WO1999031062A1 - Novel pyridine compounds - Google Patents

Abstract

Compounds represented by general formula (I) and 5-HT7 receptor-binding agents containing the same as the active ingredient wherein Ar represents optionally substituted aryl or optionally substituted heteroaryl; R1 represents hydrogen, halogeno, alkyl, alkenyl, alkyloxy, etc.; R2 and R3 independently represent each hydrogen or optionally substituted alkyl or R2 and R3 may form together with the adjacent nitrogen atom an optionally substituted heterocycle; and n is an integer of 1 to 6.

Description

 Specification

 New pyridine compounds

The present invention relates to a novel pyridine compound, a pharmacologically acceptable salt thereof, or a hydrate thereof. In particular, the compounds of the invention from acting on _{5- HT 7 (5-Hydroxy t} ryp t ami ne 7) receptor, circadian rhythm disorders therapeutics, senile sleep disorder agent, anti Utsuyaku, antianxiety It is useful as a drug, a therapeutic agent for cardiovascular disorders, a therapeutic agent for migraine, and an analgesic.

Background art

 Serotonin (5-hydroxytryptamine) is one of the physiologically active amines and functions as a kind of hormone. For example, it is present in the basal granule cells of the intestine and promotes intestinal motility. In addition, it is released into the blood from platelets during bleeding, and is involved in hemostasis by contracting capillaries. Separately, serotonin also acts as a neurotransmitter in the brain and is involved in functions such as regulating the hypnotic-wake cycle, regulating pain thresholds, and regulating body temperature. Serotonin also plays a major role in mental activity, and these functions are expressed through serotonin receptors.

In recent years, new serotonin receptor subtypes have been discovered one after another, and are now classified into seven major families. Some have their own subtypes, for a total of 14 types. Among them 5 -.... HT ₇ receptor is one of the serotonin receptor found among the most recently Veurofl, U (1993) 449-458, Proc Na i l Acad Sci USA, 90 ( 1993) 8547-8551].

5-HT ₇ receptor mRNA in the central nervous system is highly distributed in hippocampus [/. Neurochem. 63 (1994) 456-464] and hypothalamus [. J. Pharmacol. Π7 (1995) 567-666] It is known. The suprachiasmatic nucleus in the hypothalamus is said to be the source of circadian rhythm in mammals [J. Neurochem. 63— (1994) 456-464].

It has been strongly suggested that circadian rhythm disorders are associated not only with sleep disorders but also with depression [Psychiatry and Neuropharmacology, 11 (1996) 679-686]. Severe symptoms may lead to employment or inability to attend school. Many treatments have been tried for circadian rhythm abnormalities, but the effect is Not enough. In experimental systems in W ifo 5 recently - HT ₇ receptor agonists have been reported to cause a change in the circadian rhythm [Neuron,] 1 (1 993 ) 449-458]. Accordance connexion, 5 - HT ₇ receptor agonists there is a possibility that can be a circadian rhythm disorder treatment drugs and senile sleep disorder treatment. It can also be an antidepressant because of the relationship between circadian rhythm disorders and depression. Furthermore, it is known that drugs with anxiolytic effects change the circadian rhythm [Psychiatry and Neuropharmacology, ϋ (1996) 697-702], so they may be anxiolytics.

5 - HT ₇ receptor also has been shown to be distributed to the vascular system [. I ^ BS Le t t 370 (1 995) 21 5-221], 5- HT 7 receptor agonists vessel LS possible to expand is known I. Pharmacol. \ (1 995) 383] 0 cerebral vasodilation from being said to cause migraine, 5-HT ₇ receptor binding agent circulatory disorder treatment In addition to being a drug, the angelic gonist could be a migraine remedy. 5 - HT ₇ receptors associated with pain has been suggested, 5-HT ₇ receptor binding agents are also likely to be analgesic different type than the conventional.

Disclosure of the invention

An object of the present invention is to provide a novel 5-HT ₇ receptor binding agent. The present inventors have conducted intensive studies and found that the general formula (I)

In compounds represented acts on 5-HT ₇ receptor, pharmaceutically heading to be useful, the present invention has been completed.

 That is, the present invention

The following formula (I)

(Where Ar is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl: is halogen, alkyl, alkenyl, alkyloxy, alkenyloxy, alkylthio, alkenylthio, substituted or unsubstituted alkylsulfonyloxy, alkenylsulfonyl Oxy, alkylsulfonyl, alkenylsulfonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkenylsulfonyloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkylthio , substituted or unsubstituted Ariruchio, substituted or unsubstituted to the heteroaryl Arukiruokishi, substituted or unsubstituted § Li one Le sulfonyl O carboxymethyl, Heteroariru _{Suruhoniruokishi, - 0S0 2 NR 4 R 5} , - OCONR 4 R 5, - 0CSNR ₄ R ₅ ,-NR ₆ R -N (R ₈ )-(CH ₂ ) _p -NR ₉ R _{1 Q} (R ₄ and R ₅ each independently represent a hydrogen atom, alkyl, or R ₄ and R ₅ together with an adjacent nitrogen atom form a substituted or unsubstituted heterocyclic group R ₆ and R ₇ may be each independently a hydrogen atom, a substituted or unsubstituted alkyl, or R ₆ and R ₇ may be substituted or unsubstituted together with an adjacent nitrogen atom. A heterocyclic group may be formed: R ₈ is a hydrogen atom or alkyl: p is an integer of 2 to 4: R ₉ and R _{1 ()} are each independently a hydrogen atom or alkyl): R ₂ And R ₃ are each independently a hydrogen atom, substituted or unsubstituted alkyl, or R ₂ and R ₃ together form an substituted or unsubstituted heterocyclic group together with an adjacent nitrogen atom. May be:

n :! Integer from 6 to:

However, when Ar is a substituted or unsubstituted heteroaryl, is not alkyl, alkenyl or halogen. ), Or a pharmacologically acceptable salt, or a hydrate thereof.

 The present invention provides, as an embodiment, a compound represented by the following general formula (II):

(Wherein each symbol is as defined above), or a pharmacologically acceptable salt thereof, or a hydrate thereof, preferably a general formula (IV):

(Wherein each symbol is as defined above), or a pharmacologically acceptable salt, or a hydrate thereof, more preferably (1) a general formula (VI):

(Wherein each symbol is as defined above), or a pharmacologically acceptable salt, or a hydrate thereof, or (2) —general formula (VII):

(Wherein each symbol is as defined above), or a pharmacologically acceptable salt, or a hydrate thereof, or (3) —general formula (VIII):

 (Wherein each symbol is as defined above), a pharmacologically acceptable salt, or a hydrate thereof. Preferred forms of the compound (VI) are as follows.

(1) Ar is a substituted or unsubstituted aryl: R is an alkylsulfonyloxy, a substituted or unsubstituted arylalkyloxy, -OS0 ₂ NR ₄ R ₅ , or-0C0NR ₄ R ₅ (R ₄ and R ₅ is each independently hydrogen or an unsubstituted alkyl group): R ₂ and R ₃ To form a substituted or unsubstituted heterocyclic group with an adjacent nitrogen atom: Compound (VI) wherein n is 1.

(2) The compound of the above-mentioned (1), wherein Ar is substituted phenyl: R i is alkylsulfonyloxy or substituted benzyloxy: R ₂ and R ₃ together form a substituted piperazino with an adjacent nitrogen atom. VI).

 (3) The compound (VI) according to (2) above, wherein the substituted piperazino is substituted phenylbiperazino or benzofuran-17-ylpiperazino.

(4) Ar is 3-hydroxyphenyl, 3-alkoxyphenyl or 3-halogenophenyl: Ri is methylsulfonyloxy: R ₂ and R ₃ are taken together with the adjacent nitrogen atom. -The compound (VI) of the above (1), which forms (2-hydroxyphenyl) piperazino.

(5) Ar is 3-hydroxyphenyl, 3-methoxyphenyl or 3-fluorophenyl: R is methylsulfonyloxy: R ₂ and R ₃ are linked together with the adjacent nitrogen atom to form 4- ( (Hydroxyphenyl) Compound (VI) which forms piperazino.

 In another aspect, the present invention provides a compound of the general formula (III):

 (Wherein each symbol is as defined above), or a pharmacologically acceptable salt thereof, or a hydrate thereof, preferably a general formula (V):

) _n NR ₂ R ₃

(Wherein each symbol is as defined above), or a pharmacologically acceptable salt, or a hydrate thereof, more preferably (1) a general formula (IX):

(Wherein each symbol is as defined above), or a pharmacologically acceptable salt, or a hydrate thereof, or (2) —general formula (X):

(Wherein each symbol is as defined above), or a pharmacologically acceptable salt, or a hydrate thereof.

 Further, the present invention, as another aspect,

The following formula (I)

(Where

Ar is a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl: R, is hydrogen, halogen, alkyl, alkenyl, alkyloxy, alkenyloxy, alkylthio, alkenylthio, substituted or unsubstituted alkylsulfonyloxy, a Lucenylsulfonyloxy, alkylsulfonyl, alkenylsulfonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkenylsulfonyloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkylthio, substituted or unsubstituted § Li one thio, terrorist § reel alkyl O carboxymethyl to the substituted or unsubstituted, substituted or unsubstituted § Li one Le sulfonyl O carboxymethyl, hetero § reel sulfonyl O carboxymethyl, - 0S0 ₂ NR ₄ R physician - 0C0NR ₄ R ₅ ,-0 CSNR ₄ R-NR ₆ R ₇ ,-N (R ₈ )- ((:! ^,. (R ₄ and R ₅ are each independently a hydrogen atom, alkyl, or R ₄ And R ₅ may together form an substituted or unsubstituted heterocyclic group with an adjacent nitrogen atom: R ₆ and R ₇ are each independently a hydrogen atom, a substituted or unsubstituted alkyl Or R ₆ and R ₇ may together form a substituted or unsubstituted heterocyclic group with an adjacent nitrogen atom: R ₈ is a hydrogen atom or alkyl: P is 2 Integer to 4: R ₉ and R ₁₀ are each independently a hydrogen atom or an alkyl):

R ₂ and R ₃ are each independently a hydrogen atom, substituted or unsubstituted alkyl, or R ₂ and R ₃ together form an substituted or unsubstituted heterocyclic group with an adjacent nitrogen atom May be:

n is an integer of 1 to 6), or a pharmacologically acceptable salt, or a medicament containing a hydrate thereof, preferably a serotonin receptor binding agent.

Further, the present invention provides a serotonin receptor binding agent, which comprises the compound according to any one of the compounds (II) to (X) as an active ingredient. Good Mashiku as the binder are those having affinity for 5-HT ₇ receptors, i.e., Agonisuto or antagonists of 5-HT ₇ receptor, more preferably Agonisuto. Also the binder, 5 - HT ₇ useful as a therapeutic agent, such as circadian rhythm disorders and senile sleep disorders attributed to receptor, also antidepressants, anxiolytics, migraine therapeutic agents, It is also considered useful as an analgesic.

 The present invention further provides a compound of the formula (XI):

Wherein Y is an oxygen atom or a sulfur atom: R „is a halogen or —NR ₂ R ₃ : Ar, R ₂ and R! Are as defined above, or a salt thereof, and a compound represented by the general formula (XI I):

(Wherein R ₁₂ is alkyloxy, alkenyloxy, alkylsulfonyloxy, alkenylsulfonyloxy, or substituted or unsubstituted arylalkyloxy: R ₁₃ is acetyloxy, hydroxy or halogen: Ar Is the same as defined above) or a salt thereof, and a compound represented by the general formula (XIII):

(Wherein, R _{l 4} is hydrogen, alkyl, alkenyl, § reel alkyl, Heteroari Ruarukiru, alkylsulfonyl, § Luque sulfonyl sulfonyl, Arirusuruhoni Le or to Teroari one Rusuruhoniru: one of Ar of R ₁₅ and R _{l 6} shown, the other is - CH shows a _{2 NR 2 R 3: a r} , R 2 and R ₃ provides a compound or a salt thereof as defined above).

 Hereinafter, the present invention will be described in detail.

 The term "aryl", when used alone or in combination with other terms, includes phenyl, naphthyl and the like, and is preferably phenyl.

 “Heteroaryl”, when used alone or in combination with other terms, includes pyrrolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, quinolyl, furyl, benzofuryl, 2,3-dihydrobenzozofuryl, thienyl, or Benzosoxazolyl and the like are exemplified.

When these "aryl" or "heteroaryl" have a substituent, they may have the same or different one or more substituents, and the substituent may be a halogen group (F, C1, Br, etc.), hydroxyl, alkyl (methyl, Echiru etc.), tri methyl halide (CF _3), alkenyl (Eteniru, propenyl, etc.), Arukiruoki Si (methoxy, ethoxy, etc.), alkoxyalkoxy (methoxy methoxy, etc.), cyano, nitro, amino, alkyl rubamoyloxy, alkyl rubamoyloxy (methyl rubamoyloxy, etc.), alkanol (acetyl, etc.), aralkyl (benzyl, etc.), alkano It may be substituted with yloxy (such as acetyloxy), aralcanoyloxy (such as benzylcarbonyloxy), methylenedioxo, —NHCOR ₁₇ , one NR ₁₈ R ₁₉ or one C 0 NR, ₈ R _{19 and the} like. R _17, R ₁₈ and R ₁₉ each independently represent a hydrogen atom or an alkyl (methyl, Echiru etc.), also substituted or unsubstituted with the adjacent nitrogen atom becomes R, ₈ and R _{1 9} Heights cane May form a heterocyclic group (piperidino, piperazino, morpholino, pyrrolidinyl, etc.).

 Ar is preferably a substituted aryl, particularly a substituted phenyl (substituent: preferably methyl, methoxy, hydroxy, carbamoyl, methylcarbamoyl, dioxomethylene, halogen, cyano, methoxymethoxy, methyl trihalide, etc. .

 “Alkyl”, when used alone or in combination with other terms, refers to one or more of methyl, ethyl, propyl, isopropyl, tert-butyl, n-butyl, n-pentyl, n-hexyl and the like. Includes linear or branched saturated hydrocarbon chains containing 6 carbon atoms. Examples of the substituent of the substituted alkyl include hydroxy, halogen, alkyloxy, C 3 -C 6 cycloalkyl, the above aryl, and the above heteroaryl. “Alkenyl” refers to a straight or branched chain unsaturated carbon containing 2 to 6 carbon atoms such as ethenyl, probenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 1-hexenyl and the like. Includes hydrogen chains.

 “Halogen” refers to fluorine, chlorine, bromine, and iodine.

 In the alkyloxy, alkylthio, alkylsulfonyloxy, alkylsulfonyl, alkylcarbonyloxy, arylalkyloxy, and heteroarylalkyloxy of the above, each alkyl means the aforementioned alkyl. Each alkenyl in alkenyloxy, alkenylthio, alkenylsulfonyloxy, alkenylsulfonyl, and alkenylcarbonyloxy of R i means the alkenyl.

R i arylalkyloxy, arylsulfonyloxy, heteroaryl Each aryl and heteroaryl in the alkyloxy and the heteroarylsulfonyloxy have the same meanings as described above, respectively.

 Preferably, substituted arylalkyloxy, particularly substituted benzyloxy (substituents: methoxy, halogen, etc.), alkylsulfonyloxy (methylsulfonyloxy, edlsulfonyloxy, etc.), dimethylsulfamoyloxy, And dimethylcarbamoyloxy.

Each “heterocyclic group” formed by “R ₄ and R ₅ ” and “R ₆ and R ₇ ” in R _t is a group having one or more nitrogen atoms, and is 1-pyrrolidinyl, piperidino, piperazino And morpholino.

The heterocyclic group formed by `` R ₂ and R ₃ '' is a 5- to 7-membered monocyclic ring or a condensed ring thereof containing at least one nitrogen atom, and includes 1 monopyrrolidinyl, piperidino, piperazino, morpholino, Examples thereof include quinolino and their benzene condensed rings. These heterocyclic groups include alkyl, hydroxy, hydroxyalkyl, alkoxycarbonyl, phenyl, benzyl, pyridyl, pyrimidinyl, benzofuryl, 2,3-dihydrobenzofuryl, 1,4-benzodioxanyl, It may be substituted by benzophenyl, indolyl, quinolino, benzoisothiazolyl, benzimidazolyl, etc., and each of these substituents may be substituted with one or more halogen (F, Cl, Br), alkyl (Methyl, ethyl, etc.), hydroxyl group, alkoxy (methoxy, ethoxy, propoxy, etc.), alkoxyalkoxy (methoxy methoxy, etc.), nitro, cyano, carbamoyl, carbamoyloxy, alkylcarbamoyloxy (methylcarbamoyloxy) ), Methylenedioxy, Kiso, it may be substituted by -NR ₄ R ₅ or the like. R ₄ and R ₅ are as defined above. Preferred examples of the heterocyclic group formed by “R ₂ and R ₃ ” include substituted phenylpiperidino (substituent: hydroxy, methoxy, i-propoxy, cyano, etc.), benzofuran-7-ylpiperazino and the like.

n is an integer of 1 to 6, preferably 1 to 4, and more preferably 1 to 2. The "5-HT ₇ receptor binding agent" refers to a quality ones having a function of binding to 5-HT ₇ receptor, promotes or suppresses the function of the 5-HT ₇ receptor. That is, it includes an agonist or an angist for the receptor. Examples of the pharmaceutically acceptable salt of the compound of the present invention include salts formed with inorganic bases, ammonia, organic bases, inorganic acids, organic acids, basic amino acids, halogen ions and the like, or inner salts. Examples of the inorganic base include alkali metals (Na, K, etc.), alkaline earth metals (Ca, Mg, etc.), and examples of organic bases include trimethylamine, triethylamine, choline, pro-in, ethanolamine, etc. Is exemplified. Examples of the inorganic acid include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Examples of the organic acid include p-toluenesulfonic acid, methanesulfonic acid, formic acid, trifluoroacetic acid, and maleic acid. Examples of the basic amino acid include lysine, algin, ordinine, histidine and the like.

 The compound of the present invention can be orally or parenterally administered to animals including humans as a preventive or therapeutic drug for various diseases caused by serotonin receptors. Examples of the dosage form include granules, tablets, capsules, injections, suppositories and the like. In formulating, various additives such as excipients (lactose, mannitol, crystalline cellulose, starch, etc.), disintegrants (carmellose, hydroxypropylmethylcellulose, polyvinylpolypyrrolidone, etc.), binders as required (Methylcellulose, hydroxypropylcellulose, polyvinyl alcohol, etc.), lubricants (magnesium stearate, talc, etc.), stabilizers, coloring agents, and coating agents can be used. The dose may vary depending on the subject's age, body weight, symptoms, administration method, etc., but it is usually about 0.05 mg to 50 mg per day for an adult per day for oral administration in terms of the compound of the present invention. For parenteral administration, the dose is about 0.1 mg to 10 mg.

BEST MODE FOR CARRYING OUT THE INVENTION

 One of the compounds of the present invention represented by the general formula (IV) can be produced from the following reaction formulas 2-1 to 2-8.

 (Reaction formula 1 _ 1)

NaH

(20) _M e0 ^ ^0Me ₍₂₁₎

 Reflux

の. L. Miles, TM Harris and R. Hauser, J. Org. Chem., 30, 1007 (1965) Obtaining the compound (2 1) from the compound (20) according to the method,

 (Reaction formula 1-2)

 The compound (21) is reacted with ammonia to obtain a compound (22).

 Ammonia is used in an amount of 1.23 mol based on the compound (21), but usually 1.5 mol. Solvents include alcohols such as methanol, ethanol, and propanol; ethers such as tetrahydrofuran, dioxane, and dimethoxetane; aromatic hydrocarbons such as benzene, toluene, and xylene; and halogenated carbons such as dichloromethane, chloroform, and dichloroethane. Examples include hydrogens, acetonitrile, dimethylformamide and the like. The reaction temperature is usually from room temperature to 100 ° C (:, preferably, 280 ° C, and the reaction time is 13 hours. If necessary, organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, and trifluoroacetic acid are used. Add the acid.

(Reaction formula

 The compound (22) is reacted with a base and a reagent to obtain a compound (24).

When sodium hydride, potassium t-butoxide or the like is used as a base, use tetrahydrofuran or dimethylformamide as a solvent. When diisopropylethylamine is used as the base, halogenated hydrocarbons such as dichloromethane, methanol, dichloroethane, etc .; ethers such as tetrahydrofuran, dioxane, and dimethoxetane; benzene, toluene, xylene, etc. And acetonitrile, dimethylformamide, dimethylsulfoxide and the like. The alkylating agent of the reagent is methyl iodide, Lower alkyl halides such as propyl iodide, propyl bromide, isopropyl bromide, butyl bromide, pentyl bromide, hexyl bromide, benzyl bromide, benzyl chloride, and P-methoxybenzyl chloride Alkyl halides such as p-methoxybenzyl bromide, etc .; lower alkyl sulfates such as dimethyl sulfate and getyl sulfate; lower alkyl such as methyl methanesulfonate and ethyl methanesulfonate; lower alkyl sulfonates And methyl p-lower alkylarylsulfonates of toluenesulfonate. Such an alkylating agent is used in an amount of 1 to 1.3 mol based on the raw material (22).

 Also, alkylsulfonyl chlorides such as methanesulfonyl chloride, ethanesulfonyl chloride, and isopropylsulfonyl chloride, dialkylaminosulfonyl chlorides such as dimethylaminosulfonyl chloride and getylaminosulfonyl chloride. And dialkylaminocarbamoylc mouth rides such as dimethylaminocarbamoylc mouth ride, and methylaminocarbamoylc mouth ride, and alkyl chlorocarbonates such as methyl chlorocarbonate and ethyl chlorocarbonate. The reaction temperature is usually under ice cooling to 5 °, preferably under ice cooling to room temperature. Reaction time is 30 minutes to 3 hours.

(Reaction formula 1-4)

 The compound (24) is reacted with a reagent to obtain a compound (25).

As the peracid of the reagent, peracetic acid or m-chloroperbenzoic acid is used in an equimolar amount to the raw material (24), or in a slight excess (1.1 to 1.5 times the molar amount). Solvents include aromatic hydrocarbons such as benzene, toluene, and xylene, dichloromethane, and chloroform. And halogenated hydrocarbons such as dichloroethane. The reaction temperature is usually not ice-cooled or room temperature, and the reaction time is 1 to 65 hours. (Reaction formula 1-5 ')

The compound (25) is reacted with a reagent to obtain a compound (28).

 As the reagent, arylsulfonium halides such as benzenesulfonium chloride and toluenesulfonium chloride are used. Aromatic hydrocarbons such as benzene, toluene and xylene, and halogenated hydrocarbons such as dichloromethane, chloroform and dichloromethane are used as solvents. The reaction temperature is 50-150 ° C and the reaction time is 548 hours. Compound (28) can also be obtained by the following reaction formula 1-5 '.

(Reaction formula 1-5 ')

 First, compound (25) is reacted with a reagent to obtain compound (26).

 The acid anhydride used as the reagent includes acetic anhydride, propionic anhydride, butyric anhydride and the like, but acetic anhydride is preferably used. The reaction temperature is usually 70 to 130 ° C, preferably 790 ° C, and the reaction time is 100 minutes to 3 hours. Next, compound (26) is reacted with a base to obtain compound (27). Examples of the base used include caustic alkalis such as sodium hydroxide and potassium hydroxide, and alkali carbonates such as sodium carbonate and potassium carbonate. Solvents such as alcohols such as methanol, ethanol and propanol, ethers such as ethyl ether, tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene, toluene, xylene, acetonitrile, dimethylmuamide and mixtures thereof But

Four No. The reaction temperature is usually under ice cooling to 100 ° C, preferably room temperature to 50 ° C, and the reaction time is 30 minutes to 2 hours.

 Further, the compound (27) is reacted with an octalogenating agent to obtain a compound (28). Examples of the halogenating agent include thionyl chloride, thionyl bromide, phosphorus oxychloride, and phosphorus pentachloride. As a solvent, aromatic hydrocarbons such as benzene, toluene, and xylene that do not react with halogenating agents, ethers such as ethyl ether, tetrahydrofuran, and dioxane, and halogenated hydrocarbons such as dichloromethane, chloroform, and dichloroethane are used. Is done. The reaction temperature is usually from ice-cooled to 100 ° C, preferably from ice-cooled to 50, and the reaction time is from 30 minutes to 3 hours.

(Reaction formula 1-6)

 The compound (28) is reacted with a primary amine or a secondary amine to obtain a compound (1).

Primary amines include methylamine, ethylamine, propylamine, isopylpyramine, butylamine, pentylamine, hexylamine, cyclopropylamine, cyclopentylamine, cyclohexylamine, ethanolamine, dimethylaminoethylamine and ethylaminoethylamine. . Secondary amines include dimethylamine, getylamine, dipropylamine, dipropylamine, pyrrolidine, piperidine, morpholine, 4-benzylpiperidine, 4-phenylbiperidine, 4- (2-methoxyphenyl) pi Peridine, ethyl 4-piperidinecarboxylate, piperazine, 1-methylbiperazine, 2,6-dimethylbiperazine, 1-benzylpiperazine, 1-piperonylbiperazine, 1-phenylbiperazine, 1- (4 1-chlorophenyl) pirazine, 1- (4-fluorophenyl) piperazine, 1- (2-methoxyphenyl) piperazine, 1- (3-methoxyphenyl) piperazine, 1- (4-me Toxifenil) Piperazine, 1- (2-Isopropyloxyphenyl) Piperazine, 1- (2-Hydroxoxyphenyl) Piperazine, 1- (2-cyanophenyl) Piperazine, 1- (3-Cyanophenyl ) Piperazine, 1-1 (4-Cyanophenyl) Piperazine, 1-1 (3-Hydroxoxyphenyl) Piperazine, 1-1 (4-Hydroxoxyphenyl) Piperazine, 1- (3-Methoxyphenyl Le) piperazine, 1- (2-nitrophenyl) piperazine, 1- (2-pyridyl) piperazine, 1- (2-pyrimidyl) piperazine, 1-1 (benzofuran-1-yl) Perazine, 11- (benzothiophene 17-yl) piperazine, 1- (2-methoxymethyloxyphenyl) piperazine, 1-1 (3-methoxymethyloxyphenyl) piperazine And the like.

 The reaction is usually performed in a solvent. Specific examples of the solvent include ethers such as getyl ether, tetrahydrofuran, dioxane, and dimethoxetane, aromatic hydrocarbons such as benzene, toluene, and xylene, dichloromethane, chloroform, and the like. Examples include octogenated hydrocarbons such as dichloroethane, dialkyl ketones such as acetone, methylethyl ketone, and methyl isobutyl ketone, ethyl acetate, acetonitrile, dimethylformamide, and mixtures thereof.

 Usually, the primary amine or the secondary amine is used in a molar amount or a slight excess (1.1 to 3 times in molar amount) with respect to the compound (28), but it can be used in a large excess. This reaction is preferably performed in the presence of an acid acceptor. Specific examples of the acid acceptor include alkali bicarbonate such as sodium bicarbonate and potassium bicarbonate, and alkali carbonate such as sodium carbonate and potassium carbonate. However, an excess of a primary amine or a secondary amine can also be used as the acid receptor itself.

 The reaction temperature is usually from room temperature to 130, preferably from room temperature to 80 ° C, and the reaction time is from 10 minutes to 15 hours. One of the compounds of the present invention represented by the general formula (VI I) can be produced by the following Reaction Formulas 2-1 to 2-8.

(Reaction formula 2-1)

 (2-1) (2-2) Compound (2-1) power, synthesis of compound (2-2) is described in Kelly YR, LangFR, Tetrahedron Lett. 36 (30), 5319-5322 (1995). The reaction is performed under the following reaction conditions.

(Reaction formula 2-2)

(2-2) (2-3)

 The compound (2-2) is reacted with phenylboric acid to obtain a compound (2-3).

 The phenylboric acids are 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3.4-methylenedioxyphenyl, 3.4-dimethoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenylphosphoric acid and the like. Solvents include dimethoxetane, toluene and dimethylformamide. Generally, tetrakistriphenylphosphine palladium is used as a catalyst, and an aqueous solution of sodium carbonate is used as a base. The reaction temperature is usually 80 to 100 ° C, and the reaction time is 1 to 24 hours.

(Reaction formula 2-3)

(2-3) (2-4) The compound (2-4) is reacted with an alkyl halide to obtain a compound (2-4).

Acetone, methyl ethyl ketone, acetonitrile, dimethylform as solvent Amides. Arylalkyl halides include benzyl chloride, benzyl bromide, p-methoxybenzyl chloride, p-methoxybenzylbutamate, 2.4-dimethoxybenzyl chloride, 2.4-dimethoxy Benzyl bromide and the like. Examples of the base include alkali bicarbonate, alkali carbonate, caustic alkali, sodium hydride and the like.

 (2-4) (2-5)

 The compound (2-4) is reacted with a peracid to obtain a compound (2-5).

 The peracid is used in a molar amount of 1.1 to 1.5 times the molar amount of peracetic acid or m-chloroperbenzoic acid relative to the raw material (2-4).

 Solvents include aromatic hydrocarbons such as benzene, toluene and xylene, dichloromethane, and chloroform. And halogenated hydrocarbons such as dichloroethane. The reaction temperature is usually from ice-cold to room temperature, and the reaction time is 1 to 65 hours.

(Reaction formula 2-5)

(2-5) (2-6)

 The compound (2-5) is reacted with a reagent to obtain a compound (2-6).

 The acid anhydride used as the reagent includes acetic anhydride, propionic anhydride, butyric anhydride and the like, and usually acetic anhydride is used. The reaction temperature is usually from 70 to 130 ° (: preferably from 70 to 90 ° C, and the reaction time is usually from 10 minutes to 3 hours.

(Reaction formula 2-6) Ar ,, N CH ₂ OCOCH ₃ Ar N CH ₂ OH

(2-6) (2-7) Compound (2-6) is reacted with a base to obtain compound (2-7).

 Examples of the base used include caustic alkalis such as sodium hydroxide and potassium hydroxide, and alkali carbonates such as sodium carbonate and potassium carbonate. Solvents include alcohols such as methanol, ethanol, and propanol, ethers such as ethyl ether, tetrahydrofuran, and dioxane; aromatic hydrocarbons such as benzene, toluene, and xylene; acetonitrile, dimethylformamide, and the like. And mixtures thereof. The reaction temperature is usually under ice cooling to 100 ° C, preferably room temperature to 50 ° C, and the reaction time is 30 minutes to 2 hours.

(Reaction formula 2-7)

(2-7) (2-8)

 The compound (2-7) was reacted with a halogenating agent to obtain a compound (2-8).

 Halogenating agents include thionyl chloride, thionyl bromide, phosphorus oxychloride and phosphorus pentachloride. As a solvent, aromatic hydrocarbons such as benzene, toluene, and xylene that do not react with the halogenating agent, ethers such as ethyl ether, tetrahydrofuran, and dioxane, and halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane are used. used. The reaction temperature is usually under ice cooling or 100: preferably under ice cooling to 50 ° C, and the reaction time is 30 minutes to 3 hours.

(Reaction formula 2-8)

(2-8) (2-9)

 The compound (2-8) is reacted with a primary amine or a secondary amine to obtain a compound (2-9).

 Primary amines include methylamine, ethylamine, propylamine, isopyruvylamine, butylamine, pentylamine, hexylamine, cyclopropylamine, cyclopentylamine, cyclohexylamine and ethanolamine, dimethylaminoethylamine, dimethylaminoethylamine. No. Secondary amines are dimethylamine, getylamine, dipropylamine, dipropylamine, pyrrolidine, piperidine, morpholine, 4-benzylpyridine, 4-phenylbiperidine, 4- (2-methoxyphenyl) piamine. Lysine, ethyl 4-piperidinecarboxylate, piperazine, 1-methylpiperazine, 2,6-dimethylbiperazine, 1-benzylpiperazine, 1-piperonylbiperazine, 1-phenylpiperazine, 1- (4-chlorophenyl) piperazine, 1— (4-fluorophenyl) piperazine, 1— (2-methoxyphenyl) piperazine, 1-1 (3-methoxyphenyl) piperazine, 1-1 (4-methoxyphenyl) piperazine, 1- (2-isopropyloxyphenyl) piperazine, 1 _ (2-hydroxide phenyl) Le) piperazine, 1-(2-cyanophenyl) piperazine, 1-1 (3- cyanophenyl) piperazine, 1-(4-cyanophenyl) piperazine, 1-1 (3-hydroxyphenol) Lazine, 1 _ (4-hydroxy phenyl) piperazine, 1-1 (3-methoxyphenyl) piperazine, 1— (212 trophenyl) piperazine, 1-1 (2-pyridyl) Piperazine, 1- (2-pyrimidyl) piperazine, 1- (benzofuran 7-yl) piperazine, 1- (benzothiophene 7-yl) piperazine, 1- (2-me Methoxymethyloxyphenyl) piperazine, and 11- (3-methoxymethyloxyphenyl) piperazine.

The reaction is usually performed in a solvent, and specific examples of the solvent include tetrahydrofuran and dioxane. Ethers such as sun and dimethoxetane, aromatic hydrocarbons such as benzene, toluene, and xylene, halogenated hydrocarbons such as dichloromethane, chloroform, dichlorobenzene, acetone, methyl ethyl ketone, and methyl isobutyl Examples thereof include dialkyl ketones such as ketone, ethyl acetate, acetonitrile, dimethylformamide, and mixtures thereof.

 Usually, the primary amine or the secondary amine is used in a molar amount or a slight excess (1.1 to 3 times in molar amount) with respect to the compound (2-8), but a large excess can be used. This reaction is preferably performed in the presence of an acid acceptor. Specific examples of the acid acceptor include alkali carbonates such as sodium bicarbonate and potassium bicarbonate, sodium carbonate, and carbonated lime. However, a primary amine or a secondary amine can be used in excess to double as an acid acceptor.

 The reaction temperature is usually room temperature to 130 ° C, preferably room temperature to 80 ° C, and the reaction time is 10 minutes to 15 hours. One of the compounds of the present invention represented by the general formula (IX) can be produced from the following reaction formulas 3-1 to 2-2.

(Reaction formula 3-1)

 (3-1)

5-Bromo-1-chloromethylpyridine (J. Heterocyclic Chem., 29, 971 (1992)) is reacted with a primary amine or a secondary amine to obtain a compound (3-1). Primary amines include methylamine, ethylamine, propylamine, isopropylamine, butylamine, pentylamine, hexylamine, cyclopropylamine, cyclopentylamine, cyclohexylamine and ethanolamine, dimethylaminoethylamine, and dimethylaminoethylamine. Can be

The secondary amines include dimethylamine, getylamine, dipropylamine, dipropylamine, pyrrolidine, piperidine, morpholine, and 4-benzene. Rubiperidine, 4-phenylbiperidine, 4- (2-methoxyphenyl) piperidine, ethyl 4-piperidinecarboxylate, piperazine, 1-methylpiperazine, 2,6-dimethylbiperazine, 1-benzylpiperazine , 1-piperonirubiperazine, 1-phenylbiperazine, 1- (4-chlorophenyl) piperazine, 1- (4-fluorophenyl) pirazine, 1- (2-methoxyphenyl) pirazine, 1— (3-Methoxyphenyl) pirazine, 1- (4-Methoxyphenyl) pirazine, 1— (2_Isopropyloxyphenyl) pirazine, 1- (2—Hydroxoxyphenyl) Piperazine, 1- (2-cyanophenyl) piperazine, 1— (3-cyanophenyl) piperazine, 1— (4-cyanophenyl) piperazine, 1— (3— Id mouth oxyphenyl) piperazine, 1- (4-hydroxyphenyl) piperazine, 1- (3-methoxyphenyl) piperazine, 1- (3-methoxyphenyl) Perazine, 1— (2-nitrophenyl) piperazine, 1- (2-pyridyl) piperazine, 1 1- (2—pyrimidyl) piperazine, 1- (benzofuran 1-7-yl) piperazine, 1 1- (benzothiophene 17-yl) piperazine, 11- (2-methoxymethyloxyphenyl) piperazine, 11- (3-methoxymethyloxyphenyl) piperazine, etc. .

 The reaction is usually performed in a solvent. Specific examples of the solvent include ethers such as tetrahydrofuran, dioxane, and dimethoxetane, aromatic hydrocarbons such as benzene, toluene, and xylene, and halogens such as dichloromethane, chloroform and dichloroethane. Examples include fluorinated hydrocarbons, dialkyl ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone, ethyl acetate, acetonitrile, dimethylformamide, and mixtures thereof.

 Normally, the primary amine or secondary amine is used in a molar excess or a slight excess (1.1 to 3 times the molar amount) with respect to the raw materials, but a large excess can be used. This reaction is preferably performed in the presence of an acid acceptor. Specific examples of the acid acceptor include alkali bicarbonate such as sodium bicarbonate and potassium bicarbonate, and alkali carbonate such as sodium carbonate and potassium carbonate. However, an excess of a primary amine or a secondary amine can also be used as the acid receptor itself.

The reaction temperature is usually from room temperature to 130 ° C, preferably from room temperature to 80 ° C. Is 10 minutes to 15 hours

(Reaction formula 3-2)

(3-1) (3-2) The compound (3-1) is reacted with aryl boric acid to obtain the compound (3-2).

 The arylboric acids include phenylboric acid, 2-methoxyphenylboric acid, 3-methoxyphenylboric acid, 4-methoxyphenylboric acid, 3.4-methylenedioxyphenylboric acid, and 3.4-dimethoxyphenylboric acid. Acid, 2-hydroxy phenyl boric acid, 3-hydr oxy phenyl boric acid, 4-hydr oxy phenyl boric acid, 2- cyano phenyl boric acid, 3- cyano phenyl boric acid , 4-Cyanophenylboric acid, 2-Chenylboric acid, 3-Cenylboric acid, 2-furylboric acid, 3-furylboric acid and the like. Solvents include dimethyloxetane, toluene, and dimethylformamide. Generally, tetrakistriphenylphosphine palladium is used as a catalyst, and aqueous sodium carbonate solution is used as a base. The reaction temperature is usually 80 to 100 ° C, and the reaction time is 124 hours. In addition, one of the compounds of the present invention represented by the general formula (X) can also be produced by the following reaction formulas 4-1 to 4-2. The production method itself does not limit the invention in any way.

 (Reaction formula 4-1)

 (4-1)

2-Chloro-3-formyl-5-phenylpyridine (Teahedron Lett., 37, 8231, (1996)) reacts with a primary amine or a secondary amine to give compound (4-1). obtain.

 Primary amines are methylamine, ethylamine, propylamine, isopropylamine, butylamine, pentylamine, hexylamine, cyclopropylamine, cyclopentylamine, cyclohexylamine and ethanolamine, dimethylaminoethylamine, dimethylaminoethylamine. Is mentioned.

The secondary amines include dimethylamine, getylamine, dipropylamine, dipropylamine, pyrrolidine, piperidine, morpholine, 4-benzylpiperidine, 4-phenylbiperidine, 4- (2-methoxyphenyl). Piberidine, ethyl 4—piperidinecarboxylate, piperazine, 1-methylbiperazine, 2, 6—dimethylbiperazine, 1-benzylpiperazine, 1-piperonylpiperazine, 1-phenylbiperazine, 1 _ (4-chlorophenyl) piperazine, 1- (4-fluorophenyl) piperazine, 1- (2-methoxyphenyl) piperazine, 1— (3-methoxyphenyl) piperazine, 1 One (4-methoxyphenyl) piperazine, One (2-isopropyloxyphenyl) piperazine, One (21 Xyiphenyl) piperazine, 1- (2-cyanophenyl) piperazine, 1- (3-cyanophenyl) piperazine, 1- (4-cyanophenyl) pirazine, 1- (3—hydroxyphenyl) pidazine Lazine, 1- (4-hydroxyphenyl) piperazine, 1_ (3-methoxyphenyl) piperazine, 1- (3-methoxyphenyl) piperazine, 1- (2-nitrophenyl) ) Piperazine, 1 — (2-pyridyl) piperazine, 1-1 (2-pyrimidyl) piperazine, 1-(benzofuran 7-yl) piperazine, 1-(benzothiophene 1-7) G) piperazine, 1- (2-methoxymethyloxyphenyl) piperazine, 1- (3-methoxymethoxyphenyl) piperazine and the like.

As the solvent for the reductive N-alkylation reaction, halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane, and ethers such as tetrahydrofuran, dioxane and dimethoxyethane are used. Sodium triacetoxyborohydride is used as a reducing agent. The reaction temperature is under ice cooling to 80, preferably at room temperature, and the reaction time is 1 to 24 hours.

 (4-1) (4-3)

 The compound (4-1) is reacted with an alkoxide or a thiophenoxide to obtain a compound (4-3).

 The alkoxides are selected by reacting alkyl alcohols such as methanol, ethanol and propyl alcohol, and arylalkyl alcohols such as benzyl alcohol and p-methoxybenzyl alcohol with sodium hydride. Thiofenoxides can be obtained by reacting thiophenols such as thiophenol and p-methoxythiophenol with sodium hydride. As a solvent for etherification and thioetherification, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide and the like are used. The reaction temperature is under ice cooling to 80 ° C., preferably at room temperature, and the reaction time is 1 to 24 hours. One of the compounds of the present invention represented by the general formula (IX) can be produced from the following Reaction Formulas 11 to 11 according to Reaction Formulas 5-3.

 (Reaction formula 5-1)

 (5-1)

5- (2-Methoxyphenyl) -16-methoxynicotinic acid methyl ester (J. Org. Chem., 49, 5237 (1984)) is reacted with a reducing agent to obtain a compound (5-1). Examples of the reducing agent include aluminum hydrides such as lithium aluminum hydride and diisobutylaluminum hydride. Examples of the solvent include ethers such as ether and tetrahydrofuran, and aromatic hydrocarbons such as benzene and toluene. The reaction is carried out at a temperature of 70 ~ 8O :, and the reaction time is 10min ~ 3pm Between

(Reaction formula 5-2)

The compound (5-1) is reacted with a halogenating agent to obtain a compound (5-2).

 Examples of the halogenating agent include thionyl chloride, thionyl bromide, phosphorus oxychloride, and phosphorus pentachloride. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, and xylene that do not react with the halogenating agent, ethers such as dimethyl ether, tetrahydrofuran and dioxane, dichloromethane, chloroform and dichloroethane. Halogenated hydrocarbons are used. The reaction temperature is usually under ice cooling or 100 ° C., preferably under ice cooling to 50, and the reaction time is 30 minutes to 3 hours.

(Reaction formula 5-3)

 (5-2) (5-3)

 The compound (5-2) is reacted with a primary amine or a secondary amine to obtain a compound (5-2).

 Primary amines include methylamine, ethylamine, propylamine, isopyramine, butylamine, pentylamine, hexylamine, cyclopropylamine, cyclopentylamine, cyclohexylamine and ethanolamine, dimethylaminoethylamine, ethylaminoethylamine, etc. Are mentioned.

The secondary amines include dimethylamine, getylamine and dipropylamine. Min, dipropylamine, pyrrolidine, piperidine, morpholine, 4-benzyl piperidine, 4-phenylbiperidine, 4- (2-methoxyphenyl) piperidine, ethyl 4-piperidine carboxylate, pi Perazine, 1-methylpiperazine, 2,6-dimethylbiperazine, 1-benzylpiperazine, 1-piperonilpiperazine, 1-phenylbiperazine, 1- (4-chlorophenyl) piperazine, 1- (4— Fluorophenyl) piperazine, 1-1 (2-methoxyphenyl) piperazine, 1-1 (3-methoxyphenyl) piperazine, 1— (4-methoxyphenyl) piperazine, 1— (2 —Isopropyloxyphenyl) piperazine, 1- (2-hydroxyphenyl) piperazine, 1— (2-cyanophenyl) piperazine, 1— (3— Cyanophenyl) pirazine, 1- (4-cyanophenyl) pirazine, 1- (3-hydroxyphenyl) pirazine, 1— (4-hydroxyphenyl) pirazine, 1— ( 3- (methoxyphenyl) pirazine, 1- (3-methoxyphenyl) piperazine, 1- (2-ditrophenyl) piperazine, 1- (2-pyridyl) piperazine, 1-1 (2 —Pyrimidyl) piperazine, 1- (benzofuran 7-yl) piperazine, 1- (benzothiophene 7-yl) piperazine, 1- (2-methoxymethyloxyphenyl) Razine, 11- (3-methoxymethyloxyphenyl) and the like.

 The reaction is usually performed in a solvent. Specific examples of the solvent include ethers such as tetrahydrofuran, dioxane, and dimethoxetane, aromatic hydrocarbons such as benzene, toluene, and xylene, dichloromethane, chloroform, dichloroethane, and the like. Halogenated hydrocarbons, dialkyl ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, ethyl acetate, acetonitrile, dimethyl formamide, and mixtures thereof.

Usually, the primary amine or the secondary amine is used in a molar amount or a slight excess (1.1 to 3 times by molar amount) with respect to the compound (5-2), but it can be used in a large excess. This reaction is preferably performed in the presence of an acid acceptor. Specific examples of the acid acceptor include alkali carbonates such as sodium bicarbonate and potassium bicarbonate, sodium carbonate, and carbonated lime. However, a primary amine or a secondary amine can be used in excess to double as an acid acceptor. The reaction temperature is usually room temperature to 130 ° C, preferably room temperature to 80 ° C, and the reaction time is 10 minutes to 15 hours. Examples will be described below. Abbreviations are as follows.

M e = methyl; E t = ethyl; i-P r = isopropyl; MOM〇 = methoxy methoxy; M s = methanesulfonyl

[Example 1]

 Production Example of 2-Methyl-6- (2-; (Toxif I-2-yl) -4-pyridone (22-1)

Suspend 15.5 g of sodium hydride in 200 ml of 1.2-dimethoxy; t-tan and add refluxing solution of 20 g of 2.4-V tansion'one in 50 ml of 1.2-dimethoxyethane over 20 minutes while heating and refluxing in an oil bath for another 45 minutes. Reflux. Next, a solution prepared by dissolving 33.2 g of> 2-anisic acid butyl ester in 50 ml of 1.2-sitoxetane is added dropwise with heating under reflux for 20 minutes. After heating under reflux for 2 hours and cooling with ice water, (5 ml of ethanol was added to decompose excess sodium hydride, ice was added, and 120 ml of 6N hydrochloric acid was added. Extraction with I-Tel was performed, followed by brine and diluted sodium bicarbonate aqueous solution> brine. After washing with water and drying over magnesium sulfate, the solvent was removed under reduced pressure.42. Og was dissolved in toluene and the column was chromatographed on silica gel 94 g with 10 g; After elution, the solvent was removed under reduced pressure to obtain 37.58 g of the product, which was dissolved in 300 ml of! -Ethanol and added with 98 ml of 2.45N ammethanol: ethanol solution for 1 hour on an oil bath at 65 ° C. After warming, add 1.85 ml of trifluoroacetic acid and heat to reflux in an oil bath for 3 hours, remove the solvent under reduced pressure, add water, extract with hexane, wash with water, dry with magnesium sulfate, remove the solvent, and remove the crude. The product was recrystallized from methanol-acetyl acetate, and 2-tyl-6- (2-; (toxifinyl) -4-pyridone (22- 1) Obtain 22.63 g of crystals having a melting point of 182-187 ° C.Purify 11.94 g of the mother liquor residue with 50 g of silica gel and recrystallize from methanol-I-acetate to obtain 5.21 g of crystals having a melting point of 190-192 ° C. Yield 64.7¾

 NMR (CDC13) 2.32 (3H, s), 3.90 (3H, s), 6.11 (1H, br.s), 6.45 (1H, br.s), 6.97-7.50 (4H, m), 9.98 (1H, br) .s).

[Example 2-16]

The reaction was carried out in the same manner as in Example 1 to obtain 2- (tyl-6-aryl-4-pyridone (22-2) to (22-16), and the melting points and NMR are shown in Table 1. ο ε

S0 / 86df / XDd Z90l £ / 66 ΟΛΛ Table 1-2

[Example 17]

 2-Methyl-4-1 (4-me 6 — (2-methoxyphenyl) pyridine (24-1)

 (22-1) (24-1)

 3.72 g of sodium hydride was suspended in 150 ml of dimethylformamide, and the suspension was cooled on ice and stirred under stirring. And stirred at the same temperature for 15 minutes, and further stirred on an oil bath at 50 ° C for 30 minutes. Next, cool with ice water, add 28.6 g of 4-methoxybenzyl bromide and stir for 1 hour. Methanol is added to decompose excess sodium hydride, and then ice water is added to precipitate crystals. The crystals were separated by filtration and recrystallized from acetone-isopropyl ether to give 2-methyl-4- (4-methoxybenzyl) oxy-16-methoxyphenylpyridine (24-1), melting point 1 16-1 118, 36.3 g of crystals Get. Yield 8 «

NMR (CDC13) 2.56 (3H, s), 3.81 (3H, s), 3.82 (3H, s), 5.04 (2H, s), 6.69-7.73 (10H, m). [Example 1 8—4 1]

 The reaction was carried out in the same manner as in [Example 17] to obtain 2-methyl-4-alkoxy-16-arylpyridine (24-2) to (24-25). The melting points and NMR are shown in Tables 2 and 3.

Table 2

Example Compound Ar Melting point (° C) NMR (CDC 13) Example No No

 18 24-2 2 —Methoxy benzyl oil 2.56 (3H, s), 3.79 (3H

 Phenyloxy, s), 5.12 (2H, s)

 6.70-7.74 (11H, m)

19 24-3 2 —Methoxy 4 1-method 95-97 2.55 (3H, s), 3.81 (3H

 4—Chlorocibenzyl, s), 3.83 (3H, s) enyloxy 5.04 (2H, s), 6.69—

 7.72 (9H, m)

 20 24-4 2 —Methoxy methoxy 67-68 2.57 (3H, s), 3.84 (3H

 Phenyl, s), 3.86 (3H, s)

 6.64-7.71 (6H, m)

21 24-5 4—Fluoro 4 1 meter 110-111 2.57 (3H, s), 3.83 (3H

 Phenyl sibenzyl, s), 5.07 (2H, s)

 Proxy 6.69-7.95 (10H, m)

22 24-6 4-methoxy 4-methoxy 106-107 2.56 (3H, s), 3.83 (3H

 Phenyl sibenzyl, s), 3.85 (3H, s), 5.0

 7 (2H, s), 6.66 (1H, d)

 , 6.94 (2H, d), 6.96 (2 H, d), 7.05 (1H, d), 7.37 (2H, d), 7.89 (2H, d)

 23 24-7 4—Krolf methoxy 56 2.57 (3H, s), 3.89 (3H

 , S), 6.65 (1H, d), 7.0

 1 (1H, d), 7.41 (2H, d), 7.89 (2H, d)

 24 24-8 3-bromomethoxy oil 2.58 (3H, s), 3.89 (3H

 , S) 6.66 (1H, d) 7.01 (

1H, d), 7.31- 8.12 (6H, m) twenty two

 25 24-9 2 —Methoxy methoxy 69-70 57 (3H, s), 3.83 (3H, s

 ¾ C ノ ι—ι ノ, Q Q C \ c c c 1

 ), 0.oD von, S o.DO U enyl H, d), 7.13 (1H, d), 6.

 85 (IH, d), 7.43 (IH, d ofd), 7.87 (1H, d) ίϋ エ 011 L. 00 von, S ό. Oi) \ n, s), 6.64 (1H, d) , 7.0 4 (1H, d), 7.41- 7.96 (5H, m)

 Z4-11 — Uru ten 4 — "^ Uru ten +

 L. bo H, s ヽ, o.oU (.on

5 —Bromofluorobenzyl, s), 3.83 (3H, s) 5.04 enyloxy (2H, s), 6.70- 7.88 (9H, m)

 24-1 4 ー no □ ΐ: no o

 Ton Z.58 C3H, s), 3.89 (3H enyl, s), 6.65 (1H, d), 7.0

 1 (1H, d), 7.57 (2H, d), 7.83 (2H, d)

 29 24-3 1 1

 11 o-l 14 1.58 (3H, s, 3.83 (3H phenylsibenzyl, s), 5.08 (2H, s), 6.7

 3 (1H, d), 7.10 (1H, d)

 6.93-7.72 (8H, m)

30 24-14 2 —Methoxy 4 —Methoxy 139-141 2.56 (3H, s), 3.79 (3H

 5 —Fluorobenzyl, s), 3.83 (3H, s), 5.0

"" One

 Noe-I-No-Re: "Yan Kin., S, 0.oo

 7.57 (7H, m)

 31 24-15 4 Claw 4 — Metoki 88-89 2.57 (3H, s), 3.83 (3H

 Phenyl, benzyl, s), 5.07 (2H, s), 6.7

 1 (IH, d), 6.94 (2H, d)

, 7.08 (1H, d), 7.36 (2H, d), 7.41 (2H, d), 7.88 (2H, d)

[Example 4 2]

 2-Methyl-6- (2-methoxyphenyl) 4-thiopyridone (23)

 (22-1) (23)

 2-Methyl-6-methoxyphenyl 4-pyridone (22-1) 2.15 g (0.01 mol) Lawson's reagent 3.23 g (0.008 mol) Toluene 60 ml Was heated at 90 ° C. for 9 hours. After cooling on ice, the precipitated crystals were collected by filtration. The crystals were dissolved in chloroform, washed with water, dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by alumina (100 g) column chromatography. The title thiopyridone was obtained as an eluate of a mixture of formaldehyde and methanol (100: 1). Recrystallization from a mixed solvent of 1.75 g (75.8%) ethyl acetate chloroform showed a melting point of 170-172 ° C (decomposition). Thigh (CDC13) 2.36 (3H, s), 3.97 (3H, s), 7.03-7.63 (7H, m)

[Example 4 3]

 2-methyl-6- (2-methoxyphenyl) -1-methylthio-pyridine (2

4-5 1)

2-Methyl-6- (2-Methoxyphenyl) —4-thiopyridone (23) 1.65 g (0.00714 mol) and acetone 66 ml in suspension, ice Under cooling, add 5 ml of an acetone solution of 1.03 g (0.00728 mol) of methyl iodide and add at room temperature. Stirred for hours. The solvent was distilled off under reduced pressure, and the residue was purified by 50 g of alumina column chromatography. 1.75 g of 2-methyl-16- (2-methoxyphenyl) -14-methylthio-pyridine was obtained as an oily substance as an eluate of the form of ethyl acetate. Yield _{97.7% NMR (CDC1 3) 2.50} (3H, s), 2.57 (3H, s), 3.85 (3H, s), 6.90-7.72 (5H, m)

[Example 4 4]

 2-Methyl-1- (4-meth (2-methoxyphenyl) pyridine-N-methyl oxide (25)

Dissolve 26.3 g of xyphenyl) pyridine (24--1) in 200 ml of chloroform and add 20.3 g of 80% m-chloroperoxybenzoic acid under ice-cooling and add 10.3 g at the same temperature. After stirring for 23 hours, leave at room temperature for 23 hours. After adding ice water and 10 g of sodium sulfite, the mixture was made alkaline with aqueous ammonia, separated, dried over magnesium sulfate, applied to a 180 g column of silica gel, and eluted with 5% methanol / chloroform. 4- (4-Methoxybenzyloxy) -6- (2-methoxyphenyl) pyridine-N-oxide (25-1) 26.8 g was obtained. Yield 97.5%

 NMRCCDC13) 2.55 (3H, s), 3.80 (3H, s), 3.83 (3H, s), 4.99 (2H, s), 6.86-7.44 (1 OH, m).

[Example 4 5-6 6]

The reaction was carried out in the same manner as in Example 4 4 to obtain 2-methyl-4-alkoxy 16-arylpyridin-1-N-oxide (25-2) to (25-25). The melting points and NMR are shown in Tables 4 and 5. L ε

 T — Halla

0 / 86df / I3d Z; 90lC / 66 O

Table 5

[Example 6 7] 2-Chloromethyl_ 4 -methoxy-1-6- (2-methoxyphenyl) pyridine (28-31)

(25-4) (28-31)

2-methyl -4- 4-methoxy-6- (2-methoxyphenyl) pyridine-N-yl oxide (25-4) 1.63 g and para-toluenesulfonyl chloride 1.39 g Dissolve in 32 ml of benzene and heat to reflux on an oil bath for 24 hours. Add ice water, make the mixture water-soluble with ammonia water, extract with chloroform, dry with magnesium sulfate, apply to a column chromatography of 60 g of alumina, and elute with chloroform. The chloroform is removed to obtain 0.924 g of oily 2-chloromethyl-14-methoxy-16- (2-methoxyphenyl) pyridin (28-31). Yield 52.8%

 Thigh (CDC13) 3.86 (3H, s), 3.90 (3H, s), 4.71 (2H, s), 6.97-7.78 (6H, m)

 [Example 6 8-7 1]

 The reaction was carried out in the same manner as in Example 67, to give 2-methylaminomethyl compounds (28-32) to (28-35). The melting points and NMR are shown in Table 6.

 Table 6

Compound Ar R, NMR at melting point (CDC 13)

Example No No

 68 28-32 3-Br-Ph MeO oil 3.94 (3H, s), 4.70 (2H, s), 7.01 (1H, d)

 , 7.13 (1H, d), 7.29-8.15 (4H, m)

69 28-33 2-MeO, MeO 95-96 3.84 (3H, s), 3.91 (3H, s), 4.70 (2H, s)

 5-Br-Ph, 6.87 (1H, d), 7.00 (1H, d), 7.30 (1H, d

 ), 7.45 (1H, d of d), 7.92 (1H, d)

70 28-34 4-Cl-Ph MeO 87-89 3.93 (3H, s), 4.69 (2H, s), 6.99 (1H, d)

 , 7.13 (1H, d), 7.43 (2H, d), 7.92 (2H, d)

 71 28-35 4-Br-Ph MeO 3.93 (3H, s), 4.70 (2H, s), 7.00 (1H, d)

, 7.13 (1H, d), 7.48 (2H, d), 7.86 (2H, d) The compound (28) obtained by the above reaction can also be obtained by the following Examples 72 to 120.

[Example 7 2] 2-Acetoxymethyl-41- (4-methoxybenzyloxy) 6 — (2-methoxyphenyl) pyridine (26-1)

(25-1) (26-1)

 Dissolve 26.8 g of 2-methyl-4- (4-me-6- (2-methoxyphenyl) pyridine-N-oxide (25) in 134 ml of acetic anhydride.

Heat on oil bath at 75 ° C for 30 minutes. The solvent was removed under reduced pressure, the residue was dissolved in toluene, ice was added, the mixture was extracted with toluene, extracted with toluene, dried over magnesium sulfate, and purified with 90 g silica gel, and the 20% ethyl acetate-toluene mixture eluate was removed. Recrystallized from aceton-isopropyl pyruether to give 2-acetoxymethyl-41- (4-methoxybenzyloxy) -16- (2-methoxyphenyl) pyridine (26-1) with a melting point of 103-3105 23.7 g of crystals are obtained. Yield 79

 NMR (CDC13) 2.17 (3H, s), 3.82 (3H, s), 3.83 (3H, s), 5.07 (2H, s), 5.24 (2H, s), 6.8 8-7.79 (10H, m)

[Example 7 3— 9 6]

 The reaction was carried out in the same manner as in Example 72 to obtain 2-acetyloxymethyl compounds (26-2) to (26-26). The melting points and NMR are shown in Tables 7 and 8.

Four

Table 7-2

 85 26-14 3.4- 4-MeOBnO o j 1

 diMeO-Ph (3H s), 3.98 (3H, s), 5.10 (2H, s), 5.25 (2H, s), 6.85 (1H, d), 716 (IH d) 6 91-7 59 (7H m )

86 26-15 4-F-Ph MeO 60-62 2.19 (3H, s), 3.92 (3H, s 5.24

 (2H, s), 6.82 (IH, d), 7.10 (1H, d), 7.13 (2H, t) 7.95 (2H, d of d)

 87 26-16 2-Me0 MeO oil 2.18 (3H, s), 3.85 (3H, s), 3.89

 4-F-Ph (3H, s), 5.23 (2H, s), 6.69—

 7.81 (5H, m) Applied Ar R, Melting point MR (CDC 13)

Example No Object No

 0 o A-Λ-MPORTIO 1 1 2.18 (3H, s), 3.83 (3H, s 5.09 (2H,

 Methy len 112 s), 5.23 (2H, s), 6.01 (2H, s), 6.85 (e IH, d), 7.12 (1H, d), 6.86- dioxy 7.49 (7H, m)

 4 t- lilpO-Ph qo 1 2.18 (3H, s), 3.83 (3H, s), 3.86 (3H, s), 5.09 (2H, s 5.23 (2H, s), 6.84 (IH, d 6.94 (2H, d), 6.97 (2H, d), 7.15 (1H, d), 7.37 (2H, d), 7.91 (2H, d)

90 26-19 2-Furyl 4-MeOBnO oil 2.16 (3H, s), 3.83 (3H, s), 5.09 (2H, s), 5.20 (2H, s), 6.52 (1H, m), 7.04 (IH, m), 6.81 (IH, d), 6.94 (2H, d), 7.21 (IH, d), 7.37 (2H, d), 7.51 (IH, m)

91 26-20 2-MeO 50-51 2.10 (3H, s), 3.91 (3H, s), 5.21 (2H,

 Th i eny 1 s), 6, 74 (1H, d), 7.07 (IH, d), 7.09- 7.57 (3H, m)

 Q9 2fi-1 2.18 (3H, s), 3.50 (3H, s), 3.83 (3H,

 Me0CH20- s), 5.10 (2H, s), 5.24 (2H, s), 6.89 (Ph IH, d), 6.94 (2H, d), 7.20 (1H, d), 7.

 38 (2H, d), 7.06-7.64 (4H, m)

93 26-22 3-MeO-Ph 4-MeOBnO 128- 2.18 (3H s), 3.83 (3H, s 3.88 (3H,

 130 s), 5.10 (2H, s), 5.25 (2H, s), 6.88- 6.98 (4H, m), 7.20-7.54 (6 H m)

 94 26-24 3-Me -Ph 4-MeOBnO 85-86 2.18 (3H, s), 2.43 (3H, s), 3.83 (3H, s), 5.10 (2H, s), 5.26 (2H, s ), 6.87- 7.78 (10H, m)

 95 4- 4-MeOBnO 97-98 3.18 (3H, s), 3.50 (3H, s 3.83 (3H,

 Me0CH20- s), 5.10 (2H, s), 5.22 (2H, s), 5.24 (Ph 2H, s), 6.85-7.92 (10H, m)

 96 26-26 3-CN -Ph 4-MeOBnO 129- 2.19 (3H, s), 3.83 (3H, s), 5.12 (2H,

130 s), 5.25 (2H, s), 6.92-8.29 (10H, m) [Example 9 7]

 2-Hydroxyoxymethyl-1-4- (4-methoxybenzyloxy) -1-6- (2-methoxyphenyl) pyridine (27-1)

 Dissolve 23.4 g of 2-acetoxymethyl-1- (4-methoxybenzyloxy) -16- (2-methoxyphenyl) pyridine (26- 1) in 300 ml of methanol and add 2N water Add 44.6m1 of sodium oxide solution and stir at room temperature for 1 hour. Concentrate under reduced pressure and add 3.18 g of ammonium chloride and water to precipitate crystals. The crystals are filtered off and the melting point is 12 9-13 1 2-Hydroxymethyl-4-(4-Methoxybenzyloxy)-6-(2-Methoxyphenyl) pyridine (27-1) 20.8 g Get. Yield 99.5%

 NMR (CDC13) 3.83 (3H, s), 3.84 (3H, s), 4.07 (1H, br), 4.74 (2H, s), 5.07 (2H, s), 6.47-7.85 (10H, m)

[Example 9 8—1 1 9]

The reaction was carried out in the same manner as in Example 97 to obtain 2-hydromethyl bodies (27-2) to (27-24). The melting points and NMR are shown in Tables 9 and 10.

Table 9

Compound Ar R, melting point thigh (CDC 13) Example No No

 98 27-2 2-MeO, 4-4-MeOBnO 112-113 3.83 (3H, s), 3.85 (3H, s), 3.

 Cl-Ph 94 (1H, t) .4.73 (2H, d), 5.07

 (2H, s), 6.75-7.82 (9H, m)

99 27-3 4-F-Ph 4-MeOBnO 110-111 3.83 (3H, s), 3.99 (1H, t), 4.

 75 (2H, d), 5.10 (2H, s), 6.74 -7.99 (10H, m)

 100 27-4 Ph MeO oil 3.92 (3H, s), 4.12 (1H, t), 4.

 76 (2H, d), 6.69 (1H, d), 7.16 (IH, d), 7.45-8.01 (5H, m)

101 27-5 4-F-Ph H oil 4.06 (IH, br), 4.82 (2H, s), 7

 .17 (2H, m), 7.61 (IH, d), 7.1 7 (1H, d), 7.76 (IH, t), 8.01 (2H, m)

 102 27-6 2-MeO, 5- 4-MeOBnO 137-139 3.82 (6H, s), 4.00 (IH, br), 4

 F-P .75 (2H, s), 5.08 (2H, s), 6.7

5-7.64 (9H, m)

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Example No No

 112 27-16 4-MeO-Ph 4-MeOBnO oil 3.83 (3H, s), 3.86 (3H, s), 4.

 16 (1H, br, s), 4.73 (2H, s), 5.09 (2H, s), 6.69 (1H, d), 6.9 4 Ln, a, 0.9 o Ln, a), 1. lot, IH, d), 7.37 (2H, d), 7.94 (2H, d)

 113 27-17 2-Furyl 4-MeOBnO 129 3.83 (3H, s), 3.84 (1H, t), 4.

 1 U n, a), b.U9 Kin, S), b.bo (IH, m), 6.68 (1H, d), 6.94 (2 H, d), 7.08 (IH, d), 7.36 (2H, d), 7.51 (IH, m)

 114 27-18 2-Thienyl MeO oil 3.89 (3H, s), 4.71 (2H, s), 6.

 61 (IH, a), 7.07 (IH, a), 7.11 (IH, d of d), 7.39 (IH, d of d), 7.60 (IH, d of d)

115 27-19 3-M0M0-Ph 4-MeOBnO 69-70 3.51 (3H, s), 3.83 (3H, s), 4.

 75 (2H, s), 5.10 (2H, s), 5.25 (2H, s), 6.75 (IH, a), 6.94 (2 H, d), 7.21 (IH, d), 7.37 (2H, d), 7.08-7.67 (4H, m)

116 2-MeO-Ph 4-MeOBnO 117-119 3.83 (3H, s), 3.88 (3H, s), 4.

 07 (IH, br.s, 4.75 (2H, s), 5.10 (2H, s), 6.75 (IH, d), 6.9 2-6.99 (3H, m), 7.21-7.54 (6 H, s)

 11 / 27-22 o-Me-rn 4-MeUBnU 9b-98 I.44 (3H, s), i.83 (3H, s), 4.

 10 (1H, br.s), 4.75 (2H, d), 5 • 10 (2H, s), 6.75-7.81 (10H, in

 118 4MeOCH20- 4-MeOBnO 101-103 3.50 (3H, s), 3.83 (3H, s), 4.

 Ph 13 (1H, br.s), 4.73 (2H, d), 5

 .09 (2H, s), 5.23 (2H, s), 6.7 0-7.94 (10H, m)

 119 27-24 3-CN-Ph 4-MeOBnO 133-134 3.73 (1H, t), 3.83 (3H, s), 4.

77 (2H, d), 5.12 (2H, s), 6.84-8.29 (10H, m) [Example 1 20]

 2 _Chloromethyl-41- (4-methoxybenzyloxy) _6 (2-Methoxyphenyl) Pyridine (28-1)

 (27-1) (28-1)

 2-Hydroxymethyl-4 (4-methoxybenzyloxy) 6- (2-methoxyphenyl) pyridine (27-1) 23.27 g was dissolved in 470 ml of tetrakidrofuran and cooled with ice. Under stirring, 9.44 ml of thionyl chloride was added, and the mixture was stirred for 1 hour at room temperature. The tetrahydrofuran was removed under reduced pressure, ice water was added, the mixture was made alkaline with an aqueous sodium bicarbonate solution, extracted with chloroform, extracted with chloroform, dried over magnesium sulfate, and subjected to a 120 g column chromatography on silica gel 2.5 g acetonitrile. Recrystallized from isopropyl ether to give 2-chloromethyl-4- (4-methoxybenzyloxy) -16- (2-methoxyphenyl) pyridine (28-1) with a melting point of 117-119 ° C 22. 32 g are obtained. Yield 9 1.2%

 NMR (CDCl3) 3.82 (3H, s), 3.83 (3H, s), 4.70 (2H, s), 5.08 (2H, s), 6.92-7.79 (10H, m)

[Example 1 2 1— 143]

 The reaction was carried out in the same manner as in Example 20 to obtain 2-chloromethyl forms (28-2) to (28-25). The melting points and NMR are shown in Tables 11 and 12.

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[Example 144]

2- (N-ethyl-α-methyl-benzylamino) methyl-14- (4-methoxybenzyloxy) -16- (2-methoxyphenyl) pyridine (1-1)

 (28-1) Reflux

 2-chloromethyl-1- (4-me-6- (2-methoxyphenyl) pyridine (28-1) 500 mg N-ethyl-methylbenzilamine 262 mg, potassium carbonate 187 mg, potassium iodide 45 mg, acetate Tril Heat the mixture of 10 ml in an oil bath under reflux for 3.5 hours Remove the solvent under reduced pressure, dissolve the residue in toluene, apply to silica gel 6.5 g column chromatography, apply 10% ethyl acetate / toluene 62 1 mg of 2- (N-ethyl-α-methyl-benzylamino) methyl-14- (4-methoxybenzyloxy) -16- (2-methoxyphenyl) pyridine (1-1) which is eluted with the mixture and is colorless oily Yield 95.2%

 NMR (CDCl3) 1.05 (3H, t,), 1.39 (3H, d), 2.60 (2H, m) 3.71 (lH, q,), 3.81 (lH, q), 3.81 (3H, s), 3.83 ( 3H, s), 3.99 (1H, 5.06 (2H, s), 6.92-7.73 (15H, m)

[Example 145-265]

The reaction was carried out in the same manner as in Example 144 to obtain the 2-alkylaminomethyl compound (1-2) (1-122). The melting points and NMR are shown in Tables 13 to 24.

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 2-[(4-Benzofuran-1-yl) pidazine-1-ylmethyl] (3-Methoxymethylphenyl) 1-4-pyridone (29-41)

 (1-74) (29-41)

2 — [(4-Benzofuran-7-yl) piperazine-1—ylmethyl] -14- (4-Methoxybenzyloxy) -16— (3-Methoxymethylphenyl) -14-Pyridin (1-74) 7 52 mg of methanol 10 ml, tetrahydrofuran 10 m

Dissolve in the mixture of 1 and add 10% of 10% palladium on carbon and stir in hydrogen gas at room temperature for 2 hours. The palladium carbon was separated by filtration, the solvent was removed under reduced pressure, the residue was applied to a 7 g silica gel column, and eluted with 10% methanol / chloroform, and 2-([4-benzofuran-1-yl) piperazine- 1-ylmethyl] 1- 6- (3-Methoxymethylphenyl) -4-pyridone (29-41) powder 531 mg is obtained.

 Yield 95.3%, NMR (CDCl3) 2.84 (4H, m), 3.43 (4H, m), 3.47 (3H, s), 3.63 (2H, s), 5.2 l (2H, s), 6.32 (lH, d ), 6.63 (lH, d), 6.74-7.62 (7H, m)

[Example 2 9 1— 30 1]

 The reaction was carried out in the same manner as in Example 290 to obtain pyridone bodies (29-42) to (29-62). Their melting points and NMR are shown in Table 27.

≠ 21 1

(4-Monofluorophenyl) pyridine (1-123) Melting point: 121-122: 34 1 mg of crystals are obtained.

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[Example 3 4 3]

2- [4-1 (benzofuran 7-yl) piperazine 1-ylmethyl] 1-41-methansulfonyloxy _ 6- (3-hydroxy oxyphenyl) pyridine (1-1-16 4)

(1-141) ⁽¹ - ¹⁶⁴⁾

 2- [4-1 (benzofuran 7-yl) piperazine-1 1-ylmethyl] 1-4-methanesulfonyloxy-6- (3-methoxymethyloxyphenyl) pyridine (1-14-1) ) Dissolve in a mixture of 618 mg of methanol (5 ml) and tetrahydrofuran (5 ml), add 6 N hydrochloric acid (1 ml), and allow to stand at room temperature for 19 hours. The solvent was removed under reduced pressure, made alkaline with ammonia water, extracted with chloroform, dried over magnesium sulfate, and then subjected to silica gel 15 g column chromatography.20% acetonitrile / chloroform eluate 466 mg in ethanol Dissolve and add hydrochloric acid to make the hydrochloride salt and recrystallize from ethanol. 2- [4- (benzofuran-1-yl) piperazine-11-ylmethyl] -14-methanesulfonyloxy-16- (3-hide port 459 mg of crystals of (oxyphenyl) pyridine (1-164) hydrochloride, mp 185-19 It: (d) are obtained.

Yield 75.4%, NMR (CDCls) (free base) 2.88 (4H, m) _> 3.44 (4H, m), 3.26 (3H, s), 3.90 (2H, s), 6.75-7.61 (llH, m) o [Example 344-3 6 2]

The reaction was carried out in the same manner as in Example 3 43 to obtain pyridine compounds (1-165) to (1-183). The melting points and NMR are shown in Tables 32 and 33.

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 To 2- [4- (2-methoxyphenyl) pi. Rasin-1-ylmethyl] -6- (2-methoxyphenyl) -4-thi-pyridone (30-1)

 (29-1) (30-1)

To 2- [4- (2-Nutoxyphenyl) pi. Rash * in-1-y J-tyl] -6- (2-methoxyphenyl) -4-pyri vinyl (29-1)

 2. A mixture of 1.68 g (0.00415 mol) tol-Ion and 60 ml of lg (0.00519 mol) mouth-phosphorus reagent was heated at 70 ° C. for 4.5 hours. After the reaction, the solvent was distilled off. The residue was dissolved in chloroform, washed with water, dried over magnesium sulfate, and the solvent was distilled off. The residue was subjected to column chromatography on alumina (100 g), and 2- [4- (2-methoxyphenyl) pi was eluted as a form eluate at the D port. Lacin-1--1-methyl) -6- (2-methoxyphenyl) -4-thylpyridone was obtained as yellow crystals. Recrystallization from a mixed solvent of 1.13 g (51.8%) of I-ethyl acetate-chloroform D gave a (decomposition) melting point of 135-136.5.

 NMR (CDCl3) 2.78-2.82 (4H, m), 3.13-3.19 (4H, m), 3.58 (2H, s), 3.88 (3H, s), 4.00 (3H, s), 6.88-7.79 (10H, m) [Examples 364-365]

The reaction was carried out in the same manner as in Example 363 to obtain compounds (30-2) to (30-3). Their melting points and NMR are shown in Table 34.

 Table 34

 [Example 366]

2- ^[4 - ⁽² - Nutokishifue;: le) to pin. Lacin-1-ylnutyl] -6- (2-methoxyphenyl) -4-methylthiocyanate (1-184)

 (1 -184)

 (30-1)

2- [4- (2-methoxyphenyl) ar. What. Brush 'down-1- Irumechiru] -6- (2- (Tokishifueniru) -4-old t ° lithograph' down ^{(30- l) 253 mg (0} . 6 mmol) and the suspension of acetone 10 ml, ice Under cooling, 1 ml of an acetone solution of 117 mg (0.83 mmol) of methyl iodide was added and reacted at room temperature for 2 hours, the solvent was removed, and the residue was purified by column chromatography with 8 g of alumina. Crystals of [4- (2-methoxyphenyl) phenyl.lasin-1-ylnutyl] -6- (2-methoxyphenyl) -4-methylthiopyridinine were obtained 250 _mg (95.8%) of this The crystals were recrystallized from a mixed solvent of I-yl acetate-hexane to show a melting point of 122-124 ° C.

 NMR (CDC) 2.78-2.82 (4H, m), 3.13-3.19 (4H, m), 3.58 (3H, s), 3.88 (3H, s), 4.00 (3H, s), 6.88-7.79 (10H, m)

[Example 367-370] The reaction was carried out in the same manner as in Example 366 to obtain compounds of (1-185) to (1-188). Their melting points and NMR are shown in Table 35.

 Table 35

Compound (1) obtained in Example 144 can also be obtained by carrying out the reaction in the same manner as in Examples 371 to 385, and further in Example 302 shown below.

 [Example 371J

2-chloro 0-Nutyl -6. (4-Trifluoro-D-methylphenyl) -4-pyritone (31-1)

 15 ml of concentrated hydrobromic acid is added to 739 mg of 2-dimethylpentyl-4-nutoxy-6- (4-trifluronyl-tylphenylphenyl) pyris'> (28-12), and the mixture is heated and refluxed for 4 hours in an oil bath. Remove hydrobromic acid under reduced pressure, add water, make alkaline with aqueous ammonia, extract with chloroform D> Dry with magnesium sulfate, apply to silica gel 10 g column chromatography, and elute 10% metal chloroform The product was recrystallized from acetone 'Petroleum I-Tell, to give 580 mg of 2-chloro-methyl-6- (4-trimethylphenyl) -4-pyrito'> (31-l) having a melting point of 143-145.

 Yield 82.3%, NMR (d6-DMS0) 4.62 (2H, s), 6.99 (lH, d), 7.31 (lH, d), 7.84 (2H, d), 8.22 (2H, d)

[Example 372-380]

The reaction was carried out in the same manner as in Example 371 to obtain the 4-pyridone compounds (31-2) to (31-10). Their melting points and NMR are shown in Table 36.

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 (31-1)

 2-Chloromethyl-6- (4-trifluoromethylphenyl) 1-4-pyridone (31-1) 144 mg 1- (2-Methoxyphenyl) piperazine 1 15 mg Potassium carbonate 83 mg, Potassium iodide 17 mg The mixture of 10 ml of acetonitrile was heated to reflux on an oil bath for 1 hour. The solvent was removed under reduced pressure, the residue was treated with chloroform, the insolubles were removed, and the residue was subjected to 6 g column chromatography on a silica gel.The eluate of 5% methanol in chloroform was recrystallized from acetone-ether (213 mg). 2- [4- (2-Methoxyphenyl) piperazine) 1-1-Methyl] —6- (4—Trifluoromethylphenyl) — 4-pyridone with melting point 1 54—156 ° C 29—53) 1 52 mg is obtained.

Yield 68.5%, NMR (CDCl3) 2.62 (4H, m), 3.00 (4Hm), 3.65 (2H, s), 3.77 (3H, s), 6.90-7.28 (6H, m), 7.83 (2H, d ) ₎ 8.23 (2H ₎ d), 10.75 (lH, s)

[Example 382—38 5]

The reaction was carried out in the same manner as in Example 381 to obtain a pyridone form (29-54) (29-57). The melting points and NMR are shown in Table 37.

 Table 37

[Example 386]

 2- [4- (2-methoxyphenyl) piperazine-11-yl] methyl-4-chloro-1-6- (2-methoxyphenyl) pyridine.1 / 2 fumarate (1-189)

2- [4- (2-methoxyphenyl) piperazine-11-yl] methyl-6- (2-methoxyphenyl) pyridone (29-1) 2.00 g and oxychloride The mixture of 15 ml of phosphorus is stirred for 1 hour on a 50 ° C. oil bath. Remove excess phosphorus oxychloride under reduced pressure, ice on residue After adding water, the mixture is made alkaline with ammonia water, extracted with chloroform, dried over magnesium sulfate, and then subjected to 40 g of silica gel column chromatography to obtain 1.90 g of a 10% acetonitrile. Dissolve 1.90 g of eluate in methanol, add 1.03 g of fumaric acid, concentrate, add i-propyl alcohol and filter the precipitated crystals, white crystals with a melting point of 142-144 ° C 2-—4 -— (2 —Methoxyphenyl) piperazine-1-yl] methyl-4-1-chloro-6- (2-methoxyphenyl) pyridine. 1/280 fumarate (1-189) 1.80 g is obtained.

 Yield 76.6%, NMR (CDCl3) (free base) 2.79 (4H, m), 3.15 (4H, m), 3.82 (2H, s), 3.86 (3H, s), 3.88 (3H, s), 6.84- 7.42 (7H, m), 7.46 (2H, d), 7.75 (2H, d), 7.80 (lH, d of d) [Example 387]

 1-Hydroxoxy-1-2-methyl-6- (4-fluorophenyl) -15.6-Dihydropyridine (33-1)

 Dissolve 5.46 g of 2-picoline mono-N-oxide in 30 ml of dry tetrahydrofuran and dissolve 10-lg 4-fluorobromobenzene, 1.47 g magnesium, 1.2-dibromoethane 0.25 m 1, To a solution of 4-fluorophenylmagnesium bromide / tetrafuran adjusted from 70 m of dry tetrahydrofuran, add dropwise with stirring at 10 or less. Stir at 40 for 30 minutes and leave at room temperature overnight. Dissolve 4.85 g of ammonium chloride in 30 ml of water, extract with ether, dry with magnesium sulfate, remove the solvent, remove 9.49 g of the residue, apply it to 95 g of silica gel column chromatography, and apply 10% acetonitrile The eluate was recrystallized from 7.40 g of ether-petroleum ether to give a melting point of 1 1 1 8 1 1 9

6.15 g of (4-monofluorophenyl) -1-5.6-dihydropyridine (33-1) are obtained.

Yield 60.0%, NMR (CDCl3) 2.08 (3H, s), 5.79 (lH, d), 6.36 (lH, d), 6.66 (lH, d), 6.9 8-7.43 (4H, m), 7.46 (lH , d of d). [Example 388-395]

 The reaction was carried out in the same manner as in Example 387 to obtain dihydropyridines (33-2) to (33-19). The melting points and NMR are shown in Table 38.

 Table 38

 [Example 396]

2-Methyl-6- (4-fluorophenyl) pyridine-N-oxide (25- 3 1)

 (33-1) (25-31)

 Dissolve 6.17 g of 1-hydroxy-1--2-methyl-6- (4-fluorophenyl) -1-5.6-dihydropyridine (33-1) in 123 ml of methylene chloride and cool under ice-cooling. 2.3 -Dichloro-5.6-dicyanol 1.4-Benzoquinone 7.5 1 is added and stirred at room temperature for 1 hour. The insolubles were separated by filtration, the methylene chloride solution was washed with an aqueous sodium bicarbonate solution, dried over magnesium sulfate, and then applied to a column chromatograph of 120 g of alumina, eluted with 10% acetonitrile-chloroform. 6-

4.89 g of (4-monofluorophenyl) pyridine-N-year-old oxide (25-31) are obtained.

 Yield 79.9%, NMR (CDCls) 2.60 (3H, s), 7.13-7.30 (5H, m), 7.80-7.87 (2H, m). [Example 397-404]

The reaction was carried out in the same manner as in Example 396 to obtain pyridine N-oxides (25-32) to (25-39). Their melting points and NMR are shown in Table 39.

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/ 86df / IDd Z901C / 66 ΟΛ \ The compound (28) obtained from Example 67 can be obtained by the following Example 405, Example 406 or Example 410.

[Example 4 05]

 6- (3-carbamoylphenyl) 1-2-chloromethyl-14- (4-methoxybenzyloxy) pyridine (28-41)

 (28-41)

2-chloromethyl-one 6-. (3 - Shianofueniru) Single 4- (4-menu Tokishibenji Ruokishi) pyridine 1 1 4 g was dissolved in dimethyl sulfoxide 2 O m 1, potassium carbonate 4 3 m _g, 3 0% Add hydrogen oxide aqueous solution (426 mg) and stir at room temperature for 3 hours. Water was added to the reaction solution, and the precipitated crystals were collected by filtration, and the melting point of 17-2-174 was 6- (3-forcerubamoylphenyl) -12-chloromethyl-14- (4-methoxybenzyloxy). ) Pyridine (28-41) 1.18 is obtained.

Yield 98.2%, NMR (d6-DMSO) 3.77 (3H, s), 4.80 (2H ₎ s), 5.24 (2H, s), 6.98 (2H, d), 7.2 l (lH, d), 7.45 (3H , m), 7.57 (lH, t), 7.64 (lH, d), 7.94 (lH, d), 8.10 (lH, br.s), 8.25 (lH ₎ d), 8.55 (lH, s)

[Example 400]

2-Chloromethyl-4-methanesulfonyloxy-6- (2-methoxyphenyl) pyridine (28-42)

(28-42)

Dissolve 3.65 g of 2-chloromethyl-16- (2-methoxyphenyl) -14-pyridone trifluoroacetate in 150 ml of anhydrous tetrahydrofuran, 1.26 g of methanesulfonyl chloride, diisopropyl Add 2.85 g of tilamine and stir at room temperature for 24 hours. Water was added to the reaction solution, and the mixture was extracted with chloroform.The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure.The resulting residue was subjected to 40 g of silica gel column chromatography. Appendix 1: 1 Ethyl acetate · Hexane eluate was recrystallized from hexane to give 2-chloromethyl-4-methanesulfonyloxy-6- (2-methoxyphenyl) pyridine with a melting point of 95-96 ° C. (28-42) 3.08 g are obtained.

Yield 93.7%, NME (CDCl3) 3.24 (3H, s), 3.89 (3H, s), 4.75 (2H ₎ s), 7.01 (lH, d), 7.09 (lH, t), 7.35-7.47 (2H , m), 7.82 (lH, d), 7.89 (lH, dd)

[Example 407-409]

The reaction was carried out in the same manner as in Example 406 to obtain the 4-pyridine derivative (28-43) (28-45). The melting points and NMR are shown in Table 40.

 Table 40

[Example 4 10]

 2-chloromethyl-1- (2-hydroxyphenyl) 4-methanesulfonyloxy-pyridine (28-46)

(28-42) (28-46)

Dissolve 2.5 g of 2-chloromethyl-4-monomethanesulfonyloxy 6- (2-methoxyphenyl) pyridine (28-42) in 50 ml of methylene chloride and add hydrogen chloride Add 9.6 ml of a methylene chloride solution (1.6 M) and stir for 3 hours. Ice was added to the reaction solution, 8 ml of 5N hydrochloric acid was added, and the mixture was further stirred for 0.5 hours.Then, the mixture was made weakly alkaline by adding 10 g of sodium bicarbonate, extracted with chloroform, and the organic layer was saturated with sodium chloride. After washing with an aqueous solution and drying over magnesium sulfate, the solvent is distilled off under reduced pressure. The obtained residue was subjected to 30 g of column chromatography on silica gel. Recrystallize the eluate of 3% methanol 'chloroform form with ether to give 2-chloromethyl-6- (2-hydroxyphenyl) -14-methanesulfonyloxy-pyridine (28-46) with a melting point of 158-159. 1.6 1 g are obtained.

Yield 67.0%, NMR (CDCl3) 3.31 (3H, s), 4.72 (2H, s), 6.94 (lH, t), 7.04 (lH, dd), 7.31-7.40 (2H, m), 7.71-7.78 ( 2H, m) The compound (1-190) obtained in Example 306 was converted to a compound (1-190) by using the method described in Example 41 1 or Example 4 12 below. (1-19-1) was obtained.

[Example 4 1 1]

 2- (2-Hydroxyoxyphenyl) 14-Methanesulfonyloxy 6- [4- (2-Methoxyphenyl) piperazine-11-yl] methylpyridine il_190)

 2- (2-methoxyphenyl) _4-methanesulfonyloxy-6- [4- (2-methoxyphenyl) piperazine-1-yl] methylpyridine (1-127) 24 3 mg of dichloromethane 1 Dissolve in 0 ml, cool with dry ice / acetone at 178, and add 0.95 ml of a 1.6 molar solution of boron tribromide in dichloromethane under stirring, stir at the same temperature for 3 hours, and then stand at room temperature for 18 hours. After adding ice, the mixture was made alkaline with sodium bicarbonate, extracted with chloroform, dried over magnesium sulfate, and then subjected to column chromatography on 30 g of silica gel. Ethyl acetate: hexane (1: 2) mixture eluted 71 mg from the ether. Crystals with a melting point of 128-129: 2- (2-hydroxyphenyl) -4-methanesulfonyloxy 6- [4_ (2-methoxyphenyl) piperazine [Methyl] pyridine (1-190) in an amount of 44 mg.

 Yield 19.2%, NMR (CDCl3) 2.602.84 (4H, m), 3.10-.20i4H, m), 3.29 (3H, s), 3.83i2H,

02 s), 3.86 (3H, s), 6.84-7.06 (6H, m), 7.33 (lH, d of d), 7.37 (lH, d), 7.69 (lH, d), 7.74 (lH, d of d)

[Example 4 1 2]

 2- (2-Hydroxyphenyl) -1-4-Methanesulfonyloxy 6- [4- (2-Hydroxoxyphenyl) piperazine-1-1 9 1)

 (1-127) (1-191)

2- (2-Methoxyphenyl) 1-41-methanesulfonyloxy-6- [4- (2-Methoxyphenyl) piperazine-11-yl] methylpyridine (1-127) 24 lmg Is dissolved in 10 ml of dichloromethane, and 2.2 ml of a 1.6 mol solution of boron tribromide in dichloromethane is added under ice-cooling. The mixture is left at room temperature for 18 hours and refluxed for 2 hours. After adding ice and 5 ml of 1N hydrochloric acid and stirring at room temperature for 30 minutes, the mixture was made alkaline with sodium bicarbonate, sodium chloride was added, and the mixture was extracted with 10% methanol and chloroform solution, dried with magnesium sulfate and dried. The residue was subjected to column chromatography on 20 g of silica gel, and the eluate of a mixture of ethyl acetate and hexane (1: 2) was recrystallized from ether to give crystals of melting point 1 15—1 17 2— (2 —Hydroxoxyphenyl) 1-41-Methanesulfonyloxy 6— [4- (2-Hydroxoxyphenyl) pirazin-1-yl] methylpyridine (1-191), yielding 108 mg.

Yield 47.7%, NMR (CDCl3) 2.60-2.80 (4H, m), 2.92-3.00 (4H, m), 3.30 (3H, s), 3.83 (2H, s), 6.84-7.23 (6H, m), 7.32-7.38 (2H, m), 7.69 (lH, d), 7.74 (lH, d of d)

[Example 4 1 3]

2-bromo-3-hydroxy-6-methylpyridine (2_2) HO

N CH ₃ B, N, CH ₃

 (2-1) (2-2)

 6.6 g (0.06 mol) of 5-hydroxy-1-methyl-pyridine (2-1) is dissolved in 120 ml of dry pyridine, and bromine is added at an internal temperature of 15-25. 55 g (0.066 mol) of a pyridine solution 60 ml was added dropwise over 20 minutes, and the mixture was stirred at room temperature for 15 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was cooled on ice, and the precipitated crystals were collected by filtration to obtain 8.6 g of 2-bromo-13-hydroxy-16-methylpyridine. Yield 75.6% Recrystallization with ethanol gives crystals with a melting point of 188-190 ° C.

 NMR (CDCl3) 2.47 (3H, s), 5.48 (lH, br.s), 7.03 (lH, d, J = 8.4), 7.20 (lH, d, J = 8.4) [Example 4 14]

 3-Hydroxy-6-methyl-2- (2-methoxyphenyl) pyridine (2-3

)

Tetrakistriphenylphosphine palladium 92 2 mg (0.000778 mol), toluene 50 ml, pyridine 5.0 g (0.0266 mol), 2N sodium carbonate 25 m A mixture obtained by sequentially adding 4.45 g (0.0293 mol) of 1,2-methoxyphenylboric acid and 1 Oml of ethanol was heated at 90 for 4 hours. After cooling to room temperature, extraction was performed with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by column chromatography on silica gel (180 g). 3-hydroxy-6-methyl-12- (2-methoxyphenyl) pyridine (2-3) was used as the eluate of a mixture of formaldehyde and hexane (4: 1) with a melting point of 179-182 V

2.95 g (51.7%) of (decomposed) crystals were obtained.

04 NMR (CDCl3) 2.56 (3H, s), 3.95 (3H, s), 6.82 (lH, br.s), 7.04-7.27 (2H, m), 7.39-7.72 (2H, m)

[Example 4 15]

 6-Methyl-1 2— (2-methoxyphenyl) 1 3— (4

Xy) Pyridine (2-4)

576 mg (0.0144 mol) of sodium hydride was suspended in 30 ml of dimethylformamide, and the suspension was cooled on ice and stirred with 3-hydroxy-6-methyl-2- (2-methoxyphenyl) pyridine (2--3 ) 2.57 g (0.012 mol) was added, the mixture was stirred at the same temperature for 10 minutes, and further reacted at room temperature for 30 minutes. Then, under cooling with ice water, 2.9 g (0.0138 mol) of 4-methoxybenzyl bromide was added, and the mixture was reacted under the same conditions for 10 minutes and then at room temperature for 1 hour. The dimethylformamide was removed under reduced pressure, and the residue was mixed with chloroform and ice water. The mixture was stirred for 5 minutes and extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel (140 g) column chromatography. Crystals of 6-methyl-12- (2-methoxyphenyl) -13- (4-methoxybenzyloxy) pyridinine (2-4) 3.9 g (97.5%) were obtained. Recrystallization from hexane-monoether gives crystals with a melting point of 87-88 ° C.

 NMR (CDCl3) 2.53 (3H, s), 3.73 (3H, s), 3.78 (3H, s), 4.95 (2H, s), 6.80-7.38 (10H, m)

[Example 4 16]

 6-Methyl- 2 _ (2-methoxyphenyl) 3— (4

Xy) pyridine-N-oxide (2-5)

0 5

 4) (2-5)

 6-Methyl-2- (2-methoxyphenyl) 1 3- (4-me

Xy) Dissolve 4.3 g (0.0128 mol) of pyridine (2-4) in 90 ml of chloroform at room temperature, add 3.47 g of 80% methacrole perbenzoic acid under ice-cooling and add 1 47 at the same temperature. After stirring for a while, the mixture was left at room temperature for 65 hours. Ice water and 1.18 g (0.014 mol) of sodium hydrogencarbonate were added, and the mixture was stirred for 15 minutes and then separated. Dried with magnesium sulfate, alumina 1 30 g column chromatographed, 6-methyl-2- (2-methoxyphenyl) 1-3- (4-methoxybenzyloxy) 4.32 g of pyridine mono-N-oxide (2-5) were obtained. Yield 95.8% Recrystallization with a mixed solvent of ethyl acetate affords crystals with a melting point of 130.5-132.

 NMR (CDCl3) 2.13 (3H, s), 3.73 (3H, s), 3.79 (3H, s), 5.01 (2H, s), 5.20 (2H, s), 6.81-7.42 (10H, m).

[Example 4 17]

 6-acetoxymethyl-1- (4-methoxybenzyloxy) 1-2 (2-methoxyphenyl) pyridine (2-6)

 (2-5) (2-6)

Dissolve 3.7 g of 6-methyl-1- (2-methoxyphenyl) -13- (4-methoxybenzyloxy) pyridine-N-butoxide (2-5) in 30 ml of acetic anhydride 8 Heated on oil bath at 0 ° C for 2 hours. Remove the solvent under reduced pressure, dissolve the residue in After adding ice water and making it alkaline with ammonia water, extract with black-mouthed form. The extract was washed with brine, dried over magnesium sulfate, and purified with 100 g of alumina. Elution of a mixture of formaldehyde and hexane (2: 1) yields 6-acetoxymethyl-3- (4-methoxybenzyloxy) -12- (2-methoxyphenyl) pyridine as an oil. 3.1 5 g were obtained.

Yield 76.1%, NMR (CDCls) 2.13 (3H, s), 3.73 (3H, s), 3.79 (3H, s), 5.01 (2H, s), 5.20 (2H, s), 6.81-7.42 (10H, m)

[Example 4 1 8]

 6 _Hydroxyoxymethyl-2- (2-methoxyphenyl) 1-3- (4-Methoxybenzyloxy) pyridine (2-7)

 6-acetoxymethyl-3- (4-methoxybenzyloxy) -1-2- (2-methoxyphenyl) pyridine (2-6) 3.5 g (0.00891 mole) in methanol After dissolving in 25 ml, 6.7 ml (0.0134 ml) of 2N sodium hydroxide solution was added under ice cooling, and the mixture was reacted at room temperature for 6 hours. Add 4 ml of saturated ammonium chloride water and concentrate the solvent to precipitate crystals. The crystals were separated by filtration to obtain 6-hydroxymethyl-2- (2-methoxyphenyl) -13- (4-methoxybenzyloxy) pyridine (2-7). Recrystallization from 2.75 g (87.9%) of ethyl acetate-ether gives crystals with a melting point of 125-127 ° C.

NMR (CDCl3) 3.70 (lH, br.s), 3.73 (3H, s) ₎ 3.79 (3H, s), 4.72 (2H _> s), 5.00 (2H, s), 6.8 0-7.44 (10H, m)

[Example 4 1 9]

 6_Chloromethyl-2 — (2-Methoxyphenyl) — 3— (4—Methoxybenz

0 7 Ziloxy) pyridine (2-8)

 (2-7) (2-8)

 6-Hydroxymethyl-2 (2-methoxyphenyl) — 3- (4-methoxybenzyloxy) pyridine (2-7) 2.8 g (0.00798 mol) is dissolved in 70 ml of tetrahydrofuran, cooled with ice and stirred. 1.90 g (0.016 mol) of thionyl chloride was added and reacted at room temperature for 2 hours. The tetrahydrofuran was removed under reduced pressure, and the ice water was made alkaline with sodium hydrogen carbonate solution and extracted with chloroform. After drying over magnesium sulfate, the column was chromatographed on 80 g of alumina. The eluate of the mixture of formaldehyde and hexane (4: 1) was 6-chloromethyl-2- (2-methoxyphenyl) 13- (4-methoxy). Benzyloxy) pyridine (2-8) was obtained as crystals as 2.8 g. Yield 94.9% Recrystallization from hexane-ether gives crystals with melting point 77-78

NMR (CDCl3) 3.73 (3H, s), 3.79 (3H, s), 4.70 (2H, s), 5.02 (2H, s), 6.82-7.41 (lOH.m

)

[Example 420]

 3- (4-Methoxybenzyloxy) — 2- (2-Methoxyphenyl) 1 6 1 [4-1 (2-Methoxyphenyl) piperazinol 1-ylmethyl] pyridine oxalate (2-9-1) )

 6-Chloromethyl-2- (2-methoxyphenyl) _3_ (4-Methoxybenzen

08 Ziroxy) Pyridine (2-8) 50 Omg (0.013 5 mol), 1- (2-methoxyphenyl) piperazine 28 6 mg (0.0014 5 mol), Carbonic acid A mixture of 186 mg of potassium hydroxide (0.00.0135 mol), 45 mg of potassium iodide (0.02000 mol) and 1 Om 1 of acetonitrile was heated and refluxed on an oil bath for 2 hours. The solvent was removed under reduced pressure, the residue was dissolved in chloroform, and the residue was subjected to silica gel 2 O g column chromatography, and eluted with a mixture of chloroform and methanol (100: 1). Toxibenzyloxy) 1- (2-methoxyphenyl) 6- [4- (2-methoxyphenyl) piperazinol-1-ylmethyl] pyridine (2-9-1) 69 Omg was obtained. Yield 97.2%

 This oily substance was dissolved in acetone (20 ml), and an oxalic acid salt solution was prepared by adding 1.1 equivalents of an oxalic acid solution in acetone. Melting point 80-83 ° C (decomposition)

 NMR (CDCl3) (free base) 2.74-2.78 (4H, m), 3.11-3.15 (4H, m), 3.72 (3H, s), 3.78 (3H, s), 3.79 (2H, s), 3.85 ( 3H, s), 4.99 (2H, s), 6.81-7.39 (14H, m) [Example 4 2 1—4 2 3]

 Example 4 The reaction was carried out in the same manner as in Example 20, and the compounds (2-9-2) to (2-9-4) were obtained. Their melting points and NMR are shown in Table 41.

0 9

 Table 4

[Example 4 24]

 3-Hydroxy-1- (2-methoxyphenyl) 6 [4 (2-Methoxyphenyl) piperazino-1-ylmethyl 1pyridine (2-0)

3- (4-Methoxybenzyloxy) 1 2— (2-Methoxyphenyl) 6— [4- (2-Methoxyphenyl) piperazino-1-ylmethyl] pyridine (2-9-11) 5 8 Omg was dissolved in 6 ml of acetic acid, 2 ml of 48% hydrobromic acid was added under ice cooling, and the mixture was heated at 50 for 2.5 hours. Add ice water and extract with ether to remove by-products. The aqueous solution is made alkaline with aqueous ammonia and extracted with chloroform. After washing with water and drying over magnesium sulfate, the residue was applied to a column chromatograph of 20 g of alumina to obtain 434 mg of the title compound as crystals as eluate from the form of the port. Yield 97.1% hexane monoacetate Recrystallization from chill gave a pure product with a melting point of 14.5-14.7 ° C.

 NMR (CDCl3) 2.74-2.79 (4H, m), 3.11-3.15 (4H, m), 3.78 (2H, s), 3.86 (3H, s), 3.96 (3H, s), 6.84-7.72 (10H, m)

[Example 4 2 5]

 3-Methanesulfonyloxy 1 2 (2-methoxyphenyl) 1 6— [4-1 (2-methoxyphenyl) piperazino-ylmethyl] pyridine oxalate (2-11-1)

3-Hydroxy-2- (2-methoxyphenyl) 6- [4- (2-Methoxyphenyl) piperazinone 1-ylmethyl] pyridine (2-10) 122 mg (0.3 mmol) in tetrahydrofuran Dissolve in 4m1, add 15mg (0.36mmol) of sodium hydride under ice-cooling, and stir at room temperature for 30 minutes. The mixture was cooled again with ice water, added with methanesulfonyl chloride (38 mg, 0.333 mmol), and stirred at room temperature for 1.5 hours. Add ice water and extract with black-mouthed form. After drying over magnesium sulfate, it was purified with 6 g of alumina. Elution with a mixture of ethyl acetate and hexane (2: 1) yields 3-methanesulfonyloxy-1- (2-methoxyphenyl) -1-6- [4- (2-methoxyphenyl) piperazinone-1-1 [Ylmethyl] pyridine was obtained as an oil (135 mg, 93.1%). This oil was dissolved in acetone, and an oxalic acid salt was prepared by adding 1.1 equivalents of a solution of oxalic acid in acetone. With melting point 144-144 (decomposition)

 NMR (CDCl3) (free base) 2.65 (3H, s), 2.77-2.80 (4H, m), 3.12-3.17 (4H, m), 3.81 (3H, s), 3.83 (3H, s), 3.86 (3H, s), 6.84-7.76 (10H, m)

[Example 4 2 6]

The reaction was carried out in the same manner as in Example 4 25 to obtain the compound of (21-2). Melting point and NMR is shown in Table 42,

 Table 4 2

[Example 4 2 7]

 3- (4-Methoxybenzyloxy) -1-2- (2-methoxyphenyl) -16- [4- (2-Methoxymethyloxy) piperazino-1-ylmethyl] pyridine oxalate (2- 1 2)

 6- [4- (2-Hydroxyphenyl) piperazino-1-ylmethyl] -3- (4-methoxybenzyloxy) 1-2- (2-methoxyphenyl) pyridine

Dissolve (2—9—2) 7550 mg (0.00001) in 8 ml of tetrahydrofuran, add 70 mg of sodium hydride (0.0000176 mol) under ice-cooling, Stir at room temperature for 30 minutes. After cooling with ice water again, a solution of 131 mg (0.00162 mol) of chloromethyl methyl ether (1 ml) in tetrahydrofuran was added dropwise, and the mixture was reacted at room temperature for 2.5 hours. Add ice water and extract with black-mouthed form. After drying over magnesium sulfate, it was purified with silica gel 20 g. 3- (4-Methoxybenzyloxy) -12- (2-methoxyphenyl)- 6- [4-(2-Methoxymethyloxy) piperazinone 1-ylmethyl] pyridine (2-12) was obtained as an oil. 720 mg (88.5%) This oil was dissolved in acetone, and an oxalic acid solution of oxalic acid corresponding to 1.1 equivalents was added to obtain oxalate. Melting point 1 3 5 _ 1 36.5 (decomposition)

 NMR (CDCl3) (free base) 2.74-2.79 (4H, m), 3.10-3.15 (4H, m), 3.71 (3H, s), 3.

78 (3H, s), 3.85 (3H, s), 5.02i2H, s), 6.83-7.41 (10H, m)

[Example 4 2 8]

 3- (hydroxy) -1-2- (2-methoxyphenyl) -1-6- (4- (2-methoxymethyloxy) -piperazino-1-ylmethyl] pyridine (2-1-3)

3- (4-Methoxybenzyloxy) 1 2 _ (2-Methoxyphenyl) — 6— [4- (2-Methoxymethyloxy) piperazinol 1 —ylmethyl] pyridine (2-12) 6 2 Omg was dissolved in 25 ml of methanol, 5 Omg of 10% Pd-carbon powder was added, and a hydrogenation reaction was carried out under stirring at 4 atm for 40 hours. The solvent was removed under reduced pressure except for the catalyst, and the residue was purified with 20 g of alumina. The title compound was obtained as an oil as an eluate from a mixture of formaldehyde and methanol (100: 1). 2 15 mg (4 5.8%)

NMR (CDCl3) 2.72-2.76 (4H, m), 2.92-2.96 (4H, m), 3.51 (3H, s), 3.77 (2H ₎ s), 3.95 (3H, s), 5.22 (2H, s) , 6.69-7.77 (10H, m)

[Example 4 2 9]

3-Methanesulfonyloxy-2- (2-methoxyphenyl) _ 6— [4- (2-Methoxymethyloxy) piperazino-1-ylmethyl] pyridine (2-1-4)

 (2-13)

 3-Hydroxy 2- (2-methoxyphenyl)

Methyloxy) piperazino-1-ylmethyl] pyridine (2--13)

 (0.448 mmol) was dissolved in 4 ml of tetrahydrofuran, 22 mg (0.538 mmol) of sodium hydride was added under ice-cooling, and the mixture was stirred at room temperature for 40 minutes. Then, the mixture was cooled with ice water, added with methanesulfonyl chloride (56 mg, 0.493 mmol), and reacted at room temperature for 2 hours. The solvent was distilled off under reduced pressure, aqueous ammonia chloride and chloroform were added to the residue, and the organic layer was separated. After drying over magnesium sulfate, it was purified with 8 g of alumina. Elution with a mixture of formaldehyde and hexane (2: 1) was carried out using a mixture of 3-methanesulfonyloxy-2- (2-methoxyphenyl) -16- [4- (2-methoxymethyloxy) piperazin-1-ylmethyl] There were obtained 203 mg (88.3%) of pyridine (2-14) as an oil.

NMR (CDCl3) 2.56 (3H, s), 2.73-2.78 (4H, m), 3.13-3.18 (4H ₎ m), 3.51 (3H, s), 3.89 (3H, s, &, 2H, s), 5.22 (2H, s), 6.95-7.77 (10H, m)

[Example 430]

 6— [4- (2-Hydroxy) piperazino-1-ylmethyl] -3-methanesulfonyloxy-2- (2-methoxyphenyl) pyridine oxalate (2-1-5)

)

 (2-14) (2-15)

 3 1-Methanesulfonyloxy 2 (2-Methoxyphenyl) — 6— [4— (2-Methoxymethyloxy) piperazino 1-ylmethyl] pyridine (2-14)

200 mg (0.39 mmol) was dissolved in 5 ml of methanol, 5 Omg of concentrated hydrochloric acid was added, and the mixture was heated at 40 for 1 hour. Concentrate the solvent and make it alkaline with aqueous ammonia.

Four Extract with loloform. After washing with water and drying over magnesium sulfate, the column was chromatographed on silica gel 8 g, and 6- [4- (2-hydroxy) piperazino-1-ylmethyl was used as the eluate of the mixture of form-methanol (100: 1). ] — 3-Methanesulfonyloxy 2- (2-methoxyphenyl) pyridine was obtained as an oil (153 mg, 83.6%). This oily substance was dissolved in acetone, and an oxalic acid solution corresponding to 1.1 equivalents of oxalic acid was added to obtain an oxalate. Melting point 1 90.5-19 3 ° C (decomposition)

 NMR (CDCl3) 2.56 (3H, s), 2.73-2.77 (4H, m), 2.93-2.97 (4H, m), 3.81 (2H, s), 3.83 (3H, s), 6.87-7.77 (10H, m)

[Example 4 3 1]

1- (5-bromopyridine-1-3-ylmethyl) 1-41 (2-methoxyphenyl) piperazine (3-1)

 (3-1)

 To a suspension of 5-bromo-3-chloromethylpyridine hydrochloride (J. Heterocyclic Chem., 29, 971 (1992)., 1.50 g, 6.19 mmol) in acetonitrile (10 ml) was added potassium iodide (10 ml) at room temperature. 206 mg, 1.24 mmol), potassium carbonate (1.88 g, 13.6 mmol) and 1- (2-methoxyphenyl) pidazine (1.43 g, 7.43 mmol) in acetonitrile solution (15 ml) were added, and the mixture was refluxed and stirred for 3 hours. did. After the reaction mixture was filtered, the resulting residue was subjected to alumina column chromatography (Merck aluminum oxide 90, 70-230 mesh), and eluted with a mixed solvent of ethyl acetate: hexane = 1: 1 to obtain the compound ( 3-1) (2.18 g, 97%) was obtained.

In addition, a part of the compound (3-1) is dissolved in ether, and oxalic acid (1 equivalent) is added thereto to add 11- (5-bromopyridine-13-ylmethyl) -14_ (2-methoxyphenyl) pyridine. Lazine · 1.0 oxalate was obtained.

3-1: Colorless oil.Oxalate; colorless prisms, mp 225.0-230.0 ^ idee). -NMR (CDC13, free base) δ 2.60-2.74 (4H, m), 3.02-3.18 (4H, m), 3.58 (2H, s), 3.86 (3H, s), 6.84-7.04 (4H, m), 7.89 (1H, br s), 8.49 (1H, d, J = 2.1 Hz), 8.58 (IH, d, J = 2.1 Hz).

[Example 4 3 2]

 1 1 (2 — methoxyphenyl) 1 4 — (5 — (2 — methoxyphenyl) pyridin — 3 — ylmethyl) piperazine (3 — 2)

 1- (5-Bromopyridine-13-ylmethyl) -14- (2-Methoxyphenyl) piperazine (364 mg, 1.01 mmol) was dissolved in N, N-dimethylformamide (4 ml), , Ν-Dimethylformamide solution of 2-methoxyphenylboronic acid (183 mg, 1.24 mmol), tetrakistriphenylphosphinepalladium (58.0 mg, 0.05 mmol), and triethylamine (304 mg, 3.00 mmol) at room temperature (1 ml) and add 1

The mixture was stirred at 00 ° C for 19 hours.

The reaction solution is obtained by evaporating the solvent under reduced pressure, dissolving in chloroform, washing with saturated aqueous sodium hydrogen carbonate solution and brine, drying over magnesium sulfate, and evaporating the solvent under reduced pressure. The residue was subjected to aluminum chromatography chromatography (Merck alminium oxide 90, 70-230 mesh), eluted with a mixed solvent of ethyl acetate: hexane = 1: 3, and the compound (3-2) (270 mg, 69%).

Also, a part of the compound (3-2) is dissolved in ether, and oxalic acid (1 equivalent) is added.

1- (2-Methoxyphenyl) 1-41- (5- (2-methoxyphenyl) pyridine-13-ylmethyl) pidazine · 1.0 oxalate was obtained.

 3-2: Colorless oil.uxalate; colorless prisms, mp 163.0-165.0 ° C.

! H-NMR (CDC13, free base) δ 2.64-2.84 (4H, m), 3.04-3.20 (4H, m), 3.69 (2H, s), 3.83 (3H, s), 3.86 (3H, s), 6.84-7.09 (6H, m), 7.33-7.40 (IH, m), 7.88 (IH, br s), 8.52 (1H, d, J = 2.1 Hz), 8.69 (IH, d, J = 2.1 Hz). [Example 4 3 3— 4 3 6]

The melting point and 1H-NMR value of the 1- (2-methoxyphenyl) -4- (5-arylpyridine-13-ylmethyl) pidazine derivative synthesized in the same manner as in Example 4 32 The results are shown in Table 43.

Table 4 3

[Example 4 3 7]

1— (2—black mouth— 5—phenylpyridine—3_ylmethyl) 1-4— (2—methoxyphenyl) piperazine (4—1—1)

 (4-1 -1)

2 —Chloro-3 —formyl-1-5-phenylphenyl (Tetrahedron Lett., 37, 8231, (1996)., 109 mg, 0.50 mmol) was dissolved in 1,2-dichloroethane (2 ml), and the solution was heated to room temperature. I (2-Methoxyphenyl) piperazine (96.0 mg, 0.50 mmol) in 1,2-dichloroethane (15 ml), triacetoxyborohydride sodium (95%, 134 mg, 0.60 mmol) ) And stirred for 8 hours. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform.The organic layer was washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Was subjected to silica gel column chromatography (Merk Kieselgel 60, 70-230 mesh), and eluted with a mixed solvent of ethyl acetate: hexane = 1: 4 to give compound (4-1-1-1) (191 mg, 97 %).

Also, a part of the compound (4-1-1) is dissolved in ether, and oxalic acid (1 equivalent) is added thereto to give 1- (2-chloro-opening_5-phenylpyridine-13-ylmethyl) 14- (2 — Methoxyphenyl) Pirazine · 1.0 oxalate was obtained.

4- 1-1- 1: Colorless 011.Oxalate; colorless prisms, mp 158.0- 159.0 ° C.

 ! H-NMR (CDC13, free base) δ 2.78 (4H, t, J = 4.8 Hz), 3.13 (4H, t, J = 4.8 Hz), 3.69 (2H, s), 6.85-7.03 (4H, m) , 7.39-7.60 (5H, m), 8.09 (1H, d, J = 2.7 Hz), 8.51 (1H, d, J = 2.7 Hz). [Example 4 3 8]

Example 4 The same operation as in 37 was performed, and 1— (2—clo mouth—5— (2-methoxyphenyl) pyridine-13-ylmethyl) 141- (2-methoxyphenyl) piperazine

(4-1-2) was obtained.

Colorless oil.Oxalate; colorless prisms, mp 1 8.0-169.0 °.

O-NMR (CDC13, free base) δ 2.72-2.83 (4H, m), 3.07-3.20 (4H, m), 3.74 (2H, W 2 s), 3.82 (3H, s), 3.87 (3H, s), 6.84-7.09 (6H, m), 7.31-7.42 (2H, m), 8.03-8.10 (1H, m), 8.44 (1H, d, J = 2.4 Hz).

[Example 4 3 9]

 1- (2- (4-Methoxybenzyloxy) _ 5-phenylphenyl-3-ylmethyl) 1-4- (2-methoxyphenyl) piperazine (4-2-1)

 (4-1-1)

 (4-2-1)

 A solution of 4-methoxybenzyl alcohol (180 mg, 1.30 mmol) in N, N-dimethylformamide (1 ml) was added to 60% sodium hydride (50.9 mg, 1.27 mmol) at room temperature, and the mixture was stirred for 5 minutes. _ (2-Chloro-5-phenylpyridin-1-ylmethyl) — 4- (2-methoxyphenyl) piperazine (99.1 mg, 0.252 mmol) in N, N-dimethylformamide (2 ml) Was added, and the mixture was heated and stirred at 120 X: for 3 hours. Water was added to the reaction solution, and the mixture was extracted with chloroform.The organic layer was washed with saturated saline and dried over magnesium sulfate.The solvent was distilled off under reduced pressure, and the residue obtained was subjected to alumina column chromatography. The mixture was subjected to chromatography (Merck alminium oxide 90, 70-230 mesh) and eluted with a mixed solvent of ethyl acetate: hexane = 1: 1: 10 to obtain compound (4-12-111) (105 mg, 84%). .

 In addition, a part of the compound (4-2-1) is dissolved in ether, and oxalic acid (1 equivalent) is added to the solution to give 1- (2- (4-methoxybenzyloxy))-5-phenylpyridine-1-3. (4-Methyloxyphenyl) pidazine · 1.0 oxalate (4-4) was obtained.

4-2-1: Colorless oil.Oxalate; colorless prisms, mp 168.0-170.0 ° C.

! H-NMR (CDC13, free base) δ 2.68-2.82 (4H, m), 3.04-3.16 (4H, m), 3.70 (2H, s), 3.82 (3H, s), 3.85 (3H, s), 5.41 (2H, s), 6.83-7.02 (6H, m), 7.32-7.59 (7H, m), 7.93 (1H, m), 8.31 (1H, d, J = 2.7 Hz). P

[Example 440—442]

 The melting point and 1 H-NMR value of the compound synthesized in the same manner as in Example 439 are shown in Table 44 below.

Table 44

[Example 443]

 3-(4-(2-Methoxyphenyl) piperazine- 1 -ylmethyl) 5-phenyl-1 H-pyridin-2-one (4-3)

20

 (4-2-1) (4-3)

 1— (2— (4—Methoxybenzyloxy) -15—phenylpyridine —3—ylmethyl) 1.4— (2-Methoxyphenyl) pidazine (227 mg, 0.458 mmol) was added to acetic acid (2 ml), 47% hydrobromic acid (1.0 ml, 8.80 mmol) was added, and the mixture was stirred at 50 ° C for 2 hours. Water was added to the reaction mixture, the mixture was made alkaline with 5N sodium hydroxide, extracted with chloroform, the organic layer was washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue thus obtained was applied to a silica gel column chromatography (Merk Kieselgel 60, 70-230 mesh), and eluted with a mixed solvent of chloroform: methanol = 97: 3 to obtain the compound (4-3) (109 mg, 63%).

 Colorless prisms, mp 193.0- 194.0 "C.

 ! H-NMR (CD30D, free base) δ 2.72-2.81 (4H, m), 3.03-3.14 (4H, m), 3.60 (2H, s), 3.84 (3H, s), 6.85-7.03 (4H, m ), 7.29-7.55 (5H, m), 7.63 (1H, d, J = 2.4 Hz), 8.01 (1H, d, J = 2.4 Hz).

[Example 4 4 4]

 3— (4— (2-Methoxyphenyl) pirazin-1-ylmethyl) 1 1 Methyl 5—Phenyl-1 H—Pyridine-1 2—one (4 4-1)

(4-3) (4-4-1)

60% sodium hydride (24.1 mg, 0.602 mmol) in room temperature at room temperature 3- (4- (2-methoxyphenyl) piperazine-1 1-ylmethyl) — 5 —phenyl 1H-pyridi N-N-dimethylformamide solution (5 ml) of N-2-one (200 mg, 0.533 mmol) was added and stirred for 5 minutes. Then, methyl iodide (91.0 mg, 0.641 mmol) of N, N-dimethylformamide was added. Solution (1 ml) was added, and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added a saturated aqueous solution of ammonium chloride, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over magnesium sulfate. The mixture was subjected to column chromatography (Merck aluminum oxide 90, 70-230 mesh) and eluted with a mixed solvent of ethyl acetate: hexane = 3: 1 to give compound (4-4-1) (96.5 mg, 47%). Obtained.

Colorless prisms, mp 167.0- 168.0 ^.

! H-NMR (CDC13, free base) δ 2.72-2.84 (4H, m), 3.05-3.19 (4H, m), 3.65 (5H, s), 3.86 (3H, s), 6.83-7.02 (4H, m ), 7.29-7.46 (6H, m), 7.77 (1H, d, J = 1.8 Hz).

[Example 4 4 5]

Example 4 4 The same operation as in 4 was carried out, and 1 _ (4-methoxybenzyl) — 3— (4- (2-methoxyphenyl) piperazine-1-ylmethyl) — 5-phenyl-1-H One pyridine-1 2-one (4-4-2) was obtained.

Colorless prisms, mp 138.0- 139.0 ° C.

 ! H-NMR (CDC13, free base) δ 2.74-2.85 (4H, m), 3.05-3.20 (4H, m), 3.66 (2H, s), 3.79 (3H, s), 3.86 (3H, s), 5.16 (2H, s), 6.84-7.02 (6H, m), 7.28-7.44 (8H, m), 7.75 (1H, d, J = 2.4 Hz).

[Example 4 4 6]

 1-Methanesulfonyl— 3- (4- (2-Methoxyphenyl) piperazine-1-ylmethyl) -1-5-phenyl-2H-pyridine-12-one (4-5-1) and 2-methanesulfonyl 3- (4- (2-methoxyphenyl) piperazine-111-methyl) -5-phenylvinylidine (4--5-2)

twenty two

60% sodium hydride (26.0 mg, 0.650 mmol) in room temperature at room temperature 3- (4- (2-methoxyphenyl) piperazine-111-methyl) -15-phenyl-1-H-pyridin-2-one (223 mg, 0.593 mmol) in Ν, Ν-dimethylformamide (5 ml) was added and stirred for 5 minutes, and then methanesulfonyl chloride (75.0 mg, 0.655 mmol) in N, N-dimethylformamide ( 1 ml) and stirred at room temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with chloroform.The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The mixture was subjected to column chromatography (Merck alminium oxide 90, 70-230 mesh) and eluted with a mixed solvent of ethyl acetate: hexane = 1: 2. Compound (4-5-1) (135 mg, 50% ) And the compound (4-15-2) (82.0 mg, 31%) were obtained.

 In addition, a part of the compound (4-5-1) is dissolved in ether, and oxalic acid (1 equivalent) is added thereto to give 2-methanesulfonyloxy-3- (4- (2-methoxyphenyl) piperazine (1- 1-ylmethyl) -1-5-phenylviridine.1.0 oxalate was obtained. Cororless oil. Oxalate; colorless prisms, mp 161.0- 163. Ot!

! H-NMR (CDC13, free base) δ 2.70-2.82 (4H, m), 3.02-3.20 (4H, m), 3.59 (3H, s), 3.76 (2H, s), 3.86 (3H, s), 6.84-7.03 (4H, m), 7.40-7.60 (5H, m), 8.16 (IH, d, J = 2.4 Hz), 8.42 (IH, d, J = 2.4 Hz).

Colorless prisms, mp 157.0- 158.0 ° C.

^J H-NMR (CDC13, free base) δ 2.72-2.84 (4H, m), 3.05-3.24 (4H, m), 3.63 (2H, s), 3.69 (3H, s), 6.84-7.04 (4H, m ), 7.35-7.50 (5H, m), 7.87-7.89 (IH, m), 8.01 (1H, d, J = 2.4 Hz).

twenty three [Example 4 4 7]

 (6-Methoxy-5- (2-methoxyphenyl) pyridine-3-yl) Methanol (5-1)

5- (2-Methoxyphenyl) -1-6-methoxynicotinic acid methyl ester (J. Org. Chem., 49, 5237 (1984)., 1.32 g, 4.83 mmol) was dissolved in toluene (50 ml). , One seventy. To the reaction solution was added a solution of diisobutylaluminum hydride in toluene (1.01 mmol / ml, 11.6 ml, 11.7 mmol), and the mixture was stirred for 1 hour. Methanol was added to the reaction solution, and the mixture was made weakly acidic with 1N hydrochloric acid. The organic layer is washed with saturated saline, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue obtained is silica gel column chromatography (Merk Kieselgel 60, 70-230 mesh). The mixture was eluted with a mixed solvent of ethyl acetate: hexane = 1: 1 to obtain a compound (5-1) (1.22 g, 100%).

Colorless oil

 ! H-NMR (CDC13) δ 3.78 (3Η, s), 3.92 (3Η, s), 4.66 (2H, s), 6.98 (1H, d, J = 7.5 Hz), 7.01, (1H, dt, J = 7.5, 0.9 Hz), 7.24 (1H, dd, J = 7.5, 1.8 Hz), 7.35 (1H, dt, J = 7.5, 0.9 Hz), 7.59 (1H, d, J = 1.8 Hz), 8.13 (1H, d, J = 1.8 Hz). 〖Example 4 4 8]

 5 -Chloromethyl- 1 -Methoxy 3- (2-Methoxyphenyl) pyridine (5-2)

twenty four

3-yl) Methanol (1.14 _mg , 4.65 mmol) was dissolved in tetrahydrofuran (10 ml), and a solution of thionyl chloride (1.17 g, 9.84 mmol) in tetrahydrofuran (2 ml) was added at room temperature. The mixture was stirred at C for 1 hour. The solvent was distilled off from the reaction solution under reduced pressure, ice was added, extraction was performed with chloroform, the organic layer was washed with brine, dried over magnesium sulfate, and evaporated to remove the solvent under reduced pressure. The residue was subjected to silica gel column chromatography (Merk Kieselgel 60, 70-230 mesh) and eluted with a mixed solvent of ethyl acetate: hexane = 1: 6 to give compound (5-2) (809 mg, 66%) I got

Colorless needles, mp o6.0-67.0 °

 ! H-NMR (CDC13) δ 3.78 (3H, s), 3.93 (3H, s), 4.59 (2H, s), 6.97-7.05 (2H, m), 7.26 (IH, dd, J = 7.5, 1.5 Hz ), 7.36 (1H, dt, J = 7.5, 1.5 Hz), 7.56 (IH, d, J = 2.7 Hz), 8.15 (1H, d, J = 2.7 Hz).

 1— (6—Methoxy) 5— (2—Methoxyphenyl) Pyridine—3-ylmethyl) -4— (2—Methoxyphenyl) piperazine (5—3)

A solution of 5-chloromethyl-1-methoxy-3- (2-methoxyphenyl) pyridine (191 mg, 0.725 mmol) in acetonitrile (4 ml) was added at room temperature to a solution of iodide (24.0

twenty five mg, 0.145 mmol), potassium carbonate (120 mg, 0.870 mmol), and 1- (2-methoxyphenyl) pidazine (167 mg, 0.871 mmol) in acetonitrile (1 ml) were added, and the mixture was stirred at reflux for 2 hours. . After the reaction solution was filtered, the obtained residue was subjected to alumina column chromatography (Merck aluminum oxide 90, 70-230 mesh), and eluted with a mixed solvent of ethyl acetate: hexane = 1: 4 to give the compound ( 5-3) (268 mg, 97%).

 Colorless prisms, mp 144.0-145.0 ° C

 ! H-NMR (CDC13) δ 2.62-2.74 (4H, m), 3.00-3.16 (4H, m), 3.58 (2H, s), 3.79 (3H, s), 3.86 (3H, s), 3.92 (3H , s), 6.84-7.05 (6H, m), 7.26-7.38 (2H, m), 7.58 (1H, d, J = 2.4 Hz), 8.08 (1H, d, J = 2.4 Hz).

[Example 450]

 3-(2-methoxyphenyl) 1-5-(4-(2-methoxyphenyl) piperazine-1-ylmethyl)-1 H-pyridine-2-one (5-4)

 (5-3) (5-4)

1- (6-Methoxy-1-5- (2-Methoxyphenyl) pyridine-3-3-ylmethyl) 1 4- (2-Methoxyphenyl) pidazine (2.43 g, 5.80 mmol) in concentrated hydrochloric acid

(10 ml) and stirred at 100 ° C for 3 hours. After ice was added to the reaction solution, the mixture was made alkaline with 5N sodium hydroxide, extracted with chloroform, the organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (Merk Kieselgel 60, 70-230 mesh), and eluted with a mixed solvent of chloroform: methanol = 97: 3 to obtain the compound.

(5-4) (1.71 g, 73%) was obtained.

Colorless prisms, mp 207.0-208.0 ° C

 ! H-NMR (CDC) δ 2.60-2.80 (4H, m), 2.98-3.15 (4H, m), 3.45 (2H, s), 3.78

2 6 (3H, s), 3.85 (3H, s), 6.85-7.06 (6H, m), 7.27 (1H, dd, J = 7.2, 1.8 Hz), 7.34 (IH, dt, J = 7.2, 1.8 Hz), 7.38 (IH, d, J = 2.4 Hz), 7.60 (IH, d, J = 2.4 Hz).

[Example 4 5 1]

 3- (2-Methoxyphenyl) 1 5- (4- (2-Methoxyphenyl) piperazine-1-ylmethyl) 1-1-Methyl-1 H-Pyridine-1-2- (5-5-1-1 )

 (5-4) (5-5-1)

3- (2-Methoxyphenyl) -1- (4- (2-Methoxyphenyl) piperazine-1-ylmethyl) 1 H in 60% sodium hydride (23.3 _mg , 0.583 mmol) at room temperature -Pyridine-2-one (214 mg, 0.529 mmol) in Ν, Ν-dimethylformamide (4 ml) was added and stirred for 30 minutes, and methyl iodide (82.5 mg, 0.581 mmol) in Ν, Ν Ν-Dimethylformamide solution (1 ml) was added, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with chloroform.The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The compound (5-5-1) (198 mg, 89%) was purified by gel chromatography (Merck alminium oxide 90, 70-230 mesh) and eluted with a mixed solvent of ethyl acetate: hexane = 1: 1. Obtained.

Colorless prisms, mp 127.0-129. Ot

 ! H-NMR (CDC13) δ 2.60-2.74 (4H, m), 3.02-3.16 (4H, m), 3.36 (2H, s), 3.59 (3H, s), 3.80 (3H, s), 3.86 (3H , s), 6.84-7.03 (6H, m), 7.27 (IH, dd, J = 8.1, 1.8 Hz), 7.30-7.38 (3H, m), 7.46 (IH, d, J = 1.8 Hz).

[Example 4 5 2]

Example 4 51 The same operation as in 1 was carried out, and 1- (4-methoxybenzyl)-3- (2-methoxyphenyl) 5- (4- (2-methoxyphenyl) piperazine-1 —Y

2 7 1-H-pyridin_2-one (5-5-2) was obtained.

Colorless prisms, mp 115.0-116.0

 Ή-NMR (CDC13) δ 2.54-2.72 (4Η, m), 2.98-3.16 (4H, m), 3.32 (2H, s), 3.79 (3H, s), 3.80 (3H, s), 3.85 (3H, s), 5.13 (2H, s), 6.84-7.03 (8H, m), 7.23-7.45 (6H, m).

[Example 4 5 3]

 2-Synthesis of methanesulfonyloxy 3- (2-methoxyphenyl) -1-5- (4- (2-methoxyphenyl) piperazine-1-ylmethyl) pyridine (5-6)

60% sodium hydride (23.9 mg, 0.598 mmol) in room temperature 3 _ (2-Methoxyphenyl) -1-5- (4-(2-Methoxyphenyl) piperazine-1-ylmethyl) 1 1H— A solution of pyridine-2-one (202 mg, 0.497 mmol) in N, N-dimethylformamide (4 ml) was added, and the mixture was stirred for 10 minutes. Then, メ タ ン, Ν of methanesulfonyl chloride (67.0 mg, 0.585 mmol) was added. —Dimethylformamide solution (1 ml) was added, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with chloroform.The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The mixture was subjected to column chromatography (Merck alminium oxide 90, 70-230 mesh) and eluted with a mixed solvent of ethyl acetate: hexane = 1: 3 to obtain the compound (5-6) (113 mg, 47%). .

Also, a part of the compound (5-6) is dissolved in ether, and oxalic acid (1 equivalent) is added thereto to give 2-methanesulfonyloxy-3- (2-methoxyphenyl) —5 -— (4 -— (2— Methoxyphenyl) pidazine-1-ylmethyl) pyridine • 1.0 oxalate was obtained.

 Colorless oil.Oxalate; colorless powder, mp 178.0-179.0.

2 8 ! H-NMR (CDC, free base) δ 2.60-2.76 (4H, m), 3.02-3.18 (4H, m), 3.46 (3H, s), 3.63 (2H, s), 3.83 (3H, s), 3.86 (3H, s), 6.84-7.07 (6H, m), 7.24-7.29 (1H, m), 7.40 (1H, m), 7.80 (1H, d, J = 2.1 Hz), 8.26 (1H, d, J = 2.1 Hz).

(Test example)

Human 5HT ₇ receptor [Bard EN et al, J. Biol. Chem. 268 ( 1993) 23422-23426] [3 H] 5HT and number concentration of the resulting cell membrane preparation with 1 nM from HEK293 cells expressing the After incubating each of the test compound mixtures at 25 ° C for 120 minutes, suction filtration is performed on a Whatman GF / C filter. In liquid scintillation one Chillon counter one the radioactivity on the filter, to calculate the 50% inhibitory concentration of the test compound to specific ^[3 H] 5HT binding (IC ₅₀ value), Cheng-Prusoff [oc / iew. PAa Ki value was calculated from the equation Ki = IC ₅₀ / (l + [L] / Kd) of Tnaco 22 (1973) 3099-3108] <

 The concentration of the metal, Kd, indicates the dissociation constant.

 Table 4 5

Industrial applicability

The present invention compounds are particularly _{5 -HT 7 (5-Hydroxytrpta mine7} ) compounds acting on receptors in the serotonin receptors, circadian rhythm disorders therapeutics, senile sleep failure therapeutic agent, antidepressant, anti It is useful as an anxiety drug, a cardiovascular drug, a migraine drug, an analgesic drug, etc.

Claims

 The scope of the claims

-General formula (I)

 (Where

Ar is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl: is a halogen, an alkyl, an alkenyl, an alkyloxy, an alkenyloxy, an alkylthio, an alkenylthio, a substituted or unsubstituted alkylsulfonyloxy, an alkenyl Nylsulfonyloxy, alkylsulfonyl, alkenylsulfonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkenylsulfonyloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkylthio, substituted or unsubstituted Ariruchio, substituted or unsubstituted to the heteroaryl Arukiruokishi, substituted or unsubstituted § reel sulfonyl O carboxymethyl, Heteroariru _{Suruhoniruokishi, -OS0 2 NR4R5, -OCONR4R5, -OCSNR4R5} , -NR 6 R7, -N (R ₈ )-(CH ₂ ) p-NR ₉ Rio (R ₄ and R ₅ are each independently a hydrogen atom, an alkyl, or R4 and R ₅ Heights turned cane to the substituted or unsubstituted together with the adjacent nitrogen atom may form a heterocyclic group: R ₆ and R ₇ Each independently a hydrogen atom, a substituted or unsubstituted alkyl, or R ₆ and R ₇ may together form an substituted or unsubstituted heterocyclic group with an adjacent nitrogen atom: R ₈ is a hydrogen atom or alkyl: p is an integer of 2 to 4: R ₉ and R _{1 ()} are each independently a hydrogen atom

3 0 Or alkyl):

R ₂ and R ₃ each independently represent a hydrogen atom, substituted or unsubstituted alkyl, or R ₂ and R ₃ together form an substituted or unsubstituted heterocyclic group together with an adjacent nitrogen atom. May be:

n :! Integer from 6 to:

However, when Ar is a substituted or unsubstituted heteroaryl, _R may be any of alkyl, alkenyl and halogen. ) Or a pharmacologically acceptable salt thereof, or a hydrate thereof.

2. General formula (II):

(Wherein each symbol is as defined above), or a pharmacologically acceptable salt, or a hydrate thereof.

3. General formula (III):

 (Wherein each symbol is as defined above), or a pharmacologically acceptable salt, or a hydrate thereof.

4. General formula (IV):

(IV)

Ar 'N ヽ (CH ₂ ) _n NR ₂ R ₃

(Wherein each symbol is as defined above), a pharmacologically acceptable salt, or a hydrate thereof.

3 I

5. —General formula (V)

 (Wherein each symbol is as defined above), a pharmacologically acceptable salt, or a hydrate thereof.

6 — General formula (VI)

 (Wherein each symbol is as defined above), a pharmacologically acceptable salt, or a hydrate thereof.

7. General formula (VII):

 (Wherein each symbol is as defined above), a pharmacologically acceptable salt, or a hydrate thereof.

 8. General formula (VIII):

(Wherein each symbol is as defined above), a pharmacologically acceptable salt, or a hydrate thereof.

9. General formula (IX):

3 2

(Wherein each symbol is as defined above), a pharmacologically acceptable salt, or a hydrate thereof.

1 0. —General formula (X):

 (Wherein each symbol is as defined above), a pharmacologically acceptable salt, or a hydrate thereof.

1 1. A r is a substituted or unsubstituted Ariru: R is alkylsulfonyl O carboxymethyl, location換又is unsubstituted § reel alkyl O alkoxy, -OS0 ₂ NR ₄ R _5, or - OCONR ₄ R ₅ (R ₄ and R ₅ is each independently hydrogen or alkyl): R ₂ and R ₃ together form a substituted or unsubstituted heterocyclic group together with an adjacent nitrogen atom: n is 1. A compound as described.

1 2. A r is a substituted phenyl: R is an alkylsulfonyl O carboxymethyl or substituted base Njiru Okishi: R ₂ and R ₃ form a substituted piperazino together with the a connexion adjacent nitrogen atom, according to claim 1 1 compound according.

 13. The compound according to claim 12, wherein the substituted piperazino is substituted phenylpiperazino or benzofuran-7-ylpiperazino.

14. Ar is 3-hydroxyphenyl, 3-alkoxyphenyl or 3-halogenophenyl: R is methylsulfonyloxy: R ₂ and R ₃ are linked together with the adjacent nitrogen atom to form 4- (2 -Hydroxyphenyl) The compound according to claim 11, which forms piperazino.

1 5. Ar is 3-hydroxyphenyl, 3-methoxyphenyl or 3-fluorophenyl: Ri is methylsulfonyloxy: R ₂ and R ₃ are linked together with the adjacent nitrogen atom, Forming 4- (2-hydroxyphenyl) piperazino, claims

33 Item 11. The compound according to Item 11,

 16. A medicament comprising the compound according to any one of claims 1 to 15 as an active ingredient.

 1 7. General formula (I):

R (CH ₂ ) _n NR ₂ R ₃ (R

 (Where

Ar is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl: is hydrogen, halogen, alkyl, alkenyl, alkyloxy, alkenyloxy, alkylthio, alkenylthio, alkylsulfonyloxy, alkenylsulfonyloxy, alkyl Sulfinyl, alkenylsulfinyl, alkyl power ruponyloxy, alkenylcarbonyloxy, alkenylsulfonyloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkylthio, substituted or unsubstituted arylthio, substituted or unsubstituted to the hetero arylalkenyl Ruokishi, substituted or unsubstituted § Li one Le sulfonyl O carboxymethyl, hetero § reel sulfonyl J _{Reokishi, -OS0 2 NR4R 5, -OCONR4R5,} -OCSNR4R5, -NR 6 R7 -N (R ₈ )-(CH ₂ ) _P

-NR9R10 (R4 and R5 are each independently a hydrogen atom, an alkyl, or R ₄ Contact and R ₅ Heights turned cane to the substituted or unsubstituted together with the adjacent nitrogen atom may form a heterocyclic group : Re and R7 are each independently a hydrogen atom, form a substituted or unsubstituted alkyl, or R ₆ and R ₇ Heights and cane since adjacent nitrogen atom together a substituted or unsubstituted to the heterocyclic group R ₈ may be a hydrogen atom or a

3 4 Alkyl: p is an integer of 2 to 4: R ₉ and R _{1 ()} are each independently a hydrogen atom or alkyl):

R ₂ and R ₃ each independently represent a hydrogen atom, substituted or unsubstituted alkyl, or R ₂ and R ₃ together form an substituted or unsubstituted heterocyclic group together with an adjacent nitrogen atom. May be:

n is an integer of 1 to 6), or a pharmacologically acceptable salt, or a hydrate thereof, a serotonin receptor binding agent.

 18. A serotonin receptor binding agent comprising the compound according to any one of claims 1 to 15 as an active ingredient.

1 9.5 with affinity for one HT ₇ receptor, serotonin receptor binding agent according to claim 1 8.

2 0. 5 which is Agonisuto one HT ₇ receptor, according to claim 1 9 serotonin receptor binding agent according.

 21. The serotonin receptor binding agent according to any one of claims 17 to 20, which is useful as a therapeutic agent for circadian rhythm disorders.

 22. The serotonin receptor binding agent according to any one of claims 17 to 20, which is useful as a therapeutic drug for senile sleep disorder.

 23. The serotonin receptor binding agent according to claim 17 or 18, which is useful as an antidepressant, an anxiolytic, a cardiovascular disorder treatment, a migraine treatment, or an analgesic.

2 4. General formula (XI):

 (Where

 Y is an oxygen or sulfur atom:

Rii is halogen or -NR ₂ R ₃ :

Other symbols are as defined above) or a salt thereof

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25. General formula (XII):

 (Where

 Rl2 is alkyloxy, alkenyloxy, alkylsulfonyloxy, alkenylsulfonyloxy, or substituted or unsubstituted arylalkyloxy:

R ₁₃ is acetyloxy, hydroxy or halogen:

And other symbols are as defined above) or a salt thereof.

 2 6. General formula (XIII):

 Rl6

 (χπι)

 . What ,

R ₁₄

 (Where

R ₁₄ is a hydrogen atom, alkyl, alkenyl, arylalkyl, heteroarylalkyl, alkylsulfonyl, alkenylsulfonyl, arylsulfonyl or heteroarylsulfonyl:

One of Ri ₅ and Ri ₆ represents Ar, and the other represents —CH ₂ NR ₂ R ₃ ; other symbols are as defined above, or a salt thereof.

3 6