JP2003048888A - Isoindoline derivative and method for producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a novel isoindoline derivative having excellent apolipo protein (ApoB) secretion-suppressing action and serum lipid-reducing action and useful as a medicinal agent and provide a method for producing the same. SOLUTION: This isoindoline derivative is expressed by general formula [I] (wherein A expresses a nitrogen-containing aliphatic heterocyclic group; Q expresses CO or CH2 : R expresses a lower alkyl which may be substituted with a heterocyclic group which may be substituted). A pharmaceutically allowable salt of the same is also provided.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel isoindoline derivative having excellent apolipoprotein B (ApoB) secretion inhibitory action and serum lipid lowering action, which is useful as a medicine, and a process for producing the same.

[0002]

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

However, all of the amide compounds described therein are compounds having a biphenyl structure in the carboxylic acid moiety and a tetrahydroisoquinoline ring in the amine moiety, and the carboxylic acid moiety such as the compound of the present invention contains a nitrogen-containing compound. There is no description of a compound having an aliphatic heterocycle-phenyl group or a compound having an isoindoline ring in the amine portion.

[0004]

The present invention provides a novel isoindoline derivative having excellent apolipoprotein B secretion inhibitory action and serum lipid lowering action.
Furthermore, the present invention also provides a method for producing such a novel compound.

[0005]

[Means for Solving the Problems] In order to solve the problems, the inventors of the present invention, as a result of diligent research, found a novel isoindoline derivative having an apolipoprotein B secretion inhibitory effect and a serum lipid lowering effect, and made the present invention. completed.

That is, the present invention has the general formula [I]:

[0007]

[Chemical 30]

(Wherein, ring A is an optionally substituted nitrogen-containing aliphatic heterocyclic group, Q is --CO-- or --CH _2- ,
R represents a lower alkyl group substituted with an optionally substituted heterocyclic group), an isoindoline derivative or a pharmaceutically acceptable salt thereof, and a process for producing the same.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION Examples of the substituent on the ring A in the object compound [I] of the present invention include (1) a lower alkyl group which may be substituted with an aryl group or a lower alkoxy group, (2) An aryl group optionally substituted with a lower alkyl group or a cyano group, (3) a lower alkoxy group optionally substituted with an aryl group, (4) formyl group, (5) carboxyl group, (6) aryl group An optionally substituted lower alkoxycarbonyl group, (7) an aryl group-substituted lower alkanoyl group,
(8) Arylsulfonyl group, (9) Lower alkylsulfonyl group, (10) Lower alkanoyl group; Aryl lower alkanoyl group; Arylcarbonyl group; Lower alkoxycarbonyl group; Aryl lower alkoxycarbonyl group; Aryloxycarbonyl group; Arylsulfonyl group A lower alkylsulfonyl group; a lower alkyl group; a pyridyl group; a pyrazinyl group; a pyrimidinyl group; and an amino group which may be substituted with a group selected from a pyridazinyl group, (11) Formula: —CONR ³ R ⁴ (in the formula, R ³ and R ⁴ may be the same or different and each represents a group selected from a hydrogen atom, an alkyl group, an aryl lower alkyl group, a pyridyl lower alkyl group, a pyridyl group and an aryl group), 1
2) Formula:

[0010]

[Chemical 31]

And the like. (In the formula, n represents an integer of 0 to 3) and the like.

Ring A may be substituted with 1 to 3 same or different groups selected from the above substituents.

The nitrogen-containing aliphatic heterocyclic group in ring A is, for example, 3 to 3 containing 1 or 2 nitrogen atoms.
8-membered aliphatic heterocyclic group and the like can be mentioned. Specific examples thereof include an aziridinyl group, an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholino group, an azepanyl group and a diazepanyl group.

The substituent on the heterocyclic group in R of the object compound [I] of the present invention is, for example, (1) lower alkyl group, (2) lower alkoxy group, (3) lower alkoxycarbonyl group, ( 4) carboxyl group, (5) lower alkanoyl group, (6) cyano group, (7) optionally protected hydroxyl group, (8) optionally protected amino group,
(9) nitro group, (10) halogen atom, and the like.

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

Examples of the heterocyclic group for R include, for example,
Examples thereof include monocyclic or bicyclic heterocyclic groups containing 1 to 4 nitrogen atoms. Specifically, pyrrolyl group, pyrazolyl group, imidazolyl group, triazolyl group, tetrazolyl group, oxazolyl group, thiazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, indolyl group, quinolyl group, isoquinolyl group, benzimidazolyl group. Etc.

Examples of the aryl group in ring A include aryl groups having 1 to 3 rings, and specific examples thereof include a phenyl group, a naphthyl group, an anthryl group and a phenanthryl group.

When the above-mentioned object compound [I] of the present invention has a protected amino group, examples of the amino group protecting group include an optionally substituted lower alkoxycarbonyl group, an acyl group and the like. Specifically, ethoxycarbonyl group, methoxycarbonyl group, benzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group, allyloxycarbonyl group, 9-fluorenylmethoxycarbonyl group, tert-butoxycarbonyl group, 2, 2,2-trichloroethyloxycarbonyl group, formyl group, acetyl group, propionyl group,
Examples include butyryl group. Furthermore, a benzyl group, 4-
A methoxybenzyl group, an allyl group, etc. are also mentioned. Of these, a lower alkoxycarbonyl group which may be substituted is preferred, and specific examples thereof include a benzyloxycarbonyl group and a tert-butoxycarbonyl group. The protected amino group also includes, for example, the case where a phthalimido group is formed together with the protected amino group.

When the object compound [I] of the present invention has a protected hydroxyl group, the protective group for the hydroxyl group may be an optionally substituted aryl lower alkyl group, an acyl group or an optionally substituted group. There may be mentioned conventional protecting groups such as a good lower alkoxycarbonyl group and a trialkylsilyl group. Among them, the preferable one is
For example, unsubstituted aryl lower alkyl group such as benzyl group and phenethyl group, formyl group, acetyl group, propionyl group, malonyl group, acryloyl group, acyl group such as benzoyl group, lower alkoxy such as methoxycarbonyl group, ethoxycarbonyl group, etc. Examples thereof include trialkylsilyl groups such as carbonyl group, trimethylsilyl group, triethylsilyl group and tert-butyldimethylsilyl group. Furthermore, a triphenylmethyl group, a 2-cyanoethyl group and the like can also be mentioned.

Among the desired compounds [I] of the present invention, a preferred compound is ring A having the formula:

[0021]

[Chemical 32]

(Wherein R ¹ is (1) hydrogen atom, (2)
A lower alkyl group which may be substituted with a phenyl group,
(3) Phenyl group optionally substituted with a lower alkyl group or cyano group, (4) lower alkoxy group optionally substituted with a phenyl group, (5) formyl group, (6) carboxyl group, (7) A lower alkoxycarbonyl group optionally substituted with a phenyl group, (8) a lower alkanoyl group optionally substituted with a phenyl group, (9) a benzenesulfonyl group, (10) a lower alkylsulfonyl group,
(11) Lower alkanoyl group; phenyl lower alkanoyl group; phenylcarbonyl group; lower alkoxycarbonyl group; phenyl lower alkoxycarbonyl group; phenyloxycarbonyl group; phenylsulfonyl group; lower alkylsulfonyl group; lower alkyl group; pyridyl group; pyrazinyl group An amino group which may be substituted with a group selected from a pyrimidinyl group; and a pyridazinyl group, or (12) formula: —CONR ³ R ⁴ (wherein R ³ and R ⁴ may be the same or different. A hydrogen atom, an alkyl group, a phenyl lower alkyl group, a pyridyl lower alkyl group, a pyridyl group, and a phenyl group, respectively), or a (13) formula:

[0023]

[Chemical 33]

(In the formula, n represents an integer of 0 to 3), R ² represents a hydrogen atom or a lower alkoxy lower alkyl group, and Q represents —CO— or R.
But the formula:

[0025]

[Chemical 34]

(In the formula, m represents an integer of 1 to 3, W represents a pyrazolyl group which may be substituted with a group selected from the following: (1) lower alkyl group, (2) lower alkoxy group,
(3) lower alkoxycarbonyl group, (4) carboxyl group, (5) lower alkanoyl group, (6) cyano group,
(7) optionally protected hydroxyl group (8) optionally protected amino group, (9) nitro group, and (10)
A group represented by a halogen atom).

Among the object compounds [I] of the present invention, as a more preferred compound, ring A is represented by the formula:

[0028]

[Chemical 35]

(However, the symbols have the same meanings as above)
A group represented by, Q is -CO-, and R is of the formula:

[0030]

[Chemical 36]

A group represented by:

Among the object compounds [I] of the present invention, as other more preferred compounds, ring A is represented by the formula:

[0033]

[Chemical 37]

(Wherein R ¹ is (1) hydrogen atom, (2)
Phenyl lower alkyl group, (3) phenyl group, (4) lower alkoxy group optionally substituted by phenyl group,
(5) formyl group, (6) lower alkoxycarbonyl group optionally substituted with phenyl group, (7) benzenesulfonyl group, (8) lower alkoxycarbonyl group; phenyl lower alkoxycarbonyl group; phenyloxycarbonyl group; and An amino group which may be substituted with a group selected from a pyrimidinyl group, (9) Formula: —CONR ³ R ⁴ (In the formula, R ³ and R ⁴ may be the same or different, and each is an alkyl group and phenyl. Represents a group selected from the groups) or (10) formula:

[0035]

[Chemical 38]

(In the formula, n represents a group represented by 1 or 2), Q is --CO--, and R is
formula:

[0037]

[Chemical Formula 39]

A group represented by:

Among the more desirable compounds of the object compound [I] of the present invention, the ring A has the formula:

[0040]

[Chemical 40]

(Wherein R ¹ is (1) phenyl lower alkyl group, (2) phenyl lower alkoxy group, (3) phenyl lower alkoxycarbonyl group, (4) formula: —CONR ³ R ⁴ (in the formula, R ³ and R ⁴ may be the same or different and each represents a group selected from an alkyl group) or a group represented by the formula (5):

[0042]

[Chemical 41]

A group represented by
Is -CO-, R is the formula:

[0044]

[Chemical 42]

A group represented by:

Among the object compounds [I] of the present invention, as other more preferred compounds, ring A has the formula:

[0047]

[Chemical 43]

(Wherein R ¹ is (1) phenyl lower alkyl group, (2) phenyl group optionally substituted with lower alkyl group, (3) lower alkoxy group optionally substituted with phenyl group) , (4) phenyl lower alkoxycarbonyl group, (5) benzenesulfonyl group, (6) lower alkylsulfonyl group, (7) phenylcarbonyl group; lower alkoxycarbonyl group; phenyl lower alkoxycarbonyl group; phenyloxycarbonyl group; and lower An amino group which may be substituted with a group selected from an alkyl group, (8) Formula: —CONR ³ R ⁴ (In the formula, R ³ and R ⁴ may be the same or different, and each is an alkyl group or phenyl. Group and a group selected from a phenyl lower alkyl group), or a group represented by the formula (9):

[0049]

[Chemical 44]

(In the formula, n represents a group represented by 1 or 2), Q is --CO--, and R is
formula:

[0051]

[Chemical formula 45]

A group represented by:

Among the object compounds [I] of the present invention, as other more preferred compounds, ring A is represented by the formula:

[0054]

[Chemical formula 46]

(Wherein R ¹ is (1) phenyl lower alkyl group, (2) phenyl group, (3) lower alkoxy group,
(4) Arylsulfonyl group, (5) Lower alkylsulfonyl group, (6) Formula: —CONR ³ R ⁴ (In the formula, R ³ and R ⁴ may be the same or different, and each is an alkyl group and a phenyl group. Or a group represented by the formula (7):

[0056]

[Chemical 47]

A group represented by
Is -CO-, R is the formula:

[0058]

[Chemical 48]

A group represented by:

Among the object compounds [I] of the present invention, 2-[(1H-pyrazole-1
-Yl) acetyl] -5- [2- [4- (N-methyl-N
-N-butyl-carbamoyl) piperidin-1-yl]
Benzoylamino] -isoindoline, 2-[(1H-pyrazol-1-yl) acetyl] -5- [2- (4-dimethylcarbamoylpiperidin-1-yl) benzoylamino] -isoindoline, or pharmacologically thereof And an acceptable salt.

The object compound [I] of the present invention is ring A, ring A
When the above substituent and / or group R has an asymmetric atom,
Although it can exist as an optical isomer based on the asymmetric atom,
The present invention includes any of these optical isomers and mixtures thereof.

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

Therefore, the object compound [I] of the present invention or a pharmacologically acceptable salt thereof is hyperlipidemia, ischemic heart disease, atherosclerosis, coronary arteriosclerosis, hypercholesterolemia, hypertriglyceridemia. Disease, familial hyperlipidemia, hyperlipoproteinemia, arteriosclerosis, coronary arteriosclerosis, coronary heart disease, ischemic brain disease, stroke, circulatory / microcirculatory disturbance, thrombosis, hyperglycemia, diabetes, acute bleeding It is expected to be applied to the prevention and treatment of pancreatitis, obesity, steatosis, constipation, etc. Furthermore, the object compound [I] of the present invention has low toxicity and is highly safe as a medicine.

The object compound [I] of the present invention can be used in medicinal use either in a free form or in the form of a pharmacologically acceptable salt. Examples of the pharmaceutically acceptable salt of the compound [I] include inorganic acid salts such as hydrochloride, sulfate, phosphate or hydrobromide, acetate, fumarate, oxalate, citric acid. Examples thereof include salts, methanesulfonates, benzenesulfonates, organic acid salts such as tosylate salts and maleate salts, and the like. When it has a substituent such as a carboxyl group, a salt with a base (for example, sodium salt,
Alkali metal salts such as potassium salts or alkaline earth metal salts such as calcium salts).

The object compound [I] or a salt thereof of the present invention includes any of its inner salt, adduct, solvate or hydrate thereof.

The object compound [I] of the present invention or a pharmaceutically acceptable salt thereof can be administered orally or parenterally, and can be used as tablets, granules, capsules, powders and injections. , Can be used as a conventional pharmaceutical preparation such as an inhalant.

The dose of the object compound [I] of the present invention or a pharmacologically acceptable salt thereof is determined by the administration method, the age of the patient,
Although it depends on the body weight and condition, it is usually about 0.01 to 5 mg / kg per day, especially about 0.1 to 3 mg / kg per day for an injection, and usually 1 for an oral preparation.
About 0.1-100 mg / kg per day, especially about 0.1
It is preferably about 50 mg / kg. <Production of Isoindoline Derivatives> According to the present invention, the target compound [I] is prepared by the following [Method A] to [Method F] according to a conventional method.
However, the present invention is not limited to these. [Method A] The isoindoline derivative [I] which is the object compound of the present invention has the following general formula [1]:

[0068]

[Chemical 49]

(However, the symbols have the same meanings as described above.)
A carboxylic acid compound or a salt thereof represented by the general formula [2]:

[0070]

[Chemical 50]

(However, the symbols have the same meanings as above)
It can be produced by reacting with an amine compound represented by or a salt thereof. This reaction can be carried out in a solvent, in the presence of a condensing agent, in the presence or absence of an activator, and in the presence or absence of a base. The solvent may be any solvent that does not adversely affect the reaction,
For example, methylene chloride, chloroform, dimethylformamide, dimethylacetamide, tetrahydrofuran,
Toluene, benzene, 1,2-dichloroethane, 1-methyl-2-pyrrolidinone and the like can be mentioned. Examples of the condensing agent include dicyclohexylcarbodiimide (DC
C), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC.HCl), diphenylphosphoryl azide (DPPA), carbonyldiimidazole (CDI), diethyl cyanophosphonate (DEPC), diisopropylcarbodiimide ( DIP
CI), benzotriazol-1-yloxy-trispyrrolidinophosphonium hexafluorophosphate (PyBOP) and the like. Examples of the activator include 1-hydroxybenzotriazole (HOB)
t), hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP), 1-hydroxy-7-
Azabenzotriazole (HOAt), hydroxyphthalimide (HOPht), pentafluorophenol (Pfp-OH), etc. are mentioned. Examples of the base include triethylamine, diisopropylethylamine,
4-methylmorpholine, 1,8-diazabicyclo [5.
4.0] -7-undecene (DBU) and the like.

The amount of the condensing agent used can be 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to the compound [1] or [2]. The amount of the activator used is the compound [1].
Alternatively, it can be 1 to 10 equivalents, preferably 1 to 2 equivalents based on [2]. The amount of the base used is the compound [1]
Alternatively, it can be 1 to 10 equivalents, preferably 1 to 2 equivalents based on [2]. This reaction can be carried out at 0 to 100 ° C, preferably 0 to 50 ° C.

The compound [1] may be converted into a reactive derivative such as an acid chloride or a mixed acid anhydride and then reacted with the compound [2] in the presence of a base. [Method B] The isoindoline derivative [I] which is the object compound of the present invention has the following general formula [3]:

[0074]

[Chemical 51]

(Wherein Y represents a halogen atom and other symbols have the same meanings as described above), or a salt thereof, and a compound of the general formula [4]:

[0076]

[Chemical 52]

(However, the symbols have the same meanings as above)
It can also be produced by reacting with a compound represented by This reaction can be carried out in a solvent, in the presence or absence of a base, and in the presence or absence of an activator. The solvent may be any solvent that does not adversely affect the reaction, for example, methanol, ethanol,
1,3-dimethyl-2-imidazolidinone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, 1-methyl-2-pyrrolidinone and the like can be mentioned.
Examples of the base include organic bases such as triethylamine and diisopropylethylamine, and inorganic bases such as potassium carbonate, sodium carbonate and cesium carbonate.
Examples of the activator include copper (I) iodide, copper powder, palladium acetate and the like.

The amount of the base used is the same as that of compound [3] or [4].
It can be 1 to 10 equivalents, preferably 1 to 2 equivalents. The amount of the activator used can be 0.001 to 0.5 equivalents, preferably 0.05 to 0.2 equivalents, relative to compound [3] or [4]. This reaction is 0
It can be carried out at ˜150 ° C., preferably 0˜80 ° C. [Method C] Among the target compounds of the present invention, a compound of the general formula [I] in which Q is —CO—, that is, a compound of the general formula [I
-A]:

[0079]

[Chemical 53]

(However, the symbols have the same meaning as above)
The isoindoline derivative represented by is represented by the general formula [5]:

[0081]

[Chemical 54]

(However, the symbols have the same meanings as above)
And a salt thereof and a compound represented by the general formula [6]:

[0083]

[Chemical 55]

(However, the symbols have the same meanings as described above.)
It can be produced by reacting with a compound represented by or a salt thereof. This reaction can be carried out in a solvent, in the presence of a condensing agent, in the presence or absence of an activator, and in the presence or absence of a base. As the solvent, any solvent may be used as long as it does not adversely influence the reaction, and for example, those exemplified as the solvent that can be used in the reaction of the compound [1] and the compound [2] of the above [Method A] can be appropriately used. . Further, as the activator, for example, the activator exemplified in the above [Method A] can be appropriately used.

The amount of the condensing agent used can be 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to the compound [5] or [6]. The amount of the activator used is the same as that of the compound [5].
Alternatively, it can be 1 to 10 equivalents, preferably 1 to 2 equivalents based on [6]. The amount of base used is the same as compound [5].
Alternatively, it can be 1 to 10 equivalents, preferably 1 to 2 equivalents based on [6]. This reaction can be carried out at 0 to 100 ° C, preferably 0 to 50 ° C.

The compound [6] is once converted into a reactive derivative such as an acid chloride or a mixed acid anhydride,
It may be reacted with the compound [5] in the presence of a base. [Method D] Of the object compounds of the present invention, in the general formula [I], Q is —CH ₂ —, that is, the general formula [Ib]:

[0087]

[Chemical 56]

(However, the symbols have the same meanings as described above.)
The isoindoline derivative represented by is represented by the general formula [Ia]
It can be produced by subjecting a compound represented by or a salt thereof to a reduction reaction. The reduction reaction can be carried out in a solvent in the presence of a suitable reducing agent. As a solvent,
Any solvent that does not adversely affect the reaction may be used, for example,
Tetrahydrofuran, diethyl ether, dioxane,
Dimethoxyethane and the like can be mentioned. Suitable reducing agents include, for example, sodium borohydride-boron trifluoride diethyl ether complex, lithium aluminum hydride,
Aluminum hydride, lithium borohydride, borane-
Examples thereof include dimethyl sulfide complex and borane-tetrahydrofuran complex.

The amount of the reducing agent used can be 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to compound [Ia]. This reaction is −30 to 100 ° C., preferably 0 to 5
It can be carried out at 0 ° C. [Method E] Of the target compound [I] of the present invention, the compound of the general formula [I]
The isoindoline derivative represented by the formula-b] includes a compound represented by the general formula [5] or a salt thereof and a general formula [7]:

[0090]

[Chemical 57]

It can also be produced by reacting with a compound represented by the formula (wherein X represents a leaving group and other symbols have the same meanings as described above) or a salt thereof.

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

Examples of the leaving group X include halogen atoms such as fluorine atom, chlorine atom, bromine atom or iodine atom, p-toluenesulfonyloxy group, methanesulfonyloxy group, trifluoromethanesulfonyloxy group and hydroxyl group. Is mentioned.

When the leaving group X is a hydroxyl group, triphenylphosphine-diethylazodicarboxylate,
Mitsunobu reagents such as triphenylphosphine-diisopropylazodicarboxylate can also be used.

The amount of base used is the same as that of compound [5] or [7].
It can be 1 to 20 equivalents, preferably 1 to 5 equivalents. The additive may be used in an amount of 1-10 equivalents, preferably 1-5 equivalents, relative to compound [5] or [7]. This reaction can be carried out at -30 to 150 ° C, preferably 0 to 80 ° C. [Method F] Of the target compound [I] of the present invention, the compound of the general formula [I]
The isoindoline derivative represented by general formula [b] includes a compound represented by the general formula [5] or a salt thereof, and a general formula [8]:

[0096]

[Chemical 58]

(However, the symbols have the same meanings as described above.)
After the condensation reaction with the compound represented by or a salt thereof,
It can also be produced by subjecting it 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 in the condensation reaction or the reduction reaction may be any solvent that does not adversely affect the reaction, for example, methylene chloride, tetrahydrofuran, dioxane, diethyl ether, methanol, ethanol, isopropyl alcohol, 1,2-dichloroethane, water and the like. Is mentioned. Examples of the base include triethylamine, diisopropylethylamine,
4-methylmorpholine and the like can be mentioned. Examples of the reducing agent include sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, sodium triacetoxyborohydride, hydrogen-palladium carbon, sodium borohydride-acetic acid and the like.

The amount of the base used is the same as that of compound [5] or [8].
It can be 1 to 20 equivalents, preferably 1 to 5 equivalents. The reducing agent may be used in an amount of 1-10 equivalents, preferably 1-5 equivalents, relative to compound [5] or [8]. The reaction between the compounds [5] and [8] is 0.
It can be carried out at -100 ° C, preferably 0-50 ° C, and the reduction reaction of the reaction product can be carried out at -30-100 ° C, preferably 0-50 ° C.

The condensation reaction and the reduction reaction can be carried out continuously in the same reaction vessel as a reductive amination reaction.

The object compound [I] of the present invention is obtained by converting the substituent on ring A and / or the group R of the compound obtained as described above into another desired substituent by a conventional method. It can also be manufactured. Such a method for converting a substituent may be appropriately selected according to the kind of the desired substituent, but may be carried out as in (method a) to (method j), for example.

(Method a: Alkylation of hydroxyl group) The target compound [I] in which the substituent on ring A in the general formula [I] is a substituent containing a lower alkoxy group which may be substituted with an aryl group is , A corresponding compound [I] in which the substituent on the ring A is a substituent containing a hydroxyl group, and a lower alkyl halide (eg, methyl iodide, benzyl bromide) optionally substituted with an aryl group, It can be produced by reacting in the presence of (for example, sodium hydride, potassium carbonate).

(Method b: Alkylation of amino group) The target compound [I] in which the substituent on the ring A in the general formula [I] is a substituent containing a lower alkylamino group is a substituent on the ring A. Is reacted with a corresponding compound [I] wherein A is a substituent containing an amino group and a lower alkyl halide (eg, methyl iodide, benzyl bromide) in the presence of a base (eg, sodium hydride, potassium carbonate). It can be manufactured.

(Method c: Alkylation of amino group (reductive amination)) An amino group in which the substituent on ring A in the general formula [I] is substituted with a lower alkyl group or an aryl lower alkyl group (eg, dimethyl). The target compound [I], which is a substituent containing an amino group, a diethylamino group, and a benzylamino group, includes a corresponding compound [I] in which the substituent on the ring A is a substituent containing an amino group, and a lower alkanal. Alternatively, it can be produced by reacting an aryl lower alkanal (eg formaldehyde, benzaldehyde) in the presence of a reducing agent (eg sodium borohydride, sodium triacetoxyborohydride).

(Method d: alkylation of imino group in ring) The target compound [I] in which ring A in the general formula [I] contains an imino group substituted with a lower alkyl group or an aryl lower alkyl group in the ring is , A corresponding compound [I] containing an imino group (—NH—) in ring A and a lower alkanal or an aryl lower alkanal (eg, formaldehyde, benzaldehyde), a reducing agent (eg, sodium borohydride, It can be produced by reacting in the presence of hydrogenated sodium triacetoxyborohydride).

(Method e: Conversion of carboxyl group to lower alkoxycarbonylamino group) The substituent on ring A in the general formula [I] contains a lower alkoxycarbonylamino group (eg, tert-butoxycarbonylamino group). The target compound [I], which is a substituent, includes a corresponding compound [I], which is a substituent in which the substituent on ring A contains a carboxyl group, and diphenylphosphoric azide, and a base (for example,
It can be produced by reacting in the presence of (triethylamine) to give an isocyanate, and reacting this with a lower alcohol (for example, tert-butyl alcohol).

The lower alkoxycarbonylamino group can be further converted into a free amino group by a conventional deprotection reaction of the amino group.

(Method f: Introduction of heterocyclic group into amino group)
The substituent on ring A in the general formula [I] is a pyridyl group;
The target compound [I], which is a substituent containing an amino group (for example, a (pyrimidin-2-yl) amino group) substituted with a group selected from a pyrazinyl group; a pyrimidinyl group; It is produced by reacting a corresponding compound [I] in which the substituent is a substituent containing an amino group, and a corresponding halide (eg, 2-bromopyrimidine) in the presence of a base (eg, triethylamine). You can

(Method g: acylation of amino group) The substituent on ring A in the general formula [I] is a lower alkanoyl group; an aryl lower alkanoyl group; an arylcarbonyl group; a lower alkoxycarbonyl group; an aryl lower alkoxycarbonyl group. An aryloxycarbonyl group; an arylsulfonyl group; and a target compound [I] which is a substituent containing an amino group substituted with a group selected from a lower alkylsulfonyl group, wherein the substituent on ring A contains an amino group. The corresponding compound [I], which is a substituent, and a corresponding acylating agent (eg, dimethylcarbamoyl chloride,
Benzyloxycarbonyl chloride, benzenesulfonyl chloride) and a base (for example, triethylamine,
It can be produced by reacting in the presence of potassium carbonate).

(Method h: Acylation of imino group in ring) The ring A in the general formula [I] has the formula:

[0111]

[Chemical 59]

(In the formula, R ¹⁰ is a formyl group, a lower alkoxycarbonyl group which may be substituted with an aryl group,
A lower alkanoyl group optionally substituted with an aryl group, an arylsulfonyl group, a lower alkylsulfonyl group, a group represented by the formula: -CONR ³ R ⁴ (where the symbols have the same meanings as described above), or a formula:

[0113]

[Chemical 60]

(However, the symbols have the same meanings as described above.)
The object compound [I] represented by
Ring A has the formula:

[0115]

[Chemical formula 61]

A compound represented by the formula: or a salt thereof, and a compound of the formula [24]:

[0117]

[Chemical formula 62]

(Wherein, X ¹ represents a halogen atom and other symbols have the same meanings as described above), and the compound is reacted in the presence of a base (eg, triethylamine). it can. (Method i: Amidation of Carboxyl Group) The target compound [I], which is a substituent containing an optionally substituted carbamoyl group, in the ring A in general formula [I] is ring A
The corresponding compound [I] in which the above substituent is a substituent containing a carboxyl group and the corresponding amine compound (eg, dimethylamine, N-methyl-Nn-butylamine) are the same as in the above [Method A]. It can be produced by reacting with. (Method j: esterification of carboxyl group) The target compound [I] in which the substituent on ring A in the general formula [I] is a substituent containing an ester group (for example, benzyl ester).
Is produced by reacting the corresponding compound [I] in which the substituent on ring A is a substituent containing a carboxyl group with the corresponding alcohol compound (eg, benzyl alcohol) in the same manner as in the above [Method A]. can do.

[A method] to [F method] or (a
The object compound [I] of the present invention obtained by the methods (1) to (j) can be converted into a pharmacologically acceptable salt, if desired. Conversion to a pharmaceutically acceptable salt is
It may be performed according to a method known to those skilled in the art. <Production Method of Raw Material Compound> The raw material compound [1] can be produced, for example, according to the following method.

[0120]

[Chemical formula 63]

(Wherein R ⁵ represents a lower alkyl group or a benzyl group, and other symbols have the same meanings as described above) The reaction for producing compound [11] from compound [9] and compound [10] is as follows: It can be carried out in the same manner as in the above-mentioned [Method B].

The reaction for producing the compound [1] from the compound [11] is carried out under conventional hydrolysis reaction conditions (for example, sodium hydroxide-water) or hydrogenolysis reaction conditions (palladium / carbon-hydrogen). be able to.

The reaction for producing the compound [13] from the compound [12] and the compound [10] can be carried out in the same manner as in the above-mentioned [Method B].

The reaction for producing the compound [1] from the compound [13] can be carried out under a conventional hydrolysis reaction condition (for example, concentrated hydrochloric acid, concentrated sulfuric acid).

The reaction for producing compound [11] from compound [13] can be carried out under conventional solvolysis reaction conditions (eg concentrated sulfuric acid / ethanol).

Starting compound [2] ([2-a] and [2
-B]) can be produced, for example, according to the following method.

[0127]

[Chemical 64]

(However, the symbols have the same meanings as described above.) The reaction for producing the compound [15] from the isoindoline [14] and the carboxylic acid compound [6] is carried out in the same manner as in the above-mentioned [Method A]. You can The reaction for producing the compound [15] from the dichloro compound [18] and the compound [19] can be carried out in the presence of a base, or in the presence or absence of an additive. Examples of the base include sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium methoxide and the like. Examples of the additive include tetra-lower alkylammonium halides such as tetrabutylammonium chloride and tetraethylammonium chloride.

As a concrete example of this step, for example,
The reaction shown below is included.

[0130]

[Chemical 65]

The reaction for producing compound [16] from compound [15] can be carried out in the presence of a suitable nitrating agent. Suitable nitrating agents include, for example, concentrated nitric acid /
Examples thereof include concentrated sulfuric acid, potassium nitrate / concentrated sulfuric acid, potassium nitrate / trifluoroacetic acid and the like.

The reaction for producing compound [17] from compound [14] can be carried out in the same manner as the reaction for producing compound [16] from compound [15].

Compound [17] and carboxylic acid compound [6]
The reaction for producing compound [16] from can be carried out in the same manner as in the above-mentioned [Method A].

The reaction for producing the compound [2-a] from the compound [16] can be carried out in the presence of a suitable reducing agent. Examples of the reducing agent include hydrogen / palladium-carbon, lithium aluminum hydride, zinc-acetic acid, iron (II) chloride-hydrochloric acid, tin (II) chloride-hydrochloric acid, iron-hydrochloric acid,
Iron-ammonium chloride, ammonium formate / palladium-carbon and the like can be mentioned.

The reaction for producing the compound [2-b] from the compound [2-a] can be carried out in the same manner as in the above-mentioned [Method D].

In the reaction for producing the compound [2-b] from the compound [17], the same treatment (N-alkylation) as in the above-mentioned [Method E] is performed, and then the compound [2-a] is converted from the compound [16]. It can be carried out by treatment (reduction of nitro group) in the same manner as in the production reaction.

The starting compound [3] can be produced, for example, according to the following method.

[0138]

[Chemical formula 66]

(However, the symbols have the same meanings as described above.) The reaction for producing the compound [3] from the compound [2] and the compound [20] can be carried out in the same manner as in the above-mentioned [Method A].

The starting compound [5] can be produced, for example, according to the following method.

[0141]

[Chemical formula 67]

(Where the symbols have the same meaning as described above) The reaction for producing compound [21] from compound [17] is as follows:
In a solvent, di-tert-butyl dicarbonate (Boc
₂ O), in the presence or absence of a base. Examples of the solvent include tetrahydrofuran, methylene chloride, 1,2-dichloroethane, dioxane, ethyl acetate and the like. Examples of the base include triethylamine, potassium carbonate, sodium carbonate, diisopropylethylamine, sodium hydrogen carbonate, 4-dimethylaminopyridine and the like.

The reaction for producing compound [22] from compound [21] can be carried out in the same manner as the reaction for producing compound [2-a] from compound [16]. The reaction for producing the compound [23] from the compound [22] and the compound [1] can be carried out in the same manner as in the above-mentioned [Method A].

The reaction for producing the compound [5] from the compound [23] can be carried out in the presence of a deprotecting agent for the Boc-protected amino group. Examples of the deprotecting agent include hydrochloric acid-dioxane, hydrochloric acid-ethyl acetate, trifluoroacetic acid, iodotrimethylsilane and the like.

In the production of the above-mentioned target compound [I], [Ia] or [Ib], each intermediate compound is not limited to those shown in the chemical reaction, and if it does not participate in the reaction, A salt or its reactive derivative can also be used as appropriate. Examples of the salt include metal salts such as sodium, potassium, lithium, calcium and magnesium,
Pyridine, triethylamine, salts with organic bases such as diisopropylethylamine, 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,
Examples thereof include salts with organic acids such as p-toluenesulfonic acid and trifluoroacetic acid.

Further, in the production of the object compound and the starting compound of the present invention, when the starting compound or each intermediate has a functional group, appropriate protection for each functional group is carried out by a conventional synthetic chemistry method other than those shown above. A group may be introduced, and if necessary, those protecting groups may be appropriately removed.

In the present invention, examples of the alkyl group include linear or branched alkyl groups having 1 to 16 carbon atoms, and particularly those having 1 to 10 carbon atoms. Examples of the lower alkyl group or lower alkoxy group include linear or branched alkyl groups or alkoxy groups having 1 to 6 carbon atoms, and particularly those having 1 to 4 carbon atoms. Further, the lower alkanoyl group includes a linear or branched alkanoyl group having 2 to 7 carbon atoms, particularly 2 to 5 carbon atoms, and the cycloalkyl group is
Examples thereof include a cycloalkyl group having 3 to 20 carbon atoms, particularly 3 to 12 carbon atoms. Examples of cyclo lower alkyl include those having 3 to 8 carbon atoms, particularly those having 3 to 6 carbon atoms. The alkenyl group has 2 to 16 carbon atoms, especially 2 to 2 carbon atoms.
Examples thereof include linear or branched alkenyl groups having 10 carbon atoms, and examples of the lower alkenyl group include alkenyl groups having 2 to 8 carbon atoms, and particularly 2 to 4 carbon atoms. The alkylene group includes a linear or branched alkylene group having 1 to 16 carbon atoms, particularly 1 to 10 carbon atoms, and the lower alkylene group includes 1 to 8 carbon atoms, particularly 1 to 6 carbon atoms. And a straight chain or branched chain alkylene group. Further, as the halogen atom, a fluorine atom, a chlorine atom,
Examples thereof include bromine atom and iodine atom.

[0148]

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

Example 1 2- (4-benzyloxypiperidin-1-yl) benzoic acid (the crude product obtained in Reference Example 20 is used as it is), 5-amino-2-[(1H-pyrazole-1- Di) acetyl] -isoindoline 42 mg, 1-hydroxybenzotriazole 28 mg and 4-dimethylaminopyridine 21 mg dimethylformamide (2 m
l) To the solution under ice-cooling, 39 mg of 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride is added, and the mixture is stirred at room temperature. 22 hours later 1-ethyl-3-
39 mg of (3-dimethylaminopropyl) -carbodiimide hydrochloride is added, and the mixture is further stirred for 24 hours. Water is added to the reaction solution and extracted with ethyl acetate. The organic layer is washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated, the residue was purified by preparative chromatography (developing solvent; ethyl acetate), and then ethyl acetate-
2-[(1H-pyrazol-1-yl) acetyl]-was obtained by trituration with a mixed solvent of diisopropyl ether.
47 mg of 5- [2- (4-benzyloxypiperidin-1-yl) benzoylamino] -isoindoline are obtained as a colorless powder. MS (APCI) m / z; 536 (M + H), IR (N
ujol) cm ⁻¹ ; 1673, 1601.

Examples 2-15 The corresponding starting materials are treated in the same manner as in Example 1 to obtain the compounds shown in Table 1.

[0151]

[Table 1]

[0152]

[Table 2]

[0153]

[Table 3]

Example 16 (1) 2-[(1H-pyrazol-1-yl) acetyl]
-5- [2- (4-ethoxycarbonylpiperidine-1
-Yl) benzoylamino] -isoindoline (compound obtained in Example 3) 5.19 g of methanol (120
(ml) / tetrahydrofuran (120 ml) mixed solution, 1.01 g of potassium hydroxide in water (20 ml) is added, and the mixture is stirred at room temperature for 23 hours. After the reaction solution was concentrated, water was added to the residue to make the solution acidic with a 10% aqueous citric acid solution,
Extract with chloroform. The organic layer is washed with water and saturated saline and then dried over anhydrous sodium sulfate. Evaporate the solvent,
The residue was crystallized from a mixed solution of methanol-diethyl ether to give 2-[(1H-pyrazol-1-yl) acetyl] -5- [2- (4-carboxypiperidin-1-yl) benzoylamino]-. Isoindoline 4.
78 g are obtained as colorless crystals. M. p. 230-232 ° C (2) A suspension of 3.144 g of the compound obtained in (1) above in toluene (35 ml) was added with diphenylphosphoric azide 2.
010 g and triethylamine 1.05 ml are added, and the mixture is heated under reflux for 2 hours. Tert-butyl alcohol 3 in the reaction solution
Add 5 ml and heat to reflux for 16 hours. The reaction mixture is diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (developing solvent; chloroform: methanol = 100:
By purifying in 1), 2-[(1H-pyrazol-1-yl) acetyl] -5- [2- (4-tert-butoxycarbonylaminopiperidin-1-yl) benzoylamino] -isoindoline 3. 021 g are obtained as a colorless foam. MS (APCI) m / z; 545 (M + H), IR (N
ujol) cm ⁻¹ ; 1706, 1666.

Example 17 2-[(1H-pyrazol-1-yl) acetyl] -5-
[2- (4-tert-Butoxycarbonylaminopiperidin-1-yl) benzoylamino] -isoindoline (the compound obtained in Example 7 or Example 16 (2)) 3.273 g was added to 4M hydrochloric acid-dioxane solution (30 m).
l) is added dropwise and the mixture is stirred at room temperature for 7 hours. After the reaction solution was concentrated, the residue was washed with diethyl ether to give 2
-[(1H-pyrazol-1-yl) acetyl] -5-
3.176 g of [2- (4-aminopiperidin-1-yl) benzoylamino] -isoindoline trihydrochloride are obtained as a colorless solid. MS (APCI) m / z; 445 (M + H), IR (N
ujol) cm ⁻¹ ; 1661, 1609.

Example 18 2-[(1H-pyrazol-1-yl) acetyl] -5-
[2- (4-Aminopiperidin-1-yl) benzoylamino] -isoindoline-3-hydrochloride (compound obtained in Example 17) 207 mg and potassium carbonate 221 m
g ethyl acetate (4 ml) -methylene chloride (4 ml)-
To a mixed solution of water (2 ml), 56 μl of benzoyl chloride was added dropwise, and the mixture was stirred at room temperature for 5 hours. 113m potassium carbonate
g, 28 μl of benzoyl chloride are added, and 2 more at room temperature.
Stir for hours. Chloroform and water were added to the reaction solution, and the organic layer was separated, washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was subjected to column chromatography (Yamazen Co., Ltd. Ultrapack ™ diol, developing solvent; n-hexane: chloroform = 34: 66 → 0: 1).
00) and triturating the residue with diisopropyl ether to give 2-[(1H-pyrazol-1-yl) acetyl] -5- [2- (4-benzoylaminopiperidin-1-yl) benzoylamino. ] -Isoindoline 149 mg is obtained as a colorless powder. MS (APCI) m / z; 549 (M + H), IR (N
ujol) cm ⁻¹ ; 1660, 1603.

Example 19 By treating the corresponding starting material compound in the same manner as in Example 18, the compounds shown in Table 2 are obtained.

[0158]

[Table 4]

Example 20 2-[(1H-pyrazol-1-yl) acetyl] -5-
200 mg of [2- (4-aminopiperidin-1-yl) benzoylamino] -isoindoline trihydrochloride (compound obtained in Example 17) and triethylamine.
0.066 ml of benzyl chlorocarbonate was added to a solution of 216 ml of methylene chloride (10 ml) under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution is poured into water and extracted with chloroform. The organic layer is washed with a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution, and then dried over anhydrous sodium sulfate. The solvent was evaporated, the residue was purified by silica gel column chromatography (developing solvent; chloroform: methanol = 25: 1), and recrystallized from ethyl acetate to give 2-[(1H-pyrazol-1-yl). Acetyl] -5- [2- (4-benzyloxycarbonylaminopiperidin-1-yl) benzoylamino]
-117 mg of isoindoline are obtained as colorless crystals. M. p. 147.5-149.5 ° C (decomposition).

Examples 21 to 22 By treating the corresponding starting materials in the same manner as in Example 20, the compounds shown in Table 3 are obtained.

[0161]

[Table 5]

Example 23 2-[(1H-pyrazol-1-yl) acetyl] -5-
To a solution of [2- (4-aminopiperidin-1-yl) benzoylamino] -isoindoline-3-hydrochloride (the compound obtained in Example 17) 558 mg in ethanol (20 ml) was added triethylamine 836 μl and 2-bromopyrimidine 482 mg. Heat at reflux for 48 hours. The reaction solution is diluted with ethyl acetate, washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (developing solvent; chloroform:
After purification with methanol = 100: 0 → 90: 10),
By recrystallizing from methanol, 2-[(1H-pyrazol-1-yl) acetyl] -5- [2- (4- (pyrimidin-2-yl-amino) piperidin-1-yl) was obtained.
181 mg of benzoylamino] -isoindoline are obtained as colorless crystals. M. p. 149-152 ° C (decomposition).

Example 24 (1) 2-[(1H-pyrazol-1-yl) acetyl]
-5- [2- (4- (tert-butoxycarbonyl-
Methyl-amino) piperidin-1-yl) benzoylamino] -isoindoline (compound obtained in Example 9)
By treating 220 mg in the same manner as in Example 17, 2-[(1H-pyrazol-1-yl) acetyl]-
5- [2- (4-methylaminopiperidin-1-yl)
Benzoylamino] -isoindoline trihydrochloride 221
mg is obtained as an off-white solid. (2) To a mixed solution of 218 mg of the compound obtained in (1) above and 318 mg of potassium carbonate in methylene chloride (5 ml) -water (2.5 ml), 55 μl of ethyl chlorocarbonate was added.
1 is added dropwise with stirring and stirred at room temperature for 2.5 hours.
Chloroform and water are added to the reaction solution for liquid separation, the organic layer is washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent is evaporated. The residue was subjected to silica gel column chromatography (developing solvent; chloroform: methanol = 100: 0 →
95: 5) and then recrystallized from ethyl acetate to give 2-[(1H-pyrazol-1-yl) acetyl] -5- [2- (4- (ethoxycarbonyl-methyl-methyl-
Amino) piperidin-1-yl) benzoylamino]-
146 mg of isoindoline are obtained as light brown crystals. M. p. 194-198 ° C.

Example 25 2-[(1H-pyrazol-1-yl) acetyl] -5- [2- (4-carboxypiperidin-1-yl) benzoylamino] -isoindoline (Example 16) under an argon atmosphere. (Compound obtained in (1)) 500 mg, dimethylamine hydrochloride 129 mg, 1-ethyl-3- (3-
Dimethylaminopropyl) -carbodiimide / hydrochloride 4
04 mg, 1-hydroxybenzotriazole 144 m
g, 4-dimethylaminopyridine (catalytic amount) and 0.517 ml of triethylamine in methylene chloride (40 m
l) The suspension is stirred overnight at room temperature. The reaction solution is poured into dilute aqueous sodium hydrogen carbonate solution and extracted with chloroform.
The organic layer is washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, the residue was purified by silica gel column chromatography (developing solvent; chloroform: methanol = 25: 1), and recrystallized from ethyl acetate to give 2-
[(1H-pyrazol-1-yl) acetyl] -5- [2
-(4-Dimethylcarbamoylpiperidin-1-yl)
455 mg of benzoylamino] -isoindoline are obtained as colorless crystals. ¹ H-NMR (DMSOd ₆ ) ppm; 1.68-1.90 (4H, m), 2.73-2.93
(3H, m), 2.82 (3H, d, J = 1.5Hz), 3.04 (3H, s), 3.21-3.2
8 (2H, m), 4.67 (2H, d, J = 12.1Hz), 4.93 (2H, d, J = 12.5H
z), 5.18 (2H, d, J = 2.9Hz), 6.28 (1H, t, J = 2.2Hz), 7.22
(1H, t, J = 7.1Hz), 7.29-7.38 (2H, m), 7.45 (1H, d, J = 1.6
Hz), 7.52 (1H, m), 7.61 (1H, m), 7.70 (1H, d, J = 2.4H
z), 7.84 (1H, dt, J = 7.7,11.7Hz), 7.95 (1H, d, J = 8.1H
z), 11.74 (1H, d, J = 15.8Hz). MS (APCI) m / z; 501 (M + H) ⁺ . Examples 26-34 By treating corresponding starting compounds in the same manner as in Example 25 , The compounds listed in Table 4 are obtained.

[0165]

[Table 6]

[0166]

[Table 7]

Example 35 2-[(1H-pyrazol-1-yl) acetyl] -5-
[2- (4-Carboxypiperidin-1-yl) benzoylamino] -isoindoline (the compound obtained in Example 16 (1)) 142 mg, benzyl alcohol 0.0
37 ml and 1-hydroxybenzotriazole 45
64 mg of 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride was added to a solution of mg of dimethylformamide (2.5 ml) under ice cooling, and the mixture was stirred at room temperature for 24 hours and at 50 ° C. for 7 hours. . Dilute aqueous sodium hydrogen carbonate solution is added to the reaction solution, and the mixture is stirred for 1 hour and then extracted with ethyl acetate. The organic layer is washed successively with water and saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated, the residue was purified by preparative chromatography (developing solvent; chloroform: methanol = 10: 1), and then recrystallized with a mixed solvent of ethyl acetate-isopropyl ether to give 2-[(1H-pyrazole 85 mg of -1-yl) acetyl] -5- [2- (4-benzyloxycarbonylpiperidin-1-yl) benzoylamino] -isoindoline are obtained as colorless crystals. M. p. 180-183 ° C Example 36 2-[(1H-pyrazol-1-yl) acetyl] -5-
[2- (4-benzyloxycarbonylpiperazine-1
A solution of 177 mg of -yl) benzoylamino] -isoindoline (compound obtained in Example 10) in hydrogen bromide-acetic acid (3 mL) is stirred at room temperature for 5 hours. 2-[(1H-pyrazol-1-yl) acetyl] was added to the reaction solution by adding diisopropyl ether (15 mL) and stirring the mixture at room temperature for 2 hours, collecting the precipitate by filtration, washing with diisopropyl ether and drying. -5- [2- (piperazine-1
147 mg of -yl) benzoylamino] -isoindoline trihydrobromide is obtained as a colorless powder. M. p. 214-215 ° C Example 37 2-[(1H-pyrazol-1-yl) acetyl] -5-
By treating 458 mg of [2- (4-formylpiperazin-1-yl) benzoylamino] -isoindoline (the compound obtained in Example 11) in the same manner as in Example 17, 2-[(1H-pyrazole-1 -Yl) acetyl]
532 mg of -5- [2- (piperazin-1-yl) benzoylamino] -isoindoline trihydrochloride are obtained as colorless powder. MS (APCI) m / z; 431 (M + H), IR (n
ujol) cm ⁻¹ ; 1655, 1605. Example 38 2-[(1H-pyrazol-1-yl) acetyl] -5-
[2- (4-tert-butoxycarbonylpiperazine-1
-Yl) benzoylamino] -isoindoline (the compound obtained in Example 12) (1.05 g) in methanol (50
ml), and about 19% hydrochloric acid-methanol solution (10
ml) and stirred at room temperature for 20 hours. About 19 more
% Hydrochloric acid-methanol solution (10 ml) was added, and the mixture was allowed to stand at room temperature for 2
Stir for 0 hours. The solvent was distilled off under reduced pressure and the residue was dried to give 2-[(1H-pyrazol-1-yl) acetyl].
1.01 g of -5- [2- (piperazin-1-yl) benzoylamino] -isoindoline-3-hydrochloride is obtained as a white powder.

Example 39 2-[(1H-pyrazol-1-yl) acetyl] -5-
A solution of 150 mg of [2- (piperazin-1-yl) benzoylamino] -isoindoline trihydrochloride (the compound obtained in Example 37) in methylene chloride (1 ml) was cooled with ice, and triethylamine (280 μl) and benzene chloride were added. Add sulfonyl (38 μl) and stir at the same temperature for 2 hours.
The reaction solution is diluted with chloroform, washed with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (developing solvent;
2-[(1H-pyrazol-1-yl) acetyl] -5- [2- (4-benzenesulfonylpiperazine-1-) by purifying with chloroform: methanol = 50: 1) and recrystallizing with ethyl acetate. Ill) benzoylamino]
-83 mg of isoindoline are obtained as colorless crystals. M. p. 233-235 ° C. Example 40 The corresponding starting material compound is treated in the same manner as in Example 39, to give compounds in Table 5.

[0169]

[Table 8]

Example 41 2-[(1H-pyrazol-1-yl) acetyl] -5-
[2- (Piperazin-1-yl) benzoylamino] -isoindoline trihydrochloride (compound obtained in Example 37) 150 mg, triethylamine (280 μl) and benzaldehyde (31 μl) in methylene chloride (3 m
l) In solution, sodium triacetoxyborohydride 1
Add 90 mg and stir at room temperature for 24 hours. The reaction solution is diluted with chloroform, washed with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was evaporated, the residue was purified by silica gel column chromatography (developing solvent; chloroform: methanol = 50: 1), and crystallized from ethyl acetate to give 2-[(1H-pyrazole-1-
Il) acetyl] -5- [2- (4-benzylpiperazin-1-yl) benzoylamino] -isoindoline 83
mg is obtained as colorless crystals. M. p. 237-238 ° C Example 42 2-[(1H-pyrazol-1-yl) acetyl] -5-
[2- (piperazin-1-yl) benzoylamino] -isoindoline trihydrochloride (compound obtained in Example 37) 200 mg in methylene chloride (15 ml) suspension,
A solution of 200 mg of triethylamine and 60 mg of dimethylcarbamoyl chloride in methylene chloride (5 ml) was added dropwise under ice cooling. The reaction mixture is warmed to room temperature and stirred for 20 hours. Water is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The ethyl acetate layer was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate,
Concentrate under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; chloroform-chloroform: methanol = 50: 1) to give 2-[(1H-
170.6 mg of pyrazol-1-yl) acetyl] -5- [2- (4-dimethylcarbamoylpiperazin-1-yl) benzoylamino] -isoindoline are obtained as a white amorphous powder. MS (APCI) m / z; 502 (M + H), IR (Nu
jol) cm ⁻¹ ; 1671, 1633. Examples 43 to 44 The corresponding starting compounds were treated in the same manner as in Example 42 to give compounds shown in Table 6.

[0171]

[Table 9]

Example 45 (1) Under an argon atmosphere, 5-amino-2- (tert)
-Butoxycarbonyl) -isoindoline (Reference Example 37)
2.53 g of the compound obtained in (3), 2- (4-ethoxycarbonylpiperidin-1-yl) benzoic acid (the compound obtained in Reference Example 21) 2.80 g, 1-ethyl-3
-(3-Dimethylaminopropyl) -carbodiimide
Hydrochloride 2.86 g, 1-hydroxybenzotriazole 1.35 g, 4-dimethylaminopyridine (catalytic amount) and triethylamine 2.09 ml methylene chloride (8
0 ml) solution is stirred at room temperature overnight. The reaction solution is poured into dilute aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer is washed with water, 5% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, 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 = 2: 3) to give 2- (ter).
t-butoxycarbonyl) -5- [2- (4-ethoxycarbonylpiperidin-1-yl) benzoylamino]
-4.05 g of isoindoline is obtained as a colorless solid. MS (APCI) m / z; 494 (M + H), IR (n
eat) cm ⁻¹ ; 1735, 1695, 1660. (2) To a mixed solution of 4.03 g of the compound obtained in (1) above in methanol (50 ml) -tetrahydrofuran (50 ml), 800 mg of potassium hydroxide in water (15 ml).
Add solution and stir overnight at room temperature. After the reaction solution is concentrated, water is added to the residue to make the solution acidic with a 10% aqueous citric acid solution, and the solution is extracted with chloroform. The organic layer is washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent is evaporated to give 2- (tert-butoxycarbonyl).
-5- [2- (4-Carboxypiperidin-1-yl)
3.80 g of benzoylamino] -isoindoline are obtained as a colorless foam. MS (APCI) m / z; 466 (M + H), IR (n
eat) cm ⁻¹ ; 1730, 1695, 1670. (3) Under an argon atmosphere, 3.78 g of the compound obtained in (2) above, 993 mg of dimethylamine / hydrochloride, 1-
Methyl chloride (80 ml) solution of ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride 3.10 g, 1-hydroxybenzotriazole 1.10 g, 4-dimethylaminopyridine (catalytic amount) and triethylamine 3.96 ml. Is stirred at room temperature for 5.5 hours. The reaction solution is poured into dilute aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer is washed with water, 5% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (developing solvent;
After purification with chloroform: methanol = 25: 1) and recrystallization with ethyl acetate, 2- (tert-butoxycarbonyl) -5- [2- (4-dimethylcarbamoylpiperidin-1-yl) benzoylamino]- 3.31 g of isoindoline are obtained as colorless crystals. M. p. 205.0-207.0 ° C. (4) 4M hydrochloric acid-dioxane solution (50 ml) was added dropwise to a suspension of 3.15 g of the compound obtained in (3) above in dioxane (30 ml), and the mixture was stirred at room temperature overnight. The reaction solution is diluted with diethyl ether and the precipitate is collected by filtration. The obtained white powder is dissolved in water, concentrated ammonia water is added under ice cooling to make the liquid basic, and the mixture is stirred at room temperature for 2 hours. The precipitate is collected by filtration and dried to obtain 2.28 g of 5- [2- (4-dimethylcarbamoylpiperidin-1-yl) benzoylamino] -isoindoline as a light brown powder. MS (APCI) m / z; 393 (M + H), IR (n
eat) cm ⁻¹ ; 1660, 1635. (5) 1.0 g of the compound obtained in (4) above, (1H-
Pyrazol-1-yl) acetic acid (the compound obtained in Reference Example 36 (2)) 337 mg and 1-hydroxybenzotriazole 362 mg of dimethylformamide (2.5
ml) solution under ice-cooling, 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide / hydrochloride 587 m
g and stir at room temperature for 2.5 hours. A dilute aqueous solution of sodium hydrogencarbonate is added to the reaction solution, stirred for 1 hour, and then extracted with a mixed solvent of ethyl acetate-tetrahydrofuran. The organic layer is washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (developing solvent;
After purification with chloroform: methanol = 50: 1) and recrystallization from ethyl acetate, 2-[(1H-pyrazol-1-yl) acetyl] -5- [2- (4-dimethylcarbamoylpiperidine-1- Il) benzoylamino] -isoindoline (compound obtained in Example 25)
921 mg are obtained as colorless crystals.

Reference Example 1 A suspension of 58.29 g of 2-fluorobenzoic acid and 57.42 g of potassium carbonate in dimethylformamide (500 m
To l), 71.16 g of benzyl bromide is added dropwise under ice cooling. Stir at room temperature for 15 hours. The reaction solution is poured into ice water and extracted with ethyl acetate. The organic layer is washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent is distilled off, and the residue is distilled under reduced pressure to obtain 86.13 g of benzyl 2-fluorobenzoate as a pale yellow oily substance. B. p. (3 mmHg) 152-155 ° C Reference Example 2 (1) Under argon atmosphere, diisopropylamine 1.3
g in tetrahydrofuran (50 ml) under ice cooling,
1.6 Mn-butyllithium-hexane solution (8 ml)
Is added dropwise and stirred for 15 minutes. The reaction solution was cooled to −78 ° C., and 3.0 g of ethyl N-tert-butoxycarbonyl-isonipecotinate solution in tetrahydrofuran (25 m
l) is added dropwise and stirred for 1 hour. To the reaction solution, 1.03 g of tetrahydrofuran (25 m of methoxymethyl chloride)
l) Add the solution dropwise. The reaction solution is warmed to room temperature and stirred for 5 hours. The reaction solution is poured into water and extracted with ethyl acetate.
The organic layer is washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (developing solvent; n-hexane: ethyl acetate =
Purification with 6: 1) gives 2.25 g of 1-tert-butoxycarbonyl-4-ethoxycarbonyl-4-methoxymethylpiperidine as a colorless oil. MS (APCI) m / z; 302 (M + H), IR (n
eat) cm ⁻¹ ; 1731, 1694. (2) Sodium hydroxide 1.46 was added to a solution of 2.2 g of the compound obtained in (1) above in ethanol (11.7 ml).
A solution of g in water (5.84 ml) is added, and the mixture is heated under reflux for 12 hours. The reaction solution is cooled to room temperature and then concentrated. Water is added to the residue, the solution is made acidic with diluted hydrochloric acid, and extracted with chloroform. The organic layer is washed with saturated brine and dried over anhydrous sodium sulfate. By distilling off the solvent, 1-tert
2.1 g of butoxycarbonyl-4-carboxy-4-methoxymethylpiperidine are obtained as colorless oil. MS (ESI) m / z; 272 (MH), IR (ne
at) cm ⁻¹ ; 3076, 1732, 1696, 16
51. (3) A solution of 500 mg of the compound obtained in (2) above, 0.434 ml of diphenylphosphoric acid azide and 0.28 ml of triethylamine in toluene (5 ml) is heated under reflux for 30 minutes. The reaction solution is cooled to room temperature and then washed with water and saturated saline. After drying over anhydrous sodium sulfate, the solvent was evaporated, and the residue was purified by silica gel column chromatography (developing solvent; n-hexane: ethyl acetate = 5: 1) to give 1-tert-butoxycarbonyl-4-.
Isocyanato-4-methoxymethylpiperidine 443m
g as a colorless oil. MS (APCI) m / z; 271 (M + H), IR (n
eat) cm ⁻¹ ; 1695, 1590. (4) Toluene (3 ml) containing 300 mg of the compound obtained in (3) above and 0.126 ml of benzyl alcohol
The solution is heated to reflux for 48 hours. After cooling the reaction solution to room temperature, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (developing solvent; n-hexane: ethyl acetate = 4:
1-tert-butoxycarbonyl-4-benzyloxycarbonylamino-4-by purification in 1)
335 mg of methoxymethylpiperidine are obtained as a colorless oil. MS (APCI) m / z; 379 (M + H), IR (n
eat) cm ⁻¹ ; 1809, 1723, 1694, ¹
674. (5) 9.4 g and 10 of the compound obtained in (4) above
% Palladium-carbon 1.9 g of methanol (190 m
l) The suspension is stirred under hydrogen atmosphere at room temperature and atmospheric pressure for 2 hours. By removing the catalyst by filtration and concentrating the filtrate, 1-t
6.02 g of ert-butoxycarbonyl-4-amino-4-methoxymethylpiperidine are obtained as a colorless oil. MS (APCI) m / z; 245 (M + H), IR (n
eat) cm ⁻¹ ; 3367, 3301, 1692. (6) To a solution of 9.4 g of the compound obtained in (5) above in methanol (45 ml) was added a 4M hydrochloric acid-dioxane solution (45
(ml) and the mixture is stirred at room temperature for 1 hour. After the reaction solution was concentrated, the residue was triturated with diethyl ether to give a powder.
4.20 g of 4-amino-4-methoxymethylpiperidine dihydrochloride are obtained as colorless crystals. M. p. 266-268 ° C. Reference Example 3 1.541 g of methyl 2-fluorobenzoate, 1.519 g of 4-hydroxypiperidine, 2.8 triethylamine.
0 ml of 1,3-dimethyl-2-imidazolidinone (1
0 ml) solution is heated at 100 ° C. for 17 hours. The reaction solution is poured into water and extracted with ethyl acetate. The organic layer is washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (developing solvent; n-hexane: ethyl acetate = 1: 1 → 1 :).
Purification in 2) gives 1.344 g of methyl 2- (4-hydroxypiperidin-1-yl) benzoate as a yellow oil. MS (APCI) m / z; 236 (M + H), IR (n
eat) cm ⁻¹ ; 1713, 1597. Reference Example 4 To a solution of 25.75 g of benzyl 2-fluorobenzoate and 21.98 g of ethyl isonipecotate in dimethylformamide (100 ml), 23.18 g of potassium carbonate was added, and the mixture was stirred at 80 ° C. for 20 hours. The reaction solution is poured into ice water and extracted with ethyl acetate. The organic layer is washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (developing solvent; ethyl acetate: n-hexane = 1: 10) to give benzyl 2- (4-ethoxycarbonylpiperidin-1-yl) benzoate 20. 0.41 g is obtained as a pale yellow oil. MS (APCI) m / z; 368 (M + H). Reference Example 5-14 The corresponding starting material compound is treated in the same manner as in Reference Example 3 or Reference Example 4 to obtain the compounds shown in Table 7.

[0174]

[Table 10]

[0175]

[Table 11]

Reference Example 15 Methyl 2- (4-hydroxypiperidin-1-yl) benzoate (the compound obtained in Reference Example 3) 282 mg, benzyl bromide 186 μl of tetrahydrofuran (2.4 m)
l) Sodium hydride (63 mg) was added to the solution, and the mixture was stirred at room temperature for 3 days.
Stir for hours. Dimethyl sulfoxide 256μ in the reaction solution
1 and stir for a further 48 hours. After 24 hours, add 63 mg of sodium hydride. Pour the reaction solution into water,
Extract with ethyl acetate. The organic layer is washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (developing solvent;
Purification with n-hexane: ethyl acetate = 4: 1) gives 69 mg of methyl 2- (4-benzyloxypiperidin-1-yl) benzoate as a yellow oil. MS (APCI) m / z; 326 (M + H), IR (n
eat) cm ⁻¹ ; 1724, 1597. Reference Example 16 By treating the corresponding starting material compound in the same manner as in Reference Example 15, compounds shown in Table 8 are obtained.

[0177]

[Table 12]

Reference Example 17 (1) 2- (4-ethoxycarbonylpiperidine-1-
Yl) Benzyl benzoate (4.77 g), a mixed solution of 1M aqueous sodium hydroxide solution (13 ml) in ethanol (25 ml) -tetrahydrofuran (10 ml) is stirred at room temperature for 5 hours. A 2 molar equivalent aqueous citric acid solution is added to the reaction solution, and the mixture is extracted with ethyl acetate. The organic layer was extracted with an aqueous sodium hydrogen carbonate solution, and the pH of the obtained aqueous layer was adjusted to 4 with citric acid.
After adjusting to -5, sodium chloride is added and the mixture is extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, and the solvent is evaporated to obtain 2.59 g of benzyl 2- (4-carboxypiperidin-1-yl) benzoate as a colorless oil. MS (ESI) m / z; 338 (M-
H), IR (neat) cm < ^-1 >; 1704. (2) To a solution of 1.295 g of the compound obtained in (1) above in toluene (15 ml) was added diphenylphosphoric azide 1.1.
58 g and 585 μl of triethylamine are added, and the mixture is heated under reflux for 2.5 hours. Tert-butyl alcohol (30 ml) is added to the reaction solution, and the mixture is heated under reflux for 44 hours. The reaction mixture is diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was subjected to silica gel column chromatography (developing solvent; n-hexane: ethyl acetate =).
By purifying with 10: 1 → 5: 1), 2- (4-
tert-Butoxycarbonylaminopiperidine-1-
Yl) 1.008 g of benzyl benzoate is obtained as a colorless oil. MS (APCI) m / z; 411 (M + H), IR (N
ujol) cm ⁻¹ ; 1716, 1677. (3) To a solution of 1.008 g of the compound obtained in (2) above in tetrahydrofuran (15 ml), 117 mg of sodium hydride is added in several batches under ice cooling, and the mixture is stirred at room temperature for 1 hour. 183 μl of methyl iodide is added to the reaction solution, and the mixture is stirred at room temperature for 46 hours. After 18.5 hours add 550 μl of methyl iodide. The reaction solution is heated to 40 ° C., 550 μl of methyl iodide is added after 3 hours, and the mixture is stirred for 3 days. The reaction mixture is diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. Evaporate the solvent,
The residue was subjected to silica gel column chromatography (developing solvent; n-hexane: ethyl acetate = 90: 10 → 50: 5).
2) [2- (4- (tert-butoxycarbonyl-methyl-amino) piperidine-1-
Ill] a mixture of benzyl benzoate and by-products is obtained.

Reference Example 18 2- (4-amino-4-methoxymethylpiperidine-1)
-Yl) benzyl benzoate (the compound obtained in Reference Example 8) 312 mg and triethylamine 0.245 ml
0.094 ml of acetyl chloride was added to a methylene chloride (7 ml) solution of under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution is poured into water and extracted with chloroform. Water organic layer,
The extract is washed with saturated saline and dried over anhydrous sodium sulfate.
The solvent was distilled off, and the residue was subjected to silica gel column chromatography (developing solvent; n-hexane: ethyl acetate = 1: 4).
2- (4-acetylamino-4)
312 mg of benzyl-methoxymethylpiperidin-1-yl) benzoate are obtained as a pale yellow resinous product. MS (APCI) m / z; 397 (M + H), IR (n
eat) cm ⁻¹ ; 3310, 1720, 1655. Reference Example 19 (1) 820 mg of 2- (piperazin-1-yl) -benzonitrile (the compound obtained in Reference Example 11) was mixed with ethanol (2
0 ml) and slowly add 2 ml of concentrated sulfuric acid while stirring under ice cooling. The reaction mixture is heated and stirred for 4 days. The reaction mixture is cooled, made basic with a saturated aqueous sodium hydrogen carbonate solution, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 825 mg of ethyl 2- (piperazin-1-yl) -benzoate as a pale yellow oil. MS (APCI) m / z; 235 (M + H), IR (ne
at) cm ⁻¹ ; 1717, 1259, 1227. (2) 800 mg of the compound obtained in (1) above and 500 mg of triethylamine in tetrahydrofuran (15
ml) solution, di-tert-butyl dicarbonate 9
A solution of 00 mg of tetrahydrofuran (5 ml) is added dropwise at room temperature. The reaction mixture is stirred at room temperature for 20 hours, poured into water and extracted with ethyl acetate. The organic layer is washed with saturated saline and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, it was purified by silica gel column chromatography (developing solvent; chloroform) to give 2- (4-
1.078 g of ethyl tert-butoxycarbonylpiperazin-1-yl) benzoate is obtained as a pale yellow oil. MS (APCI) m / z; 335 (M + H), IR (ne
at) cm ⁻¹ ; 1697. Reference Example 20 A solution of methyl 2- (4-benzyloxypiperidin-1-yl) benzoate (the compound obtained in Reference Example 15) (56 mg) and a 1M aqueous sodium hydroxide solution (0.35 ml) in methanol (1.7 ml) at 60 ° C. For 21 hours. The reaction solution is concentrated to obtain 2- (4-benzyloxypiperidin-1-yl) benzoic acid sodium salt as a crude product. The compound is used in the next reaction without purification.

Reference Example 21 2- (4-Ethoxycarbonylpiperidin-1-yl)
Benzyl benzoate (compound obtained in Reference Example 4) 5.3
7 g and 2.5 g of 5% palladium-carbon are suspended in ethanol (100 ml), and the mixture is stirred under a hydrogen atmosphere at room temperature and atmospheric pressure for 1 hour. The catalyst was filtered off, and the filtrate was concentrated to give 2- (4-ethoxycarbonylpiperidine-1-
Il) benzoic acid 4.08 g is obtained as a colorless solid. MS (ESI) m / z; 276 (MH), IR (ne
at) cm ⁻¹ ; 1730, 1685. Reference Examples 22-34 The corresponding raw material compounds are treated in the same manner as in Reference Example 20 or Reference Example 21, to obtain the compounds shown in Table 9.

[0181]

[Table 13]

[0182]

[Table 14]

[0183]

[Table 15]

Reference Example 35 (1) A solution of tert-butyl bromoacetate (5.00 g) in dimethylformamide (20 ml) was added with pyrazole 2.0.
9 g and 7.07 g potassium carbonate are added. 1 at room temperature
After stirring for 3.5 hours at 50 ° C., the reaction solution is poured into water,
Extract with ethyl acetate. The organic layer is washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent; ethyl acetate: n-hexane = 1: 3) to give (1H-pyrazol-1-yl) acetic acid te.
4.23 g of rt-butyl are obtained as a colorless oil. (2) 4M hydrochloric acid-dioxane solution 2 was added to a solution of 4.21 g of the compound obtained in (1) above in dioxane (10 ml).
Add 5 ml and stir at room temperature for 12 hours. Diethyl ether was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour, and the precipitated powder was collected by filtration and dried under reduced pressure to give (1H-pyrazol-1-yl) acetic acid hydrochloride (3.50 g) as a colorless powder. obtain.

Reference Example 36 (1) 170 g of pyrazole and 260 m of methyl bromoacetate
1 and 414 g of potassium carbonate in acetone were added to 2
Heat to reflux for 5 hours. After cooling to room temperature, the insoluble matter is filtered off, and the filtrate is concentrated under reduced pressure. By distilling the residue,
580 g of methyl (1H-pyrazol-1-yl) acetate are obtained. B. p. 105-120.0 ° C. (15 mmHg) (2) 219 g of the compound obtained in (1) above is dissolved in 2M aqueous hydrochloric acid solution (1.5 L) and heated under reflux for 2 hours. The reaction solution is concentrated under reduced pressure to 500 ml, pH is adjusted to 0.5-0.6 by adding potassium carbonate under ice cooling, and the formed precipitate is collected by filtration and dried under reduced pressure. Recrystallization from tetrahydrofuran gives 127.3 g of (1H-pyrazol-1-yl) acetic acid. M. p. 171-172 ° C. Reference Example 37 (1) Isoindoline 22.43 g of methanol (10
The solution (0 ml) was cooled in a dry ice-acetone bath, 20.47 g of concentrated sulfuric acid was added dropwise thereto, diethyl ether was added, and the precipitated powder was collected by filtration. After drying under reduced pressure, the obtained powder is dissolved in 220 ml of concentrated sulfuric acid, and 15.8 ml of concentrated nitric acid is added dropwise under ice cooling. After stirring for 2.5 hours, the mixture is poured into ice water, sodium hydroxide (added as a solid) is added to make the mixture basic, and the mixture is extracted with ethyl acetate. Water organic layer,
After washing with saturated saline, it was dried over anhydrous sodium sulfate, and the solvent was distilled off to give 5-nitroisoindoline 2
3.0 g are obtained as crude product. (2) Di-ter was added to a solution of 2.62 g of the compound obtained in (1) above in tetrahydrofuran (40 ml) under ice cooling.
A solution of 3.86 g of t-butyl dicarbonate in tetrahydrofuran (10 ml) is added dropwise, and the mixture is stirred for 1.5 hours.
The solvent is distilled off, ethyl acetate is added to the residue, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent is distilled off. The residue was purified by silica gel column chromatography (developing solvent; n-hexane: ethyl acetate = 4: 1) and recrystallized from a mixed solution of n-hexane-ethyl acetate to give 5-nitro-2- (tert- 3.09 g of butoxycarbonyl) -isoindoline are obtained. M. p. 159-160 ° C. (3) 3.46 g and 1 of the compound obtained in the above (2)
A suspension of 0% palladium-carbon (340 mg) in tetrahydrofuran (50 ml) was stirred at room temperature under atmospheric pressure at room temperature for 1 hour.
Stir for hours. After removing the catalyst by filtration and concentrating the filtrate, the residue was purified by silica gel column chromatography (developing solvent; n-hexane: ethyl acetate = 1: 1).
5-amino-2- (tert-butoxycarbonyl)-
3.05 g of isoindoline is obtained as a colorless oil.

Reference Example 38 (1) A suspension of 6.60 g of 5-nitro-2- (tert-butoxycarbonyl) -isoindoline (the compound obtained in Reference Example 37 (2)) in dioxane (25 ml) was added,
4M hydrochloric acid-dioxane solution (40 ml) is added, and the mixture is stirred at room temperature overnight. Diethyl ether was added and the deposited precipitate was collected by filtration to obtain 5.50 g of 5-nitro-isoindoline hydrochloride as a crude product. (2) 4.72 g of the compound obtained in the above (1), (1H
-Pyrazol-1-yl) acetic acid / hydrochloride 2.89 g, 4
1-ethyl-3- (3-dimethylaminopropyl) in a solution of 30 mg of dimethylaminopyridine and 9 ml of triethylamine in dimethylformamide (70 ml).
-Add 4.90 g of carbodiimide-hydrochloride and stir overnight at room temperature. The reaction solution was poured into ice water, and the precipitated powder was collected by filtration, dried and recrystallized from a mixed solution of chloroform-methanol to give 5-nitro-2- (1H-pyrazol-1-yl) acetyl-isoindoline. 5.31 g
Is obtained as colorless crystals. M. p. 247-248 ° C. (3) A suspension of 1.005 g of the compound obtained in (2) above and 98 mg of 10% palladium-carbon in acetic acid (15 ml) is stirred under a hydrogen atmosphere at room temperature and atmospheric pressure for 1 hour.
The catalyst was removed by filtration, the filtrate was concentrated, and the residue was recrystallized with a mixed solution of chloroform-methanol to give 759 mg of 5-amino-2- (1H-pyrazol-1-yl) acetyl-isoindoline as colorless crystals. Get as. M. p. 218-219 ° C

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) C07D 403/06 C07D 403/06 (72) Inventor Koichi Nagata 1-18-5 Tajima, Saitama City Saitama Prefecture DeHeights Nishiurawa Room 202 (72) Inventor Hidenori Iwai 2-3 Kawagishi, Toda City, Saitama Prefecture F-reference (reference) 4C063 AA01 AA03 BB04 BB09 CC22 CC29 DD07 EE01 4C086 AA01 AA03 AA04 BC36 BC42 BC50 GA07 MA01 MA04 NA14 ZA14 ZA54 ZA70 ZC33 ZC35

Claims (17)

[Claims] 1. A compound represented by the general formula [I]: (In the formula, ring A is an optionally substituted nitrogen-containing aliphatic heterocyclic group, Q is —CO— or —CH ₂ —, and R is a lower group substituted by an optionally substituted heterocyclic group. An isoindoline derivative represented by (representing an alkyl group) or a pharmaceutically acceptable salt thereof. 2. A nitrogen-containing aliphatic heterocyclic group in which ring A may be substituted with a group selected from the following: (1) a lower alkyl group optionally substituted with an aryl group or a lower alkoxy group, (2) an aryl group which may be substituted with a lower alkyl group or a cyano group, (3) a lower alkoxy group which may be substituted with an aryl group,
(4) Formyl group, (5) carboxyl group, (6) lower alkoxycarbonyl group optionally substituted with aryl group, (7) lower alkanoyl group optionally substituted with aryl group, (8) arylsulfonyl group Group, (9) lower alkylsulfonyl group, (10) lower alkanoyl group; aryl lower alkanoyl group; arylcarbonyl group; lower alkoxycarbonyl group; aryl lower alkoxycarbonyl group; aryloxycarbonyl group; arylsulfonyl group; lower alkylsulfonyl group A lower alkyl group; a pyridyl group; a pyrazinyl group; a pyrimidinyl group; and an amino group which may be substituted with a group selected from a pyridazinyl group, (11) Formula: —CONR ³ R ⁴ (in the formulas, R ³ and R ⁴ May be the same or different and each is a hydrogen atom. , An alkyl group, an aryl lower alkyl group, a pyridyl lower alkyl group, a pyridyl group and an aryl group), and a compound represented by the formula (12): (In the formula, n represents an integer of 0 to 3), R
Is a lower alkyl group substituted with a heterocyclic group which may be substituted with a group selected from the following: (1) lower alkyl group, (2) lower alkoxy group,
(3) lower alkoxycarbonyl group, (4) carboxyl group, (5) lower alkanoyl group, (6) cyano group,
(7) optionally protected hydroxyl group, (8) optionally protected amino group, (9) nitro group, and (1
The compound according to claim 1, which is 0) a halogen atom. 3. The nitrogen-containing aliphatic heterocyclic group in ring A is a 3- to 8-membered aliphatic heterocyclic group containing 1 or 2 nitrogen atoms, and the heterocyclic group in R is 1 to 4 3. A monocyclic or bicyclic heterocyclic group containing 1 nitrogen atom, wherein the aryl group in ring A is a 1 to 3 ring aryl group.
The described compound. 4. The nitrogen-containing aliphatic heterocyclic group in ring A is an aziridinyl group, an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholino group,
Azepanyl group or diazepanyl group, the heterocyclic group in R is a pyrrolyl group, pyrazolyl group, imidazolyl group, triazolyl group, tetrazolyl group, oxazolyl group, thiazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, indolyl group, The compound according to claim 2, wherein the quinolyl group, isoquinolyl group or benzimidazolyl group, and the aryl group in the ring A or R is a phenyl group, a naphthyl group, an anthryl group or a phenanthryl group. 5. Ring A is of the formula: (In the formula, R ¹ is (1) a hydrogen atom, (2) a lower alkyl group optionally substituted with a phenyl group, (3) a lower alkyl group or a phenyl group optionally substituted with a cyano group, ( 4) a lower alkoxy group which may be substituted with a phenyl group, (5) formyl group, (6) carboxyl group,
(7) Lower alkoxycarbonyl group optionally substituted with phenyl group, (8) Lower alkanoyl group optionally substituted with phenyl group, (9) Benzenesulfonyl group, (10) Lower alkylsulfonyl group, (11 ) Lower alkanoyl group; phenyl lower alkanoyl group; phenylcarbonyl group; lower alkoxycarbonyl group; phenyl lower alkoxycarbonyl group; phenyloxycarbonyl group; phenylsulfonyl group; lower alkylsulfonyl group; lower alkyl group; pyridyl group; pyrazinyl group; pyrimidinyl Group; and an amino group which may be substituted with a group selected from a pyridazinyl group, (12) Formula: —CONR ³ R ⁴ (In the formula, R ³ and R ⁴ may be the same or different, and each is a hydrogen atom. , An alkyl group, a phenyl lower alkyl group, A group represented by a pyridyl lower alkyl group, a pyridyl group and a phenyl group) or a compound represented by the formula (13): (In the formula, n represents an integer of 0 to 3), R ²
Represents a hydrogen atom or a lower alkoxy lower alkyl group), Q is —CO—, and R is a group represented by the following formula: (In the formula, m represents an integer of 1 to 3, W represents a pyrazolyl group which may be substituted with a group selected from the following: (1) lower alkyl group, (2) lower alkoxy group,
(3) lower alkoxycarbonyl group, (4) carboxyl group, (5) lower alkanoyl group, (6) cyano group,
(7) optionally protected hydroxyl group (8) optionally protected amino group, (9) nitro group, and (10)
The compound according to claim 4, which is a group represented by a halogen atom). 6. Ring A is of the formula: (In the formula, R ¹ is (1) a hydrogen atom, (2) a lower alkyl group optionally substituted with a phenyl group, (3) a lower alkyl group or a phenyl group optionally substituted with a cyano group, ( 4) a lower alkoxy group which may be substituted with a phenyl group, (5) formyl group, (6) carboxyl group,
(7) Lower alkoxycarbonyl group optionally substituted with phenyl group, (8) Lower alkanoyl group optionally substituted with phenyl group, (9) Benzenesulfonyl group, (10) Lower alkylsulfonyl group, (11 ) Lower alkanoyl group; phenyl lower alkanoyl group; phenylcarbonyl group; lower alkoxycarbonyl group; phenyl lower alkoxycarbonyl group; phenyloxycarbonyl group; benzenesulfonyl group; lower alkylsulfonyl group; lower alkyl group; pyridyl group; pyrazinyl group; pyrimidinyl Group; and an amino group which may be substituted with a group selected from a pyridazinyl group, (12) Formula: —CONR ³ R ⁴ (In the formula, R ³ and R ⁴ may be the same or different, and each is a hydrogen atom. , An alkyl group, a phenyl lower alkyl group, A pyridyl lower alkyl group, a pyridyl group, and a phenyl group) or a compound of the formula (13): (In the formula, n represents an integer of 0 to 3), R is a group represented by the formula: The compound according to claim 5, which is a group represented by: 7. R ¹ is (1) hydrogen atom, (2) phenyl lower alkyl group, (3) phenyl group, (4) lower alkoxy group optionally substituted by phenyl group, (5) formyl group , (6) lower alkoxycarbonyl group optionally substituted with phenyl group, (7) benzenesulfonyl group, (8) lower alkoxycarbonyl group; phenyl lower alkoxycarbonyl group; phenyloxycarbonyl group; and pyrimidinyl group An amino group which may be substituted with a group, (9) formula: —CONR ³ R ⁴ (in the formula, R ³ and R ⁴ may be the same or different, and each is a group selected from an alkyl group and a phenyl group; Or the formula (10): The compound according to claim 6, which is a group represented by the formula (wherein n represents 1 or 2). 8. R ¹ is (1) phenyl lower alkyl group, (2) phenyl lower alkoxy group, (3) phenyl lower alkoxycarbonyl group, (4) formula: —CONR ³ R ⁴ (wherein R ³ And R ⁴ may be the same or different and each represents a group selected from an alkyl group), or a group represented by the formula (5): The compound according to claim 6, which is a group represented by: 9. R ¹ is (1) a phenyl lower alkyl group, (2) a phenyl group optionally substituted with a lower alkyl group, (3) a lower alkoxy group optionally substituted with a phenyl group, ( 4) phenyl lower alkoxycarbonyl group, (5) benzenesulfonyl group, (6) lower alkylsulfonyl group, (7) phenylcarbonyl group; lower alkoxycarbonyl group; phenyl lower alkoxycarbonyl group; phenyloxycarbonyl group; and lower alkyl group An amino group which may be substituted with a group selected from: (8) Formula: —CONR ³ R ⁴ (In the formula, R ³ and R ⁴ may be the same or different, and each is an alkyl group, a phenyl group and A group selected from a phenyl lower alkyl group),
Or, the formula (9): The compound according to claim 6, which is a group represented by the formula (wherein n represents 1 or 2). 10. R ¹ is (1) phenyl lower alkyl group, (2) phenyl group, (3) lower alkoxy group,
(4) Benzenesulfonyl group, (5) Lower alkylsulfonyl group, (6) Formula: —CONR ³ R ⁴ (In the formula, R ³ and R ⁴ may be the same or different, and each is an alkyl group and a phenyl group. Or a group represented by the formula (7): The compound according to claim 6, which is a group represented by: 11. 2-[(1H-pyrazol-1-yl) acetyl] -5- [2- [4- (N-methyl-Nn]
-Butyl-carbamoyl) piperidin-1-yl] benzoylamino] -isoindoline, 2-[(1H-pyrazol-1-yl) acetyl] -5- [2- (4-dimethylcarbamoylpiperidin-1-yl) benzoyl Amino] -isoindoline, or a pharmacologically acceptable salt thereof. 12. General formula [1]: (Wherein ring A represents an optionally substituted nitrogen-containing aliphatic heterocyclic group), or a salt thereof, and a compound of the general formula [2]: (In the formula, Q represents —CO— or CH ₂ —, and R represents a lower alkyl group substituted with an optionally substituted heterocyclic group), and a compound thereof or a salt thereof is reacted,
If desired, the product may be a pharmacologically acceptable salt, represented by the general formula [I]: (However, the symbols have the same meanings as described above), and a method for producing an isoindoline derivative or a pharmaceutically acceptable salt thereof. 13. General formula [3]: embedded image (In the formula, Y is a halogen atom, Q is -CO- or CH.
_2- , R represents a lower alkyl group substituted with an optionally substituted heterocyclic group) or a salt thereof, and a compound represented by the general formula [4]: (Wherein, ring A represents an optionally substituted nitrogen-containing aliphatic heterocyclic group) or a salt thereof is reacted with the product to form a pharmacologically acceptable salt, if desired. A compound of the general formula [I]: (However, the symbols have the same meanings as described above), and a method for producing an isoindoline derivative or a pharmaceutically acceptable salt thereof. 14. A compound represented by the general formula [5]: (Wherein ring A represents an optionally substituted nitrogen-containing aliphatic heterocyclic group) or a salt thereof, and a compound of the general formula [6]: (Wherein, R represents a lower alkyl group substituted with an optionally substituted heterocyclic group) or a carboxylic acid compound thereof or a salt thereof is reacted, and the product is optionally pharmacologically acceptable. And a general formula [I-
a]: (However, the symbols have the same meanings as described above), and a method for producing an isoindoline derivative or a pharmaceutically acceptable salt thereof. 15. A compound represented by the general formula [Ia]: (Wherein ring A represents an optionally substituted nitrogen-containing aliphatic heterocyclic group, R represents a lower alkyl group substituted by an optionally substituted heterocyclic group) or a compound thereof A compound of the general formula [Ib]: embedded image characterized in that the salt is subjected to a reduction reaction and, if desired, the product is made into a pharmacologically acceptable salt. (However, the symbols have the same meanings as described above), and a method for producing an isoindoline derivative or a pharmaceutically acceptable salt thereof. 16. A compound represented by the general formula [5]: (Wherein ring A represents an optionally substituted nitrogen-containing aliphatic heterocyclic group) or a salt thereof, and a compound of the general formula [7]: (Wherein R represents a lower alkyl group substituted with an optionally substituted heterocyclic group, X represents a leaving group) or a salt thereof, and the product is optionally pharmacologically reacted. Of the general formula [I
-B]: (However, the symbols have the same meanings as described above), and a method for producing an isoindoline derivative or a pharmaceutically acceptable salt thereof. 17. A compound represented by the general formula [5]: (Wherein ring A represents an optionally substituted nitrogen-containing aliphatic heterocyclic group) or a salt thereof, and a compound of the general formula [8]: (Wherein R represents a lower alkyl group substituted with an optionally substituted heterocyclic group) or a salt thereof is subjected to a condensation reaction, then subjected to a reduction reaction, and optionally formed. Wherein the compound is a pharmacologically acceptable salt, a compound of the general formula [Ib]: (However, the symbols have the same meanings as described above), and a method for producing an isoindoline derivative or a pharmaceutically acceptable salt thereof.