JP2002121192A - Benzoylaminoisoindoline derivative, method of producing the same and intermediate therefor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel benzoylaminoisoindoline derivative that has excellent apolipo protein B (ApoB) antisecretory action and hypolipidemic action and is useful as a medicine, a method of producing the same and a synthetic intermediate. SOLUTION: This novel compound is a benzoylaminoisoindoline derivative represented by general formula [I] (ring A is a 5- or 6-membered aromatic heterocyclic ring which may be substituted; ring B is a benzene ring which may be substituted; Q is -CO- or -CH2-; R is a lower alkyl which may be substituted or a lower alkenyl which may be substituted, a carbamoyl which may be substituted, a heterocyclic group which may be substituted and an aryl group which may be substituted) or pharmacologically acceptable salt thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel benzoylaminoisoindoline derivative which has excellent apolipoprotein B (ApoB) secretion inhibitory activity and serum lipid lowering effect and is useful as a medicine, a process for producing the same, and a synthetic intermediate thereof.

[0002]

2. Description of the Related Art International Patent Publication No. WO 96/40640 discloses 4'-trifluoromethyl-biphenyl-2-carboxylic acid [2- (thiophen-2-yl-acetyl)-].
1,2,3,4-tetrahydroisoquinolin-6-yl] -amide, 4'-trifluoromethyl-biphenyl-2-carboxylic acid [2- (pyridin-2-yl-acetyl) -1,2,3, 4-tetrahydroisoquinoline-6
-Yl] -amide and the like, and WO98 /
No. 23593 discloses 4'-trifluoromethyl-biphenyl-2-carboxylic acid [2- (2- (pyridin-2-yl) ethyl) -1,2,3,4-tetrahydroisoquinolin-6-yl]-. It has been suggested that amides and the like have an ApoB secretion inhibitory action and can be used as a serum lipid lowering agent.

However, all of the amide compounds described therein have a biphenyl structure in the carboxylic acid moiety and a tetrahydroisoquinoline ring in the amine moiety, and have an aromatic moiety in the carboxylic acid moiety such as the compound of the present invention. No compound having a heterocyclic-phenyl group or a compound having an isoindoline ring in the amine moiety is described.

[0004]

DISCLOSURE OF THE INVENTION The present invention provides a novel benzoylaminoisoindoline derivative having an excellent apolipoprotein B secretion inhibitory action and a serum lipid lowering action. Further, the present invention also provides a method for producing such a novel compound and a synthetic intermediate thereof.

[0005]

Means for Solving the Problems In order to solve the problems, the present inventors have assiduously studied and found a novel benzoylaminoisoindoline derivative having an apolipoprotein B secretion inhibitory effect and a serum lipid lowering effect. Completed the invention.

That is, the present invention provides a compound represented by the general formula [I]:

[0007]

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(Wherein, ring A is an optionally substituted 5- or 6-membered aromatic heterocyclic group, ring B is an optionally substituted benzene ring, Q is -CO- or -CH _2- , R is an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted carbamoyl group, an optionally substituted heterocyclic group, or an optionally substituted aryl A benzoylaminoisoindoline derivative or a pharmaceutically acceptable salt thereof.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The substituent on ring A in the target compound [I] of the present invention is selected from, for example, (1) trifluoromethyl group, (2) hydroxyl group, oxo group and hydroxyimino group. A lower alkyl group which may be substituted with the same or different 1 to 3 groups, (3) a lower alkyl group, a hydroxyl group, and a dialkylamino group which are substituted with 1 to 3 same or different groups selected from dialkylamino groups; A lower alkoxy group, (4) a hydroxyl group, (5) a nitro group, (6) a cyano group, (7) a lower alkyl group, a lower alkoxy lower alkyl group, a halogeno lower alkyl group, and an aryl lower alkyl group. A carbamoyl group which may be substituted with (8) an amino-protecting group,
An amino group which may be substituted with a group selected from a lower alkyl group and a lower alkylsulfonyl group, (9) a lower alkanoyloxy group which may be substituted with an aryl group, and (10) a lower alkoxycarbonyl group. Can be

Ring A may be substituted with 1 to 3 identical or different groups selected from the above (1) to (10).

The ring A includes, for example, a 5- or 6-membered aromatic heterocyclic group containing the same or different 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur atoms.

Specifically, for example, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl,
Examples thereof include a thienyl group, a pyrrolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an imidazolyl group, and a pyrazolyl group.

Examples of the substituent on ring B in the target compound [I] of the present invention include (1) a nitro group, (2) a hydroxyl group, (3) a lower alkoxy group, a hydroxyl group, an aryl group,
(Lower alkylamino) aryl group, lower alkoxycarbonyl group, lower alkenyloxycarbonyl group, carboxyl group, amino group, lower alkylamino group, lower alkylcarbamoyl group, cyano group, pyridyl group, pyrrolidinyl group, morpholinyl group, piperazinyl group, And a lower alkoxy group which may be substituted with a group selected from a lower alkylpiperazinyl group, (4) a lower alkoxycarbonyl group, (5) (i) a lower alkoxy group, an amino group, a lower alkyl group amino group, and Lower alkanoyl group substituted with 1 to 3 identical or different groups selected from lower alkoxycarbonyl group, (ii) amino-protecting group, (iii) pyridyl group, or lower alkylamino group. Good lower alkyl groups, and (iv) pyridylka A carbamoyl group optionally substituted with a group selected from a bonyl group, an amino group optionally substituted with a group selected from the group consisting of: (6) a lower alkyl group, a lower alkoxy lower alkyl group, and a lower alkylamino lower alkyl group , (7) a morpholinocarbonyl group,
(8) a cyano group, and (9) a lower alkylaminocarbonyloxy group.

Ring B may be substituted with 1 to 3 identical or different groups selected from the above (1) to (9).

When R in the object compound [I] of the present invention is an optionally substituted lower alkyl group, the substituent on the lower alkyl group includes (i) a lower alkyl group;
A lower alkoxy group; a nitro group; a lower alkoxycarbonyl group; a carboxyl group; an oxo group; a trifluoromethyl group; a carbamoyl group (the carbamoyl group is a lower alkyl group, a halogeno lower alkyl group, and a hydroxy lower alkyl group; An amino group (the amino group may be a lower alkanoyl group, a lower alkoxy lower alkanoyl group, a lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy carbonyl group, and a lower alkyl group) A cyano group; a hydroxyl group which may be protected; a halogen atom; and 1 to 3 same or different groups selected from a formyl group, which may be substituted with an aminoalkylidene group. A heterocyclic group (ii) A lower alkyl group; an amino group (the amino group is a lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkyl group, a pyridyl lower alkyl group, a lower alkylaminocarbonyl group, a halogeno lower alkylaminocarbonyl group, a lower alkanoyl group, or a halogeno lower alkanoyl A lower alkoxy group; an aryl lower alkoxy group; a benzyloxy lower alkoxy group; a lower alkylamino lower alkoxy group; a nitro group; an optionally protected hydroxyl group; a lower alkylcarbamoyl group; An aryl group or a fluorenyl group which may be substituted with the same or different 1 to 3 groups selected from an alkylcarbamoyl group and a morpholinyl group, (iii) a hydroxyl group which may be protected, and (iv) lower alkyl. , Halogeno-lower alkyl group, and a carbamoyl group which may be substituted by a group selected from benzothiazolyl group, (v) Formula:

[0016]

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(Wherein n represents an integer of 0 to 4), (vi) a lower alkoxycarbonyl group, (vi)
i) protecting group for amino group, lower alkyl group, pyridyl group,
And an amino group which may be substituted with a pyrimidinyl group, (viii) a halogen atom, and (ix) an oxo group.

The lower alkyl group for R is as defined in the above (i)
And may be substituted with 1 to 3 identical or different groups selected from-(ix).

When R in the target compound [I] of the present invention is an optionally substituted lower alkenyl group, examples of the substituent on the lower alkenyl group include an aryl group.

When R in the target compound [I] of the present invention is an optionally substituted carbamoyl group, examples of the substituent on the carbamoyl group include a lower alkyl group, a halogeno lower alkyl group, and a benzothiazolyl group. . The optionally substituted carbamoyl group includes a compound represented by the formula:

[0021]

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(Wherein m represents an integer of 0 to 4).

When R in the target compound [I] of the present invention is an optionally substituted heterocyclic group, the substituent on the heterocyclic group may be a lower alkyl group, a lower alkoxy group or a lower alkoxycarbonyl group. Groups, an amino group, a lower alkylamino group, an optionally protected hydroxyl group, an optionally protected amino group, and the like.

The heterocyclic group for R may be substituted with 1 to 3 identical or different groups selected from the above substituents.

When R in the target compound [I] of the present invention is an optionally substituted heterocyclic group, examples of the heterocyclic group include a pyridyl group, an indolyl group, a thiazolyl group, an imidazolyl group, Pyrrolyl group, pyrimidinyl group, thienyl group, benzo [b] furyl group, benzo [b]
Thienyl, pyrazolyl, triazolyl, quinolyl, isoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, 5,11-dihydro-dibenzo [b, e] [1,4] oxazepin-5-yl, dihydropyrazolyl Group, tetrazolyl group and the like.

When R in the target compound [I] of the present invention is an aryl group which may be substituted, the substituent on the aryl group may be a lower alkyl group, a lower alkoxy group, a lower alkylcarbamoyl group, a halogeno-lower group. Examples thereof include an alkylcarbamoyl group, a morpholinyl group, an amino group, a lower alkylamino group, an optionally protected hydroxyl group, and an optionally protected amino group.

The aryl group for R may be substituted with 1 to 3 identical or different groups selected from the above substituents.

When R in the target compound [I] of the present invention is an optionally substituted aryl group, specific examples of the aryl group include, for example, phenyl, naphthyl, anthranyl, phenanthrenyl and the like. No.

When the target compound [I] of the present invention has a protected amino group, examples of the protecting group for the amino group include, for example, an optionally substituted lower alkoxycarbonyl group and a lower alkenyloxycarbonyl group. An acyl group, an optionally substituted aryl group-substituted lower alkyl group, a lower alkenyl group, and the like.Specifically, an ethoxycarbonyl group, a methoxycarbonyl group,
Lower alkoxy groups such as tert-butoxycarbonyl group and 2,2,2-trichloroethyloxycarbonyl group which may be substituted with a halogen atom, benzyloxycarbonyl group and 4-methoxybenzyloxycarbonyl group. And a lower alkenyloxycarbonyl group such as an aryl group-substituted lower alkoxycarbonyl group and an allyloxycarbonyl group, and an acyl group such as a formyl group, an acetyl group, a propionyl group and a butyryl group. Furthermore, an aryl group-substituted lower alkyl group which may be substituted with a lower alkoxy group such as a benzyl group and a 4-methoxybenzyl group, a lower alkenyl group such as an allyl group, and a 9-fluorenylmethoxycarbonyl group are also included. Among these, preferred are lower alkoxycarbonyl groups which may be substituted, and specific examples include a benzyloxycarbonyl group and a tert-butoxycarbonyl group. Further, the protected amino group also includes, for example, a case where a phthalimide group is formed together with the protected amino group.

When the target compound [I] of the present invention has a protected hydroxyl group, the protecting group for the hydroxyl group may be an optionally substituted aryl lower alkyl group, an acyl group or an optionally substituted aryl group. Conventional protecting groups such as a good lower alkoxycarbonyl group and a trialkylsilyl group can be exemplified. Of these, preferred are:
For example, benzyl group, unsubstituted aryl lower alkyl group such as phenethyl group, formyl group, acetyl group, propionyl group, malonyl group, acryloyl group, acyl group such as benzoyl group, lower alkoxy such as methoxycarbonyl group and ethoxycarbonyl group. Examples include tri-lower alkylsilyl groups such as carbonyl group, trimethylsilyl group, triethylsilyl group and tert-butyldimethylsilyl group. Furthermore, a triphenylmethyl group, a 2-cyanoethyl group, etc. are also mentioned.

Among the desired compounds [I] of the present invention, preferred compounds are those wherein ring A has the formula:

[0032]

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Wherein R ¹ is a trifluoromethyl group or a lower alkanoyl group, ring B is a lower alkoxy group, a (lower alkylamino lower alkanoyl) amino group, a lower alkylamino lower alkoxy group, a lower alkylcarbamoyl group And a benzene ring which may be substituted with a group selected from a lower alkoxycarbonyl group,
Q is -CO- or _-CH 2 -, R is the following (1) to
(1) a lower alkyl group substituted with a group selected from (4): (1) a lower alkyl group substituted with a group selected from a lower alkyl group, a nitro group, a lower alkoxycarbonyl group, a cyano group, an amino group, and a hydroxy lower alkyl group; Pyrazolyl group, (2) pyridyl group, (3) tetrazolyl group,
Or a compound which is (4) a thiazolyl group optionally substituted with an amino group.

Among the desired compounds [I] of the present invention, more preferred compounds are those wherein ring A has the formula:

[0035]

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Wherein ring B is a benzene ring,
Compounds wherein Q is -CO-, and R is a pyrazolylmethyl group which may be substituted with a group selected from a lower alkyl group, a nitro group, a lower alkoxycarbonyl group, and a hydroxy lower alkyl group.

More specific examples of the target compound [I] of the present invention include, for example, 2- (1H-pyrazole-
1-yl) acetyl-5- [2- (5-trifluoromethyl-pyridin-2-yl) benzoylamino] -isoindoline, 2- (1H-pyrazol-1-yl) acetyl-5- [2- ( 5-trifluoromethyl-pyridin-2-yl) -3-methoxycarbonylbenzoylamino] -isoindoline, 2- [2- (1H-pyrazol-1-yl) ethyl] -5- [2- (5-tri Fluoromethyl-pyridin-2-yl) benzoylamino] -isoindoline or a pharmaceutically acceptable salt thereof.

When the compound on the ring A, the substituent on the ring B, and / or R has an asymmetric atom, the objective compound [I] of the present invention exists as an optical isomer based on the asymmetric atom. However, the present invention includes both of these optical isomers and mixtures thereof.

The object compound [I] of the present invention or a pharmaceutically acceptable salt thereof has an apolipoprotein B secretion inhibitory effect and exhibits an excellent serum lipid lowering effect.

Therefore, the target compound [I] of the present invention or a pharmaceutically acceptable salt thereof is preferably used for hyperlipidemia, ischemic heart disease, atherosclerosis, coronary arteriosclerosis, hypercholesterolemia, hypertriglyceridemia. Disease, familial hyperlipidemia, hyperlipoproteinemia, arteriosclerosis, coronary arteriosclerosis, coronary artery disease, ischemic brain disease, stroke, circulatory and microcirculatory disorders, thrombosis, hyperglycemia, diabetes, acute bleeding It is useful for the prevention and treatment of atopic pancreatitis, obesity, steatosis, constipation and the like. Further, the target compound [I] of the present invention has the characteristics of low toxicity and high safety as a medicine.

The objective compound [I] of the present invention can be used for a pharmaceutical use in a free form or in the form of a pharmaceutically acceptable salt. Pharmaceutically acceptable salts of compound [I] include, for example, inorganic acid salts such as hydrochloride, sulfate, phosphate or hydrobromide, acetate, fumarate, oxalate, citric acid Salts, organic acid salts such as methanesulfonate, benzenesulfonate, tosylate or maleate, and the like. When the compound has a substituent such as a carboxyl group, a salt with a base (eg, sodium salt,
Alkali metal salts such as potassium salts or alkaline earth metal salts such as calcium salts).

The target compound [I] of the present invention or a salt thereof includes any of its inner salts and adducts, solvates and hydrates thereof.

The object compound [I] of the present invention or a pharmacologically acceptable salt thereof can be administered orally or parenterally. Tablets, granules, capsules, powders and injections are also available. , Can be used as conventional pharmaceutical preparations such as inhalants.

The dose of the compound [I] of the present invention or a pharmaceutically acceptable salt thereof is determined by the method of administration, age of the patient,
Although it differs depending on the body weight and condition, injection is usually about 0.01 to 5 mg / kg, especially about 0.1 to 3 mg / kg per day, and oral is usually about 1 to 3 mg / kg.
About 0.1-100 mg / kg per day, especially about 0.1
It is preferably about 50 mg / kg.

According to the present invention, the target compound [I] can be produced by the following [Method A] to [Method H].
It is not limited to these. [Method A] The benzoylaminoisoindoline derivative represented by the target compound [I] of the present invention has the general formula [5]:

[0046]

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(However, the symbols have the same meaning as described above.)
And a salt thereof, and a general formula [6]:

[0048]

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(However, the symbols have the same meaning as described above.)
Or a salt thereof, or a carboxylic acid compound represented by the formula:

This reaction can be carried out in a solvent, in the presence of a condensing agent, in the presence or absence of an activator, in the presence or absence of a base. The solvent may be any solvent that does not adversely affect the reaction, and examples include methylene chloride, chloroform, dimethylformamide, dimethylacetamide, tetrahydrofuran, toluene, benzene, 1,2-dichloroethane, 1-methylpyrrolidinone, and the like. Examples of the condensing agent include dicyclohexylcarbodiimide (DCC), 1-ethyl-3-
(3-dimethylaminopropyl) carbodiimide hydrochloride (WSC · HCl), diphenylphosphoryl azide (DPPA), carbonyldiimidazole (CDI),
Examples thereof include diethyl cyanophosphonate (DEPC), diisopropylcarbodiimide (DIPCI), and benzotriazol-1-yloxy-trispirolidinophosphonium hexafluorophosphate (PyBOP). Examples of the activator include 1-hydroxybenzotriazole (HOBt), hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP),
1-hydroxy-7-azabenzotriazole (HOA
t), hydroxyphthalimide (HOPht), pentafluorophenol (Pfp-OH) and the like.
As the base, for example, triethylamine, diisopropylethylamine, 4-methylmorpholine, 1,8-
Diazabicyclo [5,4,0] -7-undecene (DB
U) and the like.

The amount of the condensing agent to be used is 1-10 equivalents, preferably 1-2 equivalents, relative to compound [5] or compound [6].
Equivalent amounts can be used. The amount of the activator to be used is 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to compound [5] or compound [6]. This reaction can be carried out, for example, at 0 to 100 ° C, preferably at 0 to 50 ° C.

Further, the compound [6] is converted into a reactive derivative such as an acid chloride or a mixed acid anhydride and then reacted with the compound [5] in the presence of a base to give the compound [I].
You can also get [Method B] The benzoylaminoisoindoline derivative represented by the target compound [I] of the present invention also has the general formula [1]
5]:

[0053]

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(Wherein X ¹ represents a leaving group, and other symbols have the same meanings as described above) or a salt thereof, and a general formula [16]:

[0055]

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Wherein M is the same or different selected from a hydroxyl group, a halogen atom, a cyano group, a lower alkyl group, an aryl group, a lower alkoxy group, an alkylenedioxy group, an aryloxy group, an arylenedioxy group and an arylthio group Represents a metal that may be coordinated with a substituent,
The other symbols have the same meanings as described above).

This reaction can be carried out in a solvent, in the presence of a catalyst, in the presence or absence of a base, in the presence or absence of an additive. The solvent may be any solvent that does not adversely affect the reaction, for example, methylene chloride,
Chloroform, dimethylformamide, dimethylacetamide, tetrahydrofuran, toluene, xylene,
Water, 1-methylpyrrolidinone, dimethoxyethane, dioxane, diethylamine, triethylamine and the like. Examples of the metal of M include boron, tin, silicon, zinc, magnesium, aluminum, lithium, nickel and the like. Examples of the catalyst include palladium acetate, tetrakistriphenylphosphine palladium, bistriphenylphosphine palladium dichloride, bis (dibenzylideneacetone) palladium, bisbenzonitrile palladium dichloride, and the like. Examples of the base include sodium carbonate, potassium carbonate, potassium phosphate, triethylamine, diisopropylethylamine and the like. As the additive, for example, triphenylphosphine, tri-o-toluylphosphine, tri-n-butylphosphine, copper (I) bromide, copper (I) iodide, triphenylarsine, tri (2-furyl) phosphine , Diphenylphosphinoferrocene (d
ppf), diphenylphosphinobutan (dppb),
2,6-di-tert-butyl-4-cresol and the like.

The amount of compound [16] used is the same as that of compound [1]
5], preferably 1 to 5 equivalents, preferably 1 to 1.5 equivalents. The amount of the catalyst used is the same as that of compound [15]
0.001 to 0.5 equivalent, preferably 0.0
5 to 0.2 equivalents can be used. The amount of base used is
1 to 20 equivalents, preferably 1 equivalent, relative to compound [15]
Up to 5 equivalents can be used. The amount of the additive to be used is 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to compound [15].
Equivalent amounts can be used. This reaction is carried out, for example, from 0 to 15
It can be carried out at 0 ° C, preferably at 30 to 120 ° C.

The leaving group X ¹ is a fluorine atom,
Examples include a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, and a trifluoromethanesulfonyloxy group. [Method C] Among the target compounds [I] of the present invention, compounds in which Q is -CO- in the general formula [I], that is, the general formula [Ia]:

[0060]

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The benzoylaminoisoindoline derivative represented by the general formula [13]:

[0062]

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(However, the symbols have the same meanings as described above.)
And a salt thereof, and a carboxylic acid compound represented by the general formula [2]: R-COOH [2] (wherein the symbols have the same meanings as described above) or a salt thereof. You can also.

This reaction can be carried out in a solvent, in the presence of a condensing agent, in the presence or absence of an activator, in the presence or absence of a base. The solvent may be any solvent that does not adversely affect the reaction. For example, the solvent [A
Examples of the solvents that can be used in the reaction of [Method] can be used as appropriate. In addition, as the base or the activator, for example, those exemplified in the reaction of the above [Method A] can be appropriately used.

The compound [2] is converted to a reactive derivative such as an acid chloride or a mixed acid anhydride, and then reacted with the compound [13] in the presence of a base to give the compound [I]
-A] can also be obtained. [D Method] The object compound [I] of the present invention of the general formula [I], Q is -CH ₂ - compounds in which, i.e., the general formula [I-b]:

[0066]

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(However, the symbols have the same meaning as described above.)
The benzoylaminoisoindoline derivative represented by
The compound represented by the general formula [Ia] or a salt thereof can be produced by subjecting the compound to a reduction reaction.

The reduction reaction can be carried out in a solvent in the presence of a suitable reducing agent. The solvent may be any solvent that does not adversely affect the reaction, and includes, for example, tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane and the like. Suitable reducing agents include, for example,
Examples include sodium borohydride-boron trifluoride diethyl ether complex, lithium aluminum hydride, aluminum hydride, lithium borohydride, diborane-dimethylsulfide complex, diborane-tetrahydrofuran complex, and the like.

The amount of the reducing agent to be used is 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to compound [Ia]. This reaction can be carried out, for example, at -30 to 100C, preferably at 0 to 50C. [Method E] Of the target compound [I] of the present invention, a compound represented by the general formula [I
-B] is a compound represented by the general formula [13] or a salt thereof, and a general formula [17]: R-CHO [17] (where the symbols have the same meanings as described above.) ) Or a salt thereof, followed by a reduction reaction.

The above condensation reaction can be carried out in a solvent in the presence or absence of a base, and the subsequent reduction reaction can be carried out in the presence of a reducing agent. The solvent used for the condensation reaction or the reduction reaction may be any solvent that does not adversely affect the reaction, such as methylene chloride, tetrahydrofuran, dioxane, diethyl ether, methanol, ethanol, isopropyl alcohol, 1,2-dichloroethane, water, and the like. Is mentioned. As the base, for example, triethylamine, diisopropylethylamine,
4-methylmorpholine and the like. Examples of the reducing agent include sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, sodium triacetoxyborohydride, hydrogen-palladium carbon, sodium borohydride-acetic acid, and the like.

The amount of compound [17] used is the same as that of compound [1]
3], 1 to 5 equivalents, preferably 1 to 1.5 equivalents can be used. The amount of the base used is the same as that of compound [13]
1 to 20 equivalents, preferably 1 to 5 equivalents can be used. The amount of the reducing agent to be used is 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to compound [13]. This reaction can be carried out, for example, at -30 to 100C, preferably at 0 to 50C.

The above condensation reaction and reduction reaction can also be carried out as a reductive amination reaction in one pot. [Method F] Of the target compound [I] of the present invention, a compound represented by the general formula [I
Benzoylamino isoindoline derivative represented by -b] Further, the compound or a salt thereof represented by the general formula [13], general formula _[18]: in ^{R-CH 2 -X 2 [18} ] ( wherein, ^{X 2} Represents a leaving group, and other symbols have the same meanings as described above).

This reaction can be carried out in a solvent, in the presence of a base, in the presence or absence of an additive. The solvent may be any solvent that does not adversely affect the reaction,
For example, tetrahydrofuran, dimethylformamide,
Examples include dimethylacetamide, dimethylsulfoxide, ethanol, isopropyl alcohol, acetonitrile and the like. As the base, potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine,
Examples include pyridine, sodium hydroxide, potassium hydroxide and the like. Examples of additives include sodium iodide, copper (I) iodide, copper (II) iodide, copper powder, potassium iodide, tetrabutylammonium chloride, tetraethyl And tetra-lower alkyl ammonium halides such as ammonium chloride.

The amount of compound [18] used is the same as that of compound [1]
3], 1 to 5 equivalents, preferably 1 to 1.5 equivalents can be used. The amount of the base used is the same as that of compound [13]
1 to 20 equivalents, preferably 1 to 5 equivalents can be used. The amount of the additive to be used is 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to compound [13]. This reaction can be carried out, for example, at -30 to 150 ° C, preferably at 0 to 80 ° C.

The leaving group X ² is, for example, a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, a trifluoromethanesulfonyloxy group,
-A toluenesulfonyloxy group, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a hydroxyl group and the like.

When the leaving group X ² is a hydroxyl group, a Mitsunobu reagent such as triphenylphosphine-diethylazodicarboxylate or triphenylphosphine-diisopropylazodicarboxylate can be used. [Method G] Of the target compound [I] of the present invention, the compound represented by the general formula [I
-C]:

[0077]

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(Wherein P represents a hydroxyl-protecting group, and other symbols have the same meanings as described above). The benzoylaminoisoindoline derivative represented by the general formula [13] or a salt thereof , The general formula [19]:

[0079]

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(However, the symbols have the same meanings as described above.)
Can be produced by reacting with a compound represented by the following formula:

This reaction can be carried out in a solvent, in the presence of a base, in the presence or absence of an additive. The solvent may be any solvent that does not adversely affect the reaction,
For example, methanol, ethanol, isopropyl alcohol, dimethylformamide, acetoniyl and the like can be mentioned. Examples of the base include triethylamine, diisopropylethylamine, 4-methylmorpholine and the like. Examples of the additive include ammonium chloride, tin (II) iodide and the like. [Method H] Of the target compound [I] of the present invention, a compound represented by the general formula [I
-D]:

[0082]

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(Wherein R ² represents an optionally substituted heterocyclic group or an optionally substituted aryl group, and other symbols have the same meanings as described above) The indoline derivative has the general formula [1]
3] or a salt thereof, and a compound represented by the general formula [2]
0]:

[0084]

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(However, the symbols have the same meanings as described above.)
Can be produced by reacting with a compound represented by the following formula:

This reaction can be carried out in a solvent in the presence or absence of a base or acid. The solvent may be any solvent that does not adversely affect the reaction, and examples thereof include methanol, ethanol, and propanol. Examples of the base include triethylamine, diisopropylpropylamine and the like. Examples of the acid include acetic acid, formic acid, p-toluenesulfonic acid and the like.

The target compound [I] of the present invention is obtained by converting the substituent on the ring A, the substituent on the ring B and / or the group R of the compound obtained as described above to another desired substituent. It can also be manufactured by conversion. Such a method for converting a substituent may be appropriately selected according to the type of the intended substituent, and may be carried out, for example, as in (Method a) to (Method i).

(Method a: Alkylation of Amino Group (Reductive Amination)) A substituent containing a lower alkylamino group (for example, a dimethylamino group) in which the group R in the general formula [I] may be substituted. The target compound [I] is a group R
From the corresponding compound [I], which is a substituent containing an unprotected primary or secondary amino group, and the corresponding aldehyde compound (for example, formaldehyde),
It can be manufactured by treating in the same manner as described above.

(Method b: Oximation of carbonyl group) The target compound [I] in which the substituent on ring A in the general formula [I] is a substituent containing an oxime, Can be produced by reacting the corresponding compound [I] which is a substituent containing and hydroxylamine with a conventional method.

(Method c: Amidation) The substituent on ring A, the substituent on ring B, and / or the group R in formula [I]
Is a substituent containing a carbamoyl group which may be substituted, a compound on the ring A, a substituent on the ring B, and / or a substituent in which the group R contains a carboxyl group. From the corresponding compound [I] and the corresponding primary or secondary amine compound in the same manner as in [Method A].

(Method d; N-acylation) The target compound wherein the substituent on ring A, the substituent on ring B and / or the group R in the general formula [I] is a substituent containing an acylamino group [ I] is an acylating agent corresponding to the corresponding compound [I] in which the substituent on ring A, the substituent on ring B, and / or the group R is a substituent containing an amino group (for example, picolinic acid, Dimethylaminoglycine) in the same manner as in the above [Method A].

(Method e: Substitution reaction of alkyl halide)
In the general formula [I], the group R is an optionally substituted nitrogen-containing heterocyclic group-substituted lower alkyl group (for example, 1-pyrazolylmethyl group) or lower alkylamino lower alkyl group (for example, dimethylaminomethyl group). Certain compounds [I] include a corresponding compound [I] in which the group R is a lower alkyl group (eg, a chloromethyl group) substituted with a halogen atom, and a corresponding optionally substituted nitrogen-containing heterocycle (eg, (Pyrazole) or a primary or secondary lower alkylamine (eg, dimethylamine) in the presence of a base. Examples of the base include organic bases such as triethylamine and diisopropylethylamine, and inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, cesium fluoride, and sodium hydrogen carbonate.

(Method f: Reduction Reaction of Nitro Group) The target compound in which the substituent on ring A, the substituent on ring B, and / or the group R in formula [I] is a substituent containing an amino group. [I] converts the corresponding compound [I] in which the substituent on the ring A, the substituent on the ring B, and / or the group R is a substituent containing a nitro group with a reducing agent (for example, hydrogen / palladium- (Carbon).

(Method g: Palladium Coupling and Hydrolysis) The target compound [I] in which the group R in the general formula [I] is a substituent containing an acetyl group is a compound in which the group R is a substituent containing a halogen atom. After reacting a corresponding compound [I] with tri-lower alkyl (1-lower alkoxyvinyl) tin in the presence of a catalyst (for example, bistriphenylphosphine palladium dichloride, palladium acetate, etc.),
It can be produced by hydrolysis.

(Method h: Reduction of carbonyl group) The target compound [I] in which the substituent on ring A in formula [I] and / or the group R is a substituent containing a hydroxyl group is represented by ring A
The corresponding compound [I] in which the above substituent and / or the group R is a substituent containing a carbonyl group can be prepared using a conventional reducing agent (eg, sodium borohydride, lithium aluminum hydride, lithium borohydride, etc.). It can be manufactured by processing.

(Method i: azidation and reduction reaction) A group R in the general formula [I] is an amino lower alkyl group (for example,
Compound [I] which is a substituent containing an aminomethyl group)
Is obtained by reacting a corresponding compound [I] in which the group R is a substituent containing a lower alkyl group substituted with a halogen atom (for example, a chloromethyl group) with an azidating agent, and then subjecting the compound to a reduction reaction. Can be manufactured. Examples of the azidating agent include sodium azide, trimethylsilane azide, tributyltin azide and the like.
Examples of the reducing agent include hydrogen / palladium-carbon, triphenylphosphine-water, zinc-acetic acid, sodium hydrosulfite, and the like.

(Method j: O-acylation or O-alkylation reaction) In the general formula [I], the substituent on the ring A and / or the substituent on the ring B may be an acyloxy group or a substituted group. The target compound [I], which is a substituent having a good lower alkoxy group, is the same as the corresponding compound [I], wherein the substituent on the ring A and / or the substituent on the ring B is a substituent containing a hydroxyl group, Produced by reacting an agent (eg, phenylacetyl chloride) or an optionally substituted lower alkyl halide (eg, 2-methoxyethyl chloride) in the presence of a base (eg, potassium carbonate, cesium carbonate). be able to.

(Method k: Reduction reaction of amide) General formula [I]
Wherein the substituent on ring A and / or the substituent on ring B is a substituent containing a lower alkylamino group which may be substituted, the target compound [I] is a substituent on ring A, And / or the corresponding compound [I], which is a substituent containing a lower alkanoylamino group in which the substituent on ring B may be substituted, is reacted in the presence of a reducing agent (for example, borane-dimethyl sulfide complex) It can be manufactured by the following.

[Method A] to [Method H], or (a)
The target compound [I] of the present invention obtained by the methods (Methods) to (k) can be converted to a pharmaceutically acceptable salt, if desired. Conversion to a pharmaceutically acceptable salt may be performed according to methods known to those skilled in the art.

Next, a method for preparing the starting compounds used in the above method will be described below.

Starting compounds [5] ([5-a] and [5
-B]) can be produced, for example, according to the following method.

[0102]

Embedded image

(The symbols have the same meanings as described above.) The reaction for producing compound [3] from isoindoline [1] and carboxylic acid compound [2] can be carried out in the same manner as in the above [Method A]. it can.

The reaction for producing compound [3] from dichloro compound [7] and compound [8] can be carried out in the presence of a base, in the presence or absence of an additive. Examples of the base include sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium methoxide, and the like. Examples of the additive include tetra lower alkyl ammonium halides such as tetrabutyl ammonium chloride and tetraethyl ammonium chloride.

As an example of this step, for example,

[0106]

Embedded image

The following can be mentioned.

The reaction for producing compound [4] from compound [3] can be carried out in the presence of a suitable nitrating agent. Suitable nitrating agents include, for example, concentrated nitric acid / concentrated sulfuric acid, potassium nitrate / concentrated sulfuric acid, potassium nitrate / trifluoroacetic acid and the like.

The reaction for producing compound [9] from compound [1] can be carried out in the same manner as the reaction for producing compound [4] from compound [3].

The reaction for producing the compound [4] from the compound [9] and the carboxylic acid compound [2] can be carried out in the same manner as in the above [Method A].

The reaction for producing compound [5-a] from compound [4] can be carried out in the presence of a suitable reducing agent. Examples of the reducing agent include hydrogen / palladium-carbon, lithium aluminum hydride, zinc-acetic acid, iron (II) chloride-hydrochloric acid, tin (II) chloride-hydrochloric acid, iron-hydrochloric acid,
Iron-ammonium chloride, ammonium formate / palladium-carbon and the like.

The reaction for producing the compound [5-b] from the compound [5-a] can be carried out in the same manner as in the above [Method D].

In the reaction for producing the compound [5-b] from the compound [9], the compound [5-a] is converted from the compound [4] after treating (N-alkylation) in the same manner as in the above [Method F]. It can be carried out by treating (reducing the nitro group) in the same manner as in the reaction to be produced.

When R is a lower alkyl group having a halogen atom, a substituent can be introduced on the alkyl group by reacting various nucleophiles in the presence or absence of a base. Examples of the halogen atom include a halogen atom such as a chlorine atom, a bromine atom and an iodine atom. Examples of the nucleophile include a nitrogen-containing heterocyclic group such as imidazole, pyrazole, pyrrole, indole, and triazole, or a primary or secondary lower alkylamino such as dimethylamine, diethylamine, ethylamine, morpholine, piperidine, and pyrrolidine. And the like. Examples of the base include potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, cesium fluoride, sodium hydroxide, potassium hydroxide and the like.

As an example of this step, for example,

[0116]

Embedded image

The following can be mentioned.

The starting compound [6] can be produced, for example, according to the following method.

[0119]

Embedded image

(Where X ⁰ is a hydrogen atom, a halogen atom or a trifluoromethanesulfonyloxy group, Y is a lower alkoxycarbonyl group or a mono- or di-lower alkylamino group, X ³ is a leaving group, and X ⁴ is a leaving group. Represents a group,
The other symbols have the same meanings as described above.) The reaction for producing compound [24] from compound [23] is as follows:
It can be implemented as follows.

When X ⁰ is a hydrogen atom or a halogen atom, a compound represented by the formula: MX ³ or MM is reacted in a solvent, in the presence of a base, in the presence or absence of an additive, If necessary, it can be carried out by treating with an acid. Examples of the solvent include tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane and the like. Examples of the base include n-butyllithium, sec-butyllithium and the like.
Examples of the additive include tetramethylethylenediamine, hexamethylphosphoric triamide, and the like. Examples of the acid include hydrochloric acid, sulfuric acid, and ammonium chloride.

When X ⁰ is a halogen atom or a trifluoromethanesulfonyloxy group, the compound is represented by the formula: MX ^{3 in} a solvent, in the presence of a catalyst, in the presence or absence of a base, in the presence or absence of an additive. Alternatively, the reaction can be carried out by reacting a compound represented by MM and, if necessary, treating with an acid. Examples of the solvent include dimethoxyethane, water, ethanol, toluene, dimethylformamide, acetonitrile, dioxane, dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, and a mixed solvent thereof. Examples of the catalyst include palladium acetate, tetrakistriphenylphosphine palladium, bis (diphenylphosphinoferrocene) dichloropalladium, and the like. Examples of the base include potassium acetate, potassium carbonate, sodium carbonate and the like. Examples of the additives include triphenylphosphine, tri-o-tolylphosphine, tri-n-butylphosphine, diphenylphosphinoferrocene (dppf), diphenylphosphinobutane (dppb), and 2,6-di-tert-butyl. -4-
Cresol and the like. Examples of the acid include hydrochloric acid, sulfuric acid, and ammonium chloride.

The reaction for producing compound [28] from compound [24] and compound [25] is carried out in a solvent in the presence of a catalyst.
It can be carried out in the presence or absence of a base, in the presence or absence of an additive. As the solvent, for example,
Examples include dimethoxyethane, water, ethanol, toluene, dimethylformamide, acetonitrile, dioxane, tetrahydrofuran, or a mixed solvent thereof.
Examples of the catalyst include palladium acetate, bistriphenylphosphine palladium dichloride, tetrakistriphenylphosphine palladium, bistriphenylphosphine palladium dichloride, bis (dibenzylideneacetone) palladium, bisbenzonitrile palladium dichloride, and the like. Examples of the base include potassium carbonate, sodium carbonate, potassium phosphate and the like. As the additive, for example, triphenylphosphine, tri-n-butylphosphine, tri-o-
Toluylphosphine, diphenylphosphinoferrocene (dppf), diphenylphosphinobutane (dpp
b), 2,6-di-tert-butyl-4-cresol and the like.

[0124] Specific examples of the leaving group X ³ is, for example, chlorine, bromine, halogen atom such as iodine, lower alkoxy group, a cyano group, a trifluoromethanesulfonyloxy group and the like.

[0125] formula: Specific examples of the compound represented by ^{M-X 3} include tri -n- butyl tin chloride, tri -n-
Butyltin trifluoromethanesulfonate, tri-lower alkoxyborane and the like.

Specific examples of the compound represented by the formula: MM include bispinacolato diboron, biscatecholate diboron, bistri-n-butyltin and the like.

[0127] Examples of leaving groups X ⁴ in the compound [25] or compound [27], for example, chlorine, bromine, halogen atom such as iodine, trifluoromethanesulfonyloxy group and the like.

The reaction for producing compound [16] from compound [26] can be carried out in the same manner as the reaction for producing compound [24] from compound [23].

The reaction for producing compound [28] from compound [16] can be carried out in the same manner as the reaction for producing compound [28] from compound [24]. The reaction for producing compound [6] from compound [28] can be carried out by treating with compound or acid. Examples of the acid include concentrated hydrochloric acid and sulfuric acid. Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide, lithium hydroxide-hydrogen peroxide and the like.

Incidentally, specific examples of the compound [6] include a compound represented by the general formula [6 ']:

[0131]

Embedded image

(However, the symbols have the same meanings as described above.)
Is mentioned.

The starting compound [13] can be produced, for example, according to the following method.

[0134]

Embedded image

(The symbols have the same meanings as described above.) The reaction for producing compound [10] from compound [9] is carried out in a solvent using di-tert-butyl dicarbonate (Boc ₂
It can be carried out in the presence of O), in the presence or absence of a base. Examples of the solvent include tetrahydrofuran, methylene chloride, 1,2-dichloroethane, dioxane, ethyl acetate and the like. Examples of the base include triethylamine, potassium carbonate, sodium carbonate, diisopropylethylamine, sodium hydrogencarbonate, 4-dimethylaminopyridine and the like.

The reaction for producing compound [11] from compound [10] can be carried out in the same manner as the reaction for producing compound [5-a] from compound [4].

The reaction for producing compound [12] from compound [11] and compound [6] can be carried out in the same manner as in the above [Method A].

The reaction for producing compound [13] from compound [12] can be carried out in the presence of a Boc group deprotecting agent. Examples of the Boc group deprotecting agent include hydrochloric acid-dioxane, hydrochloric acid-ethyl acetate, trifluoroacetic acid,
And iodotrimethylsilane.

The starting compound [15] can be produced, for example, according to the following method.

[0140]

Embedded image

(Wherein the symbols have the same meanings as described above) The reaction for producing compound [15] from compound [5] and compound [14] can be carried out in the same manner as in the above [Method A].

The compounds [Ia], [Ib] and [I
In producing [c] or [Id], not only the intermediate compounds shown in the above chemical reaction formula but also salts or reactive derivatives thereof as long as they do not adversely affect the reaction, It can be used as appropriate. Examples of the salt include metal salts such as sodium, potassium, lithium, calcium and magnesium, salts with organic bases such as pyridine, triethylamine and diisopropylethylamine, hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid and the like. Salts with inorganic acids, acetic acid, oxalic acid, citric acid, benzenesulfonic acid, benzoic acid, malonic acid, citric acid, formic acid, fumaric acid,
Salts with organic acids such as maleic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid and the like can be mentioned.

In the production of the target compound and the starting compound of the present invention, when the starting compound or each intermediate has a functional group, appropriate protection for each functional group may be carried out by a conventional method of synthetic chemistry in addition to the above. Groups may be introduced and their protecting groups may be removed as appropriate when no longer needed.

In the present invention, examples of the alkyl include straight or branched ones having 1 to 16 carbon atoms, particularly those having 1 to 8 carbon atoms. The lower alkyl or lower alkoxy includes linear or branched ones having 1 to 6 carbon atoms, particularly those having 1 to 4 carbon atoms. Further, the lower alkanoyl includes straight or branched ones having 2 to 7 carbon atoms, especially 2 to 5 carbon atoms.
Those having 3 to 20 carbon atoms, especially those having 3 to 12 carbon atoms are exemplified. Cyclo-lower alkyl includes those having 3 to 8 carbon atoms, particularly 3 to 6 carbon atoms. Alkenyl includes linear or branched ones having 2 to 16 carbon atoms, especially 2 to 10 carbon atoms, and lower alkenyl means those having 2 to 8 carbon atoms, especially 2 to 4 carbon atoms. No. Alkylene includes linear or branched ones having 1 to 16 carbon atoms, especially 1 to 10 carbon atoms, and lower alkylene refers to straight-chain or 1 to 6 carbon atoms, particularly 1 to 6 carbon atoms. And branched chains.
Examples of the halogen atom include fluorine, chlorine, bromine and iodine. As the heterocyclic group, for example, nitrogen,
Monocyclic, bicyclic or tricyclic heterocyclic groups containing at least one heteroatom atom selected from oxygen and sulfur are exemplified. Specifically, pyridyl group, indolyl group, thiazolyl group, imidazolyl group, pyrrolyl group, pyrimidinyl group,
Thienyl group, benzo [b] furyl group, benzo [b] thienyl group, pyrazolyl group, triazolyl group, quinolyl group,
Isoquinolyl group, phthalazinyl group, quinazolinyl group, quinoxalinyl group, 5,11-dihydro-dibenzo [b,
e] [1,4] oxazepin-5-yl group, dihydropyrazolyl group, tetrazolyl group and the like. Examples of the aryl group include a phenyl group, a naphthyl group, an anthranyl group, a phenanthryl group and the like.

[0145]

EXAMPLES Specific examples (Examples) of the target compound [I] of the present invention synthesized by the above exemplified methods are shown below, but the present invention is not limited thereto.

Example 1 (1) 699 mg of isoindoline, 900 mg of (1H-pyrazol-1-yl) acetic acid / hydrochloride (the compound obtained in Reference Example 1), 1-hydroxybenzotriazole 7
To a solution of 85 mg and 0.81 ml of triethylamine in dimethylformamide (30 ml) was added 1-ethyl-3-
1.10 g of (3-dimethylaminopropyl) -carbodiimide hydrochloride are added. After stirring at room temperature for 6 hours, the mixture is poured into ice water, and the precipitated powder is collected by filtration and dried. By recrystallization from methanol, 1.00 g of 2- (1H-pyrazol-1-yl) acetyl-isoindoline is obtained as colorless crystals. M. p. 215-217 ° C (2) 3.6 ml of concentrated nitric acid was added dropwise to a solution of 11.87 g of the compound obtained in the above (1) in 60 ml of concentrated sulfuric acid under ice-cooling.
Stir for 1 hour. The reaction solution is poured into ice water, and the deposited precipitate is separated by filtration, washed with water, and dried. Acetic acid-
By recrystallizing with a mixed solvent of water, 5-nitro-2
10.62 g of-(1H-pyrazol-1-yl) acetyl-isoindoline are obtained as colorless crystals. M. p. 247-248 ° C (3) A suspension of 1.005 g of the compound obtained in the above (2) and 98 mg of 10% palladium-carbon in acetic acid (15 ml) is stirred under a hydrogen atmosphere at room temperature and normal pressure for 1 hour.
The catalyst was removed by filtration, the filtrate was concentrated, and the residue was recrystallized with a mixed solution of chloroform-methanol to give 759 mg of 5-amino-2- (1H-pyrazol-1-yl) acetyl-isoindoline as colorless crystals. Get as. M. p. 218-219 ° C (4) 245 mg of the compound obtained in the above (3), 2-
To a solution of 296 mg of (5-trifluoromethyl-pyridin-2-yl) benzoic acid (the compound obtained in Reference Example 5 (3)) and 149 mg of 1-hydroxybenzotriazole in 5 ml of dimethylformamide (5 ml) was added a solution of 1- Add 216 mg of ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride, and stir at room temperature for 17 hours. The reaction solution was poured into 30 ml of ice water and stirred for 30 minutes.
10 ml of concentrated aqueous ammonia was added, and the precipitated crystals were collected by filtration.
After drying, the residue was recrystallized from ethyl acetate to give 2- (1
H-pyrazol-1-yl) acetyl-5- [2- (5
432 mg of -trifluoromethyl-pyridin-2-yl) benzoylamino] -isoindoline are obtained as colorless prisms. M. p. 207-209 ° C

Example 2-5 The corresponding starting compound was treated in the same manner as in Example 1 (4) to give the compounds shown in Table 1.

[0148]

[Table 1]

Example 6 5-amino-2- (1H-pyrazol-1-yl) acetyl-isoindoline (compound obtained in Example 1 (3)) 95 mg, 2- (5-trifluoromethyl-pyridine- A solution of 2-yl) benzoic acid (124 mg of the compound obtained in Reference Example 5 (3)), 0.2 ml of triethylamine and 118 mg of diethylcyanophosphonate in 4 ml of dimethylformamide is stirred at room temperature for 3 days. The reaction solution was diluted with ethyl acetate, aqueous sodium hydrogen carbonate solution,
Wash with water and saturated saline and dry over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (developing solvent; chloroform: methanol = 10).
0: 1) and recrystallized from ethyl acetate to give 2- (1H-pyrazol-1-yl) acetyl-5.
-[2- (5-trifluoromethyl-pyridin-2-yl) benzoylamino] -isoindoline (Example 1
100 mg of the compound obtained in (4) is obtained.

Examples 7-8 By treating the corresponding starting compounds in the same manner as in Example 6, the compounds shown in Table 2 are obtained.

[0151]

[Table 2]

Example 9 (1) 22.43 g of isoindoline in methanol (10
0 ml) The solution was cooled in a dry ice-acetone bath, 20.47 g of concentrated sulfuric acid was added dropwise, diethyl ether was added, and the precipitated powder was collected by filtration. After drying under reduced pressure, the resulting powder is dissolved in 220 ml of concentrated sulfuric acid, and 15.8 ml of concentrated nitric acid is added dropwise under ice cooling. After stirring for 2.5 hours, the mixture is poured into ice water, made basic by adding sodium hydroxide (added as a solid), and extracted with ethyl acetate. Water the organic layer,
After washing with saturated saline, drying over anhydrous sodium sulfate and distilling off the solvent, 5-nitroisoindoline 2 was obtained.
3.0 g are obtained as crude product. (2) 494 mg of the compound obtained in the above (1) and 1.24 g of potassium carbonate in toluene (6 ml) -water (6
0.36 ml of 2-chloroacetyl chloride is added dropwise to the mixed solution of Example 1) with stirring. The precipitated crude product was separated by filtration, washed with water, and recrystallized from ethyl acetate to obtain 576 mg of 2-chloroacetyl-5-nitro-isoindoline. M. p. 158-160 ° C. (3) 86 mg of pyrazole is added to a suspension of 76 mg of the compound obtained in the above (2) in o-xylene (3 ml).
Heat to reflux for hours. The reaction solution was poured into diisopropyl ether, and the precipitated crystals were collected by filtration to give 5-nitro-2- (1H-pyrazol-1-yl) acetyl-isoindoline (the compound obtained in Example 1 (2)) 64 m
g. (4) The compound obtained in the above (3) was prepared in Example 1 (3)
Example 1 by processing in the same manner as in (4).
(4) The compound described in (4) is obtained.

Example 10 (1) (1H-pyrazol-1-yl) acetic acid (Reference Example 2)
(Compound obtained in (2)) 2.1 ml of ethyl chlorocarbonate is added to a suspension of 2.56 g of tetrahydrofuran (50 ml) at -15 ° C. After stirring the reaction solution for 5 minutes, 3.5 ml of triethylamine is added and the mixture is further stirred for 5 minutes. 10 ml of concentrated aqueous ammonia was added to the reaction solution, and the mixture was stirred for 10 minutes. The reaction solution was concentrated, and ethyl acetate was added to the residue to form a powder, thereby obtaining 1.17 g of (1H-pyrazol-1-yl) acetamide as a crude product Get as. (2) 162 mg of the compound obtained in the above (1), α,
A solution of 187 mg of α'-dichloro-o-xylene, 184 mg of potassium hydroxide and 34.8 mg of tetrabutylammonium chloride in acetonitrile (5 ml) is stirred at room temperature overnight. The reaction solution was poured into water, and the precipitated powder was separated by filtration and recrystallized with a mixed solution of tetrahydrofuran-methanol to give 2- (1H-pyrazole-1-.
136 mg of yl) acetyl-isoindoline (the compound obtained in Example 1 (1)) are obtained as colorless crystals. (3) Using the compound obtained in the above (2) in Example 1 (2)
By performing the same processing as in (4) to (4),
The compound described is obtained.

Example 11 (1) A solution of 102 g of pyrazole and 168 g of 2-chloroacetamide in 1 L of dimethylformamide was cooled in a dry ice-acetone bath. Sodium hydroxide 7
2 g are added in several portions and stirred at room temperature for 1.5 hours.
After a solution of 262 g of o-dichloroxylene in dimethylformamide (500 ml) is added to the reaction solution, the mixture is cooled in a dry ice-acetone bath, and 132 g of sodium hydroxide is added in several portions. After stirring at room temperature for 2 hours, the reaction solution was poured into ice water (2 kg of ice, 4 L of water), the pH was adjusted to 6 to 7 by adding 10% hydrochloric acid, the precipitate was collected by filtration, washed with diisopropyl ether, and dried. . Tetrahydrofuran-
By recrystallization from methanol (1: 1), 2-
179 g of (1H-pyrazol-1-yl) acetyl-isoindoline (the compound obtained in Example 1 (1)) are obtained as colorless crystals. (2) Using the compound obtained in the above (1) in Example 1 (2)
By performing the same processing as in (4) to (4),
The compound described is obtained.

Example 12 5- [2- (5-trifluoromethyl-pyridine-2-
Yl) benzoylamino] -isoindoline dihydrochloride (compound obtained in Reference Example 14 (4)) 200 mg, 1
A suspension of 115 mg of-(2-bromoethyl) pyrazole (the compound obtained in Reference Example 4), 72 mg of sodium iodide and 303 mg of potassium carbonate in dimethylformamide (2 ml) is stirred at 50 ° C overnight. The reaction solution is poured into dilute aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate.
The organic layer is washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent is distilled off. The residue was purified by preparative chromatography (developing solvent; chloroform: methanol = 12: 1), and then recrystallized with a mixed solvent of ethyl acetate and diisopropyl ether-n-hexane to give 2- [2- (1H -Pyrazol-1-yl) ethyl] -5- [2- (5-trifluoromethyl-pyridin-2-yl) benzoylamino] -isoindoline 5
9 mg are obtained as colorless needles. M. p. 162.5-164 ° C Example 13 By treating the corresponding starting compound in the same manner as in Example 12, the compounds described in Table 3 are obtained.

[0156]

[Table 3]

Example 14 5- [2- (5-trifluoromethyl-pyridine-2-
Yl) benzoylamino] -isoindoline dihydrochloride (the compound obtained in Reference Example 14 (4)) 364 mg,
(1H-pyrazol-1-yl) acetic acid / hydrochloride (compound obtained in Reference Example 1) 156 mg, 4-dimethylaminopyridine 117 mg, triethylamine 170 mg and 1-ethyl-3- (3-dimethylaminopropyl)-
Using 199 mg of carbodiimide hydrochloride under an argon atmosphere in the same manner as in Example 1 (4),
2- (1H-pyrazol-1-yl) acetyl-5-
[2- (5-trifluoromethyl-pyridin-2-yl) benzoylamino] -isoindoline (Example 1
252 mg of the compound described in (4) are obtained as colorless prism crystals.

Examples 15 to 17 By treating the corresponding starting compounds in the same manner as in Example 14, the compounds shown in Table 4 are obtained.

[0159]

[Table 4]

Example 18 (1) Under an argon atmosphere, 5-amino-2- (1H-pyrazol-1-yl) acetyl-isoindoline (the compound obtained in Example 1 (3)) 800 mg of anhydrous tetrahydrofuran (80 ml) ) To the solution is added 625 mg of sodium borohydride. To this mixture, 3.04 g of boron trifluoride diethyl ether complex is added under ice-cooling, and the mixture is refluxed for 1 hour while gradually increasing the temperature. After cooling to room temperature, 10 ml of 10% hydrochloric acid aqueous solution is added dropwise, and the mixture is heated under reflux for 1 hour. Cool to room temperature, basify the reaction mixture with potassium carbonate (added as a solid) and extract with ethyl acetate. The organic layer is washed with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated saline, dried over anhydrous sodium sulfate, and the solvent is distilled off. The residue was purified by preparative chromatography (developing solvent; chloroform: methanol = 1).
8: 1), and then recrystallized from a mixed solution of ethyl acetate-diisopropyl ether to give 5-amino-2- [2- (1H-pyrazol-1-yl) ethyl].
-395 mg of isoindoline are obtained as colorless needles. M. p. 109-111 ° C (2) 259 mg and 2 of the compound obtained in the above (1)
Example 1 was performed using-(5-trifluoromethyl-pyridin-2-yl) benzoic acid (the compound obtained in Reference Example 5 (3)).
By performing the same treatment as in (4), 2- [2- (1H
-Pyrazol-1-yl) ethyl] -5- [2- (5-
437 mg of trifluoromethyl-pyridin-2-yl) benzoylamino] -isoindoline (the compound obtained in Example 12) are obtained.

Example 19 (1) 533 mg of 5-amino-2- (1H-pyrazol-1-yl) acetyl-isoindoline (the compound obtained in Example 1 (3)), 610 m of 2-iodobenzoic acid
g and 1-hydroxybenzotriazole 334 mg
Of dimethylformamide (10 ml) was added with 480 mg of 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride, and the mixture was stirred at room temperature for 5.5 hours. The reaction solution was poured into ice water, and the deposited precipitate was collected by filtration.
By recrystallization with a mixed solution of ethyl acetate-n-hexane, 800 mg of 2- (1H-pyrazol-1-yl) acetyl-5- (2-iodo-benzoylamino) -isoindoline is obtained as colorless needles. . MS (APCI) m / z; 473 (M + H), IR (n
^{ujol) cm -1; 1671,1644 (2} ) the compound obtained in the above (1) 300mg, 3- pyridyl tributyltin 468 mg, triphenylphosphine 33 mg, copper bromide (I) 18 mg, bis triphenylphosphine palladium dichloride 45mg and a small amount of A solution of 2,6-di-tert-butyl-p-cresol in dioxane (10 ml) is heated to reflux for 3 days. The reaction was cooled to room temperature, diluted with ethyl acetate and
A 15% aqueous solution of potassium fluoride is added and stirred. The insolubles were filtered through celite, the organic layer of the filtrate was separated, washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Preparative chromatography of the residue (developing solvent; chloroform: methanol = 20: 1)
And purified by recrystallization from a mixed solution of chloroform-methanol to give 2- (1H-pyrazole-1-.
Yl) acetyl-5- [2- (3-pyridyl) -benzoylamino] -isoindoline 57 mg is obtained. M. p. 257 ° C (decomposition)

Example 20 (1) 5- [2- (5-trifluoromethyl-pyridin-2-yl) benzoylamino] -isoindoline.2
Hydrochloride (compound obtained in Reference Example 14 (4)) 200 m
To a solution of g and triethylamine (177 mg) in methylene chloride (10 ml) were added 2-chloro-propionyl chloride (61 mg), and the mixture was stirred at room temperature for 2 hours. The reaction solution is poured into water and extracted with chloroform. The organic layer is washed with 5% aqueous hydrochloric acid, water, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, dried over anhydrous sodium sulfate, and the solvent is distilled off. The residue is purified by preparative chromatography (developing solvent; chloroform: methanol = 90: 7) to give 2- (2-chloro-1-oxopropyl).
-5- [2- (5-trifluoromethyl-pyridine-2)
-Yl) benzoylamino] -isoindoline 115m
g. MS (APCI) m / z; 474 (M + H), IR (n
ujol) cm ^-1 ; 1654, 1645, 1604 (2) Dimethylformamide (12 m2) containing 107 mg of the compound obtained in the above (1), 46 mg of pyrazole, 63 mg of anhydrous potassium carbonate and 37 mg of sodium iodide.
1) The solution is heated and stirred at 80 ° C. for 5 hours. The reaction solution is poured into dilute aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer is washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent is distilled off. The residue was purified by preparative chromatography (developing solvent; chloroform: methanol = 15: 1), and then recrystallized with a mixed solution of ethyl acetate-diisopropyl ether-n-hexane to give 2- [2- (1H -Pyrazol-1-yl) -1-oxopropyl] -5- [2- (5-trifluoromethyl-pyridin-2-yl) benzoylamino]
-63 mg of isoindoline are obtained as colorless needles. M. p. 155-157 ° C

Examples 21 to 22 By treating the corresponding starting compounds in the same manner as in Example 20, the compounds shown in Table 5 are obtained.

[0164]

[Table 5]

Example 23 (1002838) (1) To a solution of 417 mg of 3-benzyloxy-2,2-dimethylpropionic acid in 5 ml of methylene chloride was added 385 μl of oxalyl chloride and dimethylformamide (1).
And the mixture is stirred at room temperature for 1 hour. The reaction solution is concentrated and dissolved in methylene chloride (5 ml). This solution was cooled under ice-cooling to give 5- [2- (5-trifluoromethyl-pyridine-
422 mg of 2-yl) benzoylamino] -isoindoline dihydrochloride (the compound obtained in Reference Example 14 (4))
And 407 mg of triethylamine in methylene chloride (1
0 ml). After stirring at the same temperature for 30 minutes and at room temperature for 2 hours, the organic layer is washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent is distilled off. By purifying the residue by silica gel column chromatography (developing solvent; n-hexane: chloroform = 1: 1),
2- (3-benzyloxy-2,2-dimethylpropanoyl) -5- [2- (5-trifluoromethyl-pyridin-2-yl) benzoylamino] -isoindoline 1
25 mg are obtained as a colorless foam. MS (APCI) m / z; 574 (M + H), IR (N
ujol) cm ^-1 ; 1669,1603 (2) A solution of 109 mg of the compound obtained in the above (1) in ethanol (4 ml) was added with palladium hydroxide-carbon 19 m
g, and the mixture is stirred under a hydrogen atmosphere at room temperature for 28 hours. The catalyst was removed by filtration, the filtrate was concentrated, and diisopropyl ether was added to the residue.
(3-hydroxy-2,2-dimethylpropanoyl)-
5- [2- (5-trifluoromethyl-pyridine-2-
50 mg of yl) benzoylamino] -isoindoline are obtained as a colorless powder. MS (APCI) m / z; 484 (M + H), IR (N
ujol) cm ^-1 ; 3405, 1659, 1605

Reference Example 1 To a solution of tert-butyl bromoacetate (5.00 g) in dimethylformamide (20 ml), 2.09 g of pyrazole and 7.07 g of potassium carbonate were added. 1 hour at room temperature
After stirring at 50 ° C. for 3.5 hours, the reaction solution is poured into water and extracted with ethyl acetate. The organic layer is washed with water and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (developing solvent;
By purifying with ethyl acetate: n-hexane = 1: 3), (1H-pyrazol-1-yl) acetic acid tert-
4.23 g of butyl are obtained as a colorless oil. (2) A 4M hydrochloric acid-dioxane solution 2 was added to a dioxane (10 ml) solution of 4.21 g of the compound obtained in the above (1).
Add 5 ml and stir at room temperature for 12 hours. Diethyl ether was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The precipitated powder was collected by filtration and dried under reduced pressure to give (1H-pyrazol-1-yl) acetic acid / hydrochloride (3.50 g) as a colorless powder. obtain.

Reference Example 2 (1) 170 g of pyrazole, 260 m of methyl bromoacetate
of acetone and 414 g of potassium carbonate in acetone
Heat to reflux for 5 hours. After cooling to room temperature, insolubles are filtered off, and the filtrate is concentrated under reduced pressure. By distilling the residue,
580 g of methyl (1H-pyrazol-1-yl) acetate are obtained. B. p. 105-120.0 ° C (15 mmHg) (2) 219 g of the compound obtained in the above (1) is dissolved in a 2 M aqueous hydrochloric acid solution (1.5 L), and the mixture is heated under reflux for 2 hours. The reaction solution is concentrated under reduced pressure to 500 ml, pH is adjusted to 0.5-0.6 by adding potassium carbonate under ice cooling, and the resulting precipitate is collected by filtration and dried under reduced pressure. By recrystallizing with 2 L of tetrahydrofuran, (1H-pyrazol-1-yl)
127.3 g of acetic acid are obtained. M. p. 171-172 ° C

Reference Example 3 (1) To a solution of 1.0 g of 4-nitropyrazole and 1.82 g of potassium carbonate in dimethylformamide (10 ml) was added 1.81 g of tert-butyl bromoacetate under ice-cooling, followed by stirring at room temperature for 2 hours. I do. The reaction solution is poured into ice water and extracted with ethyl acetate. The organic layer is washed sequentially with water and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is distilled off, and the residue is subjected to silica gel column chromatography (developing solvent;
Purification with n-hexane: ethyl acetate = 4: 1) gives 1.88 g of tert-butyl (4-nitro-1H-pyrazol-1-yl) acetate as a pale yellow solid. MS (APCI) m / z; 228 (M + H), IR (N
(jjol) cm ^-1 ; 1749, 1705 (2) By treating 1.87 g of the compound obtained in the above (1) in the same manner as in Reference Example 1 (2), (4-nitro-
1.40 g of 1H-pyrazol-1-yl) acetic acid are obtained as colorless prisms. M. p. 156.5-157.0 ° C

Reference Example 4 6.8 g of pyrazole in dimethylformamide (10 m
l) 4 g of 60% sodium hydride is added to the solution under ice-cooling, and the mixture is stirred at room temperature for 1 hour. 1,2-dibromoethane 9
3.5 g was added under ice cooling, and the mixture was stirred at room temperature overnight. Diethyl ether is added to the reaction solution, insolubles are filtered off and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; ethyl acetate) to give 1- (2
2.0 g of (-bromoethyl) pyrazole are obtained as a colorless oil. MS (APCI) m / z; 177,175 (M + H)

Reference Example 5 (1) Under an argon atmosphere, 150 g of diisopropylbenzamide and 121 m of tetramethylethylenediamine
A solution of 1 in tetrahydrofuran (750 ml) was cooled in a dry ice-acetone bath, and a hexane solution of n-butyllithium (552 ml) was added dropwise thereto. After the addition, the mixture is further stirred for 1 hour under ice cooling. The reaction solution was cooled again in a dry ice-acetone bath, and triisopropyl borate 33 was added.
Add 7 ml. After stirring for 10 minutes, the dry ice-acetone bath was removed, and the mixture was stirred for 1.5 hours. Under ice cooling, 850 ml of diethyl ether and 85% of 10% hydrochloric acid were added to the reaction mixture.
After addition of 0 ml, the mixture is stirred vigorously for 1 hour at room temperature. The organic layer was separated, and the aqueous layer was further diluted with 500 ml of diethyl ether.
After extraction with, the organic layers are combined and washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure to obtain a crude product. (2) Under an argon atmosphere, 180.5 g of the crude product obtained in the above (1) and 130.7 g of 2-chloro-5-trifluoromethyl-pyridine were treated with dimethoxyethane (2
L) To the solution is added an aqueous solution (700 ml) of 4.04 g of palladium acetate, 18.9 g of triphenylphosphine and 249 g of potassium carbonate, and the mixture is heated under reflux overnight. The reaction solution is diluted with ethyl acetate, and the insoluble matter is filtered through celite while hot. The filtrate was concentrated, and the residue was washed with 2 L of water and 1 L of diisopropyl ether, and then recrystallized with ethyl acetate to give N, N-diisopropyl-2- (5-trifluoromethyl-pyridin-2-yl) benzoic acid. Amide 189.
93 g are obtained as colorless crystals. M. p. 191 to 192.5 ° C. (3) A solution of 189.5 g of the compound obtained in the above (2) in concentrated hydrochloric acid (2.5 L) is heated under reflux for 1.5 hours. After cooling the reaction solution to room temperature, it is concentrated under reduced pressure. The concentrated solution is diluted with water and extracted with ethyl acetate. The organic layer is washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from a mixed solution of ethyl acetate-n-hexane to obtain 115.86 g of 2- (5-trifluoromethyl-pyridin-2-yl) benzoic acid. As colorless crystals. M. p. 186.5-188.5 ° C

Reference Example 6 (1) 10.0 g of 2-iodobenzoic acid in methanol (1
(00 ml), 6 ml of thionyl chloride was added to the solution under ice cooling, and the mixture was heated under reflux for 3 hours. The reaction solution is concentrated under reduced pressure, and the ethyl acetate solution of the residue is washed with water, a saturated aqueous solution of sodium hydrogen carbonate, and a saturated saline solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (developing solvent; n-hexane: ethyl acetate = 5: 1) to give methyl 2-iodobenzoate.
53 g are obtained as a colorless oil. (2) Under an argon atmosphere, 7.87 g of the compound obtained in the above (1) and 34.83 of bistri-n-butyltin
695 mg of tetrakistriphenylphosphine palladium is added to a solution of g (150 ml) of toluene, and the mixture is heated under reflux for 47 hours. After cooling the reaction solution to room temperature, a 10% aqueous potassium fluoride solution is added, and the mixture is stirred at room temperature for 1 hour. After filtering the reaction solution through celite, the organic layer is separated from the filtrate. The organic layer is washed with water and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (developing solvent; chloroform: n-hexane = 1: 5) to obtain 7.03 g of methyl 2- (tri-n-butyltin) benzoate as colorless. Obtained as an oil. (3) Under an argon atmosphere, 639 mg of the compound obtained in the above (2), 178 mg of 2-chloro-5-trifluoromethyl-pyridine, 52 mg of triphenylphosphine,
29 mg of copper (I) bromide, a small amount of 2,6-di-tert-
70 mg of bistriphenylphosphine palladium chloride is added to a solution of butyl-p-cresol in dioxane (5 ml), and the mixture is heated under reflux for 47 hours. After cooling the reaction solution to room temperature, it is diluted with ethyl acetate, a 10% aqueous potassium fluoride solution is added, and the mixture is stirred at room temperature for 1 hour. After filtering the reaction solution through celite, the organic layer is separated from the filtrate. Water the organic layer,
After washing with saturated saline, it is dried over anhydrous sodium sulfate.
The solvent was distilled off, and the residue was subjected to silica gel column chromatography (developing solvent; ethyl acetate: n-hexane = 1: 2).
By purification in 0), 159 mg of methyl 2- (5-trifluoromethyl-pyridin-2-yl) benzoate was obtained.
As a colorless oil. MS (APCI) m / z; 282 (M + H), IR (N
eat) cm ^-1 ; 1729,1605 (4) 253 mg of the compound obtained in the above (3) and 1
A solution of M aqueous sodium hydroxide (1.35 ml) in methanol (3.0 ml) is heated and stirred at 50 ° C. for 4 hours.
After methanol is distilled off, the solution is adjusted to pH 3 with 2M aqueous hydrochloric acid, and then concentrated under reduced pressure. Ethanol was added to the residue, insolubles were removed by filtration, and the filtrate was concentrated to give 2- (5-
248 mg of trifluoromethyl-pyridin-2-yl) benzoic acid (the compound obtained in Reference Example 5 (3)) are obtained.

Reference Examples 7-8 By treating the corresponding starting compounds in the same manner as in Reference Examples 6 (3) and (4), the compounds shown in Table 6 were obtained.

[0173]

[Table 6]

Reference Example 9 (1) In an argon atmosphere, dimethylformamide (25 m 2) containing 1.00 g of methyl 2-iodobenzoate, 1.06 g of bispinacolatodiboron and 1.12 g of potassium acetate was used.
l) Add bis (diphenylphosphinoferrocene) to the solution
92 mg of dichloropalladium is added, and the mixture is heated and stirred at 80 ° C. for 2 hours. After cooling the reaction solution to room temperature, 2-chloro-
5-Trifluoromethylpyridine, 2M aqueous sodium carbonate solution (9.5 ml) and 92 mg of bis (diphenylphosphinoferrocene) dichloropalladium are added, and the mixture is heated with stirring at 80 ° C. for 2 hours. Ethyl acetate is added to the reaction solution, and the organic layer is washed with water and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (developing solvent; chloroform: n-
Hexane = 1: 6) to give 2- (5-
533 mg of methyl trifluoromethyl-pyridin-2-yl) benzoate (the compound obtained in Reference Example 6 (3)) is obtained as a colorless oil. (2) The compound obtained in the above (1) is treated in the same manner as in Reference Example 6 (4) to give 2- (5-trifluoromethyl-pyridin-2-yl) benzoic acid (Reference Example 5 (3)
Is obtained.

Reference Example 10 (1) In an argon atmosphere, 1.0 g of methyl 2-iodo-benzoate in toluene (80 ml) and ethanol (8
ml) solution, 1.22 g of 3-thiophenboronic acid, 220 mg of tetrakistriphenylphosphine palladium
And 12 ml of a 2M aqueous sodium carbonate solution.
Heat to reflux for 5 hours. After cooling the reaction solution to room temperature, it is poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (developing solvent; ethyl acetate: hexane =
1:10) to give 836 mg of methyl 2- (3-thienyl) benzoate as a pale reddish purple oil. MS (EI) m / z; 218 (M), IR (neat)
cm- ¹ ; 1725 (2) The compound obtained in the above (1) is treated in the same manner as in Reference Example 6 (4) to give 2- (3-thienyl) benzoic acid. MS (ESI) m / z; 203 (MH), IR (nu
jol) cm- ¹ ; 1695, 1675

Reference Example 11 (1) 164 mg of bistriphenylphosphine palladium dichloride was added to a solution of 500 mg of 2-bromo-methyl benzoate and 1.71 g of 2-pyridyltributyltin in dimethylformamide (10 ml) under an argon atmosphere. Heat and stir for 12 hours. After cooling the reaction solution to room temperature, it is diluted with ethyl acetate, a 10% aqueous potassium fluoride solution is added, and the mixture is stirred at room temperature for 1 hour. After filtering the reaction solution through celite, the organic layer is separated from the filtrate. The organic layer is washed with water and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by NH silica gel column chromatography (manufactured by Fuji Silysia) (developing solvent; ethyl acetate: n-hexane = 1: 2) to give 2
392 mg of methyl- (2-pyridyl) benzoate are obtained as a colorless oil. MS (APCI) m / z; 214 (M + H), IR (n
eat) cm ^-1 ; 1730 (2) The compound obtained in the above (1) is treated in the same manner as in Reference Example 6 (4) to give 2- (2-pyridyl) benzoic acid. MS (ESI) m / z; 198 (MH), IR (nu
jol) cm- ¹ ; 1690

Reference Example 12 (1) Under an argon atmosphere, dimethoxyethane (100%) of 6.61 g of 2-chloro-5-trifluoromethylpyridine and 6.55 g of 2,6-dimethylphenylboronic acid was added.
ml) solution into 204 mg of palladium acetate, 955 mg of triphenylphosphine and 11.5 mg of potassium phosphate.
Add 9 g of an aqueous solution (35 ml) and heat to reflux overnight.
After cooling the reaction solution to room temperature, it is diluted with ethyl acetate, and the insoluble matter is filtered through celite. The filtrate is concentrated, the residue is dissolved in ethyl acetate, washed with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (developing solvent; n-hexane: ethyl acetate = 100: 1 → 40: 1) to give
2.75 g of 2- (2,6-dimethylphenyl) -5-trifluoromethylpyridine are obtained as a colorless oil. MS (APCI) m / z; 252 (M + H), IR (N
^{eat) cm -1; 1607 (2} ) Under an argon atmosphere, to a mixed solution of the above (pyridine compound 730mg obtained in 1) (9 ml) and water (6 ml), at room temperature potassium permanganate 2.29g was added, Heat and stir for 48 hours. The reaction solution is returned to room temperature, 1.84 g of potassium permanganate is added, and the mixture is refluxed for 24 hours. After cooling the reaction solution to room temperature, a 10% aqueous sodium hydroxide solution (10 ml) is added, and the insoluble matter is filtered through celite. The filtrate is washed with diethyl ether, made acidic with 10% hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized with a mixed solution of ethyl acetate-diisopropyl ether to give 690 mg of 2- (5-trifluoromethyl-pyridin-2-yl) isophthalic acid.
As colorless needles. M. p. 252.0-254.0 ° C. (3) Thionyl chloride 1.11 was added to a solution of 480 mg of the compound obtained in the above (2) in methanol (12 ml) under ice cooling.
g was added dropwise and the mixture was refluxed for 20 hours. After cooling the reaction solution to room temperature, the reaction solution is concentrated. The residue is dissolved in ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate, water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (developing solvent; n-hexane: ethyl acetate = 5: 1) to give 2- (5-trifluoromethyl-pyridin-2-yl) isophthalic acid. Dimethyl (Compound 12 (3
a)) 314 mg are obtained as a colorless oil. MS (APCI) m / z; 340 (M + H), IR (N
eat) cm ^-1 ; 1731, 1607 Further, the above-mentioned saturated sodium bicarbonate washing solution was washed with ice for ¹ hour.
Acidify with 0% hydrochloric acid and extract with ethyl acetate. The organic layer is washed with saturated saline and dried over anhydrous sodium sulfate.
The solvent was distilled off, and the residue was recrystallized from a mixed solution of methanol and water to give methyl 2- (5-trifluoromethyl-pyridin-2-yl) isophthalate (compound 12).
(3b)) 76 mg are obtained as colorless needles. M. p. 158.0-159.0 ° C. (4) Compound 12 (3a) 309 obtained in the above (3)
To a solution of mg of methanol (10 ml) was added a 1 M aqueous solution of sodium hydroxide (1.1 ml) at room temperature, and the mixture was heated under reflux overnight. After cooling the reaction solution to room temperature, water is added to the residue, washed with diethyl ether, acidified with a 10% aqueous citric acid solution, and extracted with ethyl acetate. The organic layer is washed with water and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from a mixed solution of methanol and water to give 2- (5-trifluoromethyl-pyridine-2).
264 mg of methyl (-yl) isophthalate (identical to compound 12 (3b)) are obtained as colorless needles.

Reference Example 13 (1) 2-chloropyrimidine 579 under an argon atmosphere
mg and o-tolylboronic acid 816 mg in dimethoxyethane (15 ml) solution, palladium acetate 29 mg,
An aqueous solution (6.3 ml) of 134 mg of triphenylphosphine and 1.73 g of potassium carbonate is added, and the mixture is heated under reflux for 2 hours. After cooling the reaction solution to room temperature, it is diluted with ethyl acetate, and the insoluble matter is filtered through celite. The filtrate is concentrated, the residue is dissolved in ethyl acetate, washed with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (developing solvent; n-hexane: ethyl acetate = 20: 1) to give 2
795 mg of-(2-methylphenyl) pyrimidine are obtained as a colorless oil. MS (APCI) m / z; 171 (M + H), IR (N
eat) cm ^-1 ; 1569 (2) By treating 340 mg of the compound obtained in the above (1) in the same manner as in Reference Example 12 (2), 88 mg of 2-pyrimidin-2-ylbenzoic acid is obtained as a crude product. .

Reference Example 14 (1) Crude 5-nitroisoindoline (Example 9)
(Compound obtained in (1)) A solution of 3.86 g of di-tert-butyl dicarbonate in 10 ml of tetrahydrofuran was added dropwise to a solution of 2.62 g of tetrahydrofuran (40 ml) under ice-cooling, followed by stirring for 1.5 hours. . The solvent is distilled off, ethyl acetate is added to the residue, washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent is distilled off. The residue was purified by silica gel column chromatography (developing solvent; n-hexane: ethyl acetate = 4: 1),
By recrystallizing with a mixed solution of n-hexane-ethyl acetate, 3.09 g of 5-nitro-2- (tert-butoxycarbonyl) -isoindoline is obtained. M. p. 159-160 ° C (2) 3.46 g of the compound obtained in the above (1) and 1
A suspension of 340 mg of 0% palladium-carbon in tetrahydrofuran (50 ml) was added under a hydrogen atmosphere at normal pressure and room temperature for 1 hour.
Stir for hours. After removing the catalyst by filtration and concentrating the filtrate, the residue was purified by silica gel column chromatography (developing solvent; n-hexane: ethyl acetate = 1: 1) to obtain
5-amino-2- (tert-butoxycarbonyl)-
3.05 g of isoindoline are obtained as a colorless oil. MS (FAB) m / z; 235 (M + H), IR (ne
at) cm- ¹ ; 1687, 1632 (3) 217 mg of the compound obtained in the above (2), 2-
A solution of 236 mg of (5-trifluoromethyl-pyridin-2-yl) benzoic acid (the compound obtained in Reference Example 5 (3)) and 129 mg of 4-dimethylaminopyridine in methylene chloride (8 ml) was added with a solution of 1- under an argon atmosphere. Ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (212 mg) is added, and the mixture is stirred at room temperature overnight. The reaction solution is poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with chloroform. The organic layer is washed with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated saline, dried over anhydrous sodium sulfate, and the solvent is distilled off. The residue was subjected to silica gel column chromatography (developing solvent: chloroform: methanol =
30: 1) to give 375 mg of 2- (tert-butoxycarbonyl) -5- [2- (5-trifluoromethyl-pyridin-2-yl) benzoylamino] -isoindoline as a colorless foam. obtain. MS (APCI) m / z; 484 (M + H), IR (n
ujol) cm ^-1 ; 1697, 1675, 1603 (4) A 4M hydrochloric acid-dioxane solution (12 m) was added to a dioxane solution (6 ml) containing 890 mg of the compound obtained in the above (3).
and stirred at room temperature for 1 hour. Diethyl ether was added and the resulting precipitate was collected by filtration to give 5- [2-
(5-trifluoromethyl-pyridin-2-yl) benzoylamino] -isoindoline dihydrochloride 846 mg
Is obtained as a crude product. MS (APCI) m / z; 384 (M + H), IR (n
ujol) cm- ¹ ; 1661,1642,1605

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 3/06 A61P 3/06 5/00 5/00 C07D 209/44 C07D 209/44 213/55 213 / 55 401/14 401/14 403/14 403/14 409/14 409/14 (72) Inventor Koichi Nagata 1-18-5 Tajima, Saitama City, Saitama Prefecture Land Heights Nishiuraka Room 202 (72) Inventor Michiko Yasuhara 2-4-8 Nakamachi, Toda City, Saitama Prefecture Seju Ruji Fuji B-203 F-term (Reference) 4C055 AA01 BA02 BA33 BB19 CA02 CA13 CA18 CB14 DA01 DA13 DB14 4C063 AA03 BB07 BB08 CC22 CC29 CC92 DD07 EE01 4C086 AA03 BC04 GA07 BC07 GA08 MA01 MA04 NA14 ZC33 4C204 BB04 CB04 DB01 EB01 GB32

Claims (18)

[Claims] 1. A compound of the general formula [I]: (Wherein, ring A is an optionally substituted 5- or 6-membered aromatic heterocyclic group, ring B is an optionally substituted benzene ring, Q is -CO- or -CH _2- , R is substituted Represents an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted carbamoyl group, an optionally substituted heterocyclic group, or an optionally substituted aryl group Or a pharmaceutically acceptable salt thereof. 2. A 5- or 6-membered aromatic heterocyclic group in which ring A may be substituted by 1 to 3 identical or different groups selected from the following (1) to (10): ) A trifluoromethyl group, (2) a lower alkyl group optionally substituted with 1 to 3 identical or different groups selected from a hydroxyl group, an oxo group and a hydroxyimino group, (3) a lower alkoxy group, a hydroxyl group, And a lower alkoxy group which may be substituted with 1 to 3 same or different groups selected from dialkylamino groups, (4) hydroxyl group, (5) nitro group, (6) cyano group, (7) lower alkyl group A carbamoyl group which may be substituted with a group selected from a lower alkoxy lower alkyl group, a halogeno lower alkyl group, and an aryl lower alkyl group, (8)
An amino group which may be substituted with a group selected from a protecting group for an amino group, a lower alkyl group and a lower alkylsulfonyl group, (9) a lower alkanoyloxy group which may be substituted with an aryl group, and (10 ) A lower alkoxycarbonyl group, a benzene ring in which ring B may be substituted with 1 to 3 identical or different groups selected from the following (1) to (9): (1) nitro group, (2) hydroxyl group , (3) lower alkoxy group, hydroxyl group, aryl group, (lower alkylamino) aryl group, lower alkoxycarbonyl group, lower alkenyloxycarbonyl group, carboxyl group, amino group, lower alkylamino group, lower alkylcarbamoyl group, cyano group , Pyridyl group, pyrrolidinyl group, morpholinyl group,
A lower alkoxy group which may be substituted with a group selected from a piperazinyl group and a lower alkylpiperazinyl group, (4) a lower alkoxycarbonyl group, (5) (i)
A lower alkanoyl group substituted with 1 to 3 identical or different groups selected from a lower alkoxy group, an amino group, a lower alkyl group amino group, and a lower alkoxycarbonyl group, (ii) a protecting group for an amino group, (iii) A lower alkyl group optionally substituted with a pyridyl group or a lower alkylamino group, and (iv) an amino group optionally substituted with a group selected from a pyridylcarbonyl group, (6) a lower alkyl group, a lower alkoxy group A lower alkyl group, and a carbamoyl group optionally substituted with a group selected from lower alkylamino lower alkyl groups,
(7) morpholinocarbonyl group, (8) cyano group, and (9) lower alkylaminocarbonyloxy group, R
(1) a lower alkyl group which may be substituted with 1 to 3 same or different groups selected from the following (i) to (ix): (i) a lower alkyl group; a hydroxy lower alkyl group; Alkanoyl group; lower alkoxy group; nitro group; lower alkoxycarbonyl group; carboxyl group; oxo group;
A trifluoromethyl group; a carbamoyl group (the carbamoyl group may be substituted with a group selected from a lower alkyl group, a halogeno lower alkyl group, and a hydroxy lower alkyl group); an amino group (the amino group is a lower alkanoyl group; A cyano group, which may be substituted with a group selected from a lower alkoxy lower alkanoyl group, a lower alkyl group, a hydroxy lower alkyl group, a lower alkoxycarbonyl group, and a lower alkylaminoalkylidene group);
A hydroxy group which may be protected; a halogen atom; and a heterocyclic group which may be substituted with 1 to 3 same or different groups selected from formyl groups, (ii) a lower alkyl group, an amino group (the amino group The group may be substituted with a lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkyl group, a pyridyl lower alkyl group, a lower alkylaminocarbonyl group, a halogeno lower alkylaminocarbonyl group, a lower alkanoyl group, or a halogeno lower alkanoyl group. A lower alkoxy group, an aryl lower alkoxy group, a benzyloxy lower alkoxy group, a lower alkylamino lower alkoxy group, a nitro group, an optionally protected hydroxyl group, a lower alkylcarbamoyl group, a halogeno lower alkylcarbamoyl group, and a morpholinyl group. Identical Others may be substituted with 1 to 3 groups different, aryl group, or fluorenyl group, (i
ii) an optionally protected hydroxyl group, (iv) a carbamoyl group which may be substituted with a group selected from a lower alkyl group, a halogeno lower alkyl group, and a benzothiazolyl group, and (v) a compound represented by the following formula: (Where n represents an integer of 0 to 4), (v
i) a lower alkoxycarbonyl group, (vii) an amino group that may be substituted with a protecting group for an amino group, a lower alkyl group, a pyridyl group, or a pyrimidinyl group, (vii
i) a halogen atom and (ix) an oxo group, (2)
A lower alkenyl group which may be substituted with an aryl group,
(3) a carbamoyl group which may be substituted with a group selected from a lower alkyl group, a halogeno lower alkyl group and a benzothiazolyl group; (Wherein m represents an integer of 0 to 4),
(5) a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, an amino group, a lower alkylamino group,
A heterocyclic group which may be substituted with 1 to 3 identical or different groups selected from a hydroxyl group which may be protected and an amino group which may be protected, or (6)
Selected from lower alkyl groups, lower alkoxy groups, lower alkyl carbamoyl groups, halogeno lower alkyl carbamoyl groups, morpholinyl groups, amino groups, lower alkylamino groups, optionally protected hydroxyl groups, and optionally protected amino groups The compound according to claim 1, which is an aryl group optionally substituted with 1 to 3 same or different groups. 3. The 5- or 6-membered aromatic heterocyclic group is nitrogen,
The same or different 1 selected from oxygen and sulfur atoms
3. The compound according to claim 1, which is a 5- or 6-membered aromatic heterocyclic group containing four hetero atoms. 4. The 5- or 6-membered aromatic heterocyclic group is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl or pyrazolyl. The compound according to claim 1, which is a group. 5. The heterocyclic group is a pyridyl group, indolyl group, thiazolyl group, imidazolyl group, pyrrolyl group, pyrimidinyl group, thienyl group, benzo [b] furyl group, benzo [b] thienyl group, pyrazolyl group, triazolyl group. Group,
A quinolyl group, an isoquinolyl group, a phthalazinyl group, a quinazolinyl group, a quinoxalinyl group, a 5,11-dihydro-dibenzo [b, e] [1,4] oxazepin-5-yl group, a dihydropyrazolyl group, or a tetrazolyl group; Phenyl group, naphthyl group, anthranyl group,
Or a phenanthrenyl group.
A compound as described. 6. In the general formula [I], the ring A is represented by the formula: Wherein R ¹ is a trifluoromethyl group or a lower alkanoyl group, ring B is a lower alkoxy group, a (lower alkylamino lower alkanoyl) amino group, a lower alkylamino lower alkoxy group, a lower alkylcarbamoyl group, and a lower A benzene ring which may be substituted with a group selected from an alkoxycarbonyl group, a lower alkyl group in which R is substituted with a group selected from the following (1) to (4): (1) a lower alkyl group, a nitro group, A pyrazolyl group optionally substituted with a group selected from a lower alkoxycarbonyl group, a cyano group, an amino group, and a hydroxy lower alkyl group, (2) a pyridyl group, (3) a tetrazolyl group,
Or the compound according to claim 5, which is (4) a thiazolyl group optionally substituted with an amino group. 7. In the general formula [I], ring A is represented by the formula: Wherein ring B is a benzene ring and Q is -CO
The compound according to claim 6, wherein-and R are pyrazolylmethyl which may be substituted with a group selected from a lower alkyl group, a nitro group, a lower alkoxycarbonyl group, and a hydroxy lower alkyl group. 8. (2-H-pyrazol-1-yl) acetyl-5- [2- (5-trifluoromethyl-pyridin-2-yl) benzoylamino] -isoindoline;
2- (1H-pyrazol-1-yl) acetyl-5-
[2- (5-trifluoromethyl-pyridin-2-yl) -3-methoxycarbonylbenzoylamino] -isoindoline, 2- [2- (1H-pyrazol-1-yl) ethyl] -5- [2- (5-trifluoromethyl-
Pyridin-2-yl) benzoylamino] -isoindoline or a pharmaceutically acceptable salt thereof. 9. A compound of the general formula [5]: (Wherein, Q is -CO- or -CH 2 _{-, R} is optionally substituted lower alkyl group, optionally substituted lower alkenyl group, an optionally substituted carbamoyl group, substituted A heterocyclic group which may be substituted or an aryl group which may be substituted), or a salt thereof, and a general formula [6]: (Wherein ring A represents a 5- or 6-membered aromatic heterocyclic group which may be substituted, and ring B represents a benzene ring which may be substituted) or a salt thereof. Wherein, if desired, the product is converted into a pharmaceutically acceptable salt. Wherein the symbols have the same meanings as described above, or a pharmaceutically acceptable salt thereof. 10. The general formula [15]: (Wherein, ring B is an optionally substituted benzene ring, Q is —CO— or —CH ₂ —, R is an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, An optionally substituted carbamoyl group, an optionally substituted heterocyclic group, or an optionally substituted aryl group, X ¹ represents a leaving group) or a salt thereof, and a general formula [ 16]: (Wherein, ring A is an optionally substituted 5- or 6-membered aromatic heterocyclic group, M is a hydroxyl group, a halogen atom, a cyano group,
Lower alkyl group, aryl group, lower alkoxy group, alkylenedioxy group, aryloxy group, arylenedioxy group, and arylthio group, which represent a metal which may be coordinated with the same or different substituents). Reacting with a compound, if desired, converting the product to a pharmaceutically acceptable salt, characterized by the general formula [I]: Wherein the symbols have the same meanings as described above, or a pharmaceutically acceptable salt thereof. 11. The general formula [13]: (Wherein ring A represents an optionally substituted 5- or 6-membered aromatic heterocyclic group, ring B represents an optionally substituted benzene ring) or a salt thereof, and a general formula [ 2]: R-COOH [2] (wherein, R is an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted carbamoyl group, and an optionally substituted Represents a heterocyclic group or an aryl group which may be substituted)) or a salt thereof,
General formula [Ia], characterized in that the product is optionally converted into a pharmaceutically acceptable salt. Wherein the symbols have the same meanings as described above, or a pharmaceutically acceptable salt thereof. 12. A compound of the general formula [Ia]: (Wherein, ring A is an optionally substituted 5- or 6-membered aromatic heterocyclic group, ring B is an optionally substituted benzene ring, R is an optionally substituted lower alkyl group, An optionally substituted lower alkenyl group, an optionally substituted carbamoyl group, an optionally substituted heterocyclic group,
Or a salt thereof, which represents an optionally substituted aryl group) or a salt thereof, and if necessary, converts the product into a pharmacologically acceptable salt. -B]: Wherein the symbols have the same meanings as described above, or a pharmaceutically acceptable salt thereof. 13. A compound of the general formula [13]: (Wherein ring A represents an optionally substituted 5- or 6-membered aromatic heterocyclic group, ring B represents an optionally substituted benzene ring) or a salt thereof, and a general formula [ 1
7]: R-CHO [17] (wherein, R is an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted carbamoyl group, and an optionally substituted carbamoyl group. (Representing a heterocyclic group or an optionally substituted aryl group) or a salt thereof, followed by a reduction reaction, and if desired, the product can be pharmacologically acceptable. A salt of the general formula [I-
b]: Wherein the symbols have the same meanings as described above, or a pharmaceutically acceptable salt thereof. 14. A general formula [13]: (Wherein ring A represents an optionally substituted 5- or 6-membered aromatic heterocyclic group, ring B represents an optionally substituted benzene ring) or a salt thereof, and a general formula [ 1
8]: R—CH ₂ —X ² [18] (wherein, R is an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted carbamoyl group, A heterocyclic group which may be substituted, or an aryl group which may be substituted, and X ² represents a leaving group) or a salt thereof, and if necessary, the product is pharmacologically acceptable. A general salt of formula [Ib]: Wherein the symbols have the same meanings as described above, or a pharmaceutically acceptable salt thereof. 15. The general formula [13]: (Wherein ring A represents a 5- or 6-membered aromatic heterocyclic group which may be substituted, and ring B represents a benzene ring which may be substituted) or a salt thereof. 16. The general formula [5]: (Wherein, Q is -CO- or -CH 2 _{-, R} is optionally substituted lower alkyl group, optionally substituted lower alkenyl group, an optionally substituted carbamoyl group, substituted A heterocyclic group or an optionally substituted aryl group) or a salt thereof. 17. The general formula [6 ′]: (Wherein R ¹ represents a trifluoromethyl group or a lower alkanoyl group, and ring B represents an optionally substituted benzene ring) or a salt thereof. 18. A compound represented by the general formula [15]: (Wherein, ring B is an optionally substituted benzene ring, Q is —CO— or —CH ₂ —, R is an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, An optionally substituted carbamoyl group, an optionally substituted heterocyclic group, or an optionally substituted aryl group, X ¹ represents a leaving group) or a salt thereof.