WO1994027604A1

WO1994027604A1 - Medicinal use of pyridine derivative

Info

Publication number: WO1994027604A1
Application number: PCT/JP1994/000842
Authority: WO
Inventors: Hirofusa Shirai; Kenji Hanabusa; Yuki Takahashi; Fumio Mizobe; Kazunori Hanada
Original assignee: Taisho Pharmaceutical Co., Ltd.
Priority date: 1993-05-28
Filing date: 1994-05-27
Publication date: 1994-12-08
Also published as: AU6807994A

Abstract

A pyridine derivative represented by general formula (I) wherein R?1, R2 and R3¿ represent each hydrogen, (un)substituted phenyl, pyridyl, etc. It has a nerve growth factor production promoter activity or a neurotrophic factor activity. Hence it can be used as an ameliorant or remedy for symptoms or diseases accompanying peripheral nerve degeneration due to trauma, drug such as alcohol or antitumor drug, inflammation, or metabolism such as one observed in diabetes, and further of idiopathic nature. In addition, it can be used as an ameliorant or remedy for symptoms or diseases accompanying central nerve degeneration, such as senile dementia of Alzheimer type, cerebrovascular dementia, Down's syndrome, Parkinson's disease or Huntington's chorea, mental and motor incompetences caused by cerebral ischemia, cerebral infarction, cerebral hemorrhage or head injury, and spinal neuroparalysis.

Description

Pharmaceutical applications of pyridine derivatives

The present invention relates to a pharmaceutical use of a pyridin derivative having a nerve growth factor (hereinafter referred to as NGF) production promoting action or a neurotrophic factor action. More specifically, it also improves a neurodegenerative disease comprising a pyridin derivative as an active ingredient or a therapeutic pharmaceutical composition, and also improves a neurodegenerative disease comprising administering a pyridin derivative. Or treatment o

Background art

In Alzheimer's senile dementia, which has been increasing in recent years, it is suggested that degeneration and loss of acetylcholinergic neurons, which are basal ganglia neurons, are closely related to memory impairment and decreased intellectual activity. CWitehorse et al., Science, Vol. 2, pp. 115, pp. 127 (1982)].

NGF inhibits the degeneration and loss of central acetylcholinergic nerves caused by fiber cutting [Korsing et al., Neuroscience Lett., Vol. 66, p. 6 years)] and to improve the maze learning disability of old rats and to suppress the atrophy of acetylcholinergic neurons (Takashi Shigeno et al., Medical History, Vol. 144, No. 5). 579 (1996)] These are the things that NGF Arunno and Ima Type 1 have been shown to be therapeutic agents for senile dementia.

Furthermore, NGF has been confirmed to prevent hippocampal neuronal cell death in cerebral ischemic gerbils, and is considered to be useful as a therapeutic drug for stroke.

On the other hand, NGF has an effect of accelerating the recovery of peripheral nerve damage, and it has been clearly demonstrated that NGF is also useful as a therapeutic drug for peripheral neuropathy.

In addition to NGF, a large number of biological components exhibiting a survival / function maintenance activity or degenerative repair activity of nerve cells have been found, and are called neurotrophic factors. Therefore, these neurotrophic factors are considered to be useful as therapeutic agents for central neuropathy and peripheral neuropathy associated with neuronal degeneration.

Biological components called neurotrophic factors, including NGF, are all proteins. When proteins are used as therapeutic drugs for central neuropathy, it is expected that direct intraventricular administration will be required, judging from their physical properties, and there are many practical problems. Therefore, there is a demand for a therapeutic agent of a low-molecular compound having a neurotrophic factor action itself or a neurotrophic factor production-promoting action, which allows a simpler administration method.

An object of the present invention is to provide a novel physiologically active substance having one or both of an NGF production promoting action and a neurotrophic factor action, and to administer a symptom associated with neurodegeneration, improvement of a disease, and therapeutic use. This is to simplify the method.

Disclosure of the invention The present inventors have conducted various studies on a large number of compounds in order to achieve the above-mentioned object, and as a result, a certain pyridin compound was found.

The present inventors have found that the substance is a physiologically active substance having one or both of an NGF production promoting action and a neurotrophic factor action, and completed the present invention.

The purpose of the present invention is to obtain the formula (1)

[Wherein R ¹ is a hydrogen atom; an unsubstituted phenyl group; an alkyl group, a phenyl group, an alkoxy group, an alkenyloxy group, a phenyloxy group, a benzyloxy group, Tyryleneoxy, trifluoromethyl, trifluoroxy, methylthio, hydroxyl, nitro, amino, N-ethylamino Group, N, N — dimethylamino group, carboxyl group, bromomethyl group, acetamido group, cyano group, N, N — dimethylaminopropoxy group And a phenyl group substituted with at least one substituent selected from the group consisting of a halogen atom and a halogen atom; a pyridyl group; a phenyl group; a phenyl group; a phenyl group; Or a group represented by the formula (I)

(Wherein, R ⁴ and R ⁵ are the same or different and each represent a hydrogen atom; an alkyl group; or both of them represent a 5-membered ring.), And R ² and R ³ are the same or different. Differently represent a hydrogen atom; an alkyl group; an alkoxy group; a hydroxyl group; a nitro group or a halogen atom. And a pharmaceutically acceptable salt thereof as an active ingredient.

Another object of the present invention is to provide the above pyridin derivative or a pharmaceutically acceptable salt thereof for use as an active ingredient of a pharmaceutical composition. .

Furthermore, another object of the present invention is to provide the above pyridin derivative or its pharmaceutically acceptable for preparing a pharmaceutical composition for ameliorating or treating a neurodegenerative disease. In providing the use of salt.

Further, another object of the present invention is to administer an effective amount of the above-mentioned pyridin derivative or a pharmaceutically acceptable salt thereof to a human. It is to provide improvements or treatments.

BEST MODE FOR CARRYING OUT THE INVENTION

In the definition of R ¹ , R ² , and R ^{3 in} the pyridin derivative represented by the formula (I), examples of the alkyl group include, for example, methyl, ethyl, propyl, isopropyl, and butyric. And alkyl groups having 1 to 6 carbon atoms such as butyl, t-butyl, pentyl and hexyl. For example, methoxy, ethoxy, probox, isoprobox, butoxy, pentox, hexoxy, etc. And an alkoxy group having 1 to 6 carbon atoms. Examples of the alkenyloxy group include alkenyloxy having 2 to 6 carbon atoms, such as vinyloxy, aryloxy, propenyloxy, 2—propenyloxy, butenyloxy, pentenoxy, hexenyloxy, and the like. Group. Examples of the halogen atom include a halogen atom such as fluorine, chlorine, and bromine.

Pharmaceutically acceptable salts of pyridin derivatives include mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, or succinic acid, succinic acid, tartaric acid and methansulfo acid. Acid addition salts with organic acids such as acid. Examples thereof include salts with alkaline metals such as sodium and potassium, and salts with alkaline earth metals such as canolesium.

The pyridin derivative of the formula (I) of the present invention is partially a novel compound, but also includes known compounds.

In the present invention, in the formula (I), R ¹ is a hydrogen atom; a non-substituted phenyl group; or an alkyl group, a phenyl group, an alkoxy group, an alkenyloxy group, a phenyloxy group, Benzyloxy group, methylenedioxyl group, trifluoromethyl group, trifluoromethyl group, methylthio group, hydroxyl group, nitro group, amino group , N —ethyl amino group, N, N -Dimethylamino, carboxyl, and bromomethyl. Acetamido, cyano, N, N — dimethylaminophenol, poxoxy and halogen Represents a furyl group substituted by at least one substituent selected from the group consisting of atoms, and R ² and R ³ are the same or different and represent a hydrogen atom or Pyridine derivatives representing a methyl group or pharmaceutically acceptable salts thereof are preferred. In particular, in the formula (I), R ¹ represents a hydrogen atom; or a methyl group or a phenyl group substituted by an N, N-dimethylamino group; R ² , R ³ Is preferably a pyridin derivative which is the same or different and represents a hydrogen atom or methyl, or a pharmaceutically acceptable salt thereof.

The pyridin derivative of the present invention can be produced, for example, according to the following method.

1) In the formula (I), R ¹ is an unsubstituted phenyl group, or an alkyl group, a phenyl group, an anoreoxy group, an alkenyl oxy group, a phenyloxy group, N, N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N , Carboxyl, acetamido, cyano, N, N-dimethylaminopropoxy or phenyl-substituted phenyl group, Oh Ru have the pin lysyl group, thienyl group, disadvantageous group, Ri i Mi Dazo Li Le 'Motodea, is R ^2, R ^3, identical or different I hydrogen atom, a hydroxyl group, y alkyl group The pyridine derivative of the present invention, which is an alkoxy group, a nitro group or a halogen atom, is as follows. Manufacture I can do it.

That is, first, the equation (m)

R ¹ '-CH 0 (I)

(In the formula, R ″ is a phenyl group or an alkyl group, a phenyl group, an alkoxy group, an alkenyloxy group, a phenyloxy group, a benzyloxy group, a methyloxy group. Syl group, trifluoromethyl group, trifluoromethoxy group, methylthio group, nitro group, N, N—dimethylamino group, carboxyl group, Acetamido, cyano, N, N — phenylamino substituted with dimethylaminopropoxy or halogen, or pyridyl A compound represented by the formula (IV):

In the formula, R ² ′ represents a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, a nitro group or a halogen atom. By condensing the compound represented by the formula (1) in the presence of alkali.

Equation (V)

(V)

(Wherein R ¹ ′ and R ² ′ have the same meanings as described above). ·

Here, the alkali used in the condensation reaction includes sodium hydroxide, sodium hydroxide, sodium methoxide, and t-butane. Reaction solvents containing tokidide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, etc. are methanol, ethanol, etc. , N — professional, isop. Knol, t-butanol, etc. can be used alone or with the addition of water. The reaction temperature can be appropriately selected from 0 ° C to the boiling point of the solvent used.

Then, a compound of formula (V) and a compound of formula (VI)

(In the formula, R ³ ′ represents a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, a nitro group, or a halogen atom, and X represents bromine or iodine.) The pyridine derivative of the present invention can be obtained by reacting the resulting compound with ammonium acetate in the presence of ammonium acetate.

Here, ammonium acetate was used in an amount of 110 times the molar amount of the compound of the formula (V), and the reaction solvents were methanol, ethanol, and n-butyl. Nor, Isop,. Knol, t-butanol, acetic acid, etc. can be used. The reaction temperature can be appropriately selected from room temperature to the boiling point of the solvent used. 2) In the formula (I), R ^{1 is a} phenyl group substituted by an amino group, and R ² and R ³ are the same or different and are each a hydrogen atom, an alkyl group, or a nitro group. The pyridin derivative of the present invention, which is a group or a halogen atom, is a pyridin derivative of the formula (I) obtained by the above method, wherein R ¹ is an acetate amine. A phenyl group substituted with a hydrogen atom, wherein R ² and R ³ are the same or different and are a hydrogen atom, an alkyl group, a nitro group or a halogen atom; The derivative can be obtained by hydrolyzing the derivative in the presence of an acid or alkali.

3) In formula U), R ¹ is a phenyl group substituted by an N-ethylamino group, and R ² and R ² are the same or different and are a hydrogen atom, an alkyl group, an alkoxy group. Alternatively, the pyridine derivative of the present invention, which is a halogen atom, is a pyridin derivative of the formula (I) obtained by the above method, wherein R ¹ is substituted with a nitro group. Pyridin derivatives in which R ² and R ³ are the same or different and are a hydrogen atom, an alkyl group, an alkoxy group or a nitrogen atom; It can be obtained by reduction in the title.

Here, as a reduction method, a catalytic hydrogenation method using palladium carbon as a catalyst can be used.

4) In the formula (I), R ¹ is a bromomethylphenyl group, and R ² and R are the same or different and are each a hydrogen atom, an alkoxy group, a nitro group, and a halogen atom. The pyridin derivative of the present invention, which is an atom, is a pyridine derivative of the formula (I) obtained by the above method, wherein R ¹ is substituted with a methyl group. A pyridin derivative wherein R ² and R ³ are the same or different and are a hydrogen atom, an alkoxy group, a nitro group or a halogen atom Ru is possible to get Ri by the and this _(in here, as the blow motor method can and this using conventional methods, for example, halo gain down solvent, N- Bro motor co Nono click acid Lee A method of reacting with a mid can be used.

5) In the formula (I), R ¹ is a group represented by the formula (II), and R ² and R ³ are the same or different and are each a hydrogen atom, an alkoxy group, a nitro group or The pyridin derivative of the present invention, which is a halogen atom, is a pyridin derivative of the formula (I) obtained by the above method, wherein R ¹ is substituted with a bromomethyl group. A phenyl group wherein R ² and R ³ are the same or different and are hydrogen atoms, alkoxy groups, nitro groups or halogen atoms; It can be obtained by an amination reaction in which the corresponding amine is reacted.

Here, water, acetone, alcohols (eg, methanol, ethanol, etc.), getyl ether benzene, and acetonitrite are used as solvents. Rill can be used alone or as a mixture. The reaction temperature can be appropriately selected from 0 ° C. to the boiling point of the solvent used.

6) In formula (I), the pyridin derivative in which R ¹ is a phenyl group substituted with a hydroxyl group, and R ² and R ³ are hydrogen atoms is represented by R ¹ in formula (V). Is a phenyl group substituted with a hydroxyl group and R ² is a hydrogen atom [Yamamoto et al., Cem, Express, Vol. 5, pp. 365-6-36 (19 90)] and a compound of the formula (VI) wherein R 'is a hydrogen atom in the same manner as in the above-mentioned method 1).

7) In the formula ( ¹ ), in which R ¹ is a hydrogen atom and R ² and R ³ are the same or different and are a hydrogen atom or an alkyl group, the pyridin derivative of the present invention is obtained by the method of Scholtz et al.

C Chemische Berichte, Vol. 36, pp. 845 (1903)].

The pharmaceutically acceptable salt of the pyridin derivative of the present invention can be obtained by subjecting the pyridin derivative of the formula (I) to a salt-forming reaction known per se.

Table 1 shows representative pyridin derivatives of the present invention.

table 1

Compound R ¹

3 4-OMe H

-o

6 ^CH 3 HH

7 CH ₃ "HCI HH

10 Factory CH ₃ 2-N0 ₂ H

11 factory CH ₃ 3-N0 ₂ H

Compound R ¹ R '

CH,

15 H H

CH ₃

16 H H

? —

CH ₃

Compound R,

26 -FHH

29 ~ Qr HH

Compound R ¹ R '

32 -Br HH

34 Λ / factory CF ₃ HH

37 OH H H

40 -OMe HH

Compound R ¹

43 GCH ₂ -HH

47 / ^SCH 3 HH

51 ■ COOH HH

53 ~ -NHCOCH ₃ HH

Compound R ¹ R ²

54 H H

\\ /厂^NH 2

55 NH, 2HCI HH

57 -NHCH ₂ CH ₃ 2HCI HH

58 W // -N: HH

60 4 -CH ₂ Br HH

61 Factory C ^Π H2NH HH

62 Factory C ^Π H2, NH ^NX -2HCI HH

Compound R ¹

68 ~ CH ₂ N,. ■ 2HCI HH

\ \

69 \ HH

71 H H H

72 H 4-CH ₃ 4-CH.

73 H HCI 4-CH3 4 -CH ₃

74 H H

■ N

Compound R ¹ R 'R ² , oN H

77 H H

78 H H

In Table 1, compounds 2, 5, 7, 9 to 15, 17, 17, 19 to 25, 30, 33 to 36, 41 to 43, 45 to 47, 50 to 5 3, 55-57, 59-70, 73, 75.75, and 80 are new compounds.

Alan R. Katritzky et al., J. Chem. So Perkin Trans H, pp. 1041-1084 (1992) show that compounds 1, 6, 26, 28, 29, 31, 32, 40 and 46 are described; Tomoshige Kobayashi et al., Bui 1 Chem. So Jpn. Vol. 64, pp. 392 to 395. Page (1 1991) describe compounds 1, 4, 6, 27, 29, 40, 49, 58 and 76; MarVin Weiss, J. Am. Chem. So, Vol. 74, pp. 200-202 (1952), lists compounds 1, 38, 40, 44, and 58. Robert L. Frank et al., J. Am. Chem. Soc., Vol. 71, pp. 2629-26 (1949) show compounds 1, 29 , 39, and 40; Michel Simalty et al., Bull. Soc. Cini. Fr., 11, Vol. 39, pp. 39-26 (1970 ) Describes compound 18; EA Zvezdina et al., Kim. Geterotsikl. Soedin., Pp. 1025 to 1028 (1976) describe compound 18. 54 are described; Gerhard W. Fischer et al., J. Prakt. Chem., Vol. 326, pp. 287-302 (1994) describes compound 3 And 8 are listed; Naresh K. Mis hra et al., Indian J Agric. Chem. Vol. 21, pp. 91-93 (1989) describes compound 77; Rupert

Bauer et al., Z. Naturforsch., B: Chem. Sci. Vol. 43, pp. 475-48, (1988), described the compound 79 power. Compounds 74 are described in IV Shantsevoi, Nauka Farmats. Prakt., Kishinev, 43-5 From: Ref. Zh., Khim. 1985, Abstr. No. IZH210, and Di 1 they J. Prakt Chem., Vol. 102, p. 209 (1921) describes compound 37; Scholtz et al., Chemishe Berichte, Vol. 36, p. 845. (1 90 3 years) describes compounds 71 and 72. The pyridin derivative of the formula (I) of the present invention is administered orally or parenterally.

The dose of the pyridin derivative of the present invention is usually preferably 1 mg to 100 mg per day for an adult.

For oral administration, excipients, disintegrants, binders, lubricants, antioxidants, coding agents, coloring agents, flavoring agents, surfactants, plasticizers, etc. are mixed. It can be administered in the form of granules, powders, capsules, tablets, or parenteral administration by injection, infusion, or suppository.

In formulating the above, the usual formulation method can be used.

Excipients include, for example, mannitol, xylitol, sorbitol, budou sugar, sucrose, lactose, and crystal cell mouths. Tilcello ^ "Sntrium, calcium hydrogen phosphite, column starch, rice starch, corn starch, no 3D-cyclodextrin, dextrin, dextrin, tri-cyclodextrin, 3D cyclodextrin Phosphorus, carboxyvinyl polymer, light gay anhydride, titanium oxide, magnesium silicate magnesium, polyethylene glycol, Medium-chain fatty acid triglycerides and the like.

Disintegrators include low-substituted hydroxypropyl cercellose, carboxymethylcellulose, carboxymethylcellulose calcium, Call Box Me Trim, cross-force, no-mellow sodium, A-type (actile), starch, crystalline cellulose, hydroxypropyl Examples include start and partial alpha dumping.

Binders include, for example, methylcellulose, hydroxypropyl propylcellulose, hydroxypropyl propylmethylcellulose, and polyhydroxyl cellulose. Vinyl pyrrolidone, gelatin, arabia rubber, ethylcellulose, polyvinyl alcohol, pullulan, alpha , Agar, tarragant, sodium alginate propylene glycol alcohol, and the like.

Lubricants include, for example, stearic acid, magnesium stearate, calcium stearate, and poly stearate. Seals, selenol, talc, hydrogenated oil, sucrose fatty acid ester, dimethylpolysiloxane, microcrystalline wax, Mitsurou, Sarahitsu Mitsuro and the like.

Antioxidants include, for example, dibutyl hydridoxitrite (Β 、 Τ), propyl gallate, and butyl hydroxyanifur (Β Η). Η Α), 一ココ口、、, citric acid, etc.

Coating agents include, for example, hydroxypropyl methylcellulose, hydroxypropyl propylcellulose, methylcellulose Source, ethyl cellulose, hydroxypropyl methyl chloride methyl phosphate rate, hydroxypropyl Methylcellulose acetate succinate, carboxymethylcellulose, cellulose acetate phthalate, polyvinyl acetate Acetaminopropyl acetate, aminopropyl methacrylate copolymer, hydroxypropyl methylenolose acetate Xinate, methylacrylate copolymer, cellulosic acetate trimethylate (CAT), polyvinyl acetate phthalate And cell phones.

Examples of the colorant include an orange dye, titanium oxide, and the like.

Flavoring agents include citric acid, adipic acid, ascorbic acid, menthol, and the like.

Surfactants include, for example, pooxyethylene-hardened castor oil, glycerin monostearate, sorbitan monostearate, mono, . Sorbitan Lumicitrate, Sorbitan Monophosphate, Polyoxyethylene Polypropylene Block Copolymer, Polymer Examples include sorbates, sodium raurylsulfate, macrogol, and sucrose fatty acid esters.

Examples of the plasticizer include triethyl citrate and triacetin phenol.

Hereinafter, the present invention will be described in more detail with reference to Production Examples, Examples, and Test Examples.

Manufacturing example

Reference example 1 (E)-3-(4-methyl phenyl) 1-1-phenyl-2--

To a mixture of 6.0 g of acetofenonone, 6.0 g of p-tonoaldehyde and 20 ml of ethanol, the hydroxylation ability was stirred at 0 ° C. A solution prepared by dissolving 3.10 g of the aluminum in 50 ml of water was added dropwise, and the mixture was further stirred at 0 to 10 ° C. for 4 hours. After completion of the reaction, the obtained product was collected by filtration and recrystallized from ethanol to obtain 6.06 g of the title compound.

Using the corresponding acetate phenone derivative and aldehyde, the following compounds were obtained in substantially the same manner as in Reference Example 1.

(E) 1 1, 3 — diphenyl 1 2 — propene 1 1 —one

(E) — 1 — (4-Methoxy Fluorine) 1 3 — Fuel 2 — Propene 1 1 1

(E) 1-3-(3-methyl phenyl) 1-1-phenyl

— 2 — Propane 1 — On

(E) 1, 1, 3-bis (4-methylphenyl) 1-2-propene 1-on

(E)-1-(3-Fluorophenyl) 1-3-(4-Methylene phenyl) _ 2-Propene-1 1 -one

(E) 1 3 — (4 — Methylphenyl) 1 1 — (2 — 2 Trophenyl) 1 2 — Propene 1 — On

(E) 1 3 — (4 — Methylphenyl) 1 1 — (3 — 2 Trophenyl) 1 2 — Propene 1 — On

(E) One 3-(4-Methylphenyl)-One (4-Two) U o n) 1 2 — propene 1- — on

(E) -3-(4-isobutyl phenyl) 1 1-phenyl 2-propene 1-on

(E)-3-(4-hexylphenyl) 1 1-Fern 1-2-Pen 1-On

(E)-3-(4-biphenyl) 1-1 ferrule 2-propene 1-on

(E) -3-(3, 4-dimethylphenyl) 1 1-phenyl-2 1 propene 1-on

(E)-3-(2, 4 and 6)

1 _ Fe nil 1 2 — Proppen 1 1 — ON

(E) 3-(4-methyl 3-ditrophenyl) 1-1 phenyl 2-propene 1-1 on

(E) -3-(3-Fluorophenyl) 1-1 Ferrule-2-Pen-1 _ On

(E)-3 — (4-Fenorenofeninoren) 1 1 — Ferrule 2 — Hook Pen 1 — On

(E)-3-(3-phenyl) 1-1-phenyl-2-propene 1-1-on

(E)-3 — (4-chlorophenyl) 1-11 phenyl — 2 — propene 1 — on

(E) -3-(3-bromophenyl)-1 1 phenyl 1 2 _ propene 1 1-on

(E) -3-(4-bromophenyl) — 1-phenyl _ 2 — propene 1 — on (E)-3-(3-Trif-Nor-L-O-M-N-F-E-N-N-O-L)

(E) 11- (4_trino-noreo-lo-m-en-fo-en-in-ro) 111-phenyl-221-propene-111-on

(E) 13-(3-Trifluoromethyl) 1-1 1-1-2-Propene-1-On

(E)-3-(4-Trifluoromethyl) 1-1-1-1-1-2-Propene-1 1

(E) 13-(4-methoxysilane) 1-1-2-propene-1-on

(E) -3-(4-(3-methyl 2-butenyloxy) phenyl) 1 1-phenyl 1 2-propene 1 1-

(E)-3-(4-phenol) 1 1-phenyl 1 2-propylene 11 1

(E) 13- (4 1-benzyl phenyl) 1- 1 phenyl 2-pentopen 1- on

(E)-3-(3, 4 — methylene phenyl) 1 1 1 phenyl 1 2 — propylene 1 1 — on

(E) -3-3 (4-methyl phenyl) 1-11 phenyl 1 2—pron 1—on

(E)-3-(3-nitrophenyl) 1 1-vinyl 1-2-propene 1 1 1

(E)-3-(4-nitrophenyl) 1 1-phenyl 1 2-propene-1 1 (E) -3-(4-cyanophenyl) 1-1-phenyl-2-proben-1 -one

(E) -3-1 (4-acetamide) 1-1-phenyl-2-propene

(E)-1 — Fuel 3 — (2 — Ch —nore) 1 2 — Propene 1 1 1

(E)-3-1 (2-furyl) 1-1-Phenyl 1-2-Pen-1-

(E) -3-(2-imidazolyl) 1-1-phenyl-2-propene-1-on

Reference example 2

(E) -3 (2, 4 — dimethyl phenol) 1 1 phenyl propene

To a mixture of 4.50 g of acetofenonone, 2,4—5.0 g of dimethylbenzanoledaldehyde and 25 ml of ethanol was stirred at 0 ° C. A solution of 2.30 g of potassium hydroxide in 50 ml of water was added dropwise, and the mixture was stirred at 0 to 10 ° C for 5 hours.After the reaction was completed, 3N hydrochloric acid was added. The mixture was acidified and extracted with ethyl acetate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography chromatography (developing solvent; ethyl acetate: hexane = 1: 1: 10) to give an oil. 5.30 g of the title compound were obtained.

The following compounds were obtained in substantially the same manner as in Reference Example 2 using an aldehyde equivalent to acetate phenon.

(E)-3-1 (2-methyl) 1-1- — 2 — Propane 1 — On

(E) — 3 — (4 — ethynolephenyl) 1 1 1 phenyl — 2 — propylene 1 1 — on

(E) 1-3-(4-isopropenyl)-1-phenylene 2-propene-1 -one

(E) — 3 — (4 — t — butynolephenyl) 1 1 — Phenyl 2 — Propene 1 1 1

(E) — 3 — (2, 5 — dimethylphenyl) 1 1 — phenyl 2 — propene 1 — on

(E) — 3 — (2 — phenylophenyl) 1 1 — phenyl 2 — propylene 1 1 — on

(E) — 3 — (2 — phenyl) 1 1 1 phenyl — 2 — propylene 1 1 — on

(E) 1 — 3 — (2 — bromophenyl) — 1 — phenyl — 2 — propylene 1 — on

Reference example 3

(E)-3-(2-methoxyphenyl) 1 1-phenyl 2 -1-prone _-1

To a mixture of acetofenon 4.40 g, 2 — methoxybenzaldehyde 5.00 g and ethanol 3 mm1 was added water with stirring at 0 ° C. A solution of 2.30 g of potassium oxide dissolved in 50 ml of water was added dropwise, and the mixture was further stirred at 0 to 10 ° C for 7 hours. After completion of the reaction, the mixture was acidified by adding 3N hydrochloric acid, and extracted with ethyl acetate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate-hexane to obtain 8.70 g of the title compound. The following compounds were obtained in substantially the same manner as in Reference Example 3 using an aldehyde equivalent to acetate pentanone.

(E)-3-(3-methoxy phenyl) 1-1 1-1-2-1-on

(E) — 3 — (4 — (3 — dimethylaminopropyl) phenyl) 1 1 1 phenyl 2 _ 1 1 1 1 Reference example 4

(E) 1-3-(4-Carbofe ^ _) 1-1-Function 2-Prop-1-On

A mixture of 8.0 g of acetophenonone, 10.0 g of terephthalaldehyde and 40 ml of ethanol was stirred at 0 ° C to obtain a mixture of potassium hydroxide and calcium hydroxide. A solution of 4.10 g of um in 50 ml of water was added dropwise, and the mixture was further stirred at 0 to 10 ° C for 6 hours. After completion of the reaction, the mixture was acidified by adding 3N hydrochloric acid, and the obtained product was collected by filtration. The crystal was recrystallized from ethanol to give the title compound (11.93 g).

The following compound was obtained in substantially the same manner as in Reference Example 4, except that m-phthalanolaldehyde was used in place of telephthalaldehyde.

(E) One 3 — (3 — Power phenyl) One 1 — Fluorine 2 — Propene 1 — On

Reference example 5

(E) — 3 — (4 — dimethylaminophenyl) 1 1 — phenyl 2 — pen 1 — 1 — on

Acetofenon 24.0 g, p — dimethylaminobenz To a mixture of 25.0 g of aldehyde and 300 ml of ethanol was added 1.12 g of potassium hydroxide, and the mixture was stirred at 50 ° C for 8 hours. After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate-hexane to obtain 23.0 g of the title compound.

Reference example 6

(E) 1 3 — (4 1 pyridyl) 1 1 1 (4 methyl phenyl) 1 2 — Propene 1 1 — on

Metanole 20 m 1, 1 ？? To a mixed solvent of 20 ml of a sodium hydroxide aqueous solution was added 6.40 g of 4-pyridine aldehyde while stirring at 0 ° C. To this, 6.70 g of 4'-methylacetophenone was added dropwise over 30 minutes, and the mixture was further stirred at 0 to 10 ° C for 4 hours. After completion of the reaction, the obtained product was collected by filtration and recrystallized from ethanol to give 7.2 g of the title compound.

4 Use 3-pyridine aldehyde and acetophenone instead of one pyridine aldehyde and 4'-methyl acetophenone. In substantially the same manner as in Reference Example 6, the following compound was obtained.

(E)-3-(3-pyridyl) 1 1-phenyl 2-propene 1 1 1

Production Example 1

4- (4-methyl) 1-2,6-diphenylpyridine (compound 6)

(E) -3-(4-methylfurinyl) obtained in Reference Example 1 1 1 1 Ferrule 2 — Propene 1-1 — On 6.0 g, phenacinole pyridinium bromide 7.5 g and acetate To 10 and 40 g of ammonium hydroxide, 40 ml of methanol was added, and the mixture was refluxed for 10 hours. After cooling, the product was collected by filtration and recrystallized from ethanol to obtain 5.83 g of the title compound.

m. p. 1 20.5-1 21.5. C

Ή NMR (CDCls) δ (ppm); 2.45 (3H, s) ゝ 7.34 (2H, d, J = 7.9 Hz), 7.39 to 7.56 (6H, m), 7.66 (2H, d, J = 8.3 Hz) 7.88 (2H, s), 8.16 to 8.23 (4H, m)

MS (EI) 3 2 1 (M ⁺ )

(E)-3-(4-methyl phenyl) 1-1-phenyl-2 1-propene-equivalent to 1-1-ON, β-unsaturated ketone The following compounds were obtained in substantially the same manner as in Production Example 1 using

2,4,6—triphenylviridine (compound 1) mp 137.5-138.5. C

2-(2-hydroxyphenyl) 1-4, 6-diphenyl pyridine (compound 2)

m. p. 164.0-16.6,0. C

2 — (4 — methoxyphenyl) 1, 4, 6 — diphenylpyridine (compound 3)

m.p. 89.0-90.2. C

4 — (2 — Methylphenyl) 1-2, 6 — Diphenylpyridine (Compound 4)

m.p. 1 19.0 〜 1 20.0 ° C 4-(3-Methyl phenyl) 1 2, 6-Diphenyl pyridine (compound 5)

m.p.100.0 to 100.1 ° C

2,4—Bis (4-methyl phenylene) 1-6—Phenylpyridin (Compound 8)

m .ρ. 1 38.5 〜 1 40.0 ° C

2 — (3 — phenylophenyl) 1 4 — (4-methylphenyl) — 6 — phenylpyridine (compound 9)

m .ρ. 1 12.0 to 1 14.2 ° C

4 — (4 — Methyl phenyl) 1 2 — (2 — 2-Trophenyl) 1 6 — Vinyl pyridine (Compound 10)

m.p. 1 24.5 to 1 25.5 ° C

4 — (4 — Methylphenyl) 1 2 — (3 — 2-Trophenyl) 1 6 — P-vinylpyridine (Compound 11)

m.p.16.6.2 to 16.7.2 ° C

4 — (4 — Methyl phenyl) 1 2 — (4 — Nitrophenyl) _ 6 — Vinyl pyridine (Compound 12)

m.ρ.16.0-19.7 ° C

4 1 (4 — ethynolephenyl) 1, 2, 6 — Diphenylpyridine (compound 13)

m.p. 89.0-89.5 ° C

4 1 (4 — isop π-pyrphenyl) 1, 2, 6-diphenylpyridine (compound 14)

m.p. 91.7 to 92.7. C

4-1 (4-1 isobutyl) 1 2, 6-di-fu 2 Le 'pyridine (compound 15)

m.p. 79.2 to 81.0 ° C

4- (4-t-butynophenyl) 2,6-diphenylpyridine (compound 16)

m.p. 102.5 to 103.5 ° C

4 1 (4—hexylphenyl) 1 2,6—Diphenylpyridin (compound 17)

m. ρ. 50.0 to 52.0. C

4 — (4 — biphenyl) 1 2, 6 — diphenylpyridin (compound 18)

m.p. 137.6 to 138.6. C

4 1 (2, 4 — dimethyl phenyl) 1 2, 6 — diph Xylpyridine (compound 19)

m. ρ. 1 27.0 〜 1 29.0 ° C

4-(2,5-Dimethyl phenol) 12, 6-Diphenylpyridin (Compound 20)

m.p.1 ◦7.5 to 108.5. C

4-(3, 4-dimethylphenyl) 12, 6-diphenylpyridin (compound 21)

m.p. 1 24.3 to 12.5.3 ° C

4— (2,4,6—trimethylphenyl) 12,6 diphenylpyridine (compound 22)

m.p. 1 14.0 to 1 17.0 ° C

4-(4-methyl-3-nitrophenyl) 2,6 diphenylpyridin (compound 23) m.p. 1 96, 1 to 197.6 ° C-

4- (2-phenylenephenyl) -12 diphenylpyridine (compound 24)

m.p. 1 18.0 to 1 19.0 ° C

4- (3-fluorophenyl) -12 diphenylpyridin (compound 25)

m.p. 1 38.7-1 39.7 ⁰ C

4 — (41 fluorophenyl) 126 — diphenylpyridin (compound 26)

m.p. 1 40.5 to 14.2 ° C

4 I (2—Cro-phenyl) I, 2,6—Diphenylpyridine (Compound 27)

m.p.1 10.7 to 11.1.2 ° C

4 1 (3—Cross-mouth feninole) 1, 2,6 1-Divinyl pyridine (Compound 28)

m.p. 19.2-10.2.2. C

4 — (4 — phenyl phenyl) 1,2,6-diphenylpyridine (Compound 29)

m.p. 130.8-131.8. C

4 — (2 — Bromophenyl) 1, 2, 6 — divinyl pyridine (compound 30)

m.p. 74.0-76.0. C

4 _ (3 — Bromophenyl) 12, 6 — Diphenylpyridine (Compound 31)

m.p 1 33.7 to 13.4.5 ° C 4 1 (4 — Fluorophenyl) 1, 2, 6 — Diphenylpyridine (Compound 32)

m.p. 1 32.5 to 1 33.5

4 1 (3—Trifluoromethylen) 1 2,6—Divinylpyridine (Compound 33)

m.p.13.2.5 to 13.3.6. C

4- (4-trifluoromethylphenyl) 1-2,6-diphenylpyridine (compound 34)

m.p. 1 42.2 to 14.3.2 ° C

• 4- (3-trifnorolemethoxyl'phenyl) 1,2,6-diphenyl pyridine (compound 35)

m.p. 98.5 to 101.4 ° C

4 1 (4 — Trifluoromethyiphenyl) 1, 2,6-diphenyl pyridine (compound 36)

m.P. 87.3-88.3. C

4 1- (4-hydroxyphenyl) 1-2, 6-diphenylpyridine (compound 37)

m.p. 2 17.1 to 2 18.1 ° C

4 1- (2-Methoxyphenyl) 2,6—diphenylpyridin (Compound 38)

m.P. 1 18.2 to 1 18.9 ° C

4 1- (3-Methoxyphenyl) diphenylpyridin (Compound 39)

m.p. 1 24.1 to 1 25.0 ° C

4 One (4—Methoxyphenyl) 2 6—Diphenyl Pyridines (compound 40)

m. ρ. 99.5 to 10 0.3

4-(41- (3_methyl-12-butenyloxy) phenyl) -12,6-divinylpyridine (compound 41) m.p. 97.4- 9 8.3 ° C

4- (41-phenyloxyphenyl) 126 diphenylbipyridine (compound 42)

m .ρ. 1 22.8 to 1 24.1 ° C

4 — (4 1-benzyloxyphenyl) 2, 6 — divinyl pyridine (compound 43)

m.p. 1 37.4 to 138.4 ° C

4-(3, 4-Methylene dioxyphenyl) 2, 6-Divinyl pyridine (Compound 44)

m.p. 1 55.7 ~ 1 56.7 ° C

4 — (4-methylthiophenyl) 126 diphenylphenol (compound 47)

m.p.102.2 ~ 103.0 ° C

4-(3-nitrophenyl) 1-26 difuryl pyridine (compound 48)

m.ρ.1 39.1 〜 1 40.0 ° C

4-(4-Nitrophenyl) 126 diphenylpyridine (compound 49)

m.ρ. 1 88.88 to 189.4 ° C

4 — (3 — carboxyphenyl) 2, 6 — diphenylpyridine (compound 50) m.ρ.25.4.6 to 255.5 ° C.

4 — (41-carboxyphenyl) 1-2, 6 — diphenyl pyridine (compound 51)

m.p.2 23.5 to 22.5.5 ° C

4 — (4 — Cyanophenyl) 1 2, 6 — Diphenylpyridine (compound 52)

m.p. 1 92.7 to 193.7 ° C

41 (41-acetamidophenyl) 1,2,6-diphenylpyridin (compound 53)

m.p. 2 40.0 to 20.7 .7 ° C

4 — (4-Dimethylaminophenol) 1, 2, 6 — Diphenylpyridin (Compound 58)

m.p. 1 37.8 to 138.7 ° C

2, 6 — diphenyl 4 — (3 — pyridyl) pyridin (compound 7 4)

m.p. 1 62.5 to 164.0 ° C

2, 6-diphenylene 4- (2-chenyl) pyridine (compound 76)

m. ρ. 163.2 to 164.6. C

4 _ (2 — furyl) 12, 6 — diphenylbipyridine (compound 77)

m. ρ. 1 69.4-1 7 0.4

4 — (2 — imidazolinole) 1 2, 6 — dipheninolepyridine (compound 78)

m .p.> 300 ° C ^] H NMR (DMSO-de) δ (ppm); 7.49 to 7.65 (6H, m), 7.7K2H, s), 8.28 (4H, dd, J = 8.0, 1.5Hz), 8.52C2H, s)

MS (EI) 2 9 7 (M ⁺ )

2-(41-methylphenyl) 16-phenyl-14- (4-pyridyl) pyridin (compound 79)

m.ρ.1 57.8 to 15.9.3 ° C

Production Example 2

4 1 (4 1 (3-dimethylaminopropyl) phenyl) 1, 2, 6-diphenylpyridine (compound 45)

(E) —3— (4- (3-methylaminopropoxy) phenyl) obtained with reference to Reference Example 1—1—phenyl—2—propene To 3.01 g of one-one-on, 2.70 g of phenacyl pyridinium-bodied mold and 3.74 g of ammonium acetate, methanol was added. 20 ml was added and the mixture was refluxed for 10 hours. After the reaction is completed, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (developing solvent; dichloromethane: methanol = 20: 1). By purifying with, 1.61 g of the title compound was obtained.

m.p. 1 63.0 to 165.0 ° C

Production Example 3

4 1— (4—bromomethylphenyl) 1-2, —6—diphenylpyridin (compound 60)

4- (4-methylphenyl) —2,6-diphenylpyridine obtained in Production Example 1. 4.77 g, N-bromoconodic acid 90 ml of carbon tetrachloride was added to 2.64 g of the medium, and the mixture was refluxed for 6 hours. After the reaction was completed, insolubles were removed by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (developing solvent; ethyl acetate: hexane = 1:10) and recrystallized from ethyl acetate-hexane to give the title compound. 4.2 1 g was obtained.

m.p. 1 25.2 to 12.6.1 ° C

Production Example 4

4 — (4 — (N, N — dimethylaminomethyl) phenyl) — 2, 6 — diphenylpyridine (compound 63)

4- (4-bromomethylphenyl) 1-2,6-diphenylpyridine obtained in Production Example 3 0.80 g, 50% aqueous dimethylamine solution 2.1 To 0 ml, 100 ml of methanol was added, and the mixture was stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (developing solvent: dichloromethane: methanol = 20: 1). 0.65 g of the title compound was obtained as a more oily product.

_{! H NMRCCDC1 3) δ (ppm} ); 2.33C6H, s), 3.57 (2H, s) 7.40 ~ 7.57 (8H, m), 7.73 (2H, d, J = 8.2Hz), 7.90 (2H, s), 8.18 to 8.23 (4H, m)

MS (EI) 3 6 4 (M ⁺ )

The following compounds were obtained in substantially the same manner as in Production Example 4 using the corresponding amine instead of dimethylamine.

4 1 (4, 1 (N, N—Jetilaminomethyl) Nore) 1, 2,6-diphenolepyl pyridine (compound 65)

^{! H NMRCCDCh) δ (ppm)} ; 1.10 (6H, t, J = 7.1Hz), 2.60 (4H, q, J = 7.1Hz), 3.68 (2H, s), 7, 40~ 7.56 (8H, m) , 7.71 (2H, d, 8.2Hz), 7.90 (2H, s), 8.17- 8.23 (4H, m)

MS (EI) 39 2 (M ⁺ )

4- (4- (N, N-dipropylaminomethyl) phenyl) -1,2,6-diphenylpyridine (compound 67)] H NMRCCDCl ₃ ) δ (ppm ); 0.90C6H, t, J = 7.3Hz), 1.41 to 1.65 (4H, m), 2.35 to 2.52 (4H, m), 3.65C2H, s), 7.40 to 757 (8H, m), 7.71 ( 2H, d, J = 8.1Hz), 7.90 (2H, s), 8.18 to 8.24 (4H, m)

MS (EI) 4 2 0 (M ⁺ )

4- (4- (1-pyrrolidinylmethyl) phenyl)-2,6_divinylpyridine (compound 69)

H NMRCCDCl ₃ ) 5 (ppm); 1.83 to 1.91 (4H, m), 2.58 to 2.70 (4H, m), 3.77 (2H, s), 7.40 to 7.58 (8H, m), 7.72 (2H, d, J = 8.3Hz), 7.89 (2H, s), 8.17 to 8.23 (4H, m)

MS (EI) 390 (M ⁺ )

4 1 (4-(N-butylaminomethyl) phenyl) 1, 2,6-Diphenylvinylidine (compound 61)

m. p. 56. 2-57.6. C

Production Example 5

4-(4-Aminophenyl)-1-2,6-1 1 Lysine (compound 54)

To 150 g of 4- (4-acetamide phenyl) obtained by referring to Production Example 1 was added to 1.5 g of dipheninolepyridine, and 1.50 g of tritium, 100 ml of ethanol and 10 ml of water were added, and the mixture was refluxed for 46 hours. After cooling, 100 ml of water was added, and the obtained product was collected by filtration and recrystallized from ethanol to obtain 1.17 g of the title compound.

m.p. 1 87.4 to 18.8.3 ° C

Production Example 6

4- (4— (N-ethylamino) phenyl) 1,2,6—Divinylpyridine (compound 56)

To 0.58 g of 4- (4-nitrophenyl) 1-2,6-diphenylpyridine obtained by referring to Production Example 1 was added to ethanol 1 80 ml and 5%. 0.20 g of radiocarbon was added, and hydrogenation was performed at room temperature and a pressure of 3.4 kg / cm ² for 9 hours. After completion of the reaction, insolubles were removed by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (eluent; dichloromethan) and recrystallized from aqueous ethanol to give the title compound 0.2. 6 g were obtained.

m .ρ .1.0 2.2 to 104.5 ° C

Production Example 7

4- (41-methylphenyl) 1-2,6-diphenylpyridine hydrochloride (Compound 7)

A mixture of 3.0 g of 4 — (4 — methylphenyl) _ 2,6 diphenyl pyridine obtained in Production Example 1 and ethyl acetate 2 (Km 1 To the mixture was added 20 ml of a 4Ν hydrochloric acid / ethyl acetate solution with stirring, and after stirring at room temperature for 10 minutes, 50 ml of ethyl ether was added. The obtained crystals were collected by filtration to give the title compound.

1 g was obtained.

m.p.106.5 to 109.5. C

4— (4—Methylphenyl) 1-2,6—Substantially the same as in Production Example 7 using the corresponding pyridin derivative instead of diphenylbilizine As a result, the following compound was obtained.

4 — (4-1 (3-dimethylaminopropyl) phenyl)-2, 6-divinyl pyridine = dihydrochloride (compound 46)

m.p. 106.3 to 109.2 ° C

4 1- (4-aminophenyl) 1-2,6-dipheninoleviridine dihydrochloride (Compound 55)

m.p.2 76.8 to 27.8.7 ° C (decomposition)

4 — (41- (N-ethylamino) phenyl) 1, 2,6—divinylbidinine dihydrochloride (compound 57)

m.p.2 46.2 to 24.7.9 ° C (decomposition)

4 1- (4-Dimethylaminophenyl) 1,2,6-diphenylpyridin dihydrochloride (Compound 59)

m. p. 1 1 0. C! ~ 1 13.2 ° C

4 — (4 _ (N —butyraminomethyl) phenyl) ― 2,6 — divinyl pyridine = dihydrochloride (compound 62) m.p. 6 to 2 55.6 ° C (decomposition)

4-1 (4-1 (N, N-dimethylaminomethyl)) ) — 2,6 — diphenylvinylidine dihydrochloride (compound 64)

m.p. 25.26 to 253.2 ° C (decomposition)

4 (4-(N, N-methylaminomethyl) phenyl)-2, 6-divinylbidinine dihydrochloride (compound 66)

m.p. 103.0 to 106.0 ° C

4 1 (4 — (N, N — dipropylaminomethyl) phenyl) — 2,6 — divinylpyridine = dihydrochloride (compound 68)

m.p. 88.0-90, 0 ° C

4 1 (4-(1-pyrrolidinylmethyl) phenyl)-2,6-divinylpyridine nini hydrochloride (compound 70) m.p. 1 1 5. 0 to 1 18.0. C

2, 6-bis (4-methylphenyl) pyridin hydrochloride

(Compound 73)

m.p.16.4-1.165.0 ° C

2, 6-diphenyl 41- (3-pyridyl) pyridin dinihydrochloride (compound 75)

m.p. 1 12.0 to 1 15.0. C

2 — (4 — Methylphenyl) 1-6-phenyl 1-4-(4-pyridyl) pyridin dinihydrochloride (compound 80) m.p. 2 27.2 ~ 2 28.5 ° C

Example

Example 1 Tablet Prescription (per tablet)

Compound 7 30 mg Potato starch 20 mg Crystalline cellulose 20 mg Potassium methylcellulose 20 mg Hydroxydipropynolecinolose 9 mg Stearyl Magnesium phosphate 1 mg Manufacturing method

Compound 720 g, Potato starch 200 g, Crystallized cell

Four

After mixing 200 g of the raw material and 90 g of the raw material, 200 g of hydroxypropyl cellulose, the mixture was ground with a pulverizer. After that, the mixture is put into a stirring granulator, granulated by adding an appropriate amount of water, and then dried by a fluidized bed drier, and 10 g of magnesium stearate is added to the granulated product. A tableting machine was used to obtain tablets (100 mg, 6 mm diameter) containing 30 mg of compound 7.

Example 2 Granules

Prescription (in one granule)

Compound 6 100 mg White sugar 200 mg Mannitol 200 mg Corn decane 47 0 mg Hydroxypropyl propyl cellulose 20 mg Poly Solvent 800 mg Production method Compound 610 g was ground with Benomile, 200 g of sucrose and 470 g of corn starch were added and mixed, followed by mixing with hydroxypropyl pilcellulose 20 g and polysorbate in a mixture of purified water and ethanol (1: 2) (250 g) were added, followed by mixing with a mixer. This was extruded using a screen of 0.5 mm in diameter and granulated by a granulator, and then dried by a fluid bed dryer to obtain a granule containing 10% of compound 6. .

Example 3 Fine granules

Prescription (in one fine granule)

Compound 590 1100 mg Lactose 300 mg Budosugar 230 mg Corn starch 330 mg Hydroxypropyl propylcellulose 30 mg Polysorenoleate 8 0 10 mg Production method

Compound 510,000 g was ground with a jet mill, and lactose 300 g, glucose 230 g, and corn starch 330 g were obtained. In addition, after mixing, 30 g of hydroxypropyl cellulose and 800 g of polysorbate dissolved in 800 g of purified water were used as the binder. The mixture was granulated with a fluid bed granulator and dried to obtain a fine granule containing 10% of compound 59.

Example 4 powder Prescription (in one powder)

Compound 7 320 mg Lactose 800 mg Production method

A powder was prepared by uniformly mixing Compound 720 and lactose 800 g to obtain a powder containing Compound 73 at 20%.

Example 5 capsule agent

Prescription (Capsule 1 capsule_in)

Compound 750.0 mg Lactose 50.0 mg Mannitol 1 45.0 mg Low-substituted hydroxypropyl propylcellulose 15.0 mg Hydroxip mouth Pinolemeth Lucerulose 12.5 mg Polysonorate 800 10.0 mg Canoleate stearate 7.5 mg Hardened oil 10.0 mg Manufacturing method

Compound 7100 g was pulverized with ball mill, lactose 100 g, mannitol 290 g, and low-substituted hydroxypropylcellulose 30 g were added. After mixing, 25 g of hydroxypropyl methyl senorelose and 800 g of polysorbate are dissolved in 800 g of a mixture of purified water and ethanol (1: 2). The mixture was added as a binder, granulated by a fluidized bed granulator, dried, and sieved using a No. 30 sieve. this Steer Li Nsanka Le Siu arm 1 5 g, a - added hydrogenated oil 2 0 g, 3 0 0 mg was filled into No. 1 month capsule to give a mosquito capsule agent compound 7 containing 5 0 _m g Was.

Example 6 Injection

Prescription (in 1 sample for injection)

Compound 6810 mg distilled water 2 ml total

Distilled water for injection was added to and dissolved in 6810 g of the compound, and the total amount was adjusted to 2000 m1. This was dispensed into 2 ml ampules by a conventional method to obtain an injection containing 10 mg of compound 68 (0.5%, 2 ml).

Hereinafter, the present invention will be described in more detail by showing test examples. Test example

Test example 1 NGF production promoting effect test

The test for promoting NGF production was evaluated using the following method.

Specimen

Each compound shown in Table 1 was dissolved in DMS0, and the concentration was adjusted to 2 mg / ml to 50 mg / ml.

Test cells

Mouse forebrain-derived astrocytes (NGF 產 living cells) Test method

Astrocyte glial cells prepared from mouse forebrain were used in 20% fetal calf serum, 100 units Zm1 Benicillin, 100 units ίΐ Prepare 8 x 10 ⁵ cells in Z ml in Dulbecco's modified medium (Gibco, containing high glucose) containing gZm1 streptomicin. and, 9 6 Anapu les over preparative (area of Ri per culture hole 0. 3 2 cm ^2, full § manufactured le co emissions Co.) to,-out 0. 1 m 1 Z hole Zutsuma, at 37, 5 Cultured in% CO ₂ . 72 hours later, remove the medium and add 0.5 µg of bovine albumin powder (manufactured by Pharmaceutical Co., Ltd.), 100 units of Zml ぺ Nissilin 100〃g / m1 after addition of preparative Les flop preparative microstrip sheet Darube Tsu co modified Lee Monteagle medium 0 containing emissions. 1 m 1 Z holes, were cultured at 3 7 ° C, 5% C0 2. Seventy-two hours later, the medium was replaced with 0.1 ml Z-well containing various concentrations of specimens. Here, each sample was dissolved in DMS0 and added so that the final concentration would be various concentrations shown in Table 2 below. For comparison, a medium (control) containing only DMS0 was also prepared.

After culturing for 24 hours in such various media, the concentration of NGF in the media was determined by enzyme immunoassay CFurukawa et al., J. Neurochem., Vol. 40, pp. 734 (1993) Year)].

The NGF production promoting activity of the compound of the present invention

The ratio is shown by the ratio when the NGF amount of (DMSO) is set to 1.0. Table 2 shows the results. Table 2: NGF production promoting activity Specimen Concentration NGF production promoting activity Interi (DMS0) 1.0

Compound 1 25 g / ml ο

.

DU g / m 1 7.3 Compound 2

Compound 3 12 g / ml 1 9

丄_β

25 11 g / ml 1

1. Q π π / m 1 ο

Ό U rr

! ■! 5 / ill 1 3 compound 4 2 g / ml 1, 1

14

10 H g / ml 0

0 υ 1.9 Compound 52 ag / ml 0.1

10 g / ml ο o

.

D U g / m 1 1.4 Compound 6 2 g / ml 1.2

10 fi g / ml 3.2 b U 4.8 Compound 8 2 g / ml 1.4

10 ri

g / ml .0 r rj

DU g / m 12.8 Compound 92 g / ml I.3

10 g / ml 1.9 π g / ml 2.3 Compound 10 2 g / ml 1.2

10 H g / ml 1.5

50 H g / ml 2.0 Compound 11 2 fi g / ml 1.6

10 g / ml 1.5

50 a g / ml 2.5 Compound 12 2 g / ml 2.1

10 i ± g / ml 2.1

50 ag / ml 1.7 Specimen concentration NGF production promoting activity

/ ½ j½ 1 0 1

1 Jum S / III I

11 Π υ 0

50 g / ml 1.8 m; ^ π 1 A

1 j J 9 g / ΙΠ ϋ

i 1 U η ο

5 / IN 1 Otsu,,

0 Compound 15 2 g / ml 1.1

1 η υ σ S / / m 1111 9.Q

50 g / ml 2.5

1 ΎΜ 1 u; Δ 5 / HI 1 Ό

1 π υ 5 / ill 1, L

50 g / ml 2.3

100 ii g / ml 2.0 lum Ηπ 1 π

1/1 υ 〃 g / m i 1, 1

50 ii g / ml 1, 2

/ Rem ίΜπ Q

Δ,

υ g / m 1 0

50 〃 / ml 2.9

9 Ζ Π U um 11 1 g / ml 1

1 υ 〃 g / m 1 Q

50 β g / ml 3.4

1 1 Ζ g / ml 1.0

10 g / ml 3.8

50 g / ml 2.2 Compound 22 2 g / ml 2.3

10 H g / ml 2.9 ο υ, ϋ Compound 23 15 g / ml 1.9

50 / ml 3.4 Compound 24 10 Hg / ml 1.3

50 11 / ml 1.1 Compound 25 2 g / ml 3.3

10 β g / ml 4.2

50 g / ml 6.2 Dark

Sample rate NGF production promoting compound 26 2 g / ml 2.6

10 g / ml 3.9

50 // g / ml 2.3 Compound 27 2 g / ml 2.I

10 〃 g / ml 3.8

50 g / ml 7.2 Compound 8 / product b (n

U g / m 1 4

o one

1 U g / m 1

50 g / ml 3, 2 compound 29 2 pt g / ml l .9

10 H g / ml l .5

50 / g / ml 2.7 compound 30 2 // / m 1 l 2

10 g / ml 4: 3

50 H g / ml 4.2 Compound 31 2 (ig / ml 2.0

10 I g / ml 2.4

50 \ i g / ml 2.9 Compound 32 50 g / ml l.4 Compound 33 2 ag / ml 4.9

10! I g / ml 5.2 Compound 34 2 g / ml l.2

10 Si g / ml l.6

50 g / ml l .4 Compound 35 2 // g / ml l.I Compound 36 10 Hg / ml l.2 Compound 37 2 ag / ml l.I Compound 38 2 / ml l.8

10 g / ml 3.7

50 g / ml 2, 9 compounds 39 10 g / ml 3.I

50 fi g / ml 2.9 Specimen concentration NGF production promoting activity Ao

Mouth W Π 9.0 Q

丄 u 5/1111 U

50 i g / ml 1.6

Lu α α ί τ Jι A 1 9 ft Q / rr \

5/1 "i 丄

10 H g / ml 1.

50 fi g / ml 1.4 Compound 42 2 ig / ml 1.3

10 i g / ml 1.2

Π 11 1 1

s / III 1 丄 Compound 43 5 Id g / ml 1.4

50 g / ml 1.6 Compound 44 5 g / ml 1.1

50 g / ml 1.3

I m o f 1

S / III 1 丄, ό

10 H g / ml 1.1

50 Si g / ml 1.6 Compound 47 2 〃 g / ml 1.1

10 fi g / ml 1.3

im A 0 9 1 1

O s / HI 丄 * 丄

10 g / ml 1.4

50 〃 g / ml 1.1 Compound 49 25 g / ml 1.5

50 a g / ml 1.9

Lum ^ π 0 z B / g / ml

10 〃 g / ml 1.2

50 β g / ml 2.5

口 f ί ί J J 1

About 10 S / III 1 B

50 g / ml 3.3 Compound 55 2 H g / ml 1.1

10 g / ml 1.4

50 g / ml 1.8 Compound 57 2 g / ml 1.1

10 g / ml 1.1

50 g / ml 1.3 Specimen concentration 1 or NGF production promoting compound 582 Ug / ml 1.6

10 g / ml 3.3

50 Id g / ml 4.4 Compound 59 2 Id g / ml 2.4

10 p.g / ml 2.3

50 g / ml 2.7 Compound 1 ^ Compound Ί J 60 50 11 g / ml 1 1 Compound 61 50 fi g / ml 1.3 Compound 62 50 g / ml 1.6 Compound 63 50 ig / ml 1.2

Hfm 1 o

b 4 Δ g / m 1 1 0

50 g / ml 1.5

A iVm

o Δ 〃 g / m 1 0

Ten

50 Si g / ml 1.1 Compound 66 2 H g / ml 1.5

A t4n o

Formula W b 〃 g / m 1 6

1 Π o

丄 U g / m 1 1

Compound 68 2 g / ml 3.2

1 U // g / ml

Compound 69 10 Hg / ml 1.2

ί U g / m 1 I. b

1 1 Π u 〃 g / m 1 丄-1

50 g / ml 1.3 Compound 71 2 H g / ml 1.1

10 β g / ml 1.2

50 ii g / ml 1.5 Compound 72 2 a g / ml 1.5

10 Si g / ml 1.4

50 (ig / ml 1.5 Specimen NGF production promoting compound 74 2 β g / ml 1.2

10 H g / ml 4.1

50 4.2 Compound 76 2 g / ml 1.5

10 g / ml 2.3

50 H g / ml 2.1

Compound 77 10 g / ml 1.4

50 P. g / ml 2.1 Compound 78 2 U g.

10 g, 'ml 11.0

Compound 80 50 fi g / ml 28.0

Test Example 2 Neurotrophic factor action test

Neurotrophic factor action was evaluated using the following method. Specimen

The compound was dissolved in DMS and the concentration was 2 mgZml to 10 mg / ml.

Test cells

Embryonic day 1 8 R

Test method

The test cells were mixed in an equal volume of Dulbecco's minimum essential medium (manufactured by Gibco) and Ham F-12 medium (manufactured by Gibco) containing 20% fetal bovine serum in an equal volume of DF medium. X 10 ⁶ cells / ml, and transfer to a 24-well plate (area per culture hole: 2 cm3-Ning Co.) coated with polyethylene imine. Each 5 ml Z hole was sown and cultured at 37 ° C and 5% CO ₂ . 24 After 4 hours, remove the medium and The above serum-free DF medium containing the test sample at a concentration of 5 μg Zml transbrin, 5 μg Zml insulin and 20 pmoleZml progesterone 0.5 m 1 / Holes were added. Here, the compound of the present invention was dissolved in DMS0 and added so that the final concentration would be various concentrations shown in Table 3 below. For comparison, a medium containing only DMSO was also prepared.

At this stage, two identical plates were prepared. 7 2 hours after cultured in various media, Shi pair to one plates of N _{_₂} - 0 ₂ - C0 ₂ Lee Nkyubeta one (evening by Co., Ltd., BNP - 1 0 0 type) Ri by the minimum oxygen concentration Hypoxia was applied to lower the set concentration to 1 and culture for 4 hours. The other plate was left unloaded and continued to culture at 956 M r with 5% CO ₂ . After further culturing for 48 hours, the number of viable cells was quantified. Except for the culture medium, Fluorescien Diacetate (FDA) reagent was used. After washing with a phosphate buffer (pH 7.4), the fluorescence intensity (EX485 / Em530) was measured. (CytoFlour ™ 230, manufactured by Millipore)

The neurotrophic factor activity of the compound of the present invention was expressed as a ratio when the fluorescence intensity of the control (with the addition of DMS) was 1.0.

Result

Table 3 shows the results. Table 3: Neurotrophic factor activity Neurotrophic factor activity Specimen Concentration

Hypoxia no load Control (DMS0) 1.0 1.0 Compound 1 2 g / m 1.3 1.0

10 μg / m 1.2 1.5 Compound 2 10 g / m 1.7 1.8 Compound 52 μg / m 1.4 1 1.3 Compound 62 g / m 5.6 6.1

10 pi g / m 3.3 3.5 Compound 8 10 g / m 1.5 0.9 Compound 9 2 g / m 1.0 1.4

10 g / m 1.2 1.8 Compound 102 p.g / m 2.9 2.2

10 g / m 3.0 2.8 Compound 11 2 p.g / m 3.94.1.

10 g / m 6.4 6.5 Compound 12 2 u g / m 4.5 4.2

10 jd g / m 3. 4 3.8 Compound 13 2 ji g / m 1.3 1. 1.3

10 μ.g / m 1.7 1.6 Compound 14 2 g / m 3.2 2.6

10 g / m 1.7 1.9 Compound 15 2 g / m 1.4 1.7

10 g / m 2.5 2.3 Compound 16 10 g / m 1.7 1.8 Compound 17 2 g / m 2.5 2.8

10 II g / m 1.8 1.5 Compound 19 2 g / ml 1.9 1.6 Neurotrophic factor activity Specimen Concentration

Hypoxic load No load Compound 20 g / ml 2.0 1.9

1 1 9 9 9 ΎΜ 2.2

10-g / ml 4. 7 4.4 1 substance Ύ Li Li 9 〃 g / / m 1 2.2 1 7 compound 23 2 11 g / ml 1

Hibiki 1.5 u 1.2 1 Q

, ο Compound 25

Compound 26 2 g / ml 1.f

b 1, 5 丄 U i g / m 1 2 9 m.b Compound 27 2 g / ml 2. 7 3.1

1 U // g / ml 2.2 Compound 28 2 g / ml 2.0 to 7 丄 ϋ g / m 1 1.6 1 1.3 Compound 29 2 Ig / ml 0.9 I.2

I 0 g / ml 1.0 I.I compound 302 Hg / ml 3.1 3.3

1 1 U // g / ml 1. 1 1

1.5 Compound 31 2 β g / ml 1. 0 1.6

10 g / ml 1.4 0.9 rem Q 9

1 ΎΜ O σ / m

g / 1111 1.5 1 o

1. mm

10 g / ml 1.2 1.1 Compound 33 2 H g / ml 1.4 1.7

10 g / ml 1. 4 1.4 Compound 34 2 〃 g / ml 1. 3 1.7 Compound 37 2 g / ml 2. 3 2.3

10 H g / ml 3.9 4.0 Neurotrophic factor activity Specimen concentration

Hypoxic load No load Compound 38 2 U g / ml 1.U 1.1

1

Π π 1 g / ΠΙ 1 2.5 1.0 Compound 39 2 1

ig / ml 1, ί 1.1 丄 U l ± g / ml 1.3 1.8 Compound 40 2 g / ml 4.5 4.1 丄 1 Π U 〃 g / m 1 1.4 1.5 Compound 41 2 g / ml 1. 1 2. 1

10 g / ml 2.2 3.5 lum; {^ 1 o

4 g / ml 4.3 3.3

10 g / ml 3.3 2.8

/ Rem Λή, ι

1 j a 1¾J 40 Z g / ml 1.9 1.3

10 g / ml 2.4 2.18

4b o 〃 g / m 1 1.1 0.9 Compound 47 Compound 48

Compound 49 2 g / ml 1.2 i .3

1 I Π U / g / ml 2.2 2.2 Compound 52 2 ig / ml 1.1

1.2

1

Π π U g / ml 1.7 1.6 Compound 53 2 g / ml 3.1 2.6

1 π

1 U 〃 g / m 1 1.0 1.3 Compound 55 2 g / ml 3.2 3.2

10 g / ml 2.2 3.3 Compound 57 2 11 g / ml 2.7 2.9

10 a g / ml 3.4 3.8 Compound 58 2 g / ml 6.0 6.9

10 ig / ml 8.0 7.5 Neurotrophic factor activity Specimen concentration

Hypoxia / no load Compound 59 2 g / m 1 5.1 5.0

10 μ.g / ml 6.6.1 6.1 Compound 61 2 g / ml 2.3 1.6

10 I g / ml 1.6 1.2 Compound 63 2 H g / ml 2.4 3.0 Compound 62 I g / m 1 3.2 4.4 ** i Compound J 67 2 g / ml 5.8 5.7

10 g / ml 1. 3 1.6 ^ Material * J 9 l! 1 g / m l 6 3 4.3

10 a g / ml 4.1 1 2.4 Compound \ yj 70, no 2 / m 1 1 7 1.6 Compound 71 2 g / ml 2.1

10! 1 σ / m 19 5 3.0 Compound 72 2 g / ml 4.3 4.9

10 / m 15 3 5.6 Compound 74 2 β g / ml 2.3 1.9

10 β g / ml 2.5 5 1.6 ίίΑη

Compound 76 2 Ig / ml 1.2.1.1

10 g / ml 1.5 1.5

Experimental example 3 Monkeys with delayed neuronal death due to cerebral ischemia

Action test for

The inhibitory effect on neuronal damage caused by cerebral ischemia was evaluated using a gerbil_bilateral common carotid artery occlusion model.

Laboratory animals

Male gerbils weighing 6900 g (New Japan animals, Saitama Japan) were used. Test method

Gerbils were lightly anesthetized with ether and fixed in a dorsal position. After local infiltration with xylokine, the bilateral common carotid artery was exposed by incising the midline of the neck and carefully separated from the nearby vagus nerve. The artery was stopped with an aneurysm clip for 3 minutes, then the clip was removed and the skin was sutured. The sham-operated group was treated similarly except that the bilateral common carotid artery was not occluded. The animal was anesthetized with ether for 7 minutes after cerebral ischemia for 3 minutes, and the brain was perfused from the left ventricle with 10% formalin buffer. The hippocampus region was cut out as a slice with a thickness of 3 to 4 mm in an annular shape, and sections were prepared after paraffin embedding. Slices were stained with hematoxylin and eosin. Ischemic cytotoxicity was evaluated on a scale from 0 to 3. 0 (-): Normal neuron, 1 (+): Several neuronal disorders (one or several neuronal disorders), 2 (++): Many neuronal disorders, 3

(+ + +): Most neuronal disorders

Specimen

Specimens were suspended in Arabic gum and administered intraperitoneally at 20 mg / kg to 100 mg / kg immediately after completion of ischemia. The gerbil hippocampal CA1 neurons in the sham-operated group were not damaged at all, but the hippocampal CA1 neurons 7 days after ischemia in gerbils obstructed the bilateral common carotid artery for 3 minutes were revealed by light microscopy. He was clearly obstructed. However, the destruction and loss of hippocampal CA1 neurons can cause the compounds of the present invention It was suppressed by intravenous administration. Table 4 shows the results. Table 4: Effects on late-onset neuronal death

Specimen or "^ ri Number of cases Frequency of neuropathy (%)

nig / Kg 1 + + + + + + Sham operation group 1 8 100 0 0 0

3 min ischemia-8 0 12.5 0 87.5 Compound 6 100 8 25 37.5 0 37.5

3 min ischemia 8 0 12.5 0 87.5 Compound 7 20 8 0 50 0 50

50 8 25 62.5 0 12.5

100 8 25 37.5 37.5 0

3 min ischemia 8 12.5 12.5 0 75 Compound 59 100 7 42.9 14.3 14.3 28.6

3 min ischemia 8 0 12.5 0 87.5 Compound 73 100 7 14.3 42.9 28.6 14.3

Industrial applicability

NGF plays a role in maintaining the survival and function of certain types of nerve cells, and has a degenerative repair and protective action. The terpyridin derivative of the present invention has one or both of the activity of promoting NGF production and the activity of prolonging the survival of cultured cerebral cortical neurons. Therefore, the pyridin derivative of the present invention is expected to act on nerve cells directly or indirectly in vivo, and to exhibit an effect of improving and treating neuropathy associated with neurodegeneration. For example, it can be used as a therapeutic agent for traumatic, alcohol-related drugs such as anticancer drugs, inflammatory, metabolic properties such as diabetes, and symptoms associated with idiopathic peripheral neurodegeneration. Can be used. Also, symptoms associated with central neurodegeneration- Diseases, for example, Alzheimer's disease, cerebrovascular dementia, Dunn's syndrome, Parkinson's disease, Non-Tinton's chorea, cerebral ischemia, cerebral infarction, cerebral hemorrhage, head injury, etc. It can also be used as an agent for improving and treating mental and motor dysfunction, spontaneous nerve palsy, etc. that occur.

Claims

Request

1. Formula (I)

Where R ¹ is a hydrogen atom; an unsubstituted phenyl group; an alkyl group, a phenyl group, an alkoxy group, an alkenyloxy group, a phenyloxy group, a benzyloxy group , Methylenoxylsyl group, trifluoromethyl group, trifluoromethoxy group, methylthio group, hydroxyl group, nitro group, amino group, N-ethylethyl group Mino group, N, N —dimethylamino group, carboxyl group, bromomethyl group, acetamido group, cyano group, N, N—dimethylaminopropoxy group A phenyl group substituted with at least one substituent selected from the group consisting of a silyl group and a halogen atom; a pyridyl group; a phenyl group; a phenyl group; a phenyl group; A lil group; or the formula (II)

(II) (wherein, R ⁴ and R ⁵ are the same or different and are each a hydrogen atom; A alkyl group; or both of them represent a 5-membered ring. And R ² and R ³ are the same or different and represent a hydrogen atom; an alkyl group; an alkoxy group; a hydroxyl group; a nitro group and a halogen atom. ] A pharmaceutical composition comprising, as an active ingredient, the pyridin derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition according to claim 1, which is used for improving or treating a neurodegenerative disease.

3. A pyridin derivative according to claim 1 or a pharmaceutically acceptable salt thereof for use as an active ingredient of a pharmaceutical composition.

4. A pyrimidine derivative or a pharmaceutically acceptable salt thereof according to claim 3, which is a pharmaceutical composition used for ameliorating or treating a neurodegenerative disease.

5. Use of a pyridin derivative or a pharmaceutically acceptable salt thereof according to claim 1 for the manufacture of a pharmaceutical composition for ameliorating or treating a neurodegenerative disease. .

6. Improvement or improvement of a neurodegenerative disease, comprising administering to a human an effective amount of a pyridin derivative according to claim 1 or a pharmaceutically acceptable salt thereof. Treatment.