｒ_２′が、水素原子、低級アルキル基、フェニル基、ピリジル基、チエニル基もしくはベンジル基であり；または、
Ｒ_２′が、そのフェニル環上で、それぞれ、シアノ基、低級アルキル基、低級アルコキシ基、ヒドロキシ基、ハロゲン基、もしくはトリフルオロメチル基でモノ置換されたフェニル基、またはシアノ基もしくはヒドロキシ基でモノ置換されたベンジル基であるか；または
Ｒ_１′およびＲ_２′が、一緒になって、低級アルキリデン基またはジ−［（低級アルコキシもしくはヒドロキシ）−フェニル］低級アルキリデン基を表すか；または
Ｒ_１′およびＲ_２′が、一緒になって、炭素数４〜６の直鎖アルキレン基を表し；
Ｒ_３が、水素原子である。
（付記３）
前記式（II）において、
Ｒ_１′が、水素原子であり；
Ｒ_２′が、水素原子、低級アルキル基もしくはピリジル基であり；または
Ｒ_２′が、非置換またはフェニル環上で、それぞれ、シアノ基、低級アルキル基、低級アルコキシ基、ヒドロキシ基、もしくはハロゲン基でモノ置換されたフェニル基、またはシアノ基もしくはヒドロキシ基でモノ置換されたベンジル基であり；
Ｒ_３が、水素原子である、付記２記載の発現抑制剤。
（付記４）
前記式（II）において、
Ｒ_１′およびＲ_３が、水素原子であり；
Ｒ_２′が、３−ピリジル基、ｐ−シアノベンジル基、またはｐ−シアノフェニル基である、付記２または３記載の発現抑制剤。
（付記５）
下記式（III）で表される化合物を含む、付記１から４のいずれかに記載の発現抑制剤：

前記式（III）中、
Ｒ_２′は、３−ピリジル基、ｐ−シアノベンジル基、またはｐ−シアノフェニル基である。
（付記６）
レトロゾール、その塩またはそれらの溶媒和物を含む、付記１から５のいずれかに記載の発現抑制剤。
（付記７）
前記線維化誘導遺伝子は、ＴＧＦ−β（Transforming Growth Factor-β）、ＣＴＧＦ（Connective Tissue Growth Factor）、α−ＳＭＡ（α-Smooth Muscle Actin）およびＹＡＰ１（Yes-associated Protein 1）からなる群から選択された少なくとも一つを含む、付記１から６のいずれかに記載の発現抑制剤。
（付記８）
付記１から７のいずれかに記載の線維化誘導遺伝子の発現抑制剤を含む、線維症用医薬。
（付記９）
前記線維症は、肺線維症、骨髄線維症、皮膚硬化症、および動脈硬化症からなる群から選択された少なくとも一つである、付記８記載の線維症用医薬。
（付記１０）
付記１から７のいずれかに記載の線維化誘導遺伝子の発現抑制剤を含む、非アルコール性脂肪肝炎用医薬。
（付記１１）
付記１から７のいずれかに記載の線維化誘導遺伝子の発現抑制剤を含む、線維化抑制剤。
（付記１２）
前記線維化抑制剤は、非アルコール性脂肪肝炎から肝硬変への進展抑制剤である、付記１１の線維化抑制剤。
（付記１３）
対象に、付記１から７のいずれかに記載の線維化誘導遺伝子の発現抑制剤を投与する投与工程を含む、線維化誘導遺伝子の発現抑制方法。
（付記１４）
前記線維化誘導遺伝子は、ＴＧＦ−β（Transforming Growth Factor-β）、ＣＴＧＦ（Connective Tissue Growth Factor）、α−ＳＭＡ（α-Smooth Muscle Actin）およびＹＡＰ１（Yes-associated Protein 1）からなる群から選択された少なくとも一つを含む、付記１３記載の発現抑制方法。
（付記１５）
前記発現抑制剤を、ｉｎ ｖｉｔｒｏまたはｉｎ ｖｉｖｏで投与する、付記１３または１４記載の発現抑制方法。
（付記１６）
対象に、付記８または９記載の線維症用医薬を投与する投与工程を含む、線維症の治療方法。
（付記１７）
前記線維症は、肺線維症、骨髄線維症、皮膚硬化症、および動脈硬化症からなる群から選択された少なくとも一つである、付記１６記載の線維症の治療方法。
（付記１８）
対象に、付記１０記載の非アルコール性脂肪肝炎用医薬を投与する投与工程を含む、非アルコール性脂肪肝炎の治療方法。
（付記１９）
対象に、付記１１または１２記載の線維化抑制剤を投与する投与工程を含む、線維化の抑制方法。
（付記２０）
前記対象は、非アルコール性脂肪肝炎の患者であり、
前記投与工程において、前記患者に、前記線維化抑制剤を投与することにより、前記非アルコール性脂肪肝炎における線維化を抑制する、付記１９記載の線維化の抑制方法。
（付記２１）
前記対象は、非アルコール性脂肪肝炎の患者であり、
前記投与工程において、前記患者に、前記線維化抑制剤を投与することにより、前記非アルコール性脂肪肝炎から肝硬変への進展を抑制する、付記１９または２０記載の線維化の抑制方法。
（付記２２）
線維化誘導遺伝子の発現抑制に使用するための、下記式（Ｉ）で表される化合物、その塩またはそれらの溶媒和物：

前記式（Ｉ）中、
Ｒ、Ｒ_０およびＲ_１は、同じでも異なってもよく、独立して水素原子であるか；または
ＲとＲ_０とは、隣接した炭素原子上に存在し、一緒になって、それらが結合しているベンゼン環と合体してナフタレン環を形成してもよく；
Ｒ_２は、水素原子、低級アルキル基、フェニル基、シアノ−フェニル基、トリフルオロメチル−フェニル基、ハロゲン化フェニル基、低級アルコキシ−フェニル基、ヒドロキシ−フェニル基、低級アルキル−フェニル基、フェニル−低級アルキル基、ヒドロキシ−フェニル−低級アルキル基、シアノ−フェニル−低級アルキル基、ピリジル基もしくはチエニル基であるか；または
Ｒ_１とＲ_２とが、一緒になって、低級アルキリデン基もしくはジ−［（低級アルコキシもしくはヒドロキシ）−フェニル］−低級アルキリデン基を表すか；または
Ｒ_１とＲ_２とが、一緒になって、炭素数４〜６の直鎖アルキレン基もしくはオルトフェニレン架橋された炭素数２〜４の直鎖アルキレン基を表し、それらに結合している炭素原子と共に、対応する場合によりベンゾ縮合された５−、６−もしくは７員環を形成してもよく；
Ｗは、１−（1,2,4もしくは1,3,4）−トリアゾリル基または３−ピリジル基であるか；または
Ｗは、１−イミダゾリル基または低級アルキル置換−１−イミダゾリル基であり、その場合には、下記式（Ｉ′）：

で表される基は、式（Ｉ）の−Ｃ≡Ｎ基に関してフェニル環の４位に結合している。
（付記２３）
線維症の治療に使用するための、前記式（Ｉ）で表される化合物、その塩またはそれらの溶媒和物。
（付記２４）
非アルコール性脂肪肝炎の治療に使用するための、前記式（Ｉ）で表される化合物、その塩またはそれらの溶媒和物。
（付記２５）
線維化の抑制に使用するための、前記式（Ｉ）で表される化合物、その塩またはそれらの溶媒和物。<Additional notes>
Some or all of the above embodiments and examples may be described as, but not limited to, the following appendices.
(Appendix 1)
An agent for suppressing the expression of a fibrosis-inducing gene, which comprises a compound represented by the following formula (I), a salt thereof, or a solvate thereof:

In the formula (I),
R, R ₀ and R ₁ may be the same or different and are independent hydrogen atoms; or R and R ₀ are on adjacent carbon atoms and together they are bonded together. It may be combined with the benzene ring to form a naphthalene ring;
R ₂ is a hydrogen atom, a lower alkyl group, a phenyl group, a cyano-phenyl group, a trifluoromethyl-phenyl group, a halogenated phenyl group, a lower alkoxy-phenyl group, a hydroxy-phenyl group, a lower alkyl-phenyl group, and a phenyl- Is it a lower alkyl group, a hydroxy-phenyl-lower alkyl group, a cyano-phenyl-lower alkyl group, a pyridyl group or a thienyl group; or R ₁ and R ₂ together to form a lower alkylidene group or di-[ (Lower alkoxy or hydroxy) -Phenyl] -represents a lower alkylidene group; or R ₁ and R ₂ together have a linear alkylene group having 4 to 6 carbon atoms or orthophenylene crosslinked carbon atoms 2 It represents ~ 4 linear alkylene groups and may form a correspondingly benzo-condensed 5-, 6- or 7-membered ring with carbon atoms attached to them;
W is a 1- (1,2,4 or 1,3,4) -triazolyl group or 3-pyridyl group; or W is a 1-imidazolyl group or a lower alkyl-substituted-1-imidazolyl group. In that case, the following equation (I'):

The group represented by is bonded to the 4-position of the phenyl ring with respect to the -C≡N group of the formula (I).
(Appendix 2)
The expression inhibitor according to Appendix 1, which contains a compound represented by the following formula (II):

In the above formula (II),
R ₁ 'is hydrogen atom;
R ₂ ′ is a hydrogen atom, a lower alkyl group, a phenyl group, a pyridyl group, a thienyl group or a benzyl group; or
R ₂ ′ is a phenyl group mono-substituted with a cyano group, a lower alkyl group, a lower alkoxy group, a hydroxy group, a halogen group, or a trifluoromethyl group, or a cyano group or a hydroxy group, respectively, on the phenyl ring. Is it a mono-substituted benzyl group; or does R ₁ ′ and R ₂ ′ together represent a lower alkylidene group or a di-[(lower alkoxy or hydroxy) -phenyl] lower alkylidene group; or R ₁ ′ and R ₂ ′ together represent a linear alkylene group having 4 to 6 carbon atoms;
R ₃ is a hydrogen atom.
(Appendix 3)
In the above formula (II)
R ₁ 'is hydrogen atom;
R ₂ ′ is a hydrogen atom, a lower alkyl group or a pyridyl group; or R ₂ ′ is an unsubstituted or phenyl ring, cyano group, lower alkyl group, lower alkoxy group, hydroxy group or halogen group, respectively. A phenyl group mono-substituted with, or a benzyl group mono-substituted with a cyano or hydroxy group;
The expression inhibitor according to Appendix 2, wherein R _{3 is a hydrogen atom.}
(Appendix 4)
In the above formula (II)
R ₁ 'and _{R 3} is hydrogen atom;
R ₂ 'is 3-pyridyl group, p- cyanobenzyl group or p- cyano phenyl group, Appendix 2 or 3 expression inhibitor described.
(Appendix 5)
The expression inhibitor according to any one of Supplementary note 1 to 4, which contains a compound represented by the following formula (III):

In the above formula (III),
R ₂ 'is a 3-pyridyl group, p- cyanobenzyl group or p- cyanophenyl groups.
(Appendix 6)
The expression inhibitor according to any one of Supplementary note 1 to 5, which comprises letrozole, a salt thereof or a solvate thereof.
(Appendix 7)
The fibrosis-inducing gene is selected from the group consisting of TGF-β (Transforming Growth Factor-β), CTGF (Connective Tissue Growth Factor), α-SMA (α-Smooth Muscle Actin) and YAP1 (Yes-associated Protein 1). The expression inhibitor according to any one of Supplementary note 1 to 6, which comprises at least one of the above.
(Appendix 8)
A pharmaceutical for fibrosis, which comprises an agent for suppressing the expression of the fibrosis-inducing gene according to any one of Supplementary notes 1 to 7.
(Appendix 9)
The fibrosis drug according to Appendix 8, wherein the fibrosis is at least one selected from the group consisting of pulmonary fibrosis, myelofibrosis, skin sclerosis, and arteriosclerosis.
(Appendix 10)
A pharmaceutical for non-alcoholic steatohepatitis, which comprises an agent for suppressing the expression of the fibrosis-inducing gene according to any one of Supplementary notes 1 to 7.
(Appendix 11)
An antifibrosis agent comprising the expression inhibitor of the fibrosis-inducing gene according to any one of Supplementary notes 1 to 7.
(Appendix 12)
The fibrosis inhibitor is an inhibitor of progression from non-alcoholic steatohepatitis to liver cirrhosis, according to Appendix 11.
(Appendix 13)
A method for suppressing the expression of a fibrosis-inducing gene, which comprises an administration step of administering to the subject the agent for suppressing the expression of the fibrosis-inducing gene according to any one of Appendix 1 to 7.
(Appendix 14)
The fibrosis-inducing gene is selected from the group consisting of TGF-β (Transforming Growth Factor-β), CTGF (Connective Tissue Growth Factor), α-SMA (α-Smooth Muscle Actin) and YAP1 (Yes-associated Protein 1). The method for suppressing expression according to Appendix 13, which comprises at least one of the above-mentioned methods.
(Appendix 15)
The expression-suppressing method according to Appendix 13 or 14, wherein the expression-suppressing agent is administered in vitro or in vivo.
(Appendix 16)
A method for treating fibrosis, which comprises an administration step of administering the fibrosis drug according to Appendix 8 or 9 to the subject.
(Appendix 17)
The method for treating fibrosis according to Appendix 16, wherein the fibrosis is at least one selected from the group consisting of pulmonary fibrosis, myelofibrosis, skin sclerosis, and arteriosclerosis.
(Appendix 18)
A method for treating non-alcoholic steatohepatitis, which comprises an administration step of administering the drug for non-alcoholic steatohepatitis described in Appendix 10 to the subject.
(Appendix 19)
A method for suppressing fibrosis, which comprises an administration step of administering to the subject the fibrosis inhibitor according to Appendix 11 or 12.
(Appendix 20)
The subject is a patient with non-alcoholic steatohepatitis.
The method for suppressing fibrosis according to Appendix 19, wherein in the administration step, fibrosis in the non-alcoholic steatohepatitis is suppressed by administering the fibrosis inhibitor to the patient.
(Appendix 21)
The subject is a patient with non-alcoholic steatohepatitis.
The method for suppressing fibrosis according to Appendix 19 or 20, wherein in the administration step, the progression from non-alcoholic steatohepatitis to liver cirrhosis is suppressed by administering the fibrosis inhibitor to the patient.
(Appendix 22)
A compound represented by the following formula (I), a salt thereof, or a solvate thereof for use in suppressing the expression of a fibrosis-inducing gene:

In the formula (I),
R, R ₀ and R ₁ may be the same or different and are independent hydrogen atoms; or R and R ₀ are on adjacent carbon atoms and together they are bonded together. It may be combined with the benzene ring to form a naphthalene ring;
R ₂ is a hydrogen atom, a lower alkyl group, a phenyl group, a cyano-phenyl group, a trifluoromethyl-phenyl group, a halogenated phenyl group, a lower alkoxy-phenyl group, a hydroxy-phenyl group, a lower alkyl-phenyl group, and a phenyl- Is it a lower alkyl group, a hydroxy-phenyl-lower alkyl group, a cyano-phenyl-lower alkyl group, a pyridyl group or a thienyl group; or R ₁ and R ₂ together to form a lower alkylidene group or di-[ (Lower alkoxy or hydroxy) -Phenyl] -represents a lower alkylidene group; or R ₁ and R ₂ together have a linear alkylene group having 4 to 6 carbon atoms or orthophenylene crosslinked carbon atoms 2 It represents ~ 4 linear alkylene groups and may form a correspondingly benzo-condensed 5-, 6- or 7-membered ring with carbon atoms attached to them;
W is a 1- (1,2,4 or 1,3,4) -triazolyl group or 3-pyridyl group; or W is a 1-imidazolyl group or a lower alkyl-substituted-1-imidazolyl group. In that case, the following equation (I'):

The group represented by is bonded to the 4-position of the phenyl ring with respect to the -C≡N group of the formula (I).
(Appendix 23)
A compound represented by the above formula (I), a salt thereof, or a solvate thereof for use in the treatment of fibrosis.
(Appendix 24)
A compound represented by the above formula (I), a salt thereof, or a solvate thereof for use in the treatment of non-alcoholic steatohepatitis.
(Appendix 25)
A compound represented by the above formula (I), a salt thereof, or a solvate thereof for use in suppressing fibrosis.

As described above, the expression inhibitor of the present invention can suppress the expression of the fibrosis-inducing gene by containing the compound of the formula (I), a salt thereof, or a solvate thereof. That is, according to the present invention, since the expression of the fibrosis-inducing gene can be suppressed, for example, fibrosis of living tissues such as liver tissue can be suppressed, and it can be used for the treatment of fibrosis. Moreover, in NASH, fibrosis progresses. Therefore, according to the present invention, a medicine for NASH can be provided. Therefore, it can be said that the present invention is extremely useful in the field of pharmaceuticals and the like.

Claims (12)

An agent for suppressing the expression of a fibrosis-inducing gene, which comprises a compound represented by the following formula (I) or a salt thereof:

In the formula (I),
R, R ₀ and R ₁ may be the same or different and are independent hydrogen atoms; or R and R ₀ are on adjacent carbon atoms and together they are bonded together. It may be combined with the benzene ring to form a naphthalene ring;
R ₂ is a hydrogen atom, a lower alkyl group, a phenyl group, a cyano-phenyl group, a trifluoromethyl-phenyl group, a halogenated phenyl group, a lower alkoxy-phenyl group, a hydroxy-phenyl group, a lower alkyl-phenyl group, and a phenyl- Is it a lower alkyl group, a hydroxy-phenyl-lower alkyl group, a cyano-phenyl-lower alkyl group, a pyridyl group or a thienyl group; or R ₁ and R ₂ together to form a lower alkylidene group or di-[ (Lower alkoxy or hydroxy) -Phenyl] -represents a lower alkylidene group; or R ₁ and R ₂ together have a linear alkylene group having 4 to 6 carbon atoms or orthophenylene crosslinked carbon atoms 2 It represents ~ 4 linear alkylene groups and may form a correspondingly benzo-condensed 5-, 6- or 7-membered ring with carbon atoms attached to them;
W is a 1- (1,2,4 or 1,3,4) -triazolyl group or 3-pyridyl group; or W is a 1-imidazolyl group or a lower alkyl-substituted-1-imidazolyl group. In that case, the following equation (I'):

The group represented by is bonded to the 4-position of the phenyl ring with respect to the -C≡N group of the formula (I). The expression inhibitor according to claim 1, which comprises a compound represented by the following formula (II):

In the above formula (II),
R ₁ 'is hydrogen atom;
R ₂ ′ is a hydrogen atom, a lower alkyl group, a phenyl group, a pyridyl group, a thienyl group or a benzyl group; or
R ₂ ′ is a phenyl group mono-substituted with a cyano group, a lower alkyl group, a lower alkoxy group, a hydroxy group, a halogen group, or a trifluoromethyl group, or a cyano group or a hydroxy group, respectively, on the phenyl ring. Is it a mono-substituted benzyl group; or does R ₁ ′ and R ₂ ′ together represent a lower alkylidene group or a di-[(lower alkoxy or hydroxy) -phenyl] lower alkylidene group; or R ₁ ′ and R ₂ ′ together represent a linear alkylene group having 4 to 6 carbon atoms;
R ₃ is a hydrogen atom. In the above formula (II)
R ₁ 'is hydrogen atom;
R ₂ ′ is a hydrogen atom, a lower alkyl group or a pyridyl group; or R ₂ ′ is an unsubstituted or phenyl ring, cyano group, lower alkyl group, lower alkoxy group, hydroxy group or halogen group, respectively. A phenyl group mono-substituted with, or a benzyl group mono-substituted with a cyano or hydroxy group;
The expression inhibitor according to claim 2, wherein R _{3 is a hydrogen atom.} In the above formula (II)
R ₁ 'and _{R 3} is hydrogen atom;
R ₂ 'is 3-pyridyl group, p- cyanobenzyl group, or a p- cyanophenyl group, according to claim 2 or 3 expression inhibitor according. The expression inhibitor according to any one of claims 1 to 4, which comprises a compound represented by the following formula (III):

In the above formula (III),
R ₂ 'is a 3-pyridyl group, p- cyanobenzyl group or p- cyanophenyl groups. The expression inhibitor according to any one of claims 1 to 5, which comprises letrozole or a salt thereof. The fibrosis-inducing gene consists of a group consisting of TGF-β (Transforming Growth Factor-β), CTGF (Connective Tissue Growth Factor), α-SMA (α-Smooth Muscle Actin), and YAP1 (Yes-associated Protein 1). The expression inhibitor according to any one of claims 1 to 6, which comprises at least one selected. A medicament for fibrosis, which comprises an agent for suppressing the expression of the fibrosis-inducing gene according to any one of claims 1 to 7. The fibrosis drug according to claim 8, wherein the fibrosis is at least one selected from the group consisting of pulmonary fibrosis, myelofibrosis, skin sclerosis, and arteriosclerosis. A medicament for non-alcoholic steatohepatitis, which comprises an agent for suppressing the expression of the fibrosis-inducing gene according to any one of claims 1 to 7. An antifibrosis agent comprising the expression inhibitor of the fibrosis-inducing gene according to any one of claims 1 to 7. The fibrosis inhibitor according to claim 11, wherein the fibrosis inhibitor is an agent for suppressing the progression of non-alcoholic steatohepatitis to liver cirrhosis.

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