WO2002014276A1

WO2002014276A1 - Benzoylaminoisoindoline compounds, processes for the preparation of the same and intermediates for the synthesis thereof

Info

Publication number: WO2002014276A1
Application number: PCT/JP2001/006843
Authority: WO
Inventors: Harutami Yamada; Akira Ando; Hiroyuki Kawanishi; Koichi Nagata; Mikiko Yasuhara
Original assignee: Tanabe Seiyaku Co., Ltd.
Priority date: 2000-08-10
Filing date: 2001-08-09
Publication date: 2002-02-21
Also published as: AU2001277727A1

Abstract

Benzoylaminoisoindoline compounds of the general formula [I] useful as drugs, or pharmacologically acceptable salts thereof; processes for the preparation of the compounds or the salts; and intermediates for the synthesis thereof; [I] wherein A is a substituted or unsubstituted 5- or 6-membered aromatic heterocyclic group; B is a substituted or unsubstituted benzene ring; Q is CO- or CH2-; and R is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted carbamoyl, a substituted or unsubstituted heterocyclic group, or substituted or unsubstituted aryl.

Description

Description Benzoylaminoisoindoline compounds, their production methods and their synthetic intermediates

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

WO 96/40640 discloses 4,1-trifluoromethyl-piphenyl-2-carboxylic acid [2- (thiophen-1-yl-1-acetyl) -1,1,2,3,4-tetrahydroisoquinoline 1-6-yl] 1-amide, 4,1-trifluoromethyl-1-biphenyl-12-carboxylic acid [2- (pyridine-1-2-ylua cetyl) -1,2,3,4-tetrahydroisoquinoline-1-6-yl ] -Amid et al. And WO 98/23593 disclose 4,1-trifluoromethyl-1-biphenyl-12-carboxylic acid [2- (2- (pyridine-12-yl) ethyl) -1 It has been suggested that 1,2,3,4-tetrahydroisoquinoline-1-6-yl] -amide and the like have an inhibitory effect on ApoB secretion and can be used as a serum lipid-lowering agent.

However, all of the amide compounds described in these publications are compounds having a biphenyl structure in the carboxylic acid portion and a tetrahydroisoquinoline ring in the amine portion. There is no description of a compound having an aromatic heterocyclic monophenyl group or a compound having an isoindoline ring in the amine moiety.

The present invention provides a novel benzoylaminoisoindoline compound 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 an intermediate for synthesizing the same. Is what you do. Summary of the Invention

In order to solve the problems, the present inventors have conducted intensive studies and, as a result, have found a novel benzoylaminoisoindoline compound having an apolipoprotein B secretion inhibitory action and a serum lipid lowering action, and completed the present invention. .

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

In the formula, ring Α is a substituted or unsubstituted 5- or 6-membered aromatic heterocyclic group, ring B is a substituted or unsubstituted benzene ring, Q is one C〇 or _CH ₂ —,

R represents a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkenyl group, a substituted or unsubstituted radical group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted aryl group A benzoylaminoisoindoline compound represented by the formula: or a pharmaceutically acceptable salt thereof. BEST MODE FOR CARRYING OUT THE INVENTION

Examples of the substituent on ring A in the target compound [I] of the present invention include: (1) a trifluoromethyl group,

(2) an unsubstituted lower alkyl group, or a lower alkyl group substituted with 1 to 3 identical or different groups selected from a hydroxyl group, an oxo group and a hydroxyimino group, (3) an unsubstituted lower alkoxy group, or a lower A lower alkoxy group substituted with 1 to 3 same or different groups selected from an alkoxy group, a hydroxyl group and a dialkylamino group,

(4) hydroxyl group, (5) nitro group,

(6) cyano group,

(7) an unsubstituted rubamoyl group or a lower alkyl group, provided that a labamoyl group substituted with a group selected from a lower alkoxy lower alkyl group, a halogeno lower alkyl group and a lower aryl alkyl group;

(8) an unsubstituted amino group, or a protecting group for an amino group, an amino group substituted with a group selected from a lower alkyl group and a lower alkylsulfonyl group,

(9) an unsubstituted lower alkanoyloxy group, or a lower alkanoyloxy group substituted with an aryl group,

(10) A lower alkoxy group such as a ruponyl group.

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

Ring A includes, for example, a 5- or 6-membered aromatic heterocyclic group containing 1 to 4 identical or different heteroatoms selected from nitrogen, oxygen and sulfur atoms. Specific examples include a pyridyl group, a pyrimidinyl group, a virazinyl group, a pyridazinyl group, a furyl group, a phenyl 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) hydroxyl group,

(3) Unsubstituted lower alkoxy group, or 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 A lower alkoxy group substituted with a group selected from alkyl rubamoyl, cyano, pyridyl, piperidinyl, morpholinyl, piperazinyl and lower alkylpiperazinyl;

(4) a lower alkoxycarbonyl group,

(5) unsubstituted amino group, or (i) lower alkoxy group, amino group, lower alkyl group A lower alkanoyl group substituted with 1 to 3 identical or different groups selected from a kill group, an amino group and a lower alkoxycarbonyl group, (ii) a protecting group for an amino group, (iii) an unsubstituted lower alkyl group, or pyridyl A lower alkyl group substituted with a group or a lower alkylamino group, and (iV) a pyridylcarbonyl group, an amino group substituted with a group selected from the group consisting of:

(6) an unsubstituted rubamoyl group, or a labamoyl group substituted with a group selected from a lower alkyl group, a lower alkoxy lower alkyl group and a lower alkylamino lower alkyl group;

(7) morpholinocarbonyl group,

(8) a cyano group,

(9) A lower alkylaminocarbonyloxy group and the like.

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

When R in the target compound [I] of the present invention is a substituted or unsubstituted lower alkyl group, the substituent on the lower alkyl group is

(i) an unsubstituted heterocyclic group or a lower alkyl group; a hydroxy lower alkyl group; a lower alkenyl group; a lower alkoxy group; a nitro group; a lower alkoxycarbonyl group; a carbonyl group; an oxo group; A methyl group; an unsubstituted rubamoyl group, or a labamoyl group substituted with a group selected from a lower alkyl group, a halogeno lower alkyl group and a hydroxy lower alkyl group; an unsubstituted amino group or a lower alkanoyl group; An amino group 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 alkenylaminoalkylidene group; a cyano group; an optionally protected hydroxyl group 1 to 3 identical or different halogen atoms; and a formyl group In substituted heterocyclic group,

(ii) an unsubstituted aryl or unsubstituted fluorenyl group or a lower alkyl group; an unsubstituted amino group or a lower alkanol group, a lower alkoxycarbonyl group, a lower alkyl group, a pyridyl lower alkyl group, or a lower alkylaminocarboxy group An amino group substituted with a halogeno group, a halogeno lower alkylaminocarbonyl group, a lower alkanoyl group or a halogeno lower alkazoyl group; a lower alkoxy group; an aryl lower alkoxy group; a benzyloxy lower alkoxy group; a lower alkylamino lower alkoxy group; A hydroxyl group or a protected hydroxyl group; a lower alkyl group rubamoyl group; a halogeno lower alkyl group rubamoyl group; and one or three same or different groups selected from morpholinyl groups, an aryl group or a fluorenyl group,

(iiii) a hydroxyl group or a protected hydroxyl group,

(i V) an unsubstituted rubamoyl group, or a labamoyl group substituted with a group selected from a lower alkyl group, a halogeno lower alkyl group, and a benzothiazolyl group;

In the formula, n represents an integer of 0 to 4,

A group represented by

(V i) a lower alkoxycarbonyl group,

(vii) an amino group substituted with an unsubstituted amino group or a protecting group for an amino group, a lower alkyl group, a pyridyl group or a pyrimidinyl group,

(V i i i) a halogen atom,

(ix) oxo group and the like.

The lower alkyl group for R may be unsubstituted or substituted with one to three identical or different groups selected from the above (i) to (iX).

When R in the target compound [I] of the present invention is a substituted or unsubstituted 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 a substituted or unsubstituted rubamoyl group, the substituent on the rubamoyl group may be a lower alkyl group or a halogeno group. Examples include a lower alkyl group and a benzothiazolyl group. Also, the substituted or unsubstituted carbamoyl group includes a compound represented by the formula:

In the formula, m represents an integer of 0 to 4,

And the like.

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

The heterocyclic group for R may be unsubstituted or 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 a substituted or unsubstituted heterocyclic group, examples of the heterocyclic group include a pyridyl group, an indolyl group, a thiazolyl group, an imidazolyl group, and a pyrrolyl group. , Pyrimidinyl, chenyl, benzo [b] furyl, benzo [b] chenyl, pyrazolyl, triazolyl, quinolyl, isoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, 5,11-dihydro-dibenzo [b, e] [1, 4] oxazepine-15-yl group, dihydrovirazolyl group, tetrazolyl group and the like.

When R in the target compound [I] of the present invention is a substituted or unsubstituted aryl group, examples of the substituent on the aryl group include a lower alkyl group, a lower alkoxy group, a lower alkyl group, a lubamoyl group, and a halogeno lower alkyl group. Examples include a rubamoyl group, a morpholinyl group, an amino group, a lower alkylamino group, a hydroxyl group, a protected water rooster, a protected amino group, and the like.

The aryl group in R may be unsubstituted or 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 a substituted or unsubstituted aryl group, specific examples of the aryl group include a phenyl group, a naphthyl group, an anthranyl group, and a phenanthrenyl group.

When the target compound [I] of the present invention has a protected amino group, examples of the protecting group for the amino group include a substituted or unsubstituted lower alkoxycarbonyl group, lower alkenyloxycarbonyl group, and acyl group. And a substituted or unsubstituted aryl group-substituted lower alkyl group, lower alkenyl group and the like. Specific examples include an ethoxycarbonyl group, a methoxycarbonyl group, a tert-butoxycarbonyl group, a 2,2,2-trichloromethyl group. Substituted or unsubstituted with a halogen atom such as a thioloxycarbonyl group, or substituted or unsubstituted with a lower alkoxy group such as a lower alkoxycarbonyl group, a benzyloxycarbonyl group, or a 4-methoxybenzyloxycarbonyl group. Aryl group substituted lower alkoxy group, aryloxy group牴級 alkenyl O propoxycarbonyl alkenyl group such as a formyl group, Asechiru group, a propionyl group, etc. Ashiru groups such Puchiriru group. Furthermore, a lower alkoxy group such as a benzyl group or a 4-methoxybenzyl group, or an unsubstituted aryl group substituted with a lower alkyl group, a lower alkenyl group such as an aryl group, or a 9-fluorenyl methoxycarbonyl group And the like. Of these, a substituted or unsubstituted lower alkoxycarbonyl group is preferred, and specific examples thereof include a benzyloxycarbonyl group and a tert-butoxycarbonyl group. The protected amino group also includes, for example, a case where a phthalimid 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 a substituted or unsubstituted aryl lower alkyl group, an acyl group, a substituted or unsubstituted lower alkoxycarbonyl group. And common protecting groups such as trialkylsilyl group and the like. Among them, preferred are, for example, unsubstituted aryl aryl lower alkyl groups such as benzyl group and phenethyl group, formyl group, acetyl group, propionyl group, malonyl group, acryloyl group, benzoyl group, etc., methoxycarbonyl group, Ethoxycarbonyl group, etc. And lower alkoxy groups such as trialkylsilyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl and the like. Further, a triphenylmethyl group, a 2-cyanoethyl group and the like can be mentioned. Among the target compounds [I] of the present invention, preferred compounds are those wherein ring A has the formula:

Is a ring represented by

R ¹ is a trifluoromethyl group or a lower alkynyl group,

Ring B is substituted with an unsubstituted benzene ring or a group selected from a lower alkoxy group, a (lower alkylamino lower alkanol) amino group, a lower alkylamino lower alkoxy group, a lower alkyl group and a lower alkoxycarbonyl group Benzene ring,

Q is CO— or one CH ₂ —,

R is a lower alkyl group substituted by a group selected from the following (1) to (4):

(1) an unsubstituted pyrazolyl group or a pyrazolyl 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;

(2) a pyridyl group,

(3) a tetrazolyl group, or

(4) A compound which is an unsubstituted thiazolyl group or a thiazolyl group substituted with an amino group.

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

Is a ring represented by Ring B is a benzene ring,

Q is — C〇—,

Compounds in which R is an unsubstituted pyrazolylmethyl group or a virazolylmethyl group 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-pyrazol ^ "l_1_yl) acetyl-1 5-[2-(5-trifluoromethyl) Pyridine-1-yl) benzoylamino] -isoindoline, 2- (1H-pyrazole_1-yl) acetyl-5- [2- (5-trifluoromethyl-pyridine-12-yl) -1-3-methoxy Carboel benzoylamino] one isoindoline,

2— [2— (1H-pyrazole-1-yl) ethyl] —5— [2- (5-Trifluoromethyl-pyridine-1-yl) benzoylamino] —isoindoline or its pharmacologically Acceptable salts are included.

When the substituent on ring A, the substituent on ring B, and Z or R have an asymmetric atom, the target compound [I] of the present invention can exist as an optical isomer based on the asymmetric atom. However, the present invention includes both of these optical isomers and mixtures thereof.

The target 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 objective compound [I] of the present invention or a pharmaceutically acceptable salt thereof is hyperlipidemia, ischemic heart disease, atherosclerosis, coronary atherosclerosis, 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 sexually transmitted inflammation, obesity, steatosis, constipation, etc. Further, the target compound [I] of the present invention has the characteristics of low toxicity and high safety as a medicine.

The target compound [I] of the present invention may be in a free form or a pharmacologically acceptable salt. Can also be used for pharmaceutical applications. Pharmaceutically acceptable salts of compound [I] include, for example, inorganic salts such as hydrochloride, sulfate, phosphate or bromide hydrochloride, acetate, fumarate, oxalate And organic acid salts such as citrate, methanesulfonate, benzenesulfonate, tosylate and maleate. In the case of having a substituent such as a sulfoxyl group, a salt with a base (for example, an alkali metal salt such as a sodium salt or a potassium salt or an alkaline earth metal salt such as a calcium salt) can be mentioned.

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

The target compound [I] of the present invention or a pharmaceutically acceptable salt thereof can be administered orally or parenterally, and tablets, granules, capsules, powders, injections, B It can be used as conventional pharmaceutical preparations such as fillers.

The dosage of the compound of interest [I] of the present invention or a pharmaceutically acceptable salt thereof varies depending on the administration method, age of the patient, weight and condition. 0.01 SmgZkg, especially about 0.1 to 3 mg / kg, for oral preparation, usually about 0.1 to per day; L 00 mg / kg, especially about 0.1 to 5 Omg / kg Is preferred.

According to the present invention, the target compound [I] can be produced by the following (Method A) to (Method H), but is not limited thereto.

(Method A)

The benzoylaminoisoindoline compound represented by the target compound [I] of the present invention has the general formula [5]:

However, each symbol has the same meaning as described above,

And a salt thereof, and a general formula [6]

However, each symbol has 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 group. Any solvent may be used as long as it does not adversely affect the reaction. For example, methylene chloride, methylformamide, dimethylformamide, dimethylacetamide, tetrahydrofuran, toluene, benzene, 1,2 —Dichloroethane, 1-methylpyrrolidinone and the like. Examples of the condensing agent include dicyclohexyl carpoimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide 'hydrochloride (WS C · HC 1), diphenyl phosphoryl azide (DPPA) , Carbonyldiimidazole (CDI), getylcyanophosphonate (DEPC), diisopropylcarboimide (DIPCI), benzotriazole-111-yloxytrispyrrolidinophosphonium hexafluorophosphate (PyBOP), etc. No. Examples of the activator include 1-hydroxybenzotriazole (HOBt), hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP), and 1-hydroxy-7-azabenzotriazole (HOB). HOA t), hydroxyphthalimid (HOP ht), pentafluorophenol (P fp-OH) and the like. Examples of the base include triethylamine, diisopropylethylamine, 4-methylmorpholine, 1,8-diazavic mouth [5.4.0] -7-pandacene (DBU) and the like.

The amount of the condensing agent to be used is 1 to 10 equivalents, preferably,; with respect to compound [5] or compound [6]; ~ 2 equivalents can be used. The amount of the activating agent to be used is 1 to: 0 equivalent, preferably 1 to 2 equivalent, relative to compound [5] or compound [6]. Can be. This reaction can be carried out, for example, at 0 to L 0 ° C, preferably at 0 to 50 ° C.

Compound [I] can also be obtained by converting compound [6] to a reactive derivative such as an acid chloride or a mixed acid anhydride and then reacting with compound [5] in the presence of a base.

(Method B)

The benzoylaminoisoindoline compound represented by the target compound [I] of the present invention also has the general formula [15]:

In the formula, 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]:

In the formula, M is 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 which may be coordinated by the same or different substituents, and other symbols have the same meanings as described above.

Can also be produced by reacting with a compound represented by the formula:

This reaction can be carried out in a solvent, in the presence of a catalyst, in the presence or absence of a base, or 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, getylamine, triethylamine and the like. As metal of M, for example, Examples 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. Additives include, for example, triphenylphosphine, tri0-tolylphosphine, tri-n-butylphosphine, copper (I) bromide, copper (I) iodide, triphenylenylsine, tri (2-furyl) Examples include phosphine, diphenylphosphinophenol (dppf), diphenylphosphinobutane (dppb), 2,6-ditert-butyl-4-cresol, and the like. The amount of compound [16] to be used is 1 to 5 equivalents, preferably 1 to 1.5 equivalents, relative to compound [15]. The amount of the catalyst to be used is 0.001 to 0.5 equivalent, preferably 0.05 to 0.2 equivalent, relative to compound [15]. The used amount of ^ 使用 can be 1 to 20 equivalents, preferably 1 to 5 equivalents, relative to compound [15]. The amount of the additive to be used may be 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to compound [15]. This reaction can be carried out, for example, at 0 to 150 ° C, preferably at 30 to 120 ° C. As the leaving group X ^1, a fluorine atom, a chlorine atom, a halogen atom such as a bromine atom or an iodine atom, Ru triflumizole Ruo b methanesulfonyl O carboxymethyl group and the like.

(Method C)

Among the target compound [I] of the present invention, a compound in which Q is —CO— in the general formula [I], that is, a general formula [I-a]:

[I-a]

The benzoylaminoisoindoline compound represented by the general formula [13]

However, each word has the same meaning as above,

And a salt thereof, and a general formula [2]:

R-C00H [2] wherein the symbols have the same meanings 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 group. The solvent may be any solvent that does not adversely affect the reaction, and for example, those exemplified as the solvent that can be used in the reaction of the above (Method A) can be used as appropriate. As the base or the activating agent, for example, those exemplified in the reaction of the above (Method A) can be used as appropriate.

In addition, compound [Ia] can be obtained by converting compound [2] to a reactive derivative such as an acid chloride or a mixed acid anhydride and then reacting with compound [13] in the presence of a base.

(Method D)

Of the target compound [I] of the present invention, a compound in which Q is —CH ₂ — in the general formula [I], that is, a general formula [I-b]:

[Ib]

However, each symbol has the same meaning as described above,

The benzoylaminoisoindoline 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 examples thereof include tetrahydrofuran, getyl ether, dioxane, and dimethoxyethane. Suitable reducing agents include, for example, sodium borohydride sodium borotriethyl diethyl ether complex, lithium aluminum hydride, aluminum hydride, lithium borohydride, diborane-dimethyl sulfide 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 [I-a]. This reaction is, for example, _30 to 100. C, preferably at 0-50 ° C.

(Method E)

Among the target compound [I] of the present invention, the benzoylaminoisoindoline compound represented by the general formula [I-b] is also a compound represented by the general formula [13] or a salt thereof, and a compound represented by the general formula [17]:

R-CHO [17]

However, the symbols have the same meaning as described above,

Can also be produced by subjecting a aldehyde compound represented by or a salt thereof to a condensation reaction and then subjecting the compound to 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, getyl ether, methanol, ethanol, isopropyl alcohol, and the like. 1,2-dichloroethane, water and the like. Bases include, for example, triethylamine, diisopropyl Luethylamine, 4-methylmorpholine and the like. Examples of the reducing agent include sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, sodium triacetoxyborohydride, monoparadium hydrogen hydrogen, sodium borohydride-acetic acid, and the like.

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

The above condensation reaction and reduction reaction can also be carried out in one pot as a reductive amination reaction.

(F method)

Among the target compounds [I] of the present invention, the benzoylaminoisoindoline compound represented by the general formula [I-b] is also a compound represented by the general formula [13] or a salt thereof, and the general formula [18]:

R-CH ₂ -X ² [18] wherein X ² represents a leaving group, and other symbols have the same meanings as described above. Can be. 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, and examples include tetrahydrofuran, dimethylformamide, dimethylacetamide, dimethylsulfoxide, ethanol, isopropyl alcohol, and acetonitrile. Examples of the base include potassium carbonate, sodium carbonate, triethylamine, disopropylethylamine, pyridine, and hydroxy [arsenic acid, potassium hydroxide, and the like.Additives include sodium iodide and iodide. Copper (I) Copper lower iodide ammonium, such as copper iodide (11), copper powder, potassium iodide, tetrabutylammonium chloride, and tetraethylammonium chloride. ゥ Muhalide and the like.

The amount of compound [18] to be used is 1 to 5 equivalents, preferably 1 to 1.5 equivalents, relative to compound [13]. The amount of the base to be used is 1-20 equivalents, preferably 1-5 equivalents, relative to compound [13]. The amount of the additive to be used may be 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to compound [13]. This reaction can be carried out, for example, at a temperature of from 30 to 150 ° C, preferably from 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 p-toluenesulfonyloxy group, a methanesulfonyloxy group And trifluoromethansulfonyloxy group, hydroxyl group and the like.

Further, when the leaving group X ² is a hydroxyl group, Mitsunobu reagents such as triphenylphenylphosphine-diethylazodicarboxylate and triphenylphenylphosphine-diisopropylazodioxycarbonylate can be used.

(G method)

Of the target compound [I] of the present invention, a compound represented by the general formula [I-c]:

In the formula, P represents a hydroxyl-protecting group, and other symbols have the same meanings as described above.

The benzoylaminoisoindoline compound represented by the general formula [13] or a salt thereof is represented by the general formula [19]:

However, the symbols have the same meaning 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, and examples thereof include methanol, ethanol, isopropyl alcohol, dimethylformamide, and acetoniryl. Examples of the base include, for example, triethylamine, disodium, and the like. Examples include propylethylamine, 4-methylmorpholine, etc. Examples of the additive include ammonium chloride, tin (II) iodide, and the like.

(H method)

Among the target compound [I] of the present invention, a compound represented by the general formula [I_d]:

In the formula, R ² represents a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted aryl group, and other symbols have the same meanings as described above.

The benzoylaminoisoindoline conjugate represented by the general formula [13] and a salt thereof and a general formula [20]:

^ R ² [20]

However, the symbols have the same meaning as described above,

Can be produced by reacting 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 includes, for example, methanol, ethanol, propanol, etc. Examples of the base include triethylamine, disopropylamine, 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 converts the substituent on ring A, the substituent on ring B and / or the group R of the compound obtained as described above to another desired substituent. Can also be produced. The method for converting such a substituent is described in What is necessary is just to select suitably according to the kind of substituent which is a target, For example, it can implement as (method a)-(method i).

(Method a: alkylation of an amino group (reductive amination))

The target compound [I] in which the group R in the general formula [I] is a substituent containing a substituted or unsubstituted lower alkylamino group (eg, a dimethylamino group) is a primary or secondary compound in which the group R is not protected. It can be produced from the corresponding compound [I], which is a substituent containing a secondary amino group, and the corresponding aldehyde compound (eg, formaldehyde) by treating in the same manner as in the above (Method E).

(Method b: oximation of carbonyl group)

The target compound [I] in which the substituent on the ring A in the general formula [I] is an oxime-containing substituent is a corresponding compound in which the substituent on the ring A is a carboxy-containing substituent. [I] can be produced by reacting hydroxylamine with a conventional method.

(Method c: amidation)

In the general formula [I], the target 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 substituted or unsubstituted carbamoyl group is represented by a ring A From the corresponding primary compound or secondary amine compound corresponding to the above substituent, the substituent on ring B, and / or the corresponding compound [I] in which the group R is a substituent containing a carboxyl group, (Method A) It can be manufactured by treating in the same manner as described above.

(Method d; N-acylation)

In the general formula [I], the target 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 an acylamino group, is a substituent on the ring A, The corresponding compound [I] in which the substituent on the ring B and / or the group R is a substituent containing an amino group and a corresponding acylating agent (for example, picolinic acid, dimethylaminoglycine) can be obtained by the above-mentioned (Method A). )).

(Method e: substitution reaction of alkyl halide)

In the general formula [I], the group R is a substituted or unsubstituted nitrogen-containing heterocyclic group-substituted lower group The compound [I] which is an alkyl group (for example, 1-pyrazolylmethyl group) or a lower alkylamino lower alkyl group (for example, dimethylaminomethyl group) is a lower alkyl group in which the group R is substituted with a halogen atom (for example, , A chloromethyl group) and a corresponding substituted or unsubstituted nitrogen-containing heterocycle (eg, virazole) or a primary or secondary lower alkylamine (eg, dimethylamine). It can be produced by reacting in the presence. 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, 7] potassium oxide, cesium fluoride, and sodium hydrogen carbonate. Is mentioned.

(Method f: reduction reaction of nitro group)

In the general formula [I], the target 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 an amino group is a compound on the ring A, The reaction is carried out by reacting the corresponding compound [I], wherein the substituent on B and / or the group R is a substituent containing a nitro group, in the presence of a reducing agent (for example, hydropalladium-carbon). Can be.

(g method: palladium coupling puyo hydrolysis)

The target compound [I] in which the group R in the general formula [I] is a substituent containing an acetyl group is the same as the corresponding compound [I] in which the group R is a substituent containing a halogen atom. It can be produced by reacting with (lower alkoxyvinyl) tin in the presence of a catalyst (for example, bis triphenylphenylphosphine palladium dichloride, palladium acetate, etc.) and then hydrolyzing.

(Method h: reduction of carbonyl group)

The target compound [I] in which the substituent on the ring A and / or the group R in the general formula [I] is a substituent containing a hydroxyl group is a compound having the substituent on the ring A and Z or the group R is a compound having a hydroxyl group. The corresponding compound [I], which is a substituent containing a group, can be produced by treating with a conventional reducing agent (for example, sodium borohydride, lithium aluminum hydride, lithium borohydride, etc.). it can. (Method i: azidation and reduction reaction)

The compound [I] in which the group R in the general formula [I] is a substituent containing an amino lower alkyl group (eg, an aminomethyl group) is a lower alkyl group in which the group R is substituted with a halogen atom (eg, chloromethyl The corresponding compound [I], which is a substituent containing the group (I), is reacted with an azidating agent, and then subjected to a reduction reaction to produce the compound (I). Examples of the azidating agent include sodium azide, trimethylsilane azide, triptyltin azide and the like. Examples of the reducing agent include hydrogen / palladium monocarbon, triphenylphosphine-water, zinc-acetic acid, hydrosulfite sodium and the like.

(Method j: 0-acylation or 0-alkylation reaction)

The target compound [I] in which the substituent on the ring A and / or the substituent on the ring B in the general formula [I] is a substituent containing an acyloxy group or a substituted or unsubstituted lower alkoxy group, The corresponding compound [I], wherein the substituent on A and / or the substituent on ring B is a hydroxyl-containing substituent, and a acylating agent (eg, phenyl acetyl chloride) or a substituted or unsubstituted lower It can be produced by reacting with an alkyl halide (for example, 2-methoxethyl chloride) in the presence of (for example, potassium carbonate or cesium carbonate).

(Method k: amide reduction reaction)

In the general formula [I], the substituent on ring A, and / or the substituent on ring B is a substituent containing a substituted or unsubstituted lower alkylamino group. The corresponding compound [I], wherein the substituent on ring A, and the substituent on Z or ring B are a substituent containing a substituted or unsubstituted lower alkanoylamino group, with a reducing agent (for example, borane (Dimethyl sulfide complex).

The desired compound [I] of the present invention obtained as described in the above (Method A) to (Method H) or (Method a) to (Method k) may be converted into a pharmaceutically acceptable salt, if desired. It can also be converted. Conversion to a pharmaceutically acceptable salt may be performed according to methods known to those skilled in the art. Next, a method for adjusting the raw material mixture used in the above method will be described below. The starting compound [5] ([5-a] and [5-b]) can be produced, for example, according to the following method.

[7]

R—CONH ₂

[8]

However, the words have the same meaning 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).

Also, a compound [3] is produced from a dichloro compound [7] and a compound [8]. The reaction can be carried out in the presence of a base, in the presence or absence of an additive. As the base, for example, sodium hydroxide, hydroxylating water, sodium hydride, potassium hydride, sodium methoxide and the like can be mentioned. Examples of the additive include tetra-lower alkyl ammonium halides such as tetrabutylammonium chloride and tetraethylammonium chloride. As an example of this process, for example,

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 monoacetic acid, chloridite (II) —hydrochloric acid, tin (II) chloride—hydrochloric acid, iron monohydrochloride, iron monochloride ammonium, and formic acid. Ammonia / palladium-single carbon.

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

The reaction for producing compound [5-b] from compound [9] is the same as the reaction (N-alkylation) in the same manner as in the above (Method F), followed by the reaction for producing compound [5-a] from compound [4] (Reduction of nitro group) 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 nucleophilic agent include a nitrogen-containing heterocyclic group such as imidazole, pyrazole, pyrrole, indole, and triazole; or a primary or secondary lower group such as dimethylamine, getylamine, ethylamine, morpholine, piperidine, and pyrrolidine. Examples include an alkylamino group and the like. Examples of the base include potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, potassium, cesium fluoride, sodium hydroxide, potassium hydroxide and the like.

As an example of this process, for example,

2 ^C 0 ₃

Aceton

Is mentioned.

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

MX ³ MX ³ or or

M-M, r M-M

[28] [6]

Where X. 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, X ⁴ is a leaving group, and The symbols have the same meaning as described above.

The reaction for producing compound [24] from compound [23] can be carried out as follows.

When X ⁰ is a hydrogen atom or a halogen atom, a compound represented by the formula: M—X ³ or M—M is reacted in a solvent, in the presence of a base, in the presence or absence of an additive. And, if necessary, treatment with an acid. Examples of the solvent include tetrahydrofuran, dioxane, dimethyl ether, dimethoxetane and the like. Examples of the base include n-butyl lithium, sec_butyl lithium and the like. Examples of the additive include tetramethylethylenediamine, hexamethylphosphoric triamide, and the like. Examples of the acid include hydrochloric acid, sulfuric acid, and salted ammonium.

When X ⁰ is a halogen atom or a trifluoromethanesulfonyloxy group, 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 formula: M—X ³ or The reaction can be carried out by reacting the compounds represented by MM and, if necessary, treating with an acid. Examples of the solvent include dimethoxetane, water, ethanol, toluene, dimethylformamide, acetonitrile, dioxane, dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, and a mixed solvent thereof. Examples of the catalyst include palladium sulphate, tetrakistriphenylphosphine palladium, bis (diphenylphosphinophenocene) dichloropalladium and the like. Examples of the base include acetic acid potassium, lithium carbonate, sodium carbonate and the like. The additives include, for example, triphenylphosphine, tri-tolylphosphine, tri-n-butylphosphine, diphenylphosphinophene benzene (dppf), diphenylphosphinobutane (dppb), 2, 6 —Gee tert-butyl-1-4-cresol; Examples of the acid include hydrochloric acid, sulfuric acid, and ammonium chloride.

The reaction to produce compound [28] from compound [24] and compound [25] is performed 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. Can be implemented. Examples of the solvent include dimethoxetane, water, ethanol, toluene, dimethylformamide, acetonitrile, dioxane, tetrahydrofuran or a mixed solvent thereof. Examples of the catalyst include palladium acetate, bistriphenyl and the like. Phosphine palladium dichloride, tetrakistriphenylphosphine, radium, bistriphenylphosphine Palladium dichloride, bis (dibenzylideneacetone) ino, "radium, bisbenzonitrile palladium dichloride and the like. Examples of the base include potassium carbonate, sodium carbonate and potassium phosphate. Is, for example, triphenylphosphine, tri-n-butylphosphine, tri-10-tolylphosphine, diphenylphosphinophenocene (dppf). Diphenylphosphineobutane (dppb), 2,6-di-tert. —Butyl 4-cresol and the like.

Specific examples of the leaving group X ^3, e.g., chlorine, bromine, halogen atom such as iodine, lower alkoxy group, Shiano group, triflate Ruo b methanesulfonyl two Ruokishi group, and the like.

Specific examples of the compound represented by the formula: M—X ³ include tri-n-butyltin sulfide, tri-n-butyltin trifluoromethanesulfonate, and tri-lower alkoxyborane.

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

Specific examples of the leaving group X ⁴ in the compound [25] or compound [27], for example, chlorine, bromine, halogen atom such as iodine, triflate Ruo b methanesulfonyl two Ruokishi group, and the like.

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

The reaction for producing compound [6] from compound [28] can be carried out by treating the compound with an acid or a base. Examples of the acid include concentrated hydrochloric acid and sulfuric acid. Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide, lithium hydroxide and hydrogen peroxide.

Specific examples of the compound [6] include a compound represented by the general formula [6,]: [6,]

However, the symbols have the same meaning as described above,

Is mentioned.

Starting compound [13] can be produced, for example, according to the following method,

However, Boc represents a tert-butoxycarbonyl group, and other symbols have the same meanings as described above.

The reaction for producing the compound [1 0] from the compound [9] in a solvent, di- tert - can presence Petit dicarbonate (Bo c ₂ 0), carried out the presence or absence of a base. Examples of the solvent include tetrahydrofuran, methylene chloride, 1,2-dichloroethane, dioxane, ethyl acetate and the like. Bases include, for example, triethylamine, potassium carbonate, sodium carbonate, diisopropylethylamine, sodium carbonate, and 4-dimethylaminopyri. Gin 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] is as described above.

It can be carried out in the same manner as in (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 deprotecting agent for the Boc group include hydrochloric acid-dioxane, ethyl acetate monohydrochloride, trifluoroacetic acid, and pseudotrimethylsilane.

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

Amidification

However, each symbol has the same meaning 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).

In producing the above-mentioned compounds [I-a], [I-b], [I_c], or [Id], each intermediate compound has an adverse effect on the reaction as well as the one shown in the above chemical reaction formula. If it does not affect, a salt thereof or a reactive derivative thereof can also 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, disopropylethylamine, hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, Salts with inorganic acids such as phosphoric acid, acetic acid, oxalic acid, citric acid, benzenesulfonic acid, benzoic acid, malonic acid, citric acid, formic acid, fumaric acid, maleic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoro Salts with organic acids such as acetic acid O

Further, when the starting compound or each of the intermediates has a functional group in the production of the target compound of the present invention and the raw material conjugate, if the raw material compound or each of the intermediates has a functional group, it may be appropriately applied to each functional group by a conventional method of synthetic chemistry in addition to the above. Such protecting groups may be introduced as appropriate, and if unnecessary, those protecting groups may be appropriately removed.

In the present invention, examples of the alkyl include a linear or branched alkyl having 1 to 16 carbon atoms, and particularly an alkyl 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. In addition, lower alkanoyl includes linear or branched ones having 2 to 7 carbon atoms, particularly 2 to 5 carbon atoms, and cycloalkyl includes 3 to 20 carbon atoms, particularly 3 to 12 'are mentioned. Cyclo-lower alkyl includes those having 3 to 8 carbon atoms, especially 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 2 to 8 carbon atoms, particularly 2 to 16 carbon atoms. There are four. Alkylene includes linear or branched ones having 1 to 16 carbon atoms, especially 1 to 10 carbon atoms.Lower alkylenes include 1 to 8 carbon atoms, particularly 1 to 6 carbon atoms. And a linear or branched one. Halogen atoms include fluorine, chlorine, bromine or iodine. Examples of the heterocyclic group include a monocyclic, bicyclic, or tricyclic heterocyclic group containing at least one heteroatom atom selected from nitrogen, oxygen, and sulfur. Specifically, pyridyl group, indolyl group, thiazolyl group, imidazolyl group, pyrrolyl group, pyrimidinyl group, chenyl group, benzo [b] furyl group, benzo [b] chenyl group, pyrazolyl group, triazolyl group, quinolyl group, Isoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, 5,11 dihydrodibenzo [b, e] [1,4] oxazepine-15-yl, dihydrovirazolyl, tetrazolyl No. Examples of the aryl group include a phenyl group, a naphthyl group, an anthranyl group, and a phenanthryl group. Example

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

Example 1

(1) Isoindoline 699 mg, (1H-pyrazole-1-yl) acetic acid-hydrochloride (compound obtained in Reference Example 1) 900 mg, 1-hydroxybenzotriazole 785 mg and triethylamine 0.81 ml To a solution of the above in dimethylformamide (30 ml), 1.10 g of 1-ethyl-3_ (3-dimethylaminopropyl) -carposimide.hydrochloride was added. After stirring at room temperature for 6 hours, the mixture was poured into ice water, and the precipitated powder was collected by filtration and dried. By recrystallization from methanol, 1.0 g of 2- (1H-pyrazol-1-yl) acetyl-isoindoline was obtained as colorless crystals.

M. p. 215-21 7 ° C

(2) 3.6 ml of concentrated nitric acid was added dropwise to a solution of 1.87 g of the compound obtained in (1) above in 60 ml of concentrated sulfuric acid under water cooling, and the mixture was stirred for 1 hour. The reaction solution was poured into ice water, and the deposited precipitate was separated by filtration, washed with water, and dried. The resulting crude product was recrystallized from a mixed solvent of acetic acid and water to give 10.62 g of 5--2-trou-2- (1H-pyrazole-1-yl) acetyl-isoindoline as colorless crystals. Was.

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 on carbon in acetic acid (15 ml) was 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 from a mixed solution of chloroform-methanol to give 5-amino-2- (1H-pyrazole-1-yl) acetyl-isoindoline 759 mg were obtained as colorless crystals.

M. p. 218-21 9 ° C

(4) 245 mg of the compound obtained in (3) above, 2- (5-trifluoromethylpyridine-1-yl) benzoic acid (the compound obtained in Reference Example 5 (3)) 296 mg and 1-hydroxybenzotria Sol 149mg dimethylform To an amide (5 ml) solution, under ice cooling, 216 mg of 1-ethyl-3_ (3-dimethylaminobutyral pill) monocarbodiimide hydrochloride was added, and the mixture was stirred at room temperature for 17 hours. The reaction mixture was poured into ice water (30 ml), stirred for 30 minutes, concentrated ammonia water (10 ml) was collected, the precipitated crystals were collected by filtration, dried, and recrystallized from ethyl acetate to give 2- (1H-pyrazole- 432 mg of 1-yl) acetyl-5- [2- (5- (trifluoromethyl-1-pyridine-12-yl) benzoylamino] -isoindoline was obtained as colorless prisms.

M. p. 207-209 ° C

Example 2-5

The corresponding starting compounds were treated in the same manner as in Example 1 (4) to give the compounds shown in Table 1.

Table 1

Example 6

5-amino-1_ (1H-pyrazole-11-yl) acetyl-isoindoline (compound obtained in Example 1 (3)) 95 mg, 2- (5-trifluoromethylpyridin-1-yl) benzoic acid ( A solution of 124 mg of the compound obtained in Reference Example 5 (3), 0.2 ml of triethylamine and 118 ml of getylcyanophosphonate in dimethylformamide (4 ml) was stirred at room temperature for 3 days. Dilute the reaction mixture with ethyl acetate and wash with aqueous sodium bicarbonate, water and brine And dried over anhydrous sodium sulfate. The solvent is distilled off, and the residue is purified by silica gel column chromatography (developing solvent; chloroform: methanol = 100: 1), and recrystallized from ethyl acetate to give 2- (1H-pyrazole-1-y). L) acetyl-5- [2- (5-trifluoromethyl-1-pyridine-12-yl) benzoylamino] -isoindoline (the compound obtained in Example 1 (4)) 10 Omg was obtained.

Example 7-8

The corresponding starting compound was treated in the same manner as in Example 6 to obtain the compounds shown in Table 2.

Table 2

Example 9

(1) A solution of 22.43 g of isoindoline in methanol (100 ml) was cooled in a dry ice-acetone bath, 20.47 g of concentrated sulfuric acid was added dropwise, and getyl ether was added. I filtered it. After drying under reduced pressure, the obtained powder was dissolved in 220 ml of concentrated sulfuric acid, and 15.8 ml of concentrated nitric acid was added dropwise under ice cooling. twenty five After stirring for an hour, the mixture was poured into ice water, sodium hydroxide (added as a solid) was added to make the mixture basic, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 53.0-nitroisoindrin as a crude product.

(2) To a mixed solution of 494 mg of the compound obtained in (1) above and 1.24 g of potassium carbonate in toluene (6 ml) -water (6 ml), 0.36 ml of 2-chloroacetyl chloride was stirred. While dripping. The precipitated crude product was separated by filtration, washed with water, and then recrystallized from ethyl acetate to obtain 576 mg of 2-chloroacetyl-5-nitroisoindoline.

M. p. 158-160 ° C-

(3) To a suspension of 76 mg of the compound obtained in (2) above in 0-xylene (3 ml) was added 86 mg of pyrazole, and the mixture was heated under reflux for 22 hours. The reaction solution was poured into diisopropyl ether, and the precipitated crystals were collected by filtration to give 5-nitro-12- (1H-pyrazole-1-yl) acetyl-isoindoline (the compound obtained in Example 1 (2)). ) 64 mg was obtained.

(4.) The compound obtained in the above (3) was treated in the same manner as in Examples 1 (3) and (4) to obtain the compound described in Example 1 (4).

Example 10

(1) (1H-Pyrazol-1-yl) acetic acid (the compound obtained in Reference Example 2 (2)) 2. To a suspension of 56 g of tetrahydrofuran (50 ml) at 150 ° C Ethyl carbonate 2. lm 1 was added. After stirring the reaction solution for 5 minutes, 3.5 ml of triethylamine was added, and the mixture was further stirred for 5 minutes. After adding 10 ml of concentrated aqueous ammonia to the reaction solution and stirring for 10 minutes, the reaction solution is concentrated, and ethyl acetate is added to the residue to form a powder, thereby obtaining (111_pyrazole-1-yl) acetic acid amide 1.17 g was obtained as a crude product.

(2) 162 mg of the compound obtained in the above (1), 《, 《, 1-chloro- 1-xylene 187 mg, hydroxylated potassium 184 mg, and tetrabutylammonium chloride 34.8 mg of acetonitrile (5 ml) Stir solution overnight at room temperature did. The reaction mixture was poured into water, and the precipitated powder was filtered off and recrystallized from a mixed solution of tetrahydrofuran and methanol to give 2- (1H-pyrazole-1-yl) acetyl-isoindoline (Example 1 The compound obtained in (1)) 136 mg was obtained as colorless crystals.

(3) The compound obtained in the above (2) was treated in the same manner as in Examples 1 (2) to (4) to obtain the compound described in Example 1 (4).

Example 1 1

(1) A solution of 102 g of pyrazole and 168 g of 2-chloroacetamide in dimethylformamide (1 L) was cooled in a dry ice-acetone bath. 72 g of sodium hydroxide was added in several portions, and the mixture was stirred at room temperature for 1.5 hours. After a solution of 262 g of 0-dichloroxylene in dimethylformamide (500 ml) was added to the reaction mixture, the mixture was cooled in a dry ice-acetone bath, and 132 g of sodium hydroxide was 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% aqueous hydrochloric acid, and the precipitate was collected by filtration and washed with diisopropyl ether. After drying. By recrystallization from tetrahydrofuran-methanol (1: 1), 179 g of 1- (1H-pyrazole-111-yl) acetyl-isoindoline (the compound obtained in Example 1 (1)) was obtained as colorless crystals. As obtained.

(2) The compound obtained in the above (1) was treated in the same manner as in Examples 1 (2) to (4) to obtain the compound described in Example 1 (4).

Example 12

5- [2- (5-Trifluoromethyl-pyridine-1-yl) benzoylamino] -isoindoline 'dihydrochloride (Compound obtained in Reference Example 14 (4)) 200 mg, 1— (2— Bromethyl) Pyrazole (Compound obtained in Reference Example 4) A suspension of dimethylformamide (2 ml) containing 115 mg, 72 mg of sodium iodide and 303 mg of potassium carbonate was stirred at 50 ° C overnight. The reaction solution was poured into dilute aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. Prepare the residue After purification by active chromatography (developing solvent; chloroform: methanol = 12: 1), recrystallization from a mixed solvent of ethyl acetate and diisopropyl ether-n-^^ xane gave 2- [2 — (1H-Pyrazole-11-yl) ethyl] -1-5- (2- (5-Trifluoromethyl-pyridine-12-yl) benzoylamino] -isoindoline 59 mg as colorless needles Obtained.

M. p. 162.5-164 ° C

Example 13

The corresponding starting compound was treated in the same manner as in Example 12, thereby obtaining the compounds shown in Table 3.

Table 3

Example 1

5- [2- (5-trifluoromethyl-1-pyridine-1-yl) benzoylamino] -isoindoline dihydrochloride (compound obtained in Reference Example 1 (4)) 36 4 mg, (1H- Pyrazole-1-yl) Acetic acid 'hydrochloride (Compound obtained in Reference Example 1) 156 mg, 4-dimethylaminopyridine 117 mg, triethylamine 17 Omg and 1-ethyl-3- (3-dimethylaminopropyl) One-strength Luposimide 'hydrochloride (199 mg) was treated in the same manner as in Example 1 (4) under an argon atmosphere to give 2- (1H-pyrazole-11-yl) acetyl —5— [2- (5-Trifluoromethyl-pyridine-12-yl) benzoylamino] -isoindoline (the compound described in Example 1 (4)) (252 mg) was obtained as colorless prism crystals.

Examples 15-17

The corresponding starting material was treated in the same manner as in Example 1 to obtain the compounds shown in Table 4.

Table 4

Example 18

(1) Under an argon atmosphere, 5-amino-2- (1H-pyrazole-1-yl) acetyl-isoindoline (the compound obtained in Example 1 (3)) was added to a solution of 800 mg of anhydrous tetrahydrofuran (80 ml). 625 mg of sodium borohydride were added. To this mixture, add ice-cooled boron trifluoride getyl ether complex 3. The weight of 04 g was increased, and the mixture was refluxed for 1 hour while gradually raising the temperature. After cooling to room temperature, 1 Oml of 10% hydrochloric acid was added dropwise, and the mixture was heated under reflux for 1 hour. After cooling to room temperature, potassium carbonate (added as a solid) was added to make the reaction mixture basic, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by preparative chromatography (developing solvent; chloroform: methanol = 18: 1), and recrystallized from a mixed solution of ethyl ethyl diisopropyl ether to give 5-amino-2- [2 — (1H-Pyrazole-11-yl) ethyl] 395 mg of monoisoindoline was obtained as colorless needles.

M. p. 109-111 ° C

(2) 259 mg of the compound obtained in the above (1) and 2_ (5-trifluoromethyl-1-pyridine-12-yl) benzoic acid (the compound obtained in Reference Example 5 (3)) were used in Example 1 (4 2) [2- (1H-pyrazol-1-yl) ethyl] —5— [2- (5- (trifluoromethyl-pyridine-1-yl) benzoylamino] 437 mg of isoindoline (the compound obtained in Example 12) was obtained.

Example 19

(1) 5-amino-1 2- (1H-pyrazole_1-yl) acetyl-isoindolin (compound obtained in Example 1 (3)) 533 mg, 2-odobenzoic acid 610 mg and 1 To a solution of _ hydroxybenzotriazole (334 mg) in dimethylformamide (10 ml) was added 48 mg of 1-ethyl-3- (3-dimethylaminopropyl) -carboximide.hydrochloride, and the mixture was stirred at room temperature for 5.5 hours. The reaction mixture was poured into ice water, and the deposited precipitate was collected by filtration and recrystallized with a mixed solution of ethyl acetate-n-hexane to give 2- (1H-pyrazole-1-yl) acetyl-5- ( 2-Odobenzoylamino) -isoindoline (80 Omg) was obtained as colorless needles.

MS (APC I) m / z; 473 (M + H), IR (nu jo 1) cm "¹; 1 671, 1644 (2) 300 mg of the compound obtained in the above (1), 468 mg of 3-pyridyltriptyltin, 33 mg of triphenylphosphine, 18 mg of bromide steel (I), 45 mg of bistriphenylphenylphosphine palladium dichloride and a small amount of 2,6- A dioxane solution (10 ml) of di-tert-butyl-p-cresol was heated and flown for 3 days. The reaction solution was cooled to room temperature, diluted with ethyl acetate, further added with 15 ml of a 10% aqueous potassium fluoride solution, and stirred. The insoluble material was filtered through celite, the organic layer of the filtrate was separated, washed with water and saturated food, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue is purified by preparative chromatography (developing solvent; chloroform: methanol: = 20: 1), and recrystallized from a mixed solution of chloroform-methanol to give 2- (1H-pyrazole). 1-yl) acetyl-5- [2- (3-pyridyl) -benzoylamino] -isoindolin 57 mg was obtained.

M. p. 257 ° C (fine

Example 20

(1) 5- [2- (5- (trifluoromethyl-1-pyridine-1-yl) benzoylamino] -isoindoline 'dihydrochloride (Compound obtained in Reference Example 14 (4)) 200 mg and triethylamine To a solution of 177 mg of methylene chloride (10 ml) was added 61 mg of 2-chlorope pionyl chloride, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water and extracted with black-mouthed form. The organic layer was washed with 5% aqueous hydrochloric acid, water, a saturated aqueous solution of sodium bicarbonate, and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by preparative chromatography (eluent; chloroform: methanol = 90: 7) to give 2- (2-chloro-1-oxopropyl) -1-5- [2- (5-trifluoromethyl). There was obtained 115 mg of 1-pyridine-2-yl) benzoylamino] -isindolin.

MS (APC I) m / z; 474 (M + H), IR (nujol) cm—1 654, 1645, 1604

(2) 107 mg of the compound obtained in (1) above, 46 mg of pyrazole, anhydrous carbon A solution of 63 mg of potassium acid and 37 mg of sodium iodide in dimethylformamide (12 ml) was heated and stirred at 80 for 5 hours. The reaction solution was poured into dilute aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and a saturated solution of mjce, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by preparative chromatography (developing solvent: chloroform: methanol: 15: 1), and then recrystallized from a mixed solution of ethylethyldiisopropyl acetate-n-hexane. 2_ [2- (1H-pyrazole-1-yl) -1-oxopropyl]-5- [2- (5_ (trifluoromethyl-pyridine-1-2-yl) benzoylamino] -isoindoline 63 mg It was obtained as colorless needles.

M. p. 155-157

Example 21-22

The corresponding starting compound was treated in the same manner as in Example 20, thereby obtaining the compounds shown in Table 5.

¾ 5 ¾

Example 23

(1) To a solution of 417 mg of 3-benzyloxy-2,2-dimethylpropionic acid in methylene chloride (5 ml) was added oxalyl chloride 3851 and dimethylformamide (one drop), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated and dissolved in methylene chloride (5 ml). This solution was cooled under ice-cooling to give 422 mg of 5- [2- (5-trifluoromethyl-pyridine-12-yl) benzoylamino] -isoindoline 'dihydrochloride (the compound obtained in Reference Example 14 (4)). And 407 mg of triethylamine were added dropwise to a methylene chloride (10 ml) solution. After stirring at the same temperature for 30 minutes and at room temperature for 2 hours, the organic layer was washed with water and a saturated diet, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (developing solvent; n-hexane: chloroform = 1: 1) to give 2- (3_benzyloxy-2,2-dimethylpropanoyl) -1 5_ [2— 125 mg of (5-trifluoromethyl-pyridine-1-yl) benzoylamino] -isoindoline were obtained as a colorless foam.

MS (APC I) m / z; 574 (M + H), IR (Nujo 1) cm- ¹ ; 1 669, 1603

(2) To a solution of 109 mg of the compound obtained in (1) above in ethanol (4 ml) was added 19 mg of palladium hydroxide-carbon, and the mixture was stirred under a hydrogen atmosphere at room temperature for 28 hours. The catalyst was filtered off, the filtrate was concentrated, diisopropyl ether was added to the residue, and the precipitated powder was collected by filtration to give 2- (3-hydroxy-12,2-dimethylpropanol) 15- [2--(5 —Trifluoromethyl-pyridine-12-yl) benzoylamino] —isoindoline 5 Omg was obtained as a colorless powder. MS (APC I) m / z; 484 (M + H), IR (Nu jo 1) cm- ¹ ; 3 405, 1659, 1605

Reference example 1

To a solution of tert-butyl bromoacetate (5.00 g) in dimethylformamide (20 ml) was added 2.09 g of pyrazole and 7.07 g of potassium carbonate. After stirring for 1 hour at room temperature and 3.5 hours at 50 ° C, pour the reaction mixture into water and extract with ethyl acetate did. Water the organic layer,

Dry over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography ^ "(developing solvent; ethyl acetate: n-hexane = 1: 3) to give (1H-pyrazol-1-yl) tert-butyl acetate. 4.2 g of the compound obtained in (1) above was obtained as a colorless oily substance (2) Into a solution of 4.2 lg of dioxane (10 ml) was added 25 ml of a 4 M hydrochloric acid-dioxane solution, and the mixture was heated at room temperature for 12 minutes. Getyl 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-pyrazole-11-yl) acetic acid'hydrochloric acid. 3.50 g of the salt were obtained as a colorless powder.

Reference example 2

(1) An acetone suspension of 170 g of pyrazole, 260 ml of methyl bromoacetate and 414 g of potassium carbonate was heated under reflux for 25 hours. After cooling to room temperature, insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was distilled to obtain 580 g of methyl (1H-virazol-1-yl) acetate.

B. p. 105-120.0 ° C (15mmHg)

(2) 219 g of the compound obtained in the above (1) was dissolved in a 2 M aqueous hydrochloric acid solution (1.5 L), and the mixture was heated under reflux for 2 hours. The reaction solution was concentrated to 500 ml under reduced pressure, potassium carbonate was added under ice cooling to adjust the pH to 0.5-0.6, and the resulting precipitate was collected by filtration and dried under reduced pressure. By recrystallization from 2 L of tetrahydrofuran, 127.3 g of (1H-pyrazole-1-yl) acetic acid was obtained.

M. p. 171—172. C

Reference example 3

(1) To a solution of 4-nitropyrazole 1.Og and potassium carbonate 1.82 g in dimethylformamide (1 Oml), add tert-bromo-1-acetate (1.81 g) under ice-cooling and stir at room temperature for 2 hours. did. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed successively 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; n-hexane: ethyl acetate = 4: 1) to give (4-t 1H-Pyrazole-1-yl) tert-butyl acetate (1.88 g) was obtained as a pale yellow solid.

MS (APC I) m / z; 228 (M + H), IR (nujo 1) cm "¹; 1 749, 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-1H-pyrazole-1-yl) acetic acid 1.40 g was obtained as colorless prisms.

M. p. 156.5-157.0. C

Reference example 4

To a solution of pyrazole (6.8 g) in dimethylformamide (10 ml) was added 4 g of 60% sodium hydride under ice-cooling, and the mixture was stirred at room temperature for 1 hour. 93.5 g of 1,2-dibromoethane was added under ice-cooling, and the mixture was stirred at room temperature overnight. Getyl ether was added to the reaction solution, insolubles were removed by filtration, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate) to give 2.0 g of 1- (2-bromoethyl) pyrazole as a colorless oil.

MS (APC I) m / z; 177, 175 (M + H)

Reference example 5

(1) In an argon atmosphere, a solution of 150 g of diisopropylbenzamide and 121 ml of tetramethylethylenediamine in tetrahydrofuran (750 ml) was cooled in a dry ice-acetone bath, and then added to n-butyllithium. A hexane solution (552 ml) was added dropwise. After the dropwise addition, the mixture was further stirred for 1 hour under ice cooling. The reaction solution was cooled again in a dry ice-acetone bath, and 337 ml of triisopropyl borate was added. After stirring for 10 minutes, the dry ice / acetone bath was removed, and the mixture was stirred for 1.5 hours. Under ice-cooling, ethyl ether 85 Om1 and 850 ml of 10% aqueous hydrochloric acid were added to the reaction solution, and the mixture was vigorously stirred at room temperature for 1 hour. The organic layer was separated, the aqueous layer was further extracted with 500 ml of getyl ether, and the organic layers were combined and washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a crude product. (2) Under an argon atmosphere, a solution of 180.5 g of the crude product obtained in (1) above and 130.7 g of 2-chloro-5-trifluoromethyl-pyridine in dimethoxetane (2 L) was added with acetic acid. An aqueous solution (700 ml) of 4.04 g of palladium, 18.9 g of triphenylphosphine and 249 g of potassium carbonate was added, and the mixture was heated under reflux overnight. The reaction solution was diluted with ethyl acetate, and the insolubles were filtered through celite while hot. The filtrate is concentrated, and the residue is washed with 2 L of water and 1 L of diisopropyl ether, and recrystallized with ethyl acetate to give N, N-diisopropyl-1- (5-trifluoromethyl-1-pyridine-12-yl). 189.93 g of benzoic acid amide was obtained as colorless crystals.

M.p. 191-29.2 ° C

(3) A solution of 189.5 g of the compound obtained in the above (2) in concentrated hydrochloric acid (2.5 L) was heated under reflux for 1.5 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. The concentrated solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with a saturated saline solution 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 give 15.86 g of 2- (5-trifluoromethylpyridine-1-2-yl) benzoic acid (11.86 g) as colorless Obtained as crystals. M. p. 186.5-; 188.5. C

Reference example 6

(1) To a solution of 10.O g of 2-odobenzoic acid in methanol (100 ml) was added 6 ml of thionyl chloride under ice-cooling, and the mixture was heated under reflux for 3 hours. The reaction solution was concentrated under reduced pressure, and the ethyl acetate solution of the residue was 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 obtain 10.53 g of methyl 2-iodobenzoate as a colorless oily substance.

(2) Under an argon atmosphere, to a solution of 7.87 g of the compound obtained in (1) above and 34.83 g of bistree n-butyltin in toluene (150 ml) was added 695 mg of tetrakistriphenylphosphine palladium. , Reflux for 47 hours did. After cooling the reaction solution to room temperature, 10% aqueous potassium fluoride solution was added, and the mixture was stirred at room temperature for 1 hour. After filtering the reaction solution through celite, an organic layer was separated from the filtrate. The organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent is distilled off, and the residue is purified by silica gel column chromatography (developing solvent; chloroform: n-hexane = 1: 5) to give methyl 2- (tree n-butyltin) benzoate 7. 0.3 g was obtained as a colorless oil.

(3) Under argon atmosphere, 63 9 mg of the compound obtained in (2) above, 2-chloro-5-trifluoromethyl-pyridine 178 mg, triphenylphosphine 52 mg, copper (I) bromide 2 To a solution of 9 mg of a small amount of 2,6-di-tert-butyl-p-cresol in dioxane (5 ml) was added 7 Omg of bistriphenylphosphine palladium chloride, and the mixture was heated and refluxed for 47 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, 10% aqueous potassium fluoride solution was added, and the mixture was stirred at room temperature for 1 hour. After filtering the reaction solution through celite, an organic layer was separated from the filtrate. The organic layer was 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; ethyl acetate: n-hexane = 1: 20) to give 2- (5-trifluoromethyl-1-pyridine-12-). G) Methyl benzoate (159 mg) was obtained as a colorless oil. MS (A PC I) m / z; 28 2 (M + H), IR (neat) cm- ¹ ; 17 29, 16 05

(4) A solution of 53 mg of the compound obtained in the above (3) and a 1 M aqueous sodium hydroxide solution (1.35 ml) in methanol (3. Oml) was added to 50. The mixture was heated and stirred for 4 hours. After methanol was distilled off, the solution was 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-trifluoromethyl-1-pyridine-11-yl) benzoic acid (Reference Example 5 (3)). Obtained compound) 248 mg was obtained.

Reference Example 7-8

The compounds shown in Table 6 were obtained by treating the corresponding original conjugate in the same manner as in Reference Examples 6 (3) and (4). Table 6

Reference example number Ring A Physical constant, etc.

7 M.p.144.0- 147.5 ° C

8 Not yet

Reference Example 9

(1) Under an argon atmosphere, bis (diphenylphosphinophine efflux) was added to a solution of 1.00 g of methyl 2-benzoate, 1.068 g of bispinacolato dipolone, 1.068 g of potassium acetate, and 12 g of dimethylformamide (25 ml). Sen) Dichloropalladium (92 mg) was calorie-heated and stirred at 80 ° C for 2 hours. After the reaction solution was cooled to room temperature, 2-chloro-1,5-trifluoromethylpyridine, 2M aqueous solution of sodium carbonate (9: 5 ml), bis (diphenylphosphinophene lipocene) dichloropalladium 92 mg were added. In addition, the mixture was heated and stirred at 80 ° C for 2 hours. Ethyl acetate was added to the reaction solution, and the organic layer was washed with water and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is distilled off, and the residue is purified by silica gel column chromatography (developing solvent; black form: n-^^ xane = 1: 6) to give 2- (5-trifluoromethyl-1-pyridine-12-yl) 533 mg of methyl benzoate (the compound obtained in Reference Example 6 (3)) was obtained as a colorless oil.

(2) The compound obtained in (1) above was treated in the same manner as in Reference Example 6 (4). Thus, 2- (5-trifluoromethyl-pyridine-1-yl) benzoic acid (the compound obtained in Reference Example 5 (3)) was obtained.

Reference Example 10

(1) In an argon atmosphere, add 1.O g of methyl 3-benzoate to a solution of 1.O g of toluene (8 Oml) and ethanol (8 ml).

2 g, 22 Omg of tetrakistriphenylphosphine palladium and 12 ml of a 2M aqueous solution of sodium carbonate were added, and the mixture was heated under reflux for 3.5 hours. After the reaction solution was cooled to room temperature, it was 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 purified by silica gel column chromatography (developing solvent; ethyl acetate: hexane = 1: 10) to give a residue. 2- (3-Chenyl) methyl benzoate

836 mg were obtained 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) was treated in the same manner as in Reference Example 6 (4) to give 2- (3-Chenyl) benzoic acid.

MS (ES I) m / z; 203 (M−H), IR (nujo 1) cm— ¹ ; 16

95, 1675

Reference Example 11

(1) Under an argon atmosphere, to a solution of 500 mg of 2-bromo-methyl benzoate and 1.71 g of 2-pyridyltriptyltin in dimethylformamide (10 ml), 164 mg of bistriphenylphosphine palladium dichloride was added. The mixture was heated to 0 ° C and stirred for 12 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, 10% aqueous potassium fluoride solution was added, and the mixture was stirred at room temperature for 1 hour. After filtering the reaction solution through celite, the organic layer was separated from the filtrate. The organic layer was 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 Silica) (developing solvent; ethyl acetate: n-hexane = 1: 2) to give 2- (2-pyridyl) benzoic acid. 392 mg of methyl acid salt was obtained as a colorless oil. MS (APC I) m / z; 21 (M + H), IR (neat) cm- ¹ ;

30

(2) The compound obtained in the above (1) was treated in the same manner as in Reference Example 6 (4) to give 2- (2-pyridyl) benzoic acid.

MS (ES I) m / z; 198 (M−H), IR (nujo 1) cm ” ¹ ; 16 90

Reference Example 12

(1) Under an argon atmosphere, 2-chloro-5-trifluoromethylpyridine 6.

To a solution of 61 g and 2.55 g of 2,6-dimethylphenylporonic acid in dimethoxyethane (100 ml) were added 204 mg of palladium acetate, 955 mg of triphenylphosphine and 11.59 g of potassium phosphate in an aqueous solution ( 35 ml) and heated under reflux overnight. After cooling the reaction solution to room temperature, it was diluted with ethyl acetate, and the insoluble matter was filtered through celite. The filtrate was concentrated, the residue was dissolved in ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. The solvent is distilled off, and the residue is subjected to silica gel column chromatography (developing solvent; n-hexane: ethyl acetate 100:

Purification by 1 → 40: 1) gives 2- (2,6-dimethylphenyl)

2.75 g of 5-trifluoromethylpyridine was obtained as a colorless oil.

MS (APC I) m / z; 252 (M + H), IR (Ne at) cm— ¹ ; 16

07

(2) Under an argon atmosphere, add 2.29 g of potassium permanganate at room temperature to a mixed solution of 730 mg of the compound obtained in (1) above and 9 ml of pyridine and 6 ml of water at room temperature for 48 hours. The mixture was heated and stirred. The reaction solution was returned to room temperature, and 1.84 g of potassium permanganate was added thereto, followed by heating and refluxing for 24 hours. After cooling the reaction solution to room temperature, a 10% aqueous sodium hydroxide solution (10 ml) was added, and the insolubles were filtered through celite. The filtrate was washed with getyl ether, acidified with 10% hydrochloric acid, and extracted with ethyl acetate. The organic layer was 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 ethyl ethyl diisopropyl ether to give 2- (5-trifluoromethyl-pyridine-1-yl) iso-yl. 690 mg of phthalic acid were obtained as colorless needles.

M. p. 252. 0 -254. 0. C

(3) To a solution of 48 Omg of the compound obtained in the above (2) in methanol (12 ml) was added dropwise 1.11 g of salt fondionil under ice cooling, and the mixture was refluxed for 20 hours. After cooling the reaction solution to room temperature, the reaction solution was concentrated. The residue was dissolved in ethyl acetate, washed with saturated aqueous 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-pyridine-1-y). M) 314 mg of dimethyl isophthalate (Compound 12 (3a)) was obtained as a colorless oil.

MS (APC I) m / z; 340 (M + H), IR (N eat) cm- ¹ ; 17 31, 1607

The saturated sodium bicarbonate washing solution was acidified with 10% hydrochloric acid under ice-cooling, and extracted with ethyl acetate. The organic layer was 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 76 mg of methyl 2- (5-trifluoromethyl-pyridine-12-yl) isophthalate (Compound 12 (3b)). Obtained as colorless needles.

M. p. 158.0-159.0. C

(4) To a solution of 309 mg of the compound 12 (3a) obtained in (3) above in methanol (1 Oml) was added a 1 M aqueous sodium hydroxide solution (1.1 ml) at room temperature, and the mixture was heated under reflux overnight. After cooling the reaction solution to room temperature, water was added to the residue, washed with getyl ether, made acidic with a 10% aqueous solution of citric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was reconstituted with a mixed solution of methanol and water. According to the statement, methyl 2- (5-trifluoromethyl-pyridine-12-yl) isophthalate (compound 12 (3b) 264 mg were obtained as colorless needles.

Reference Example 13

(1) Under an argon atmosphere, 2-cyclopyrimidine 579 mg and 0_tolyl An aqueous solution (6.3 ml) of 29 mg of palladium acetate, 134 mg of triphenylphenylphosphine and 1.73 g of potassium carbonate was added to a solution of borax acid 816 mg in dimethoxetane (15 ml), and the mixture was heated under reflux for 2 hours. After the reaction solution was cooled to room temperature, it was diluted with ethyl acetate, and insolubles were filtered through celite. The filtrate was concentrated, the residue was 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 795 mg of 2- (2-methylphenyl) pyrimidine as a colorless oil. Obtained.

MS (APC I) m / z; 171 (M + H), IR (Ne at) cm- ¹ ; 15 69

(2) The compound 34 Omg obtained in the above (1) was treated in the same manner as in Reference Example 12 (2) to give 2-pyrimidine-12-ylbenzoic acid 88 mg as a crude product. .

Reference example 1

(1) Crude product of 5-nitroisodyndrin (compound obtained in Example 9 (1)) 2. To a solution of 62 g of tetrahydrofuran (40 ml) was added ice-cooled solution of g-tert-butyldicarbonate. 86 g of a tetrahydrofuran (10 ml) solution was added dropwise, and the mixture was stirred for 1.5 hours. The solvent was distilled off, and ethyl acetate was added to the residue. The residue was washed with water and a saturated food, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (developing solvent; n-hexane: ethyl acetate = 4: 1), and recrystallized from a mixed solution of n-hexane-ethyl acetate to give 5-nitro-2- ( (tert-butoxycarponyl) monoisoindolin 3.09 g was obtained.

M. p. 159 to 160 ° C

(2) A suspension of 3.46 g of the compound obtained in the above (1) and 340 mg of 10% palladium-carbon in tetrahydrofuran (50 ml.) Was stirred under a hydrogen atmosphere at normal pressure and room temperature for 1 hour. 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). As a result, 5-amino-2- (tert-butyloxycarbonyl) -1-isoindoline 3.05 was obtained as a colorless oil.

MS (FAB) m / z; 235 (M + H), IR (neat) cm- ¹ ; 168 7, 1632

(3) 217 mg of the compound obtained in the above (2), 2- (5-trifluoromethyl-2-pyridine-1-yl) benzoic acid (compound obtained in Reference Example 5 (3)) 236 mg and 4-dimethylaminopyridine 1-Ethyl-3- (3-dimethylaminopropyl) -carbodiimide.hydrochloride 2 121118 was stirred in 129 mg of a solution of methylene chloride (8 ml) in an argon atmosphere at room temperature overnight at room temperature. The reaction solution was poured into a saturated aqueous solution of sodium hydrogencarbonate, and extracted with chloroform. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, water, and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (developing solvent; chloroform: methanol = 30: 1) to give 2- (tert-butoxycarbonyl) -1- [2- (5-trifluoro). 375 mg of methyl-1-pyridin-2-yl) benzoylamino] -isoindoline was obtained as a colorless foam.

MS (APC I) m / z; 484 (M + H), IR (nujol) cm-1 697, 1675, 1603

(4) To a dioxane solution (6 ml) containing 89 Omg of the compound obtained in the above (3), 12 ml of a 4 M hydrochloric acid-dioxane solution was added, and the mixture was stirred at room temperature for 1 hour. After getyl ether was added and the resulting precipitate was collected by filtration, 846 mg of 5- [2- (5-trifluoromethyl-pyridine-12-yl) benzoylamino] -isoindoline dihydrochloride was obtained as a crude product.

MS (APC I) m / z; 384 (M + H), IR (nujo 1) cm— ¹ ; 1661, 1642, 1605 Industrial applicability

According to the present invention, excellent apolipoprotein B (ApoB) secretion inhibitory action and blood A novel benzoylaminoisoindolin compound having a clear lipid lowering effect and useful as a medicament, a process for producing the same, and a synthetic intermediate thereof are provided.

Claims

In the general formula [I], ring A is a substituted or unsubstituted 5- or 6-membered aromatic heterocyclic group, ring B is a substituted or unsubstituted benzene ring, and Q is Or one CH 2—, R is a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkenyl group, a substituted or unsubstituted radical group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted heterocyclic group. A benzoylaminoisoindoline compound represented by or a pharmacologically acceptable thereof, which represents a substituted aryl group; 2. ring A is an unsubstituted 5- or 6-membered aromatic heterocyclic group; 5) or 6-membered substituted with 1 to 3 identical or different groups selected from 1) to (10) (1) trifluoromethyl group, (2) unsubstituted lower alkyl group, or hydroxyl group, oxo 1 to 3 identical or different groups selected from hydroxyimino groups (3) an unsubstituted lower alkoxy group, or a lower alkoxy group substituted with 1 to 3 identical or different groups selected from the group consisting of a lower alkoxy group, a hydroxyl group and a dialkylamino group; ) Hydroxyl group, (5) nitro group, (6) cyano group, (7) unsubstituted rubamoyl group or group selected from lower alkyl group, lower alkoxy lower alkyl group, halogeno lower alkyl group and aryl lower alkyl group (8) Unsubstituted amino group, or amino group substituted with a group selected from an amino group-protecting group, lower alkyl group and lower alkylsulfonyl group; (9) unsubstituted lower alkanoyl group A lower alkanoyloxy group substituted with a oxy or aryl group, and (10) a lower alkoxycarbonyl group, wherein ring B is an unsubstituted benzene Or a benzene ring substituted by 1 to 3 identical or different groups selected from the following (1) to (9): (1) nitro group, (2) hydroxyl group, (3) unsubstituted lower alkoxy Group or 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 alkyl group rubamoyl Group, cyano group, pyridyl group, pyrrolidinyl group, morpholinyl group, piperazinyl group and lower alkylpiperazinyl group, lower alkoxy group substituted with a group selected from (4) lower alkoxycarbonyl group, (5) unsubstituted amino group Or (i) a lower alkoxy group, an amino group, a lower alkyl group, an amino group, and a lower alkoxy group Lower alkanoyl group substituted with 1 to 3 identical or different selected groups, (ii) protecting group for amino group, (iii) unsubstituted lower alkyl group, or substituted with pyridyl group or lower alkylamino group. An amino group substituted with a group selected from the group consisting of a lower alkyl group, and (iv) a pyridylcarbonyl group; (6) an unsubstituted rubamoyl group, or a lower alkyl group, a lower alkoxy lower alkyl group, and a lower alkylamino lower alkyl group A carbamoyl group substituted with a group selected from the group consisting of (7) a morpholinocarbonyl group, (8) a cyano group, and (9) a lower alkylaminocarbonyloxy group;

(1) An unsubstituted lower alkyl group, or a lower alkyl group substituted with 1 to 3 identical or different groups selected from (i) to (ix) of the following:

(i) an unsubstituted heterocyclic group or a lower alkyl group; a hydroxy lower alkyl group; a lower alkanoyl group; a lower alkoxy group; a nitro group; a lower alkoxycarbonyl group; a carbonyl group; an oxo group; An unsubstituted rubamoyl group or a labamoyl group substituted with a group selected from a lower alkyl group, a halogeno lower alkyl group and a hydroxy lower alkyl group; an unsubstituted amino group or a lower alkanoyl group, a lower alkoxy lower alkanoyl group; An amino group substituted with a group selected from a group selected from the group consisting of a group selected from the group consisting of a lower alkyl group, a hydroxy lower alkyl group, a hydroxy lower alkyl group, a lower alkoxycarbonyl group and a lower alkylaminoalkylidene group; a cyano group; a hydroxyl group or a protected hydroxyl group; Same or different 1 to 3 selected from formyl groups Substituted heterocyclic group group,

(ii) an unsubstituted aryl or unsubstituted fluorenyl group, or a lower alkyl group; an unsubstituted amino group, or a lower alkanol group, a lower alkoxycarbonyl group, a lower alkyl group, a pyridyl lower alkyl group, a lower alkylaminocarbonyl group, An amino group substituted with 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 aryl group or a fluorenyl group substituted with 1 to 3 same or different groups selected from the group consisting of a hydroxyl group, a lower alkyl group, a rubamoyl group; a halogeno lower alkyl group, and a morpholinyl group;

(iiii) a hydroxyl group or a protected hydroxyl group,

(iv) an unsubstituted rubamoyl group or a labamoyl group substituted with a group selected from a lower alkyl group, a halogeno lower alkyl group and a benzothiazolyl group;

In the formula, n represents an integer of 0 to 4,

A group represented by

(V i) a lower alkoxycarbonyl group,

(vii) an unsubstituted amino group or an amino group substituted with a protecting group for an amino group, a lower alkyl group, a pyridyl group or a pyrimidinyl group;

(V i i i) a halogen atom, and

(i X) oxo group,

(2) an unsubstituted lower alkenyl group or a lower alkenyl group substituted with an aryl group,

(3) an unsubstituted rubamoyl group, or a labamoyl group substituted with a group selected from a lower alkyl group, a halogeno lower alkyl group and a benzothiazolyl group;

Equation (4):

In the formula, m represents an integer of 0 to 4,

A group represented by

(5) Unsubstituted heterocyclic group, or lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, amino group, lower alkylamino group, optionally protected hydroxyl group and optionally protected amino group A heterocyclic group substituted with 1 to 3 identical or different groups selected from

(6) Unsubstituted aryl group, or lower alkyl group, lower alkoxy group, lower alkylcarbamoyl group, halogeno lower alkyl group, rubamoyl group, morpholinyl group, amino group, lower alkylamino group, optionally protected hydroxyl group and protecting group An aryl group substituted with 1 to 3 identical or different groups selected from amino groups which may be protected, 2. The compound according to claim 1, which is:

3.5 The 5- or 6-membered aromatic heterocyclic group is 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. 3. The compound according to item 1 or 2 above.

The 4.5- or 6-membered aromatic heterocyclic group is a pyridyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl group, furyl group, chenyl group, pyrrolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, imidazolyl group, or birazolyl group. A compound according to claim 1 or 2.

5. The heterocyclic group is a pyridyl group, an indolyl group, a thiazolyl group, an imidazolyl group, a pyrrolyl group, a pyrimidinyl group, a phenyl group, a benzo [b] furyl group, a benzo [b] chenyl group, a pyrazolyl group, a triazolyl group, Quinolyl group, isoquinolyl group, phthalazinyl group, quinazolinyl group, quinoxalinyl group, 5,11-dihydro-dibenzo [b, e] [1,4] oxazepine-15-yl group, dihydropyrazolyl group, or tetrazolyl group The compound according to any one of claims 1 to 3, wherein the aryl group is a phenyl group, a naphthyl group, an anthranyl group, or a phenanthrenyl group.

6. In the general formula [I], ring A is a group represented by the formula:

Is a ring represented by

R ¹ is a trifluoromethyl group or a lower alkanoyl group,

Ring B is substituted with an unsubstituted benzene ring or a group selected from a lower alkoxy group, a (lower alkylamino lower alkanol) amino group, a lower alkylamino lower alkoxy group, a lower alkyl group, and a lower alkoxycarbonyl group. Benzene ring,

R is a lower alkyl group substituted by a group selected from the following (1) to (4): (1) an unsubstituted pyrazolyl group, or a lower alkyl group, a nitro group, a lower alkoxy group A bisazolyl group substituted with a group selected from the group consisting of a carbyl group, a cyano group, an amino group and a hydroxy lower alkyl group;

(2) a pyridyl group,

(3) a tetrazolyl group, or

(4) The compound according to claim 5, which is an unsubstituted thiazolyl group or a thiazolyl group substituted with an amino group.

7. —In general formula [I], ring A is of the formula:

Is a ring represented by

Ring B is a benzene ring,

Q-CO-,

7. The method according to claim 6, wherein R is an unsubstituted pyrazolylmethyl group or a virazolylmethyl group substituted with a group selected from a lower alkyl group, a nitro group, a lower alkoxycarbonyl group and a hydroxy lower alkyl group. Compound.

8.2— (1H—Pyrazole-1-yl) acetyl _5— [2- (5-Trifluoromethyl-pyridine-1-yl) benzoylamino] isoindolin, 2- (1H—pyrazole-1 1 —Yl) acetyl-5- [2- (5-trifluoromethyl-pyridine-12-yl) -13-methoxycarbonylbenzoylamino] isoindolin,

2- [2- (1H-Pyrazole-1-yl) ethyl] -1-5- [2- (5-Trifluoromethyl-pyridine-12-yl) benzoylamino] -isoindoline or its pharmaceutically acceptable salt.

9. General formula [5〗:

In the formula, Q is one CO— or one CH ₂ —, R is a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkenyl group, a substituted or unsubstituted rubamoyl group, a substituted or unsubstituted heterocyclic group Represents a cyclic group or a substituted or unsubstituted aryl group;

Or a salt thereof, and a general formula [6]:

In the formula, Ring A represents a substituted or unsubstituted 5- or 6-membered aromatic heterocyclic group, Ring B represents a substituted or unsubstituted benzene ring,

Reacting with a carboxylic acid compound represented by the formula (I) or a salt thereof, if desired, to obtain a pharmacologically acceptable salt of the product.

However, each word has the same meaning as above,

A process for producing a benzoylaminoisoindoline compound or a pharmaceutically acceptable salt thereof represented by

10. —General formula [15]:

In the formula, Ring B is a substituted or unsubstituted benzene ring, Q is one CO— or one CH ₂ —, R is a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkenyl group, a substituted or unsubstituted Radicals, substituted or substituted Is an unsubstituted heterocyclic group, or a substituted or unsubstituted aryl group, X ¹ represents a leaving group,

And a salt thereof, and a general formula [16]:

In the formula, ring A is a substituted or unsubstituted 5- or 6-membered aromatic heterocyclic group, M is a hydroxyl group, a halogen atom, a cyano group, a lower alkyl group, an aryl group, a lower alkoxy group, an alkylenedioxy group, or an aryloxy group. A metal which may be coordinated by the same or different substituents selected from a group, an arylenedioxy group and an arylthio group;

Reacting with a compound represented by the general formula [I], wherein the product is converted into a pharmaceutically acceptable salt, if desired.

However, each symbol has the same meaning as described above,

1 1. General formula [1 3]:

In the formula, Ring A represents a substituted or unsubstituted 5- or 6-membered aromatic heterocyclic group, Ring B represents a substituted or unsubstituted benzene ring, Or a salt thereof, and a general formula [2]: '

R-C00H [2] In the formula, R is a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkenyl group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted heterocyclic group, or a substituted Or a carboxylic acid compound represented by the formula or a salt thereof, which represents an unsubstituted aryl group, and optionally converting the product to a pharmacologically acceptable salt, characterized by the general formula [Ia ]:

However, each symbol has the same meaning as described above,

12. General formula [I—a]:

In the formula, ring A is a substituted or unsubstituted 5- or 6-membered aromatic heterocyclic group, ring B is a substituted or unsubstituted benzene ring, R is a substituted or unsubstituted lower alkyl group, substituted or unsubstituted Represents a lower alkenyl group, a substituted or unsubstituted carpamoyl group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted aryl group;

A compound represented by the general formula [Ib], which is subjected to a reduction reaction, if necessary, to obtain a pharmacologically acceptable salt of the product.

However, each symbol has the same meaning as described above,

13. General formula [13]:

Or a salt thereof, and a general formula [17]:

R-CHO-[17] wherein R is a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkenyl group, a substituted or unsubstituted rubamoyl group, a substituted or unsubstituted heterocyclic group, Or a condensation reaction with an aldehyde compound or a salt thereof, which represents a substituted or unsubstituted aryl group, is subjected to a reduction reaction, and if necessary, the product is converted into a pharmacologically acceptable salt. The general formula [I-Ib]:

However, each symbol has the same meaning as described above, Or a pharmaceutically acceptable salt thereof.

14. General formula [13]:

And a salt thereof, and a general formula [18]:

R-CH ₂ -X ² [18] wherein R is a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkenyl group, a substituted or unsubstituted radical group, a substituted or unsubstituted heterocyclic group A group or a substituted or unsubstituted aryl group, X ² represents a leaving group,

Reacting with a compound represented by the formula (I) or a salt thereof, and converting the product into a pharmacologically acceptable salt, if desired.

However, each symbol has the same meaning as described above,

15. General formula [13]:

Wherein ring A is a substituted or unsubstituted 5- or 6-membered aromatic heterocyclic group,

B represents a substituted or unsubstituted benzene ring,

Or a salt thereof.

16. General formula [5]:

Or a salt thereof.

17. General formula [6 ']:

In the formula, R ¹ represents a trifluoromethyl group or a lower alkanoyl group, and ring B represents a substituted or unsubstituted benzene ring.

Or a salt thereof.

18. [1 5]:

In the formula, ring B is a substituted or unsubstituted benzene ring, Q is one CO— or one CH ₂ —, R is a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkenyl group, a substituted or unsubstituted X ¹ represents a leaving group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted aryl group;

Or a salt thereof.