WO2002098871A1

WO2002098871A1 - Phenylcarboxamides and process for preparation thereof

Info

Publication number: WO2002098871A1
Application number: PCT/JP2002/005356
Authority: WO
Inventors: Masayuki Annaka; Naoyuki Harada; Hidekazu Tsujishima; Koichi Nagata; Mayumi Takano
Original assignee: Tanabe Seiyaku Co., Ltd.
Priority date: 2001-06-01
Filing date: 2002-05-31
Publication date: 2002-12-12

Abstract

Phenylcarboxamides represented by the general formula [I] or pharmacologically acceptable salts thereof; and a process for preparation of both: [I] wherein A is a nitrogen-containing aliphatic heterocyclic group which may be substituted; Y is =CH- or =N-; R2 is a group represented by the general formula [II]: [II] (wherein m is an integer of 0 to 3; and R6 is an organic group) or the like; and R3 is hydrogen or halogeno.

Description

Description Phenylcarboxamide compounds and their production

The present invention relates to a novel phenylcarboxamide compound which has an excellent apolipoprotein B (ApoB) secretion inhibitory action and a serum lipid lowering action and is useful as a medicine, and a method for producing the same. Background art

International Patent Publication WO 96 40640 discloses that 4′-trifluoromethyl-biphenyl-2-carboxylic acid [2- (thiophen-1-yl-acetyl) —1,2,3,4-tetrahydroisoquinoline 1-6-yl] monoamide, 4'-trifluoromethyl-biphenyl-2-carboxylic acid [2- (pyridine-2-ylurea cetyl) -1,2,3,4-tetrahydroisoquinoline-1-6-yl International Patent Application WO 98/23593 discloses that 4′-trifluoromethyl-piphenyl-2-carboxylic acid [2- (2- (pyridine-2-yl) ethyl) 1 , 2,3,4-tetrahydroisoquinoline-6-yl] monoamide and the like, and WOO032582 discloses 4'-trifluoromethyl-piphenyl-2-carboxylic acid [4- (4- (3 —Cyanobenzyl) pyridine-1) phenyl) etc. It has been suggested that it has an oB secretion inhibitory effect and can be used as a serum lipid lowering agent.

However, all of the amide compounds described therein are compounds having a substituted biphenyl group in the carboxylic acid portion of the amide, and the nitrogen-containing aliphatic compound is contained in the carboxylic acid portion as in the compound of the present invention. No compound having a heterocyclic monophenyl group is described.

An object of the present invention is to provide an excellent apolipoprotein B secretion inhibitory effect and a serum lipid lowering effect. It is an object of the present invention to provide a novel phenylcarboxamide compound. Further, the present invention also provides a method for producing such a novel compound.

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

That is, the present invention provides:

In the formula, ring A represents an optionally substituted nitrogen-containing aliphatic heterocyclic group,

Y represents = CH— or = N—,

R ² is given by equation (1):

NHR ⁶

N, CH

V I m In the formula, m is an integer of 0 to 3, R ⁶ represents an organic group,

A group represented by

Formula (2): — (CH ₂ ) _P -NHR ⁷

Wherein p is an integer of 1 to 6, R ⁷ represents an organic group,

A group represented by or

Formula (3): — CONH— (CH ₂ ) _Q -R ⁸

Wherein Q is an integer from 1 to 6, and R ⁸ is an optionally substituted heterocyclic Represents a group,

Represents a group represented by

R ³ represents a hydrogen atom or a halogen atom,

Or a pharmaceutically acceptable salt thereof, and a method for producing the same. BEST MODE FOR CARRYING OUT THE INVENTION

Examples of the substituent on ring A in the target compound [I] of the present invention include: (1) an aryl lower alkyl group,

(2) Aryl group,

(3) aryl lower alkoxy group,

(4) carboxyl group,

(5) a lower alkoxycarbonyl group optionally substituted with an aryl group,

(6) a lower alkyl group; a lower alkanoyl group; an aryl lower alkanol group; a lower alkoxycarbonyl group; and an amino group which may be substituted with a group selected from an aryl lower alkoxycarbonyl group;

Equation (7): _C〇NR ⁴ R ⁵

In the formula, R ⁴ and R ⁵ may be the same or different and each represent a group selected from a hydrogen atom, an alkyl group, an aryl lower alkyl group, a pyridyl lower alkyl group, and an aryl group.

A group represented by

Equation (8):

Wherein n is an integer from 0 to 3,

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

Examples of the nitrogen-containing aliphatic heterocyclic group in ring A include a 3- to 8-membered aliphatic heterocyclic group containing one or two nitrogen atoms. Specific examples include an aziridinyl group, an azetidinyl group, a pyrrolidinyl group, a piperidino group, a piperazinyl group, a morpholino group, a azepanyl group, and a diazepanyl group.

As R ² in the target compound [I] of the present invention,

(1 set:

NHR ⁶

_N , y ^CH 2 / m

Wherein m is an integer from 0 to 3, and R ⁶ is

(i) a lower alkyl group,

(ii) a lower alkanoyl group,

(iiii) a lower alkoxycarbonyl group,

(iV) a lower alkyl group; an amino group which may be protected; a hydroxyl group which may be protected; a cyano group; and a nitrogen-containing aromatic heterocyclic ring which may be substituted with a group selected from a halogen atom. Group,

(V) arylsulfonyl group, or

(V i) represents a lower alkylsulfonyl group,

A group represented by

Formula (2): — (CH ₂ ) _P — NHR ⁷

Wherein p is an integer from 1 to 6, and R ⁷ is

(i) a lower alkyl group,

(ii) a lower alkanoyl group,

(iii) a lower alkoxycarbonyl group, (iv) a lower alkyl group; an optionally protected amino group; an optionally protected hydroxyl group; a cyano group; and a nitrogen-containing aromatic heterocyclic group optionally substituted by a group selected from halogen atoms. ,

(V) arylsulfonyl group,

(V i) a lower alkylsulfonyl group,

(V i i) an aromatic heterocyclic group-substituted sulfonyl group, or

(vii i) represents a di-lower alkylphosphono group,

A group represented by

(3) Formula: — CONH— (CH ₂ ) _q -R ⁸

Wherein Q is an integer of 1 to 6, and R ⁸ is a nitrogen-containing aromatic heterocyclic group which may be substituted with a group selected from the following:

(i) a lower alkyl group,

(ii) an amino group which may be protected,

(iii) an optionally protected hydroxyl group,

(i V) a cyano group, and

(V) a halogen atom,

Represents

And the like.

Examples of the nitrogen-containing aromatic heterocyclic group for R ⁶ , R ^7, or R ⁸ include a monocyclic or bicyclic nitrogen-containing aromatic heterocyclic group containing 1 to 4 nitrogen atoms. . Specifically, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, quinolyl, isoquinolyl Quinazolinyl group, purinyl group, 1H-indazolyl group, cinnolinyl group, quinoxalinyl group, furazinyl group, pteridinyl group and the like.

As the aromatic heterocyclic group of the aromatic heterocyclic group-substituted sulfonyl group at R ⁷ Is, for example, a monocyclic or bicyclic aromatic heterocyclic group containing the same or different 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur. Specifically, a furyl group, a cyenyl group, a pyrrolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an imidazolyl group, a pyrazolyl group, a triazolyl group, a tetrazolyl group, a pyridyl group, a pyrimidinyl group, a virazinyl group, a pyridazinyl group, and an indolyl group Groups, quinolyl group, isoquinolyl group, quinazolinyl group, purinyl group, 1H-indazolyl group, cinnolinyl group, quinoxalinyl group, furazinyl group, pteridinyl group and the like.

Examples of the aryl group in the substituent on ring A and the aryl group in the arylsulfonyl group in R ⁶ or R ⁷ include a phenyl group, a naphthyl group, an anthryl group, a phenanthryl group and the like.

When the target compound [I] of the present invention has a protected amino group, examples of the protecting group for the amino group include a lower alkoxycarbonyl group, an optionally substituted lower alkoxycarbonyl group, and the like; Specifically, ethoxycarbonyl, methoxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, aryloxycarbonyl, 9-fluorenylmethoxycarbonyl, tert-butoxycarbonyl , 2,2,2-trichloroethyloxycarbonyl group, formyl group, acetyl group, propionyl group, butylyl group and the like. Further, a benzyl group, a 4-methoxybenzyl group, an aryl group and the like can also be mentioned. Of these, a lower alkoxycarbonyl group which may be substituted may be mentioned, and specific examples thereof include a benzyloxycarbonyl group and a tert-butoxycarbonyl group. The protected amino group also includes, for example, a case where a phthalimide group is formed together with the protected amino group.

When the target compound [I] of the present invention has a protected hydroxyl group, the protecting group for the hydroxyl group may be an optionally substituted aryl lower alkyl group, an acyl group, or a substituted Good lower alkoxycarbonyl group, trialkyl Conventional protecting groups such as a silyl group can be exemplified. Of these, preferred are, for example, unsubstituted aryl aryl lower alkyl groups such as benzyl group and phenethyl group, formyl group, acetyl group, propionyl group, malonyl group, acryl group such as acryloyl group and benzoyl group, and methoxycarbonyl. And lower alkylcarbonyl groups such as ethoxycarbonyl group, and trialkylsilyl groups such as trimethylsilyl group, triethylsilyl group and tert-butyldimethylsilyl group. Further, a triphenylmethyl group, a 2-cyanoethyl group and the like can be mentioned. Among the target compounds [I] of the present invention, preferred compounds are those wherein ring A has the formula:

R ¹ゝ no where R ¹ is

(1) a phenyl lower alkyl group,

(2) phenyl group,

(3) phenyl lower alkoxy group,

(4) a lower alkoxycarbonyl group which may be substituted with a phenyl group; (5) a lower alkyl group; a lower alkenyl group; a phenyl lower alkenyl group; a lower alkoxycarbonyl group; and a phenyl lower alkoxyl group. An amino group which may be substituted with a group selected from

(6) Formula: — CONR ⁴ R ⁵

In the formula, R ⁴ and R ⁵ may be the same or different, and each represents a group selected from a hydrogen atom, an alkyl group, a phenyl lower alkyl group, a pyridyl lower alkyl group, and a phenyl group. , Or,

Wherein n is 1 or 2,

Represents a group represented by

Is a group represented by

Is equation (1):

No m

Wherein m is 1 or 2, and R ⁶ is

(i) a lower alkoxycarbonyl group,

(ii) a pyrimidinyl group which may be substituted with a group selected from a lower alkyl group, an amino group, and a cyano group, or

(iiii) benzenesulfonyl group,

Represents

A group represented by

Formula (2): — (CH ₂ ) p-NHR ⁷

Wherein p is 1 or 2, and R ⁷ is

(i) a lower alkoxycarbonyl group,

(ii) a pyrimidinyl group optionally substituted with a group selected from a lower alkyl group, an amino group, and a cyano group;

(i i i) a benzenesulfonyl group,

(iv) a chenylsulfonyl group, or

(V) a di-lower alkylphosphono group,

Represents

A group represented by or

Formula (3): — CONH— (CH ₂ ) _q -R ⁸

In the formula, Q is 1 or 2, and R ⁸ represents a pyridyl group, a pyrimidinyl group, a pyrazinyl group, or a pyridazinyl group, And a compound represented by the following formula:

Among the target compounds [I] of the present invention, more preferred compounds include those represented by the formula:

Where R ¹ is

(1) a phenyl lower alkyl group,

(2) phenyl group,

(3) phenyl lower alkoxy group,

(4) a lower alkoxycarbonyl group optionally substituted with a phenyl group,

(5) a lower alkyl group; a lower alkynyl group; a phenyl lower alkenyl group; a lower alkoxycarbonyl group; and an amino group which may be substituted with a group selected from a phenyl lower alkenyl group.

(6) Formula: — CONR ⁴ R ⁵

Equation (7):

Wherein n is 1 or 2,

Represents a group represented by

Is a group represented by 丫 is = (： ^^ one,

R ² is the formula (1):

In the formula, R ⁶ represents a lower alkoxycarbonyl group, a pyrimidinyl group, or a benzenesulfonyl group,

A group represented by

(2) Formula: ― (CH ₂ ) _P -NHR ⁷

Wherein p is 1 or 2, and R ⁷ represents a lower alkoxycarbonyl group, a pyrimidinyl group, or a benzenesulfonyl group,

A group represented by or

Equation (3):

Where q is 1 or 2,

And a compound represented by the following formula:

Specific examples of more preferred compounds of the object compound [I] of the present invention include, for example, R ¹ is an N, N-dimethylcarbamoyl group, an N-methyl-N_n-butylcarbamoyl group, an N-phenylcarbamoyl group, —Benzylcarbamoyl, N-methyl-N— (2- (2-pyridyl) ethyl) rubamoyl, pyrrolidinocarbonyl, piperidinocarbonyl, benzyloxycarbonyl, benzyloxy, phenyl, 3— A phenylpropyl group, an N-methyl-N-ethoxycarbonylamino group, a benzyloxycarbonylamino group or the like, wherein R ² is a (2-pyrimidinyl) aminomethyl group, a 2- (2-pyrimidinyl) aminoethyl Group, 2- (benzenesulfonylamino) ethyl group, 3- (2-pyrimidinyl) aminopyrrolidino group, 3- (methoxycarbonyl Amino) pyrrolidino group, N- (2- (2-pyridyl) ethyl) rubamoyl group; and compounds in which R ³ is a hydrogen atom or a chlorine atom.

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

R ¹

In the formula, R ¹ represents a phenyl lower alkyl group,

A group represented by

R ² is the formula (1):

In the formula, R ⁶ represents a lower alkoxycarbonyl group or a pyrimidinyl group,

A group represented by or

Formula (2): — (CH ₂ ) p-NHR ⁷

In the formula, p represents 1 or 2, R ⁷ represents a pyrimidinyl group or a benzenesulfonyl group,

A group represented by

R ³ is a hydrogen atom,

The compound which is is mentioned. Specifically, 2_ [4 -— (2- (4- (3-phenylpropyl) piperidine-1-yl) benzoylamino) benzylamino] pyrimidine,

1- [4- (4- (4- (3-phenylpropyl) piperidine-111-benzyl) benzoylamino) phenyl] -1-3-methoxycarbonylaminopyrrolidine, or a pharmaceutically acceptable salt thereof Salt. When the substituent on ring A and / or R ² has an asymmetric atom, the target compound [I] of the present invention can exist as an optical isomer based on the asymmetric atom. It includes both isomers and mixtures thereof.

The target compound [I] 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 target compound [I] of the present invention or a pharmacologically acceptable salt thereof includes hyperlipidemia, ischemic heart disease, atherosclerosis, coronary atherosclerosis, hypercholesterolemia, hypertriglyceridemia. , Familial hyperlipidemia, hyperlipoproteinemia, arteriosclerosis, coronary atherosclerosis, coronary heart disease, ischemic brain disease, stroke, circulatory and microcirculatory disorders, thrombosis, hyperglycemia, diabetes, acute bleeding適用 Applicable to prevention and treatment of inflammation, obesity, steatosis, constipation, etc. Furthermore, the target compound [I] of the present invention has the characteristics of low toxicity and high safety as a medicine.

The target compound [I] of the present invention can be used in a free form or in the form of a pharmaceutically acceptable salt for pharmaceutical use. Pharmaceutically acceptable salts of compound [I] include, for example, inorganic salts such as hydrochloride, sulfate, phosphate or hydrobromide, acetate, fumarate, oxalate, and the like. Organic salts such as citrate, methanesulfonate, benzenesulfonate, tosylate or maleate are listed. When it has a substituent such as a carboxyl group, a salt with a base (for example, an alkali metal salt such as a sodium salt or a potassium salt or an alkaline earth metal salt such as a calcium salt) can be mentioned.

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

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

The dose of the compound of interest [I] of the present invention or a pharmaceutically acceptable salt thereof varies depending on the administration method, age, weight, and condition of the patient. About 0.01 to 5 mg / kg per day, especially about 0.1 to 3 mg / kg, for oral preparation, usually about 0.1 to 10 Omg / kg, especially about 0.1 to 10 mg / day.

It is preferred to be about 1 to 5 Omg / kg.

Method for producing phenylcarboxamide compound>

According to the present invention, the target compound [I] can be produced by the following [Method A] to [Method E] according to a conventional method, but is not limited thereto.

[Method A]

The phenylcarpoxamide compound represented by the target compound [I] of the present invention has the general formula [1]:

Wherein the symbols have the same meanings as described above,

And a carboxylic acid compound represented by the general formula [2]

Wherein the symbols have the same meanings as described above,

Or a salt thereof.

This reaction can be carried out in a solvent, in the presence of a condensing agent, in the presence or absence of an activator, in the presence or absence of a base group. The solvent may be any solvent that does not adversely affect the reaction. Examples of the solvent include methylene chloride, chloroform, dimethylformamide, dimethylacetamide, tetrahydrofuran, toluene, benzene, 1,2-dichloroethane, and 1,1-dichloroethane. Methylpyrrolidinone and the like. Examples of the condensing agent include dicyclohexyl carbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and hydrochloride (WS C · HC 1), diphenylphosphoryl azide (DPPA), carbonyldiimidazole (CD I), getylcyanophosphonate (DEPC), diisopropyl carbodiimide (DI PC I), benzotriazole-l-oxyl Rispyrrolidinophosphonium hexafluorophosphate (PyBOP) and the like. Examples of the activator include 1-hydroxybenzotriazole (HOBt), hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP), 1-hydroxy-7-azabenzotriazole (HOAt), Examples include hydroxyfurimide (HOPht) and penfluorophenol (PfP-OH). Examples of the base include triethylamine, diisopropylethylamine, 4-methylmorpholine, 1,8-diazabicyclo [5,4.0] -17-indene (DBU) and the like.

The amount of the condensing agent to be used may be 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to compound [1] or [2]. The amount of the activator to be used may be 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to compound [1] or [2]. The amount of the base to be used may be 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to compound [1] or [2].

This reaction can be carried out at 0 to 100 t, preferably at 0 to 50 t.

Further, the compound [1] may be once converted into a reactive derivative such as an acid chloride or a mixed acid anhydride, and then reacted with the compound [2] in the presence of a base.

[Method B]

The phenylcarpoxamide compound represented by the target compound [I] of the present invention has the general formula [3]:

In the formula, X represents a halogen atom, and other symbols have the same meanings as described above. And a salt thereof, and a general formula [4]:

Wherein the symbols have the same meanings as described above,

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

This reaction can be carried out in a solvent, in the presence or absence of a base, or in the presence or absence of an activator. The solvent may be any solvent that does not adversely affect the reaction. For example, methanol, ethanol, 1,3-dimethyl-2-imidazolidinone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, 1-methyl-2 —Pyrrolidinone and the like. Examples of the base include organic bases such as triethylamine and diisopropylethylamine, and inorganic bases such as potassium carbonate, sodium carbonate and cesium carbonate. Examples of the activator include copper (I) iodide, copper powder, palladium acetate and the like.

The amount of the base to be used may be 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to compound [3] or [4]. The amount of the activator to be used may be 0.001 to 0.5 equivalent, preferably 0.05 to 0.2 equivalent, relative to compound [3] or [4].

This reaction can be carried out at 0 to 15 °, preferably 0 to 80.

[Method C]

Among the target compounds of the present invention, in the general formula [I], R ² is a group represented by the formula:

^{1 m}

Wherein the symbols have the same meanings as described above, A compound represented by the general formula [I-a]

Wherein the symbols have the same meanings as described above,

The phenylcarboxamide compound represented by the general formula [5]

Wherein the symbols have the same meanings as described above,

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

R ⁶ — X ² [6]

In the formula, X ² represents a leaving group, and other symbols have the same meanings as described above, and can be produced by reacting with a compound represented by the formula or a salt thereof.

This reaction can be carried out in a solvent, in the presence or absence of a base. The solvent may be any solvent that does not adversely affect the reaction, and examples thereof include water, ethanol, dimethylformamide, ethyl acetate, chloroform, methylene chloride, and a mixed solvent thereof. Examples of the base include triethylamine, diisopropylethylamine, potassium carbonate, sodium carbonate and the like.

The amount of the base to be used may be 1-20 equivalents, preferably 1-5 equivalents, relative to compound [5] or [6]. This reaction can be carried out at a temperature of from 30 to 15 ??, preferably from 0 to 80. The leaving group X ² includes a halogen atom, a trifluoromethanesulfonyloxy group and the like.

[Method D]

Further, among the target compounds of the present invention, R ² in the general formula [I] is represented by the formula:

-(CH ₂ ) _P — NHR ⁷

Wherein the symbols have the same meanings as described above,

A compound represented by the formula: [I—b]:

Wherein the symbols have the same meanings as described above,

The phenylcarpoxamide compound represented by the general formula [7]

Wherein the symbols have the same meanings as described above,

Or a salt thereof, and a general formula [8]:

R ⁷ — X ² [8]

In the formula, X ² represents a leaving group, and other symbols have the same meanings as described above, and can be produced by reacting with a compound represented by the formula or a salt thereof. This reaction can be carried out in a solvent, in the presence or absence of a base. The solvent may be any solvent that does not adversely affect the reaction. For example, those exemplified as the solvent that can be used in the reaction of compound [5] with compound [6] in the above [Method C] may be used as appropriate. it can. Also, as the base, for example, the bases exemplified in the above [Method C] can be used as appropriate.

The amount of the base to be used may be 1 to 20 equivalents, preferably 1 to 10 equivalents, relative to compound [7] or [8].

This reaction can be carried out at 0 to 150, preferably 0 to 80 :.

[Method E]

Further, among the target compounds of the present invention, R ² in the general formula [I] is represented by the formula: -CONH- (CH ₂ ) _q -R ⁸

Wherein the symbols have the same meanings as described above,

A compound represented by the general formula [I-c]:

[ I c ]

Wherein the symbols have the same meanings as described above,

The phenylcarboxamide compound represented by the general formula [9]

Wherein the symbols have the same meanings as described above,

A carboxylic acid compound or a salt thereof represented by the general formula [10]

H. N (CH ₂ ) _n -R ⁸ [10] Wherein the symbols have the same meanings as described above,

Or a salt thereof.

This reaction can be carried out in a solvent, in the presence of a condensing agent, in the presence or absence of an activator, in the presence or absence of a base group. The solvent may be any solvent that does not adversely affect the reaction. For example, those exemplified as solvents that can be used in the reaction of compound [1] with compound [2] in the above [Method A] may be appropriately used. Can be used. In addition, as the base or the activator, for example, the base or the activator exemplified in the above [Method A] can be appropriately used.

The amount of the condensing agent to be used can be 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to compound [9] or [10]. The amount of the activator to be used may be 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to compound [9] or [10]. The amount of the base to be used may be 1-10 equivalents, preferably 1-2 equivalents, relative to compound [9] or [10].

This reaction can be carried out at 0 to 100T: preferably 0 to 5O ^ C. The target compound [I] of the present invention is also produced by further converting the substituent on R ¹ and / or R ^{2 of the} compound obtained as described above to another desired substituent. be able to. Such a method for converting a substituent may be appropriately selected according to the type of the desired substituent, and may be carried out, for example, as in (Method a) to (Method f).

(Method a: Alkylation of hydroxyl group)

The target compound [I] in which the substituent on the ring A in the general formula [I] is an aryl lower alkoxy group, is a compound having a hydroxyl group as a substituent on the ring A and an aryl lower alkyl halide (for example, benzyl bromide). ) In the presence of a base (eg, sodium hydride, potassium carbonate).

(Method b: alkylation of an amino group)

Wherein the substituent on ring A in the general formula [I] is a lower alkylamino group. Compound [I] is obtained by converting a corresponding compound [I] in which the substituent on ring A is an amino group and a lower alkyl halide (eg, methyl iodide) to a base (eg, sodium hydride, potassium carbonate). It can be produced by reacting in the presence.

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

The target compound [I] in which the substituent on the ring A in the general formula [I] is a lower alkylamino group (for example, a dimethylamino group, a getylamino group) is a corresponding compound [where the substituent on the ring A is an amino group] I] and a lower alkanal (eg, formaldehyde) in the presence of a reducing agent (eg, sodium borohydride, sodium triacetoxyborohydride).

(Method d: acylation of an amino group)

The target compound [I] wherein the substituent on ring A in the general formula [I] is an amino group substituted with a group selected from a lower alkanoyl group; an aryl lower alkanoyl group; a lower alkoxycarbonyl group; and an aryl lower alkoxycarbonyl group. ] Is a reaction between a corresponding compound [I] in which the substituent on ring A is an amino group and a corresponding acylating agent or the like (eg, benzyloxycarbonyl chloride) with a base (eg, triethylamine, potassium carbonate) It can be produced by reacting in the presence.

(Method e: amidation of the carbonyl group)

The substituent on ring A in the general formula [I] is represented by the formula:

— CONR ⁴ R ⁵

Wherein the symbols have the same meanings as described above,

Or a group represented by the formula:

Wherein the symbols have the same meanings as above, The target compound [I], which is a group represented by, is a corresponding compound [I] in which the substituent on ring A is a carboxyl group,

HNR ⁴ R ⁵

Wherein the symbols have the same meanings as described above,

Or a compound represented by the formula:

No n

Wherein the symbols have the same meanings as described above,

Can be produced by reacting the compound of the formula with the same method as in the above [Method A].

(Method f: Carboxyl group esterification)

The target compound [I] in which the substituent on the ring A in the general formula [I] is an aryl lower alkoxy group (for example, a benzyloxycarbonyl group) is a corresponding compound [I] in which the substituent on the ring A is a carboxyl group. And a corresponding aryl lower alcohol (for example, benzyl alcohol) in the same manner as in the above [Method A].

The target compound [I] of the present invention obtained as described in the above [Method A] to [Method E] or [Method a] to [Method f] may be converted into a pharmacologically acceptable salt, if desired. It can also be converted. Conversion to a pharmaceutically acceptable salt may be performed according to a conventional method known to those skilled in the art.

Manufacturing method of raw material compounds>

Starting compound [1] can be produced, for example, according to the following method. COOR ^y

[1]

In the formula, R ⁹ represents a lower alkyl group or a benzyl group, and other symbols have the same meanings as described above.

The reaction for producing compound [12] from compound [11] and compound [4] can be carried out in the same manner as in the above [Method B].

The reaction to produce compound [1] from compound [12] must be carried out under conventional hydrolysis reaction conditions (for example, sodium hydroxide-monohydrate) or hydrogenolysis reaction conditions (palladium-carbon monohydrogen). Can be.

Starting compound [2-a] (starting compound used to produce final compound [I-a] of compound [2] used in method A) and [5] must be produced, for example, according to the following method Can be.

In the formula, X ¹ represents a halogen atom, P represents a protecting group for an amino group, and other symbols have the same meanings as described above.

The reaction to produce compound [15] from compound [13] and compound [14] is a solution. It can be carried out in a medium, in the presence or absence of a base. The solvent may be any solvent that does not adversely affect the reaction, and examples thereof include 1,3-dimethyl-2-imidazolidinone, dimethylformamide, and dimethylacetamide. Examples of the base include triethylamine, diisopropylethylamine, potassium carbonate, sodium carbonate and the like.

The reaction for producing the compound [16] from the compound [15] can be carried out under conventional reduction reaction conditions (for example, palladium monocarbon hydrogen, iron-ammonium chloride).

The reaction for producing compound [18] from compound [16] and compound [1] can be carried out in the same manner as in the above [Method A].

The reaction for producing compound [5] from compound [18] is carried out using a conventional protected amino group deprotecting agent (for example, trifluoroacetic acid, monodioxane hydrochloride solution, trimethylsilane iodide, palladium / carbon-hydrogen, etc. The same shall apply hereinafter).

The reaction for producing compound [17] from compound [16] can be carried out in the presence of a conventional protected amino group deprotecting agent.

The reaction for producing compound [2-a] from compound [17] and compound [6] can be carried out in the same manner as in the above-mentioned [Method C].

Examples of the protecting group P for an amino group include a methoxycarbonyl group, a lower alkoxycarbonyl group such as a tert-butoxyl propyl group, a benzyloxycarbonyl group, and the like.

Starting compound [2-b] (starting compound used for producing final compound [I_b] of compound [2] used in method A) and [7] are produced, for example, according to the following method be able to.

[19] [20]

In the formula, the symbols have the same meaning as described above.

The reaction for producing the compound [20] from the compound [19] can be carried out in the presence of a conventional reducing agent (for example, a polan'dimethylsulfide complex). The reaction for producing the compound [21] from the compound [20] can be carried out in the presence of a conventional protecting agent for an amino group (for example, ditert-butyl dicarbonate).

The reaction for producing compound [22] from compound [21] can be carried out in the presence of a conventional reducing agent (for example, palladium carbon monohydrogen).

The reaction for producing compound [24] from compound [22] and compound [1] can be carried out in the same manner as in the above [Method A].

The reaction for producing compound [7] from compound [24] can be carried out in the presence of a conventional protected amino group deprotecting agent.

The reaction for producing the compound [23] from the compound [22] can be carried out in the presence of a conventional protected amino group deprotecting agent.

The reaction for producing compound [2-b] from compound [23] and compound [8] can be carried out in the same manner as in the above-mentioned [Method C].

Starting compound [2-c] (starting compound used for producing final compound [I_c] among compound [2] used in method A) and [9] can be produced, for example, according to the following method. it can.

[25] [27] [28]

In the formula, R ²¹ represents a lower alkyl group, and other symbols have the same meanings as described above.

The reaction for producing compound [26] from compound [25] and compound [10] can be carried out in the presence or absence of a solvent or in the presence of a base. The solvent may be any solvent that does not adversely affect the reaction, and examples thereof include methylene chloride and tetrahydrofuran. As the base, for example, pyridine, trie Tilamine, disopropylethylamine and the like.

The reaction for producing compound [2-c] from compound [26] can be carried out in the presence of a conventional reducing agent (eg, palladium / carbon-hydrogen).

The reaction to produce compound [27] from compound [25] is a lower alcohol (R ²

¹ 〇H).

The reaction for producing compound [28] from compound [27] can be carried out in the presence of a conventional reducing agent (for example, palladium Z-carbon monohydrogen, iron monochloride ammonium).

The reaction for producing compound [29] from compound [28] and compound [1] can be carried out in the same manner as in the above [Method A].

The reaction for producing the compound [9] from the compound [29] can be carried out under conventional hydrolysis reaction conditions (for example, sodium hydroxide / aqueous solution).

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

[30] [2] [3]

Wherein the symbols have the same meanings as described above,

The reaction for producing compound [3] from compound [30] and compound [2] can be carried out in the same manner as in the above [Method A].

In producing the target compound [I], [I-a], [I-b] or [I-c], each intermediate compound is involved not only in the chemical reaction but also in the reaction. If not, its salt or its reactive derivative can also be used as appropriate. Examples of the salt include metal salts such as sodium, potassium, lithium, calcium, and magnesium, salts with organic bases such as pyridine, triethylamine, diisopropylethylamine, and the like, hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, Salts with inorganic acids such as phosphoric acid, acetic acid, oxalic acid, citric acid, benzenesulfonic acid, benzoic acid, malon Examples thereof include salts with organic acids such as acid, cunic acid, formic acid, fumaric acid, maleic acid, methanesulfonic acid, p-toluenesulfonic acid, and trifluoroacetic acid.

Further, in the production of the target compound of the present invention and the starting compound, when the starting compound or each intermediate has a functional group, in addition to the above, an appropriate protecting group for each functional group may be obtained by a conventional method of synthetic chemistry. And protecting groups may be appropriately removed when unnecessary.

In the present invention, examples of the alkyl group include linear or branched ones having 1 to 16 carbon atoms, and particularly those having 1 to 10 carbon atoms. The lower alkyl group or lower alkoxy group includes straight or branched ones having 1 to 6 carbon atoms, particularly those having 1 to 4 carbon atoms. In addition, a lower alkanoyl group is a straight-chain or branched-chain one having 2 to 7 carbon atoms, especially 2 to 5 carbon atoms, and a cycloalkyl group is 3 to 20 carbon atoms, especially Those having 3 to 12 carbon atoms are exemplified. The cyclo lower alkyl group includes those having 3 to 8 carbon atoms, particularly those having 3 to 6 carbon atoms. The alkenyl group includes a linear or branched chain having 2 to 16 carbon atoms, particularly 2 to 10 carbon atoms, and the lower alkenyl group includes 2 to 8 carbon atoms, particularly 2 carbon atoms. ~ 4 are listed. The alkylene group includes a linear or branched one having 1 to 16 carbon atoms, particularly 1 to 10 carbon atoms, and the lower alkylene includes 1 to 8 carbon atoms, particularly 1 to 6 carbon atoms. And a linear or branched one. Further, halogen atoms include fluorine, chlorine, bromine or iodine. Example

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

Example 1

2- (4-aminobenzylamino) pyrimidine (compound obtained in Reference Example 5) 580 mg, 2- [4- (3-phenylpropyl) piperidine-1-yl] an Benzoic acid (compound obtained in Reference Example 4) A solution of 984 mg, 35 mg of 4-dimethylaminopyridine and 43 lmg of 1-hydroxybenzotriazole in 15 ml of dimethylformamide (15 ml) was added under ice-cooling to 1-ethyl-3-amine. 616 mg of (3-dimethylaminopropyl) -carposimide.hydrochloride was added, and the mixture was stirred at room temperature for 18 hours. After 14 hours on the way, 278 mg of 1-ethyl-3- (3-dimethylaminopropyl) monocarbodiimide hydrochloride was added. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with concentrated aqueous ammonia, water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue is purified by silica gel chromatography (developing solvent; hexane: ethyl acetate = 2: 1), and recrystallized with a mixed solvent of ethyl diisopropyl acetate to obtain 2_ [4_ (2- 779 mg of (4- (3-phenylpropyl) piperidine-1-yl) benzoylamino) benzylamino] pyrimidine was obtained as colorless crystals.

M. p. 137.5-138.5

Example 2-3

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

Table 1

Reference example 1

To a suspension of dimethylformamide (500 ml) containing 58.29 g of 2-fluorobenzoic acid and 57.42 g of potassium carbonate, 71.16 g of benzylbenzene bromide was added dropwise under ice-cooling. Stirred at room temperature for 15 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was distilled under reduced pressure to obtain 86.13 g of benzyl 2-fluorobenzoate as a pale yellow oil.

B. p. (3mmHg) 152-1551:

Reference example 2

(1) To a solution of 25.75 g of benzyl 2-fluorobenzoate and 21.98 g of ethyl isodipecotate in 100 ml of dimethylformamide, add 23.18 g of potassium carbonate and stir at 80 for 20 hours. did. Pour the reaction solution into ice water and add vinegar Extracted with acid ethyl. The organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent is distilled off, and the residue is purified by silica gel column chromatography (developing solvent; ethyl acetate: n-hexane = 1:10) to give 2- (4-ethoxyethoxycarbonylbiperidine-1-yl). 20.4 1 g of benzyl benzoate was obtained as a pale yellow oil.

MS (APC I) m / z; 368 (M + H).

(2) A mixed solution of 4.77 g of the compound obtained in the above (1), a 1 M aqueous sodium hydroxide solution (13 ml) in ethanol (25 ml) -tetrahydrofuran (10 ml) was stirred at room temperature for 5 hours. To the reaction solution was added a 2 molar equivalent aqueous solution of citric acid, and the mixture was extracted with ethyl acetate. The organic layer was extracted with an aqueous sodium hydrogen carbonate solution, and the pH of the obtained aqueous layer was adjusted to 415 with citric acid. Then, sodium chloride was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 2.59 g of benzyl 2- (4-potassium lipoxypiperidine-1-yl) benzoate as a colorless oil.

MS (ES I) m / z; 338 (MH), IR (neat) cm "¹; 1 70 4.

(3) A solution of 1.0 g of the compound obtained in the above (2), dimethylamine, hydrochloride (405 mg), triethylamine (0.7 ml) and 1-hydroxybenzotriazole (405 mg) in methylene chloride (10 ml) was added to ice solution. Under cooling, 7-64 mg of 1-ethyl-3- (3-dimethylaminopropyl) -carboimide.hydrochloride was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with chloroform, washed with water, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and dried over anhydrous sodium sulfate. The solvent is distilled off, and the residue is purified by silica gel column chromatography (developing solvent; n-hexane: ethyl acetate = 1: 2) to give 2- (4-dimethyl-rubamoylbiperidine). 9) 976 mg of benzyl benzoate was obtained as a colorless oil.

MS (APC I) m / z: 367 (M + H), IR (neat) cm—17 20, 1642.

(4) A suspension of 97 Omg of the compound obtained in the above (3) and 10 Omg of 10% palladium on carbon in 10 mL of ethanol was stirred under a hydrogen atmosphere at room temperature and normal pressure for 3 hours. The catalyst was removed by filtration, the filtrate was concentrated, and the residue was triturated with n-hexane to give 595 mg of 2- (4-dimethylcarbamoylbiperidine-11-yl) benzoic acid as a colorless powder As obtained.

MS (AP CI) m / z: 277 (M + H), IR (nujo 1) cm ^-1 : 1 626.

Reference example 3

The corresponding starting compounds were treated in the same manner as in Reference Example 2 (1) to give the compounds shown in Table 2.

Table 2

R ¹

Reference example number R ¹ R Physical constant, etc.Oil

3 ^ 0 -COOBn MS (APCI) m / z; 414 (M + H)

IR (neat) cm— ¹ ; 1723, 1596

Bn: benzyl group Reference example 4

The compound obtained in Reference Example 3 was treated in the same manner as in Reference Example 2 (4) to give the compounds described in Table 3. Table 3

R ¹

Reference example number R ¹ R Physical constant, etc.

4 -C00H M. p. 113.5-115

Reference example 5

A solution of 489 mg of 4-aminobenzylamine, 701 mg of 2-bromopyrimidine and 1.7 ml of triethylamine in ethanol (8 ml) was heated under reflux overnight. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from a mixed solution of ethyl isopropyl ether acetate to obtain 408 mg of 2- (4-aminobenzylamino) pyrimidine as colorless prism crystals. M. p. 136—139

Reference example 6

(1) A solution of 705 mg of p-fluoronitrobenzene, 1.44 g of 3-methoxycarbonylaminopyrrolidine hydrochloride and 2 ml of triethylamine in 10 ml of a 1,3-dimethyl-2-imidazolidinone (100 ml) was added. For 1 hour. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from a mixed solution of ethyl acetate-isopropyl ether to give 1- (4-nitro- 1.16 g of mouth phenyl) -3-methoxycarbonylaminopyrrolidine were obtained as yellow needles.

M. p. 173-174

(2) The compound obtained in (1) above was suspended in a mixed solution of 1.09 g and 10% palladium-carbon (300 mg) in tetrahydrofuran (25 ml) -methanol (25 ml) under a hydrogen atmosphere at room temperature and normal pressure. Stir for 2 hours. The catalyst was removed by filtration, the filtrate was concentrated, and the residue was crystallized from a mixed solution of ethyl isopropyl ether to give 903 mg of 1- (4-aminophenyl) -13-methoxycarbonylaminopyrrolidine as colorless prisms. Obtained.

Industrial Applicability in M. p. 149-151

The target compound [I] of the present invention or a pharmacologically acceptable salt thereof has an apolipoprotein B secretion inhibitory effect and shows excellent adoption of serum lipid lowering.

Therefore, the target compound [I] of the present invention or a pharmaceutically acceptable salt thereof is preferably hyperlipidemia, ischemic heart disease, atherosclerosis, coronary atherosclerosis, hypercholesterolemia, hypertriglyceridemia. , Familial hyperlipidemia, hyperlipoproteinemia, arteriosclerosis, coronary atherosclerosis, coronary heart disease, ischemic brain disease, stroke, circulatory and microcirculatory disorders, thrombosis, hyperglycemia, diabetes, acute hemorrhagic It can be applied to the prevention and treatment of knee inflammation, obesity, steatosis, constipation, etc.

Claims

In the general formula [I]: one blue, ring A represents a nitrogen-containing aliphatic heterocyclic group which may be substituted, represents == ^^ _ or = N—, and R2 represents (1 ) Formula: Range NHR6 H N, m In the formula, m is an integer of 0 to 3, R 6 represents an organic group, a group represented by the following formula: (2) Formula: One (CH2) P-NHR7 Formula In the formula, p is an integer of 1 to 6, R 7 represents an organic group, a group represented by or a formula (3): — CONH— (CH2) Q-R8 wherein Q is 1 to 6 Is an integer, R8 represents an optionally substituted heterocyclic group, represents a group represented by, R3 represents a hydrogen atom or a halogen atom, and represents a phenylcarboxamide compound represented by or a pharmaceutically acceptable salt thereof. Possible salt. 2. Nitrogen-containing aliphatic heterocycle in which ring A may be substituted with a group selected from the following

(1) aryl lower alkyl group, (2) Aryl group,

(3) aryl lower alkoxy group,

(4) carboxyl group,

(5) a lower alkoxycarbonyl group which may be substituted with an aryl group,

(6) a lower alkyl group; a lower alkyl group; an aryl lower alkyl group; a lower alkoxycarbonyl group; and a aramino group which may be substituted with a group selected from an aryl lower alkoxycarbonyl group;

(7) Formula: _CONR ⁴ R ⁵

In the formula, R ⁴ and R ⁵ may be the same or different and each represents a group selected from a hydrogen atom, an alkyl group, an aryl lower alkyl group, a pyridyl lower alkyl group, and an aryl group.

A group represented by or

Equation (8): / n

Where n is an integer from 0 to 3,

A group represented by

And

R ² is represented by the following equation (1):

NHR ⁰ CH

N, m wherein m is an integer from 0 to 3, and R ⁶ is

(i) a lower alkyl group,

(ii) a lower alkanoyl group,

(iii) a lower alkoxycarbonyl group, (iv) a lower alkyl group; an amino group which may be protected; a hydroxyl group which may be protected; a cyano group; and a nitrogen-containing aromatic heterocyclic group which may be substituted with a group selected from a halogen atom;

(V) arylsulfonyl group, or

(vi) represents a lower alkylsulfonyl group,

A group represented by

Formula (2): One (CH ₂ ) _P -NHR ⁷

Wherein p is an integer from 1 to 6, and R ⁷ is

(i) a lower alkyl group,

(ii) a lower alkanoyl group,

(iiii) a lower alkoxycarbonyl group,

(iV) a lower alkyl group; an amino group which may be protected; a hydroxyl group which may be protected; a cyano group; and a nitrogen-containing aromatic heterocyclic group which may be substituted with a group selected from halogen atoms. ,

(V) arylsulfonyl group,

(V i) a lower alkylsulfonyl group,

(V i i) an aromatic heterocyclic group-substituted sulfonyl group, or

(vii i) represents a di-lower alkylphosphono group,

A group represented by or

Formula (3): — CONH— (CH ₂ ) _Q -R ⁸

(i) a lower alkyl group,

(ii) an amino group which may be protected,

(iii) an optionally protected hydroxyl group,

(i V) a cyano group, and

(V) a halogen atom, Represents

2. The compound according to claim 1, which is a group represented by the formula:

3. The compound according to claim 2, wherein the nitrogen-containing aliphatic heterocyclic group in ring A is a 3- to 8-membered aliphatic heterocyclic group having one or two nitrogen atoms.

4. R ² is the formula (1):

Where m is an integer from 0 to 3, and R ⁶

(i) a lower alkyl group,

(ii) a lower alkanoyl group,

(i i i) a lower alkoxycarbonyl group,

(iv) a lower alkyl group; an optionally protected amino group; an optionally protected hydroxyl group; a cyano group; and one to four nitrogen atoms which may be substituted with a group selected from halogen atoms. A monocyclic or bicyclic nitrogen-containing aromatic heterocyclic group,

(V) arylsulfonyl group, or

(V i) represents a lower alkylsulfonyl group,

A group represented by

Formula (2): — (CH ₂ ) _P -NHR ⁷

Wherein p is an integer from 1 to 6, and R ⁷ is

(i) a lower alkyl group,

(ii) a lower alkanoyl group,

(i i i) a lower alkoxycarbonyl group,

(iV) a lower alkyl group: an amino group which may be protected; a hydroxyl group which may be protected; a cyano group; and 1 to 4 nitrogen atoms which may be substituted with a group selected from a halogen atom. Containing a monocyclic or bicyclic nitrogen-containing aromatic heterocyclic group,

(V) arylsulfonyl group,

(vi) a lower alkylsulfonyl group, (vii) a sulfonyl group substituted with a monocyclic or bicyclic aromatic heterocyclic group containing 1 to 4 hetero atoms which are the same or different and selected from nitrogen, oxygen and sulfur, or

(vii i) represents a di-lower alkylphosphono group,

A group represented by or

(3) Formula: _C〇NH_ (CH ₂ ) _q -R ⁸

In the formula, q is an integer of 1 to 6, and R ⁸ is a monocyclic or bicyclic nitrogen-containing aromatic heterocycle containing 1 to 4 nitrogen atoms which may be substituted with a group selected from the following. Formula group:

(i) a lower alkyl group,

(ii) an amino group which may be protected,

(iiii) an optionally protected hydroxyl group,

(i V) a cyano group, and

(V) a halogen atom,

Represents

4. The compound according to claim 3, which is a group represented by the formula:

5. When the 3- to 8-membered aliphatic heterocyclic group containing one or two nitrogen atoms in ring A is an aziridinyl group, azetidinyl group, pyrrolidinyl group, piperidino group, piperazinyl group, morpholino group, azepanyl group, diazepanyl group 5. The compound according to claim 3 or 4, which is:

6. A monocyclic or bicyclic nitrogen-containing aromatic heterocyclic group containing 1 to 4 nitrogen atoms in R ⁶ , R ⁷ or R ⁸ is a pyrrolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an imidazolyl group , Pyrazolyl group, triazolyl group, tetrazolyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl group, indolyl group, quinolyl group, isoquinolyl group, quinazolinyl group, purinyl group, 1H-indazolyl group, cinnolinyl group, quinoxalinyl group 5. The compound according to claim 4, which is a phthalazinyl group or a pteridinyl group.

7. A sulfonyl group substituted with a monocyclic or bicyclic aromatic heterocyclic group containing 1 to 4 hetero atoms which are the same or different and selected from nitrogen, oxygen and sulfur in R ⁷ is a furyl. Group, chenyl group, pyrrolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, imidazolyl group, pyrazolyl group, triazolyl group, tetrazolyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl group, indolyl group, quinolyl group, quinolyl group 5. The compound according to claim 4, which is a sulfonyl group substituted by a group selected from a group, a quinazolinyl group, a purinyl group, a 1H_indazolyl group, a cinnolinyl group, a quinoxalinyl group, a furazinyl group, and a pteridinyl group.

8. The aryl group in ring A is a phenyl, naphthyl, anthryl, or phenanthryl group, and the arylsulfonyl group in R ⁶ or R ⁷ is a phenyl, naphthyl, anthryl, and phenanthryl group 5. The compound according to claim 4, which is a sulfonyl group substituted with a group selected from:

9. Ring A has the formula:

R in ^one two formulas, R ¹ is,

(1) a phenyl lower alkyl group,

(2) phenyl group,

(3) phenyl lower alkoxy group,

(4) a lower alkoxycarbonyl group which may be substituted with a phenyl group; (5) a lower alkyl group; a lower alkanol group; a phenyl lower alkanol group; a lower alkoxycarbonyl group; and a phenyl lower alkoxy group selected from the group consisting of a phenyl group. An amino group optionally substituted with

(6) Formula: One CONR ⁴ R ⁵ In the formula, R ⁴ and R ⁵ may be the same or different, and each represents a group selected from a hydrogen atom, an alkyl group, a phenyl lower alkyl group, a pyridyl lower alkyl group, and a phenyl group. , Or,

Equation (7): n

Wherein n is 1 or 2,

Represents a group represented by

Is a group represented by

Is equation (1):

Wherein m is 1 or 2, and R ⁶ is

(i) a lower alkoxycarbonyl group,

(ii) a pyrimidinyl group which may be substituted with a group selected from a lower alkyl group, an amino group, or a cyano group, or

(iiii) benzenesulfonyl group,

Represents

A group represented by

(2) Formula: ― (CH ₂ ) _P -NHR ⁷

Wherein p is 1 or 2, and R ⁷ is

(i) a lower alkoxycarbonyl group,

(ii) a pyrimidinyl group optionally substituted with a group selected from a lower alkyl group, an amino group, and a cyano group; (iii) a benzenesulfonyl group,

(iv) a chenylsulfonyl group, or

(V) a di-lower alkylphosphono group,

Represents

A group represented by or

(3) Formula: One C〇NH_ (CH ₂ ) _Q -R ⁸

In the formula, Q is 1 or 2, and R ⁸ represents a pyridyl group, a pyrimidinyl group, a pyrazinyl group, or a pyridazinyl group,

5. The compound according to claim 4, which is a group represented by the formula:

10. Ring A has the formula:

Where R ¹ is

(1) a phenyl lower alkyl group,

(2) phenyl group,

(3) phenyl lower alkoxy group,

(4) a lower alkoxycarbonyl group which may be substituted with a phenyl group,

Equation (6): One C〇NR ⁴ R ⁵

In the formula, R ⁴ and R ⁵ may be the same or different, and each represents a group selected from a hydrogen atom, an alkyl group, a phenyl lower alkyl group, a pyridyl lower alkyl group, and a phenyl group. , Or, Equation (7):

Wherein n is 1 or 2,

Represents a group represented by

Is a group represented by

Y is two CH_,

R ² is the formula (1):

A group represented by

Formula (2): — (CH ₂ ) _P -NHR ⁷

A group represented by or

Equation (3):

Where Q is 1 or 2,

10. The compound according to claim 9, which is a group represented by the formula:

1 1. R ¹ is a phenyl lower alkyl group,

R ² is the formula (1):

A group represented by or

(2) Formula: ― (CH ₂ ) _P -NHR ⁷

Wherein p is 1 or 2, R ⁷ represents a pyrimidinyl group or a benzenesulfonyl group,

Is a group represented by

11. The compound according to claim 10, wherein R ³ is a hydrogen atom.

12. 2- [4- (2- (4- (3-phenylpropyl) piperidine-11-yl) benzoylamino) benzylamino] pyrimidine,

1- [4- (2- (4-I- (3-phenylpropyl) piperidine-1-yl) benzoylamino) phenyl] -3-methoxycarbonylaminopyrrolidine, or their pharmaceutically acceptable salt.

13. General formula [1]:

In the formula, ring A represents an optionally substituted nitrogen-containing aliphatic heterocyclic group, and a carboxylic acid compound represented by the following formula or a salt thereof, and a general formula [2]:

Where Y represents = CH— or = N—,

R ² is given by equation (1):

NHR ⁰ _y ^CH 2 no m In the formula, m is an integer of 0 to 3, R ⁶ represents an organic group, a group represented by

Formula (2): — (CH ₂ ) _p -NHR ⁷

Wherein p is an integer of 1 to 6, R ⁷ represents an organic group,

A group represented by or

(3) Formula: — CONH— (CH ₂ ) _Q — R ⁸

Wherein Q is an integer of 1 to 6, and R ⁸ represents an optionally substituted heterocyclic group,

Represents a group represented by

R ³ represents a hydrogen atom or a halogen atom,

Wherein the product is converted into a pharmaceutically acceptable salt, if desired, by reacting the compound with an amine compound represented by the formula:

Wherein the symbols have the same meanings as described above,

A method for producing a phenylcarpoxamide compound or a pharmaceutically acceptable salt thereof represented by the formula:

14. General formula [3]:

[3]

In the formula, X represents a halogen atom,

丫 represents = 〇 ^^ — or = N—,

R ² is given by equation (1):

NHR ⁶ ^CH2 , m wherein m is an integer of 0 to 3, and R ⁶ represents an organic group;

A group represented by

(2) Formula: One (CH ₂ ) _P — NHR ⁷

Wherein p is an integer of 1 to 6, R ⁷ represents an organic group,

A group represented by or

(3) Formula: —CONH— (CH ₂ ) _q -R ⁸

In the formula, q is an integer of 1 to 6, and R ⁸ represents an optionally substituted heterocyclic group,

Represents a group represented by

R ³ represents a hydrogen atom or a halogen atom,

And a salt thereof, and a general formula [4]:

Wherein ring A represents a nitrogen-containing aliphatic heterocyclic group which may be substituted, and reacting with a compound represented by the formula (1), and if necessary, converting the product into a pharmaceutically acceptable salt. The general formula [I]:

Wherein the symbols have the same meanings as described above,

A method for producing a phenylcarboxamide compound or a pharmaceutically acceptable salt thereof represented by the formula:

15. General formula [5]:

Y represents = CH_ or = N—,

m is an integer from 0 to 3,

R ³ represents a hydrogen atom or a halogen atom,

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

R ⁶ -X ² [6]

Wherein R ⁶ represents an organic group, X ² represents a leaving group,

Reacting with a compound represented by the following formula (I) or a salt thereof, and converting the product into a pharmacologically acceptable salt, if desired, characterized by the general formula [Ia]:

[Ia]

Wherein the symbols have the same meanings as described above,

1 6. General formula [7]:

In the formula, ring A represents an optionally substituted nitrogen-containing aliphatic heterocyclic group, and 丫 is? 1- or = 1 ^-

p is an integer from 0 to 3,

R ³ represents a hydrogen atom or a halogen atom,

Or a salt thereof, and a general formula [8]:

R ⁷ -X ² [8]

Wherein R ⁷ represents an organic group, X ² represents a leaving group,

Reacting with a compound represented by the formula (I) or a salt thereof, and converting the product into a pharmacologically acceptable salt if desired, characterized by the general formula [I-b]:

Wherein the symbols have the same meanings as described above,

1 7. General formula [9]:

In the formula, ring A represents an optionally substituted nitrogen-containing aliphatic heterocyclic group, Y represents two CH— or = N—,

R ³ represents a hydrogen atom or a halogen atom,

And a carboxylic acid compound or a salt thereof represented by the following general formula [10]:

H ₂ N- (CH ₂ ) _Q -R ⁸ [10] wherein Q is an integer of 1 to 6, and R ⁸ represents an optionally substituted heterocyclic group;

Wherein the product is converted to a pharmaceutically acceptable salt, if desired, by reacting the compound with an amine compound represented by the formula: or a salt thereof;

Wherein the symbols have the same meanings as described above,

18. A pharmaceutical composition comprising the compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof as an active ingredient.

1 9. The pharmaceutical composition according to claim 18, which is an apolipoprotein B secretion inhibitor. object.

20. The pharmaceutical composition according to claim 18, which is a serum lipid-lowering agent.

2 1. Hyperlipidemia, ischemic heart disease, atherosclerosis, coronary atherosclerosis, hypercholesterolemia, hypertriglyceridemia, familial hyperlipidemia, hyperlipoproteinemia, arteriosclerosis, coronary artery It is a preventive and therapeutic agent for sclerosis, coronary heart disease, ischemic brain disease, stroke, circulatory and microcirculatory disorders, thrombosis, hyperglycemia, diabetes, acute hemorrhagic inflammation, obesity, steatosis, constipation, etc. The pharmaceutical composition according to any one of claims 18 to 20.