JP2019182764A - Medicine for prevention and treatment of chronic fatty disease - Google Patents

Abstract

[Object] To provide an anti-fibrotic effect on non-alcoholic steatohepatitis (NASH) by nintedanib. The present invention provides a composition for preventing, ameliorating, or treating chronic fatty liver disease, having the chemical structural formula of Formula I described herein. The composition of the present invention is useful for preventing, ameliorating, or treating lifestyle-related inflammatory diseases. Further, the compositions of the present invention are useful for preventing, ameliorating or treating non-alcoholic diseases, more preferably non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH). [Selection diagram] None

Description

  The present invention relates to a medicament for the prevention and treatment of chronic fatty diseases.

  Nonalcoholic steatohepatitis (NASH) is known as a typical disease of chronic fatty disease. NASH is now recognized as a cause of liver fibrosis, and it is said that this disease may progress to cirrhosis and hepatocellular carcinoma.

  Nintedanib (NTN) is an ordinarily available inhibitor of indolinone-derived receptor tyrosine kinase (RTK) with anti-angiogenic and anti-tumor activity. NTN is clinically used to treat idiopathic pulmonary fibrosis.

  Non-alcoholic fatty liver disease (NAFLD), which is known as a representative example of chronic fatty disease, is an important issue in public health due to the large number of patients. Among them, non-alcoholic steatohepatitis (NASH) is defined as a more advanced state of NAFLD characterized by a specific pattern of steatosis, altered inflammation, and hepatocyte damage, accompanied by subjective symptoms. It has been pointed out that it may cause liver damage, induce liver fibrosis and cirrhosis, and cause hepatocellular carcinoma.

As a result of extensive research, the present inventors have found that the general formula substituted at the 6-position

Of indolinone, their tautomers, diastereomers, enantiomers, mixtures thereof and compositions thereof inhibit the progression of NASH by inhibiting hepatocyte apoptosis ( Each substituent may be any as defined elsewhere herein.)

  In another aspect, the present invention provides for assessing biochemical and histological changes in a NASH model, such as a mouse model. Therefore, the present invention further provides a clinically useful diagnostic method for chronic fatty liver disease such as NASH and screening method for drugs.

For example, the present invention provides the following items.
(Item 1)
A composition for preventing, ameliorating or treating chronic fatty liver disease, wherein the composition has the general formula substituted at position 6

[Where,
X represents an oxygen atom or a sulfur atom,
R ₁ Represents a hydrogen atom or a group used for prodrug formation,
R ₂ Is a carboxy group, linear or branched C _1-6 -Alkoxycarbonyl group, C _4-7 -Cycloalkoxycarbonyl group or aryloxycarbonyl group,
Linear or branched C _1-6 -Alkoxycarbonyl groups (which are phenyl, heteroaryl, carboxy, C _1-3 -Alkoxycarbonyl group, aminocarbonyl group, C _1-3 -Alkylamino-carbonyl group or di- (C _1-3 -Alkyl) -aminocarbonyl group substituted at the end),
Linear or branched C _2-6 -Alkoxycarbonyl groups (which are chlorine or hydroxy groups, C _1-3 -Alkoxy group, amino group, C _1-3 -Alkylamino or di- (C _1-3 -Alkyl) -amino groups are substituted at the end)
Aminocarbonyl group or methylaminocarbonyl group, if necessary, hydroxy group or C at the 2-position of ethyl group _1-3 Represents an ethylaminocarbonyl group optionally substituted by an alkoxy group, or
R _Four Is an aminosulfonyl-phenyl group or N- (C _1-5 -Alkyl) -C _1-3 If it does not represent an -alkylaminocarbonyl-phenyl group, it is also di- (C _1-2 -Alkyl) -aminocarbonyl group may be represented,
R _Three Is a hydrogen atom, C _1-6 -Alkyl group, C _3-7 -Cycloalkyl group, trifluoromethyl group or heteroaryl group,
Phenyl group or naphthyl group; fluorine atom, chlorine atom, bromine atom or iodine atom, trifluoromethyl group, C _1-3 -Alkyl group or C _1-3 A phenyl group or naphthyl group mono- or di-substituted by an alkoxy group (in the case of di-substitution, the substituents may be the same or different, and the above-mentioned unsubstituted phenyl group, naphthyl group and one Substituted and disubstituted phenyl and naphthyl groups are further
Hydroxy group, hydroxy-C _1-3 -Alkyl group or C _1-3 -Alkoxy-C _1-3 -Alkyl groups,
Cyano group, carboxy group, carboxy-C _1-3 -Alkyl group, C _1-3 -Alkoxycarbonyl group, aminocarbonyl group, C _1-3 -Alkylamino-carbonyl group or di- (C _1-3 -Alkyl) -aminocarbonyl group,
Nitro group,
Amino group, C _1-3 -Alkylamino group, di- (C _1-3 -Alkyl) -amino or amino-C _1-3 -Alkyl groups,
C _1-3 -Alkylcarbonylamino group, N- (C _1-3 -Alkyl) -C _1-3 -Alkylcarbonylamino group, C _1-3 -Alkylcarbonylamino-C _1-3 -Alkyl group, N- (C _1-3 -Alkyl) -C _1-3 -Alkylcarbonylamino-C _1-3 -Alkyl group, C _1-3 -Alkylsulfonylamino group, C _1-3 -Alkylsulfonylamino-C _1-3 -Alkyl group, N- (C _1-3 -Alkyl) -C _1-3 -Alkylsulfonylamino-C _1-3 -Alkyl or aryl-C _1-3 -Alkylsulfonylamino group,
Cycloalkylamino group, cycloalkyleneimino group, cycloalkyleneiminocarbonyl group, cycloalkyleneimino-C _1-3 -Alkyl group, cycloalkyleneiminocarbonyl-C _1-3 -Alkyl group or cycloalkyleneiminosulfonyl-C _1-3 -Alkyl group (having 4 to 7 ring members in each case) (in each case, the methylene group at the 4-position of the 6-membered or 7-membered cycloalkyleneimino group is an oxygen atom or a sulfur atom, a sulfinyl group, a sulfonyl group,- NH group or -N (C _1-3 -Optionally substituted with an -alkyl) group), or
Heteroaryl group or heteroaryl-C _1-3 -May be substituted by an alkyl group)
Represents
R _Four Is C _3-7 -Cycloalkyl group (methylene group at 4-position of 6-membered or 7-membered cycloalkyl group is an amino group, C _1-3 -Alkylamino or di- (C _1-3 -Alkyl) -amino group may be substituted, or -NH group or -N (C _1-3 -Optionally substituted with an -alkyl) group), or
R ₆ A phenyl group substituted by [this further comprises a fluorine, chlorine, bromine or iodine atom, C _1-5 -Alkyl group, trifluoromethyl group, hydroxy group, C _1-3 -Alkoxy group, carboxy group, C _1-3 -Alkoxycarbonyl group, amino group, acetylamino group, C _1-3 -Alkyl-sulfonylamino group, aminocarbonyl group, C _1-3 -Alkyl-aminocarbonyl group, di- (C _1-3 -Alkyl) -aminocarbonyl group, aminosulfonyl group, C _1-3 -Alkyl-aminosulfonyl group, di- (C _1-3 -Alkyl) -aminosulfonyl group, nitro group or cyano group may be mono- or di-substituted, and these substituents may be the same or different, and
R ₆ Is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom,
Cyano group, nitro group, amino group, C _1-5 -Alkyl group, C _3-7 -Cycloalkyl group, trifluoromethyl group, phenyl group, tetrazolyl group or heteroaryl group,
formula

(Wherein the hydrogen atoms bonded to the nitrogen atom are each independently C _1-3 -May be substituted by an alkyl group)
Base of
C _1-3 -Alkoxy group, C _1-3 -Alkoxy-C _1-3 -Alkoxy group, phenyl-C _1-3 -Alkoxy group, amino-C _2-3 -Alkoxy group, C _1-3 -Alkylamino-C _2-3 -Alkoxy group, di- (C _1-3 -Alkyl) -amino-C _2-3 -Alkoxy group, phenyl-C _1-3 -Alkylamino-C _2-3 -Alkoxy group, N- (C _1-3 -Alkyl) -phenyl-C _1-3 -Alkylamino-C _2-3 -Alkoxy group, C _5-7 -Cycloalkylenimino-C _2-3 -Alkoxy group or C _1-3 -Alkyl mercapto groups,
Carboxy group, C _1-4 -Alkoxycarbonyl group, aminocarbonyl group, C _1-3 -Alkylamino-carbonyl group, N- (C _1-5 -Alkyl) -C _1-3 -Alkylaminocarbonyl group, phenyl-C _1-3 -Alkylamino-carbonyl group, N- (C _1-3 -Alkyl) -phenyl-C _1-3 -Alkylamino-carbonyl group, piperazinocarbonyl group or N- (C _1-3 -Alkyl) -piperazinocarbonyl group,
C _1-3 -Alkylaminocarbonyl group or N- (C _1-5 -Alkyl) -C _1-3 -Alkylaminocarbonyl group (the alkyl moiety is a carboxy group or C _1-3 Substituted by alkoxycarbonyl groups or di- (C at the 2 or 3 position thereof _1-3 -Alkyl) -amino group, piperazino group, N- (C _1-3 -Alkyl) -piperazino group or 4-7 membered cycloalkyleneimino group)
C _3-7 -Cycloalkylcarbonyl group (methylene group at 4-position of 6-membered or 7-membered cycloalkyl moiety is amino group, C _1-3 -Alkylamino or di- (C _1-3 -Alkyl) -amino group may be substituted, or -NH group or -N (C _1-3 -Optionally substituted with an -alkyl) group),
4- to 7-membered cycloalkyleneimino group (the methylene group bonded to the imino group may be substituted with a carbonyl group or a sulfonyl group, or
The cycloalkylene moiety may be fused to a phenyl ring, or
1 or 2 hydrogen atoms are each C _1-3 Optionally substituted by an alkyl group and / or
In each case, the 4-position methylene group of the 6-membered or 7-membered cycloalkyleneimino group is a carboxy group, C _1-3 -Alkoxycarbonyl group, aminocarbonyl group, C _1-3 -Alkylaminocarbonyl group, di- (C _1-3 -Alkyl) -aminocarbonyl group, phenyl-C _1-3 -Alkylamino group or N- (C _1-3 -Alkyl) -phenyl-C _1-3 May be substituted by an -alkylamino group, or
Oxygen or sulfur atom, sulfinyl group, sulfonyl group, -NH group, -N (C _1-3 -Alkyl) group, -N (phenyl) group, -N (C _1-3 -Alkylcarbonyl) group or -N (benzoyl) group).
R ₇ C replaced by _1-4 -Alkyl group (R ₇ Is C _3-7 -Cycloalkyl group (methylene group at 4-position of 6-membered or 7-membered cycloalkyl group is an amino group, C _1-3 -Alkylamino or di- (C _1-3 -Alkyl) -amino group may be substituted, or -NH group or -N (C _1-3 -Alkyl) group may be substituted, or
In a 5- to 7-membered cycloalkyl group,-(CH ₂ ) ₂ The group may be substituted by a -CO-NH group and-(CH ₂ ) _Three The group may be substituted by a —NH—CO—NH group or a —CO—NH—CO group, or — (CH ₂ ) _Four The group may be substituted by a -NH-CO-NH-CO group, in which case the hydrogen atom bonded to the nitrogen atom is C _1-3 -May be substituted by an alkyl group),
An aryl group or heteroaryl group,
Hydroxy group or C _1-3 -Alkoxy groups,
Amino group, C _1-7 -Alkylamino group, di- (C _1-7 -Alkyl) -amino group, phenylamino group, N-phenyl-C _1-3 -Alkyl-amino group, phenyl-C _1-3 -Alkyl-amino group, N- (C _1-3 -Alkyl) -phenyl-C _1-3 -Alkylamino or di- (phenyl-C _1-3 -Alkyl) -amino group,
ω-hydroxy-C _2-3 -Alkyl-amino group, N- (C _1-3 -Alkyl) -ω-hydroxy-C _2-3 -Alkyl-amino group, di- (ω-hydroxy-C _2-3 -Alkyl) -amino group, di- (ω- (C _1-3 -Alkoxy) -C _2-3 -Alkyl) -amino group or N- (dioxolan-2-yl) -C _1-3 -Alkyl-amino groups,
C _1-3 -Alkylcarbonylamino-C _2-3 -Alkyl-amino or C _1-3 -Alkylcarbonylamino-C _2-3 -Alkyl-N- (C _1-3 -Alkyl) -amino group,
C _1-3 -Alkylsulfonylamino group, N- (C _1-3 -Alkyl) -C _1-3 -Alkyl-sulfonylamino group, C _1-3 -Alkylsulfonylamino-C _2-3 -Alkyl-amino or C _1-3 -Alkylsulfonylamino-C _2-3 -Alkyl-N- (C _1-3 -Alkyl) -amino group,
Hydroxycarbonyl C _1-3 -Alkylamino group or N- (C _1-3 -Alkyl) -hydroxycarbonyl C _1-3 -Alkyl-amino groups,
Guanidino group (one or two hydrogen atoms are each C _1-3 -May be substituted by an alkyl group),
Formula -N (R ₈ ) -CO- (CH ₂ ) _n -R ₉ (II)
Base of
(Where
R ₈ Is a hydrogen atom or C _1-3 -Represents an alkyl group,
n represents one of the numbers 0, 1, 2, or 3, and
R ₉ Is an amino group, C _1-4 -Alkylamino group, di- (C _1-4 -Alkyl) -amino, phenylamino, N- (C _1-4 -Alkyl) -phenylamino, benzylamino, N- (C _1-4 -Alkyl) -benzylamino or C _1-4 -Alkoxy group, 4- to 7-membered cycloalkyleneimino group (in each case, the methylene group at the 4-position of the 6-membered or 7-membered cycloalkyleneimino group is an oxygen atom or sulfur atom, sulfinyl group, sulfonyl group, -NH group,- N (C _1-3 -Alkyl) group, -N (phenyl) group, -N (C _1-3 -Alkylcarbonyl) group or -N (benzoyl) group), or when n represents one of the numbers 1, 2 or 3, it may also represent a hydrogen atom) ,
Formula -N (R _Ten )-(CH ₂ ) _m -(CO) _o -R ₁₁ (III)
Base of
(Where
R _Ten Is a hydrogen atom, C _1-3 -Alkyl group, C _1-3 -Alkylcarbonyl group, arylcarbonyl group, phenyl-C _1-3 -Alkylcarbonyl group, C _1-3 -Alkylsulfonyl group, arylsulfonyl group or phenyl-C _1-3 -Represents an alkylsulfonyl group,
m represents one of the numbers 1, 2, 3 or 4;
o may represent the number 1 or, if m represents one of the numbers 2, 3 or 4, o may also represent the number 0; and
R ₁₁ Is an amino group, C _1-4 -Alkylamino group, di- (C _1-4 -Alkyl) -amino, phenylamino, N- (C _1-4 -Alkyl) -phenylamino, benzylamino, N- (C _1-4 -Alkyl) -benzylamino group, C _1-4 -Alkoxy group or C _1-3 -Alkoxy-C _1-3 -Alkoxy group, di- (C _1-4 -Alkyl) -amino-C _1-3 -Alkylamino group (C at the 1 position if necessary) _1-3 -May be substituted by an alkyl group) or a 4-7 membered cycloalkyleneimino group (the cycloalkylene moiety may be fused to a phenyl ring, or in each case a 6 or 7 membered cycloalkyleneimino) The 4-position methylene group is an oxygen atom or sulfur atom, sulfinyl group, sulfonyl group, -NH group, -N (C _1-3 -Alkyl) group, -N (phenyl) group, -N (C _1-3 -Alkylcarbonyl) group or -N (benzoyl) group may be substituted))
C _4-7 -Cycloalkylamino group, C _4-7 -Cycloalkyl-C _1-3 -Alkylamino group or C _4-7 -Cycloalkenylamino group (the 1-position of the ring is not contained in the double bond, and each of the above groups is further substituted at the amino nitrogen atom position by C _5-7 -Cycloalkyl group, C _2-4 -Alkenyl group or C _1-4 -May be substituted by an alkyl group),
4- to 7-membered cycloalkyleneimino group (the cycloalkylene moiety is a phenyl group or an oxazolo group, an imidazolo group, a thiazolo group, a pyridino group, a pyrazino group or a pyrimidino group (optionally a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, a nitro group) Group, C _1-3 -Alkyl group, C _1-3 -Optionally substituted with an alkoxy group or an amino group) and / or
1 or 2 hydrogen atoms are each C _1-3 -Alkyl group, C _5-7 Optionally substituted by a cycloalkyl group or a phenyl group and / or
The 5-position methylene group of the 5-membered cycloalkyleneimino group is a hydroxy group, hydroxy-C _1-3 -Alkyl group, C _1-3 -Alkoxy group or C _1-3 -Alkoxy-C _1-3 -May be substituted by an alkyl group,
A 6-membered or 7-membered cycloalkyleneimino group in each case the 3- or 4-position methylene group is a hydroxy group, hydroxy-C _1-3 -Alkyl group, C _1-3 -Alkoxy group, C _1-3 -Alkoxy-C _1-3 -Alkyl group, carboxy group, C _1-4 -Alkoxycarbonyl group, aminocarbonyl group, C _1-3 -Alkylaminocarbonyl group, di- (C _1-3 -Alkyl) -aminocarbonyl group, phenyl-C _1-3 -Alkylamino group or N- (C _1-3 -Alkyl) -phenyl-C _1-3 Optionally substituted by an -alkyl-amino group, or
Oxygen or sulfur atom, sulfinyl group, sulfonyl group, -NH group, -N (C _1-3 -Alkyl-) group, -N (phenyl) group, -N (phenyl-C _1-3 -Alkyl-) group, -N (C _1-3 -Alkylcarbonyl) group, -N (C _1-4 -Hydroxycarbonyl) group, -N (C _1-4 -Alkoxycarbonyl) group, -N (benzoyl-) group or -N (phenyl-C _1-3 -Alkylcarbonyl) group may be substituted,
The methylene group bonded to the imino nitrogen atom of the cycloalkyleneimino group may be substituted with a carbonyl group or a sulfonyl group, or a cycloalkyleneimino condensed with a 5- to 7-membered monocyclic cycloalkyleneimino group or phenyl group In the group, two methylene groups bonded to the imino nitrogen atom may each be substituted by a carbonyl group)
Represents), or
R ₆ Is C _1-4 -Alkyl group (this is a carboxy group, C _1-3 -Alkoxycarbonyl group, aminocarbonyl group, C _1-3 -Alkylaminocarbonyl group or di- (C _1-3 -Alkyl) -aminocarbonyl groups or 4-7 membered cycloalkyleneiminocarbonyl groups)
N- (C _1-3 -Alkyl) -C _2-4 -Acylamino group (which is a carboxy group or C _1-3 Further substituted by an alkoxycarbonyl group),
Formula -N (R ₁₂ ) -CO- (CH ₂ ) _p -R ₁₃ (IV)
Base of
(Where
R ₁₂ Is a hydrogen atom, C _1-6 -Alkyl group or C _3-7 -Cycloalkyl group or C _1-3 -Alkyl group (phenyl, heteroaryl, trifluoromethyl, hydroxy, C _1-3 -Alkoxy group, aminocarbonyl group, C _1-4 -Alkylamino-carbonyl group, di- (C _1-4 -Alkyl) -amino-carbonyl group, C _1-3 -Alkylcarbonyl group, C _1-3 -Alkyl-sulfonylamino group, N- (C _1-3 -Alkyl) -C _1-3 -Alkyl-sulfonylamino group, C _1-3 -Alkyl-aminosulfonyl group or di- (C _1-3 -Alkyl) -aminosulfonyl group) and
p represents one of the numbers 0, 1, 2 or 3, and
R ₁₃ Is the above group R ₇ Or, when p represents one of the numbers 1, 2 or 3, it may also represent a hydrogen atom)
Formula -N (R ₁₄ )-(CH ₂ ) _q -(CO) _r -R ₁₅ (V)
Base of
(Where
R ₁₄ Is a hydrogen atom, C _1-4 -Alkyl group, C _1-3 -Alkylcarbonyl group, arylcarbonyl group, phenyl-C _1-3 -Alkylcarbonyl group, heteroarylcarbonyl group, heteroaryl-C _1-3 -Alkylcarbonyl group, C _1-4 -Alkylsulfonyl group, arylsulfonyl group, phenyl-C _1-3 -Alkylsulfonyl group, heteroarylsulfonyl group or heteroaryl-C _1-3 Represents an -alkyl-sulfonyl group,
q represents one of the numbers 1, 2, 3 or 4;
r may represent the number 1 or, if q is one of the numbers 2, 3 or 4, it may also represent the number 0;
R ₁₅ Is the above group R ₇ Mean)
Formula -N (R ₁₆ ) -SO ₂ -R ₁₇ (VI)
Base of
(Where
R ₁₆ Is a hydrogen atom or C _1-4 -Alkyl group (if necessary, cyano group, trifluoromethyl-carbonylamino group or N- (C _1-3 -Alkyl) -trifluoromethyl-carbonylamino group), and
R ₁₇ Is C _1-3 -Represents an alkyl group),
Di- (C _1-3 -Alkyl) -amino-C _1-3 -Alkylcarbonyl group or di- (C _1-3 -Alkyl) -amino-C _1-3 -Alkyl-sulfonyl and di- (C _1-3 -Alkyl) -aminocarbonyl-C _1-3 An amino group substituted by an alkyl group, or
N- (C _1-3 -Alkyl) -C _1-5 -Alkylsulfonylamino group or N- (C _1-3 -Alkyl) -phenylsulfonylamino group (the alkyl part is further substituted by a cyano group or a carboxy group)
Represents
R ₆ All the single-bonded or condensed phenyl groups contained in the group described in the above are fluorine atom, chlorine atom, bromine atom or iodine atom, C _1-5 -Alkyl group, trifluoromethyl group, hydroxy group, C _1-3 -Alkoxy group, carboxy group, C _1-3 -Alkoxycarbonyl group, aminocarbonyl group, C _1-4 -Alkylamino-carbonyl group, di- (C _1-4 -Alkyl) -amino-carbonyl group, aminosulfonyl group, C _1-3 -Alkyl-aminosulfonyl group, di- (C _1-3 -Alkyl) -aminosulfonyl group, C _1-3 -Alkyl-sulfonylamino, mono- or di-substituted by nitro or cyano groups, these substituents may be the same or different, or two of the phenyl groups The adjacent hydrogen atom may be substituted by a methylenedioxy group), and
R _Five Is a hydrogen atom or C _1-3 -Represents an alkyl group,
The aryl group is optionally a fluorine atom, chlorine atom, bromine atom or iodine atom, cyano group, trifluoromethyl group, nitro group, carboxy group, aminocarbonyl group, C _1-3 -Alkyl group or C _1-3 -Means a phenyl group or a naphthyl group which may be mono- or di-substituted by an alkoxy group,
The heteroaryl group is optionally C in the carbon skeleton. _1-3 Means a monocyclic 5- or 6-membered heteroaryl group optionally substituted by an alkyl group,
The 6-membered heteroaryl group contains 1, 2 or 3 nitrogen atoms, and
The 5-membered heteroaryl group is optionally C _1-3 -Alkyl group or phenyl-C _1-3 An imino group optionally substituted by an alkyl group, an oxygen atom or a sulfur atom or
C if necessary _1-3 -Alkyl group or phenyl-C _1-3 An imino group optionally substituted by an alkyl group, or an oxygen or sulfur atom and further a nitrogen atom or
C if necessary _1-3 -Alkyl group or phenyl-C _1-3 An imino group optionally substituted by an alkyl group and two nitrogen atoms,
In addition, the phenyl ring may be fused to the monocyclic heterocyclic group through two adjacent carbon atoms, and the bond may be linked through a nitrogen atom or through a carbon atom in the heterocyclic moiety or a fused phenyl ring. Happens through
Some or all of the hydrogen atoms in the alkyl moieties contained in the above alkyl and alkoxy groups or in the previously defined groups of formula I may be substituted with fluorine atoms, and
The hydrogen atom of the carboxy group present or the hydrogen atom bonded to the nitrogen atom may each be substituted by a group that can be cleaved in vivo.)
Or a tautomer, diastereomer or enantiomer, a mixture thereof, or a pharmaceutically acceptable salt thereof.
(Item 2)
In the indolinone, their tautomers, diastereomers or enantiomers, mixtures thereof or pharmaceutically acceptable salts thereof,
R ₁ And R _Three Is as defined above, and
X represents an oxygen atom,
R ₂ Is a carboxy group, linear or branched C _1-6 -Alkoxycarbonyl group, C _5-7 -Cycloalkoxycarbonyl group or phenoxycarbonyl group,
Linear or branched C _1-3 -Alkoxycarbonyl groups (which are phenyl, heteroaryl, carboxy, C _1-3 -Alkoxycarbonyl group, aminocarbonyl group, C _1-3 -Alkylaminocarbonyl group or di- (C _1-3 -Alkyl) -aminocarbonyl group substituted at the end),
Linear or branched C _2-3 -Alkoxycarbonyl groups (which are chlorine, hydroxy, C _1-3 -Alkoxy group, amino group, C _1-3 -Alkylamino or di- (C _1-3 -Alkyl) -amino groups are substituted at the end)
Aminocarbonyl group or methylaminocarbonyl group, if necessary, hydroxy group or C at the 2-position of ethyl group _1-3 Represents an ethylaminocarbonyl group optionally substituted by an alkoxy group, or
R _Four Is an aminosulfonyl-phenyl group or N- (C _1-5 -Alkyl) -C _1-3 If it does not represent an -alkylaminocarbonyl-phenyl group, it is also di- (C _1-2 -Alkyl) -aminocarbonyl group may be represented,
R _Four Is C _3-7 -Cycloalkyl group (methylene group at 4-position of 6-membered or 7-membered cycloalkyl group is an amino group, C _1-3 -Alkylamino or di- (C _1-3 -Alkyl) -amino group may be substituted, or -NH group or -N (C _1-3 -Optionally substituted with an -alkyl) group), or
R ₆ A phenyl group substituted by [this further comprises a fluorine, chlorine or bromine atom, C _1-3 -Alkyl group, trifluoromethyl group, hydroxy group, C _1-3 -Alkoxy group, carboxy group, C _1-3 -Alkoxycarbonyl group, amino group, acetylamino group, aminocarbonyl group, C _1-3 -Alkyl-aminocarbonyl group, di- (C _1-3 -Alkyl) -aminocarbonyl group, nitro group or cyano group may be mono- or di-substituted, and these substituents may be the same or different, and
R ₆ Is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom,
Cyano group, nitro group, amino group, C _1-5 -Alkyl group, C _3-7 -Cycloalkyl group, trifluoromethyl group, phenyl group, tetrazolyl group or heteroaryl group,
formula
(In the formula, the hydrogen atom bonded to the nitrogen atom is C _1-3 -May be substituted by an alkyl group)
Base of
C _1-3 -Alkoxy group, amino-C _2-3 -Alkoxy group, C _1-3 -Alkylamino-C _2-3 -Alkoxy group, di- (C _1-3 -Alkyl) -amino-C _2-3 -Alkoxy group, phenyl-C _1-3 -Alkylamino-C _2-3 -Alkoxy group, N- (C _1-3 -Alkyl) -phenyl-C _1-3 -Alkylamino-C _2-3 -Alkoxy group, pyrrolidino-C _2-3 -Alkoxy group, piperidino-C _2-3 -Alkoxy group or C _1-3 -Alkyl mercapto groups,
Carboxy group, C _1-4 -Alkoxycarbonyl group, aminocarbonyl group, C _1-3 -Alkylamino-carbonyl group, phenyl-C _1-3 -Alkylamino-carbonyl group or N- (C _1-3 -Alkyl) -phenyl-C _1-3 -Alkylamino-carbonyl group,
C _3-7 -Cycloalkylcarbonyl group (methylene group at 4-position of 6-membered or 7-membered cycloalkyl moiety is -NH group or -N (C _1-3 -Optionally substituted with an -alkyl) group),
4- to 7-membered cycloalkyleneimino group (the methylene group bonded to the imino group may be substituted with a carbonyl group or a sulfonyl group, or
1 or 2 hydrogen atoms are each C _1-3 Optionally substituted by an alkyl group and / or
In each case, the 4-position methylene group of the 6-membered or 7-membered cycloalkyleneimino group is a carboxy group, C _1-3 -Alkoxycarbonyl group, aminocarbonyl group, C _1-3 -Alkylaminocarbonyl group, di- (C _1-3 -Alkyl) -aminocarbonyl group, phenyl-C _1-3 -Alkylamino group or N- (C _1-3 -Alkyl) -phenyl-C _1-3 May be substituted by an -alkylamino group, or
Oxygen or sulfur atom, sulfinyl group, sulfonyl group, -NH group or -N (C _1-3 -Optionally substituted with an -alkyl) group),
R ₇ C substituted at the end by _1-4 -Alkyl group (R ₇ Is C _5-7 -Cycloalkyl group (methylene group at the 4-position of 6-membered or 7-membered cycloalkyl group is -NH group or -N (C _1-3 -Alkyl) group may be substituted, or
In a 5- to 7-membered cycloalkyl group,-(CH ₂ ) ₂ The group may be substituted by a -CO-NH group and-(CH ₂ ) _Three The group may be substituted by a -NH-CO-NH- group or-(CH ₂ ) _Four The group may be substituted by a -NH-CO-NH-CO group, in which case the hydrogen atom bonded to the nitrogen atom is C _1-3 -May be substituted by an alkyl group),
A phenyl group or a heteroaryl group,
Hydroxy group or C _1-3 -Alkoxy groups,
Amino group, C _1-6 -Alkylamino group, di- (C _1-6 -Alkyl) -amino group, phenylamino group, N-phenyl-C _1-3 -Alkyl-amino group, phenyl-C _1-3 -Alkylamino group, N- (C _1-3 -Alkyl) -phenyl-C _1-3 -Alkylamino or di- (phenyl-C _1-3 -Alkyl) -amino group,
ω-hydroxy-C _2-3 -Alkyl-amino group, N- (C _1-3 -Alkyl) -ω-hydroxy-C _2-3 -Alkyl-amino group, di- (ω-hydroxy-C _2-3 -Alkyl) -amino group, di- (ω- (C _1-3 -Alkoxy) -C _2-3 -Alkyl) -amino group or N- (dioxolan-2-yl) -C _1-3 -Alkyl-amino groups,
C _1-3 -Alkylcarbonylamino-C _2-3 -Alkyl-amino or C _1-3 -Alkylcarbonylamino-C _2-3 -Alkyl-N- (C _1-3 -Alkyl) -amino group,
C _1-3 -Alkylsulfonylamino group, N- (C _1-3 -Alkyl) -C _1-3 -Alkylsulfonylamino group, C _1-3 -Alkylsulfonylamino-C _2-3 -Alkyl-amino or C _1-3 -Alkylsulfonylamino-C _2-3 -Alkyl-N- (C _1-3 -Alkyl) -amino group,
Hydroxycarbonyl C _1-3 -Alkylamino group or N- (C _1-3 -Alkyl) -hydroxycarbonyl C _1-3 -Alkyl-amino groups,
Guanidino group (hydrogen atom is C _1-3 -May be substituted by an alkyl group),
Formula -N (R ₈ ) -CO- (CH ₂ ) _n -R ₉ (II)
Base of
(Where
R ₈ Is a hydrogen atom or C _1-3 -Represents an alkyl group,
n represents one of the numbers 0, 1, 2, or 3, and
R ₉ Is an amino group, C _1-3 -Alkylamino group, di- (C _1-3 -Alkyl) -amino, phenylamino, benzylamino or C _1-4 -Alkoxy group, 5- to 7-membered cycloalkyleneimino group (the methylene group at the 4-position of the piperidino group is an oxygen atom or a sulfur atom, -NH group, -N (C _1-3 -Alkyl) group, -N (phenyl) group, -N (C _1-3 -Alkylcarbonyl) group or -N (benzoyl) group), or when n represents one of the numbers 1, 2 or 3, it may also represent a hydrogen atom) ,
Formula -N (R _Ten )-(CH ₂ ) _m -(CO) _o -R ₁₁ (III)
Base of
(Where
R _Ten Is a hydrogen atom, C _1-3 -Alkyl group, C _1-3 -Alkylcarbonyl group or C _1-3 -Represents an alkylsulfonyl group,
m represents one of the numbers 1, 2 or 3,
o represents the number 1 or, if m represents one of the numbers 2 or 3, o may also represent the number 0; and
R ₁₁ Is an amino group, C _1-3 -Alkylamino group, di- (C _1-3 -Alkyl) -amino group, C _1-4 -Alkoxy group or C _1-3 -Alkoxy-C _1-3 -Alkoxy group or 5- to 7-membered cycloalkyleneimino group (the methylene group at the 4-position of the piperidino group is an oxygen atom or a sulfur atom, -NH group, -N (C _1-3 -Alkyl) group, -N (phenyl) group, -N (C _1-3 -Alkylcarbonyl) group or -N (benzoyl) group may be substituted))
C _4-7 -Cycloalkylamino group or C _4-7 -Cycloalkenylamino group (position 1 of the ring is not contained in the double bond),
A 4- to 7-membered cycloalkyleneimino group (the cycloalkylene moiety may be fused to a phenyl group, or
1 or 2 hydrogen atoms are each C _1-3 Optionally substituted by an alkyl group and / or
The methylene group at the 3-position of the pyrrolidino group is a hydroxy group or C _1-3 -May be substituted by an alkoxy group,
In each case, the 4-position methylene group of the 6-membered or 7-membered cycloalkyleneimino group is a hydroxy group, hydroxy-C _1-3 -Alkyl group, C _1-3 -Alkoxy group, carboxy group, C _1-3 -Alkoxycarbonyl group, aminocarbonyl group, C _1-3 -Alkylaminocarbonyl group, di- (C _1-3 -Alkyl) -aminocarbonyl group, phenyl-C _1-3 -Alkylamino group or N- (C _1-3 -Alkyl) -phenyl-C _1-3 Optionally substituted by an -alkyl-amino group, or
Oxygen or sulfur atom, sulfinyl group, sulfonyl group, -NH group, -N (C _1-3 -Alkyl) group, -N (phenyl) group, -N (phenyl-C _1-3 -Alkyl) group, -N (C _1-3 -Alkylcarbonyl) group, -N (C _1-4 -Alkoxycarbonyl) group, -N (benzoyl) group or -N (phenyl-C _1-3 -Alkylcarbonyl) group may be substituted,
The methylene group bonded to the imino nitrogen atom of the cycloalkyleneimino group may be substituted with a carbonyl group or a sulfonyl group, or a cycloalkyleneimino condensed with a 5- to 6-membered monocyclic cycloalkyleneimino group or phenyl group In the group, two methylene groups bonded to the imino nitrogen atom may each be substituted by a carbonyl group)
Represents), or
R ₆ Is C _1-4 -Alkyl group (this is a carboxy group, C _1-3 -Alkoxycarbonyl group, aminocarbonyl group, C _1-3 -Alkylaminocarbonyl group or di- (C _1-3 -Alkyl) -aminocarbonyl group or substituted at the end by a 4-7 membered cycloalkyleneiminocarbonyl group),
Formula -N (R ₁₂ ) -CO- (CH ₂ ) _p -R ₁₃ (IV)
Base of
(Where
R ₁₂ Is a hydrogen atom, C _1-3 -Alkyl group, C _5-7 -Cycloalkyl group, phenyl-C _1-3 -Alkyl groups or heteroaryl-C _1-3 -Represents an alkyl group, and
p represents one of the numbers 0, 1, 2 or 3, and
R ₁₃ Is the above group R ₇ Or, when p represents one of the numbers 1, 2 or 3, it may also represent a hydrogen atom)
Formula -N (R ₁₄ )-(CH ₂ ) _q -(CO) _r -R ₁₅ (V)
Base of
(Where
R ₁₄ Is a hydrogen atom, C _1-4 -Alkyl group, C _1-3 -Alkylcarbonyl group, phenylcarbonyl group, phenyl-C _1-3 -Alkylcarbonyl group, heteroarylcarbonyl group, heteroaryl-C _1-3 -Alkylcarbonyl group, C _1-4 -Alkylsulfonyl group, phenylsulfonyl group, phenyl-C _1-3 -Alkylsulfonyl group, heteroarylsulfonyl group or heteroaryl-C _1-3 Represents an -alkyl-sulfonyl group,
q represents one of the numbers 1, 2, 3 or 4;
r may represent the number 1 or, if q is one of the numbers 2, 3 or 4, it may also represent the number 0;
R ₁₅ Is the above group R ₇ Mean)
Formula -N (R ₁₆ ) -SO ₂ -R ₁₇ (VI)
Base of
(Where
R ₁₆ Is a hydrogen atom or C _1-4 -Alkyl group (if necessary, cyano group, trifluoromethyl-carbonylamino group or N- (C _1-3 -Alkyl) -trifluoromethyl-carbonylamino group), and
R ₁₇ Is C _1-3 -Represents an alkyl group),
Di- (C _1-3 -Alkyl) -amino-C _1-3 -Alkylcarbonyl group or di- (C _1-3 -Alkyl) -amino-C _1-3 -Alkyl-sulfonyl and di- (C _1-3 -Alkyl) -aminocarbonyl-C _1-3 -Represents an amino group substituted by an alkyl group,
R ₆ All the single-bonded or condensed phenyl groups contained in the group described in the above are fluorine atom, chlorine atom or bromine atom, C _1-3 -Alkyl group, trifluoromethyl group, hydroxy group, C _1-3 -Alkoxy group, carboxy group, C _1-3 -Alkoxycarbonyl group, aminocarbonyl group, C _1-3 -Alkyl-aminocarbonyl group, aminosulfonyl group, C _1-3 May be mono- or di-substituted by alkyl-aminosulfonyl group, nitro group or cyano group, these substituents may be the same or different, or two of the phenyl groups The adjacent hydrogen atom may be substituted by a methylenedioxy group), and
R _Five Is a hydrogen atom or C _1-3 -Represents an alkyl group,
The heteroaryl group is optionally C in the carbon skeleton. _1-3 -Means pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl or triazolyl, optionally substituted by alkyl The hydrogen atom bonded to the atom is C _1-3 -Alkyl group or phenyl-C _1-3 A 5-membered heteroaryl group optionally substituted by an -alkyl group and containing at least one imino group is bonded via a carbon atom or a nitrogen atom;
The hydrogen atom bonded to the nitrogen atom in the above group may be substituted with a group that can be cleaved in vivo,
Each of the carboxy groups contained in the above groups may be substituted with a group that can be cleaved in vivo,
Item 2. The item according to Item 1, wherein some or all of the hydrogen atoms in the alkyl moiety and the alkyl moiety contained in the alkyl group and alkoxy group or in the previously defined group of formula I may be substituted with a fluorine atom. Composition.
(Item 3)
In the indolinone, their tautomers, diastereomers or enantiomers, mixtures thereof or pharmaceutically acceptable salts thereof,
X represents an oxygen atom,
R ₁ Represents a hydrogen atom,
R ₂ Is a carboxy group, linear or branched C _1-4 -Alkoxycarbonyl group or phenoxycarbonyl group,
Linear or branched C _1-3 -Alkoxycarbonyl groups (which are phenyl, carboxy, C _1-3 -Alkoxycarbonyl group, aminocarbonyl group, C _1-3 -Alkylaminocarbonyl group or di- (C _1-3 -Alkyl) -aminocarbonyl group substituted at the end),
Linear or branched C _2-3 -Alkoxycarbonyl group (which is a hydroxy group, C _1-3 -Alkoxy group, amino group, C _1-3 -Alkylamino or di- (C _1-3 -Alkyl) -amino groups are substituted at the end)
Aminocarbonyl group or methylaminocarbonyl group, if necessary, hydroxy group or C at the 2-position of ethyl group _1-3 Represents an ethylaminocarbonyl group optionally substituted by an alkoxy group, or
R _Four Is an aminosulfonyl-phenyl group or N- (C _1-5 -Alkyl) -C _1-3 If it does not represent an -alkylaminocarbonyl-phenyl group, it is also di- (C _1-2 -Alkyl) -aminocarbonyl group may be represented,
R _Three Is C _1-4 -Alkyl or phenyl group (this is a fluorine atom, chlorine atom or bromine atom, trifluoromethyl group, C _1-3 -Alkyl group, hydroxy group or C _1-3 -Optionally substituted by an alkoxy group)
R _Four Is C _5-6 -Cycloalkyl group (methylene group at 4-position of cyclohexyl group is amino group, C _1-3 -Alkylamino or di- (C _1-3 -Alkyl) -amino group may be substituted, or -NH group or -N (C _1-3 -Optionally substituted with an -alkyl) group),
Phenyl group; C _1-3 -Alkyl group, C _1-3 A phenyl group disubstituted by alkoxy or nitro groups (these substituents may be the same or different), or
R ₆ A phenyl group substituted by (which may be further substituted by a fluorine atom, a chlorine atom or a bromine atom, an amino group or a nitro group,
R ₆ Is a fluorine atom, a chlorine atom or a bromine atom,
C _1-3 -Alkyl group, C _1-3 -Alkoxy, nitro, amino or C _5-6 -Cycloalkyl group,
A pyrrolyl, pyrazolyl, imidazolyl, triazolyl or tetrazolyl group bonded through a carbon atom (the heteroaromatic group in the carbon skeleton is C _1-3 A hydrogen atom optionally substituted by an alkyl group or bonded to a nitrogen atom is C _1-3 -Alkyl group or phenyl-C _1-3 -May be substituted by an alkyl group),
formula
Base of
Carboxy group, C _1-4 -Alkoxycarbonyl group, phenyl-C _1-3 -Alkylamino-carbonyl group or C _5-7 -Cycloalkylcarbonyl group,
5-membered or 6-membered cycloalkyleneimino group (the methylene group at the 4-position of the piperidino group is an oxygen atom or a sulfur atom, -NH group or -N (C _1-3 -Optionally substituted with an -alkyl) group),
R ₇ Unbranched C substituted at the end by _1-3 -Alkyl group (R ₇ Is C _5-7 -Cycloalkyl group (in a 5- or 6-membered cycloalkyl group,-(CH ₂ ) ₂ The group may be substituted by a -CO-NH group and-(CH ₂ ) _Three The group may be substituted by a -NH-CO-NH- group or-(CH ₂ ) _Four The group may be substituted by a -NH-CO-NH-CO group, in which case the hydrogen atom bonded to the nitrogen atom is C _1-3 -May be substituted by an alkyl group),
A pyrrolyl group, pyrazolyl group, imidazolyl group or triazolyl group bonded via a phenyl group or pyridinyl group or a carbon atom or nitrogen atom (the heteroaromatic group in the carbon skeleton is C _1-3 A hydrogen atom optionally substituted by an alkyl group or bonded to a nitrogen atom is C _1-3 -May be substituted by an alkyl group),
Hydroxy group or C _1-3 -Alkoxy groups,
Amino group, C _1-6 -Alkylamino group, di- (C _1-6 -Alkyl) -amino group, phenylamino group, N-phenyl-C _1-3 -Alkylamino group, phenyl-C _1-3 -Alkylamino group or N- (C _1-3 -Alkyl) -phenyl-C _1-3 -Alkylamino group,
ω-hydroxy-C _2-3 -Alkyl-amino group, N- (C _1-3 -Alkyl) -ω-hydroxy-C _2-3 -Alkyl-amino group, di- (ω-hydroxy-C _2-3 -Alkyl) -amino or di- (ω- (C _1-3 -Alkoxy) -C _2-3 -Alkyl) -amino group,
C _1-3 -Alkylcarbonylamino-C _2-3 -Alkyl-amino or C _1-3 -Alkylcarbonylamino-C _2-3 -Alkyl-N- (C _1-3 -Alkyl) -amino group,
C _1-3 -Alkylsulfonylamino group, N- (C _1-3 -Alkyl) -C _1-3 -Alkylsulfonylamino group, C _1-3 -Alkylsulfonylamino-C _2-3 -Alkylamino group or C _1-3 -Alkylsulfonylamino-C _2-3 -Alkyl-N- (C _1-3 -Alkyl) -amino group,
Hydroxycarbonyl C _1-3 -Alkylamino group or N- (C _1-3 -Alkyl) -hydroxycarbonyl C _1-3 -Alkyl-amino groups,
Guanidino group (hydrogen atom is C _1-3 -May be substituted by an alkyl group),
Formula -N (R ₈ ) -CO- (CH ₂ ) _n -R ₉ (II)
Base of
(Where
R ₈ Is a hydrogen atom or C _1-3 -Represents an alkyl group,
n represents one of the numbers 0, 1, 2, or 3, and
R ₉ Is an amino group, C _1-3 -Alkylamino group, di- (C _1-3 -Alkyl) -amino group or C _1-4 -Alkoxy group, 5-membered or 6-membered cycloalkyleneimino group (the methylene group at the 4-position of the piperidino group is -NH group, -N (C _1-3 -Alkyl) group or -N (C _1-3 -Alkylcarbonyl) group), or when n represents one of the numbers 1, 2 or 3, R ₉ May also represent a hydrogen atom),
Formula -N (R _Ten )-(CH ₂ ) _m -(CO) _o -R ₁₁ (III)
Base of
(Where
R _Ten Is a hydrogen atom or C _1-3 -Represents an alkyl group,
m represents one of the numbers 1, 2 or 3,
o represents the number 1 or, if m represents one of the numbers 2 or 3, o may also represent the number 0; and
R ₁₁ Is an amino group, C _1-3 -Alkylamino group, di- (C _1-3 -Alkyl) -amino group, C _1-4 -Alkoxy or methoxy-C _1-3 -Alkoxy group or 5- or 6-membered cycloalkyleneimino group (the methylene group at the 4-position of the piperidino group is -NH group, -N (C _1-3 -Alkyl) group or -N (C _1-3 -Optionally substituted with an -alkylcarbonyl) group))
An azetidino group, a pyrrolidino group, a piperidino group, a 2,6-dimethyl-piperidino group, a 3,5-dimethyl-piperidino group or an azepino group (the methylene group at the 3-position of the pyrrolidino group may be substituted by a hydroxy group,
The 4-position methylene group of the piperidino group is a hydroxy group, hydroxy-C _1-3 -Alkyl group or C _1-3 May be substituted by an alkoxy group, or
Oxygen or sulfur atom, sulfinyl group, sulfonyl group, -NH group, -N (C _1-3 -Alkyl) group, -N (C _1-3 -Alkylcarbonyl) group, -N (benzoyl) group or -N (phenyl-C _1-3 -Alkylcarbonyl) group may be substituted,
(The methylene group bonded to the imino nitrogen atom of the pyrrolidino group, piperidino group or piperazino group may be substituted with a carbonyl group)
Represents), or
R ₆ Is straight chain C _1-3 -Alkyl group (this is a carboxy group or C _1-3 -Substituted at the end by an alkoxycarbonyl group),
Formula -N (R ₁₂ ) -CO- (CH ₂ ) _p -R ₁₃ (IV)
Base of
(Where
R ₁₂ Is a hydrogen atom, C _1-3 -Alkyl group or phenyl-C _1-3 -Represents an alkyl group,
p represents one of the numbers 0, 1 or 2, and
R ₁₃ Is an amino group, C _1-4 -Alkylamino group, di- (C _1-4 -Alkyl) -amino, benzylamino, N- (C _1-3 -Alkyl) -benzylamino group, C _1-3 -Alkoxy-C _1-3 -Alkylamino group, N- (C _1-3 -Alkyl) -C _1-3 -Alkoxy-C _1-3 -Alkylamino group, di- (2-methoxy-ethyl) -amino group, di- (ω-hydroxy-C _2-3 -Alkyl) -amino group or aminocarbonyl-methyl-N- (methyl) -amino group,
A pyrrolyl, pyrazolyl or imidazolyl group bonded through a nitrogen atom (optionally C _1-3 -May be substituted by an alkyl group),
Pyrrolidino, piperidino, morpholino, thiomorpholino or piperazino (optionally in position 4 _1-3 -Alkyl group, phenyl-C _1-3 -Alkyl group, C _1-3 -Alkylcarbonyl group or C _1-4 -Which may be substituted by an alkoxycarbonyl group), or when n represents the number 1 or 2, it may also represent a hydrogen atom),
Formula -N (R ₁₄ )-(CH ₂ ) _q -(CO) _r -R ₁₅ (V)
Base of
(Where
R ₁₄ Is a hydrogen atom, C _1-4 -Alkyl group, C _1-3 -Alkylcarbonyl group, phenylcarbonyl group, phenyl-C _1-3 -Alkylcarbonyl group, furyl-carbonyl group, pyridinyl-carbonyl group, furyl-C _1-3 -Alkylcarbonyl, pyridinyl-C _1-3 -Alkylcarbonyl group, C _1-4 -Alkylsulfonyl group, phenylsulfonyl group or phenyl-C _1-3 -Represents an alkylsulfonyl group,
q represents one of the numbers 1, 2 or 3;
r may represent the number 1 or, if q is one of the numbers 2 or 3, it may also represent the number 0; and
R ₁₅ Is an amino group, C _1-4 -Alkylamino group, di- (C _1-4 -Alkyl) -amino, phenylamino, N- (C _1-4 -Alkyl) -phenylamino, benzylamino or N- (C _1-4 -Alkyl) -benzylamino group), or
Formula -N (R ₁₆ ) -SO ₂ -R ₁₇ (VI)
Base of
(Where
R ₁₆ Is a hydrogen atom or C _1-3 -Alkyl group (if necessary, cyano group, trifluoromethyl-carbonylamino group or N- (C _1-3 -Alkyl) -trifluoromethyl-carbonylamino group), and
R ₁₇ Is C _1-3 -Represents an alkyl group),
R ₆ All the single-bonded or condensed phenyl groups contained in the group described in the above are substituted by fluorine atom, chlorine atom or bromine atom, methyl group, trifluoromethyl group, methoxy group, nitro group or cyano group May be), and
R _Five Represents a hydrogen atom,
The hydrogen atom bonded to the nitrogen atom in the above group may be substituted with an acetyl group or a tert.butoxycarbonyl group,
3. Composition according to item 1 or 2, wherein the carboxy group contained in the above group may also be present in the form of a tert. Butoxycarbonyl precursor group. .
(Item 4)
In the indolinone, their tautomers, diastereomers or enantiomers, mixtures thereof or pharmaceutically acceptable salts thereof,
X represents an oxygen atom,
R ₁ And R _Five Each represents a hydrogen atom,
R ₂ Represents a methoxycarbonyl group, an ethoxycarbonyl group or an aminocarbonyl group,
R _Three Represents a phenyl group, and
R _Four Is R ₆ Represents a monosubstituted phenyl group by
R ₆ N-methyl-imidazol-2-yl group,
Unbranched C _1-3 -Alkyl group (this is C at the end _1-4 -Alkylamino group, di- (C _1-4 -Alkyl) -amino group, substituted by piperidino group or 2,6-dimethyl-piperidino group),
Formula -N (R ₁₂ ) -CO- (CH ₂ ) _p -R ₁₃ (IV)
Base of
(Where
R ₁₂ Is C _1-3 -Represents an alkyl group,
p represents one of the numbers 1 or 2, and
R ₁₃ Is di- (C _1-3 -Alkyl) -amino group), or
Formula -N (R ₁₄ )-(CH ₂ ) _q -(CO) _r -R ₁₅ (V)
Base of
(Where
R ₁₄ Is C _1-3 -Alkylcarbonyl group or C _1-3 -Represents an alkylsulfonyl group,
q represents one of the numbers 1, 2 or 3;
r may represent the number 1 or, if q is one of the numbers 2 or 3, r may also represent the number 0; and
R ₁₅ Is di- (C _1-3 Represents an -alkyl) -amino group)
The composition according to any one of items 1 to 3, which represents
(Item 5)
Said indolinone, their tautomers, diastereomers or enantiomers, mixtures thereof or pharmaceutically acceptable salts thereof are
(a) 3-Z- [1- (4- (piperidin-1-yl-methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone,
(b) 3-Z-[(1- (4- (piperidin-1-yl-methyl) -anilino) -1-phenyl-methylene] -6-carbamoyl-2-indolinone,
(c) 3-Z- [1- (4- (piperidin-1-yl-methyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone,
(d) 3-Z- [1- (4- (dimethylaminomethyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone,
(e) 3-Z- [1- (4-((2,6-dimethyl-piperidin-1-yl) -methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone,
(f) 3-Z- [1- (4- (N- (2-dimethylamino-ethyl) -N-acetyl-amino) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone ,
(g) 3-Z- [1- (4- (N- (3-Dimethylamino-propyl) -N-acetyl-amino) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone ,
(h) 3-Z- [1- (4- (N- (2-dimethylamino-ethyl) -N-methylsulfonylamino) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone ,
(i) 3-Z- [1- (4- (dimethylaminomethyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone,
(j) 3-Z- [1- (4- (N-acetyl-N-dimethylaminocarbonylmethyl-amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone,
(k) 3-Z- [1- (4-ethylaminomethyl-anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone,
(l) 3-Z- [1- (4- (1-Methyl-imidazol-2-yl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone,
(m) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl-N-methyl-amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone,
(n) 3-Z- [1- (4- (N- (2-dimethylamino-ethyl) -N-methylsulfonylamino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone ,
(o) 3-Z- [1- (4- (N- (3-Dimethylamino-propyl) -N-methylsulfonylamino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone ,
(p) 3-Z- [1- (4- (N-dimethylaminocarbonylmethyl-N-methylsulfonyl-amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone,
(q) 3-Z- [1- (4- (N-((2-dimethylamino-ethyl) -carbonyl) -N-methylamino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl- 2-indolinone,
(r) 3-Z- [1- (4- (N- (2-dimethylamino-ethyl) -N-acetyl-amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone as well as
(s) 3-Z- [1- (4-methylaminomethyl-anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone,
5. Composition according to any one of items 1 to 4, comprising these tautomers, diastereomers or enantiomers, mixtures thereof or pharmaceutically acceptable salts thereof.
(Item 6)
3-Z- [1- (4- (N-((4-Methyl-piperazin-1-yl) -methylcarbonyl) -N-methylamino) -anilino) -1-phenylmethylene] -6-methoxycarbonyl- A composition for preventing, ameliorating or treating chronic fatty liver disease, comprising 2-indolinone, a tautomer thereof or a pharmaceutically acceptable salt.
(Item 7)
The composition according to any one of items 1 to 6, further comprising one or more inert carriers and / or diluents as necessary.
(Item 8)
The composition according to any one of Items 1 to 7, wherein the chronic fatty liver disease is an inflammatory disease.
(Item 9)
The composition according to any one of Items 1 to 8, wherein the chronic fatty liver disease is a symptomatic disease related to lifestyle habits.
(Item 10)
10. The composition according to any one of items 1 to 9, wherein the chronic fatty disease is non-viral.
(Item 11)
The composition according to any one of Items 1 to 10, wherein the chronic fatty liver disease is a non-alcoholic disease.
(Item 12)
The composition according to any one of Items 1 to 11, wherein the chronic fatty liver disease comprises non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH).
(Item 13)
13. The composition according to any one of items 1 to 12, wherein the chronic fatty liver disease comprises nonalcoholic steatohepatitis (NASH).
(Item 14)
14. The composition according to any one of items 1 to 13, wherein the chronic fatty liver disease comprises Matteoni classification Type 4 of non-alcoholic steatohepatitis (NASH).
(Item 15)
15. The composition according to any one of items 1 to 14, wherein the prevention, amelioration or treatment includes prevention, amelioration or treatment of liver fibrosis.
(Item 16)
The composition according to any one of items 1 to 15, wherein the prevention, amelioration or treatment is prevention or improvement or treatment at an early stage of the chronic fatty liver disease.
(Item 17)
17. The composition according to any one of items 1 to 16, wherein the composition is administered orally.
(Item 18)
General formula substituted at position 6 for preventing, ameliorating or treating chronic fatty liver disease

Indolinone, their tautomers, diastereomers or enantiomers, mixtures thereof or pharmaceutically acceptable salts thereof
[Where,
X represents an oxygen atom or a sulfur atom,
R ₁ Represents a hydrogen atom or a group used for prodrug formation,
R ₂ Is a carboxy group, linear or branched C _1-6 -Alkoxycarbonyl group, C _4-7 -Cycloalkoxycarbonyl group or aryloxycarbonyl group,
Linear or branched C _1-6 -Alkoxycarbonyl groups (which are phenyl, heteroaryl, carboxy, C _1-3 -Alkoxycarbonyl group, aminocarbonyl group, C _1-3 -Alkylamino-carbonyl group or di- (C _1-3 -Alkyl) -aminocarbonyl group substituted at the end),
Linear or branched C _2-6 -Alkoxycarbonyl groups (which are chlorine or hydroxy groups, C _1-3 -Alkoxy group, amino group, C _1-3 -Alkylamino or di- (C _1-3 -Alkyl) -amino groups are substituted at the end)
Aminocarbonyl group or methylaminocarbonyl group, if necessary, hydroxy group or C at the 2-position of ethyl group _1-3 Represents an ethylaminocarbonyl group optionally substituted by an alkoxy group, or
R _Four Is an aminosulfonyl-phenyl group or N- (C _1-5 -Alkyl) -C _1-3 If it does not represent an -alkylaminocarbonyl-phenyl group, it is also di- (C _1-2 -Alkyl) -aminocarbonyl group may be represented,
R _Three Is a hydrogen atom, C _1-6 -Alkyl group, C _3-7 -Cycloalkyl group, trifluoromethyl group or heteroaryl group,
Phenyl group or naphthyl group; fluorine atom, chlorine atom, bromine atom or iodine atom, trifluoromethyl group, C _1-3 -Alkyl group or C _1-3 A phenyl group or naphthyl group mono- or di-substituted by an alkoxy group (in the case of di-substitution, the substituents may be the same or different, and the above-mentioned unsubstituted phenyl group, naphthyl group and one Substituted and disubstituted phenyl and naphthyl groups are further
Hydroxy group, hydroxy-C _1-3 -Alkyl group or C _1-3 -Alkoxy-C _1-3 -Alkyl groups,
Cyano group, carboxy group, carboxy-C _1-3 -Alkyl group, C _1-3 -Alkoxycarbonyl group, aminocarbonyl group, C _1-3 -Alkylamino-carbonyl group or di- (C _1-3 -Alkyl) -aminocarbonyl group,
Nitro group,
Amino group, C _1-3 -Alkylamino group, di- (C _1-3 -Alkyl) -amino or amino-C _1-3 -Alkyl groups,
C _1-3 -Alkylcarbonylamino group, N- (C _1-3 -Alkyl) -C _1-3 -Alkylcarbonylamino group, C _1-3 -Alkylcarbonylamino-C _1-3 -Alkyl group, N- (C _1-3 -Alkyl) -C _1-3 -Alkylcarbonylamino-C _1-3 -Alkyl group, C _1-3 -Alkylsulfonylamino group, C _1-3 -Alkylsulfonylamino-C _1-3 -Alkyl group, N- (C _1-3 -Alkyl) -C _1-3 -Alkylsulfonylamino-C _1-3 -Alkyl or aryl-C _1-3 -Alkylsulfonylamino group,
Cycloalkylamino group, cycloalkyleneimino group, cycloalkyleneiminocarbonyl group, cycloalkyleneimino-C _1-3 -Alkyl group, cycloalkyleneiminocarbonyl-C _1-3 -Alkyl group or cycloalkyleneiminosulfonyl-C _1-3 -Alkyl group (having 4 to 7 ring members in each case) (in each case, the methylene group at the 4-position of the 6-membered or 7-membered cycloalkyleneimino group is an oxygen atom or a sulfur atom, a sulfinyl group, a sulfonyl group,- NH group or -N (C _1-3 -Optionally substituted with an -alkyl) group), or
Heteroaryl group or heteroaryl-C _1-3 -May be substituted by an alkyl group)
Represents
R _Four Is C _3-7 -Cycloalkyl group (methylene group at 4-position of 6-membered or 7-membered cycloalkyl group is an amino group, C _1-3 -Alkylamino or di- (C _1-3 -Alkyl) -amino group may be substituted, or -NH group or -N (C _1-3 -Optionally substituted with an -alkyl) group), or
R ₆ A phenyl group substituted by [this further comprises a fluorine, chlorine, bromine or iodine atom, C _1-5 -Alkyl group, trifluoromethyl group, hydroxy group, C _1-3 -Alkoxy group, carboxy group, C _1-3 -Alkoxycarbonyl group, amino group, acetylamino group, C _1-3 -Alkyl-sulfonylamino group, aminocarbonyl group, C _1-3 -Alkyl-aminocarbonyl group, di- (C _1-3 -Alkyl) -aminocarbonyl group, aminosulfonyl group, C _1-3 -Alkyl-aminosulfonyl group, di- (C _1-3 -Alkyl) -aminosulfonyl group, nitro group or cyano group may be mono- or di-substituted, and these substituents may be the same or different, and
R ₆ Is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom,
Cyano group, nitro group, amino group, C _1-5 -Alkyl group, C _3-7 -Cycloalkyl group, trifluoromethyl group, phenyl group, tetrazolyl group or heteroaryl group,
formula

(Wherein the hydrogen atoms bonded to the nitrogen atom are each independently C _1-3 -May be substituted by an alkyl group)
Base of
C _1-3 -Alkoxy group, C _1-3 -Alkoxy-C _1-3 -Alkoxy group, phenyl-C _1-3 -Alkoxy group, amino-C _2-3 -Alkoxy group, C _1-3 -Alkylamino-C _2-3 -Alkoxy group, di- (C _1-3 -Alkyl) -amino-C _2-3 -Alkoxy group, phenyl-C _1-3 -Alkylamino-C _2-3 -Alkoxy group, N- (C _1-3 -Alkyl) -phenyl-C _1-3 -Alkylamino-C _2-3 -Alkoxy group, C _5-7 -Cycloalkylenimino-C _2-3 -Alkoxy group or C _1-3 -Alkyl mercapto groups,
Carboxy group, C _1-4 -Alkoxycarbonyl group, aminocarbonyl group, C _1-3 -Alkylamino-carbonyl group, N- (C _1-5 -Alkyl) -C _1-3 -Alkylaminocarbonyl group, phenyl-C _1-3 -Alkylamino-carbonyl group, N- (C _1-3 -Alkyl) -phenyl-C _1-3 -Alkylamino-carbonyl group, piperazinocarbonyl group or N- (C _1-3 -Alkyl) -piperazinocarbonyl group,
C _1-3 -Alkylaminocarbonyl group or N- (C _1-5 -Alkyl) -C _1-3 -Alkylaminocarbonyl group (the alkyl moiety is a carboxy group or C _1-3 Substituted by alkoxycarbonyl groups or di- (C at the 2 or 3 position thereof _1-3 -Alkyl) -amino group, piperazino group, N- (C _1-3 -Alkyl) -piperazino group or 4-7 membered cycloalkyleneimino group)
C _3-7 -Cycloalkylcarbonyl group (methylene group at 4-position of 6-membered or 7-membered cycloalkyl moiety is amino group, C _1-3 -Alkylamino or di- (C _1-3 -Alkyl) -amino group may be substituted, or -NH group or -N (C _1-3 -Optionally substituted with an -alkyl) group),
4- to 7-membered cycloalkyleneimino group (the methylene group bonded to the imino group may be substituted with a carbonyl group or a sulfonyl group, or
The cycloalkylene moiety may be fused to a phenyl ring, or
1 or 2 hydrogen atoms are each C _1-3 Optionally substituted by an alkyl group and / or
In each case, the 4-position methylene group of the 6-membered or 7-membered cycloalkyleneimino group is a carboxy group, C _1-3 -Alkoxycarbonyl group, aminocarbonyl group, C _1-3 -Alkylaminocarbonyl group, di- (C _1-3 -Alkyl) -aminocarbonyl group, phenyl-C _1-3 -Alkylamino group or N- (C _1-3 -Alkyl) -phenyl-C _1-3 May be substituted by an -alkylamino group, or
Oxygen or sulfur atom, sulfinyl group, sulfonyl group, -NH group, -N (C _1-3 -Alkyl) group, -N (phenyl) group, -N (C _1-3 -Alkylcarbonyl) group or -N (benzoyl) group).
R ₇ C replaced by _1-4 -Alkyl group (R ₇ Is C _3-7 -Cycloalkyl group (methylene group at 4-position of 6-membered or 7-membered cycloalkyl group is an amino group, C _1-3 -Alkylamino or di- (C _1-3 -Alkyl) -amino group may be substituted, or -NH group or -N (C _1-3 -Alkyl) group may be substituted, or
In a 5- to 7-membered cycloalkyl group,-(CH ₂ ) ₂ The group may be substituted by a -CO-NH group and-(CH ₂ ) _Three The group may be substituted by a —NH—CO—NH group or a —CO—NH—CO group, or — (CH ₂ ) _Four The group may be substituted by a -NH-CO-NH-CO group, in which case the hydrogen atom bonded to the nitrogen atom is C _1-3 -May be substituted by an alkyl group),
An aryl group or heteroaryl group,
Hydroxy group or C _1-3 -Alkoxy groups,
Amino group, C _1-7 -Alkylamino group, di- (C _1-7 -Alkyl) -amino group, phenylamino group, N-phenyl-C _1-3 -Alkyl-amino group, phenyl-C _1-3 -Alkyl-amino group, N- (C _1-3 -Alkyl) -phenyl-C _1-3 -Alkylamino or di- (phenyl-C _1-3 -Alkyl) -amino group,
ω-hydroxy-C _2-3 -Alkyl-amino group, N- (C _1-3 -Alkyl) -ω-hydroxy-C _2-3 -Alkyl-amino group, di- (ω-hydroxy-C _2-3 -Alkyl) -amino group, di- (ω- (C _1-3 -Alkoxy) -C _2-3 -Alkyl) -amino group or N- (dioxolan-2-yl) -C _1-3 -Alkyl-amino groups,
C _1-3 -Alkylcarbonylamino-C _2-3 -Alkyl-amino or C _1-3 -Alkylcarbonylamino-C _2-3 -Alkyl-N- (C _1-3 -Alkyl) -amino group,
C _1-3 -Alkylsulfonylamino group, N- (C _1-3 -Alkyl) -C _1-3 -Alkyl-sulfonylamino group, C _1-3 -Alkylsulfonylamino-C _2-3 -Alkyl-amino or C _1-3 -Alkylsulfonylamino-C _2-3 -Alkyl-N- (C _1-3 -Alkyl) -amino group,
Hydroxycarbonyl C _1-3 -Alkylamino group or N- (C _1-3 -Alkyl) -hydroxycarbonyl C _1-3 -Alkyl-amino groups,
Guanidino group (one or two hydrogen atoms are each C _1-3 -May be substituted by an alkyl group),
Formula -N (R ₈ ) -CO- (CH ₂ ) _n -R ₉ (II)
Base of
(Where
R ₈ Is a hydrogen atom or C _1-3 -Represents an alkyl group,
n represents one of the numbers 0, 1, 2, or 3, and
R ₉ Is an amino group, C _1-4 -Alkylamino group, di- (C _1-4 -Alkyl) -amino, phenylamino, N- (C _1-4 -Alkyl) -phenylamino, benzylamino, N- (C _1-4 -Alkyl) -benzylamino or C _1-4 -Alkoxy group, 4- to 7-membered cycloalkyleneimino group (in each case, the methylene group at the 4-position of the 6-membered or 7-membered cycloalkyleneimino group is an oxygen atom or sulfur atom, sulfinyl group, sulfonyl group, -NH group,- N (C _1-3 -Alkyl) group, -N (phenyl) group, -N (C _1-3 -Alkylcarbonyl) group or -N (benzoyl) group), or when n represents one of the numbers 1, 2 or 3, it may also represent a hydrogen atom) ,
Formula -N (R _Ten )-(CH ₂ ) _m -(CO) _o -R ₁₁ (III)
Base of
(Where
R _Ten Is a hydrogen atom, C _1-3 -Alkyl group, C _1-3 -Alkylcarbonyl group, arylcarbonyl group, phenyl-C _1-3 -Alkylcarbonyl group, C _1-3 -Alkylsulfonyl group, arylsulfonyl group or phenyl-C _1-3 -Represents an alkylsulfonyl group,
m represents one of the numbers 1, 2, 3 or 4;
o may represent the number 1 or, if m represents one of the numbers 2, 3 or 4, o may also represent the number 0; and
R ₁₁ Is an amino group, C _1-4 -Alkylamino group, di- (C _1-4 -Alkyl) -amino, phenylamino, N- (C _1-4 -Alkyl) -phenylamino, benzylamino, N- (C _1-4 -Alkyl) -benzylamino group, C _1-4 -Alkoxy group or C _1-3 -Alkoxy-C _1-3 -Alkoxy group, di- (C _1-4 -Alkyl) -amino-C _1-3 -Alkylamino group (C at the 1 position if necessary) _1-3 -May be substituted by an alkyl group) or a 4-7 membered cycloalkyleneimino group (the cycloalkylene moiety may be fused to a phenyl ring, or in each case a 6 or 7 membered cycloalkyleneimino) The 4-position methylene group is an oxygen atom or sulfur atom, sulfinyl group, sulfonyl group, -NH group, -N (C _1-3 -Alkyl) group, -N (phenyl) group, -N (C _1-3 -Alkylcarbonyl) group or -N (benzoyl) group may be substituted))
C _4-7 -Cycloalkylamino group, C _4-7 -Cycloalkyl-C _1-3 -Alkylamino group or C _4-7 -Cycloalkenylamino group (the 1-position of the ring is not contained in the double bond, and each of the above groups is further substituted at the amino nitrogen atom position by C _5-7 -Cycloalkyl group, C _2-4 -Alkenyl group or C _1-4 -May be substituted by an alkyl group),
4- to 7-membered cycloalkyleneimino group (the cycloalkylene moiety is a phenyl group or an oxazolo group, an imidazolo group, a thiazolo group, a pyridino group, a pyrazino group or a pyrimidino group (optionally a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, a nitro group) Group, C _1-3 -Alkyl group, C _1-3 -Optionally substituted with an alkoxy group or an amino group) and / or
1 or 2 hydrogen atoms are each C _1-3 -Alkyl group, C _5-7 Optionally substituted by a cycloalkyl group or a phenyl group and / or
The 5-position methylene group of the 5-membered cycloalkyleneimino group is a hydroxy group, hydroxy-C _1-3 -Alkyl group, C _1-3 -Alkoxy group or C _1-3 -Alkoxy-C _1-3 -May be substituted by an alkyl group,
A 6-membered or 7-membered cycloalkyleneimino group in each case the 3- or 4-position methylene group is a hydroxy group, hydroxy-C _1-3 -Alkyl group, C _1-3 -Alkoxy group, C _1-3 -Alkoxy-C _1-3 -Alkyl group, carboxy group, C _1-4 -Alkoxycarbonyl group, aminocarbonyl group, C _1-3 -Alkylaminocarbonyl group, di- (C _1-3 -Alkyl) -aminocarbonyl group, phenyl-C _1-3 -Alkylamino group or N- (C _1-3 -Alkyl) -phenyl-C _1-3 Optionally substituted by an -alkyl-amino group, or
Oxygen or sulfur atom, sulfinyl group, sulfonyl group, -NH group, -N (C _1-3 -Alkyl-) group, -N (phenyl) group, -N (phenyl-C _1-3 -Alkyl-) group, -N (C _1-3 -Alkylcarbonyl) group, -N (C _1-4 -Hydroxycarbonyl) group, -N (C _1-4 -Alkoxycarbonyl) group, -N (benzoyl-) group or -N (phenyl-C _1-3 -Alkylcarbonyl) group may be substituted,
The methylene group bonded to the imino nitrogen atom of the cycloalkyleneimino group may be substituted with a carbonyl group or a sulfonyl group, or a cycloalkyleneimino condensed with a 5- to 7-membered monocyclic cycloalkyleneimino group or phenyl group In the group, two methylene groups bonded to the imino nitrogen atom may each be substituted by a carbonyl group)
Represents), or
R ₆ Is C _1-4 -Alkyl group (this is a carboxy group, C _1-3 -Alkoxycarbonyl group, aminocarbonyl group, C _1-3 -Alkylaminocarbonyl group or di- (C _1-3 -Alkyl) -aminocarbonyl groups or 4-7 membered cycloalkyleneiminocarbonyl groups)
N- (C _1-3 -Alkyl) -C _2-4 -Acylamino group (which is a carboxy group or C _1-3 Further substituted by an alkoxycarbonyl group),
Formula -N (R ₁₂ ) -CO- (CH ₂ ) _p -R ₁₃ (IV)
Base of
(Where
R ₁₂ Is a hydrogen atom, C _1-6 -Alkyl group or C _3-7 -Cycloalkyl group or C _1-3 -Alkyl group (phenyl, heteroaryl, trifluoromethyl, hydroxy, C _1-3 -Alkoxy group, aminocarbonyl group, C _1-4 -Alkylamino-carbonyl group, di- (C _1-4 -Alkyl) -amino-carbonyl group, C _1-3 -Alkylcarbonyl group, C _1-3 -Alkyl-sulfonylamino group, N- (C _1-3 -Alkyl) -C _1-3 -Alkyl-sulfonylamino group, C _1-3 -Alkyl-aminosulfonyl group or di- (C _1-3 -Alkyl) -aminosulfonyl group) and
p represents one of the numbers 0, 1, 2 or 3, and
R ₁₃ Is the above group R ₇ Or, when p represents one of the numbers 1, 2 or 3, it may also represent a hydrogen atom)
Formula -N (R ₁₄ )-(CH ₂ ) _q -(CO) _r -R ₁₅ (V)
Base of
(Where
R ₁₄ Is a hydrogen atom, C _1-4 -Alkyl group, C _1-3 -Alkylcarbonyl group, arylcarbonyl group, phenyl-C _1-3 -Alkylcarbonyl group, heteroarylcarbonyl group, heteroaryl-C _1-3 -Alkylcarbonyl group, C _1-4 -Alkylsulfonyl group, arylsulfonyl group, phenyl-C _1-3 -Alkylsulfonyl group, heteroarylsulfonyl group or heteroaryl-C _1-3 Represents an -alkyl-sulfonyl group,
q represents one of the numbers 1, 2, 3 or 4;
r may represent the number 1 or, if q is one of the numbers 2, 3 or 4, it may also represent the number 0;
R ₁₅ Is the above group R ₇ Mean)
Formula -N (R ₁₆ ) -SO ₂ -R ₁₇ (VI)
Base of
(Where
R ₁₆ Is a hydrogen atom or C _1-4 -Alkyl group (if necessary, cyano group, trifluoromethyl-carbonylamino group or N- (C _1-3 -Alkyl) -trifluoromethyl-carbonylamino group), and
R ₁₇ Is C _1-3 -Represents an alkyl group),
Di- (C _1-3 -Alkyl) -amino-C _1-3 -Alkylcarbonyl group or di- (C _1-3 -Alkyl) -amino-C _1-3 -Alkyl-sulfonyl and di- (C _1-3 -Alkyl) -aminocarbonyl-C _1-3 An amino group substituted by an alkyl group, or
N- (C _1-3 -Alkyl) -C _1-5 -Alkylsulfonylamino group or N- (C _1-3 -Alkyl) -phenylsulfonylamino group (the alkyl part is further substituted by a cyano group or a carboxy group)
Represents
R ₆ All the single-bonded or condensed phenyl groups contained in the group described in the above are fluorine atom, chlorine atom, bromine atom or iodine atom, C _1-5 -Alkyl group, trifluoromethyl group, hydroxy group, C _1-3 -Alkoxy group, carboxy group, C _1-3 -Alkoxycarbonyl group, aminocarbonyl group, C _1-4 -Alkylamino-carbonyl group, di- (C _1-4 -Alkyl) -amino-carbonyl group, aminosulfonyl group, C _1-3 -Alkyl-aminosulfonyl group, di- (C _1-3 -Alkyl) -aminosulfonyl group, C _1-3 -Alkyl-sulfonylamino, mono- or di-substituted by nitro or cyano groups, these substituents may be the same or different, or two of the phenyl groups The adjacent hydrogen atom may be substituted by a methylenedioxy group), and
R _Five Is a hydrogen atom or C _1-3 -Represents an alkyl group,
The aryl group is optionally a fluorine atom, chlorine atom, bromine atom or iodine atom, cyano group, trifluoromethyl group, nitro group, carboxy group, aminocarbonyl group, C _1-3 -Alkyl group or C _1-3 -Means a phenyl group or a naphthyl group which may be mono- or di-substituted by an alkoxy group,
The heteroaryl group is optionally C in the carbon skeleton. _1-3 Means a monocyclic 5- or 6-membered heteroaryl group optionally substituted by an alkyl group,
The 6-membered heteroaryl group contains 1, 2 or 3 nitrogen atoms, and
The 5-membered heteroaryl group is optionally C _1-3 -Alkyl group or phenyl-C _1-3 An imino group optionally substituted by an alkyl group, an oxygen atom or a sulfur atom or
C if necessary _1-3 -Alkyl group or phenyl-C _1-3 An imino group optionally substituted by an alkyl group, or an oxygen or sulfur atom and further a nitrogen atom or
C if necessary _1-3 -Alkyl group or phenyl-C _1-3 An imino group optionally substituted by an alkyl group and two nitrogen atoms,
In addition, the phenyl ring may be fused to the monocyclic heterocyclic group through two adjacent carbon atoms, and the bond may be linked through a nitrogen atom or through a carbon atom in the heterocyclic moiety or a fused phenyl ring. Happens through
Some or all of the hydrogen atoms in the alkyl moieties contained in the above alkyl and alkoxy groups or in the previously defined groups of formula I may be substituted with fluorine atoms, and
The hydrogen atom of the carboxy group present or the hydrogen atom bonded to the nitrogen atom may each be substituted by a group that can be cleaved in vivo].
(Item 19)
Item 18. The indolinone, item tautomer, diastereomer or enantiomer, mixture thereof, or a pharmaceutically acceptable salt thereof according to item 18, further comprising the feature according to any one or more of items 2-17. Possible salt.
(Item 20)
General formula substituted at the 6-position

Indolinone, their tautomers, diastereomers or enantiomers, mixtures thereof or pharmaceutically acceptable salts thereof
[Where,
X represents an oxygen atom or a sulfur atom,
R ₁ Represents a hydrogen atom or a group used for prodrug formation,
R ₂ Is a carboxy group, linear or branched C _1-6 -Alkoxycarbonyl group, C _4-7 -Cycloalkoxycarbonyl group or aryloxycarbonyl group,
Linear or branched C _1-6 -Alkoxycarbonyl groups (which are phenyl, heteroaryl, carboxy, C _1-3 -Alkoxycarbonyl group, aminocarbonyl group, C _1-3 -Alkylamino-carbonyl group or di- (C _1-3 -Alkyl) -aminocarbonyl group substituted at the end),
Linear or branched C _2-6 -Alkoxycarbonyl groups (which are chlorine or hydroxy groups, C _1-3 -Alkoxy group, amino group, C _1-3 -Alkylamino or di- (C _1-3 -Alkyl) -amino groups are substituted at the end)
Aminocarbonyl group or methylaminocarbonyl group, if necessary, hydroxy group or C at the 2-position of ethyl group _1-3 Represents an ethylaminocarbonyl group optionally substituted by an alkoxy group, or
R _Four Is an aminosulfonyl-phenyl group or N- (C _1-5 -Alkyl) -C _1-3 If it does not represent an -alkylaminocarbonyl-phenyl group, it is also di- (C _1-2 -Alkyl) -aminocarbonyl group may be represented,
R _Three Is a hydrogen atom, C _1-6 -Alkyl group, C _3-7 -Cycloalkyl group, trifluoromethyl group or heteroaryl group,
Phenyl group or naphthyl group; fluorine atom, chlorine atom, bromine atom or iodine atom, trifluoromethyl group, C _1-3 -Alkyl group or C _1-3 A phenyl group or naphthyl group mono- or di-substituted by an alkoxy group (in the case of di-substitution, the substituents may be the same or different, and the above-mentioned unsubstituted phenyl group, naphthyl group and one Substituted and disubstituted phenyl and naphthyl groups are further
Hydroxy group, hydroxy-C _1-3 -Alkyl group or C _1-3 -Alkoxy-C _1-3 -Alkyl groups,
Cyano group, carboxy group, carboxy-C _1-3 -Alkyl group, C _1-3 -Alkoxycarbonyl group, aminocarbonyl group, C _1-3 -Alkylamino-carbonyl group or di- (C _1-3 -Alkyl) -aminocarbonyl group,
Nitro group,
Amino group, C _1-3 -Alkylamino group, di- (C _1-3 -Alkyl) -amino or amino-C _1-3 -Alkyl groups,
C _1-3 -Alkylcarbonylamino group, N- (C _1-3 -Alkyl) -C _1-3 -Alkylcarbonylamino group, C _1-3 -Alkylcarbonylamino-C _1-3 -Alkyl group, N- (C _1-3 -Alkyl) -C _1-3 -Alkylcarbonylamino-C _1-3 -Alkyl group, C _1-3 -Alkylsulfonylamino group, C _1-3 -Alkylsulfonylamino-C _1-3 -Alkyl group, N- (C _1-3 -Alkyl) -C _1-3 -Alkylsulfonylamino-C _1-3 -Alkyl or aryl-C _1-3 -Alkylsulfonylamino group,
Cycloalkylamino group, cycloalkyleneimino group, cycloalkyleneiminocarbonyl group, cycloalkyleneimino-C _1-3 -Alkyl group, cycloalkyleneiminocarbonyl-C _1-3 -Alkyl group or cycloalkyleneiminosulfonyl-C _1-3 -Alkyl group (having 4 to 7 ring members in each case) (in each case, the methylene group at the 4-position of the 6-membered or 7-membered cycloalkyleneimino group is an oxygen atom or a sulfur atom, a sulfinyl group, a sulfonyl group,- NH group or -N (C _1-3 -Optionally substituted with an -alkyl) group), or
Heteroaryl group or heteroaryl-C _1-3 -May be substituted by an alkyl group)
Represents
R _Four Is C _3-7 -Cycloalkyl group (methylene group at 4-position of 6-membered or 7-membered cycloalkyl group is an amino group, C _1-3 -Alkylamino or di- (C _1-3 -Alkyl) -amino group may be substituted, or -NH group or -N (C _1-3 -Optionally substituted with an -alkyl) group), or
R ₆ A phenyl group substituted by [this further comprises a fluorine, chlorine, bromine or iodine atom, C _1-5 -Alkyl group, trifluoromethyl group, hydroxy group, C _1-3 -Alkoxy group, carboxy group, C _1-3 -Alkoxycarbonyl group, amino group, acetylamino group, C _1-3 -Alkyl-sulfonylamino group, aminocarbonyl group, C _1-3 -Alkyl-aminocarbonyl group, di- (C _1-3 -Alkyl) -aminocarbonyl group, aminosulfonyl group, C _1-3 -Alkyl-aminosulfonyl group, di- (C _1-3 -Alkyl) -aminosulfonyl group, nitro group or cyano group may be mono- or di-substituted, and these substituents may be the same or different, and
R ₆ Is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom,
Cyano group, nitro group, amino group, C _1-5 -Alkyl group, C _3-7 -Cycloalkyl group, trifluoromethyl group, phenyl group, tetrazolyl group or heteroaryl group,
formula

(Wherein the hydrogen atoms bonded to the nitrogen atom are each independently C _1-3 -May be substituted by an alkyl group)
Base of
C _1-3 -Alkoxy group, C _1-3 -Alkoxy-C _1-3 -Alkoxy group, phenyl-C _1-3 -Alkoxy group, amino-C _2-3 -Alkoxy group, C _1-3 -Alkylamino-C _2-3 -Alkoxy group, di- (C _1-3 -Alkyl) -amino-C _2-3 -Alkoxy group, phenyl-C _1-3 -Alkylamino-C _2-3 -Alkoxy group, N- (C _1-3 -Alkyl) -phenyl-C _1-3 -Alkylamino-C _2-3 -Alkoxy group, C _5-7 -Cycloalkylenimino-C _2-3 -Alkoxy group or C _1-3 -Alkyl mercapto groups,
Carboxy group, C _1-4 -Alkoxycarbonyl group, aminocarbonyl group, C _1-3 -Alkylamino-carbonyl group, N- (C _1-5 -Alkyl) -C _1-3 -Alkylaminocarbonyl group, phenyl-C _1-3 -Alkylamino-carbonyl group, N- (C _1-3 -Alkyl) -phenyl-C _1-3 -Alkylamino-carbonyl group, piperazinocarbonyl group or N- (C _1-3 -Alkyl) -piperazinocarbonyl group,
C _1-3 -Alkylaminocarbonyl group or N- (C _1-5 -Alkyl) -C _1-3 -Alkylaminocarbonyl group (the alkyl moiety is a carboxy group or C _1-3 Substituted by alkoxycarbonyl groups or di- (C at the 2 or 3 position thereof _1-3 -Alkyl) -amino group, piperazino group, N- (C _1-3 -Alkyl) -piperazino group or 4-7 membered cycloalkyleneimino group)
C _3-7 -Cycloalkylcarbonyl group (methylene group at 4-position of 6-membered or 7-membered cycloalkyl moiety is amino group, C _1-3 -Alkylamino or di- (C _1-3 -Alkyl) -amino group may be substituted, or -NH group or -N (C _1-3 -Optionally substituted with an -alkyl) group),
4- to 7-membered cycloalkyleneimino group (the methylene group bonded to the imino group may be substituted with a carbonyl group or a sulfonyl group, or
The cycloalkylene moiety may be fused to a phenyl ring, or
1 or 2 hydrogen atoms are each C _1-3 Optionally substituted by an alkyl group and / or
In each case, the 4-position methylene group of the 6-membered or 7-membered cycloalkyleneimino group is a carboxy group, C _1-3 -Alkoxycarbonyl group, aminocarbonyl group, C _1-3 -Alkylaminocarbonyl group, di- (C _1-3 -Alkyl) -aminocarbonyl group, phenyl-C _1-3 -Alkylamino group or N- (C _1-3 -Alkyl) -phenyl-C _1-3 May be substituted by an -alkylamino group, or
Oxygen or sulfur atom, sulfinyl group, sulfonyl group, -NH group, -N (C _1-3 -Alkyl) group, -N (phenyl) group, -N (C _1-3 -Alkylcarbonyl) group or -N (benzoyl) group).
R ₇ C replaced by _1-4 -Alkyl group (R ₇ Is C _3-7 -Cycloalkyl group (methylene group at 4-position of 6-membered or 7-membered cycloalkyl group is an amino group, C _1-3 -Alkylamino or di- (C _1-3 -Alkyl) -amino group may be substituted, or -NH group or -N (C _1-3 -Alkyl) group may be substituted, or
In a 5- to 7-membered cycloalkyl group,-(CH ₂ ) ₂ The group may be substituted by a -CO-NH group and-(CH ₂ ) _Three The group may be substituted by a —NH—CO—NH group or a —CO—NH—CO group, or — (CH ₂ ) _Four The group may be substituted by a -NH-CO-NH-CO group, in which case the hydrogen atom bonded to the nitrogen atom is C _1-3 -May be substituted by an alkyl group),
An aryl group or heteroaryl group,
Hydroxy group or C _1-3 -Alkoxy groups,
Amino group, C _1-7 -Alkylamino group, di- (C _1-7 -Alkyl) -amino group, phenylamino group, N-phenyl-C _1-3 -Alkyl-amino group, phenyl-C _1-3 -Alkyl-amino group, N- (C _1-3 -Alkyl) -phenyl-C _1-3 -Alkylamino or di- (phenyl-C _1-3 -Alkyl) -amino group,
ω-hydroxy-C _2-3 -Alkyl-amino group, N- (C _1-3 -Alkyl) -ω-hydroxy-C _2-3 -Alkyl-amino group, di- (ω-hydroxy-C _2-3 -Alkyl) -amino group, di- (ω- (C _1-3 -Alkoxy) -C _2-3 -Alkyl) -amino group or N- (dioxolan-2-yl) -C _1-3 -Alkyl-amino groups,
C _1-3 -Alkylcarbonylamino-C _2-3 -Alkyl-amino or C _1-3 -Alkylcarbonylamino-C _2-3 -Alkyl-N- (C _1-3 -Alkyl) -amino group,
C _1-3 -Alkylsulfonylamino group, N- (C _1-3 -Alkyl) -C _1-3 -Alkyl-sulfonylamino group, C _1-3 -Alkylsulfonylamino-C _2-3 -Alkyl-amino or C _1-3 -Alkylsulfonylamino-C _2-3 -Alkyl-N- (C _1-3 -Alkyl) -amino group,
Hydroxycarbonyl C _1-3 -Alkylamino group or N- (C _1-3 -Alkyl) -hydroxycarbonyl C _1-3 -Alkyl-amino groups,
Guanidino group (one or two hydrogen atoms are each C _1-3 -May be substituted by an alkyl group),
Formula -N (R ₈ ) -CO- (CH ₂ ) _n -R ₉ (II)
Base of
(Where
R ₈ Is a hydrogen atom or C _1-3 -Represents an alkyl group,
n represents one of the numbers 0, 1, 2, or 3, and
R ₉ Is an amino group, C _1-4 -Alkylamino group, di- (C _1-4 -Alkyl) -amino, phenylamino, N- (C _1-4 -Alkyl) -phenylamino, benzylamino, N- (C _1-4 -Alkyl) -benzylamino or C _1-4 -Alkoxy group, 4- to 7-membered cycloalkyleneimino group (in each case, the methylene group at the 4-position of the 6-membered or 7-membered cycloalkyleneimino group is an oxygen atom or sulfur atom, sulfinyl group, sulfonyl group, -NH group,- N (C _1-3 -Alkyl) group, -N (phenyl) group, -N (C _1-3 -Alkylcarbonyl) group or -N (benzoyl) group), or when n represents one of the numbers 1, 2 or 3, it may also represent a hydrogen atom) ,
Formula -N (R _Ten )-(CH ₂ ) _m -(CO) _o -R ₁₁ (III)
Base of
(Where
R _Ten Is a hydrogen atom, C _1-3 -Alkyl group, C _1-3 -Alkylcarbonyl group, arylcarbonyl group, phenyl-C _1-3 -Alkylcarbonyl group, C _1-3 -Alkylsulfonyl group, arylsulfonyl group or phenyl-C _1-3 -Represents an alkylsulfonyl group,
m represents one of the numbers 1, 2, 3 or 4;
o may represent the number 1 or, if m represents one of the numbers 2, 3 or 4, o may also represent the number 0; and
R ₁₁ Is an amino group, C _1-4 -Alkylamino group, di- (C _1-4 -Alkyl) -amino, phenylamino, N- (C _1-4 -Alkyl) -phenylamino, benzylamino, N- (C _1-4 -Alkyl) -benzylamino group, C _1-4 -Alkoxy group or C _1-3 -Alkoxy-C _1-3 -Alkoxy group, di- (C _1-4 -Alkyl) -amino-C _1-3 -Alkylamino group (C at the 1 position if necessary) _1-3 -May be substituted by an alkyl group) or a 4-7 membered cycloalkyleneimino group (the cycloalkylene moiety may be fused to a phenyl ring, or in each case a 6 or 7 membered cycloalkyleneimino) The 4-position methylene group is an oxygen atom or sulfur atom, sulfinyl group, sulfonyl group, -NH group, -N (C _1-3 -Alkyl) group, -N (phenyl) group, -N (C _1-3 -Alkylcarbonyl) group or -N (benzoyl) group may be substituted))
C _4-7 -Cycloalkylamino group, C _4-7 -Cycloalkyl-C _1-3 -Alkylamino group or C _4-7 -Cycloalkenylamino group (the 1-position of the ring is not contained in the double bond, and each of the above groups is further substituted at the amino nitrogen atom position by C _5-7 -Cycloalkyl group, C _2-4 -Alkenyl group or C _1-4 -May be substituted by an alkyl group),
4- to 7-membered cycloalkyleneimino group (the cycloalkylene moiety is a phenyl group or an oxazolo group, an imidazolo group, a thiazolo group, a pyridino group, a pyrazino group or a pyrimidino group (optionally a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, a nitro group) Group, C _1-3 -Alkyl group, C _1-3 -Optionally substituted with an alkoxy group or an amino group) and / or
1 or 2 hydrogen atoms are each C _1-3 -Alkyl group, C _5-7 Optionally substituted by a cycloalkyl group or a phenyl group and / or
The 5-position methylene group of the 5-membered cycloalkyleneimino group is a hydroxy group, hydroxy-C _1-3 -Alkyl group, C _1-3 -Alkoxy group or C _1-3 -Alkoxy-C _1-3 -May be substituted by an alkyl group,
A 6-membered or 7-membered cycloalkyleneimino group in each case the 3- or 4-position methylene group is a hydroxy group, hydroxy-C _1-3 -Alkyl group, C _1-3 -Alkoxy group, C _1-3 -Alkoxy-C _1-3 -Alkyl group, carboxy group, C _1-4 -Alkoxycarbonyl group, aminocarbonyl group, C _1-3 -Alkylaminocarbonyl group, di- (C _1-3 -Alkyl) -aminocarbonyl group, phenyl-C _1-3 -Alkylamino group or N- (C _1-3 -Alkyl) -phenyl-C _1-3 Optionally substituted by an -alkyl-amino group, or
Oxygen or sulfur atom, sulfinyl group, sulfonyl group, -NH group, -N (C _1-3 -Alkyl-) group, -N (phenyl) group, -N (phenyl-C _1-3 -Alkyl-) group, -N (C _1-3 -Alkylcarbonyl) group, -N (C _1-4 -Hydroxycarbonyl) group, -N (C _1-4 -Alkoxycarbonyl) group, -N (benzoyl-) group or -N (phenyl-C _1-3 -Alkylcarbonyl) group may be substituted,
The methylene group bonded to the imino nitrogen atom of the cycloalkyleneimino group may be substituted with a carbonyl group or a sulfonyl group, or a cycloalkyleneimino condensed with a 5- to 7-membered monocyclic cycloalkyleneimino group or phenyl group In the group, two methylene groups bonded to the imino nitrogen atom may each be substituted by a carbonyl group)
Represents), or
R ₆ Is C _1-4 -Alkyl group (this is a carboxy group, C _1-3 -Alkoxycarbonyl group, aminocarbonyl group, C _1-3 -Alkylaminocarbonyl group or di- (C _1-3 -Alkyl) -aminocarbonyl groups or 4-7 membered cycloalkyleneiminocarbonyl groups)
N- (C _1-3 -Alkyl) -C _2-4 -Acylamino group (which is a carboxy group or C _1-3 Further substituted by an alkoxycarbonyl group),
Formula -N (R ₁₂ ) -CO- (CH ₂ ) _p -R ₁₃ (IV)
Base of
(Where
R ₁₂ Is a hydrogen atom, C _1-6 -Alkyl group or C _3-7 -Cycloalkyl group or C _1-3 -Alkyl group (phenyl, heteroaryl, trifluoromethyl, hydroxy, C _1-3 -Alkoxy group, aminocarbonyl group, C _1-4 -Alkylamino-carbonyl group, di- (C _1-4 -Alkyl) -amino-carbonyl group, C _1-3 -Alkylcarbonyl group, C _1-3 -Alkyl-sulfonylamino group, N- (C _1-3 -Alkyl) -C _1-3 -Alkyl-sulfonylamino group, C _1-3 -Alkyl-aminosulfonyl group or di- (C _1-3 -Alkyl) -aminosulfonyl group) and
p represents one of the numbers 0, 1, 2 or 3, and
R ₁₃ Is the above group R ₇ Or, when p represents one of the numbers 1, 2 or 3, it may also represent a hydrogen atom)
Formula -N (R ₁₄ )-(CH ₂ ) _q -(CO) _r -R ₁₅ (V)
Base of
(Where
R ₁₄ Is a hydrogen atom, C _1-4 -Alkyl group, C _1-3 -Alkylcarbonyl group, arylcarbonyl group, phenyl-C _1-3 -Alkylcarbonyl group, heteroarylcarbonyl group, heteroaryl-C _1-3 -Alkylcarbonyl group, C _1-4 -Alkylsulfonyl group, arylsulfonyl group, phenyl-C _1-3 -Alkylsulfonyl group, heteroarylsulfonyl group or heteroaryl-C _1-3 Represents an -alkyl-sulfonyl group,
q represents one of the numbers 1, 2, 3 or 4;
r may represent the number 1 or, if q is one of the numbers 2, 3 or 4, it may also represent the number 0;
R ₁₅ Is the above group R ₇ Mean)
Formula -N (R ₁₆ ) -SO ₂ -R ₁₇ (VI)
Base of
(Where
R ₁₆ Is a hydrogen atom or C _1-4 -Alkyl group (if necessary, cyano group, trifluoromethyl-carbonylamino group or N- (C _1-3 -Alkyl) -trifluoromethyl-carbonylamino group), and
R ₁₇ Is C _1-3 -Represents an alkyl group),
Di- (C _1-3 -Alkyl) -amino-C _1-3 -Alkylcarbonyl group or di- (C _1-3 -Alkyl) -amino-C _1-3 -Alkyl-sulfonyl and di- (C _1-3 -Alkyl) -aminocarbonyl-C _1-3 An amino group substituted by an alkyl group, or
N- (C _1-3 -Alkyl) -C _1-5 -Alkylsulfonylamino group or N- (C _1-3 -Alkyl) -phenylsulfonylamino group (the alkyl part is further substituted by a cyano group or a carboxy group)
Represents
R ₆ All the single-bonded or condensed phenyl groups contained in the group described in the above are fluorine atom, chlorine atom, bromine atom or iodine atom, C _1-5 -Alkyl group, trifluoromethyl group, hydroxy group, C _1-3 -Alkoxy group, carboxy group, C _1-3 -Alkoxycarbonyl group, aminocarbonyl group, C _1-4 -Alkylamino-carbonyl group, di- (C _1-4 -Alkyl) -amino-carbonyl group, aminosulfonyl group, C _1-3 -Alkyl-aminosulfonyl group, di- (C _1-3 -Alkyl) -aminosulfonyl group, C _1-3 -Alkyl-sulfonylamino, mono- or di-substituted by nitro or cyano groups, these substituents may be the same or different, or two of the phenyl groups The adjacent hydrogen atom may be substituted by a methylenedioxy group), and
R _Five Is a hydrogen atom or C _1-3 -Represents an alkyl group,
The aryl group is optionally a fluorine atom, chlorine atom, bromine atom or iodine atom, cyano group, trifluoromethyl group, nitro group, carboxy group, aminocarbonyl group, C _1-3 -Alkyl group or C _1-3 -Means a phenyl group or a naphthyl group which may be mono- or di-substituted by an alkoxy group,
The heteroaryl group is optionally C in the carbon skeleton. _1-3 Means a monocyclic 5- or 6-membered heteroaryl group optionally substituted by an alkyl group,
The 6-membered heteroaryl group contains 1, 2 or 3 nitrogen atoms, and
The 5-membered heteroaryl group is optionally C _1-3 -Alkyl group or phenyl-C _1-3 An imino group optionally substituted by an alkyl group, an oxygen atom or a sulfur atom or
C if necessary _1-3 -Alkyl group or phenyl-C _1-3 An imino group optionally substituted by an alkyl group, or an oxygen or sulfur atom and further a nitrogen atom or
C if necessary _1-3 -Alkyl group or phenyl-C _1-3 An imino group optionally substituted by an alkyl group and two nitrogen atoms,
In addition, the phenyl ring may be fused to the monocyclic heterocyclic group through two adjacent carbon atoms, and the bond may be linked through a nitrogen atom or through a carbon atom in the heterocyclic moiety or a fused phenyl ring. Happens through
Some or all of the hydrogen atoms in the alkyl moieties contained in the above alkyl and alkoxy groups or in the previously defined groups of formula I may be substituted with fluorine atoms, and
The hydrogen atom of the carboxy group present or the hydrogen atom bonded to the nitrogen atom may each be substituted by a group that can be cleaved in vivo.)
A method for preventing, ameliorating or treating chronic fatty liver disease in a subject, wherein an effective amount of is administered to a subject in need thereof.
(Item 21)
Item 21. The method of item 20, further comprising the feature of any one or more of items 2-17.
(Item 22)
Use of the compound described in item 1 for producing a medicament for preventing, ameliorating or treating chronic fatty liver disease.
(Item 23)
Item 22. The use according to Item 22, further comprising the features according to any one or more of Items 2-17.

  In the present invention, it is intended that the one or more features described above can be provided in further combinations in addition to the specified combinations. Still further embodiments and advantages of the invention will be recognized by those of ordinary skill in the art upon reading and understanding the following detailed description as needed.

  According to the present invention, prevention, amelioration or treatment of chronic fatty liver disease such as NASH is achieved.

FIG. 1 shows that wild-type mice were fed a breeding feed for 6 weeks (control group), CDAHFD was fed for 6 weeks, and B6J NASH mice (NASH group) and CDAHFD were administered for 6 weeks. FIG. 2 shows micrographs of liver tissue sections taken from mice of B6J NASH mice (nintedanib group) given and administered with nintedanib and stained with hematoxylin and eosin (HE). The left panel shows a photograph taken at a magnification of 10 times, and the right panel shows a photograph taken at a magnification of 40 times. FIG. 2 shows that wild-type mice were fed a breeding feed for 6 weeks (control group), CDAHFD was fed for 6 weeks and solvent administered B6J NASH mice (NASH group) and also CDAHFD for 6 weeks. The micrograph when the liver tissue section | slice extract | collected from the mouse | mouth of the B6J NASH mouse (nintedanib group) which was given over and administered nintedanib was dye | stained by the Masson trichrome method is shown. The left panel shows a photograph taken at a magnification of 10 times, and the right panel shows a photograph taken at a magnification of 40 times. FIG. 3 shows that wild-type mice were fed a breeding feed for 6 weeks (control group), CDAHFD was fed for 6 weeks and solvent administered B6J NASH mice (NASH group) and also CDAHFD for 6 weeks. 1 is a graph comparing the area of fibrosis when a tissue section of liver collected from a mouse of a B6J NASH mouse (nintedanib group) given nintedanib was stained by Masson trichrome method. FIG. 4 shows that wild-type mice were fed a breeding feed for 6 weeks (control group), CDAHFD was fed for 6 weeks and solvent administered B6J NASH mice (NASH group) and CDAHFD were also fed for 6 weeks. Serum aspartate transaminase (AST), alanine aminotransaminase (ALT), alkaline phosphatase (ALP), triglyceride (TG), non-esterified in sera collected from mice of B6J NASH mice (nintedanib group) given It is a graph which shows the density | concentration of a fatty acid (NEFA) and a cytokeratin 18 (CK18) fragment | piece.

  Hereinafter, the present invention will be described with reference to the best mode. Throughout this specification, it should be understood that the singular forms also include the plural concept unless specifically stated otherwise. Thus, it should be understood that singular articles (eg, “a”, “an”, “the”, etc. in the case of English) also include the plural concept unless otherwise stated. In addition, it is to be understood that the terms used in the present specification are used in the meaning normally used in the art unless otherwise specified. Thus, unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification, including definitions, will control.

Definitions As used herein, the term “chronic fatty liver disease” refers to a condition in which a large amount of fat accumulates chronically in the liver. Chronic means that symptoms develop gradually and the treatment and course is prolonged. Factors that cause chronic diseases include, but are not limited to, age, sex, lifestyle, genetic factors, obesity, various hormone abnormalities, intake of some drugs, and the like. Therefore, chronic fatty liver disease is completely different from “acute” fatty liver disease, with different pathological conditions and causes, and different treatment and prevention methods.

  As used herein, the term “inflammatory disease” refers to a disease accompanied by inflammation, and when fatty liver disease is referred to as inflammatory disease, it refers to any fatty liver disease associated with inflammation. It is understood that non-alcoholic steatohepatitis (NASH) and the corresponding alcoholic steatohepatitis are also included in the fatty liver disease that is an inflammatory disease.

  As used herein, the term “inflammatory disease associated with lifestyle habits” refers to a disease accompanied by inflammation with lifestyle habits as the main factor. Examples of lifestyle habits in the present invention include, but are not limited to, exercise amount, nutritional balance, smoking, alcohol intake, and sleep time. “Inflammatory disease” is used in the meaning normally used in the art, and means a disease characterized by a local reaction of a tissue that occurs against damage to a living body. In certain embodiments, the inflammatory disease in the present invention is an inflammatory disease associated with the liver.

  As used herein, the term “non-alcoholic disease” is a generic term for diseases that are not primarily caused by alcohol consumption. Subjects suffering from non-alcoholic diseases include not only subjects who do not consume alcohol at all, but also subjects who consume a small amount of alcohol (in men, the weight of pure ethanol consumed per day is less than 30 g). Yes, for women, the weight of pure ethanol taken per day is less than 20 g). A typical non-alcoholic disease is non-alcoholic fatty liver.

  As used herein, the term “non-alcoholic fatty liver (NAFL)” is used in the sense normally used in the art and is non-alcoholic, characterized by the accumulation of fat in the liver. However, it means a disease in which no infiltration of inflammatory cells into the liver is observed. NAFL is a fatty liver disease with relatively light symptoms and good prognosis, but may progress to more severe diseases such as NASH or cirrhosis. In contrast to non-alcoholic fatty liver, there is also a disease called “alcoholic fatty liver”, which is mainly due to alcohol consumption. Nonalcoholic fatty liver and alcoholic fatty liver differ in the presence or absence of alcohol consumption, but the pathology of these fatty livers is similar, and these differences may disappear after 20 years from onset. It has been reported.

  As used herein, the term “non-alcoholic steatohepatitis (NASH)” is used in the sense commonly used in the art and includes fat accumulation in hepatocytes, hepatocyte balloon-like degeneration (ballooning degeneration), apoptosis. , Infiltration of inflammatory cells into the central venous region of the liver, macrophage surrounding and phagocytosing and processing fatty liver cells (hCLS), liver disease with excessive extracellular matrix deposition in the liver To do.

  As used herein, the term “Matteoni classification” is used in the meaning normally used in the art, and is a classification method for determining the severity of fatty liver disease based on the state of fatty liver disease. Matteoni classification includes (1) hepatocyte steatosis in liver tissue, (2) inflammatory cell infiltration, (3) ballooning hepatocyte swelling, and (4) liver fibrosis. This is a technique for classifying NAFLD into four types, Type 1 to Type 4, based on the presence or absence of (fibrosis) and (5) Mallory-Denk bodies. Matteoni Type 1 shows only hepatocyte steatosis, Type 2 shows hepatocyte steatosis only infiltration of inflammatory cells, Type 3 shows hepatocyte balloon-like swelling, and Type 4 shows Type 3 in addition to Type 3 And type 3 and 4 are diagnosed as NASH.

  As used herein, the term “liver fibrosis” refers to the formation of excess fibrous connective tissue during liver repair or reaction processes. Fibrosis itself does not cause symptoms, but severe fibrosis causes cirrhosis and complications, resulting in symptoms. There are many types of fibrosis and many causes. For example, in NASH, fibrosis is seen when it progresses to type 4. At this stage, you must also consider the risk of progression to cirrhosis and liver cancer. Further, fibrosis is also caused by a chemical substance (for example, carbon tetrachloride) (which can be expressed as acute fibrosis), but accumulation of fat in the liver is not recognized, and the chronic fatty liver of the present invention. It differs in character from fibrosis in the disease (which can be described as chronic fibrosis). Without wishing to be bound by theory, acute fibrosis and chronic fibrosis have completely different pathological aspects, so it can be said that the prevention and treatment are also completely different pathological conditions. Cannot be mutually referred to in the development of preventive and therapeutic drugs.

  Fibrotic tissue replaced with hepatocytes has no hepatocyte function. In addition, fibrotic tissue impedes blood flow to and within the liver, restricting blood supply to hepatocytes, resulting in hepatocyte death, thereby furthering fibrosis progression. obtain. However, as described above, since fibrosis in a chronic disease is different from an acute one, it is considered that a separate measure is required. Therefore, there is almost no effective therapeutic method in the past.

  The composition of the present invention is effective for treatment and prevention of diseases such as cirrhosis and hepatocellular carcinoma in which NASH is further advanced in addition to NAFL and NASH. The composition of the present invention is also effective for the treatment and prevention of alcoholic fatty liver.

  As used herein, “preventing” means preventing or at least delaying the disease, disorder or condition by any means before the disease, disorder or condition targeted by the present invention occurs. Or, even if the cause of a disease, disorder or symptom itself occurs, it means a state in which the cause of the disorder does not occur.

  As used herein, “treatment” refers to stopping, preferably curing, the progression of a disease, disorder or symptom that has already developed and is a target of the present invention.

  As used herein, “ameliorating” is to stop or alleviate, in whole or in part, the progression of a disease, disorder or symptom that is already onset of the present invention. Say.

As used herein, “C _1-6 ” means having 1 to 6 carbon atoms. The same applies to other numbers. For example, “C _1-4 ” means 1 to 4 carbon atoms.

  As used herein, “heteroatom” means an atom other than carbon, such as an oxygen atom, a nitrogen atom, or a sulfur atom.

  As used herein, “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Preferably they are a fluorine atom or a chlorine atom. More preferably, it is a fluorine atom. The “halogen atom” is sometimes referred to as “halogen”, but the present invention is not limited thereto.

As used herein, “alkyl group” refers to a linear or branched saturated hydrocarbon group, and “C _1-6 alkyl group” refers to a linear or branched carbon atom. It means a saturated hydrocarbon group of 1 to 6. The “C _1-6 alkyl group” is preferably “C _1-4 alkyl group”, more preferably “C _1-3 alkyl group”, still more preferably “C _1-2 alkyl group”. is there. Specific examples of the “C _1-6 alkyl group” include, but are not limited to, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tert-butyl, sec-butyl, isopentyl, neopentyl, tert-pentyl, 1,2-dimethylpropyl and the like can be mentioned.

As used herein, “cycloalkyl group” refers to a cyclic saturated hydrocarbon group, and “C _3-7 cycloalkyl group” refers to a cyclic saturated hydrocarbon group having 3 to 7 carbon atoms. To do. The “C _3-7 cycloalkyl group” is preferably “C _4-7 cycloalkyl group”, or may be “C _5-7 cycloalkyl group” or “C _6-7 cycloalkyl group”.

As used herein, an “alkenyl group” refers to a straight or branched chain unsaturated hydrocarbon group containing one or more carbon-carbon double bonds, “C _The “ _2-6 alkenyl group” means a linear or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms containing one or more carbon-carbon double bonds. The “C _2-6 alkenyl group” is preferably a “C _2-4 alkenyl group”. Specific examples of “C _2-6 alkenyl group” include, but are not limited to, for example, vinyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, A 2-methyl-1-propenyl group, a 2-methyl-2-propenyl group and the like can be mentioned.

As used herein, a “cycloalkenyl group” refers to a cyclic unsaturated hydrocarbon group containing one or more carbon-carbon double bonds, and includes a “C _3-7 cycloalkenyl group”. "Means a cyclic unsaturated hydrocarbon group of 3 to 7 carbon atoms containing one or more carbon-carbon double bonds. The “C _3-7 cycloalkenyl group” is preferably “C _4-7 cycloalkenyl group”, or may be “C _5-7 cycloalkenyl group” or “C _6-7 cycloalkenyl group”.

As used herein, “alkynyl group” refers to a straight or branched unsaturated aliphatic hydrocarbon group having one or more triple bonds, and “C _2-6 alkynyl group” refers to It means a straight-chain or branched unsaturated aliphatic hydrocarbon group having 2 to 6 carbon atoms having one or more triple bonds. The “C _2-6 alkynyl group” is preferably a “C _2-4 alkynyl group”. Specifically, although not limited thereto, for example, ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 1-methyl-2-propynyl group, 3-butynyl group, 1-pentynyl group, Examples include 1-hexynyl group.

As used herein, “cycloalkynyl group” refers to a cyclic unsaturated hydrocarbon group having one or more triple bonds, and “C _3-7 cycloalkynyl group” refers to 1 or 2 A cyclic unsaturated hydrocarbon group having 3 to 7 carbon atoms having at least three triple bonds is meant. The “C _3-7 cycloalkynyl group” is preferably “C _4-7 cycloalkynyl group”, or may be “C _5-7 cycloalkynyl group” or “C _6-7 cycloalkynyl group”.

As used herein, the generic expression “alicyclic group” refers to a monocyclic or polycyclic non-aromatic hydrocarbon ring, and includes “C _3-20 alicyclic group” and Means a monocyclic or bicyclic non-aromatic hydrocarbon ring having 3 to 20 carbon atoms, partly having an unsaturated bond, partly having a crosslinked structure, partly spirolated And those having 1 or 2 carbonyl structures. The “alicyclic group” includes a cycloalkyl group, a cycloalkenyl group, a cycloalkynyl group, and a derivatized cycloalkoxy group, cycloalkenyloxy group, cycloalkynyloxy group, and the like. The “C _3-20 alicyclic group” is preferably “C _3-10 alicyclic group”, and more preferably “C _3-6 alicyclic group”. Specific examples of “C _3-20 alicyclic group” include, but are not limited to, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclohexazinyl group, A cycloheptazinyl group, a cyclooctazinyl group, adamantyl, norbornyl, etc. are mentioned.

Specific examples of the “C _3-20 alicyclic group” having a partially crosslinked structure include, but are not limited to, those having the structures shown below.

The “C _3-20 alicyclic group” includes a compound condensed with an aromatic ring. Specific examples include groups represented by the following.

As used herein _{"C 3-10} cycloaliphatic radical" among the _{"C 3-20} cycloaliphatic radical", _{"C 3-10} alicyclic group" is a monovalent group Meaning a substituent.

As used herein, “aryl” refers to a monocyclic or polycyclic aromatic hydrocarbon ring, “C _6-10 aryl” refers to a monocyclic having 6 to 10 carbon atoms, Alternatively, it means a bicyclic aromatic hydrocarbon ring, and specific examples include a phenyl group, a 1-naphthyl group, and a 2-naphthyl group. C _6-10 aryl is preferably C ₆ or C ₁₀ aryl.

  As used herein, “heteroaryl” refers to monocyclic or polycyclic aromatic heterocycles containing heteroatoms, and “5-membered or 6-membered heteroaryl” refers to oxygen atoms, nitrogen atoms and It means a monocyclic aromatic heterocycle consisting of 5 to 6 atoms, including the same or different 1 to 4 heteroatoms selected from the group consisting of sulfur atoms.

  As used herein, a “5- to 10-membered heteroaryl” includes from 1 to 4 heteroatoms that are the same or different selected from the group consisting of oxygen, nitrogen and sulfur atoms. It means a monocyclic or bicyclic aromatic heterocycle consisting of 1 atom.

  Specific examples of “6-membered heteroaryl” in the present specification include, but are not limited to, pyridine, pyridazine, pyrimidine, pyrazine and the like.

  Specific examples of “5-membered heteroaryl” herein include, but are not limited to, for example, thiophene, pyrrole, thiazole, isothiazole, pyrazole, imidazole, furan, oxazole, isoxazole, oxadiazole, thiadiazole , Triazole, tetrazole and the like, preferably triazole, tetrazole or thiadiazole, more preferably thiadiazole.

As used herein, an “alkoxy group” refers to an “alkyloxy group”, a “C _1-6 alkoxy group” means a “C _1-6 alkyloxy group”, and the C _1-6 alkyl moiety has the same meaning as above _{C 1-6} alkyl group. The “C _1-6 alkoxy group” is preferably a “C _1-4 alkoxy group”, more preferably a “C _1-3 alkoxy group”, and still more preferably a “C _1-2 alkoxy group”. . Specific examples of the “C _1-6 alkoxy group” include, but are not limited to, for example, methoxy group, ethoxy group, propoxy group, butoxy group, isopropoxy group, isobutoxy group, tert-butoxy group, sec-butoxy group , Isopentyloxy group, neopentyloxy group, tert-pentyloxy group, 1,2-dimethylpropoxy group and the like. As used herein, “C _4-7 cycloalkoxy group” means “C _4-7 cycloalkyloxy group”, wherein the C _4-7 cycloalkyl moiety is the above C _4-7 cycloalkyl group. Synonymous with group.

In the present specification, the aryl part of the “aryloxy group” has the same meaning as the above aryl. For example, when the aryl moiety has 6 to 10 carbon atoms, it is referred to as “C _6-10 aryloxy group”, preferably “C ₆ or C ₁₀ aryloxy group”. Specific examples of the “C _6-10 aryloxy group” include, but are not limited to, a phenoxy group, a 1-naphthyloxy group, a 2-naphthyloxy group, and the like.

  In the present specification, for example, a compound having a carboxy group includes a compound in which the carboxy group is an alkoxycarbonyl group, a compound in which the alkylthiocarbonyl group is formed, or a compound in which the alkylaminocarbonyl group is formed.

In the present specification, specifically, the “alkylcarbonyl group” means a carbonyl group substituted with an “alkyl group”. The “alkylcarbonyl group” is preferably “C _1-6 alkylcarbonyl group” or “C _1-4 alkylcarbonyl group”. Specific examples of the “C _1-6 alkylcarbonyl group” include, but are not limited to, acetyl group, propionyl group, butyryl group, and the like.

  Further, for example, in the case of a compound having an amino group, the amino group is substituted with an acyl group to become an acylamino group, the compound is substituted with an alkoxycarbonyl group to become an alkoxycarbonylamino group, or an acyloxymethylamino group is obtained. The compound or the compound which became hydroxylamine is mentioned.

  Further, for example, in the case of a compound having a hydroxyl group, a compound in which the hydroxyl group is substituted with the acyl group to become an acyloxy group, a compound in which a phosphoric acid ester is formed, or a compound in which an acyloxymethyloxy group is formed can be mentioned.

  In the present specification, the substituent in “optionally substituted” preferably includes a substituent such as the following substituent (group) α. That is, the substituent (group) α is halogen, hydroxy, alkoxy, halogenoalkoxy, hydroxyalkoxy, alkoxyalkoxy, acyl, acyloxy, carboxy, alkoxycarbonyl, amino, acylamino, alkylamino, imino, hydroxyimino, alkoxyimino, alkylthio. Carbamoyl, alkylcarbamoyl, hydroxyalkylcarbamoyl, sulfamoyl, alkylsulfamoyl, alkylsulfinyl, alkylsulfonylamino, alkylsulfonylalkylamino, alkylsulfonylimino, alkylsulfinylamino, alkylsulfinylalkylamino, alkylsulfinylimino, cyano, nitro, Carbocyclic and heterocyclic groups (each carbocyclic and heterocyclic ring is halogenated Alkyl, a group consisting of even be) optionally substituted with one or more groups selected from the group consisting of hydroxy and alkoxy.

  In the present specification, examples of the alkyl moiety of the group used for the prodrug formation of the compound used in the present invention include the alkyl group, and the alkyl group may be substituted with, for example, an alkoxy group. Preferable examples include the following.

  For example, for a compound in which a carboxy group is converted to an alkoxycarbonyl group, alkoxycarbonyl such as methoxycarbonyl or ethoxycarbonyl, methoxymethoxycarbonyl, ethoxymethoxycarbonyl, 2-methoxyethoxycarbonyl, 2-methoxyethoxymethoxycarbonyl or Examples include alkoxycarbonyl substituted with an alkoxy group such as valoyloxymethoxycarbonyl.

  As used herein, “pharmaceutically acceptable salts” mean acid addition salts and base addition salts that are pharmaceutically acceptable. “Pharmaceutically acceptable salts” include, but are not limited to, for example, acetate, propionate, butyrate, formate, trifluoroacetate, maleate, fumarate, tartrate, citric acid, Acid, stearate, succinate, ethyl succinate, malonate, lactobionate, gluconate, glucoheptonate, benzoate, methanesulfonate, benzenesulfonic acid, paratoluenesulfonate ( Tosylate), lauryl sulfate, malate, ascorbate, mandelate, saccharate, xinafoate, pamoate, cinnamate, adipate, cysteine salt, N-acetylcysteine salt, Hydrochloride, hydrobromide, phosphate, sulfate, hydroiodide, nicotinate, oxalate, picrate, thiocyanate, undecanoic acid Acid addition salts such as acrylic acid polymer salts and carboxyvinyl polymers; inorganic base addition salts such as lithium salts, sodium salts, potassium salts and calcium salts; organic base addition salts such as morpholine and piperidine; amino acids such as aspartic acid and glutamic acid And an addition salt.

  The compound of the present invention can be administered by oral administration or parenteral administration, directly or by using a suitable dosage form into a preparation, medicament or pharmaceutical composition. Specific examples of these dosage forms include, but are not limited to, tablets, capsules, powders, granules, solutions, suspensions, injections, patches, cataplasms, and the like. In addition, these preparations can be produced by known methods using additives that are used as usual pharmaceutical additives.

  These additives include excipients, disintegrants, binders, fluidizers, lubricants, coating agents, solubilizers, solubilizers, thickeners, dispersants, stabilizers depending on the purpose. , Sweeteners, flavors and the like can be used. Specific examples of these additives include, but are not limited to, lactose, mannitol, crystalline cellulose, low-substituted hydroxypropylcellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxy Examples thereof include propylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, talc, medium chain fatty acid triglyceride, hard fat, soybean lecithin and the like.

  The dose of the compound or salt of the present invention, composition, medicine, etc. is appropriately selected depending on the animal to be administered, administration route, disease, patient age, weight and symptoms. For example, in the case of oral administration, for adults, the lower limit is 0.01 mg (preferably 100 mg) and the upper limit is 10,000 mg (preferably 6000 mg) per day, and this amount can be once or several times a day. Can be administered separately.

  The administration timing of the compound or salt of the present invention, the composition, the medicine, etc. is not limited, and these may be administered to the administration subject simultaneously with other drugs (therapeutic agents, prophylactic agents, etc.), with a time difference. May be administered. Moreover, it is good also as a combination of the compound of this invention and another chemical | medical agent. The dosage of other drugs can be appropriately selected based on the clinically used dose. In addition, the compounding ratio of the compound or salt of the present invention, composition, medicine or the like and other drugs can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like.

  Such medicaments, formulations, and pharmaceutical compositions may be prepared using any technique known in the art, with the compounds of the present invention and / or additional agents as needed, together or separately, as a combination or As a separate drug, it can be produced by mixing with any appropriate component, and using any technique known in the art, an appropriate formulation such as a tablet, capsule, powder, granule, liquid It can be formulated into a suspension, injection, patch, or cataplasm. Where the compound of the invention and / or the additional agent is prepared as separate agents, it may be provided as a kit of two agents, provided as a single agent of one component and the other component simultaneously or differently. Sometimes it may be provided with instructions (such as package inserts) that indicate that it will be administered in combination.

  When the compound of the present invention is used as a pharmaceutical active ingredient, it is not intended to be used only for humans, but is also used for other animals other than humans (cats, dogs, cows, chickens, fish, etc.). It is possible.

  Hereinafter, the production method of the compound of the present invention will be described with examples, but the present invention is not limited to these examples.

(Manufacturing method)
Although the compound of this invention is not limited to these, For example, it can manufacture with the manufacturing method described below. These production methods can be improved as appropriate based on the knowledge of a person skilled in organic synthetic chemistry. In the following production method, as a compound used as a raw material, a salt thereof may be used as long as the reaction is not hindered.

  The compound of the present invention or a salt thereof can be produced by referring to the technique described in Japanese Patent No. 4021664 and other documents.

  In the above production method, even if the use of a protecting group is not specifically indicated, if any functional group other than the reactive site changes depending on the reaction conditions, or is not suitable for carrying out the treatment after the reaction. In some cases, the compound other than the reaction point is protected as necessary, and the target compound can be obtained by deprotection after completion of the reaction or after a series of reactions. Protective groups used in these processes are described in literature (TW Greene and PGM Wuts, “Protective Group in Organic Synthesis”, 3rd Ed., John Wiley and Sons, Inc., New York (1999)). The usual protecting groups can be used. The introduction and removal of the protecting group can be performed by a method commonly used in organic synthetic chemistry (for example, the method described in the above document) or a method analogous thereto.

  The starting materials and intermediates in the above production method can be purchased as commercially available products, or can be obtained by synthesizing according to known methods from methods described in known literature or known compounds. These starting materials and intermediates may be used as long as they do not interfere with the reaction.

The intermediates and target compounds in the above production method can be converted into other compounds included in the present invention by appropriately converting their functional groups. Conversion of functional groups in that case, the method conventionally used in organic synthetic chemistry (for example, RC Larock, "Comprehensive Organic Transformations ", 2 nd Ed., John Wiley and Sons, inc., Is described in New York (1999) Etc.) or a method according to them.

  The inert solvent that can be used in the above production method is a solvent that does not react with raw materials, reagents, bases, acids, catalysts, ligands, etc. used in the reaction (sometimes referred to as “raw materials used in the reaction”). means. Further, even when the solvent used in each step reacts with the raw material used in the reaction, it can be used as an inert solvent as long as the target reaction proceeds and the target compound is obtained.

(Description of Preferred Embodiment)
Hereinafter, preferred embodiments of the present invention will be described. The embodiments provided below are provided for a better understanding of the present invention, and it is understood that the scope of the present invention should not be limited to the following description. Therefore, it is obvious that those skilled in the art can make appropriate modifications within the scope of the present invention with reference to the description in the present specification. It will also be appreciated that the following embodiments of the invention may be used alone or in combination.

  In addition, each of the embodiments described below shows a comprehensive or specific example. Numerical values, shapes, materials, constituent elements, arrangement positions and coupling forms of constituent elements, steps, order of steps, and the like shown in the following embodiments are merely examples, and are not intended to limit the scope of the claims. In addition, among the constituent elements in the following embodiments, constituent elements that are not described in the independent claims indicating the highest concept are described as optional constituent elements.

(Composition)
In one aspect, the present invention provides a composition, a medicament, and a therapeutic method for preventing, ameliorating, or treating chronic fatty liver disease. The compositions, medicaments and therapies of the invention have the general formula substituted at the 6-position

Of indolinone, their tautomers, diastereomers, enantiomers, mixtures (sometimes referred to collectively herein as “compounds”) and their salts, especially their pharmaceutically acceptable Including or using a salt (wherein R _{1 to} R ₅ are any of those described elsewhere herein. The invention also prevents, ameliorates or treats chronic fatty liver disease) To the above indolinones, their tautomers, diastereomers, enantiomers, mixtures and their salts, in particular their pharmaceutically acceptable salts.

In a preferred embodiment, R _{1 to} R ₅ and other substituents in the formula may be the substituents described in item 1 above. In a more preferred embodiment, R _{1 to} R ₅ and other substituents in the formula may be those described in item 2 above. In a further preferred embodiment, R _{1 to} R ₅ and other substituents in the formula may be the substituents described in item 3 above. In a further preferred embodiment, R _{1 to} R ₅ and other substituents in the formula may be those described in item 4 above. In a further preferred embodiment, R _{1 to} R ₅ and other substituents in the formula may be the substituents described in item 5 above.

  While not wishing to be bound by theory, indolinones, their tautomers, diastereomers or enantiomers, mixtures thereof, or pharmaceutically acceptable salts thereof used in the present invention have similar functions and Has a working effect.

In a preferred specific embodiment, said indolinone, their tautomers, diastereomers or enantiomers, mixtures thereof or pharmaceutically acceptable salts thereof are
(a) 3-Z- [1- (4- (piperidin-1-yl-methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone,
(b) 3-Z-[(1- (4- (piperidin-1-yl-methyl) -anilino) -1-phenyl-methylene] -6-carbamoyl-2-indolinone,
(c) 3-Z- [1- (4- (piperidin-1-yl-methyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone,
(d) 3-Z- [1- (4- (dimethylaminomethyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone,
(e) 3-Z- [1- (4-((2,6-dimethyl-piperidin-1-yl) -methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone,
(f) 3-Z- [1- (4- (N- (2-dimethylamino-ethyl) -N-acetyl-amino) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone ,
(g) 3-Z- [1- (4- (N- (3-Dimethylamino-propyl) -N-acetyl-amino) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone ,
(h) 3-Z- [1- (4- (N- (2-dimethylamino-ethyl) -N-methylsulfonylamino) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone ,
(i) 3-Z- [1- (4- (dimethylaminomethyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone,
(j) 3-Z- [1- (4- (N-acetyl-N-dimethylaminocarbonylmethyl-amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone,
(k) 3-Z- [1- (4-ethylaminomethyl-anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone,
(l) 3-Z- [1- (4- (1-Methyl-imidazol-2-yl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone,
(m) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl-N-methyl-amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone,
(n) 3-Z- [1- (4- (N- (2-dimethylamino-ethyl) -N-methylsulfonylamino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone ,
(o) 3-Z- [1- (4- (N- (3-Dimethylamino-propyl) -N-methylsulfonylamino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone ,
(p) 3-Z- [1- (4- (N-dimethylaminocarbonylmethyl-N-methylsulfonyl-amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone,
(q) 3-Z- [1- (4- (N-((2-dimethylamino-ethyl) -carbonyl) -N-methylamino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl- 2-indolinone,
(r) 3-Z- [1- (4- (N- (2-dimethylamino-ethyl) -N-acetyl-amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone as well as
(s) 3-Z- [1- (4-methylaminomethyl-anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone,
These tautomers, diastereomers or enantiomers, mixtures thereof, or pharmaceutically acceptable salts thereof can be used.

More preferably, the composition of the present invention comprises 3-Z- [1- (4- (N-((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methylamino) -anilino)- 1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, its tautomers or pharmaceutically acceptable salts.
Even more preferably, the present invention may include a component known as Nintedanib (NTN) and may be provided as a pharmaceutical product known as OFEF® or an equivalent product (eg, a generically acceptable pharmaceutical product). .

  The present invention can be used to prevent, ameliorate or treat chronic fatty liver disease. Chronic fatty liver disease is a disease characterized by the accumulation of fat in the liver. Chronic fatty liver disease is a completely different disease from acute liver disease caused by compound toxicity. In addition, "fatty liver" itself is caused by excessive accumulation of fat in the liver due to daily life, and "fatty liver disease" is a disease that occurs when the "fatty liver" state continues for a longer time Therefore, “fatty liver disease” is usually a chronic disease, and in that sense, “fatty liver disease” usually corresponds to “chronic fatty liver disease”.

  In one embodiment, the chronic fatty liver disease targeted by the present invention is an inflammatory disease. Examples of inflammatory diseases include non-alcoholic steatohepatitis (NASH), but it is thought that steatohepatitis caused by alcohol has a common factor with non-alcoholic steatohepatitis (NASH). It will be appreciated that the invention is applicable to inflammatory chronic fatty liver disease.

  In one embodiment, the present invention is useful for the prevention, amelioration or treatment of inflammatory diseases associated with lifestyle habits. Most of the causes of chronic fatty liver disease are due to disorder of lifestyle such as exercise amount, nutritional balance, smoking, alcohol consumption, sleep time, etc., and it is reasonably estimated that it is generally effective for diseases caused by these causes can do.

  In another embodiment, the present invention is useful for the prevention, amelioration or treatment of non-alcoholic chronic fatty liver disease. It is understood that non-alcoholic chronic fatty liver disease is considered to have a non-alcoholic cause and is included in this definition even if the subject subsequently ingests alcohol.

  In another embodiment, the present invention is useful for the prevention, amelioration or treatment of non-alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH). NAFL is considered to be a disease with relatively light symptoms and good prognosis among fatty liver diseases, but it is known that a certain degree of subjects progress to nonalcoholic steatohepatitis (NASH), Prevention or early treatment of NAFL may be useful.

  Although not wishing to be bound by theory, the present invention is useful for the prevention, amelioration or treatment of nonalcoholic steatohepatitis (NASH), and in particular, the effect of Type 4 on nonalcoholic steatohepatitis (NASH) in the Matteoni classification Can be said to be remarkable. In Matteoni classification, the severity of fatty liver disease is determined based on the status of fatty liver disease, but Type 4 recognizes liver fibrosis in addition to Type 3, and as demonstrated in the Examples, It has been found that fibrosis is suppressed in chronic fatty liver disease, and is interpreted in the art as being useful for the prevention, amelioration, or treatment of this advanced severity of chronic fatty liver disease. Although fibrosis itself does not cause symptoms, severe fibrosis causes liver cirrhosis and complications. Therefore, suppression of fibrosis in chronic diseases is an important Merckumar, and the present invention has a preventive or therapeutic effect. What is found is desirable. The present invention is useful for the prevention, improvement or treatment of fibrosis associated with fatty liver disease.

  In another embodiment, the present invention is useful for the prevention or early improvement or treatment of chronic fatty liver disease. In the present invention, in the development of chronic fatty liver disease, even when administered at a stage where the onset is not sufficiently confirmed (level of 3-4 weeks where onset is clearly confirmed in 6 weeks), It is because it is evaluated that it can have a sufficient function as a preventive agent since healing is seen. Without being bound by theory, the indoline compounds according to the present invention include platelet derived growth factor receptors (PDGFR) α and β, fibroblast growth factor receptors (FGFR) 1, 2 and 3, and vascular endothelium. Inhibiting fibroblast proliferation, migration and transformation by competitively binding to the growth factor receptor (VEGFR) ATP binding pocket and blocking intracellular signaling, resulting in tissue fibrosis It is thought to be suppressed.

  The route for administering the composition of the present invention to a subject is not particularly limited as long as it is available. In the most preferred embodiment, the compositions of the invention are administered by oral administration.

In certain embodiments, the compositions of the invention are administered as soft capsules that optionally contain additives in addition to the compounds of general formula (I) herein. In the most preferred embodiment, the composition of the present invention comprises medium chain fatty acid triglycerides, hard fat and soy lecithin as additives. In certain embodiments, the soft capsule is composed of gelatin, glycerin, titanium oxide, ferric oxide and yellow ferric oxide.
Furthermore, the composition of this invention can also be administered using the same dosage form as OFEF (registered trademark) (Nintedanib ethanesulfonate, Boehringer Ingelheim) or a generic agent thereof.

  In this specification, “or” is used when “at least one or more” of the items listed in the text can be adopted. The same applies to “or”. In this specification, when “within the range of two values” is specified, the range includes the two values themselves.

  References such as scientific literature, patents and patent applications cited herein are hereby incorporated by reference in their entirety to the same extent as if each was specifically described.

  The present invention has been described with reference to the preferred embodiments for easy understanding. In the following, the present invention will be described based on examples, but the above description and the following examples are provided only for the purpose of illustration, not for the purpose of limiting the present invention. Accordingly, the scope of the present invention is not limited to the embodiments or examples specifically described in the present specification, but is limited only by the scope of the claims.

(Example 1: Confirmation of NTN effect on chronic fatty liver disease using NASH model)
In this example, a mouse model is used to confirm whether the active ingredient of the present invention is effective for chronic fatty liver disease.

(Experimental method)
(Administration to mice)
Six C57BL / 6J mice (10 weeks old, male) and 12 B6J NASH mice (10 weeks old, male) were purchased from Charles River Japan. B6J NASH mice are spontaneously established NASH model mice. C57BL / 6J mice were normal mice that did not develop NASH, and were used as a group that did not develop fibrosis (control group).

  C57BL / 6J mice (control group) have a breeding feed, B6J NASH mice have 60 kcal% fat and 0.1% methionine and no choline L-amino acid diet (CDAHFD60, Research Diet stock) Company) for 4 weeks. Thereafter, 6 of the B6J NASH mice received nintedanib (60 mg / kg / day, nintedanib group) (LC Laboratories), the remaining 6 mice received the solvent (NASH group) once a day for 2 weeks. Orally administered. All mice were then euthanized by exsanguination from the abdominal aorta under deep anesthesia with sevoflurane (Wako Pure Chemical Industries, Ltd.), and blood samples and livers were collected.

(Blood sample preparation and measurement and tissue observation)
Serum was collected by allowing the blood sample to stand at room temperature for 1 hour and then centrifuging at 1500 × g and stored at −80 ° C. until analysis. Serum aspartate transaminase (AST), alanine aminotransaminase (ALT), alkaline phosphatase (ALP), triglyceride (TG) and non-esterified fatty acid (NEFA) concentrations were measured by an automated analyzer (HITACHI 7180). Serum cytokeratin 18 (CK18) fragment was detected by enzyme-linked immunosorbent assay (ELISA). The liver was fixed with formalin for 24 hours, embedded in paraffin, and sliced using a microtome. Each tissue section slide was then stained with hematoxylin and eosin (HE) to assess the level of steatohepatitis. Paraffin-embedded sections were stained by Masson Trichrome (MT) method to evaluate liver fibrosis. The significance level was set at p <0.05. Statistical analysis was performed with GraphPad Prism 4.03 software. For statistical analysis, the Bonferroni method was used to compare between the control group and the NASH group and between the NASH group and the nintedanib group.

Results The results of HE staining of liver tissue in the NASH group revealed the accumulation of lipid droplets, and further showed a significantly higher fibrosis level compared to the control group. In contrast, the nintedanib group showed significantly lower fibrosis levels than the NASH group.

The ALT and ALP levels in the NASH group were 6.3 and 2.1 times higher than those in the control group, respectively. As for AST, the NASH group showed a 6.7-fold increase compared to the control group. In contrast, for TG and NEFA, there was no significant difference between the two groups. CK18 reflecting the activity of apoptosis was 4.3 times higher in the NASH group than in the control group.
On the other hand, no statistically significant difference was observed in the biochemical analysis and CK18 measurement between the nintedanib group and the NASH group.

Discussion Nintedanib showed a marked antifibrotic effect in NASH mice. Nintedanib provides effects on the ATP binding sites of receptors such as platelet derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR). Intracellular signaling appears to have been blocked by nintedanib and may have resulted in antifibrotic effects by inhibiting fibroblast transformation controlled by cytokines and growth factors such as TGF-β Sex is conceivable. Furthermore, it was revealed that the level of fibrosis was maintained in the nintedanib-administered group, indicating that nintedanib suppresses the progression of fibrosis in the liver and is effective in preventing fibrotic diseases. Suggest. This result demonstrates that nintedanib, a drug for idiopathic pulmonary fibrosis, can also be repositioned for the treatment of NASH.
In addition, in the biochemical analysis and CK18 measurement between the nintedanib group and the NASH group, the statistically significant difference was not observed because the administration period of nintedanib was as short as 2 weeks and the mice used in the study It is conceivable that there are a small number of individuals, and that there are elevated liver enzymes (ALT values, AST values) as a side effect of nintedanib (over 10%). It can be evaluated as useful for the prevention, improvement and treatment of fatty liver disease.
In addition, a significant change in CK18 in the NASH model can be used as a biomarker indicating NASH disease progression and characterizes a marked increase in liver enzymes and histological findings in liver fibrosis in a mouse model It is.

(Example 2: Dry ampoule)
(1) Dry ampoule containing 75 mg of active substance per 10 ml Composition:
Active substance 75.0mg
Mannitol 50.0mg
Water for injection QS 10.0ml
The prepared active substances nintedanib and mannitol are dissolved in water. After packaging, the solution is lyophilized. The product is dissolved in water for injection to make a ready-to-use solution.
(2) Dry ampoule containing 35 mg of active substance per 2 ml Composition:
Active substance 35.0mg
Mannitol 100.0mg
Water for injection QS 2.0ml
Preparation:
The active substances nintedanib and mannitol are dissolved in water. After packaging, the solution is lyophilized. The product is dissolved in water for injection to make a ready-to-use solution.

(Example 3: Tablet)
(1) Tablet containing 50 mg of active substance Composition:
(1) Active substance 50.0mg
(2) Lactose 98.0mg
(3) Corn starch 50.0mg
(4) Polyvinylpyrrolidone 15.0mg
(5) Magnesium stearate 2.0mg
215.0mg
Preparation:
(1), (2) and (3) are mixed together and granulated with the aqueous solution of (4). Add (5) to the dried granular material. This mixture is pressed into a tablet that is bi-planar, with facets on both sides and split notches on one side. Tablet diameter: 9 mm.
(2) Tablets containing 350 mg of active substance Composition:
(1) Active substance 350.0mg
(2) Lactose 136.0 mg
(3) Corn starch 80.0mg
(4) Polyvinylpyrrolidone 30.0mg
(5) Magnesium stearate 4.0 mg
600.0mg
Preparation:
(1), (2) and (3) are mixed together and granulated with the aqueous solution of (4). Add (5) to the dried granular material. This mixture is pressed into a tablet that is bi-planar, with facets on both sides and split notches on one side. Tablet diameter: 12 mm.

(Example 4: Capsule)
(1) Capsules containing 50 mg of active substance Composition:
(1) Active substance 50.0mg
(2) Dried corn starch 58.0mg
(3) Powdered lactose 50.0mg
(4) Magnesium stearate 2.0mg
160.0mg
Preparation:
Grind (1) with (3). This trituration is added to the mixture of (2) and (4) with vigorous stirring. This powder mixture is filled into size 3 hard gelatin capsules in a capsule filling machine.
(2) Capsules containing 350 mg of active substance Composition:
(1) Active substance 350.0mg
(2) Dried corn starch 46.0mg
(3) Powdered lactose 30.0mg
(4) Magnesium stearate 4.0 mg
430.0mg
Preparation:
Grind (1) with (3). This trituration is added to the mixture of (2) and (4) with vigorous stirring. This powder mixture is filled into size 0 hard gelatin capsules in a capsule filling machine.

(Example 5: Suppository)
Suppository containing 100 mg of active substance Composition:
Active substance 100mg
Polyethylene glycol (MW 1500) 600.0 mg
Polyethylene glycol (M.W.6000) 460.0 mg
Polyethylene sorbitan monostearate 840.0mg
2,000 mg
Preparation:
Polyethylene glycol is melted with polyethylene sorbitan monostearate. The active substance ground at 40 ° C. is uniformly dispersed in the melt. Cool to 38 ° C and pour into a slightly cooled suppository mold.

(Example 6: Soft capsule)
Soft capsule containing 100 mg of active substance Composition:
(1) Active substance 100.0mg
(2) Medium chain fatty acid triglyceride appropriate amount (3) hard fat appropriate amount (4) soybean lecithin 1.2mg
442.0mg
Preparation:
(1) to (4) are mixed by a method known to those skilled in the art, and this mixture is filled into soft gelatin capsules with a capsule filling machine.

(Example 7: Soft capsule)
Soft capsules containing 150 mg of active substance Composition:
(1) Active substance 150.0mg
(2) Medium chain fatty acid triglyceride appropriate amount (3) hard fat appropriate amount (4) soybean lecithin 1.8mg
Approximately 627.0 mg
Preparation:
(1) to (4) are mixed by a method known to those skilled in the art, and this mixture is filled into soft gelatin capsules with a capsule filling machine.

  As mentioned above, although this invention has been illustrated using preferable embodiment of this invention, this invention should not be limited and limited to this embodiment. It is understood that the scope of the present invention should be construed only by the claims. It is understood that those skilled in the art can implement an equivalent range from the description of specific preferred embodiments of the present invention based on the description of the present invention and common general technical knowledge. Patents, patent applications, and documents cited herein should be incorporated by reference in their entirety, as if the contents themselves were specifically described herein. Understood.

  The present invention has utility in the prevention, amelioration or treatment of chronic fatty liver disease.

Claims (10)

A composition for preventing, ameliorating or treating chronic fatty liver disease, wherein the composition has the general formula substituted at position 6

[Where,
X represents an oxygen atom or a sulfur atom,
R ₁ represents a hydrogen atom or a group used for prodrug formation,
R ₂ is a carboxy group, a linear or branched C _1-6 -alkoxycarbonyl group, a C _4-7 -cycloalkoxycarbonyl group or an aryloxycarbonyl group,
Straight chain or branched C _1-6 -alkoxycarbonyl group (which includes phenyl, heteroaryl, carboxy, C _1-3 -alkoxycarbonyl, aminocarbonyl, C _1-3 -alkyl in the alkyl moiety) Terminally substituted by an amino-carbonyl group or a di- (C _1-3 -alkyl) -aminocarbonyl group),
Straight chain or branched C _2-6 -alkoxycarbonyl group (which includes a chlorine atom or a hydroxy group, a C _1-3 -alkoxy group, an amino group, a C _1-3 -alkylamino group or a di- ( C _1-3 -alkyl) -amino group substituted at the end),
Represents an aminocarbonyl group or a methylaminocarbonyl group, and an ethylaminocarbonyl group optionally substituted by a hydroxy group or a C _1-3 -alkoxy group at the 2-position of the ethyl group, or
If R ₄ does not represent an aminosulfonyl-phenyl group or an N- (C _1-5 -alkyl) -C _1-3 -alkylaminocarbonyl-phenyl group, it is also di- (C _1-2 -alkyl)- May represent an aminocarbonyl group;
R ₃ is a hydrogen atom, a C _1-6 -alkyl group, a C _3-7 -cycloalkyl group, a trifluoromethyl group or a heteroaryl group,
Phenyl group or naphthyl group; phenyl group or naphthyl mono- or di-substituted by fluorine atom, chlorine atom, bromine atom or iodine atom, trifluoromethyl group, C _1-3 -alkyl group or C _1-3 -alkoxy group Group (in the case of disubstitution, the substituents may be the same or different, and the above-mentioned unsubstituted phenyl group and naphthyl group, and mono- and di-substituted phenyl group and naphthyl group are further represented by hydroxy group, hydroxy group, -C _1-3 -alkyl group or C _1-3 -alkoxy-C _1-3 -alkyl group,
Cyano group, carboxy group, carboxy-C _1-3 -alkyl group, C _1-3 -alkoxycarbonyl group, aminocarbonyl group, C _1-3 -alkylamino-carbonyl group or di- (C _1-3 -alkyl) -Aminocarbonyl group,
Nitro group,
An amino group, a C _1-3 -alkylamino group, a di- (C _1-3 -alkyl) -amino group or an amino-C _1-3 -alkyl group,
C _1-3 -alkylcarbonylamino group, N- (C _1-3 -alkyl) -C _1-3 -alkylcarbonylamino group, C _1-3 -alkylcarbonylamino-C _1-3 -alkyl group, N- (C _1-3 -alkyl) -C _1-3 -alkylcarbonylamino-C _1-3 -alkyl group, C _1-3 -alkylsulfonylamino group, C _1-3 -alkylsulfonylamino-C _1-3- An alkyl group, N- (C _1-3 -alkyl) -C _1-3 -alkylsulfonylamino-C _1-3 -alkyl group or aryl-C _1-3 -alkylsulfonylamino group,
Cycloalkylamino group, cycloalkyleneimino group, cycloalkyleneiminocarbonyl group, cycloalkyleneimino-C _1-3 -alkyl group, cycloalkyleneiminocarbonyl-C _1-3 -alkyl group or cycloalkyleneiminosulfonyl-C _1-3 -Alkyl group (having 4 to 7 ring members in each case) (in each case, the methylene group at the 4-position of the 6-membered or 7-membered cycloalkyleneimino group is an oxygen atom or sulfur atom, sulfinyl group, sulfonyl group,- May be substituted by NH group or -N (C _1-3 -alkyl) group), or may be substituted by heteroaryl group or heteroaryl-C _1-3 -alkyl group)
Represents
R ₄ represents a C _3-7 -cycloalkyl group (the methylene group at the 4-position of the 6-membered or 7-membered cycloalkyl group is an amino group, a C _1-3 -alkylamino group or di- (C _1-3 -alkyl)- May be substituted by an amino group, or may be substituted by an —NH group or —N (C _1-3 -alkyl) group), or a phenyl group substituted by a group R ₆ [this is further fluorine Atom, chlorine atom, bromine atom or iodine atom, C _1-5 -alkyl group, trifluoromethyl group, hydroxy group, C _1-3 -alkoxy group, carboxy group, C _1-3 -alkoxycarbonyl group, amino group, Acetylamino group, C _1-3 -alkyl-sulfonylamino group, aminocarbonyl group, C _1-3 -alkyl-aminocarbonyl group, di- (C _1-3 -alkyl) -aminocarbonyl group, aminosulfonyl group, C _1-3 - alkyl - aminosulfonyl group, di - (C _1-3 - alkyl) - A Nosuruhoniru group, may be mono- or disubstituted by nitro group or a cyano group, the substituents may be the same, or may be different, also
R ₆ is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom,
Cyano group, nitro group, amino group, C _1-5 -alkyl group, C _3-7 -cycloalkyl group, trifluoromethyl group, phenyl group, tetrazolyl group or heteroaryl group,
formula

(Wherein the hydrogen atom bonded to the nitrogen atom may in each case be independently substituted by a C _1-3 -alkyl group)
Base of
C _1-3 -alkoxy group, C _1-3 -alkoxy-C _1-3 -alkoxy group, phenyl-C _1-3 -alkoxy group, amino-C _2-3 -alkoxy group, C _1-3 -alkylamino -C _2-3 -alkoxy group, di- (C _1-3 -alkyl) -amino-C _2-3 -alkoxy group, phenyl-C _1-3 -alkylamino-C _2-3 -alkoxy group, N- (C _1-3 -alkyl) -phenyl-C _1-3 -alkylamino-C _2-3 -alkoxy group, C _5-7 -cycloalkyleneimino-C _2-3 -alkoxy group or C _1-3 -alkyl Mercapto group,
Carboxy group, C _1-4 -alkoxycarbonyl group, aminocarbonyl group, C _1-3 -alkylamino-carbonyl group, N- (C _1-5 -alkyl) -C _1-3 -alkylaminocarbonyl group, phenyl- C _1-3 -alkylamino-carbonyl group, N- (C _1-3 -alkyl) -phenyl-C _1-3 -alkylamino-carbonyl group, piperazinocarbonyl group or N- (C _1-3 -alkyl ) -Piperazinocarbonyl group,
A C _1-3 -alkylaminocarbonyl group or N- (C _1-5 -alkyl) -C _1-3 -alkylaminocarbonyl group (the alkyl moiety is substituted by a carboxy group or a C _1-3 -alkoxycarbonyl group, or Substituted at the 2- or 3-position by a di- (C _1-3 -alkyl) -amino group, piperazino group, N- (C _1-3 -alkyl) -piperazino group or 4- to 7-membered cycloalkyleneimino group Is)
C _3-7 -cycloalkylcarbonyl group (the methylene group at the 4-position of the 6-membered or 7-membered cycloalkyl moiety is an amino group, a C _1-3 -alkylamino group or a di- (C _1-3 -alkyl) -amino group) Or may be substituted by a —NH group or a —N (C _1-3 -alkyl) group),
A 4- to 7-membered cycloalkyleneimino group (the methylene group bonded to the imino group may be substituted by a carbonyl group or a sulfonyl group, or the cycloalkylene moiety may be fused to a phenyl ring, or 1 One or two hydrogen atoms may be each substituted by a C _1-3 -alkyl group, and / or in each case the 4-position methylene group of the 6-membered or 7-membered cycloalkyleneimino group is a carboxy group C _1-3 -alkoxycarbonyl group, aminocarbonyl group, C _1-3 -alkylaminocarbonyl group, di- (C _1-3 -alkyl) -aminocarbonyl group, phenyl-C _1-3 -alkylamino group or N- (C _1-3 -alkyl) -phenyl-C _1-3 -alkylamino group may be substituted, or oxygen atom or sulfur atom, sulfinyl group, sulfonyl group, -NH group, -N ( C _1-3 -alkyl) group, -N (phenyl) group, -N (C _1-3 -alkylcarbonyl) group or -N (benzoyl) group).
A C _1-4 -alkyl group substituted by a group R ₇ (R ₇ is a C _3-7 -cycloalkyl group (the methylene group at the 4-position of the 6-membered or 7-membered cycloalkyl group is an amino group, C _1-3- May be substituted by an alkylamino group or a di- (C _1-3 -alkyl) -amino group, or may be substituted by an —NH group or —N (C _1-3 -alkyl) group, or In the 5- to 7-membered cycloalkyl group, the — (CH ₂ ) ₂ group may be substituted by a —CO—NH group, and the — (CH ₂ ) ₃ group may be a —NH—CO—NH group or —CO— NH-CO group may be substituted by, or - (CH _{2) 4} group may be substituted by -NH-CO-NH-CO group, in each case, hydrogen bonded to the nitrogen atom The atom may be substituted by a C _1-3 -alkyl group),
An aryl group or heteroaryl group,
A hydroxy group or a C _1-3 -alkoxy group,
Amino group, C _1-7 -alkylamino group, di- (C _1-7 -alkyl) -amino group, phenylamino group, N-phenyl-C _1-3 -alkyl-amino group, phenyl-C _1-3 -Alkyl-amino group, N- (C _1-3 -alkyl) -phenyl-C _1-3 -alkylamino group or di- (phenyl-C _1-3 -alkyl) -amino group,
ω-hydroxy-C _2-3 -alkyl-amino group, N- (C _1-3 -alkyl) -ω-hydroxy-C _2-3 -alkyl-amino group, di- (ω-hydroxy-C _2-3 -Alkyl) -amino, di- (ω- (C _1-3 -alkoxy) -C _2-3 -alkyl) -amino or N- (dioxolan-2-yl) -C _1-3 -alkyl-amino Group,
A C _1-3 -alkylcarbonylamino-C _2-3 -alkyl-amino group or a C _1-3 -alkylcarbonylamino-C _2-3 -alkyl-N- (C _1-3 -alkyl) -amino group,
C _1-3 -alkylsulfonylamino group, N- (C _1-3 -alkyl) -C _1-3 -alkyl-sulfonylamino group, C _1-3 -alkylsulfonylamino-C _2-3 -alkyl-amino group Or a C _1-3 -alkylsulfonylamino-C _2-3 -alkyl-N- (C _1-3 -alkyl) -amino group,
Hydroxycarbonyl C _1-3 -alkylamino group or N- (C _1-3 -alkyl) -hydroxycarbonyl C _1-3 -alkyl-amino group,
A guanidino group (one or two hydrogen atoms each _optionally substituted by a C _1-3 -alkyl group),
Formula -N (R ₈ ) -CO- (CH ₂ ) _n -R ₉ (II)
Group of
R ₈ represents a hydrogen atom or a C _1-3 -alkyl group,
n represents one of the numbers 0, 1, 2, or 3, and
R ₉ is an amino group, C _1-4 -alkylamino group, di- (C _1-4 -alkyl) -amino group, phenylamino group, N- (C _1-4 -alkyl) -phenylamino group, benzylamino A group, N- (C _1-4 -alkyl) -benzylamino group or C _1-4 -alkoxy group, 4- to 7-membered cycloalkyleneimino group (in each case the 4-position of a 6-membered or 7-membered cycloalkyleneimino group) The methylene group is oxygen atom or sulfur atom, sulfinyl group, sulfonyl group, -NH group, -N (C _1-3 -alkyl) group, -N (phenyl) group, -N (C _1-3 -alkylcarbonyl) A group or an -N (benzoyl) group), or when n represents one of the numbers 1, 2 or 3, it may also represent a hydrogen atom)
Formula -N (R ₁₀ )-(CH ₂ ) _m- (CO) _o -R ₁₁ (III)
Group of
R ₁₀ is a hydrogen atom, C _1-3 -alkyl group, C _1-3 -alkylcarbonyl group, arylcarbonyl group, phenyl-C _1-3 -alkylcarbonyl group, C _1-3 -alkylsulfonyl group, arylsulfonyl group Or a phenyl-C _1-3 -alkylsulfonyl group,
m represents one of the numbers 1, 2, 3 or 4;
o may represent the number 1 or, if m represents one of the numbers 2, 3 or 4, o may also represent the number 0; and
R ₁₁ is an amino group, C _1-4 -alkylamino group, di- (C _1-4 -alkyl) -amino group, phenylamino group, N- (C _1-4 -alkyl) -phenylamino group, benzylamino Group, N- (C _1-4 -alkyl) -benzylamino group, C _1-4 -alkoxy group or C _1-3 -alkoxy-C _1-3 -alkoxy group, di- (C _1-4 -alkyl) -Amino-C _1-3 -alkylamino group (optionally substituted at the 1-position by a C _1-3 -alkyl group) or a 4- to 7-membered cycloalkyleneimino group (the cycloalkylene moiety is attached to the phenyl ring) The methylene group at the 4-position of the 6-membered or 7-membered cycloalkyleneimino group may be an oxygen atom or a sulfur atom, a sulfinyl group, a sulfonyl group, an —NH group, —N (C _{1 -3} -alkyl), -N (phenyl), -N (C _1-3 -alkylcarbonyl) or -N (benzoyl) groups May represent))
C _4-7 -cycloalkylamino group, C _4-7 -cycloalkyl-C _1-3 -alkylamino group or C _4-7 -cycloalkenylamino group (the 1-position of the ring is contained in the double bond) Each of the above groups may be further substituted at the amino nitrogen atom position by a C _5-7 -cycloalkyl group, a C _2-4 -alkenyl group or a C _1-4 -alkyl group),
4- to 7-membered cycloalkyleneimino group (the cycloalkylene moiety is a phenyl group or an oxazolo group, an imidazolo group, a thiazolo group, a pyridino group, a pyrazino group or a pyrimidino group (optionally a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, a nitro group) group, C _1-3 - alkyl group, C _1-3 - alkoxy group or amino group may be fused to may) be substituted with, and / or one or two hydrogen atoms are each C _It may be substituted with a _1-3 -alkyl group, a C _5-7 -cycloalkyl group or a phenyl group, and / or the 3-position methylene group of the 5-membered cycloalkyleneimino group is a hydroxy group, hydroxy-C _1- Optionally substituted by a ₃ -alkyl group, a C _1-3 -alkoxy group or a C _1-3 -alkoxy-C _1-3 -alkyl group,
When the 6- or 7-membered cycloalkyleneimino group has a 3- or 4-position methylene group, respectively, a hydroxy group, a hydroxy-C _1-3 -alkyl group, a C _1-3 -alkoxy group, or a C _1-3 -alkoxy group -C _1-3 -alkyl group, carboxy group, C _1-4 -alkoxycarbonyl group, aminocarbonyl group, C _1-3 -alkylaminocarbonyl group, di- (C _1-3 -alkyl) -aminocarbonyl group, May be substituted by phenyl-C _1-3 -alkylamino group or N- (C _1-3 -alkyl) -phenyl-C _1-3 -alkyl-amino group, or oxygen or sulfur atom, sulfinyl group , Sulfonyl group, -NH group, -N (C _1-3 -alkyl-) group, -N (phenyl) group, -N (phenyl-C _1-3 -alkyl-) group, -N (C _1-3 -Alkylcarbonyl) group, -N (C _1-4 -hydroxycarbonyl) group, -N (C _1-4 -alkoxycarbonyl) group, -N (benzoyl-) group or -N (phenyl-C _1- Optionally substituted by a ( _3- alkylcarbonyl) group,
The methylene group bonded to the imino nitrogen atom of the cycloalkyleneimino group may be substituted with a carbonyl group or a sulfonyl group, or a cycloalkyleneimino condensed with a 5- to 7-membered monocyclic cycloalkyleneimino group or phenyl group In the group, two methylene groups bonded to the imino nitrogen atom may each be substituted by a carbonyl group)
Represents), or
R ₆ is a C _1-4 -alkyl group (this is a carboxy group, a C _1-3 -alkoxycarbonyl group, an aminocarbonyl group, a C _1-3 -alkylaminocarbonyl group or di- (C _1-3 -alkyl)- Substituted with an aminocarbonyl group or a 4-7 membered cycloalkyleneiminocarbonyl group),
An N- (C _1-3 -alkyl) -C _2-4 -acylamino group (which is further substituted in its alkyl part by a carboxy group or a C _1-3 -alkoxycarbonyl group),
Formula -N (R ₁₂ ) -CO- (CH ₂ ) _p -R ₁₃ (IV)
Group of
R ₁₂ represents a hydrogen atom, a C _1-6 -alkyl group, a C _3-7 -cycloalkyl group, or a C _1-3 -alkyl group (at the terminal, a phenyl group, a heteroaryl group, a trifluoromethyl group, a hydroxy group, C _{1 -3} -alkoxy group, aminocarbonyl group, C _1-4 -alkylamino-carbonyl group, di- (C _1-4 -alkyl) -amino-carbonyl group, C _1-3 -alkylcarbonyl group, C _1-3 -Alkyl-sulfonylamino group, N- (C _1-3 -alkyl) -C _1-3 -alkyl-sulfonylamino group, C _1-3 -alkyl-aminosulfonyl group or di- (C _1-3 -alkyl) -Substituted by an aminosulfonyl group) and p represents one of the numbers 0, 1, 2 or 3, and
R ₁₃ means the group R ₇ described above, or when p represents one of the numbers 1, 2 or 3, it may also represent a hydrogen atom)
Formula -N (R ₁₄ )-(CH ₂ ) _q- (CO) _r -R ₁₅ (V)
Group of
R ₁₄ is a hydrogen atom, C _1-4 -alkyl group, C _1-3 -alkylcarbonyl group, arylcarbonyl group, phenyl-C _1-3 -alkylcarbonyl group, heteroarylcarbonyl group, heteroaryl-C _1-3 -Represents an alkylcarbonyl group, a C _1-4 -alkylsulfonyl group, an arylsulfonyl group, a phenyl-C _1-3 -alkylsulfonyl group, a heteroarylsulfonyl group or a heteroaryl-C _1-3 -alkyl-sulfonyl group,
q represents one of the numbers 1, 2, 3 or 4;
r may represent the number 1 or, if q is one of the numbers 2, 3 or 4, it may also represent the number 0;
R ₁₅ means the group R ₇ above),
Formula -N (R ₁₆ ) -SO ₂ -R ₁₇ (VI)
Group of
R ₁₆ is a hydrogen atom or a C _1-4 -alkyl group (optionally substituted with a cyano group, a trifluoromethyl-carbonylamino group or an N- (C _1-3 -alkyl) -trifluoromethyl-carbonylamino group at the terminal) May represent) and
R ₁₇ represents a C _1-3 -alkyl group),
Di- (C _1-3 -alkyl) -amino-C _1-3 -alkylcarbonyl group or di- (C _1-3 -alkyl) -amino-C _1-3 -alkyl-sulfonyl group and di- (C _{1 -3} -alkyl) -aminocarbonyl-C _1-3 -alkyl substituted with an amino group, or
N- (C _1-3 -alkyl) -C _1-5 -alkylsulfonylamino group or N- (C _1-3 -alkyl) -phenylsulfonylamino group (the alkyl moiety is further substituted by a cyano group or a carboxy group) ing)
Represents
All the single-bonded or condensed phenyl groups contained in the group described in R ₆ are fluorine atom, chlorine atom, bromine atom or iodine atom, C _1-5 -alkyl group, trifluoromethyl group, Hydroxy group, C _1-3 -alkoxy group, carboxy group, C _1-3 -alkoxycarbonyl group, aminocarbonyl group, C _1-4 -alkylamino-carbonyl group, di- (C _1-4 -alkyl) -amino -Carbonyl group, aminosulfonyl group, C _1-3 -alkyl-aminosulfonyl group, di- (C _1-3 -alkyl) -aminosulfonyl group, C _1-3 -alkyl-sulfonylamino group, nitro group or cyano group May be mono- or di-substituted, and these substituents may be the same or different, or two adjacent hydrogen atoms of the phenyl group may be substituted by a methylenedioxy group. May represent), and
R ₅ represents a hydrogen atom or a C _1-3 -alkyl group,
If necessary, the aryl group is a fluorine atom, chlorine atom, bromine atom or iodine atom, cyano group, trifluoromethyl group, nitro group, carboxy group, aminocarbonyl group, C _1-3 -alkyl group or C _1-3 -alkoxy group. Means a phenyl group or naphthyl group which may be mono- or di-substituted by
A heteroaryl group means a monocyclic 5- or 6-membered heteroaryl group optionally substituted by a C _1-3 -alkyl group in the carbon skeleton;
The 6-membered heteroaryl group contains 1, 2 or 3 nitrogen atoms, and the 5-membered heteroaryl group is optionally substituted by a C _1-3 -alkyl group or a phenyl-C _1-3 -alkyl group An imino group which may be substituted, an oxygen atom or a sulfur atom, or an optionally substituted imino group or oxygen atom or sulfur atom which may be substituted by a C _1-3 -alkyl group or phenyl-C _1-3 -alkyl group, and further A nitrogen atom or optionally an imino group optionally substituted by a C _1-3 -alkyl group or a phenyl-C _1-3 -alkyl group and two nitrogen atoms,
In addition, the phenyl ring may be fused to the monocyclic heterocyclic group through two adjacent carbon atoms, and the bond may be linked through a nitrogen atom or through a carbon atom in the heterocyclic moiety or a fused phenyl ring. Happens through
Some or all of the hydrogen atoms in the alkyl moieties contained in the above alkyl and alkoxy groups or in the previously defined groups of formula I may be substituted by fluorine atoms, or present carboxy groups And each hydrogen atom bonded to a nitrogen atom may be substituted with a group that can be cleaved in vivo.]
Of indolinone, their tautomers, diastereomers, enantiomers, mixtures thereof and salts thereof.   The composition according to claim 1, wherein the chronic fatty liver disease is an inflammatory disease.   The composition according to claim 1 or 2, wherein the chronic fatty liver disease is non-viral.   The composition according to any one of claims 1 to 3, wherein the chronic fatty liver disease is a non-alcoholic disease.   The composition according to any one of claims 1 to 4, wherein the chronic fatty liver disease includes non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH).   The composition according to any one of claims 1 to 5, wherein the chronic fatty liver disease comprises nonalcoholic steatohepatitis (NASH).   The composition according to any one of claims 1 to 6, wherein the chronic fatty liver disease comprises Type 4 of Matteoni classification of nonalcoholic steatohepatitis (NASH).   The composition according to any one of claims 1 to 7, wherein the prevention, improvement or treatment includes prevention, improvement or treatment of liver fibrosis.   The composition according to any one of claims 1 to 8, wherein the prevention, improvement or treatment is prevention or improvement or treatment of the chronic fatty liver disease at an early stage.   The composition according to claim 1, wherein the composition is administered orally.