JP2003231635A - Medicinal composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a medicinal composition having excellent apolipoprotein B (ApoB) antisecretory action and serum lipid lowering action and useful for preventing and treating hyperlipemia. <P>SOLUTION: This medicinal composition comprises a benzoylaminoisoindoline derivative represented by formula [I] (wherein the ring A is a 5 or 6-membered aromatic heterocyclic group which may be substituted; the ring B is a benzene ring which may be substituted; Q is CO or CH<SB>2</SB>; R is a lower alkyl group which may be substituted, a carbamoyl group which may be substituted, a heterocyclic group which may be substituted or an aryl group, or the like, which may be substituted) or its pharmacologically acceptable salt as an active ingredient. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a pharmaceutical composition comprising a benzoylaminoisoindoline derivative or a pharmacologically acceptable salt thereof having an excellent apolipoprotein B (ApoB) secretion inhibitory action and serum lipid lowering action as an active ingredient. Regarding

[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 are aromatic in the carboxylic acid moiety such as the compound of the present invention. Compounds having a heterocycle-phenyl group and compounds having an isoindoline ring in the amine part are not described.

[0004]

DISCLOSURE OF THE INVENTION The present invention provides a pharmaceutical composition comprising a novel benzoylaminoisoindoline derivative having a superior apolipoprotein B secretion inhibitory action and a serum lipid lowering action or a pharmaceutically acceptable salt thereof as an active ingredient. It is to provide things.

[0005]

The present invention has the general formula [I]

[0006]

[Chemical 6]

(Wherein, ring A is an optionally substituted 5- or 6-membered aromatic heterocyclic group, ring B is an optionally substituted benzene ring, Q is -CO- or -CH _2- , R is an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted carbamoyl group, an optionally substituted heterocyclic group, or an optionally substituted aryl The present invention provides a pharmaceutical composition comprising a benzoylaminoisoindoline derivative represented by a group) or a pharmacologically acceptable salt thereof as an active ingredient.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION In the compound [I] which is the active ingredient of the present invention, examples of the substituent on ring A include
(1) a trialkyl group, (2) a hydroxyl group, an oxo group, and a lower alkyl group optionally substituted by 1 to 3 groups which are the same or different and are selected from a hydroxyimino group, (3) a lower alkoxy group, The same or different 1 to 3 selected from a hydroxyl group and a di-lower alkylamino group
Lower alkoxy group optionally substituted with one group,
(4) hydroxyl group, (5) nitro group, (6) cyano group,
(7) a carbamoyl group optionally substituted with a group selected from a lower alkyl group, a lower alkoxy lower alkyl group, a halogeno lower alkyl group, and an aryl lower alkyl group, (8) an amino group protecting group, a lower alkyl group, And an amino group which may be substituted with a group selected from a lower alkylsulfonyl group, (9) a lower alkanoyloxy group which may be substituted with an aryl group, and (10) a lower alkoxycarbonyl group.

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

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

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

In the compound [I] which is the active ingredient of the present invention, the substituent on the ring B is, for example, (1) nitro group, (2) hydroxyl group, (3) lower alkoxy group, hydroxyl group,
Aryl group, (lower alkylamino) aryl group, lower alkoxycarbonyl group, lower alkenyloxycarbonyl group, carboxyl group, amino group, lower alkylamino group, lower alkylcarbamoyl group, cyano group, pyridyl group, pyrrolidinyl group, morpholinyl group, A lower alkoxy group which may be substituted with a group selected from a piperazinyl group and a lower alkylpiperazinyl group, (4) a lower alkoxycarbonyl group, (5) (i) a lower alkoxy group, an amino group, a lower alkylamino group , And the same or different 1 selected from lower alkoxycarbonyl groups
A lower alkanoyl group substituted with three groups, (ii) a protecting group for an amino group, (iii) a pyridyl group, or a lower alkyl group optionally substituted with a lower alkylamino group, and (iv) a pyridylcarbonyl group An amino group which may be substituted with a group selected from, a (6) lower alkyl group, a lower alkoxy lower alkyl group, and a carbamoyl group which may be substituted with a group selected from lower alkylamino lower alkyl group, ( 7) Morpholinocarbonyl group, (8) cyano group, (9) lower alkylaminocarbonyloxy group and the like.

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

In the compound [I] which is an active ingredient of the present invention, when R is an optionally substituted lower alkyl group, the substituent on the lower alkyl group is (i) a lower alkyl group; hydroxy lower Alkyl group; lower alkanoyl group; lower alkoxy group; nitro group; lower alkoxycarbonyl group; carboxyl group; oxo group; trifluoromethyl group; carbamoyl group (wherein the carbamoyl group is a lower alkyl group, a halogeno lower alkyl group, and a hydroxy lower alkyl An amino group (which may be substituted with a group selected from the group); the amino group is a lower alkanoyl group, a lower alkoxy lower alkanoyl group, a lower alkyl group, a hydroxy lower alkyl group, a lower alkoxycarbonyl group, and a lower alkylaminoalkylidene. Substituted with a group selected from the group A cyano group; an optionally protected hydroxyl group; a halogen atom; and a heterocyclic group which may be substituted with 1 to 3 identical or different groups selected from formyl groups, (ii) lower Alkyl group; amino group (wherein the amino group is a lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkyl group, a pyridyl lower alkyl group, a lower alkylaminocarbonyl group, a halogeno lower alkylaminocarbonyl group, a lower alkanoyl group,
Or a halogeno lower alkanoyl group may be substituted); lower alkoxy group; aryl lower alkoxy group; benzyloxy lower alkoxy group; lower alkylamino lower alkoxy group; nitro group; optionally protected hydroxyl group; lower alkylcarbamoyl Group; halogeno lower alkylcarbamoyl group; and aryl group or fluorenyl group, which may be substituted with 1 to 3 same or different groups selected from morpholinyl group, (iii)
A carbamoyl group optionally substituted with a group selected from an optionally protected hydroxyl group, (iv) lower alkyl group, halogeno lower alkyl group, and benzothiazolyl group, (v) formula:

[0015]

[Chemical 7]

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

The lower alkyl group for R is the above (i).
It may be substituted with 1 to 3 groups that are the same or different and are selected from to (ix).

In the compound [I] which is the active ingredient of the present invention, when R is a lower alkenyl group which may be substituted, examples of the substituent on the lower alkenyl group include an aryl group and the like.

In the compound [I] which is an active ingredient of the present invention, when R is an optionally substituted carbamoyl group, the substituent on the carbamoyl group is a lower alkyl group, a halogeno lower alkyl group or a benzothiazolyl group. Etc. Further, the carbamoyl group which may be substituted has a formula:

[0020]

[Chemical 8]

(In the formula, m represents an integer of 0 to 4) and the like.

In the compound [I] which is an active ingredient of the present invention, when R is an optionally substituted heterocyclic group, the substituent on the heterocyclic group is a lower alkyl group,
Examples thereof include a lower alkoxy group, a lower alkoxycarbonyl group, an amino group, a lower alkylamino group, an optionally protected hydroxyl group, and an optionally protected amino group.

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

In the compound [I] which is the active ingredient of the present invention, when R is an optionally substituted heterocyclic group, examples of the heterocyclic group include pyridyl group, indolyl group and thiazolyl group. , Imidazolyl group, pyrrolyl group, pyrimidinyl group, thienyl group, benzo [b] furyl group, benzo [b] thienyl group, pyrazolyl group, triazolyl group, quinolyl group, isoquinolyl group, phthalazinyl group, quinazolinyl group, quinoxalinyl group, 5, 11-dihydro-dibenzo [b, e] [1,4] oxazepine-
Examples include 5-yl group, dihydropyrazolyl group, tetrazolyl group and the like.

In the compound [I] which is the active ingredient of the present invention, when R is an optionally substituted aryl group, the substituent on the aryl group is a lower alkyl group,
Examples thereof include a lower alkoxy group, a lower alkylcarbamoyl group, a halogeno lower alkylcarbamoyl group, a morpholinyl group, an amino group, a lower alkylamino group, an optionally protected hydroxyl group, and an optionally protected amino group.

The aryl group in R may be substituted with 1 to 3 same or different groups selected from the above-mentioned substituents.

In the compound [I] which is the active ingredient of the present invention, when R is an optionally substituted aryl group, specific examples of the aryl group include, for example, phenyl group, naphthyl group, anthryl group, Examples thereof include a phenanthryl group.

The above-mentioned compound [I] which is the active ingredient of the present invention.
In the case of having a protected amino group, examples of the protecting group for the amino group include an optionally substituted lower alkoxycarbonyl group, a lower alkenyloxycarbonyl group, an acyl group, and an optionally substituted aryl group. Examples thereof include a substituted lower alkyl group and a lower alkenyl group, and specific examples include an ethoxycarbonyl group, a methoxycarbonyl group, a tert-butoxycarbonyl group, 2,2,2.
Substitution of an aryl group which may be substituted with a lower alkoxycarbonyl group such as a 2-trichloroethyloxycarbonyl group which may be substituted with a halogen atom, a benzyloxycarbonyl group or a 4-methoxybenzyloxycarbonyl group which may be substituted with a lower alkoxy group Examples thereof include lower alkenyloxycarbonyl groups such as lower alkoxycarbonyl group and allyloxycarbonyl group, and acyl groups such as formyl group, acetyl group, propionyl group and butyryl group. Furthermore, an aryl group-substituted lower alkyl group which may be substituted with a lower alkoxy group such as a benzyl group and a 4-methoxybenzyl group, a lower alkenyl group such as an allyl group, a 9-fluorenylmethoxycarbonyl group and the like can be 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. Further, as the protected amino group,
For example, it also includes the case of forming a phthalimido group together with a protected amino group.

When the compound [I], which is the active ingredient 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 a substituted group. There may be mentioned conventional protecting groups such as lower alkoxycarbonyl group and trialkylsilyl group which may be present. Of these, preferred are, for example, benzyl group, unsubstituted aryl lower alkyl group such as phenethyl group, formyl group, acetyl group, propionyl group, malonyl group, acryloyl group, benzoyl group and other acyl groups, methoxycarbonyl group, Lower alkoxycarbonyl group such as ethoxycarbonyl group, trimethylsilyl group, triethylsilyl group, te
Examples thereof include tri-lower alkylsilyl groups such as rt-butyldimethylsilyl group. Furthermore, a triphenylmethyl group,
A 2-cyanoethyl group and the like can also be mentioned.

As a specific example of the compound [I], for example, in the general formula [I], ring A may be substituted with 1 to 3 groups selected from a trifluoromethyl group and a lower alkanoyl group. It is a 5- or 6-membered aromatic heterocyclic group, ring B is a benzene ring which may be substituted with a lower alkoxycarbonyl group, and Q is -CO- or -CH.
2-, wherein R is a lower alkyl group substituted with a group selected from a 5- to 6-membered heterocyclic group optionally having a substituent (nitro group, lower alkoxycarbonyl group, etc.) and a hydroxyl group Etc.

Among the compounds [I] which are the active ingredients of the present invention, a preferred compound is ring A having the formula:

[0032]

[Chemical 9]

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

Among the compounds [I] which are the active ingredients of the present invention, a more preferred compound is ring A having the formula:

[0035]

[Chemical 10]

And a ring B is a benzene ring,
Examples thereof include a compound in which Q is —CO— and R is a pyrazolylmethyl group which may be substituted with a group selected from a lower alkyl group, a nitro group, a lower alkoxycarbonyl group, and a hydroxy lower alkyl group.

More specific examples of the compound [I] which is the active ingredient of the present invention include 2- (1H-pyrazol-1-yl) acetyl-5- [2- (5-trifluoro). Methyl-pyridin-2-yl) benzoylamino] -isoindoline, 2- (1H-pyrazole-1-
Yl) acetyl-5- [2- (5-trifluoromethyl-pyridin-2-yl) -3-methoxycarbonylbenzoylamino] -isoindoline, 2- [2- (1H-
Pyrazol-1-yl) ethyl] -5- [2- (5-trifluoromethyl-pyridin-2-yl) benzoylamino] -isoindoline or a pharmaceutically acceptable salt thereof.

The compound [I] which is the active ingredient of the present invention is
When the substituent on ring A, the substituent on ring B, and / or R has an asymmetric atom, it can exist as an optical isomer based on the asymmetric atom. It includes any of the mixtures.

The compound [I], which is the active ingredient of the present invention, or a pharmaceutically acceptable salt thereof has an apolipoprotein B secretion inhibitory action and exhibits an excellent serum lipid lowering action.

Therefore, the compound [I] which is the active ingredient of the present invention or a pharmaceutically acceptable salt thereof is
Ischemic heart disease, atherosclerosis, coronary arteriosclerosis, hypercholesterolemia, hypertriglyceridemia, familial hyperlipidemia, hyperlipoproteinemia, arteriosclerosis, coronary atherosclerosis,
It is useful for the prevention and treatment of coronary artery disease, ischemic brain disease, stroke, circulatory / microcirculatory disorders, thrombosis, hyperglycemia, diabetes, acute hemorrhagic pancreatitis, obesity, steatosis, constipation and the like. Furthermore, the compound [I], which is the active ingredient of the present invention, has low toxicity and is highly safe as a medicine.

The compound [I] which is the active ingredient of the present invention is
It can be used in medicinal use either in free form or in the form of a pharmaceutically acceptable salt. Examples of the pharmacologically acceptable salt of the compound [I] include hydrochloride, sulfate,
Inorganic acid salts such as phosphate or hydrobromide, acetate,
Examples thereof include organic acid salts such as fumarate, oxalate, citrate, methanesulfonate, benzenesulfonate, tosylate and maleate. Further, when it has a substituent such as a carboxyl group, a salt with a base (for example, an alkali metal salt such as sodium salt, potassium salt or the like, or an alkaline earth metal salt such as calcium salt) is included.

The compound [I] or a pharmaceutically acceptable salt thereof, which is the active ingredient of the present invention, includes any of its inner salts, adducts, solvates or hydrates thereof.

The compound [I] or a pharmaceutically acceptable salt thereof, which is the active ingredient of the present invention, can be administered orally or parenterally, and can be used as tablets, granules, capsules and powders. It can be used as a conventional pharmaceutical preparation such as an injection, an inhalant and the like.

The dose of the compound [I] or a pharmaceutically acceptable salt thereof, which is the active ingredient of the present invention, varies depending on the administration method, age, weight and condition of the patient. Usually, about 0.01 to 5 mg / kg per day, especially about 0.1 to 3 mg / kg, and usually about 0.1 to 100 mg / kg per day, especially about 0.1 to 50 mg for an oral preparation. / Kg is preferable.

The compound [I] which is the active ingredient of the present invention is
It can be produced by the following [Method A] to [Method H]. [Method A] The compound [I], which is the active ingredient of the present invention, is represented by the general formula [5]:

[0046]

[Chemical 11]

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

[0048]

[Chemical 12]

(However, the symbols have the same meanings as described above.)
It can be produced by reacting with a carboxylic acid compound represented by or a salt thereof.

This reaction is carried out in a solvent (methylene chloride, dimethylformamide, etc.) with a condensing agent (1-ethyl-3- (3-
Dimethylaminopropyl) carbodiimide, hydrochloride, etc.)
In the presence or absence of an activator (1-hydroxybenzotriazole, etc.), or in the presence of a base (triethylamine, 1,8-diazabicyclo [5,4,0] -7-undecene, etc.) It can be carried out in the presence.

The condensing agent can be used in an amount of 1 to 10 equivalents based on the compound [5] or the compound [6]. The activator can be used in an amount of 1 to 10 equivalents based on the compound [5] or the compound [6]. This reaction can be carried out, for example, at 0 to 100 ° C.

Further, the compound [I] can be obtained by converting the compound [6] into a reactive derivative such as an acid chloride and then reacting it with the compound [5] in the presence of a base. [Method B] The compound [I] which is the active ingredient of the present invention also comprises
General formula [15]:

[0053]

[Chemical 13]

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

[0055]

[Chemical 14]

(In the formula, M is the same or different selected from a hydroxyl group, a halogen atom, a cyano group, a lower alkyl group, an aryl group, a lower alkoxy group, an alkylenedioxy group, an aryloxy group, an arylenedioxy group and an arylthio group. Represents a metal which may be coordinated with a substituent,
Other symbols have the same meaning as described above), and can also be produced by reacting with a compound represented by the above.

This reaction is a solvent (methylene chloride, water, etc.)
Medium, in the presence of a catalyst (palladium acetate, tetrakistriphenylphosphine palladium, etc.), in the presence or absence of a base (sodium carbonate, triethylamine, etc.), and in the presence or absence of an additive (triphenylphosphine, etc.) can do. Examples of the metal of M include boron, tin, silicon, zinc, magnesium, aluminum, lithium and nickel.

The amount of the compound [16] used is the same as that of the compound [1].
5] can be used in an amount of 1 to 5 equivalents. The catalyst can be used in an amount of 0.001 to 0.5 equivalent based on compound [15]. The base can be used in an amount of 1 to 20 equivalents based on compound [15]. The additive can be used in an amount of 1 to 10 equivalents based on the compound [15]. This reaction can be carried out, for example, at 0 to 150 ° C.

Examples of the leaving group X ¹ include halogen atom such as chlorine atom or bromine atom, trifluoromethanesulfonyloxy group and the like. [Method C] Of the compound [I] which is the active ingredient of the present invention,
In the general formula [I], a compound in which Q is —CO—, that is, the general formula [Ia]:

[0060]

[Chemical 15]

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

[0062]

[Chemical 16]

(However, the symbols have the same meanings as above)
Manufactured by reacting a compound represented by the formula (1) or a salt thereof with a carboxylic acid compound represented by the general formula [2]: R-COOH [2] (where the symbols have the same meaning as described above) or a salt thereof. You can also

This reaction can be carried out in a solvent, in the presence of a condensing agent, in the presence or absence of an activator, and in the presence or absence of a base. As the solvent, the above-mentioned [A
Method] can be appropriately used as exemplified as the solvent that can be used in the reaction. Also, as a base or activator,
For example, those exemplified in the reaction of the above [Method A] can be appropriately used.

Further, after converting the compound [2] into a reactive derivative such as acid chloride, the compound [13] is added in the presence of a base.
Compound [Ia] can also be obtained by reacting with. [Method D] Of the compound [I] which is the active ingredient of the present invention,
A compound of the general formula [I], in which Q is —CH ₂ —,
That is, the general formula [Ib]:

[0066]

[Chemical 17]

(However, the symbols have the same meanings as described above.)
The benzoylaminoisoindoline derivative represented by
The compound represented by the general formula [Ia] or a salt thereof is treated with a suitable reducing agent (sodium borohydride-boron trifluoride diethyl ether complex, lithium aluminum hydride, etc.) in a solvent (tetrahydrofuran, etc.). Can be manufactured. The reducing agent may be used in an amount of 1 to 10 equivalents based on the compound [Ia]. This reaction can be carried out, for example, at -30 to 100 ° C. [Method E] Of the compound [I] which is the active ingredient of the present invention,
The benzoylaminoisoindoline derivative represented by the general formula [Ib] also includes a compound represented by the general formula [13] or a salt thereof, and a compound represented by the general formula [17]: R-CHO [17] (where the symbols are the same as those described above). It can also be produced by subjecting an aldehyde compound represented by the same meaning) to a condensation reaction with an aldehyde compound or a salt thereof, followed by reduction.

The above condensation reaction can be carried out in a solvent (methylene chloride, water, etc.) in the presence or absence of a base (triethylamine etc.), and the subsequent reduction reaction is carried out in the same solvent as above with a reducing agent ( It can be carried out in the presence of sodium borohydride, etc.).

The amount of the compound [17] used is the same as that of the compound [1].
3] to 1 to 5 equivalents can be used. The base can be used in an amount of 1 to 20 equivalents based on the compound [13]. The amount of the reducing agent used is 1 to the compound [13].
10 equivalents can be used. This reaction is, for example, -3
It can be carried out at 0 to 100 ° C. [Method F] Of the compound [I] which is the active ingredient of the present invention,
The benzoylaminoisoindoline derivative represented by the general formula [Ib] also includes a compound represented by the general formula [13] or a salt thereof, and a compound represented by the general formula [18]: R—CH ₂ —X ² [18] (formula In the above, X ² represents a leaving group, and other symbols have the same meanings as described above), and the compound can also be produced.

In this reaction, the solvent (tetrahydrofuran etc.)
Medium, in the presence of base (potassium carbonate, etc.), additives (sodium iodide, tetraethylammonium chloride, etc.)
Can be carried out in the presence or absence of.

The amount of the compound [18] used is the same as that of the compound [1].
3] can be used in an amount of 1 to 5 equivalents. The base may be used in an amount of 1 to 20 equivalents based on compound [13]. The additive can be used in an amount of 1 to 10 equivalents based on the compound [13]. This reaction can be carried out, for example, at -30 to 150 ° C.

Examples of the leaving group X ² include a halogen atom such as a bromine atom or an iodine atom, a trifluoromethanesulfonyloxy group, a hydroxyl group and the like.

When the leaving group X ² is a hydroxyl group, a Mitsunobu reagent such as triphenylphosphine-diethylazodicarboxylate can be used. [Method G] Of the compound [I] which is the active ingredient of the present invention,
General formula [Ic]:

[0074]

[Chemical 18]

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

[0076]

[Chemical 19]

(However, the symbols have the same meanings as above)
It can be produced by reacting with a compound represented by

This reaction can be carried out in a solvent (such as methanol) in the presence of a base (such as triethylamine) and in the presence or absence of an additive (such as ammonium chloride). [Method H] Of the compound [I] which is the active ingredient of the present invention,
General formula [Id]:

[0079]

[Chemical 20]

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

[0081]

[Chemical 21]

(However, the symbols have the same meanings as above)
It can be produced by reacting with a compound represented by

This reaction can be carried out in a solvent (such as methanol) in the presence or absence of a base (such as triethylamine) or an acid (such as acetic acid).

The compound [I] which is the active ingredient of the present invention is
Substituent on ring A, ring B of the compound obtained as described above
It can also be produced by converting the above substituent and / or group R into another desired substituent. Such a method for converting a substituent may be appropriately selected depending on the kind of the desired substituent, and for example, (method a) to (i method)
Can be implemented as follows.

(Method a: Alkylation of amino group (reductive amination)) Substituent containing a lower alkylamino group (eg dimethylamino group) which may be substituted for the group R in the general formula [I]. The compound [I] is a compound [I] corresponding to the corresponding compound [I], which is a substituent in which the group R contains an unprotected primary or secondary amino group, and the above-mentioned [Method E]. It can be manufactured by treating in the same manner as.

(Method b: Oxidation of carbonyl group) In the compound [I] in which the substituent on ring A in the general formula [I] is a substituent containing an oxime, the substituent on ring A has a carbonyl group. It can be produced by reacting the corresponding compound [I], which is a substituent contained, with hydroxylamine by a conventional method.

(Method c: amidation) In the general formula [I], the substituent on ring A, the substituent on ring B, and / or the group R
Compound [I], which is a substituent containing an optionally substituted carbamoyl group, is a substituent on ring A, a substituent on ring B, and / or a group R is a substituent containing a carboxyl group. It can be produced from a corresponding compound [I] and a corresponding primary or secondary amine compound by treating in the same manner as in [Method A].

(Method d; N-acylation) The substituent on ring A, the substituent on ring B, and / or the group R in formula [I]
[I], wherein is a substituent containing an acylamino group
Is a substituent on ring A, a substituent on ring B, and / or a group R
Can be produced by treating the corresponding compound [I] in which is a substituent containing an amino group and the corresponding acylating agent (picolinic acid, dimethylaminoglycine, etc.) in the same manner as in the above [Method A]. .

(Method e: Substitution reaction of alkyl halide)
The group R in the general formula [I] is an optionally substituted nitrogen-containing heterocyclic group substituted lower alkyl group (eg, 1-pyrazolylmethyl group) or lower alkylamino lower alkyl group (eg, dimethylaminomethyl group) A compound [I] includes a corresponding compound [I] in which the group R is a lower alkyl group substituted with a halogen atom (eg, a chloromethyl group), and a corresponding optionally substituted nitrogen-containing heterocycle (eg, Pyrazole) or a primary or secondary lower alkylamine (eg, dimethylamine) in the presence of a base (triethylamine, sodium carbonate, etc.).

(Method f: Reduction Reaction of Nitro Group) A compound in which the substituent on ring A, the substituent on ring B and / or the group R in the general formula [I] is a substituent containing an amino group [ I] is a substituent on ring A, a substituent on ring B, and /
Alternatively, it can be produced by reacting the corresponding compound [I] in which the group R is a substituent containing a nitro group, in the presence of a reducing agent (eg hydrogen / palladium-carbon).

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

(Method h: Reduction of Carbonyl Group) The compound [I] in which the substituent on the ring A and / or the group R in the general formula [I] is a hydroxyl group-containing substituent is a substituent on the ring A. And / or the corresponding compound [I] in which the group R is a substituent containing a carbonyl group can be produced by treating with a conventional reducing agent (eg sodium borohydride etc.).

(Method i: azidation and reduction reaction) The group R in the general formula [I] is an amino lower alkyl group (for example,
Aminomethyl group-containing substituent [I]
Is a corresponding compound [I] in which the group R is a substituent containing a lower alkyl group (for example, a chloromethyl group) substituted with a halogen atom, and an azidating agent (sodium azide etc.)
It can be produced by reacting with, followed by reduction reaction. Examples of the reducing agent include hydrogen / palladium-carbon and the like.

(Method j: O-acylation or O-alkylation reaction) Substituents on ring A in the general formula [I], and /
Alternatively, the compound [I] in which the substituent on ring B is a substituent containing an acyloxy group or an optionally substituted lower alkoxy group is a substituent on ring A and / or a substituent on ring B. Is a hydroxyl group-containing substituent, the corresponding compound [I] and an acylating agent (phenylacetyl chloride, etc.) or an optionally substituted lower alkyl halide (2-methoxyethyl chloride, etc.), and a base (potassium carbonate, etc.). ) It is possible to produce by reacting in the presence of.

(Method k: Reduction Reaction of Amide) General Formula [I]
The compound [I] in which the substituent on ring A and / or the substituent on ring B in is a substituent containing an optionally substituted lower alkylamino group is Alternatively, it is produced by reacting the corresponding compound [I], which is a substituent containing an optionally substituted lower alkanoylamino group, on the ring B in the presence of a reducing agent (borane / dimethyl sulfide complex etc.). be able to.

[A method] to [H method] or (a
The compound [I] obtained by the methods (1) to (k) can be converted into a pharmaceutically acceptable salt by a conventional method.

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

Starting compound [5] ([5-a] and [5-]
b]) can be produced, for example, as follows.

[0099]

[Chemical formula 22]

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

The reaction for producing the compound [3] from the dichloro compound [7] and the compound [8] is carried out in the presence of a base (sodium hydroxide etc.), an additive (tetrabutyl ammonium chloride etc.) or It can be carried out in the absence.

As an example of this step, for example,

[0103]

[Chemical formula 23]

And the like.

The reaction for producing the compound [4] from the compound [3] can be carried out in the presence of an appropriate nitrating agent (concentrated nitric acid / concentrated sulfuric acid, etc.).

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

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

The reaction for producing the compound [5-a] from the compound [4] can be carried out in the presence of a suitable reducing agent (hydrogen / palladium-carbon, etc.).

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

In the reaction for producing the compound [5-b] from the compound [9], the same treatment (N-alkylation) as in the above [Method F] is performed, and then the compound [5-a] is converted to the compound [4]. It can be carried out by treatment (reduction of nitro group) in the same manner as in the reaction for production.

When R is a lower alkyl group having a halogen atom (bromine atom etc.), various nucleophiles (imidazole, pyrazole, pyrrole, indole, etc.) can be prepared in the presence or absence of a base (potassium carbonate etc.). It is also possible to introduce a substituent on the alkyl group by reacting a nitrogen-containing heterocyclic group such as triazole or a primary or secondary lower alkylamino group such as dimethylamine, morpholine, piperidine, pyrrolidine, etc. it can.

As an example of this step, for example,

[0113]

[Chemical formula 24]

And the like.

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

[0116]

[Chemical 25]

(In the formula, X ⁰ represents a hydrogen atom, a halogen atom or a trifluoromethanesulfonyloxy group, Y represents a lower alkoxycarbonyl group or a mono- or di-lower alkylamino group, X ³ and X ⁴ represent a leaving group, The other symbols have the same meanings as above. The reaction for producing compound [24] from compound [23] can be carried out as follows.

When X ⁰ is a hydrogen atom or a halogen atom,
In a solvent (such as tetrahydrofuran), in the presence of a base (n- butyl lithium, etc.), presence or absence of an additive (tetramethylethylenediamine, etc.), the formula: M-X ³ or M
It can be carried out by reacting the compound represented by -M and, if necessary, treating with an acid (hydrochloric acid etc.).

When X ⁰ is a halogen atom or a trifluoromethanesulfonyloxy group, it is present in a solvent (dimethoxyethane, water etc.) in the presence of a catalyst (palladium acetate etc.) and in the presence or absence of a base (potassium acetate etc.). , In the presence or absence of additives (triphenylphosphine, etc.),
Formula: reacting a compound represented by ^{M-X 3} or M-M,
If necessary, it can be carried out by treating with an acid (hydrochloric acid or the like).

The reaction for producing compound [28] from compound [24] and compound [25] is carried out in the presence of a catalyst (palladium acetate etc.) in a solvent (dimethoxyethane, water etc.) and a base (potassium carbonate etc.). It can be carried out in the presence or absence, or in the presence or absence of an additive (triphenylphosphine and the like).

Specific examples of the leaving group X ³ include a halogen atom, a lower alkoxy group, a cyano group, a trifluoromethanesulfonyloxy group and the like.

Specific examples of the compound represented by the formula: M-X ³ include tri-n-butyltin chloride and tri-n-.
Butyltin trifluoromethanesulfonate, tri-lower alkoxyborane and the like can be mentioned, and specific examples of the compound represented by the formula: MM include bispinacolate diboron,
Examples thereof include biscatecholate diboron and bistrin-butyltin.

Specific examples of the leaving group X ⁴ in the compound [25] or the compound [27] include, for example, a halogen atom,
Examples thereof include trifluoromethanesulfonyloxy group.

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

The reaction for producing compound [28] from compound [16] can be carried out in the same manner as the reaction for producing compound [28] from compound [24]. The reaction for producing the compound [6] from the compound [28] can be carried out by treating with an acid (concentrated hydrochloric acid or the like) or a base (sodium hydroxide or the like).

A specific example of the compound [6] is represented by the general formula [6 ′]:

[0127]

[Chemical formula 26]

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

The starting compound [13] can be produced, for example, as follows.

[0130]

[Chemical 27]

(However, symbols have the same meanings as described above.) The reaction for producing the compound [10] from the compound [9] is carried out in a solvent (tetrahydrofuran etc.) with di-tert-butyl dicarbonate (Boc ₂ O). It can be carried out in the presence or absence of a base (triethylamine etc.).

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

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

The reaction for producing the compound [13] from the compound [12] can be carried out in the presence of a deprotecting agent for the Boc group (hydrochloric acid-dioxane etc.).

The raw material compound [15] can be produced, for example, as follows.

[0136]

[Chemical 28]

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

The above compounds [Ia], [Ib], [I]
-C] or [Id], each intermediate compound is not limited to those shown in the above reaction scheme, and its salt or its reactive derivative may be appropriately used as long as it does not adversely affect the reaction. You can Examples of the salt include, for example,
Metal salts such as sodium, salts with organic bases such as pyridine,
Examples thereof include salts with inorganic acids such as hydrochloric acid and salts with organic acids such as acetic acid.

Further, in the production of the compound which is the active ingredient of the present invention and the starting material compound, when the starting material compound or each intermediate has a functional group, each functional group is added to the functional group by a conventional method of synthetic chemistry other than those shown above. It is possible to introduce a suitable protecting group and, if necessary, remove said protecting group.

In the present invention, examples of the alkyl include linear or branched ones having 1 to 16 carbon atoms, and particularly ones having 1 to 8 carbon atoms. Examples of lower alkyl or lower alkoxy include linear or branched ones having 1 to 6 carbon atoms, and particularly ones having 1 to 4 carbon atoms. Further, the lower alkanoyl includes a straight or branched chain having 2 to 7 carbon atoms, especially 2 to 5 carbon atoms, and the cycloalkyl has 3 to 20 carbon atoms, especially 3 to 12 carbon atoms. The following are listed. Examples of cyclo lower alkyl include those having 3 to 8 carbon atoms, particularly those having 3 to 6 carbon atoms. What is alkenyl?
Examples thereof include linear or branched ones having 2 to 16 carbon atoms, especially 2 to 10 carbon atoms, and examples of lower alkenyl include those having 2 to 8 carbon atoms, especially 2 to 4 carbon atoms. Examples of the alkylene include linear or branched ones having 1 to 16 carbon atoms, particularly 1 to 10 carbon atoms, and lower alkylene includes 1 to 8 carbon atoms, particularly 1 to 1 carbon atoms.
6 may be a straight chain or branched chain. Examples of the halogen atom include fluorine, chlorine, bromine and iodine. Examples of the heterocyclic group include nitrogen, oxygen,
Mention may be made of 5- to 15-membered monocyclic, bicyclic or tricyclic heterocyclic groups containing at least one heteroatom selected from sulphur. Specifically, pyridyl group, indolyl group, thiazolyl group, imidazolyl group, pyrrolyl group, pyrimidinyl group, thienyl group, benzo [b] furyl group, benzo [b] thienyl group, pyrazolyl group, triazolyl group, quinolyl group, isoquinolyl group. Group, phthalazinyl group, quinazolinyl group, quinoxalinyl group, 5,11-dihydro-dibenzo [b, e] [1,4] oxazepin-5-yl group,
Examples thereof include dihydropyrazolyl group and tetrazolyl group. Examples of the aryl group include a phenyl group, a naphthyl group, an anthryl group, a phenanthryl group and the like.

[0141]

[Experimental Example] Experimental Example 1 (ApoB secretion inhibitory effect) Human hepatoma-derived cells HepG2
(ATCC No .: HB-8065) was seeded in each well of a 96-well plate so as to be 50% confluent, and PR was prepared by adding inactivated 10% fetal bovine serum.
MI-1640 medium (Nikken Biology, 200 μL / well)
Was cultured for at least 48 hours until it reached 80% confluence (37 ° C., 5% CO ₂ ). After completion of the culture, the medium was exchanged, and dimethyl sulfoxide (DMSO final concentration:
5%) dissolved in various concentrations of the sample to the medium
Cultured for 6 hours. After completion of the culture, the culture supernatant (50 μL) of HepG2 cells was collected, diluted 15-fold with the medium, and then ELI.
A sample for ApoB quantification by the SA method (100 μL / well) was used. In the ELISA method, the anti-human ApoB monoclonal antibody (H45635) was used as the primary antibody.
M, manufactured by Biodesign), and an anti-human ApoB polyclonal antibody (K45253B,
405-490 nm using a Biodesign product)
The absorbance at was measured. The amount of ApoB in the sample was obtained from the above absorbance and a calibration curve prepared in advance using ApoB obtained from human plasma. Sample non-treatment group (D
The ApoB amount of MSO addition only) and normalized as 100%, _{IC 50} values were calculated. (Results) The results are shown in Table 1.

[0142]

[Table 1]

Experimental Example 2 (Blood triglyceride lowering effect in Triton-loaded rats) Male SD preliminarily bred for 2 weeks under backlit day and night
Rats (SPF, 8 weeks old, SLC) were used. Tr
Iton-WR1339 (nonionic surfactant; manufactured by Nacalai Tesque, Inc., abbreviated as Triton hereinafter) was dissolved in physiological saline at 250 mg / mL. The sample is vehicle [10% 1-methyl-2-pyrrolidone (manufactured by Tokyo Kasei), 80% water, 5% Cremophor EL (manufactured by Sigma) and 5% ethanol mixed solvent or 0.25% carboxymethylcellulose (CMC). )] Was dissolved or suspended, and then orally administered to the rat. T 1 hour after sample administration
Ritone was administered into the tail vein (250 mg / kg).
After that, the total cholesterol (TC) and triglyceride (TG) concentrations in plasma were measured over time using a cholestezyme and a triglycezyme (both manufactured by Eiken Chemical Co., Ltd.). In the sample non-administration group, Triton was administered 1 hour after the administration of the vehicle containing no sample. The rats to which only the vehicle was administered served as a control group. The difference between the TG value of the sample non-administration group and the TG value of the control group is set to 100%,
[TG value of sample and Triton administration group-TG of control group
Value] was calculated as 50%, and this was used as the ED ₅₀ value. (Results) The results are shown in Table 2.

[0144]

[Table 2]

Experimental Example 3 (Blood triglyceride lowering action in olive oil-loaded rats) 7 to 8 week-old male SD rats (body weight: 208)
˜313 g, made by SLC) was fed preliminarily for 1 week with normal feed and water ad libitum. 0.25% of the sample in the rat
A carboxymethyl cellulose (CMC) suspension was orally administered (10 mL / kg). Olive oil (10 mL / kg) was orally administered 1 hour after the sample administration, and plasma triglyceride level and cholesterol level were measured 4 hours after the sample administration. Sample-free group does not contain sample 0.2
Olive oil was administered 1 hour after the administration of 5% CMC. The rats to which only 0.25% CMC was administered were used as a control group. Plasma triglyceride (TG) and cholesterol (Chol) levels were quantified by using plasma obtained by centrifuging blood collected from the subclavian vein or abdominal aorta as a sample, and using triglyceme and cholestezyme (both Eiken Chemical Manufactured). The difference between the TG value of the sample non-administration group and the TG value of the control group is set to 100%, and the [TG value of the sample and olive oil administration group-TG value of the control group] is 5
The dose of 0% was calculated and used as the ED ₅₀ value. (Results) The results are shown in Table 3.

[0146]

[Table 3]

[0147]

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

Production Example 1 (1) 699 mg of isoindoline, (1H-pyrazol-1-yl) acetic acid / hydrochloride (900 mg of the compound obtained in Reference Example 1), 1-hydroxybenzotriazole 7
To a solution of 85 mg and triethylamine 0.81 ml in dimethylformamide (30 ml), 1-ethyl-3-
Add 1.10 g of (3-dimethylaminopropyl) -carbodiimide hydrochloride. After stirring at room temperature for 6 hours, the mixture is poured into ice water, and the precipitated powder is collected by filtration and dried. Recrystallization from methanol gives 1.00 g of 2- (1H-pyrazol-1-yl) acetyl-isoindoline as colorless crystals. M. p. 215-217 ° C. (2) To a solution of 11.87 g of the compound obtained in (1) above in 60 ml of concentrated sulfuric acid, 3.6 ml of concentrated nitric acid was added dropwise under ice cooling.
Stir for 1 hour. The reaction solution is poured into ice water, the deposited precipitate is filtered, washed with water, and dried. The resulting crude product was treated with acetic acid-
By recrystallizing with a mixed solvent of water, 5-nitro-2
10.62 g of-(1H-pyrazol-1-yl) acetyl-isoindoline are obtained as colorless crystals. M. p. 247-248 ° C (3) A suspension of 1.005 g of the compound obtained in (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 (4) 245 mg of the compound obtained in the above (3), 2-
A solution of 296 mg of (5-trifluoromethyl-pyridin-2-yl) benzoic acid (the compound obtained in Reference Example 5 (3)) and 149 mg of 1-hydroxybenzotriazole in dimethylformamide (5 ml) was cooled with ice to give 1-. Ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (216 mg) is added, and the mixture is stirred at room temperature for 17 hours. After pouring the reaction solution into 30 ml of ice water and stirring for 30 minutes,
10 ml of concentrated aqueous ammonia was added, and the precipitated crystals were collected by filtration,
After drying, it was recrystallized from ethyl acetate to give 2- (1
H-pyrazol-1-yl) acetyl-5- [2- (5
432 mg of -trifluoromethyl-pyridin-2-yl) benzoylamino] -isoindoline are obtained as colorless prism crystals. M. p. 207-209 ° C

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

[0150]

[Table 4]

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

Production Example 7-8 The corresponding starting material compound was treated in the same manner as in Production Example 6 to obtain the compounds shown in Table 5.

[0153]

[Table 5]

Production Example 9 (1) Isoindolin 22.43 g of methanol (10
(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) 494 mg of the compound obtained in (1) above and 1.24 g of potassium carbonate in toluene (6 ml) -water (6
0.36 ml of 2-chloroacetyl chloride is added dropwise to the mixed solution of (ml) under stirring. The precipitated crude product is separated by filtration, washed with water, and recrystallized from ethyl acetate to obtain 576 mg of 2-chloroacetyl-5-nitro-isoindoline. M. p. 158-160 ° C. (3) 86 mg of pyrazole was added to a suspension of 76 mg of the compound obtained in (2) above in o-xylene (3 ml).
Heat to reflux for hours. The reaction solution was poured into diisopropyl ether, and the precipitated crystals were collected by filtration to give 5-nitro-2- (1H-pyrazol-1-yl) acetyl-isoindoline (the compound obtained in Production Example 1 (2)) 64m.
get g. (4) The compound obtained in the above (3) is used in Production Example 1 (3).
Production Example 1 by treating in the same manner as in (4)
(4) The compound as described is obtained.

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

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

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

Production Example 13 By treating the corresponding starting material compound in the same manner as in Production Example 12, compounds shown in Table 6 are obtained.

[0159]

[Table 6]

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

Production Example 15-17 The corresponding starting material compound is treated in the same manner as in Production Example 14 to obtain the compounds shown in Table 7.

[0162]

[Table 7]

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

Production Example 19 (1) 5-amino-2- (1H-pyrazol-1-yl) acetyl-isoindoline (compound obtained in Example 1 (3)) 533 mg, 2-iodobenzoic acid 610 m
g and 1-hydroxybenzotriazole 334 mg
1-Ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (480 mg) is added to the dimethylformamide (10 ml) solution of, and the mixture is stirred at room temperature for 5.5 hours. The reaction solution was poured into ice water, and the deposited precipitate was collected by filtration,
By recrystallizing with a mixed solution of ethyl acetate-n-hexane, 800 mg of 2- (1H-pyrazol-1-yl) acetyl-5- (2-iodo-benzoylamino) -isoindoline is obtained as colorless needle crystals. . MS (APCI) m / z; 473 (M + H), IR (n
ujol) cm ⁻¹ ; 1671, 1644 (2) 300 mg of the compound obtained in the above (1), 3-pyridyltributyltin 468 mg, triphenylphosphine 33 mg, copper (I) bromide 18 mg, bistriphenylphosphine palladium dichloride 45 mg and a small amount. A solution of 2,6-di-tert-butyl-p-cresol in dioxane (10 ml) is heated under reflux for 3 days. The reaction solution was cooled to room temperature, diluted with ethyl acetate, and further diluted with ethyl acetate.
% Potassium fluoride aqueous solution (15 ml) is added and the mixture is stirred. The insoluble matter is filtered through Celite, the organic layer of the filtrate is separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure. Preparative chromatography of the residue (developing solvent; chloroform: methanol = 20: 1)
After being purified by the method described above, it was recrystallized from a mixed solution of chloroform-methanol to give 2- (1H-pyrazole-1-
57 mg of yl) acetyl-5- [2- (3-pyridyl) -benzoylamino] -isoindoline are obtained. M. p. 257 ℃ (decomposition)

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

Production Examples 21-22 The corresponding starting material compounds are treated in the same manner as in Production Example 20 to obtain the compounds shown in Table 8.

[0167]

[Table 8]

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

Reference Example 1 Pyrazole (2.09 g) and potassium carbonate (7.07 g) are added to a solution of tert-butyl bromoacetate (5.00 g) in dimethylformamide (20 ml). 1 hour at room temperature,
After stirring at 50 ° C. for 3.5 hours, the reaction solution is poured into water and extracted with ethyl acetate. The organic layer is washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (developing solvent;
By purification with ethyl acetate: n-hexane = 1: 3, (1H-pyrazol-1-yl) acetic acid tert-
4.23 g of butyl are obtained as a colorless oil. (2) 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 2 (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. By recrystallizing with 2 L of tetrahydrofuran, (1H-pyrazol-1-yl)
127.3 g of acetic acid are obtained. M. p. 171-172 ° C

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

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

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

Reference Example 6 (1) 2-iodobenzoic acid 10.0 g of methanol (1
(00 ml), thionyl chloride (6 ml) was added to the solution under ice cooling, and the mixture was heated under reflux for 3 hours. The reaction solution is concentrated under reduced pressure, and the ethyl acetate solution of the residue is washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was evaporated, the residue was purified by silica gel column chromatography (developing solvent; n-hexane: ethyl acetate = 5: 1), and methyl 2-iodobenzoate 10.
53 g are obtained as a colorless oil. (2) 7.87 g of the compound obtained in the above (1) and 34.83 of bistri-n-butyltin under an argon atmosphere.
To a solution of g in toluene (150 ml), 695 mg of tetrakistriphenylphosphine palladium is added, and the mixture is heated under reflux for 47 hours. The reaction solution is cooled to room temperature, 10% aqueous potassium fluoride solution is added, and the mixture is stirred at room temperature for 1 hour. The reaction solution is filtered through Celite, and the organic layer is separated from the filtrate. The organic layer is washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (developing solvent; chloroform: n-hexane = 1: 5) to give 7.02 g of methyl 2- (tri-n-butyltin) benzoate as colorless. Obtained as an oil. (3) Under an argon atmosphere, 639 mg of the compound obtained in (2) above, 178 mg of 2-chloro-5-trifluoromethyl-pyridine, 52 mg of triphenylphosphine,
Copper (I) bromide 29 mg, a small amount of 2,6-di-tert-
70 mg of bistriphenylphosphine palladium chloride is added to a dioxane (5 ml) solution of butyl-p-cresol, and the mixture is heated under reflux for 47 hours. The reaction solution is cooled to room temperature, diluted with ethyl acetate, added with 10% aqueous potassium fluoride solution, and stirred at room temperature for 1 hour. The reaction solution is filtered through Celite, and the organic layer is separated from the filtrate. 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; ethyl acetate: n-hexane = 1: 2).
0) to give 2- (5-trifluoromethyl-pyridin-2-yl) benzoate methyl 159 mg.
As a colorless oil. MS (APCI) m / z; 282 (M + H), IR (N
eat) cm ⁻¹ ; 1729, 1605 (4) 253 mg and 1 of the compound obtained in the above (3)
A solution of M sodium hydroxide aqueous solution (1.35 ml) in methanol (3.0 ml) is heated with stirring at 50 ° C. for 4 hours.
Methanol is distilled off, the solution is adjusted to pH 3 with 2M aqueous hydrochloric acid, and then concentrated under reduced pressure. Ethanol is added to the residue, the insoluble matter is removed by filtration, and the filtrate is concentrated to give 2- (5-
248 mg of trifluoromethyl-pyridin-2-yl) benzoic acid (the compound obtained in Reference Example 5 (3)) is obtained.

Reference Example 7-8 The corresponding starting material compounds were treated in the same manner as in Reference Examples 6 (3) and (4) to obtain the compounds shown in Table 9.

[0176]

[Table 9]

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

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

Reference Example 11 (1) Under argon atmosphere, to a solution of methyl 2-bromo-benzoate (500 mg) and 2-pyridyltributyltin (1.71 g) in dimethylformamide (10 ml) was added bistriphenylphosphine palladium dichloride (164 mg), and the mixture was heated to 100 ° C. Heat and stir for 12 hours. The reaction solution is cooled to room temperature, diluted with ethyl acetate, added with 10% aqueous potassium fluoride solution, and stirred at room temperature for 1 hour. The reaction solution is filtered through Celite, and the organic layer is separated from the filtrate. The organic layer is washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by NH silica gel column chromatography (manufactured by Fuji Silysia Chemical Ltd.) (developing solvent; ethyl acetate: n-hexane = 1: 2) to give 2
392 mg of methyl-(2-pyridyl) benzoate are obtained as a colorless oil. MS (APCI) m / z; 214 (M + H), IR (n
eat) cm ⁻¹ ; 1730 (2) By treating the compound obtained in (1) above in the same manner as in Reference Example 6 (4), 2- (2-pyridyl) benzoic acid is obtained. MS (ESI) m / z; 198 (M-H), IR (nu
jol) cm ⁻¹ ; 1690

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

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

Reference Example 14 (1) 5-Nitroisoindoline crude product (Example 9)
(Compound obtained in (1)) To a solution of 2.62 g of tetrahydrofuran (40 ml), a solution of 3.86 g of di-tert-butyl dicarbonate in tetrahydrofuran (10 ml) was added dropwise under ice cooling, and the mixture was 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),
Recrystallization from a mixed solution of n-hexane-ethyl acetate gives 3.09 g of 5-nitro-2- (tert-butoxycarbonyl) -isoindoline. M. p. 159-160 ° C. (2) 3.46 g and 1 of the compound obtained in the above (1)
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. MS (FAB) m / z; 235 (M + H), IR (ne
at) cm ⁻¹ ; 1687, 1632 (3) Compound 217 mg obtained in the above (2), 2-
A solution of 236 mg of (5-trifluoromethyl-pyridin-2-yl) benzoic acid (the compound obtained in Reference Example 5 (3)) and 129 mg of 4-dimethylaminopyridine in methylene chloride (8 ml) was charged with 1-under an argon atmosphere. Add ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (212 mg) and stir at room temperature overnight. The reaction mixture is poured into saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer is washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and the solvent is evaporated. The residue is subjected to silica gel column chromatography (developing solvent; chloroform: methanol =
30: 1) to give 375 mg of 2- (tert-butoxycarbonyl) -5- [2- (5-trifluoromethyl-pyridin-2-yl) benzoylamino] -isoindoline as colorless foam. obtain. MS (APCI) m / z; 484 (M + H), IR (n
ujol) cm ⁻¹ ; 1697, 1675, 1603 (4) To a solution of 890 mg of the compound obtained in the above (3) in dioxane (6 ml), a 4 M hydrochloric acid-dioxane solution 12 m is added.
1 and then stirred at room temperature for 1 hour. By adding diethyl ether and collecting the deposited precipitate by filtration, 5- [2-
(5-Trifluoromethyl-pyridin-2-yl) benzoylamino] -isoindoline dihydrochloride 846 mg
As a crude product. MS (APCI) m / z; 384 (M + H), IR (n
ujol) cm ⁻¹ ; 1661, 1642, 1605

─────────────────────────────────────────────────── ─── Continued Front Page (51) Int.Cl. ⁷ Identification Code FI Theme Coat (Reference) A61P 1/18 A61P 1/18 3/04 3/04 3/06 3/06 3/10 3/10 7 / 02 7/02 9/00 9/00 9/10 9/10 101 101 25/00 25/00 25/28 25/28 43/00 111 43/00 111 C07D 401/14 C07D 401/14 // C07D 403/14 403/14 409/14 409/14 (72) Inventor Koichi Nagata 1-18-5 Tajima, Saitama City, Saitama Prefecture Land Heights Nishiurawa Room 202 (72) Inventor Mikiko Yasuhara 2-chome, Nakamachi, Toda City, Saitama Prefecture No. 4 No. 8 Seju Fuji B-203 F term (reference) 4C063 AA03 BB09 CC22 CC29 CC92 DD07 EE01 4C086 AA01 AA02 BC17 BC36 BC42 GA04 GA07 GA08 MA01 MA04 NA14 ZA02 ZA15 ZA36 ZA45 ZA54 ZA66 ZA70 C33 ZC35 ZC02 ZC02

Claims (12)

[Claims] 1. A compound represented by the general formula [I]: (In the formulae, ring A is an optionally substituted 5- or 6-membered aromatic heterocyclic group, ring B is an optionally substituted benzene ring, Q is —CO— or —CH ₂ —, and R is substituted. Represents an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted carbamoyl group, an optionally substituted heterocyclic group, or an optionally substituted aryl group. ) A pharmaceutical composition comprising a benzoylaminoisoindoline derivative or a pharmaceutically acceptable salt thereof represented by the formula (1) as an active ingredient. 2. A 5- or 6-membered aromatic heterocyclic group in which ring A may be substituted with 1 to 3 same or different groups selected from the following (1) to (10): (1 ) Trifluoromethyl group, (2) hydroxyl group, oxo group, and lower alkyl group which may be substituted with 1 to 3 same or different groups selected from hydroxyimino group, (3) lower alkoxy group, hydroxyl group, And the same or different 1 to 3 selected from di-lower alkylamino groups
Lower alkoxy group optionally substituted with one group,
(4) hydroxyl group, (5) nitro group, (6) cyano group,
(7) a carbamoyl group optionally substituted with a group selected from a lower alkyl group, a lower alkoxy lower alkyl group, a halogeno lower alkyl group, and an aryl lower alkyl group, (8) an amino group protecting group, a lower alkyl group, And an amino group which may be substituted with a group selected from a lower alkylsulfonyl group, (9) a lower alkanoyloxy group which may be substituted with an aryl group, and (1
0) A lower alkoxycarbonyl group and ring B have the following (1)
A benzene ring which may be substituted with 1 to 3 same or different groups selected from (9): (1) nitro group, (2) hydroxyl group, (3) lower alkoxy group, hydroxyl group, aryl group, ( Lower alkylamino) aryl group, lower alkoxycarbonyl group, lower alkenyloxycarbonyl group, carboxyl group, amino group, lower alkylamino group, lower alkylcarbamoyl group, cyano group, pyridyl group, pyrrolidinyl group, morpholinyl group,
Lower alkoxy group optionally substituted with a group selected from piperazinyl group and lower alkylpiperazinyl group, (4) lower alkoxycarbonyl group, (5) (i)
Lower alkoxy group, amino group, lower alkylamino group,
And a lower alkanoyl group substituted by the same or different 1 to 3 groups selected from the following, and a lower alkoxycarbonyl group, (ii) a protecting group for an amino group, (iii) a pyridyl group, or a lower alkylamino group. Optionally lower alkyl group, and (iv) pyridylcarbonyl group, optionally substituted amino group,
(6) a carbamoyl group which may be substituted with a group selected from a lower alkyl group, a lower alkoxy lower alkyl group, and a lower alkylamino lower alkyl group, (7) a morpholinocarbonyl group, (8) a cyano group, and ( 9)
Lower alkylaminocarbonyloxy group, R is (1)
The same or different 1 selected from the following (i) to (ix)
A lower alkyl group which may be substituted with 3 to 3 groups: (i) a lower alkyl group; a hydroxy lower alkyl group; a lower alkanoyl group; a lower alkoxy group; a nitro group; a lower alkoxycarbonyl group; a carboxyl group; an oxo group;
Trifluoromethyl group; carbamoyl group (the carbamoyl group may be substituted with a group selected from a lower alkyl group, a halogeno lower alkyl group, and a hydroxy lower alkyl group); an amino group (the amino group is a lower alkanoyl group, A lower alkoxy lower alkanoyl group, a lower alkyl group, a hydroxy lower alkyl group, a lower alkoxycarbonyl group, and a lower alkylaminoalkylidene group may be substituted); a cyano group;
A hydroxyl group which may be protected; a halogen atom; and a heterocyclic group which may be substituted with 1 to 3 same or different groups selected from a formyl group, (ii) a lower alkyl group; an amino group (the amino group). The group may be substituted with a lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkyl group, a pyridyl lower alkyl group, a lower alkylaminocarbonyl group, a halogeno lower alkylaminocarbonyl group, a lower alkanoyl group, or a halogeno lower alkanoyl group) Lower alkoxy group; aryl lower alkoxy group; benzyloxy lower alkoxy group; lower alkylamino lower alkoxy group; nitro group; optionally protected hydroxyl group; lower alkylcarbamoyl group; halogeno lower alkylcarbamoyl group; and morpholinyl group Same Others may be substituted with 1 to 3 groups different, aryl group, or fluorenyl group, (i
ii) an optionally protected hydroxyl group, (iv) a carbamoyl group optionally substituted with a group selected from a lower alkyl group, a halogeno lower alkyl group, and a benzothiazolyl group, (v) formula: (In the formula, n represents an integer of 0 to 4), (v
i) a lower alkoxycarbonyl group, (vii) an amino group-protecting group, a lower alkyl group, a pyridyl group, or an amino group which may be substituted with a pyrimidinyl group, (vii
i) a halogen atom, and (ix) an oxo group, (2)
A lower alkenyl group which may be substituted with an aryl group,
(3) a carbamoyl group optionally substituted with a group selected from a lower alkyl group, a halogeno lower alkyl group, and a benzothiazolyl group, (4) formula: (In the formula, m represents an integer of 0 to 4),
(5) lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, amino group, lower alkylamino group,
A heterocyclic group which may be substituted with 1 to 3 same or different groups selected from an optionally protected hydroxyl group and an optionally protected amino group, or (6)
Selected from a lower alkyl group, a lower alkoxy group, a lower alkylcarbamoyl group, a halogeno lower alkylcarbamoyl group, a morpholinyl group, an amino group, a lower alkylamino group, an optionally protected hydroxyl group, and an optionally protected amino group. The pharmaceutical composition according to claim 1, which is an aryl group which may be substituted with 1 to 3 groups which are the same or different. 3. A 5- or 6-membered aromatic heterocyclic group is nitrogen,
1 or the same or different selected from oxygen and sulfur atoms
The pharmaceutical composition according to claim 1 or 2, which is a 5- or 6-membered aromatic heterocyclic group containing 4 heteroatoms. 4. A 5- or 6-membered aromatic heterocyclic group is a pyridyl group, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl group, a furyl group, a thienyl group, a pyrrolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an imidazolyl group or a pyrazolyl group. The pharmaceutical composition according to claim 1 or 2, which is a group. 5. The heterocyclic group is a pyridyl group, an indolyl group, a thiazolyl group, an imidazolyl group, a pyrrolyl group, a pyrimidinyl group, a thienyl group, a benzo [b] furyl group, a benzo [b] thienyl group, a pyrazolyl group, a triazolyl group. Base,
A quinolyl group, an isoquinolyl group, a phthalazinyl group, a quinazolinyl group, a quinoxalinyl group, a 5,11-dihydro-dibenzo [b, e] [1,4] oxazepin-5-yl group, a dihydropyrazolyl group, or a tetrazolyl group or an aryl group, The pharmaceutical composition according to claim 2, 3 or 4, which is a phenyl group, a naphthyl group, an anthryl group, or a phenanthryl group. 6. In the general formula [I], ring A is selected from a trifluoromethyl group and a lower alkanoyl group.
It is a 5- or 6-membered aromatic heterocyclic group which may be substituted with 3 groups, ring B is a benzene ring which may be substituted with a lower alkoxycarbonyl group, and Q is -CO- or-. CH2-, which may be substituted with a group selected from a nitro group and a lower alkoxycarbonyl group;
The pharmaceutical composition according to claim 1, which is a lower alkyl group substituted with a group selected from a 6-membered heterocyclic group and a hydroxyl group. 7. In the general formula [I], ring A has the formula: R ¹ is a trifluoromethyl group or a lower alkanoyl group, ring B is a lower alkoxy group, a (lower alkylamino lower alkanoyl) amino group, a lower alkylamino lower alkoxy group, a lower alkylcarbamoyl group, and a lower ring. A benzene ring optionally substituted with a group selected from an alkoxycarbonyl group, a lower alkyl group in which R is substituted with a group selected from the following (1) to (4): (1) a lower alkyl group, a nitro group, A pyrazolyl group optionally substituted with a group selected from a lower alkoxycarbonyl group, a cyano group, an amino group, and a hydroxy lower alkyl group, (2) pyridyl group, (3) tetrazolyl group,
Alternatively, the pharmaceutical composition according to claim 5, which is (4) a thiazolyl group optionally substituted with an amino group. 8. In the general formula [I], ring A has the formula: , A ring B is a benzene ring, and Q is -CO.
The pharmaceutical composition according to claim 7, wherein R and R are pyrazolylmethyl groups which may be substituted with a group selected from a lower alkyl group, a nitro group, a lower alkoxycarbonyl group and a hydroxy lower alkyl group. 9. 2- (1H-pyrazol-1-yl) acetyl-5- [2- (5-trifluoromethyl-pyridin-2-yl) benzoylamino] -isoindoline,
2- (1H-pyrazol-1-yl) acetyl-5-
[2- (5-Trifluoromethyl-pyridin-2-yl) -3-methoxycarbonylbenzoylamino] -isoindoline, 2- [2- (1H-pyrazol-1-yl) ethyl] -5- [2- (5-trifluoromethyl-
A pharmaceutical composition comprising a pyridin-2-yl) benzoylamino] -isoindoline or a pharmacologically acceptable salt thereof as an active ingredient. 10. The pharmaceutical composition according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8 or 9, which is an apolipoprotein B secretion inhibitor. 11. A serum lipid lowering agent according to claim 1, 2.
The pharmaceutical composition according to 3, 4, 5, 6, 7, 8 or 9. 12. Hyperlipidemia, ischemic heart disease, atherosclerosis, coronary arteriosclerosis, hypercholesterolemia, hypertriglyceridemia, familial hyperlipidemia, hyperlipoproteinemia,
Prevention and treatment of arteriosclerosis, coronary arteriosclerosis, coronary artery disease, ischemic brain disease, stroke, circulatory / microcirculatory disorders, thrombosis, hyperglycemia, diabetes, acute hemorrhagic pancreatitis, obesity, steatosis or constipation An agent, claim 1, 2, 3, 4, 5, 6,
The pharmaceutical composition according to 7, 8 or 9.