WO2002060876A1 - Triaryl compounds and utilization thereof - Google Patents

Abstract

Compounds represented by the following general formula (I) or pharmaceutically acceptable salts thereof which have an effect of potentiating the expression of LDL receptor gene and are useful in treating hyperlipemia: (I) wherein a, b and c independently represent each C-H or N; R1s independently represent each hydroxy, halogeno, etc.; m is from 0 to 3; D represents 1,3-phenylenediyl, etc.; Y represents an optionally represented benzene ring or a heterocycle; and Z represents -CONR2S(O)nR3, etc. (wherein n is 1 or 2; R2 represents H or optionally substituted alkyl; and R3 represents optionally substituted alkyl, phenyl, etc.); and LDL receptor gene expression potentiating agents containing these compounds as the active ingredient.

Description

 Description Triaryl compounds and their applications Technical fields

 The present invention relates to an LDL receptor gene expression enhancer useful as a therapeutic agent for hyperlipidemia, and in particular, relates to a novel triaryl compound having an LDL receptor gene expression-enhancing effect, and an LDL containing the compound as an active ingredient. The present invention relates to a receptor gene expression enhancer. Background art

 The low density lipoprotein (LDL) receptor in hepatocytes plays an important role in regulating blood cholesterol levels. In other words, inhibition of cholesterol synthesis in hepatocytes by a 3-hydroxy-3-methyldaltaryl coenzyme A (HMG-CoA) reductase inhibitor indirectly increased LDL receptor expression, and consequently LDL receptor It has been shown that LDL uptake by blood increases, leading to a decrease in blood cholesterol.

Disclosure of the invention

 HMG-CoA reductase inhibitors have received high clinical reputation as drugs that can lower blood cholesterol. However, in patients with familial hypercholesterolemia who have high serum cholesterol levels or patients with coronary artery disease, it has a sufficient effect to lower the target serum cholesterol level to the target low level. In addition, there is a need for a therapeutic agent for hyperlipidemia that is effective for such patients and has a sharper blood LDL concentration lowering effect. BEST MODE FOR CARRYING OUT THE INVENTION

HMG-CoA reductase inhibitors promote LDL receptor synthesis indirectly through inhibition of cholesterol synthesis, whereas LDL receptor gene expression enhancers more directly activate LDL receptor. By promoting synthesis, sharper blood LD It can be expected to show the effect of lowering L concentration.

 Upstream of each LDL receptor gene, there is a sequence called SRE (Sterol Regulatory Element), which is regulated by intracellular free cholesterol (Goldstein & Brown, Nature, 343, 425). , 1990). In recent years, a substance that binds to 1 ^ 0 and 31 £ of the receptor gene has 31 £ 8? (31 ^ binding protein) (Goldstein, Brown et al., The Journal of Biological Chemistry, 268, 14497, 1993) It has been reported that the binding of this SREBP to the SDL of the LDL receptor gene activates the transcription of the LDL receptor gene (Goldstein, Brown et al., Cell, Vol. 75, 187, 1993). Year Old Goldstein, Brown et al., Proceeding of the Natural Academy of

Science, Vol. 90, 1 1603, 1993). By utilizing these effects and selectively activating LDL receptor expression, it is possible to develop drugs with a new mechanism of action that lower blood cholesterol.

 The present invention provides an LDL receptor gene expression enhancer that directly or indirectly controls LDL receptor synthesis at the gene transcription level and is useful for treating hyperlipidemia. The present invention also provides novel compounds useful for controlling LDL receptor synthesis, lowering serum LDL cholesterol levels, and preventing and treating arteriosclerosis.

 That is, the present invention relates to a novel triaryl compound having the following LDL receptor gene expression enhancing action, or an LDL receptor gene expression enhancer and a therapeutic agent for hyperlipidemia containing the same.

 More specifically, the present invention includes the following embodiments.

[1] General formula (I)

 [Wherein, a, b, and c each independently represent a group represented by the formula: C—H or a nitrogen atom.

R ¹ is substituted by the number of m, and each independently represents a hydroxy group, a halogen atom, a nitro group, a cyano group, an optionally substituted alkoxy group, an optionally substituted alkoxycarbonyl group, a carboxy group, Amino group which may be substituted, substitution An optionally substituted amide group, an optionally substituted urea group, a mercapto group, an optionally substituted sulfonamide group, an optionally substituted alkyl group, an optionally substituted alkenyl group, or formula: represents a group represented by a ^{_{C (0) NHS0 2 R 3a}} ( representing the R ³ i7 alkyl group).

m represents 0 to 3.

 D is a general formula (I Ia) to (I I f):

 (In the formula, d represents an oxygen atom or a sulfur atom.

e, f, g and h each independently represent a group represented by the formula: C-H or a nitrogen atom, except that e, f and g are simultaneously a nitrogen atom.

j represents a group represented by an optionally substituted formula: one CH ₂ — or one NH—. When e, f or g is a group represented by the formula: C—H, one or more of those hydrogen atoms may be independently substituted.) Represents a group to be formed.

Y represents an optionally substituted benzene ring or an optionally substituted hetero ring.

Z is the formula: - CONR to display the group represented by ² S (O) _n R ³ or single ^{_{S (O) n NR 4 R}} 5.

n represents 1 or 2.

R ² and R ⁴ each independently represent a hydrogen atom or an optionally substituted alkyl group.

R ³ is an optionally substituted alkyl group, an optionally substituted phenyl group, an optionally substituted aralkyl group, an optionally substituted cycloalkyl group, and an optionally substituted A cycloalkenyl group or an optionally substituted hetero ring Represents a group.

R ⁵ represents a hydrogen atom, an optionally substituted alkyl group, or an optionally substituted acyl group]

Or a pharmaceutically acceptable salt thereof.

 (2) a is a nitrogen atom,

b and c each independently represent a group represented by the formula: C—H or a nitrogen atom, wherein D may be substituted;

Is a group represented by any of

Y is an optionally substituted benzene ring or an optionally substituted piperidine ring,

Z is a group represented by the formula: one CONHS (0) ₂ R ³ or one S (0) ₂ NHR ⁵ ,

R 3 is an optionally substituted alkyl group, an optionally substituted phenyl group, or an optionally substituted aralkyl group,

R ⁵ is a hydrogen atom or an optionally substituted acyl group,

The compound according to [1], wherein R ¹ and m are the same as defined in [1], or a pharmaceutically acceptable salt thereof.

 (3) a is a nitrogen atom,

b and c are groups represented by the formula: C-H,

Formula in which D may be substituted:

Is a group represented by

 Y is an optionally substituted benzene ring,

Z is a group represented by the formula: one CONHS (0) ₂ R ³ or one S (0) ₂ NHR ⁵ , R ³ is an optionally substituted alkyl group or an optionally substituted phenyl group,

'' R ⁵ is a hydrogen atom or an optionally substituted acyl group,

The compound according to [1], wherein R ¹ and m are the same as defined in [1], or a pharmaceutically acceptable salt thereof.

 [4] An LDL receptor gene expression enhancer comprising the compound according to any one of [1] to [3] or a pharmaceutically acceptable salt thereof as an active ingredient.

 [5] A therapeutic agent for hyperlipidemia comprising the compound according to any one of [1] to [3] or a pharmaceutically acceptable salt thereof as an active ingredient.

 [6] A pharmaceutical composition comprising the compound according to any one of [1] to [3] or a pharmaceutically acceptable salt thereof, and a usual pharmaceutical carrier.

 Hereinafter, terms used in the present specification will be described in detail.

One or more substituents in the “optionally substituted benzene ring” and the “optionally substituted phenyl group” may be substituted. Examples of such a substituent include a halogen atom and Ci. Cs haloalkyl group, C ₁ -C ₈ alkyl group, C ₂ -C ₈ alkenyl group, Ci Cs alkoxy group, hydroxy group, nitro group, cyano group, mercapto group, formula: 1 s Alkyl), alkoxy group, ester group, amino group which may be substituted, amide group which may be substituted, urea group which may be substituted, sulfone which may be substituted And a group represented by the following formula: 1 C (0) NHSO ₂ (C ₁ -C ₈ alkyl) (in the above formula, p is 0, 1 or 2; the same applies hereinafter). .

 Examples of the aryl moiety of the “aralkyl group” used by itself or as a part of another substituent include an aryl group having a carbon number of 10 or less such as phenyl, 1- or 2-naphthyl, and an alkyl moiety such as methyl And alkyl groups having 5 or less carbon atoms, such as ethyl, propyl, and butyl. Representative aralkyl groups include, for example, benzyl, 1- or 2-phenethyl.

The substituent in the “optionally substituted aralkyl group” may have one or more substituents on the aryl moiety and / or the alkyl moiety. Examples of such a substituent include a halogen atom, C ₁ ~C ₈ haloalkyl group, Ci Cg Al Kill group, C ₂ -C ₈ 7 Luque - le group, C Cs alkoxy group, hydroxy group, nitro port group, a mercapto group, the formula: a group represented by one _{S (O) p (C 1} ~C 8 alkyl) A carboxy group, an ester group, an optionally substituted amino group, an optionally substituted amide group, an optionally substituted urea group, an optionally substituted sulfonamide group, and a formula: -C And (0) NHSO ₂ (C ₁ -C ₈ alkyl).

"Alkyl group", as part of its own or another substituent, system unless otherwise otherwise indicated, a saturated hydrocarbon radical straight or branched chain having a carbon number of c E ~ C _8, Straight or branched chain groups such as methinole, ethinole, n-propynole, isopropinole, n-petinole, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, 2-methylpentyl, etc. And higher homologues and isomers.

One or more substituents in the “optionally substituted alkyl group” may be substituted, and examples of such a substituent include a halogen atom, a Ci Cs alkoxy group, a hydroxy group, a mercapto group, Expression: _S Cs alkyl), _{3 to 8} cycloalkyl groups, optionally substituted amino groups, optionally substituted heterocyclic groups, and the like.

 Examples of the “optionally substituted alkoxy group” include a group in which one oxygen atom is bonded to a bonding site of an optionally substituted alkyl group.

 Examples of the “optionally substituted alkoxycarbonyl group” include groups in which the oxygen atom side of a group represented by the formula: —OC (= 0) — is bonded to a bonding site of an optionally substituted alkyl group. .

A “haloalkyl group” by itself or as part of another substituent, unless otherwise indicated, is a straight chain having one or more halogen atoms of one or more of Ci Cs carbon atoms. Or a branched saturated hydrocarbon group, such as trifluoromethyl, trichloromethinole, tribromomethyl, difluoromethyl, monofluoromethyl, 1,1-diphenyloleethyl, 2,2,2-triphenylenoethyl, ぺemissions tough Norre O Roe chill, 1, 1 Jikuroro 2, 2, 2-tri unloading Leo Roe Chino les, Bruno Nafuruoro _n - represents a straight or branched chain groups, such as heptyl - butyl, Nonafuruoro one _t. A “cycloalkynole group” by itself or as part of another substituent is a cyclic saturated hydrocarbon group having from ₃ to ₈ carbon atoms, unless otherwise specified, cyclopropynole, cyclobutyl, cyclobutyl It represents a cyclic saturated hydrocarbon group such as pentynole, cyclohexyl, cyctopeptinole, and cycoctyl, and a higher saturated hydrocarbon group such as cycdecyl and cycdodecinole.

The "cycloalkenyl group", by itself or as a part of another substituent, is a cyclic saturated hydrocarbon group having a carbon number of C ₃ -C ₈ unless otherwise specified, and is cyclopropenyl, cyclobutene 1-inole, cyclopentene 1-inole, cyclopentene 1-in-yl, cyclopentene 1-inole, cyclohexene 1-inole, cyclohexene 1-2-yl, 2,5-cyclohexenegen Cyclic unsaturated hydrocarbon groups such as 11-yl, cycloheptene-11-yl, cycloheptene-1-2-yΛ ^, cyclootaten-1-yΛ ^, and cyclootaten-12-yl .

 Examples of the substituent in the “optionally substituted cycloalkyl group” and the “optionally substituted cycloalkyl group” include the same groups as the above-mentioned “optionally substituted alkyl group”. No.

“Arkeel group” means a linear or branched monounsaturated hydrocarbon group having a carbon number of c _{2 to} c ₈ , unless otherwise specified. For example, bier, 1-propenyl, Examples include allyl, isoprobe, multiple butyr isomers, and may include higher homologues and isomers. One or more substituents in the “optionally substituted alkenyl group” may be substituted, and examples of such a substituent include a halogen atom, a V alkoxy group, a hydroxy group, a mercapto group, and a compound represented by the formula: A group represented by S (0) _p (C i -C ₈ alkyl), an optionally substituted amino group, and the like;

 “Mouth” or “halogen atom” means a bromide, bromo, phenolic, or aldehyde.

The `` optionally substituted amide group '' is a group represented by one NR <sup>6</sup> COR <sup>7</sup> , wherein R <sup>6</sup> is a hydrogen atom, Ci Cs alkyl or the like, and R <sup>7</sup> is a ~ <sub>8</sub> haloalkyl group, Ci Cs alkynole group, C <sub>2</sub> -C <sub>8</sub> alkyl group, C <sub>3</sub> -C <sub>8</sub> cycloalkyl group, phenyl group, aralkyl group, heterocyclic group and the like. The `` optionally substituted urea group '' is a group represented by _NR ⁸ CONR ⁹ R ¹⁰ , wherein R ⁸ and R ⁹ each independently represent a hydrogen atom, C ₁ -C ₈ alkyl, etc. the R ^10, C ₁ ~C ₈ haloalkyl group, C ₁ -C ₈ alkyl group, C ₂ ~ C ₈ alkenyl group, C ₃ -C ₈ cycloalkyl group, phenyl group, Ararukiru group, heterocyclic group and the like to No.

A group represented by "sulfonamide de group which may be substituted" hard NR ¹¹ S0 ₂ R ^12, a hydrogen atom as R ^11, C ₁ ~C ₈ alkyl and the like, is set to R ¹² A C Cg haloalkyl group, a C Cs alkyl group, a C ₂ -C ₈ alkenyl group, a C ₃ -C ₈ cycloalkyl group, a phenyl group, an aralkyl group, a heterocyclic group and the like.

A `` substituted amino group '' is one in which one or both of the hydrogens of the amino group is independently substituted with, for example, a C ₈ alkyl group, a C ₂ -C ₈ alkenyl group, a C Cs alkoxy group, a hydroxy group or the like. Means an amino group.

 The “heterocycle” includes a 5-membered or 6-membered aromatic heterocycle or a saturated or unsaturated aliphatic heterocycle, such as a pyridine ring, an imidazole ring, a pyrazine ring, a pyrimidine ring, and a pyridazine. Ring, thiazole ring, isothiazole ring, isothiazoline ring, oxazole ring, isooxazole ring, isoxazoline ring, furan ring, thiophene ring, pyrrole ring, pyrroline ring, pyrrolidine ring, pyrazoline ring, imidazoline ring, tetrahydropyran ring, tetrahydrofuran ring, tetrahydrofuran ring 5- or 6-membered ring composed of 1 to 4 heteroatoms and carbon atoms selected from nitrogen, oxygen and sulfur atoms, such as the dolothophene ring, pyrrolidine ring and piperidine ring. Mouth rings.

Examples of the substituent for the “heterocycle” include a halogen atom, a C ₁ -C ₈ alkyl group,

C ₂ -C ₈ alkenyl group, Ci Cs alkoxy group, hydroxy group, a mercapto group, the formula: _S Alkyl), a carboxy group, an ester group, an amino group, an alkylamino group and the like, and one or two substituents are independently selected.

The term "heterocyclic group" means a group in which a hydrogen atom of the above "heterocyclic group" is changed to a bond, and the substituent of the "heterocyclic group" is the same as the substituent of the above "heterocyclic group" One. In the groups represented by the general formulas (IIa) to (IIf), the substituent of j and the substitution when e, f, g and h are groups represented by the formula: C—H the group, eg if a halogen atom, CC s alkyl group, a substituted C i C s alkyl group, C ₂ -C ₈ alkenyl group, CC s alkoxy group, hydroxy group, a mercapto group, the formula: a S And substituents such as a group represented by Cs alkyl), a carboxy group, an ester group, and an optionally substituted amino group.

 “Ester group” means an esterified carboxyl group, and includes, for example, an alkoxycarbonyl group, an aryloxycarbonyl group, an aralkyloxycarbonyl group, and the like. Representative examples of the "ester group" include, for example, methoxycarbonyl, ethoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, 1- or 2-phenethyloxycarbol, and the like.

 Examples of the “optionally substituted acyl group” include an optionally substituted alkanol group, an optionally substituted cycloalkyl group, and an optionally substituted perylyl group.

 Examples of the “optionally substituted alkanoyl group” include a group in which a carbonyl group is substituted at the terminal of the above-mentioned optionally substituted alkyl group, and a “optionally substituted cycloalkylcarbonyl group. '' Includes a group in which a carbonyl group is substituted at the terminal of the optionally substituted cycloalkyl group.Examples of the `` optionally substituted aryloyl group '' include the phenyl which may be substituted. Examples include a group in which a terminal group is substituted by a functional group.

 In the triaryl conjugate of the present invention represented by the general formula (I), preferably, a is a nitrogen atom, and b and c are each independently a group represented by the formula: C—H or a nitrogen atom. More preferably, a is a nitrogen atom, and b and c are both groups represented by the formula: C—H.

D is preferably the following formula A group represented by the formula:

In a group represented by these groups, a halogen atom, Ci Cg alkyl group, substitution Ci Cs alkyl group, C ₂ -C ₈ alkenyl group, C Cs alkoxy group, hydrin proxy group, a mercapto group, the formula: 1 to 3 substituents selected from a group represented by one SiO ^ Ci Cs alkyl) (where p is an integer of 0 to 3), a carboxyl group, an ester group, and an amino group which may be substituted. It may be substituted.

 Y is preferably an optionally substituted benzene ring or an optionally substituted piperidine ring, and more preferably an optionally substituted benzene ring.

Preferred Z is a group represented by the formula: — CONHS (0) ₂ R ³ or _S (0) ₂ NHR ⁵ , wherein R ³ is preferably an optionally substituted alkynole group, optionally substituted A phenyl group or an optionally substituted aralkyl group, more preferably an optionally substituted alkyl group or an optionally substituted phenyl group, and R ⁵ is preferably a hydrogen atom or a substituted Is an optionally substituted acyl group.

Further preferred R ³ is unsubstituted C ₁ -C ₈ alkyl group or a halogen atom, water group, and one to three amino Flip substituted with a substituent E ~ Ji ₈ alkyl group selected from alkoxy groups, or, Unsubstituted phenyl, or selected from halogen, hydroxyl, alkoxy, and carboxyl: A phenyl group substituted with up to 3 substituents. Still more preferably, R ⁵ is a hydrogen atom, a Ci Cg alkanoyl group (which may be substituted with 1 to 3 substituents selected from a halogen atom, a hydroxyl group, and an alkoxy group), or C ₃ to C ₃ . Cycloalkyl group Selected from the following: Or 3 substituents).

As R ¹ , any of the above substituents may be included as a preferable one, but ^one not substituted by R ¹ , that is, m = 0 is particularly preferable.

 As described above, the active ingredient of the medicament of the present invention includes a pharmaceutically acceptable salt of the triaryl compound represented by the above formula (I). Certain compounds of the present invention react with a number of inorganic, organic or inorganic bases to form pharmaceutically acceptable salts. Examples of the acid usually used to form an acid addition salt include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid. Examples of the organic carboxylic acid include formic acid, acetic acid, fumaric acid, maleic acid, malic acid, tartaric acid, aspartic acid, and glutamic acid. Examples of the sulfonic acid include methanesulfonic acid, benzenesnolephonic acid, p-to / reensnorephonic acid, hydroxybenzenesnolefonic acid, dihydroxybenzenesulphonic acid and the like. Base addition salts include those derived from inorganic bases such as ammonium, alkali metal or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Useful bases for producing base addition salts include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate. And the like. The potassium and sodium salts are particularly preferred.

 Further, the triaryl conjugate or a salt thereof as an active ingredient of the medicament of the present invention may be an anhydride, a hydrate such as a monohydrate or a dihydrate, or a solvate. Good.

 The compound of the present invention can be synthesized, for example, by the following method.

(A) Among the compounds of the present invention represented by the general formula (I), the compound of the formula (VII) wherein Z is -CONR ² S (0) _n R ³ is, for example, a compound represented by the formula (VII) It can be synthesized by reacting a compound represented by V) with a compound represented by formula (VI) in the presence of a condensing agent. a ヽ CT ヽ COOH (V)

Condensing agent HNR ² S (0) _n R ³ (VI)

( ^Vl1 )

[In the figure, a, b, c, D, Y, R \ R ² , R ³ , m, and n are the same as above.] As the organic solvent used in the present production method, an organic solvent which is anti-inert For example, halogenated hydrocarbon solvents such as carbon tetrachloride, dichloromethane, and 1,2-dichloroethane; ether solvents such as getyl ether, tetrahydrofuran and 1,4-dioxane; N, N-dimethylformamide ( DMF) and the like. Examples of the condensing agent used in the reaction include dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), N-ethyl-1-N'-3-dimethylaminopropylcarbodiimide (EDC = WSC I) and its hydrochloride (WSC I · HC 1), benzotriazole-11-yl lute tris (dimethylamino) phosphonium hexafluorophosphoride (BOP), diphenylphosphoryl azide (DP PA) and other peptide bond formation. Condensing agent, carboerdiimidazole (CD 1), 2-ethoxy-1-ethoxycarbone 1,2-dihydroquinoline (E EDQ), triphenylphosphine carbon tetrachloride, getyl cyanophosphonate, diphenylphospho Loazide and the like.

 Additives used for the purpose of accelerating the condensation reaction or suppressing side reactions include N-hydroxysuccinimide (HONSu) and 1-hydroxybenzotriazole (HOB t;). And 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine (HOOB t).

The amount of the compound represented by the formula (VI) and the condensing agent relative to the compound represented by the formula (V) in the above reaction is not particularly limited, but is usually about 1 to 4 times the molar equivalent. Preferably, the above-mentioned additive is equimolar to twice molar equivalent to the condensing agent. Amounts are preferred.

 The reaction temperature is preferably in the range of room temperature to reflux temperature, and the reaction time is preferably about 30 minutes to 24 hours.

(B) The compound represented by the formula (VII) can also be obtained by reacting the compound represented by the formula (VA) with a compound represented by the formula (VI) in the presence of a base group. Can be synthesized. (VA)

HNR ² S (0) _n FT (VI)

[In the figure, a, b, c, D , Y, RR 2, R 3, m, and n are as defined above. X represents a halogen atom]

 Examples of the organic solvent used in the reaction include organic solvents inert to the reaction, for example, aromatic hydrocarbon solvents such as toluene, benzene, cyclobenzene, and xylene; and halogens such as carbon tetrachloride, dichloromethane, and 1,2-dichloroethane. Hydrocarbon solvents; ketone solvents such as methyl ethyl ketone and methyl isobutyl ketone; and ether solvents such as methyl ether, tetrahydrofuran and 1,4-dioxane.

Examples of the base used in the reaction, Toryechiruamin, Jie isopropyl E chill § Min, dimethylcarbamoyl Aminobirijin, pyridine, New, Nyu- dimethyl § diphosphoric, New, Nyu- _tertiary Amin such as Jechiruanirin or, or hydrogenated Natoriumu And hydrogenation power alkali metal hydrides such as lime.

The amounts of the compound represented by the formula (VI) and the base relative to the compound represented by the formula (VA) in the above reaction are not particularly limited, but the compound represented by the formula (VI) is usually the same. About 1 to 2 times molar equivalent, and about 1 to about 1 molar excess of base are preferable. A base may be used as a reaction solvent.

 The reaction is preferably performed at room temperature to reflux temperature, and the reaction time is preferably about 30 minutes to 24 hours.

 (C) Among the compounds of the present invention represented by the above general formula (I), compounds represented by the following formula (X) wherein a is a nitrogen atom, and b and c are groups represented by the formula: C—H Is, for example, the expression (V

The compound represented by III) and the compound represented by the formula (IX) can be synthesized by reacting in the presence of a base.

 (VIII)

 0

 Me person "'D (IX)

(X)

 [D, Y, R Ζ, and m are the same as above]

 Solvents used in this production method include alcohols such as methanol, ethanol, n-butanol and t-butanol.

 Examples of the base used in the reaction include metal alkoxides such as sodium methoxide, sodium ethoxide, and t-butoxy potassium; inorganic bases such as sodium hydroxide and hydroxylated lime; and organic bases such as pyridine and pyrrolidine. Are mentioned. The amount of the compound represented by the formula (IX) relative to the compound represented by the formula (VIII) in the above reaction is not particularly limited, but it is usually preferably about 1 to 2 molar equivalents. The amount used is preferably about four times the molar equivalent of the catalyst. The reaction temperature is preferably in the range of room temperature to reflux temperature, and the reaction time is preferably about 30 minutes to 24 hours.

(D) of the present invention I匕合compound represented by the above general formula (I), Z has the formula: A S (0) _n NR ⁴ The compound represented by the formula (XIII), which is a group represented by R ⁵ , is obtained by, for example, reacting a compound represented by the formula (XI) with a compound represented by the formula (XI I) in the presence of a base By doing so, they can be synthesized. ^(XI)

R ⁵ — X (XII)

[In the figure, a, b, c, D , Y, R \ R 4, R 5, m, and n are as defined above. X represents a halogen atom]

 Examples of the organic solvent used in this production method include ketone solvents such as acetone, methyl ethyl ketone, and methyl isobutyl ketone, ether solvents such as tetrahydrofuran and 1,4-dioxane, N, N-dimethylformamide, and dimethyl sulfoxide. And the like.

 Examples of the base used for the reaction include organic basic substances such as triethylamine, diisopropylethylamine, dimethylaminopyridine, pyridine, N, N-dimethylaniline, N, N-jethylayulin, and water. Inorganic salt substances such as sodium oxide, potassium hydroxide, sodium hydrogen carbonate, potassium carbonate and the like can be mentioned. In the case of an inorganic basic substance, it is used in the form of a solid, preferably a powder, dispersed in a reaction solvent.

 The amount of the compound represented by the formula (XII) is usually 1 to 3 equivalents to the compound represented by the formula (XI), and the amount of the base used is the amount of the compound represented by the formula (XII). The ratio is usually 1 to 3 equivalents to 1 equivalent of the product.

The reaction temperature is usually in the range of room temperature to 150 ° C, preferably in the range of 50 to 120 ° C, and the reaction time is usually 30 minutes to 48 hours. (E) The compound represented by the formula (V), which is a starting material in the reaction of the above (A), is, for example, The compound can be synthesized by reacting a compound represented by the formula (XIV) with a compound represented by the formula (XV) in the presence of a palladium complex.

Pd complex (HO) ₂ BY-COOH (XV)

( ^V )

 [In the figure, a, b, c, .D, Y, R and m are the same as above. E represents a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group or a trifluorosulfonyloxy group;

The palladium (P d) complex used in the present _{process, P d (PPh 3) 4} [Ph represents a phenylene Le group. Hereinafter the _{same], P dC 1 2 (PPh} 3) 2, Pd [(o- to 1) 3 P] 2 C 1 2 [o- to 1 represents a Orutotoriru group. Hereinafter the _{same], P dC 1 2 (dppf} ) [dppf is 1, 1'_ bis - represents a (Jifue Ruhosufuino) Hue spout. Hereinafter the same _{shall], P d C 1 3 (} dppf) · CH 2 C 1 2S P d 2 (dba) 3 · CHC 1 3 [dba represents dibenzamidodiphenyl Rua seton. Hereinafter the same], and the like, also include _{P d 2 (dba) 3 ·} CHC 1 3, P d (OAc) 2 [Ac represents an Asechiru group. Also be used the same] or P d (dba) ₃ and to prepare a tertiary phosphine or P dC 1 ₂ L ₂ type palladium in the reaction system from bidentate coordination possible Bisufu Osufin (II) complex or less can (L is, PP h ₃ (tertiary e Sufuin or dppe such triphenyl phosphine) (l, 2-bis (diphenyl phosphine Ino) Etan) and dppf (1, 1, one-bis (diphenyl phosphine Ino ) Represents a bisphosphine capable of bidentate coordination such as b).

Examples of the organic solvent used in the present production method include organic solvents inert to the reaction, for example, aromatic hydrocarbon solvents such as toluene, benzene, benzene, xylene, etc., carbon tetrachloride, dichloromethane, 1,2-dichloroethane. Halogenated hydrocarbons such as Solvent, ketone solvents such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; ether solvents such as tetrahydrofuran and 1,4-dioxane; and polar solvents such as N, N-dimethylformamide and dimethyl sulfoxide. Examples of the base used in the reaction include organic basic substances such as getylamine, triethylamine, and diisopropylethylamine, and inorganic basic substances such as sodium hydroxide, sodium hydroxide, sodium hydrogencarbonate, and sodium carbonate. Is mentioned.

 The amount of the Pd complex used is usually 0.1 to 1 equivalent per 1 equivalent of the compound represented by the formula (XIV), and the amount of the base used is 1 equivalent of the compound represented by the formula (XIV) The ratio is usually 1 to 3 equivalents.

 (F) In addition to the reaction of the above (E), the compound represented by the formula (V) is obtained by converting the compound represented by the formula (XVI) into a compound represented by the formula (XVII) in the presence of a palladium complex. It can also be synthesized by reacting with a compound.

 [In the figure, a, b, c, D, Y, R and m are the same as above. X represents a halogen atom]

 The Pd complex, the solvent, the base, the reaction temperature, the reaction time and the like in the present production method are the same as those in the reaction of the above (E).

(G) Further, among the compounds represented by the formula (V), a compound represented by the formula (XIX) in which a is a nitrogen atom, and b and c are groups represented by the formula: C—H, The compound represented by the formula (VIII) can be synthesized by reacting the compound represented by the formula (XVIII) in the presence of a base.

 (VIII)

 o

+, _Yヽ (XVIII)

 Me eight D ヽ COOH

 [D, Y, R and m are the same as above]

 The solvent, base, reaction temperature, reaction time and the like in this reaction are the same as those in the above-mentioned reaction (C).

(H) The compound represented by the formula (VA), which is a starting material in the reaction of the above (B), can be produced from the compound represented by the formula (V) by various methods known to those skilled in the art. , for example, X is a chlorine atom in the compounds represented by formula (VA), what is a bromine atom, for example the formula: by reaction with I匕合compound represented by SOX _2, can be synthesized.

 [In the figure, a, b, c, D, Y, R and m are the same as above. X represents a chlorine atom or a bromine atom]

Reaction solvents include aromatics such as toluene, benzene, benzene, xylene, etc. A halogenated hydrocarbon-based solvent such as an aromatic carbon-based solvent, carbon tetrachloride, dichloromethane, and 1,2-dichloromethane are used, but no solvent may be used. If necessary, DMF, hexamethylphosphoramide (HMPA), triethylamine, pyridine, iodine, zinc chloride, or the like may be added as a catalyst. DMF, HMPA, triethylamine, pyridine may be used as a catalyst. It can also be used as a solvent.

Formula to the compound of formula (V): the amount of the compound represented by the SOX _2, the magnification power> et excess molar equivalents is preferred.

 The reaction temperature is preferably from room temperature to the reflux of the solvent, and the reaction time is preferably from about 15 minutes to 24 hours.

 After completion of the reaction, the derivatives and intermediates obtained by these production methods are subjected to ordinary processes known to those skilled in the art such as water washing, extraction, drying, concentration, etc., and, if necessary, column chromatography, recrystallization, known to those skilled in the art. It can be obtained by performing other purification operations.

 The compounds represented by the general formulas (VI), (VI11), (IX), (XI), (XI1), (XIV;) to (XVIII) are all compounds known from the group of known compounds. It is a compound that can be easily synthesized.

 Further, in the case where a functional group which may cause a side reaction in the above-mentioned production, a protective group can be introduced into the functional group, followed by condensation and deprotection to synthesize the compound. Protection and deprotection of reactive functional groups can be accomplished by methods known to those skilled in the art, for example, Green, T.W. and Wuts, P.G.M., Protective Groups in Organic Synthesis, John Wiley &

It can be performed by the method described in Sons, Inc. (1999).

The compound of formula (I) or a salt thereof can be administered orally or parenterally when using it as a medicine. That is, it can be orally administered in the form of commonly used dosage forms, for example, tablets, capsules, syrups, suspensions, and the like, or in the form of solutions, emulsions, suspensions, and other liquid forms. It can be administered parenterally in the form of injections. It can also be administered rectally in the form of suppositories. In addition, the above-mentioned suitable dosage form can be produced by mixing the active compound with an acceptable usual carrier, excipient, binder, stabilizer and the like. When used in the form of an injection, an acceptable buffer, solubilizing agent, isotonic agent and the like can be added. The dosage and frequency of administration vary depending on the symptoms, age, body weight, and dosage form, but it is usually about 1 to 200 mg, preferably 5 to 1000 mg, orally per day for adults. May be administered in a dose of 0.1 to 50 Omg once or in several divided doses.

Example

 Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the present invention is not limited thereto.

3, 1 ァ 1 チ 1 フ 1 二 -biphenyl 2—4—-Snolehonamide

 Degas a solution of 4-bromobenzenesulfonamide (5 g, 21.3 mmol) and 3-acetyl phenylporonic acid (6.98 g, 42.6 mmol) in N, N-dimethylformamide (10 Om 1). In a nitrogen stream, triethylamine (11.8m1, 84.9mmol) and [1,1-bis (dipheninolefosfuino) phenoctene] dichloronorradidium (II) dichloromethane complex (1: 1) (1.22 g, 1.49 mmol) and the mixture was stirred at 80 ° C for 5 hours. The reaction solution is distilled off, and the residue is purified by silica gel gel chromatography (formula methanol = 100: 1 → 50: 1 → 30: 1 → 20: 1) to give 3′-acetylethyl. There was obtained 1,1,1-biphenyl-2-sulfonamide (4.91 g, 17.8 mmol, 84%).

NMR δ (DMSO-d ₆ ): 8.26 (1H, t, J = 1.7 Hz), 8.00—8.03 (2H, m), 7.96 (2H, d, J = 8.8 Hz), 7.93 (2H, d, J = 8.8 Hz), 7.67 (1H, t, J = 7.8 Hz),

7.45 (2H, br s), 2.68 (3H, s)

Reference example 2

 N-Acetinolay 4-Bromobenzene snorehonamide

 To a solution of 4-bromobenzenesulfonamide (2 g, 8.51 mmol) in acetone (40 ml), add potassium carbonate (2.35 g, 17.0 mmol) and acetyl chloride (0.5 g).

The mixture was heated at reflux for 2 hours. Water (1 ml) was added to distill off the solvent, and acetone was added to the residue to dissolve the residue, and insolubles were separated by filtration. The solvent in the filtrate was distilled off, and acetone (2 Oml) and getyl ether (5 Om 1) were added to the residue, followed by repulp washing. The solid is collected by filtration and dried to give N-acetyl- 4-bromo. Benzene sulphone (2.36 g, 8.50 mmol, 99%) was obtained.

¾-thigh δ (DMS0-d ₆ ): 7.63 (2H, d, J = 8.5 Hz), 7.53 (2H, d, J = 8.5 Hz), 1.61 (3H, s)

Reference example 3

N-Acetyl_3, 1-Acetyl-1, 1, 1, 1-biphen-2-ru 4-Sulfonamide

 It was produced in the same manner as in Reference Example 1 using N-acetyl-4-bromobenzenesulfonamide and 3-acetylphenylporonic acid.

^ -NMR δ (DMS0-d ₆ ): 12.2 (1H, br s), 8.26 (1H, t, J = 1.7 Hz), 7.97—8.03 (6H, m), 7.67 (1H, t, J = 7.8 Hz) ), 2.66 (3H, s), 1.93 (3H, s)

Reference example 4

 N-propionyl 3'-acetyl-1, 1'-biphenyl-14-sulfonamide 3'-acetyl-1,1-biphenyl-4-sulfonamide and propionyl chloride were produced in the same manner as in Reference Example 2.

¾-NMR δ (DMSO—d ₆ ): 8.23 (1H, t, J = 1.6 Hz), 7.97—7.99 (2H, m), 7.89 (2H, d, J = 8.4 Hz), 7.81 (2H, d, J = 8.4 Hz), 7.65 (1H, t, J = 7.7 Hz),

2.67 (3H, s), 2.03 (2H, q, J = 7.5 Hz), 0.87 (3H, t, J = 7.5 Hz)

Reference example 5

 2 _ (3-bromophenyl) quinoline

 Under a nitrogen stream, a solution of 3-bromoacetophenone (1.99 ml, 15.0 mmole) and 2-aminobenzaldehyde (2.0 g, 16.5 mmol) in ethanol (4 Oml) was added with sodium ethoxide (2.04 g, 30.0 mmol) and stirred at room temperature for 4 hours. The solvent was distilled off, and the residue was partitioned with water and ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The crude product obtained by distilling off the solvent was purified by silica gel column chromatography (ethyl hexane monoacetate = 10: 1) to give 2_ (3-bromophenyl) quinoline (3.95 g, 13.9 mmol, 93%). %).

- Ran _{6 (CDC1 3): 8.36 (} 1H, t, J = 1.8 Hz), 8.25 (1H, d, J = 8.6 Hz), 8.16 (1H, d, J = 8.4, 1.1 Hz), 8.08 (1H, ddd, J = 7.8, 1.8, 1.0 Hz), 7.85 (1H, d, J = 8.6 Hz), 7.85 (1H, dd, J = 8.1, 1.4 Hz), 7.75 (1H, ddd, J = 8, 6.9, 1.4 Hz), 7.59 (1H, ddd, J = 7.8, 1.8, 1.0 Hz), 7.55 (1H, ddd, J = 8.1, 6.9, 1.1 Hz), 7.40 (1H, t, J = 7.8 Hz)

Reference example 6

 3,1- (2-quinolyl) 1-1,1,1-biphenyl-1-carboxylic acid hydrochloride

 Degas a solution of 2- (3-bromophenyl) -quinoline (11.25 g, 39.4 mmol) and 4-carboxyphenylporonic acid (13.1 g, 79.2 mmol) in N, dimethylformamide (30 Oml), and remove nitrogen. Under a stream of air, triethylamine (22.0 m1, 158 mmole) and [1,1-bis (dipheninolefosfuino) phenacene] dichloromethane palladium (II) dichloromethane complex (1: 1) (2.24 g, 2.74 mmol) ) And stirred at 65 ° C. overnight. The solvent was distilled off, and the residue was adjusted to pH 6 with 0.1 N hydrochloric acid and water, and partitioned and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The crude product obtained was purified by silica gel column chromatography (ethyl hexane monoacetate = 10: 1 → 1: 1 → 1: 9) to give 3 '-(2-quinolinol) 1-1,1' -Bifeninoleic 4-phenolic acid was obtained. This was dissolved in tetrahydrofuran (40 Om 1), 1N hydrogen chloride chloride methylene solution (90 m 1) was added, and the mixture was stirred at room temperature for 2 hours. The resulting crystals are collected by filtration, and the solid is washed with tetrahydrofuran and diethyl ether and dried to give 3 '-(2-quinolyl) -1,1, -biphenyl-14-carboxylic acid · hydrochloride (8.18). g, 22.6 mmol, 89%).

NMR-NMR δ (DMS0-d ₆ ): 8.64 (1H, d, J = 8.7 Hz), 8.59 (1H, m), 8.37 (1H, d,

J = 8.7 Hz), 8.33 (1H, m), 8.20 (1H, d, J = 8.6 Hz), 8.08—8.11 (3H, m), 7.83-7.95 (4H, m), 7.35-7.75 (2H, m )

Reference Example 7

 N— (4-acetylphenyl) acetamide

Under a nitrogen stream, a solution of 4-aminoacetophenone (15.Og, O.ll lmol) and triethylamine (23ml, 0.165mol) in methylene chloride (150ml) was mixed with acetyl chloride (150ml) under ice cooling. 26.8 ml, 0.165 mol) was added dropwise over 30 minutes. The reaction solution was stirred at room temperature for 1 hour, water was added, and the mixture was partitioned and extracted with black hole form. The organic layer was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated saline, and dried over anhydrous magnesium sulfate. did. Diethyl ether was added to the crude product obtained by distilling off the solvent, repulp washing was performed, and the solid was collected by filtration to give N- (4-acetylphenyl) acetoamide (16.3 g, 91.8 mmol, 83% ).

- image _{R δ (CDC1 3): 7.94} (2H, d, J = 8.5 Hz), 7.62 (2H, d, J = 8.5 Hz), 2.58 (3H, s), 2.22 (3H, s)

Reference Example 8

 N— (4-Acetyl-1-2-bromophenyl) acetamide

 Under a stream of nitrogen, bromine (5.2 ml, 101.5 mmol) was added to a solution of N- (4-acetinolefenyl) acetamide (10.24 g, 57.8 mmol) in water (102.511 ml) and water (102.5 ml). ) Was added dropwise over 1 hour, and the mixture was stirred at room temperature for 18 hours. An aqueous solution (11) of sodium bisulfite (2 g) was added to the reaction solution, and the mixture was partitioned and extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The crude product obtained by evaporating the solvent is purified by silica gel gel chromatography (hexane monoacetate = 2: 1 → 1: 1) to give N- (4-acetyl_2-promophenyl). ) Acetoamide (9.87 g, 38.5 mmol) was obtained.

One _{NMR δ (CDC1 3): 8.53} (1H, d, J = 8.6 Hz), 8.17 (1H, d, J = 2.0 Hz), 7.89 (1H, dd, J = 8.6, 2.0 Hz), 7.82 (1H, br s), 2.57 (3H, s), 2.29 (3H, s)

Reference Example 9

1- (4-amino-3-3-bromophenyl) ethanone

 A 6 N hydrochloric acid (37.2 g) solution of N- (4-acetyl-2-bromophenyl) acetoamide (9.3 g, 36.3 mmol) was heated under reflux for 30 minutes. Water was added to the reaction solution, which was partitioned and extracted with getyl ether. The pH of the aqueous layer was adjusted to 11 with a 10 N aqueous sodium hydroxide solution, and the mixture was partitioned and extracted with getyl ether. The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The crude product obtained by distilling off the solvent is purified by silica gel / column chromatography (ethyl hexane monoacetate = 2: 1 → 1: 1) to give 1- (4-amino-13-bromophenyl) ethanone (7.13 g, 33.3 mmol) was obtained.

- thigh _{δ (CDC1 3): 8.06 (} 1H, d, J = 2.0 Hz), 7.74 (1H, dd, J = 8.4, 2.0 Hz), 6.75 (1H, d, J = 8.4 Hz), 4.58 (2H, br s), 2.50 (3H, s)

Reference Example 10

 (4) Acet / Lee (2) Bromobenzonitrile

 Concentrated hydrochloric acid (9.2 ml) was added to an acetone (65 ml) solution of 1_ (4-amino-3-bromophenyl) ethanone (6.84 g, 32.0 mmol), and sodium nitrite (2.42 g, 35 .1 mmol) aqueous solution (1 Om 1) was added dropwise. The reaction solution was neutralized with an aqueous sodium carbonate solution, and added dropwise to a suspension of potassium cyanide (10.4 g, 160 mmol) and copper cyanide (11.5 g, 128 mmol) in water (100 ml). The reaction solution was stirred at 50 ° C for 2 hours, water was added, and the mixture was partitioned and extracted with a black hole form. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The crude product obtained by evaporating the solvent was subjected to silica gel gel chromatography (hexane monoacetate = 10: 1 → 8: 1 → 6: Purification by 1) gave 4-acetyl-2-bromobenzonitrile (4.29 g, 19.2 millimonole, 60%).

- Anonymous _{δ (CDC1 3): 8.23 (} 1H, d, J = 1.5 Hz), 7.96 (1H, dd, J = 8.0, 1.5 Hz), 7.78 (1H, d, J = 8.0 Hz), 2.64 (3H, s)

4-acetyl-2-bromobenzoic acid

 Concentrated sulfuric acid (12 ml), water (12 ml) and acetic acid (12 ml) were added to 4-acetyl_2-bromobenzonitrile (2.41 g, 10.8 mmol) and dissolved, and the mixture was heated under reflux for 3 hours. After cooling the reaction solution, the pH was adjusted to 11 with a 10 N aqueous sodium hydroxide solution, and the mixture was partitioned and extracted with ethyl acetate. The aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid and partitioned and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The crude product obtained by distilling off the solvent was purified by silica gel column chromatography (chloroform-methanol-ammonia water = 40: 1: 0.1) to give 4-acetyl-2-bromobenzoic acid (1.59). g, 6.54 mmol).

 -丽 R δ (DMSO—): 13.8 (1H, br s), 8.16 (1H, d, J = 1.3 Hz), 7.98 (1H, dd, J = 8.0, 1.3 Hz), 7.82 (1H, d, J = 8.0 Hz), 2.61 (3H, s)

Reference example 1 2

2-bromo-14- (2-quinolyl) benzoic acid It was produced in the same manner as in Reference Example 5 using 4-acetyl_2-bromobenzoic acid and 2-aminobenzaldehyde.

¾-NMR δ (DMS0-d ₆ ): 13.5 (1H, br s), 8.61 (1H, d, J = 1.6 Hz), 8.52 (1H, d, J = 8.7 Hz), 8.36 (1H, dd, J) = 8.1, 1.6 Hz), 8.25 (1H, d, J = 8.7 Hz), 8.12 (1H, dd, J = 8.4, 1, 1 Hz), 8.04 (1H, dd, J = 8.0, 1.4 Hz), 7.92 (1H, d, J = 8.1 Hz), 7.82 (1H, ddd, J = 8.4, 6.9, 1.4 Hz), 7.64 (1H, ddd, J = 8.0, 6.9, 1.1 Hz)

Reference Example 13

 [2-Bromo-4- (2-quinolyl) phenyl] methanol

 In a solution of 2-bromo-1- (2-quinolyl) benzoic acid (2.07 g, 6.31 mmol) in tetrahydrofuran (10 Oml), borane-tetrahydrofuran complex and tetrahydrofuran solution (1M, 12.6 ml, 12.6 mmol) ) And stirred at room temperature for 14 hours. Methanol was added to distill off the solvent, and the residue was partitioned and extracted with water and ethyl acetate. The organic layer was dried with anhydrous sodium sulfate. The crude product obtained by distilling off the solvent is purified by silica gel column chromatography (ethyl hexane monoacetate = 8: 1 → 6: 1 → 5: 1) to give [2-promo-1- (2-quinolyl). ) [Phenyl] methanol (1.01 g, 3.21 mmol, 51%) was obtained.

_{-NMR δ (CDC1 3): 8.} 2 (1H, d, J = 1.7 Hz), 8.25 (1H, d, J = 8.6 Hz), 8.18 (1H, dd, J = 8.4, 1.1 Hz), 8.11 ( 1H, dd, J = 8.0, 1.7 Hz), 7.86 (1H, d, J = 8.6 Hz), 7.84 (1H, d, J = 8.1, 1.4 Hz), 7.75 (1H, ddd, J = 8.4, 6.9,

1.4 Hz), 7.64 (1H, d, J = 8.0 Hz), 7.56 (1H, ddd, J = 8.1, 6.9, 1.1 Hz), 4.83 (2H, d, J = 6.0 Hz), 2.18 (1H, t, (J = 6.0 Hz)

Reference Example 14

 2- [3-Bromo-4-[[[tert-p-tinole (diphenyl) silinole] oxy [methyl] phenyl] quinoline

Under a stream of nitrogen, a solution of [2-bromo_4- (2-quinolinole) phenyl] methanol (353 mg, 1.13 mmol) in N, N-dimethylformamide (6 m 1) Mouth diphenylsilane (322 μl, 1.24 mmol), imidazole (92 mg, 1.35 mmol) and 4-dimethylaminopyridine (1 Omg, 0.1 mg). 08 mmol) and stirred at room temperature for 2 days. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The crude product obtained by distilling off the solvent is purified by silica gel column chromatography (ethyl monoacetate = 100: 1-> 50: 1-> 30: 1-> 20: 1). Bromo-1-[[[tert-butyl (diphenyl) silyl] oxy] methyl] phenyl] quinoline (592 mg, 1.07 millimonole, 95%) was obtained.

_{¾-NMR δ (CDC1 3)} : 8.35 (1H, d, J = 1.7 Hz), 8.14-8.21 (3H, m), 7.90 (1H, d, J = 8.1 Hz), 7.79-7.85 (2H, m) , 7.69-7.75 (5H, m), 7.49-7.54 (1H, m), 7.36-7.44 (6H, m), 4.87 (2H, s), 1.15 (9H, s)

Reference Example 15

 2 '-[[[tert-Butyl (diphenyl) silyl] oxy] methyl] -1,5,1- (2-quinolyl) 1-1,1'-biphenyl-14,4-Rubonic acid

 2- [3-bromo-14-[[[tert-butyl (diphenyl) silyl] oxy] methyl] phenyl] quinoline and 4-carboxyphenylboronic acid were prepared in the same manner as in Reference Example 6. .

— NMR δ (DMS0-d ₆ ): 13.0 (1H, s), 8.47 (1H, d, J = 8.7 Hz), 8.38 (1H, dd, J = 8.2, 1.8 Hz), 8.25 (1H, d, J) = 8.7 Hz), 8.16 (1H, d, J = 1.8 Hz), 8.06 (1H, dd, J = 8.5, 1.0 Hz), 8.01 (1H, dd, J = 8.0, 1.5 Hz), 7.95 (2H, d , J = 8.2 Hz), 7.81 (1H, d, J = 8.2 Hz), 7.78 (1H, ddd, J = 8.5, 7.0, 1.5 Hz), 7.60 (1H, ddd, J = 8.0, 7.0, 1.0 Hz) , 7.48-7.53 (6H, m), 7.42—7.46 (2H, m), 7.36-7.40 (4H, m), 4.72 (2H, s), 0.96 (9H, s)

Reference Example 16

N — [[2 '— [[[tert-Butyl (diphenyl) silyl] oxy] methyl] -5' — (2-quinolyl) -1-1,1'-biphenyl-2-yl] Methanesulfonamide 2 '-[[[tert-Butyl (diphenyl) silyl] oxy] methyl] -15'-(2-quinolyl) -11,1,1-biphenyl-2-carboxylic acid N, N-dimethyl To a solution of formamide (1 ml) was added 1,1'-forced noreboenoresimidazole (17 mg, 0.103 mmol), and the mixture was stirred at room temperature for 13.5 hours. To the reaction mixture was added methanesulfonamide (1 1.5 mg, 0.121 mmol) and 1,8-diazabisic [5.4.0] 7-ene (18 At 1, 0.120 mmol) was added and the mixture was further stirred at 80 ° C for 4 hours. The reaction solution was distilled off, water and chloroform were added to the residue, and the mixture was partitioned and extracted. The organic layer was dried over anhydrous magnesium sulfate. The crude product obtained by distilling off the solvent was purified by silica gel column chromatography (chlorophonolem → chlorophonolem-methanolone == 50: 1 → 30: 1) and ODS chromatography (methanol-water) to give N. — [[2 '_ [[[tert-Butyl (diphenyl) silinole] oxy] methyl] _ 5' — (2-quinolyl) -1,1,1-biphenyl-1-yl] carbinole! Methanesulfonamide (28.5 mg, 0.0425 mmol, 54%).

Ή-NMR δ (DMSO-d ₆ ): 8.38 (1H, d, J = 8.6 Hz), 8.09-8.15 (2H, m), 7.98- 8.05 (4H, ra), 7.93 (1H, d, J = 8.0 Hz), 7.74-7.81 (2H, m), 7.55-7.59 (5H, m), 7.31-7.3 (8H, ra), 4.70 (2H, s), 3.14 (3H, s), 1.03 (9H, s) Reference example 17

 1- [3-Hydroxy-5- (methoxymethoxy) phenyl] ethanone

 In a solution of 3,5-dihydroxyacetophenone (5.21 g, 34.2 millimonoles) in tetrahydrofuran (3 Oml), diisopropylethylamine (11.9 ml, 68.4 mmol) and chloromethinolemethyl ether (2.60 ml, 34.2 mmol) and stirred for 14 hours. The solvent was distilled off, and the residue was partitioned and extracted with water, saturated saline and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The crude product obtained by distilling off the solvent is purified by silica gel gel chromatography (Chrome-form-methanol = 100: 1) and purified to give [3-hydroxy-15- (methoxymethoxy) phenyl]. ] Ethanone (2.27 g, 11.7 millimono, 34%) was obtained.

-Bandwidth R δ (DMSO-d ₆ ): 9.73 (1H, s), 6..90-7.01 (2H, m), 6.64-6.67 (1H, m), 5.17 (2H, s), 3.39 (3H, s), 2.49 (3H, s) ―

Reference Example 18

3— (Methoxy methoxy) mono 5— (2-Quinolyl) phenol

 11 [3-Hydroxy-5- (methoxymethoxy) phenyl] ethanone and 2-aminobenzaldehyde were produced in the same manner as in Reference Example 5.

-Δ (DMSO-d ₆ ): 9.58 (1H, s). 8.38 (1H, d, J = 8.8 Hz), 7.88-8.06 (3H, m), 7.69-7.78 (1H, m), 7.52-7.60 (1H, m), 7.25—7.33 (2H, m), 6. 8- 6.56 (1H, m), 5.23 (2H, s), 3.44 (3H, s)

Reference Example 19

 3- (Methoxymethoxy) -1-5- (2-quinolyl) phenyltrifluoromethanesulfonate

 3- (Methoxy methoxy) -1- (2-quinolyl) phenol (1.88 g, 6.6

8 mmol) of triethylamine (1.4 Om 1, 10.0 mmol) and trifluoromethanesulfonic anhydride (1.12 m 1, 6.68 mmol) under ice-cooling. In addition, the mixture was stirred at room temperature for 14 hours. The reaction solution was diluted with chloroform, washed with saturated saline, and dried over potassium carbonate. The crude product obtained by distilling off the solvent was purified by silica gel column chromatography (hexane monoacetate = 20: 1) to give 3- (methoxymethoxy) -15- (2-quinolyl). Phenyl trifluoromethanesulfonate (2.26 g, 5.48 mmol, 82%) was obtained.

NMR δ (DMSO-d ₆ ): 8.51 (1H, d, J = 8.8 Hz), 8.22 (1H, d, J = 8.8 Hz), 8.10 (1H, d, 8.4 Hz), 7.95-8.06 (3H, m), 7.78-7.86 (1H, m), 7.58-7.67

(1H, m), 7.25-7.31 (1H, m), 5.38 (2H, s), 3.45 (3H, s)

Reference Example 20

 3,1- (Methoxymethoxy) -5 '-(2-quinolyl) -1, -Bifu-norre-4

 The compound was produced in the same manner as in Reference Example 6 using 3- (methoxymethoxy) -1- (2-quinolyl) pheninoletritrifluoromethanesulfonate and 4-carboxyphenylporonic acid.

-Thigh δ (DMSO-d ₆ ): 8.46 (1H, d, J = 8.8 Hz), 8.25 (1H, d, J = 8.8 Hz), 8.13-8.22 (1H, m), 8.05-8.13 (3H, m ), 7.90 (2H, d, J = 8.4 Hz), 7.73-7.82 (1H, m), 7.55-7.63 (1H, m). 7.43-7.7 (1H, m). 5.39 (2H, s), 3.48 (3H, s)

Reference Example 21

N — [[3,1- (Methoxymethoxy) -1.5,1- (2-quinolyl) -1-1,1'-biphenyl-2-y / re] canoleponinole] methansnorehonamide It was produced in the same manner as in Reference Example 16 using 3,1- (methoxymethoxy) -15,1- (2-quinolyl) 1-1, -biphenyl-carboxylic acid.

ΉNMR 6 (DMS0-d ₆ ): 12.2 (1H, br s), 8.50 (1H, d, J = 8.7 Hz), 8.31 (1H, d, J = 8.7 Hz), 8.23 (1H, t, J = 1.5 Hz), 8.09-8.11 (1H, m), 8.06 (2H, d, J = 8.6 Hz), 8.03 (1H, dd, J = 8.0, 1.0 Hz), 7.99 (1H, t, J = 1.5 Hz) ), 7.98 (2H, d, J = 8.6 Hz), 7.80 (1H, ddd, J = 8.3, 6.9, 1.3 Hz), 7.62 (1H, ddd, J = 8.0, 6.9, 1.0 Hz), 7.51 (1H, t, J = 1.5 Hz), 5.41 (3H, s), 3.46 (3H, s), 3.39 (3H, s)

Reference Example 22

2_ [3— (1,4-dioxer 8 _azaspiro [4.5] dec 8-inole) phenyl] quinoline.

 Under a nitrogen stream, 2- (3-bromophenyl) quinoline (40 Omg, 1.41 mmol), 1,4-dioxa_8-azaspiro [4.5] _decane (272 μ1, 2.11 mmol) and sodium tert-butoxide A solution of (204 mg, 2.11 mmol) in toluene (2 Oml) was degassed and dichlorobis (tree o_tolylphosphine) palladium (II) (llmg, 0.141 mmol) was added. The mixture was stirred at C for 7 hours. Water was added to the reaction solution, and the mixture was partitioned and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The crude product obtained by distilling off the solvent is purified by silica gel column chromatography (ethyl hexane monoacetate = 6: 1 → 5: 1 → 4: 1) to give 2- [3- (1,4-dioxer 8). —Azaspiro [4.5] dec_8-yl) phenyl] quinoline (428 mg, 0.83 mmol, 59%) was obtained.

Ή one _{MR δ (CDC1 3): 1.86} (4H, dd, J = 5.7, 5.7 Hz), 3.42 (4H, dd, J = 5.7, 5.7 Hz), 3.94 (4H, s), 7.02 (1H, dd, J = 8.1, 2.6 Hz), 7.36 (1H, dd, J = 7.9, 7.9 Hz), 7.46 (1H, dd, J = 7.4, 7.4 Hz), 7.53 (1H, d, J = 7.7 Hz),

7.68 (1H, m), 7.74-7.81 (3H, m), 8.11 (1H, d, J = 8.6 Hz), 8.16 (1H, d, J = 8.4 Hz)

Reference Example 23

1— [3- (2-quinolyl) phenyl] —4—piberidinone 2- [3_ (1,4-dioxa-18-azaspiro [4.5] dec-18-yl) phenyl] quinoline (420 mg, 1.21 millimono) of acetone (1 Om 1) and water ( 2m 1) P-Toluenesulfonic acid monohydrate (254 mg, 1.33 mmol) was added to the solution, and the mixture was heated under reflux for 10 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and water, and partitioned and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting crude product was purified by silica gel column chromatography (ethyl hexane monoacetate = 4: 1 → 3: 1 → 2: 1) to give 1_ [3- (2-quinolyl) phenyl] -4-1piperidinone (345 mg, 1.14 mmol, 94%).

¾-NMR δ (DMS0_d ₆ ): 2.60 (4H, dd, J = 6.0, 6.0 Hz), 3.71 (4H, dd, J = 6.0, 6.0 Hz), 7.07 (1H, dd, J = 8.3, 2.5 Hz) , 7.43 (1H, dd, J = 7.9, 7.9 Hz),

7.52 (1H, m), 7.56 (1H, m), 7.72 (1H, m), 7.84 (3H, ra), 8.19 (2H, m) Reference example 24

 1- [3- (2-quinolyl) phenyl] -1 4-piperidinecarbonitrile

 Under a nitrogen stream, 1- [3- (2-quinolyl) phenyl] -1-piperidinone (219 mg, 0.724 mmol) and ρ-toluenesulfonylmethyl isocyanide (14

1 mg, 0.724 mmol) of ethylene glycol dimethyl ether (2.5 m 1) in 110 g of potassium tert-butoxide (146 mg, 1.30 mmol) of tert-butanol (0. 5 ml) solution was added dropwise. The reaction was warmed to room temperature and stirred for 14 hours. The reaction solution was poured into water and partitioned and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The crude product obtained by distilling off the solvent was purified by silica gel column chromatography (hexane monoethyl acetate = 4: 1 → 3: 1) to give 1- [3- (2-quinolyl) phenyl. ] —4-Pyridine campolenitrile (67.5 mg, 0.215 mmol, 30%) was obtained.

_{¾-NMR δ (CDC1 3)} : 2.06 (4H, m), 2.80 (1H, m), 3.19 (2H, m), 3.53 (2H, m), 7.01 (1H, dd, J = 8.1, 2.5 Hz) , 7.41 (1H, dd, J = 7.9, 7.9 Hz), 7.52

(1H, m), 7.58 (1H, d, J = 7.7Hz), 7.73 (1H, m), 7.83 (3H, m), 8.19 (2H, m)

Reference Example 25

1- [3- (2_quinolyl) phenyl] -1-4-piperidinecarboxylic acid Under a stream of nitrogen, 1- [3- (2-quinolyl) phenyl] -14-piperidinecarbonitrile (80 mg, 0.255 mmolole) in water (0.5 ml) and drunk acid (0.5 m 1) To the mixture was added concentrated sulfuric acid (0.5 ml), and the mixture was stirred at 100 ° C for 2 hours. The reaction solution was put on ice, neutralized with a 2N aqueous sodium hydroxide solution, and partitioned and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The crude product obtained by distilling off the solvent is purified by silica gel chromatography (chloroform → Kuguchiguchi form-methanol = 100: 1 → 50: 1) to give 1- [3_ (2-quinolyl). ) Fenyl] -4-piperidinecarboxylic acid (46.2 mg, 0.138 mmol, 54%) was obtained.

-Bandwidth R δ (DMS0-d ₆ ): 1.67 (2H, ra), 1.93 (2H, m), 2.40 (1H, in), 2.84 (2H, m), 3.74 (2H, m), 7.08 (1H, m), 7.37 (1H, dd, J = 8.0, 8.0 Hz), 7.57 (1H, m), 7.63 (1H, d, J = 7.5 Hz), 7.78 (2H, m), 7.97 (1H, d, J = 7.9 Hz), 8.05 (1H, d, J = 8.7 Hz), 8.15 (1H, d, J = 8.6 Hz), 8.1 (1H, d, J = 8.6 Hz) Reference Example 26

4-Methoxycarbonylninolebenzaldehyde oxime chloride

 Using 4-methoxycarbonylbenzaldehyde (8.2 g, 50 mmol) and xylamine hydrochloride (3.5 g, 50 mmol), described in the literature (Robert K. Howe et al., J. Heterocyclic Chem., 19, 721 ( 1982)) to obtain 4-methoxycarberbenzaldehyde oxime (5.66 g). Next, 4-methoxycarbonylbenzaldehyde oxime (2.24 g, 12.5 mmol) and NC

Using S (1.67 g, 12.5 mmol), 4-methoxycarbonylbenzaldaldehyde doxime chloride (2.51 g, 59%).

_{- MR δ (CDC1 3):} 3.95 (3H, s), 7.93 (2H, d, J = 8.6 Hz), 8.03 (1H, S), 8.08 (2H, d,] = 8.6 Hz)

Reference Example 27

Methyl 4 one [5 i (2 Kinorinore) Single _three to iso O hexa benzoisothiazolyl Honoré] benzoate

Using 4-methoxycarbonylbenzaldehyde oxime chloride (0.34 g, 1.6 millimonole) and 2-vinylquinoline (0.25 g, 1.6 mmol), Methyl 4- [5- (2-quinolyl) -12-isoxazoline-13-yl] with reference to the method described in the literature (Robert K. Howe et al., J. Heterocyclic Chem., 19, 721 (1982)) Benzoate (0.35 g, 66%) was obtained.

_{¾- NMR δ (CDC1 3):} 3.88-3.98 (2H, m), 3.94 (3H, s), 6.07 (1H, dd, J = 10.4, 7.6 Hz), 7.56 (1H, t, J = 7.4 Hz) , 7.71 (1H, d, J = 8.5 Hz), 7.74 (1H, t, J = 7.7 Hz), 7.80 (2H, d, J = 8.3 Hz), 7.84 (1H, d, J = 8.1 Hz), 8.05 —8.09 (3H, m), 8.22 (1H, d, J = 8.5 Hz)

Reference Example 28

 4- [5— (2-quinolyl) -1-3-isosazozolyl] benzoic acid

 Methyl 4- [5- (2-quinolyl) -1 3-isoxazolinole] benzoate (15

A mixture of Omg, 0.45 mmol), lithium hydroxide (54 mg, 2.25 mmol), water (1 ml), tetrahydrofuran (2 ml), and methanol (10 ml) was stirred at room temperature for 38 hours. Water (10 ml) and a 2N aqueous hydrogen sulfate aqueous solution (1.15 ml) were added, and the mixture was concentrated under reduced pressure to remove tetrahydrofuran and methanol. The precipitated crystals were collected by filtration, washed with water and dried under reduced pressure to obtain 4- [5- (2-quinolyl) -13-isosoxazolyl] benzoic acid (140 mg, 97%).

One _{NMR δ (CDC1 3): 3.89-4.00} (2H, m), 6.09 (1H, dd, J = 10.7, 7.6 Hz), 7.55-7.58 (1H, m), 7.72 (1H, d, J = 8.5 Hz ), 7.72-7.76 (1H, m), 7.82-7.85 (3H, m), 8.08 (1H, d, J = 8.4 Hz), 8.13 (2H, d, J = 8.5 Hz), 8.23 (1H, d, (J = 8.5 Hz)

Example 1

 3,1- (2-quinolyl) 1-1, -biphenyl 4-sulfonamide

 Under a stream of nitrogen, 3'-acetyl-1,1,1-biphenyl-2-4-sulfonamide (2.

To a suspension of 5 g, 9.08 mmol) and 2-aminobenzaldehyde (1.65 g, 13.6 mmol) in ethanol (10 Oml) was added sodium ethoxide (2.47 g,

36.3 mmol) and stirred at 60 for 5 hours. The pH of the reaction solution was adjusted to 5 with a 5% aqueous hydrogen sulfate aqueous solution, and the solvent was distilled off. The residue was dissolved in chloroform-methanol (10: 1), the insolubles were removed by filtration, and the solvent was distilled off. The residue is purified by silica gel column chromatography (Kuroguchi Roho / REM → Chlorophonorem-Methanol) = 50: Purification by 1 → 20: 1) gave 3,1- (2-quinolyl) 1-1, -bipheninole-14-sulfonamide (1.76 g, 4.88 mmol).

- thigh _{δ (DMS0-d 6):} 8.58 (1H, t, J = 1.6 Hz), 8.52 (1H, d, J = 8.6 Hz), 8.36 (1H, d, J = 7.9 Hz), 8.32 (1H, d, J = 8.6 Hz), 8.12 (1H, d, J = 8.4, 1.0 Hz), 8.02-8.05 (1H, ra), 8.03 (2H, d, J = 8.5 Hz), 7.96 (2H, d, J = 8.5 Hz), 7.88 (1H, d, J = 7.9 Hz), 7.81 (1H, ddd, J = 8.4, 6.9, 1.4 Hz), 7.71 (1H, t, J = 7.9 Hz), 7.63 (1H, ddd , J = 8.0, 6.9, 1.0 Hz), 7.5 (2H, br s)

 N-acetyl-3 '-(2_quinolinole) -1,1,1-biphenyl-1-4-sulfonami K

 N-acetinolate 3′-acetinolate 1,1,1-biphenyl-2-sulfonamide and 2-aminobenzaldehyde were produced in the same manner as in Example 1.

¾-NMR δ (DMS0-d ₆ ): 12.17 (1H, br s), 8.58 (1H, t, J = 1.6 Hz), 8.51 (1H, d, J = 8.6 Hz), 8.36 (1H, ddd, J) = 7.8, 1.6, 1.3 Hz), 8.31 (1H, d, J = 8.6 Hz), 8.11 (1H, dd, J = 8.4, 1.0 Hz), 7.99-8.04 (5H, m), 7.87 (1H, ddd, J =

7.8, 1.6, 1.3 Hz), 7.80 (1H, ddd, J = 8.4, 6.9, 1.3 Hz), 7.70 (1H, t, J = 7.8 Hz), 7.62 (1H, ddd, J = 8.0, 6.9, 1.0 Hz) ), 1.92 (3H, s)

Example 3

 N-propio-lu 3 '-(2-quinolyl) -1,1, -biphenyl-14-sulfonamide

It was produced in the same manner as in Example 1 using N-propionyl 3,1-acetyl-1,4-biphenyl-14-sulfonamide and 2-aminobenzaldehyde. — NMR δ (DMSO- d ₆ ): 12.1 (1H, s), 8.60 (1H, s), 8.52 (1H, d, J = 8.7 Hz), 8.38 (1H, d, J = 7.8 Hz), 8.32 ( 1H, d, J = 8.7 Hz), 8.12 (1H, d, J = 8.4 Hz), 8.02-8.08 (5H, m), 7.89 (1H, d, J = 7.8 Hz), 7.79-7.83 (1H, m ), 7.72

(1H, t, J = 7.8 Hz), 7.61-7.65 (1H, m), 2.26 (2H, q, J = 7.4 Hz), 0.91 (1H, t, J = 7.4 Hz)

Example 4

N-Ptyryl-1 3 '-(2-quinolyl) -1 1,1'-biphenyl-1 4-Sulfonami K

 In a solution of 3'-acetyl-1,1,1-biphenyl-14-sulfonamide (68.8 mg, 0.25 mmol) in acetone (5 ml), putyryl chloride (401, 0.385 mmol) and potassium carbonate (86.4 mg) , 0.625 mmol) and heated to reflux for 2 hours. The pH was adjusted to 4 with a 2 N aqueous potassium hydrogen sulfate solution, and the solvent was distilled off. To the residue was added chloroform-methanol (2: 1) to dissolve the residue, the insolubles were filtered off, and the solvent was distilled off.

 Ethanol (4 ml) was added to the residue to dissolve it. 2-Aminobenzaldehyde (60.6 mg, 0.5 mmol) and sodium ethoxide (68.lmg, 1 mmol) were added, and the mixture was heated under reflux for 4 hours and 11 hours Stir at room temperature. The pH of the reaction solution was adjusted to 5 with a 2 N aqueous solution of potassium hydrogen sulfate, and the mixture was partitioned and extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The crude product obtained by distilling off the solvent is purified by silica gel column chromatography (black-mouthed form) and purified with N-butylyl 3,1- (2-quinolyl) _1,1,1-biphenyl-2-sulfonamide (60.8%). mg, 0.141 mmol, 56%).

- Anonymous _{δ (DMS0-d 6):} 12.1 (1H, s), 8.60 (1H, s), 8.52 (1H, d, J = 8.7 Hz), 8.38 (1H, d, J = 7.8 Hz), 8.33 ( 1H, d, J = 8.7 Hz), 8.12 (1H, d, J = 8.4 Hz), 8.07 (2H, d, J = 8.6 Hz), 8.01-8.04 (3H, m), 7.89 (1H, d, J = 7.8 Hz), 7.79-7.83 (1H, m), 7.72 (1H, t, J = 7.8 Hz), 7.61-7.65 (1H, m), 2.21 (2H, t, J = 7.4 Hz), 1.45 (2H , qt, J = 7.4, 7.4 Hz), 0.78 (3H, t, J = 7.4 Hz) Example 5

 N-Benzoyl 3,1- (2-quinolinole) 1-1,1,1-biphenyl-2-4-Sulfonamide trifluoroacetate

 To a solution of 3,1- (2-quinolinole) _1,1, -biphenyl_4-sulfonamide (72. lmg, 0.2 mmol) in acetone (4 ml) was added potassium carbonate (69.lmg, 0.1 ml).

5 mmol) and benzoyl chloride (85 ju 0.73 mmol) were added, and the mixture was heated under reflux for 6 hours. The reaction mixture was heated with chloroform-tetrahydrofuran (1: 1, 10 ml), the insolubles were collected by filtration, and the solvent was distilled off. The residue is purified by high-performance liquid chromatography to give N-benzoyl-1 '-(2-quinolyl) -1,1,1-bifu. An enyl-4-sulfonamide.trifluoroacetate salt (7.8 mg, 0.013 mmol, 6.7%) was obtained.

-Belt δ (DMS0-d ₆ ): 12.6 (1H, br s), 8.60 (1H, s), 8.52 (1H, d, J = 8.6 Hz), 8.38 (1H, d, J = 7.7 Hz), 8.33 (1H, d, J = 8.6 Hz), 8.08-8.15 (5H, m), 8.04 (1H, d, J = 7.9 Hz), 7.89 (3H, m), 7.81 (1H, dd, J = 8.2, 7.2 Hz), 7.72 (1H, t, J = 7.7 Hz), 7.61-7.66 (2H, ra), 7.49-7.53 (2H, m)

Example 6

 N-cyclohexylcarbonyl 3, _ (2-quinolyl) -1,1,1, -biphenyl-2-sulfonamide trifluoroacetate

 The compound was prepared in the same manner as in Example 5 using 3 ′ _ (2-quinolyl) -11,1′-biphenyl-14-sulfonamide and hexylcarbonyl chloride.

— NMR δ (DMSO— d ₆ ): 12.1 (1H, s), 8.60 (1H, s), 8.56 (1H, d, J = 8.7 Hz), 8.79 (1H, d, J = 7.9 Hz), 8.34 ( 1H, d, J = 8.7 Hz), 8.14 (1H, dd, J = 8.3, 0.9 Hz), 8.08 (2H, d, J = 8.6 Hz), 8.05-8.06 (1H, m), 8.02 (2H, d , J = 8.6 Hz), 7.91 (1H, d, J = 7.9 Hz), 7.83 (1H, ddd, J = 8.3, 7.0, 1.2 Hz), 7.73

(1H, t, J = 7.9 Hz), 7.65 (1H, ddd, J = 7.9, 7.0, 0.9 Hz), 2.21-2.28 (1H, m), 1.61-1.72 (4H, m), 1.53-1.59 (1H , ra), 1.09-1.23 (5H, m)

Example 7

 N _ [[3,1- (2-quinolinol) 1-1,1,1-biphenyl-2-yl] carbonyl] methanesulfonamide

3,1- (2-quinolinole) _ 1,1'-bipheninolee4 To a solution of mono-olevonic acid · hydrochloride (100 mg, 0.276 mmol) in N, N-dimethylformamide, add triethylamine (38.5 μl, 0.276 mmol) and 1, -carbodilidimidazole (58.2 mg, 0.359 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Methanesulfonamide (39.4 mg, 0.414 mmol) and 1,8-diazabicyclo [5.4.0] indene-7-ene (61.4 _β 0.414 mmol) were added to the reaction solution, and the mixture was further stirred at 90 ° for 2 hours. . The solvent was distilled off, and the residue was partitioned by adding stomal form and a phosphate buffer solution (# 6.86). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained crude product is subjected to silica gel column chromatography (1 The second round: chloroform-methanol = 50: 1, the second round: hexane monoethyl acetate = 1: 1) was purified to give N-[[3 '-(2-quinolyl) -1,1-bipheninole-4 _ [Yl] caprolponyl] methanesulfonamide (38.5 g, 0.0957 mmol, 35%) was obtained.

— NMR δ (DMS0-d ₆ ): 8.58—8.62 (1H, m), 8.51 (1H, d, J = 8.6 Hz), 8.28—8.38 (2H, m), 8.07-8.14 (3H, m), 7.95 -8.06 (3H, m), 7.87-7.92 (1H, m), 7.77-7.83 (1H, m), 7.67-7.74 (1H, m), 7.58-7.66 (1H, m), 3.41 (3H, s) Example 8

 Ν-[[2 '-(Hydroxymethyl) -5'-(2-quinolinol) -11,1,1-biphenyl-2-yl] carbol] methanesulfonamide trifluoroacetate

 Ν — [[2, _ [[[tert-butyl (diphenyl) silyl] oxy] methyl] -1 5 '— (2-quinolyl) -1,1,1'-biphenyl-14-inole] carbonyl] methanesulfonamide ( To a solution of 28.5 mg (0.0425 millimonole) in tetrahydrofuran (2 ml) was added a solution of tetrabutylammonium fluoride (18 mg, 0.0689 mmol) in tetrahydrofuran (2 ml), and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction solution, and the mixture was partitioned and extracted with chloroform. The crude product obtained by evaporating the organic layer is purified by silica gel column chromatography (cloform form-methanol = 20: 1 → 10: 1) and high-performance liquid chromatography, and Ν — [[2'— (Hydroxymethyl) 1.5,1- (2-quinolyl) 1-1, —biphenyl41-yl] carbonyl] methanesulfonamide trifluoroacetate (3.4 mg, 0.0064 mmol,

15%).

_{¾-NMR 5 (CD 3 0D} ): 8.55 (1H, d, J = 8.6 Hz), 8.20 (1H, dd, J = 8.1, 1.8 Hz), 8.15 (1H, d, J = 8.6 Hz), 8.10 ( 1H, d, J = 8.7 Hz), 8.08 (1H, d, J = 1.8 Hz), 8.01-8.04 (3H, m), 7.83-7.86 (2H, m), 7.64-7.68 (3H, m), 4.61 (2H, s), 3.40 (3H, s)

Example 9

 N — [[[3'-Hydroxy-1 5 '-(2-quinolyl) -1,1, -biphenyl-2-yl] canoleboninole] methansnorehonamide

N— [[3 '— (Methoxy methoxy) 1-5, 1 (2-quinolinole) 1 1, 6N Hydrochloric acid was added to a solution of —4- [yl] caprolponyl] methanesulfonamide (106 mg, 0.229 mmol) in tetrahydrofuran (10 ml), and the mixture was stirred at room temperature for 15 hours. The pH of the reaction solution was adjusted to 6 with a 5% aqueous carbon dioxide solution, and the solvent was distilled off. To the residue was added chloroform-methanol (1: 1, 5 Oml), and the insolubles were filtered off. The crude product obtained by evaporating the solvent of the filtrate was purified by silica gel column chromatography (form: methanol = 50: 1 → 10: 1 → 5: 1) to obtain N _ [[3, There was obtained 1-hydroxy-5,1- (2-quinolyl) -1,1,1-biphenyl 4-inole] -propionyl] methanesulfonamide (90.3 mg, 0.216 mmol, 94%).

^ -NMR δ (DMS0-d ₆ ): 12.2 (1H, br s), 9.86 (1H, s), 8.47 (1H, d, J = 8.7

Hz), 8.25 (1H, d, J = 8.7 Hz), 8.08 (1H, d, J = 8.8 Hz), 8.05 2H, d, J = 8.4 Hz), 8.01 (1H, d, J = 8.5 Hz), 7.78 (1H, t, J = 1.7 Hz), 7.83 (2H, d, J = 8.4 Hz), 7.77-7.81 (2H, m), 7.59-7.63 (1H, m), 7.21 (1H, t, J = 1.7 Hz), 3.18 (3H, s)

Example 10

 N-[[1- [3- (2-quinolyl) phenyl] -4-piperidyl] carbonyl] methane sulfonamide

 It was produced in the same manner as in Example 7 using 1- [3- (2-quinolyl) phenyl] -4-piperidinecarboxylic acid.

— NMR δ (DMSO— d ₆ ): 11.8 (1H, s), 8.43 (1H, d, J = 8.6 Hz), 8.14 (1H, d, J = 8.6 Hz), 8.06 (1H, dd, J = 8) , 1.0 Hz), 7.99 (1H, dd, J = 7.9, 1.5 Hz), 7.80 (1H, m), 7.77 (1H, ddd, J = 8.4, 6.8, 1.5 Hz), 7.65 (1H, d, J = 8.1 Hz), 7.58 (1H, ddd, J = 7.9, 6.8, 1.1 Hz), 7.37 (1H, t, J = 8.1 Hz), 7.09 (1H, m), 3.84-3.88 (2H, m), 3.23 (3H, s), 2.72-2.81 (2H, m), 1.89-1.92 (2H, m), 1.66-1.74 (2H, m)

Example 1 1

 N— [4— [5— (2-quinolyl) -1-3-isosazozolyl] benzoyl] methanesulfonamide

Example using 4- [5- (2-quinolyl) -1-3-isoxazolyl] benzoic acid Ί It was manufactured in the same manner as described above.

- thigh _{δ (DMSO- d 6): 2.84} (3H, s), 3.89 (1H, d, J = 17.1, 7.8 Hz), 3.99 (1H, d, J = 17.1, 11.0 Hz), 5.97 (1H, dd , J = 11.0, 7.9 Hz), 7.59-7.72 (4H, m), 7.75-7.80 (1H, m), 7.98-8.03 (4H, m), 8.44 (1H, d, J = 8.5 Hz) Test example 1 LDL receptor activity measurement

Using a human liver-derived cultured cell line Hep G2, the LDL receptor activity of the test compound was measured. Cells were seeded in 96-well plates at a concentration of 1 × 10 ⁵ ce 11 s / 1, 150 ^ 1 / we 11 (day 1). On the third day, the medium was replaced with a medium containing lipoprotein-depleted serum, 25-hydroxycholesterol, and a test compound. On day 4, 1, 1 'dioctadecyl-3,3,3', 3'-tetramethylindocyanate norlevocyanin perchlorate (1, r-dioctadecyl-3,3,3 ', 3) LDL particles labeled with '-tetraraethyl indocarbo-cyanine perchlorate (hereinafter abbreviated as DiI) (Molecular Probe) were added, and the mixture was incubated at 37 ° C and 5% CO ₂ for 4 hours. After washing with phosphate buffered saline (PBS), the cells are lysed with 0.1 IN aqueous solution of NaOH and 0.1% sodium dodecyl sulfate (SDS), and the amount of DiI in the lysate is measured by fluorescence (excitation light). 530 nm, fluorescence 590 nm). Furthermore, the protein concentration of the solution in which the cells were lysed was measured, and the amount of LDL bound to the cells was determined based on the amount of DiI per unit protein amount. Non-specific binding of LDL to cells was determined by mixing excess (X30) unlabeled LDL with labeled LDL and adding to the experimental system.

 The compound of Example 2 had an excellent LD compared to the control group at 0.15 M.

It showed an effect of increasing the protein content of the L receptor. Industrial applicability

 The compound represented by the general formula (I) can increase the amount of the LDL receptor by increasing the expression (mRNA amount) of the LDL receptor gene, and can lower the serum cholesterol. Therefore, it can be used as a therapeutic drug for hyperlipidemia.

Claims

General formula (I)

 [Wherein, a, b, and c each independently represent a group represented by the formula: C—H or a nitrogen atom.

 Contract

R ¹ is substituted by the number of m, and each independently represents a hydroxy group, a halogen atom, a nitro group, a cyano group, an optionally substituted alkoxy group, or an optionally substituted

Alkoxycarbonyl group, carboxy group, amino group which may be substituted, amide group which may be substituted, urea group which may be substituted, mercapto group,

An optionally substituted sulfonamide group, an optionally substituted alkyl group, an optionally substituted alkenyl group, or a formula: _C (0) NHSO ₂ R ^3a (R ^3a represents an alkyl group) Represents the group represented.

m represents 0 to 3.

 D is a general formula (I Ia) to (I I f):

 (In the formula, d represents an oxygen atom or a sulfur atom.

e, f, g and h each independently represent a group represented by the formula: C_H or a nitrogen atom, except that e, f and g are simultaneously a nitrogen atom.

j represents a group represented by an optionally substituted formula: one CH ₂ — or one NH—. When e, f or g is a group represented by the formula: C—H, one or more of those hydrogen atoms may be independently substituted. Represents a group represented by Y represents an optionally substituted benzene ring or an optionally substituted hetero ring.

Ζ formula: _CONR to display the group represented by ² S (O) _n R ³ or single ^{_{S (0) n NR 4 R}} 5.

n represents 1 or 2.

R ² and R ⁴ each independently represent a hydrogen atom or an optionally substituted alkyl group.

R ³ is an optionally substituted alkyl group, an optionally substituted phenyl group, an optionally substituted aralkyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl Represents a group or a heterocyclic group which may be substituted.

R ⁵ represents a hydrogen atom, an optionally substituted alkyl group, or an optionally substituted acyl group]

Or a pharmaceutically acceptable salt thereof.

2. a is a nitrogen atom,

b and c each independently represent a group represented by the formula: C—H or a nitrogen atom, wherein D may be substituted:

Is a group represented by any of

 Y is an optionally substituted benzene ring or an optionally substituted piperidine ring,

Z is a group represented by the formula: one CONHS (0) ₂ R ³ or one S (O) ₂ NHR ⁵ , wherein R ³ is an optionally substituted alkyl group, an optionally substituted phenyl group, Or an optionally substituted aralkyl group,

R ⁵ is a hydrogen atom or an optionally substituted acyl group, The compound of claim 1, wherein R ¹ and m are the same as defined in claim 1, or a pharmaceutically acceptable salt thereof.

 3. a is a nitrogen atom,

b and c are groups represented by the formula: C—H,

Formula in which D may be substituted:

Is a group represented by

γ is an optionally substituted benzene ring,

Z is a group represented by the formula: one CONHS (O) ₂ R ³ or one S (O) ₂ NHR ⁵ , and R ³ is an optionally substituted alkyl group or an optionally substituted phenyl group. Yes,

R ⁵ is a hydrogen atom or an optionally substituted acyl group,

The compound of claim 1, wherein R ¹ and m are the same as defined in claim 1, or a pharmaceutically acceptable salt thereof.

4. An LDL receptor gene expression enhancer comprising the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient.

 5. A therapeutic agent for hyperlipidemia comprising the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient.

 6. A pharmaceutical composition comprising the compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, and a usual pharmaceutical carrier.