WO1994020476A1

WO1994020476A1 - Novel heterocyclic compound

Info

Publication number: WO1994020476A1
Application number: PCT/JP1993/001233
Authority: WO
Inventors: Hisashi Takasugi; Atsushi Kuno; Mitsuru Ohkubo
Original assignee: Fujisawa Pharmaceutical Co., Ltd.
Priority date: 1993-03-02
Filing date: 1993-09-01
Publication date: 1994-09-15
Also published as: AU4982293A

Abstract

A compound useful as a medicine, represented by the following general formula, a pharmaceutically acceptable salt thereof, and a medicinal composition containing the same and having an acetylcholinesterase inhibitor activity: M-W-Y-A-Q wherein M represents a group represented by general formula (a) (wherein R?1 and R2¿ represent each hydrogen, etc., and Z represents S or O), etc.; W represents a bond, lower alkylene, etc.; Y represents lower alkylene, -NH-, -C(=O)-, etc.; A represents a bond or lower alkylene; and Q represents a group represented by general formula (b) (wherein R4 represents lower alkyl, etc.), etc.

Description

Specification

New complex compound technology

The present invention relates to a novel heterocyclic compound having an acetylcholinesterase inhibitory action and a strong affinity for a muscarinic receptor, and is used in the medical field.

Background art

There are many known acetylcholinesterase inhibitors, but the heterocyclic compound represented by the following general formula (I) of the present invention is not known.

Disclosure of the invention

Although acetylcholinesterase inhibitors are known, the present invention has been made with the aim of developing even more excellent pharmaceuticals.

The present invention relates to a novel heterocyclic compound and a pharmaceutically acceptable salt thereof.

More specifically, the present invention relates to acetylcholinesterase inhibitors, and thus to amnesia and dementia (for example, senile dementia of Alzheimer type, vascular dementia, etc.). The present invention relates to a novel heterocyclic compound which is useful for the prevention and treatment of diseases of the central nervous system such as cerebrovascular disorders, and pharmaceutically acceptable salts thereof.

The heterocyclic compounds targeted by the present invention are novel and are represented by the following general formula (I): M-W-Y-A-Q (I)

[Where M is the formula:

(In the formula, R ¹ is hydrogen, lower alkyl, a heterocyclic group which may have a suitable substituent, or a heterocyclic group which may have a suitable substituent. The

R ² represents hydrogen, lower alkyl, a heterocyclic group which may have a suitable substituent, or phenyl which may have a suitable substituent; Or,

R 丄 and R ² combine with each other to form the formula:

Forming a group of

Z represents S or 0, respectively) or a group represented by

Expression:

(Wherein R ¹ and R ² are each as defined above)

W represents a bond, lower alkylene or lower alkylene,

Y is lower alkylene,

-NH—, -C

II

0 formula: one CO—-

(Wherein R ³ represents hydrogen or lower alkyl.) Or a group of the formula:

— CH—

Wherein R ⁷ represents hydroxy or protected hydroxy.

A represents a bond or lower alkylene,

Q is the formula:

R 8

, R ⁹ Wherein R ⁸ represents lower alkyl and R ⁹ represents alk (lower) alkyl.

(Wherein, R ⁴ represents a lower alkyl or an al (lower) alkyl which may have a suitable substituent).] A target compound of the present invention ( I) can be manufactured by the following methods. Manufacturing method (1)

M-W-COOH

(Π a)

Or to its carboxy group

^ 5 sex derivatives

Is their salt

R 3

M-W-CON-A-Q

(la)

Or its salt Manufacturing method (2)

H

M-W-CON-A-Q

(lb)

Or its salt 1 salt

(I c)

Or salt production method (3)

Or its salt

Or its salt manufacturing method (4)

MW ¹ -CHO

(E) or its salt

(Ie) or its salt Production method (5)

(If) or its salt Protecting group

(Ig)

Or its salt manufacturing method (6)

(Ig)

Or its salt

Conversion

(Ih)

Or its salt

Where R ¹ R ² R, M, W, A, Q, and

Y is each as defined above,

RI is lower alkyl,

X ¹ and X ² each represent an acid residue,

w ¹ is a bond, a ~ c ₅ A Ruki-les-down or is c 2 C 5 Anoreke two-les-down, R 7

Represents a protected hydroxy.

The starting compounds or their salts can be produced by the following methods. Manufacturing method (A)

Or its salt

Or its salt

Manufacturing method (B)

Or its salt

Or its salt Production method (c)

Or its salt

M yuan

Or its salt Production method (D)

(V)

Or its salt

Or its salt Production method (E)

MHVT-CHO

(Kb)

Or its salt

-W ² -CH = CH-COOH

(XII)

Or its salt

② Restitution

-W ² -CH ₂ CH ₂ -COOH

(ΧΙΠ)

Or its salt Production method (F)

Or its salt

R ¹¹ -X ⁴

① (XV)

Or its salt

\ 1

(xvi) or its salt

(XV¾) or its salt Production method (G)

CN-W-Y-A-Q

闺

Or its salt

Salt

Or its salt Production method (H)

CN-W-Y-A-Q

(ΧΥΠί) or its salt

Or its salt Production method (I)

(Ilia) or its salt

(Vffia)

Or its salt

In the above formula, R R M, W, W 1 Z, Y, A, Q and X ^ are each as defined above,

R 5 is carboxyl or protected carboxyl, R 6 is lower alkyl,

R 10 is a low-grade alkoxy,

R is lower alkyl,

W 2 represents a bond, c] to c ₄ alkylene or c ₂ -C alkylene,

X ³ and X ⁴ each represent an acid residue. Suitable pharmaceutically acceptable salts of the compound (I) are conventional non-toxic salts, for example, salts with inorganic bases, such as alkali metal salts (eg, For example, sodium salt, potassium salt, etc., alkaline earth metal salts (eg, calcium salt, magnesium salt, etc.), ammonium salt; organic base and Salts, for example, organic base salts (for example, triethylamine salt, pyridin salt, picolinate salt, ethanolamine salt, triethanolamine salt, diethanolamine salt) Inorganic acid addition salts (for example, hydrochloride, hydrobromide, sulfate, phosphoric acid) such as cyclohexylamine and N, N'-dibenzylethylenediamine. Salts, etc.); organic carboxylic acid or sulfonate addition salts (for example, formate, acetate, Li Furuo Russia 醉酸 salt, Maleate, tartrate, fumarate, methansulfonate, benzenesulfonate, toluenesulfonate, etc.); basic And salts with bases or acid addition salts, such as salts with acidic amino acids (eg, arginine, asno, laginic acid, glutamic acid, etc.). I will.

In the description above and below, preferred and specific examples of various definitions that the present invention does not include within its scope are described in detail below.

The term "lower" is used to mean a group having 1 to 6, preferably 1 to 4 carbon atoms, unless otherwise specified.

Suitable lower alkyl moieties in the terms “lower alkyl” and “al (lower) alkyl” include methyl, ethinole, propinole, isopro pinole. Linear or branched having 1 to 6 carbon atoms, such as butyl, butynole, isobutyl, secondary butyl, tertiary butyl, pentyl, tertiary pentyl, hexyl, etc. Among them, preferred are those having 1 to 4 carbon atoms.

Suitable "lower grades" include methoxy, ethoxy, proboxy, isoproboxy, butoxy, isobutoxy, and secondary butoxy. , Tertiary butoxy, pentoxy, tertiary pentoxy, hexyloxy, etc., linear or branched having 1 to 6 carbon atoms. Others are listed. Preferred "heterocyclic groups" are saturated or unsaturated monocyclic or polycyclic heterocycles containing at least one heteroatom, such as an oxygen, sulfur or nitrogen atom. It means a ring group.

More preferred heterocyclic groups include the following heterocyclic groups: 3- to 8-membered unsaturated heterocyclic groups containing 1-4 nitrogen atoms, For example, pyrrolyl, pyrrolinole, imidazolinole, virazolinole, pyridyl and its N-oxide, dihydroxypyridyl, tetrahydrolin Pyridyl, pyrimidinole, pyrazinyl, pyridazinyl, triazolinole (for example, 4H—1, 2, 41 triazole, 1H-11, 2,3—triazolinole, 2H—1,2,3—triazolinole, etc., tetrazole (for example, 1H—tetrazole), 2 H — tetrazolinol, etc.), dihydrotriazine (for example, 4, 5 — dihydro1-1, 2, 4-triazine) Les, 2, 5 - di-heat mud-1, 2, 4 one Application Benefits A Jiniru, etc.), etc.;

3- to 8-membered saturated heterocyclic group containing 1 to 4 nitrogen atoms, such as azetidinyl, pyrrolidinole, imidazolidinyl, piperidinole, virazolidinyl, piperazinyl What

A fused unsaturated heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolinole, isoindolinole, indlizinyl, benzoimidazolinole, quino Linole, Isoquinolinole, Indazolinole, Benzotriazolinole, Tetrazolopyridyl, Tetrazolopyridinil (for example, Tetozo) La Zoro [1, 5 — b] pyridazinyl), dihydrotriazolopyridazinyl, etc .;

A 3- to 8-membered unsaturated heterocyclic group containing 1-2 oxygen atoms and 1-3 nitrogen atoms, such as oxazolyl, isoxozolinole, oxaziazolinole (for example, 1,2,4-oxaziazinolole, 1,3,41-oxaziazinolyl, 1,2,5—oxaziazinolinole, etc.);

3- to 8-membered saturated heterocyclic group containing 1-2 oxygen atoms and 1-3 nitrogen atoms, for example, morpholinyl; 1-2 oxygen atoms and 1-3 A condensed unsaturated heterocyclic group containing a nitrogen atom of, for example, benzoxazolyl, benzoxazole, etc .;

3- to 8-membered unsaturated heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, 1,3—thiazolinole, 1,2—thiazolinole, thiazo Linole, thiadiazolyl (for example, 1,2,4-thiadiazolinole, 1,3,4-thiadiazolinole, 1,2,5—thiadiazolinole, 1,2,3— Thia diazo linole);

3- to 8-membered saturated heterocyclic group containing 1-2 sulfur atoms and 1-3 nitrogen atoms, such as thiazolidinyl; 3- to 8-membered unsaturated containing one sulfur atom Heterocyclic groups, such as chenyl;

Condensed unsaturated heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as benzothiazolyl and benzothiadiazolinole; Suitable "lower alkylenes" include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, and hexaalkylene. Examples thereof include straight-chain or branched-chain ones having 1 to 6 carbon atoms, such as methylene, methylenolethylene, ethynoleethylene, and propylene, and more. A good example is

^C l ~ ^c ₄ A Ruki les emissions and the like.

Suitable “lower alkenylene” include vinylene, plorenylene, 1 — (or 2 —) butenylene, 1 — (or 2 — or 3 —) Pentenlen, 1 — (or 2 — or 3 —) Hexenylene, Methynorebiren, Ethilbiniren, 1 (or 2 — or 3 —) methylprodilelen, 1-1 (or 2 — or 3 —) ethynoleprodilene, 1 — (or 2 — or 3 — or 4) C 2 -C 6 straight or branched chain, such as 1- (or 2-) butenylene, is a more preferred example. Represents C ₂ -C ₄ alkenylene.

Preferred “aryl” in the word “aryl” and “al (lower) alkyl” include phenyl, naphthyl and the like. A more preferred example is finninore.

Suitable “protected carboxyls” include esterified potato reboxes and the like. Suitable examples of the ester moiety of the esterified carboxy include lower alkyl esters (eg, methyl ether tenol, etinoles tenenole, propyles tenore, isopro). Pinores tenoré, butinoles tenoré, isoftinoles tenorée, tertiary butinoles tenoré, pentinores tenoré, hexinore stele, etc.) Lower alkyl esters having at least one suitable substituent, for example, lower alkyl esters, for example, lower alkyl esters [for example, acetoxyl methyl esters, propioninoleo, etc.] Kisme Chinoles Tenoré, Butyri Luo Kisime Chinoles Tenoré, Valle Rinoréo Kisime Chinoles Tenoré, Pinot Roy Norero Kisime Chinoles Tenoré, Hexano y Noreo Kisime Chinoles Tener, 1 (or 2 —) Acetoki Sheil Estel, 1 (or 2 — or 3 —) Acetoki Propirester, 1 1 (or Is 2 — or 3 — or 4 1) acetoxybutyl ester, 1 (or 2-) propionylethyl ester, 1 — (or 2 — or 3 —) ) Propionylo xypro pilester, 1 (or 2-) butyrinoleki schi チル l 、 ster, 1 ((or 2) iso butylinoleki シェ kis til stel, 1 （(or 2 —) 1) (or 2—) Hexano y Noreleki Shechilles ter, Isobuchi linoleo Kisme chinores tenoré, 2 — echinolebuty Tenoré, 3, 3 — dimethyl olebuti linoleo xyletinolester, 11 (or 2 —) pentanolelo chyletinole estole, etc.], low-grade anorecan Sukulehonir low-level alkyl ester (for example, 2—mesylethyl ester), mono (or di- or tri) halo-lower-level alkyl ester Nore (for example, 2 — Edo Echinore Estenore, 2, 2, 2 — Tricycloethylester, etc.), lower grades, lower grades, lower grades, etc. [for example,ト, ェ, ポ, ニ, プ, t, t, t, t, t, t, t, t, t, t, t, t, t, t, t, t Or 2 —) mexican bonillo kischi エス estel, i-i (or 2 —) ethno bonni boninole Is 2 —) isoproxy boninole boninoleo キノチ、フ, phthalidylden (lower) alkylester, or (5-lower alkynole)ー 2 — oxo 1, 3 — gio solone 41 yl) (lower) alkyl ester [for example (5 — methino 2-oxo 1, 3 — Dioxole I 4 — Innore) Mechinore Estenore, (5 — Echinore 1 2 — Oxoso 1, 3 — Dioxono 1 4 Inore) Mechinorees Ter; lower acre kenil ester (for example, vinyl ester, arinore estenole); lower alkynyl ester (for example, Chininole stenole, propininole:!: Stenole, etc.); may have at least one suitable substituent (s), and may have at least one suitable substituent. For example, Ben Gilles Tenoré, 4-Mexican Tenoré Tenoré, 412 Trove Ginores Tenoré, Fénécénétélés Tenoré, Tritínoresénéténée, Benz Hydronéléséténée, Bis (Methoxy Fenile) Métinole Estele, 3, 4- Dimetoxy Benzil Tenoret, 4-Hydroxy 1-3, 5 — Zt-butynolene And at least one suitable substituent; aryl ester (for example, peninole stainless), 41 Lorenzo Tenoré, Trinolle Tenoré, t-Butinore Fénénorés Tenoré, Kisiri Norés Tenoré, Mesicinoles Tenoré, Taménoles Tenoré, etc.); Tarry styrene; and so on.

Suitable “acid residues” include halogen (eg, chlorine, bromine, iodine or fluorine); alkanoyloxy (eg, acetoxy, etc.). ), Low-grade alkanols (e.g., methansulfoninoleux), and more preferably halogen. is there.

Suitable "protected hydroxy" include acyloxy; phenyl-lower alkyl optionally having one or more suitable substituents (e.g., benzyloxy). And hydroxy substituted with a conventional protecting group such as tetramethylhydrobilanyl.

A preferred "acyl moiety" in the expression "acyloxy" includes carbamoyl, an aliphatic acyl group, and an aromatic or heterocyclic ring-containing amino acid. And a sil group. Preferable examples of the acyl include lower-alkanols (for example, honole minole, acetyl, propionyl, butyrinole, isobutylinole, norenorinole).ソ, ヽヽレレレレレレレレレレ低低低低低低低低低低低低低低低低低低低低低低低低；低低低低低Shika Norebonil, Pro Pok Shikanorebonil, Isopro Pok Shikanoleponil, Tokishi no boninore, tertiary butoxy boninore, pentino okinore boninore, hexinore boninore, etc.); lower a Luke down the scan Norre e nil (for the Ebame Shinore, Etta down the scan Norre ho Ninore, Puronoヽ⁰ down scan Norre e Ninore, Lee Sopuronoヽ⁰ down scan Norre host two Norre, porcine down the scan Norre host two Norre Arinoles Norehonil (for example, Huininores Norehoninore, Toshinore etc.); Aroinore (for example-Benzoinore, Tonoleinole, Kishi) Loinore, naphthoinole, phthaloinole, indano knoboninole, etc.); (lower) anorecanoi inole (for example, pheninoleacetyl, phenylpropionyl) Etc.); (Lower) alkoxycarbonyl (for example, penzinoleoxycanolevonyl, phenethyloxycarbonyl, etc.).

Suitable rC—Cranolylene includes methylene, ethylene, trimethylene, tetramethylene, pentamethylene, methylene, and the like. Examples thereof include linear or branched ones such as chinolemethylene, ethynoleethylene, and propylene.

Suitable “Ju-Ju alkylene” includes methylene, ethylene, trimethylene, tetramethylene, ethylethylene, propylene And straight-chain or branched-chain ones.

Preferred “c ₂ to C _r alkenylene” include vinylene, prophenylene, 1- (or 2 —) butenylene, 1- 1 (or 2 — or Or 3-) pentenelen, methylvinylene, ethylvinylene, 11 (or 2 — or 3 —) methylpropenylene, 11 ( Or 2 — or 3 —) Chilpropenylene, 1 (or 2 — or 3 — or 4 1) Methynole 1 — (or 2 —) Straight chain or branched, such as butenylene Examples include chain-like ones.

Suitable “c ₂ to alkenylene” includes vinylene, propylene, 11- (or 2-) butenylene, methylvinylene, ethynolevine. Examples thereof include straight-chain or branched-chain compounds such as len, and 11 (or 2 — or 3 —) methylprobenylene.

A preferred "substituent" in the expression "optionally substituted aryl" is a lower alkyl (for example, methyl, ethylenol, Propyl, Isopropynole, Butyl, Isobutyl, Tertiary Butynole, Pentinole, Neopentyl, Tertiary Pentyl, Hexyl, etc., Lower Alkoxy (for example) Methoxy, ethoxy, proboxy, isopropoxy, isobutoxy, tertiary butoxy, pentyloxy, neopentinoreoxy, tertiary pentinoleo Kish, hexyloxy, etc.), lower alkenyl (for example, vinyl, 1-vinyl, 1-methyl, 1- or 2-- or 3—Butenyl, 1 1 or 2 — or 3 — or 4 1 pen Tenyl, 1 or 2 — or 3 — or 4 1 or 5> xenyl, etc.), lower alkyl

(For example, ethininole, 1-propyninole, propargyl, 1-methinole-proparginole, 1- or 2-- or 3--butynyl, 1- or 2-- or 3-- or 4 To one pen, 1 to 1 or 2 — or 3 — or 4 to 1 or 5 — Kishinir etc.), Mono (or Ji or Tri) Haro low-grade Akureku Kure (for example, Funole Oro Mechinore, Gifoleno Lo Mechinore, Trif Cleo Lo Mechinore, Chlo Lo Mechinore, Jiklo Lo Mechinore, Trikuro Lo Mechinore, Bromo Mechinore, Jibokumo Mechinore, Trib Lomo Me Chinore, 1 or 2—Hornoolechil, 1 or 2—Bromodechil, 1 or 2—Chlorochinole, 1, 1 Phenoolecinole, 2,2—difluoroethyl, etc.), halogens (eg, chlorine, bromine, fluorine, iodine), carboxy, protected carboxy as described above. , Hydroxy, protected hydroxy, aryl (e.g. vinyl) Lower alkyl such as naphthyl), lower phenolic phenol (lower) such as benzene, phenyl phenol, phenolic phenol, etc. Alkyl (lower alkyl moieties cited above), protected carboxyl (lower) anoalkyl (lower alkyl moieties as exemplified above) Cited and protected carboxyl moieties may be those cited above), nitro, amino, protected amino, di-lower alkylamino ( For example, dimethylamino, diethylinomino, diisopropinoleamino, ethylmethylamino, isopropinolemethinoleamino, etinoleisopropinomino, etc. , Hydroxy lower alkyl, protected hydroxy lower phenol, acyl ole, cyano, mentole, lower alkyl thio (eg, methyl thio, ethyl thio, etc.) , Propiorchio, Isopropiorchio, Buti Norchio ), Imino, etc.

Suitable "protected amino" includes acylamino (for the acyl part, the one exemplified above is cited).

A preferred “substituent” in the expression “heterocyclic group optionally having substituent (s)” is a lower alkyl (for example, methyl, ethyl, and methyl). Ropinole, isopropyl, butyryl, isobutyl, tertiary butyl, pentyl, neopentyl, tertiary pentyl, hexyl, etc., and lower alkoxy (for example, Tokishi, Etokishi, Pro Bokshi, Isopropokishi, Isobutoki, Tertiary Butoxy, Pentyloxy, Neopentillo, Tertiary Pentyloxy, Hexyloxy, etc.), lower alkenyl (for example, vinyl, vinyl alcohol, vinyl, 1-methyl alcohol, 1- or 2-- Is 3 — buten, 1 or 2 — or 3 — or 4 1 pen 1 or 2 — or 3 — or 4 1 or 5 — hexenyl, etc., lower alkynyl (for example, ethynyl, 1-propynyl, propargyl, 1- Methinolepropargyl, 1 or 2 — or 3 — butynyl, 1 1 or 2 — or 3 — or 4 1 pentyl, 1 1 or 2 — or Is 3 — or 4 1 or 5 — hexinyl, etc., mono (or di or tri), halo low-grade quinole (for example, funore oromechi) Nore, diphne ore, nore, trifle ore, nore, ore, dilo, ore, etc.), halo Gen (eg salt , Bromine, fluorine, iodine), card box, protected card box, hydroxy, protected hydroxy box, aryl (for example, phenyl) , Naphthyl, etc.), lower phenyl alcohol (for example, benzene, phenyl phenol, phenyl propyl, etc.), lower phenols such as phenol, etc .; ) Alkyl, protected cardbox (lower) Alkyl, nitro, amino, protected amino, di (lower) alkylamino (for example, dimethylamino) , Getylua mino, diisopropinorea mino, etilomethinoa mino, isopropinore methinorea mino, etinolaysopropinorea mino, etc.), hydroxy (lower) alkyl, protected Hi Loxy (lower) alkyl, cyano, mercapto, lower alkylthio (eg, methylthio, ethylthio, propylthio, isopropylthio, butylthio, etc.), imino, etc. .

A suitable “substituent” in the expression “Alkyl (lower alkyl) which may have a suitable substituent” includes lower alkyl (for example, methylol, ethyl, Propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, neopentyl, tertiary pentyl, hexyl, etc., lower phenolic (eg, methoxy) , Ethoxy, propoxy, isopro box, isobutoki, tertiary butoxy, pentyloxy, neopentyloxy, tertiary pentyloxy, Hexyloxy, etc.), lower alkenyl (for example, vinyl, 1-propene, aryl, 1-methyl phenol) Nole, 1 or 2 — or 3 — butenyl, 1 or 2 1 or 3 — or 4 1-pentenyl, 1 1 or 2 — or 3 — or Or 4 1 or 5 — hexenyl, etc.), low-grade anorekininole (for example, ethinil, 1-propyninole, propargyl, 1-methinolebrono, ^0- no-reginole, 1 1 or 2 — Or 3 —butynyl, 1 1 or 2 — or 3 — or 4 1 pen, 1 1 or 2 — or 3 — or 4 1 or 5. —Hexinyl, etc., mono (or di or tri), halo lower alkyl (for example, fluoromethyl, diphnolelomethine, trifnelelomethinele) , Chloromethylinole, dichloromethinole, trichloromethinole, etc.), halogen ( For example, chlorine, bromine, fluorine, iodine), carboxy, protected carboxy, hydroxy, protected hydroxy, and aryl (for example, phenyl, naphthyl) Lower alkyl, carboxy (lower) alkyl, protected carboxyl (for example, benzyl, phenyl, phenyl propyl, etc.); (Lower) alkyl, nitro, amino, protected amino, di (lower) alkylamino (for example, dimethylamino, genoa amino, diiso) Lopinoremino, ethilmethylamino, isopropinolemetinolemino, ethiluisopropilamino, etc.), hydroxy (lower) alkyl, protected hydroxy (low) Grade) alkyl, cyano, mercapto, lower alkylthio (eg, methylthio, ethylthio, propylthio, isopropylthio, butylthio, etc.), Mino and the like.

The production methods of the target compound and the starting compound are described in detail below.

Manufacturing method (1)

The compound (Ia) or a salt thereof is a compound (Ila) or a reactive derivative of the carboxyl group or a salt thereof with the compound (III) or a reactive derivative thereof. Alternatively, it can be produced by reacting with a salt thereof.

As a suitable reactive derivative of the compound (III), a Schiff base-type imine formed by the reaction of the compound (III) with a phenolic compound such as phenolic anhydride or ketone can be used. Or its enamine tautomer, compound (III), bis (trimethylinoleyl) acetamide, mono (trimethylinolecillin) acetamide Toamide [for example, N— (trimethylsilyl) acetamide], bis (trimethyltinsilino) or bis (trimethyltinsilino) is due to its reaction with silyl compounds such as urine. And a derivative formed by the reaction of compound (III) with phosphorus trichloride or phosgene.

Suitable reactive derivatives at the carboxyl group of the compound (IIa) include acid halides, acid anhydrides, active amides, active esters, and the like. Preferred examples of such reactive derivatives include acid chlorides; acid azides; substituted phosphoric acids (eg, dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, Benzylphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid (For example, methansulphonic acid), aliphatic carboxylic acids

(For example, acetic acid, propionic acid, butyric acid, isobutyric acid, bivalic acid, pentanoic acid, isopentanic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.) A mixed acid anhydride with an acid such as an aromatic carboxylic acid (for example, benzoic acid); a symmetrical acid anhydride

Imidazole, 4-monosubstituted imidazole, dimethylpyrazole, triazonole, 1-hydroxyl-1H-benzotriazole or tetrazole Activated amides; Activated estenores [for example, methinoles estenore, echinoles estenore, cyano mesinoles estenoles, mexico mesinoles estenores, dimesino lesメノ ([(CH.) ₂ N + = CH テノテテ、ビビビビビビ p p p p p p ((((((((( Nores Tenoré, Tri-clo mouth Fentinoles Tenoret, Pentaklorofenore Nores Estenore, Mesinore Feno Noleste Tenoré, Fenini Norea Zofuji Noles te Nore E Ninorecho Estenore, p — Nitrohu Enorecho Estenore, p — Cle Ginorechoes Tenore, Power Le Bocci Me Cinorecho Es Tenore, Villa Ninoles Ter, Piri Ginolles Tenore, Piperi Gibrees tenoré, 8 — quinolinolechoester, etc.) or N — hydroxy compound [for example, N, N — dimethylol hydroxinolemin, 1 — hee DROXY 1 (1H) 1 PYRIDON, N — HYDROXY SHICIN IMID, N — HYDROXY SHIFT IMIDE, 1 – HYDRO Xy 1H—benzotriazole, etc.]. These reactive derivatives are used in the compound (I It may be selected appropriately according to the type of I a).

The reaction is usually carried out in a conventional solvent, for example, water, alcohol (for example, methanol, ethanol, etc.), acetate, dioxane, acetone. Tonitrinole, chlorophonolem, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethinole honolem amide, The reaction should be performed in an organic solvent that does not adversely affect pyridin or other reactions. These conventional solvents may be used as a mixture with water.

In this reaction, when the compound (IIa) is used in the form of a free acid or a salt thereof, the N, N'-dicyclohexyl phenol can be used. , N-cyclohexylone N, 1-monocyclohexyl olefin, N-cyclohexylone 1 N, 1 (4-Jetinorea) Bodiimide, N, N, 1-Jetilka Norrevoimid, N, N, -Isopropinoreca-norrevoimid, N-Ethyl-N'-1 (3-Dimethinorea Mino N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N Min, dipheninoleketene N-cyclohexinolemin Xylene acetylene, 1-vinyl alcohol, 1-chloroethylene, trialkyl phosphite, ethyl polyphosphate, isopropyl polyphosphate, oxy Phosphorus dichloride (phosphoryl chloride), phosphorus trichloride, thionyl chloride, oxalyl chloride, lower alkyl haloformate (for example, black mouth ethyl formate, black mouth isopropionate, etc.) ), Tri-Finore Hos Fin, 2—Echinorre 7 ー Hydroxybenzoi soxazolidium salt, hydroxide 2 — ethinole 5 — (m — snorefofeninole) isosoxazolium inner salt, 1-1 (p — black mouth 6-chloro-1H-benzotriazole, N, N-dimethylformamide and thionyl chloride, phosgene, The reaction is carried out in the presence of a conventional condensing agent such as so-called Vilsmeier reagent, which is prepared by the reaction with trichloromethyl formate, phosphorus oxychloride, etc. Is preferred.

When the starting compound is in a liquid state, it can be used as a solvent.

The reaction is carried out using alkali metal bicarbonate, tri (lower) alkylamines, pyridines, N—lower alkylmonohololin, N,

N—Can also be performed in the presence of an inorganic or organic base, such as di (lower) alkyl benzylamine.

The reaction temperature is not particularly limited, but usually the reaction is performed without cooling or under caloric heat.

Manufacturing method (2)

Compound (Ic) or a salt thereof can be produced by reacting compound (Ib) or a salt thereof with compound (IV) or a salt thereof.

The reaction is usually carried out in a conventional solvent, for example, alcohol (for example, methanol, ethanol, ethylene glycol, etc.), chlorofonolem, and ethanol. -Tenore, tetrahydrofuran, benzene, N, N-dimethinole honoleum amide, or any other organic solvent that does not adversely affect the reaction. The reaction temperature is not particularly limited, but the reaction is usually performed without cooling or heating.

The reaction is usually carried out with an alkali metal hydroxide, alkaline metal bicarbonate, alkaline metal carbonate, alkaline metal acetate, tri (lower) alkylamine, alkaline metal Hydride, pyridin, norethidin, picolin, dimethinorea minopyridine, N-lower alkylmorpholine, N, N-di (lower) alkylben Performed in the presence of an inorganic or organic base such as ziramine, N, N-di (lower) alkylaniline. When the base and Z or the starting compound are in liquid form, they can be used as a solvent.

Manufacturing method (3)

Compound (Id) or a salt thereof can be produced by reacting compound (V) or a salt thereof with compound (VIII) or a salt thereof.

The reaction is usually carried out with alcohol (for example, methanol, ethanol, etc.), benzene, N, N, N-dimethylformamide, tetrahydrofuran. The reaction is performed in a solvent such as lofuran, toluene, methylene chloride, ethylene dichloride, chloroformolem, or getyl ether, or any other solvent that does not adversely influence the reaction.

The reaction temperature is not particularly limited, but the reaction is usually carried out without heating or under heating.

Manufacturing method (4)

Compound (Ie) or a salt thereof is compound (IX) or Can be produced by reacting the salt thereof with the compound (IIIa) or a salt thereof, and subjecting the resulting compound to a reduction reaction.

This reduction is carried out by a conventional method, including chemical reduction and catalytic reduction.

Suitable reducing agents to be used for chemical reduction include hydrides (eg, hydrogen iodide, hydrogen sulfide, aluminum hydride, sodium borohydride, cyanoborohydride) Sodium or a metal (for example, tin, zinc, iron, etc.) or a metal compound (for example, chromium chloride, chromium acetate, etc.) and an organic acid Is a combination with an inorganic acid (for example, formic acid, acetic acid, propionic acid, triphenolic acetic acid, p-tonolenosorenoic acid, hydrochloric acid, hydrobromic acid, etc.) .

Suitable catalysts to be used for the catalytic reduction are platinum catalysts (for example, platinum plate, spongy platinum, platinum black, platinum in the form of colloid, platinum oxide, platinum wire, etc.), palladium catalysts (for example, For example, spongy, ⁰ radium, no, ⁰ radium black, palladium oxide, palladium charcoal, colloidal palladium, palladium palladium sulfate, palladium Z carbonate Nickel catalysts (for example, reduced nickel oxide, nickel oxide, and Raney nickel), cobalt catalysts (for example, reduced nickel oxide, and Raney nickel). Such as cobalt, iron catalysts (eg, reduced iron, Raney iron, etc.), copper catalysts (eg, reduced copper, Raney copper, Ullman copper, etc.) . Reactions are usually performed in water, alcohol (eg, methanol, ethanol), N, N—dimethylmethonolone amide, tetrahydrofuran The reaction is carried out in a solvent such as lan, a mixture thereof, or any other solvent that does not adversely influence the reaction.

Further, when the acids to be used for the chemical reduction are liquid, they can be used as a solvent.

The reaction temperature is not particularly limited, but usually the reaction is carried out without cooling or heating.

Manufacturing method (5)

Compound (Ig) or a salt thereof can be produced by subjecting compound (I （) or a salt thereof to an elimination reaction of a hydroxy protecting group.

Suitable methods for this elimination reaction include conventional methods such as hydrolysis and reduction.

(i) For hydrolysis:

The hydrolysis is preferably performed in the presence of a base or an acid, including Lewis acid.

Suitable bases include alkali metals (for example, sodium, potassium, etc.), alkaline earth metals (for example, magnesium, canoleum, etc.). ), These hydroxides, carbonates or bicarbonates, tri (lower) alkylamines (such as trimethinoreamin, triethinoreamin), Inorganic and organic bases such as picolin, 1,5—diazabicyclo [4.3.0] non-5-ene I can do it.

Suitable acids include organic acids (eg, formic acid, diacid, propionic acid, trichloroacetic acid, trifluoroacetic acid) and inorganic acids (eg, hydrochloric acid). , Hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.).

Desorption with a Lewis acid such as trihalodiacid (eg, trichlorosulfuric acid, trifluoacetic acid, etc.) requires a cation trapping agent (eg, Aniso It is preferable to carry out the program in the presence of a file or a folder.

The reaction is usually carried out in water, alcohol (eg, methanol, ethanol, isopropynoreal), tetrahydrofuran, zeolite, etc. Conventional such as xan, dichloromethane, ethylene dichloride, chlorofonolem, N, N-dimethylformamide, N, N-dimethylacetamide Perform in a solvent or any other organic solvent that does not adversely affect the reaction.

Of these solvents, hydrophilic solvents may be used as a mixture with water.

The reaction temperature is not particularly limited, but the reaction is usually performed without cooling or heating.

(i i) In case of reduction:

The reduction is carried out by standard methods including chemical reduction and catalytic reduction.

1

Suitable reducing agents to be used for chemical reduction are metals (eg, tin, zinc, iron, etc.) or metal compounds (eg, chlorides). Chromium, chromium acetate, etc.) and organic or inorganic acids (for example, formic acid, acetic acid, propionic acid, trifluoric acid, P-toluenesulfonic acid, hydrochloric acid, bromide) Hydrogen acid, etc.).

Suitable catalysts to be used for the catalytic reduction are platinum catalysts (for example, platinum plate, spongy platinum, platinum black, platinum in the form of colloid, platinum oxide, platinum wire, etc.), palladium catalysts (such as For example, spongy palladium, palladium black, palladium oxide, phosphorus, ^0- radio charcoal, colloidal palladium, palladium palladium sulfate, palladium palladium carbonate, etc. ), Nickel catalysts (for example, reduced nickel, nickel oxide, Raney 12), cobalt catalysts (for example, reduced cobalt, Ranekobalt, etc.), Conventional catalysts such as copper catalysts (eg, reduced copper, Raney copper, Ullman copper) and iron catalysts (eg, reduced iron, Raney iron, Ullman iron).

This reduction is usually carried out with water, methanol, ethanol, prono, and so on. Performed in conventional solvents that do not adversely affect the reaction, such as phenolic, N, N—dimethinolehonoleamide, dimethyl ether, dioxane, tetrahydrofuran, and mixtures thereof. I do.

The reaction temperature for this reduction is not particularly limited, but usually the reaction is carried out without cooling or heating. Manufacturing method (6)

Compound (Ih) or a salt thereof can be produced by subjecting compound (Ig) or a salt thereof to an oxidation reaction.

Oxidation is carried out according to a conventional method. Suitable oxidizing agents include dimethinoles norrexide and N, N, -dicyclohexylcarbodiimide, lower alkanoic anhydrides (eg, anhydrous acetic acid), and the like. Pentoxide, sulfur trioxide pyridin, N-nitrosuccinimide (for example, N-chlorosuccinimide), oxalyl chloride, etc. Combinations.

The reaction is carried out in the presence of an acid.

Suitable acids include organic acids (eg, formic acid, sulfuric acid, propionic acid, dichloroacetic acid, trifluoroacetic acid, etc.) and inorganic acids (eg, hydrochloric acid) , Hydrobromic acid, phosphoric acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.).

The reaction may be an alkali metal (for example, sodium, potassium hydroxide), an alkali metal hydroxide (for example, sodium hydroxide, potassium hydroxide, etc.). ), Alkaline metal bicarbonates (eg, sodium bicarbonate, potassium bicarbonate), alkaline metal bicarbonates (eg, sodium carbonate, potassium carbonate, etc.) ), Tri-lower alkylamines (for example, trimethylamine, triethylamine, diisopropinoleamine, etc.), alkali metal hydrides (for example, hydrogenated Aluminum, etc.), Alkali metal lower-grade alkoxy (for example, sodium methoxide, sodium ethoxy) ), Pyridines (eg, pyridin, norethidin, picolin, dimethylaminopyridine), N—lower alkynole The reaction may be performed in the presence of an inorganic base or an organic base such as phosphorus, N, N—di-lower phenol benzoylamin, and N, N—di-lower alkylanilin. .

When the base, acid and / or starting compound are in liquid form, they can also be used as solvents.

This reaction is usually carried out in water, alcohol (for example, methanol, ethanol, etc.), benzene, N, N-dimethyl-honolemamide, tetrahydro. Solvents such as Drofuran, Toluene, Methylene Chloride, Ethylene Dichloride, Chlorohonolem, Dioxan, and Jethyl Ether, and adversely affect other reactions Not performed in any solvent. These conventional solvents may be used by mixing with water.

Manufacturing method (A)

Compound (IIb) or a salt thereof can be produced by reacting compound (V) or a salt thereof with compound (VI) or a salt thereof.

The reaction is usually carried out with water, ethanol (for example, methanol, ethanol, ethanol), tetrahydrofuran, zeolite, etc. Conventional solvents such as xan, black formaldehyde, methylene chloride, dimethyl acetate amide, N, N-dimethylformamide, and other adverse effects on the reaction Perform in any organic solvent that does not. Of these solvents, hydrophilic solvents may be used by mixing with water.

The reaction temperature is not particularly limited, but usually the reaction is performed without cooling or heating.

Manufacturing method (B)

Compound (IId) or a salt thereof can be produced by reacting compound (IIc) or a salt thereof with compound (VII) or a salt thereof.

The reaction is usually alcohol (for example, methanol, ethanol, ethylene glycol, etc.), chlorophonolem, ethereal, tetrahydro. The reaction is carried out in a conventional solvent such as drofuran, benzene, and acetate, or any other organic solvent that does not adversely influence the reaction.

Reactions include alkali metal hydroxides, alkali metal carbonates, alkali metal carbonates, alkali metal acetates, tri (lower) alkylamines, pyridines, and lutidines. Inorganic bases such as, picolin, dimethylaminopyrrolidine, N-lower alkyl morpholine, N, N-di-lower alkylbenzilamin, N, N-di-lower alkyl aniline Can be performed even in the presence of an organic base. When the base and / or the starting compound are liquid, they can be used as a solvent. Manufacturing method (C)

Compound (IIe) or a salt thereof is compound (IId) Alternatively, it can be produced by subjecting the salt to a reduction reaction. The reduction is carried out in accordance with the usual methods of reducing pyridin rings to 1,2,5,6—tetrahydropyridinine rings, including chemical and catalytic reductions. Do

Suitable reducing agents to be used for chemical reduction are hydrides (eg, hydrogen iodide, hydrogen sulfide, aluminum hydride, sodium borohydride, etc.) or Metals (for example, tin, zinc, iron, etc.) or metal compounds, substances (for example, chromium chloride, chromium acetate, etc.) and organic or inorganic acids (for example, formic acid, Combination with acetic acid, propionic acid, trifluoroacetic acid, P-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.).

Suitable catalysts to be used for catalytic reduction are platinum catalysts (for example, platinum plate, spongy platinum, platinum black, platinum-like platinum, platinum oxide, platinum wire, etc.), palladium catalysts (for example, Spongy palladium, no, .radium black, no oxide, ⁰ radium, no, .radiodium charcoal, colloidal palladium, no, .radiodium / sulphate Nickel catalysts (for example, reduced nickel, nickel oxide, Rane-122), and cobalt catalysts (for example, radium barium carbonate). For example, reduced cobalt, Ranekobalt, etc., iron catalysts (eg, reduced iron, Raney iron, etc.), copper catalysts (eg, reduced copper, Raney copper, Ullman copper, etc.) It is a common practice.

Reduction is usually carried out with water, alcohol (for example, methanol, ethanol, etc.), N, N-dimethylthionoremamine. The reaction is carried out in a conventional solvent such as tetrahydrofuran, a mixture thereof, or any other solvent that does not adversely influence the reaction. Among these solvents, a hydrophilic solvent may be used by mixing with water.

When the above-mentioned acids to be used for chemical reduction are liquid, they can be used as a solvent.

The reaction temperature for this reduction is not particularly limited, but usually the reaction is carried out without cooling or heating.

Manufacturing method (D)

Compound (IXa) or a salt thereof can be produced by reacting compound (V) or a salt thereof with compound (X) or a salt thereof.

This reaction can be carried out by the method disclosed in Production Example 7 or a method analogous thereto.

Manufacturing method (E) -①

The compound (XII) or a salt thereof can be produced by reacting the compound (IXb) or a salt thereof with the compound (XI) or a salt thereof.

This reaction can be carried out by the method disclosed in Production Example 8 or a method analogous thereto.

Manufacturing method (E) -②

Compound (XIII) or a salt thereof can be produced by subjecting compound (XII) or a salt thereof to a reduction reaction.

This reaction can be carried out by the method disclosed in Production Example 9 or a method analogous thereto. Manufacturing method (F) -①

Compound (XVI) or a salt thereof can be produced by reacting compound (XIV) or a salt thereof with compound (XV) or a salt thereof.

This reaction can be carried out by the method disclosed in Production Example 11 or a method analogous thereto.

Manufacturing method (F) -②

Compound (XVI) or a salt thereof can be produced by subjecting compound (XVI) or a salt thereof to a reduction reaction.

This reaction can be carried out by the method disclosed in Production Example 12 or a method analogous thereto.

Manufacturing method (G)

The compound (VIII) or a salt thereof can be produced by reacting the compound (XVII) or a salt thereof with the compound (XIX) or a salt thereof.

This reaction can be carried out by the method disclosed in Production Example 17 or a method analogous thereto.

Manufacturing method (H)

The compound (VIII) or a salt thereof can be produced by reacting the compound (XXIII) or a salt thereof with the compound (XX) or a salt thereof.

This reaction can be carried out by the method disclosed in Production Example 19 or a method analogous thereto.

Manufacturing method (I)

Compound (VIIIa) or a salt thereof is compound (II) It can be produced by reacting Ia) or a salt thereof with compound (XXI).

This reaction can be carried out by the method disclosed in Production Example 20 or a method analogous thereto.

Suitable salts of the target compound and the starting compound in the methods (1) to (6) and (I) to (I) include those exemplified for the compound (I). Preferred specific examples of the target compound (I) are as follows.

M is the formula:

R 丄

(Wherein R ¹ is hydrogen; lower alkyl; contains 1 to 4 nitrogen atoms, and is selected from the group consisting of lower alkyl, lower alkoxy, nitro, and halogen) Unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heterocyclic ring which may have 3 (more preferably 1 or 2) substituents Base

[Preferably, pyridyl or lower alkyltetrahydropyridyl]; or lower alkyl, lower alkoxy, acylamino, lower alkylthio, halogenogen, etc. 1 to 3 (more preferably 1 or 2) substituents selected from the group consisting of Preference is given to phenyl, lower alkylphenol, mono (or di) lower phenolic phenyl, halophenyl. Two-way, two-way phenyl, lower phenol, lower phenol, or lower alkanoinorea phenyl).

R ² is hydrogen; lower alkyl; contains 1 to 4 nitrogen atoms, and is selected from ^ consisting of lower alkyl, lower alkoxy, nitro and halogen. 3 to 8 (more preferably 5 or 6 members) which may have 1 to 3 (more preferably 1 or 2) substituents Heterocyclic groups [preferably pyridyl or lower phenol] or lower alkyl, lower alkyl, lower alkoxy, acylamino, halo A phenyl which may have from 1 to 3 (more preferably 1 or 2) substituents selected from the group consisting of gen and ditoxin [ Or more preferably phenyl, ditrophenyl, or lower alkoxyphenyl) or

R ¹ and R 2 combine with each other to form

Forming a group of

Z represents S or 0, respectively) or a group represented by

Expression:

(Wherein R ¹ and R ² are each as defined above),

W is a bond, lower alkylene or lower alkylene,

Y is lower alkylene,

-H-, one C one

0

formula

Wherein R is hydrogen or lower alkyl, or a group of the formula:

Where R 'is a hydroxy or protected hydroxy [more preferably an acyloxy, particularly preferably a lower alkanoinoleoxy]. Yes, A is a bond or lower alkylene,

Q is the formula:

(Wherein R ⁸ is a lower alkyl group, and R ⁹ is an al (lower) alkyl group [more preferably, a lower alkyl group, particularly preferably a lower alkyl group]. Or a group of the formula:

(In the formula, R ⁴ is lower alkyl, or an optionally substituted alkyl (lower) alkyl [preferably lower alkyl, lower alkoxy, lower alkylthio, 1-3 selected from the group consisting of halogen and nitro

(More preferably one or two) but also phenyl (lower) alkyl; particularly preferably benzyl or halobendinole). It is a group of

The target compound (I) of the present invention and a pharmaceutically acceptable salt thereof have strong acetylethylcholinesterase inhibitory activity, but almost no inhibitory activity against butyrinolecholinesterase. Not shown. That is, the target compound of the present invention

(I) and its pharmaceutically acceptable salts are selective inhibitors of acetylcholinesterase and are therefore amnestic, dementia (eg Alzheimer's senile) dementia, It is useful for the treatment of central nervous system diseases such as vascular dementia and cerebrovascular disease.

The pharmacological test data of the compound (I) are shown below to show the usefulness of the compound (I).

In the following tests, “Example 2 — (1)” means the compound produced in Example 2 — (1).

[A] Inhibition of acetate cholesterol esterase

(I) Test method:

The acetylcholinesterase inhibitory effect was measured by the method (enzyme analysis method) described in C 1 inica Chimica Acta, 115 (1 1981) 163-170. . The acetylcholinesterase used in this study was obtained from rat striatum.

(I I) Test results:

The target compound (I) or a pharmaceutically acceptable salt thereof is generally used in mammals including humans in conventional pharmaceutical preparations, for example, capsules, microcapsules, tablets, granules, and powders. It is administered in the form of, for example, troches, syrups, aerosols, inhalants, solutions, injections, emollients, and emulsions.

The pharmaceutical composition of the present invention is commonly used for pharmaceutical use. Various organic or inorganic carriers, such as excipients (eg, sucrose, starch, mannitol, sonoleitol, lactose, glucose, cellulose) , Tanolek, phosphoric acid phosphate, calcium carbonate, etc.), binders (for example, cellulose, methyl phenol resin, hydroxypropyl phenol resin, poly lipase) Lopinole pyrrolidone, gelatin, arabia rubber, polyethylene glycol, sucrose, starch, etc.), disintegrants (for example, sucrose, canoleboxime tylsenorreose, cal Calcium salt of boxymethyl cellulose, hydroxypropyl mouth pinorestat, sodium glycol starch, sodium bicarbonate, potassium phosphate, Calcium citrate ), Lubricants (for example, magnesium stearate, tanolek, sodium laurenole sulfate), and flavoring agents (for example, quinone). Acids, menthol, glycin, orange powder, etc.), preservatives (eg sodium benzoate, sodium bisulfite, methylparaben, propylparaben) ), Stabilizing agents (for example, citric acid, sodium citrate, drunkic acid, etc.), emollients (for example, methylcellulose, polyvinylpyrrole) Lordon, aluminum stearate, etc.), dispersants, aqueous diluents (eg, water), base mixes (eg, cocoa butter, polyethylate) Lengkoll, white petrolatum, etc.) may be blended.

In general, a single dose of 0.0 lmg / kg to 10 mg / kg of active ingredient should be administered 1 to 4 times a day, but the age, weight, condition or administration of the patient Depending on the method The amount may be increased or decreased.

The following Production Examples and Examples have been set forth to illustrate the invention. Production Example 1

(1) Bromine (4.0 mL) was added to a solution of 3-propioninolepyridine (10 g) in a clonominal honolem (10 O mL) solution at room temperature for 15 minutes, and this mixture was added. Is heated under reflux for 6 hours. After cooling, the mixture was evaporated under reduced pressure, and the residue was dissolved in N, N-dimethylformamide (5 ml), and the mixture was mixed with ethynole = 2—amino2—thioxacetate. (14.8 g). The mixture is stirred and heated at 100 for 30 minutes. After cooling, the mixture is poured into water, washed with ethyl acetate, adjusted to pH 8.0 with an aqueous solution of potassium carbonate, and extracted with ethyl acetate. The exudate is dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was recrystallized from ether to give 2-ethoxycarbonyl.

5 — Methanol 4 1 (Pyridine 1 3 — Tinole) Thiazole

(5.38 g).

mp: 71-72 ° C

IR (nuclear) = 1700, 1590, 1565 cm ^-1

NMR (CDCln, δ): 1.37 (3Η, t, J = 7.2Hz), 2.67 (3H, s), 4.9 (2H, q, J = 7.2Hz), 7.39 (1H, dd, J = 4.8) ,

7.9Hz), 8.04 (1H, d, J = 7.9Hz), 8.62 (1H, d,

J = 4.8Hz), 8.90 (1H, s)

Elemental analysis: As C ₁₂ H ₁₂ N ゥ 0 ₂ S Calculated value: C 58.04, H 4.87, N 11.28 Actual value: C 58.01, H 4.57, N 11.16 Production Example 11 The following compound is obtained in the same manner as in (1). (2) 2 —Ethoxy phenol (4-pyridine) thiazole mp: 65-66 ° C

1

IR (Nujiol): 1725, 1590, 1570 cm '

NR (CDCI3.δ-): 1.47 (3Η, t, J = 7.1Hz), 4.52 (2H, q, J = 7.1Hz), 7.37 (1H, dd, J = 5.0, 8.ORz), 7.87 (lH , s), 8.29 (1H, d, J = 8.0Hz), 8.61 (lH, d,

J = 5.0Hz), 9.15 (1H, s)

Mass (M / Z) ': 234 (+) Elemental analysis: as the _{_{_{_{C n H 1Q N 2 0 2}}}} S

Calculated value: C 56.39, H 4.30, N 11.95 Actual value: C 56.15, H 4.26, N 12.03 Production example 2

(1) 2 — Ethanol boninole 5 — Methylenol 41 (pyridin 13 — yl) Acetate of thiazole (1,0 g) and methyl iodide The solution is stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue was recrystallized from ether to give 2 — ethoxy oleponinole 4-1 (1-methyl-3-pyridinio) 1-5-methinorethazole. 1 g (1.2 g) is obtained.

mp: 208-209 ° C (decomposition)

IR (Nudiyol): 1720, 1640, 1495 cm- ¹ _{NMR (DMSO-d 6, a} ): 1.35 (3H, t, J = 7.1H z), 2.79 (3H, s), 4.42 (2H, q, J = 7.1Hz), 4.47 (3H, s),

8.26 (1H, dd, J = 6.0, 8.2Hz), 8.87 (1H, d,

.. J = 8.2Hz), 9.05 (1H, d J = 6 OHz), 9.34 (lH, s) Elemental _{_{_{analysis: C 13 H 15 IN 2 0}}} . As S

Calculated value: C 40.01, H 3.87, N 7.18 Actual value: C 40.10, H 3.80, N 6.94 Production example 2 — The following compound is obtained in the same manner as (1).

(2) 2 — Ethanol

3-pyridinio) thiazole. Mp: 151-153. C (decomposition)

IR (Nudiol): · '1730, 1630, 1590, 1520 cm ^-1

_{NMR (DMS0-d 6, δ} ~): 1.38 (3Η, t, J = 7.1Hz), 4.45 (2H, q, J = 7.1Hz), 4.47 (3H, s), 8.25 (1H, dd,

J = 6.1, 8.2Hz). 8.97 (lH, s), 9.02 (1H, d,

J = 6.1Hz), 9.10 (1H, d, J = 8.2Hz), 9.61 (1H, s) Elemental analysis: As C ₁₂ H ₁₃ IN ₂₀ _o S

Calculated value: C 38.31, H 3.48, N 7.45 Actual value: C 38.39, H 3.38, N 7.08 Production Example 3

2 —Ethoxy boninole 4 1 (1 methinole 3 — pyridinone) 1 5 — methane thiazolone phenol (1.0 g) 5 ml)-Cool the water (8 ml) solution to 0 ° C and stir. Sodium borohydride (0.19 g) is added over 30 minutes. Mix the mixture for another 30 minutes After stirring for 10 minutes, 10% hydrochloric acid (15 ml) is added thereto. Adjust the pH of the mixture to 10.5 with an aqueous solution of potassium carbonate, and extract with ethyl acetate (50 ml). The exudate is washed with water and brine, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure to give 2-ethoxycarbonyl 2- (1-methylethylene 1,2,5). , 6-Tetrahydroxypyridine 3-Inole)-1-5-Methinolethiazonole (0.6 g) as an oil.

IR (thin layer): 1705, 1510 era- ¹

_{NMR (CDC1 3,): 1.42} (3H, t, J = 7 · 1 Hz), 2.40-2.45

(2H, m), 2.47 (3H, s), 2.57 (3H, s), 2.59-2.67

(2H, m), 3.34-3.38 (2H, m), 4.44 (2H, q,

J = 7.1Hz), 5.95-6.01 (1H, m)

Mass (M / Z): 266 (M ⁺ )

Production Example 4

2 — Ethanol (14-ml) (1-methino 3-pyridinio) thiazolone chloride (3.0 g) of methanol (30 ml) — Cool the water (15 ml) solution to 0 ° C and stir. Sodium borohydride (0.6 g) is added over 30 minutes. After the mixture was stirred for another 30 minutes, 10% hydrochloric acid (10 ml) was added thereto. The mixture was adjusted to pH 0.0 with an aqueous solution of potassium carbonate, and extracted with ethyl acetate (50 ml). The extract was washed with water and brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give 2-methyl carbonyl. 1,2,5,6—Tetrahydropyridine-1 3—inole) thiazole (0.9 g) is obtained. mp: 83—84 ° C

IR (Nudiol): 3200, 1725 era " ¹ NR (CDCl, ^): 2.40-2.45 (2H, m), 2.47 (3H, s),

2.59 (2H, t, J = 5.2Hz), 3.50 (2H, ID), 4.01 (3H, s), 6.76 (1H, m), 7.29 (1H, s)

Mass (M / Z): 238 (M +) Elemental analysis: as a _{_{_{_{C u H 14 N 2 0 2}}}} S

Calculated values: C 55.44, H 5.92, N 11.75

Found: C 55.18, H 5.98, N 11.61

Production Example 5

(1) To a solution of 4,1-closed propiovanonone (5.43 g) in methylene chloride (50 ml) was added pyridinium hydrobromide perbromide (1). 0.3 g) and 30% hydrogen bromide acetic acid (5 ml) are added at room temperature. After 2 hours, pour the mixture into ice water. The organic layer is separated, washed with water, saturated sodium hydrogen carbonate solution and brine, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was dissolved in N, N-dimethylformamide (5 ml), and the solution was mixed with ethynole = 2—amino-2—thioxoacetate (2.76 g) ). Heat the mixture at 60 ° C for 2 hours. After cooling, pour the mixture into water and extract with ethyl acetate. The extract is dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is chromatographed on silica gel and chromatographed. Eluted with L-methanol (98: 2), and eluted with 41- (41-cloth phenol) 12-ethoxycarbinole 5-methylthiazole (1 98 g).

IR (thin layer): 1720 cm— ¹ NMR (CDCI3.δ ') ^: 1.43 (3Η, t, J = 7.1 Hz), 2.62 (3H, s), 4.7 (2H, q, J = 7.1 Hz) , 7.41 (2H, d,

J = 8.7Hz), 7.61 (2H, d, J = 8.7Hz)

Mass (m / z): 281 (M + of free compound) Production Example 5 — The following compound is obtained in the same manner as (1).

(2) 2 — Ethoxylane Boninole 1 _ (2 — Ethanol) 5 — Methinolethiazol

IR (thin layer): 1710 cm ^-1

NMR (CDCI3, ^): 1.41 (3H, t, J = 7.2Hz), 2.38 (3H, s), 3.79 (3H, s), 4.46 (2H, q, J = 7.2Hz), 6.96

(1H, d, J = 8.0Hz), 7.03 (1H, d, J = 7.4Hz), 7.33-

7.41 (2H, m)

Mass (m / z): 277 (M ⁺ )

(3) 2 — Ethoxy cane Boninole 5 — Methinole 4 1

(412 Trofe Ninore) Chia Zol mp: 109-lil

IR: 1730, 1600 cm " ¹

NMR (DMS0-d ₆ , 5 ·): 1.36 (3H, t, J = 7.1 Hz), 2.72 (3H, s), 4.40 (2H, q, J = 7.1 Hz), 7.99 (2H, d,

J = 9.0Hz), 8.33 (2H , d, J = 9.0Hz) Elemental analysis: as the _{_{_{_{C 13 H 12 N 2 0 4}}}} S Calculated value: C 53.41, H 4.13, N 9.58 Actual value: C 53.50, H 3.98, N 9.53

Mass (m / z): 292 (M ⁺ )

(4) Ethanol Cannole Poninole 41 (4-Metnole Feninole) 1 5-Mett Norrethia Zonore

IR (thin layer): 1700 cm— ¹

_{NMR (CDC1 3 δ-.):} 1.43 (3Η, t, J = 7.1Hz), 2.39 (3H, s), 2.62 (3H, s), 4.47 (2H, q, J = 7.1Hz), 7.24

(2H, d, J = 7.4Hz), 7.55 (2H, d, J = 7.4Hz)

Mass (m / z): 261 (M ⁺ )

(5) 2 —Ethoxy boninone 4 — (4-Acetylaminophenol) — 5 —Methyltiazole Rap: 186-188 ° C

IR (Nudiol): 3450, 1710, 1680, 1590 cm ^-1

NMR (DMS0-d _fi , δ ~) 1.34 (3Η, t, J = 7.1Hz), 2.08

(3H, s), 2.63 (3H, s), 4.37 (2H, q, J = 7-1Hz),

.7.61 (2H, d, J = 6.7Hz), 7.71 (2H, d, J = 6.7Hz)

10.10 (1H, s)

Mass (m / z): 304 ( ⁺ )

(6) 2 —Ethoxy cane Poninole 4 1 (3—Methoxy feni 2) 1 5 —Metinolethia zole rap: 70-72 ° C 'IR (Nudiyol): 1730, 1600 cm ^-1

NMR (CDCl, 5 ·): 1.43 (3H, t, J = 7, 1Hz), 2.62 (3H, s), 3.85 (3H, s), 4.43 (2H, q, J = 7.1Hz), 6.89- 6.95 (IH, m), 7.19-7.39 (3H, m)

Mass (m / z): 277 (M ⁺ )

(7) 2—Ethoxy boninole 5 and 6—Jihdro

4 H — benzo [6,7] cyclohepta [1,2—d] thiazole

IR (thin layer): 1730 cm " ¹

NMR (CDCl, ^): 1.45 (3H, t, J = 7.1Hz), 2.22-2.36

(2H, m), 2.70-2.85 (2H, in), 2.92-3.07 (2H, m),

4.48 (2H, q, J = 7.1Hz), 7.20-7.38 (3H, m),

7.96-8.01 (IH, m)

Mass (ra / z): 273 (M ⁺ )

(8) 2 — Ethoxy Canole Boninole

IM thin layer): 1710 cm ^-1

_{NMR (CDC1 3,): 1.46} (3H, t, J = 7.1 H z), 4.50 (2H, q, J = 7.1Hz), 7.33-7.50 (3H, m), 7.74 (lH, s),

7.92-7.98 (2H, m)

Mass (m / z): 233 (M ⁺ )

Production Example 6 Production Example 11 The following compounds are obtained in the same manner as in (1) and (5). 2 — ethoxycarbone 4 1 (3,4-methoxin) 1 5 — methinoretia

mp: 93-94 "C

IR (Nudiyol): 1710, 1600, 1590 cm— ¹

NMR (CDCl, ^): 1.44 (3H, t, J = 7.1 Hz), 2.62 (3H, s), 3.93 (3H, s), 3.94 (3H, s), 4.47 (2H, q, J = 7.1 Hz), 6.92 (1H, d, J = 8.5Hz), 7.15 (lH, d,

J = 8.5Hz), 7.24 (1H, s)

Mass (m / z): 307 ( ⁺ )

Production Example 7

N, N-dimensions of (2—bromopropioninole) benzene (8.1 g) and 2,2—di (methoxy) thioacetamide (10.28 g) Heat the mixture in Chinole Honoremamide (25 ml) at 50 ° C for 30 minutes. Then the mixture is poured into water, extracted with ethyl acetate and concentrated under reduced pressure. The residue is dissolved in a mixture of concentrated sulfuric acid (0.5 ml) and acetate (50 ml). After stirring this solution for 30 minutes, it is subjected to an evaporation operation under reduced pressure, and is extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was chromatographed on silica gel and eluted with chloroform, and 2-honoleminole 5-methylenol 4-phenylthiazole (2.7 g). Rap: 47-48 ° C

IR (Nudiyol;): 1670 cm ^-1

_{NR (CDC1 3, ^):} 2.68 (3H, s), 7.37-7.54 (3H, m), 7.65-7.70 (2H, m), 9.96 (1H, s)

Mass (m / z): 203 (M ⁺ ) Elemental analysis: CnHgNOS · 0.1H

Calculated value: C 64.43, H 4.52, N 6.83 Actual value: C 64.55, H 4.38, N 6.82 Production example 8

2—Honore Minole 5—Methinole 4

(1.0 g), malonic acid (2.05 g) and a mixture of piberidine (0.24 ml) in pyridine (10 ml).

Reflux for 1 hour. After cooling, the mixture is evaporated under reduced pressure, acidified with 10% hydrochloric acid, and extracted with ethyl acetate. The extract is washed successively with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was pulverized with ether, and 2-[(E) 12-Karboki Shetenil] 14-4-phenylene 5-methinorethiazolone (0.68 g) Get. mp: 211-213 ° C

IR: 1680, 1620 cm "" 丄

NMR (DMS0-d ₆ , ^): 2.60 (3H, s), 6.61 (lH, d,

J = 15.8Hz), 7.37-7.72 (6H, m), 12.78 (1H, s) Mass (m / z): 245 (M ⁺ ) Production Example 9

2 — [(E) 1 2 — Power Revolving Sheeninore] 1-4 Phenolinole 5 — Methinorethia sonole (0.7 g) and palladium hydroxide (II) (0.15 g) The mixture in tetrahydrofuran (15 ml) is hydrogenated at normal pressure for 8 hours. The palladium hydroxide (II) is removed, and the solution is concentrated under reduced pressure. The obtained precipitate is washed with ether to obtain 2- (2-canolepoxytinole) -141-phen-2-ole-5-methinoretia-zinole (0.7 g).

mp: 172-174 ° C

IR (thin layer): 3460, 1720 cm ¹

NMR (DMS0-d ₆ , ^): 2.51 (3H, s), 2.78 (2H, t,

J = 7.1Hz), 3.25 (2H „t, J = 7.1Hz), 7.36-7.53

(3H, ra), 7.64-7.69 (2H, m)

Mass (m / z): 247 (M ⁺ ) Production Example 10

(1) A solution of Shionodani Snorreflefinolole (3.33 ml) in methylene chloride (5 ml) was prepared by adding 3-acetylmethylinolepyridine (5.60 g) in methylene chloride. (50 ml) at room temperature. After stirring the mixture for 2 hours, it is subjected to evaporation under reduced pressure. Residue and ethyl = 2—A mixture of amino 2-thioxacetate (6.622) in ^ [, N-dimethyl honoleamide (5 ml) was added to 10 ml. Stir at 0 ° C for 1 hour. The mixture is cooled to room temperature, poured into water, adjusted to pH 9.5 with an aqueous solution of potassium carbonate, and extracted with ethyl acetate. Extraction The product is washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was applied to silica gel chromatography and eluted with a black hole form, and 2-ethoxy carbonyl resin 4-methino resin 5-(pyridine (1) Preparation of thiazole (2.7 g). mp: 67—69 ° C

IR (Nujol): 1740, 1580, 1560 cm ^-1

NMR (CDC1.3.): 4.44 (3H, t, J = 7.1 Hz), 2.61 (3H, s), 4.51 (2H, q, J = 7.1Hz), 7.45 (1H, ddd, J = 0.8,

4.8, 8.0Hz), 7.83 (1H, ddd, J = 0.8, 8.0Hz),

8.67 (1H, dd, J = 0.8, 4.8Hz), 8.77 (1H, dd,

(J = 0.8, 0.8Hz)

Mass (m / z): 248 (M ⁺ ) Elemental analysis: As C ₁₂ H ₁₂ N ₂₀ oS

Calculated value: C 58.04, H 4.87, N 11.28 Actual value: C 57.11, H 4.87, N 11.29

The following compounds were obtained in the same manner as in Production Example 10 — (1).

(2) 2 — Ethanol boninole 5 — (4 — menthol) 1 -4 Methyl thiazolone mp: 55-56 "C

IR: 1720, 1600 cm- ¹

NMR (CDC1 ゥ,): 1.44 (3H, t, J = 7.1 Hz), 2.57 (3H, s), 3.86 (3H, s), 4.52 (2H, q, J = 7.1 Hz), 6.97

(2H, d, J = 10.3Hz), 7.0 (2H, d, J = 10.3Hz) Production example 1 1

2 — ethoxy canoleboninole 4 — methinolate 5 — (pyridin 3 — yl) thiazone (2. O g) and methyl iodide (1.26 g) in acetone ( After stirring the solution at room temperature overnight, it is concentrated under reduced pressure. The residue was recrystallized from ether acetate to give 2-ethoxycarbonyl-4-methyl-5-(1-methoxy-13-pyridinio) thiazole. 26 g) are obtained. mp: 209-210'C

IR (Nudiol): 1720, 1640, 1500 cm ¹

_{NMR (DMS0-d 6, S} ): 1.36 (3H, t, J = 7 · OH z), 2.60 (3H, s), 4.43 (2H, q, J = 7.0Hz), 4.45 (3H, s),

8.29 (1H, dd, J = 6.0, 8.0Hz), 8.81 (1H, d,

J = 8.0Hz), 9.09 (1H, d, J = 6.0Hz), 9.36 (1H, s) Production example 1 2

2—Ethoxy bonole 1-Metinole 5- (1—Methinole 3—Pyrigino) Chia zonole horde (1.0 g) 5 ml) — To the solution of water (8 ml), add sodium borohydride (0.2 g) at 0 ° C for 30 minutes. After stirring the mixture for 30 minutes, 10% hydrochloric acid was added.

(10 ml) and then with an aqueous solution of potassium carbonate.

Adjust to 9.5 and exude with ethyl acetate. The extract is washed successively with water and saline, dried over magnesium sulfate, concentrated under reduced pressure, and concentrated to 2-ethoxycarbonyl 2-4-methyl-5-(1-methyltinole 1, 2, 5 , 6 — Tetrahidori Gin-3- (inole) thiazole (0.6 g) is obtained as an oil.

NMR. (CDCU): 4.42 (3H, t, J = 7.1 Hz), 2.44 (3H, s), 2.47 (3H, s), 2.53 (2H, s). 2.60 (2H, t, J = 5.3Hz) ), 3.17 (2H, dd, J = 2.6, 4.5Hz), 4.44

(2H, q, J = 7.1Hz), 6.08 (1H, m)

Mass (m / z): 266 ( ⁺ ) Production Example 13

1: Metabolism of 16- (3-cyanopropylidene) pyridin (8.13 g) and diacid platinum (0.8 g) in methanol (16 (0 ml) is hydrogenated at normal pressure for 30 minutes. The catalyst is removed and the liquid is evaporated under reduced pressure. The residue was subjected to silica gel chromatography, eluted with chloroform (98: 2), and purified by chromatography (98: 2). — Inore) Butyronitrile

(7.80 g).

IR (thin layer): 2250 cm ^-1

NMR (CDCI3.δ-): 1.27-1.43 (5H, m), 1.59-1.66 (4H, m), 1.78-2.00 (2H, m), 2.32 (2H, t, J = 7.0Hz), 2.86-2.92 (2H, m), 3.50 (2H, s),

7.20-7.33 (5H, m)

Mass (m / z): 241 (M ⁺ -l) Production Example 14

4 To the solution of butyronitrinole (7.71 g) in tocreene (80 ml) was added. 0.95 M hydrogenated diisobutynoleanolene hexane (35.lml) is added at 160 ° C and the mixture is stirred at room temperature for 1 hour. To this, add a saturated ammonium chloride solution (100 ml). After stirring the mixture for 1 hour, 5% sulfuric acid (1.50 ml) is added. The aqueous layer is separated, made basic with saturated aqueous solution of potassium carbonate, and extracted with ethyl acetate. The extract is washed with water and brine, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure to obtain 0.41- (1-benzyldipyridine-141-yl) butanal. (4.70 g) as an oil.

IR (thin layer): 1720 era " ¹

_{NMR (CDC1 3, ^):} 1.25 - 1.28 (6H, m), 1.56-1.67

(4H, m), 1.88-1.93 (2H, m), 2.37-2.48 (1H, m),

2.85-2.91 (2H, m), 3.49 (2H, s), 7.19-7.32 (5H, m), 9.74-9.76 (lH, ra)

Mass (m / z): 244 (M ⁺ -l) Production Example 15

4 (1: N-N-pyrrolidine) 4-butanol (4.66 g), cyanated trimethylen-silyl (3.04 ml) and yo Stir the mixture of zinc iodide (100 mg) at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in a mixture of 10% hydrochloric acid (30 ml) and acetone (15 ml). After stirring this solution for 1 hour, make it basic with saturated potassium carbonate solution and extract with ethyl acetate. The extract is washed with water and saline, and dried over magnesium sulfate Then, the solvent is distilled off under reduced pressure. The residue was recrystallized from hexane to give 5-(1-1-biperidine-14-inole)-1-2-hydroxypentannitrinole (3.9 0 g). mp: 92-94 ° C

IR (nujile): 3400 cm " ¹

_{NMR (CDC1 3 δ-.):} 1.26-1.32 (5Η, m), 1.47-1.50

(2H, m), 1.64-1.83 (4H, m), 1.92-2.02 (211, m),

2.89-2.94 (2H, m), 3.52 (2H, s), 4.35 (lH, t,

J = 6.6Hz), 7.19-7.41 (5H, m)

FAB Mass: 273 (M ⁺ + l) Production Example 16

5 — (1 Benzinole perylene resin) 1 2 — Hydroxypentane 2 Trinole (3.77 g) and Triethylamine ( A solution of acetyl chloride (1.18 m1) in methylene chloride (5 ml) was added dropwise to the mixture in 2.31 ml) in methylene chloride (40 ml) at 0 ° C. . The mixture is stirred at room temperature for 1 hour, and water is added thereto. The mixture was extracted with methylene chloride, and the exudate was washed with water and brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give 2-acetoxy. -5-(1-Penzinole biperidine 14-yl) Pentane ditrinole (3.50 g) is obtained as an oil.

IR (thin layer): 1750 cm

NMR (one CDC,): 1.24-1.31 (5H, m), 1.42-1.66

(4H, m), 1.82-1.98 (4H, m), 2.13 (3H, s), 2.85- 2.90 (2H, m), 3.8 (2H, s), 5.31 (1H, t,

J = 6.7Hz), 7.19-7.41 (5H, m)

Mass (m / z): 314 (M ⁺ ) Production example 1 7 2 — Acetoxy 5 — (1-Penzinole biperidine-1 4-inole) A mixture of ethanol (3.33 g) and triethylamine (20 ml) in ethanol (40 ml) was blown with hydrogen sulfide at 5 ° C for 2 hours, and the mixture was cooled to room temperature. Stir for 1 hour. The precipitate is collected, washed with cold ethanol and ether, and then 2-acetate 5-(1-benzene piperidine 14-1-phenol) pen Obtain tanchoamide (2.59 g). mp: 135-137. C

IR (Nujiyoru): 3480, 3130, 1740, 1620 cm -1 NMR (D S0-d 6,): 1.16 - 1.28 (7H, m), 1.56-1.61

(2H, m), 1.70-1.93 (3H, m), 2.08 (3H, m), 2.74-

2.80 (2H, m), 3.31-3.35 (1H, m), 3.42 (2H, s),

5.11 (1H, dd, J = 4.6, 7.8Hz), 7.20-7.39 (5H, ra),

9.19 (1H, s), 9.76 (1H, s)

FAB Mass: 349 (M ⁺ + l) Production Example 18 A solution of thiobenzamide (3.0 g) and ethyl bromopyruvinate (2.7 ml) in ethanol for 2 hours Heat under reflux. After cooling, the mixture is subjected to an evaporation operation, and then ethyl acetate and water are added to the residue to separate layers. Organic layer After washing with sodium chloride solution and drying over magnesium sulfate, the solvent is distilled off under reduced pressure. The residue is subjected to silica gel chromatography, and a mixture of black-holm and methanol is obtained.

Eluted with (98: 2), collect the field containing the target compound, evaporate the solvent, and remove the solvent to form 4-ethoxythiocyanol-poninole 2 -phenylthiazole (3.1 g). As an oil.

IR (thin layer): 1720 cm— ¹

_{NMR (CDC1 3,): 1.434} (3H, t, J = 7 · 1 H z), 4.45 (2H, q, J = 7.1Hz), 7.42-7.49 (3H, m), 7.97-8.06 (2H, m ), 8.16 (1H, s)

Mass (m / z): 233 (M ⁺ )

Production example 1 9

1 Benzinolene 4- (4-cyanobutynole) pyridine (2.0 g) and thioacetamide (1.76 g) in 4N hydrogen chloride-dioxane (20 g) Heat the mixture under reflux for 3 hours. After cooling, the solvent is distilled off under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution is added to the residue, which is extracted with ethyl acetate. The organic layer is washed with water and brine, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was subjected to silica gel chromatography, eluted with a mixture of chloroform and methanol (98: 2), the fraction containing the target compound was collected, and the solvent was removed. Evaporate to give 5 — (1-benzinolepiperidine-14-yl) pentanthioamide (0.8 g).

mp: 124-127. C IR (nuclear): 3200, 1640, 1580 cm ^-1

_{NMR (D S0-d 6,} ^): 1.06 - 1.21 (7H, m), 1.56-1.65 (4H, m), 1.81-2.01 (2H f m), 2.42-2.51 (2H, m),

2.73-2.79 (2H, m), 3.41 (2H, s), 7.17-7.34 (5H _rm )

Mass (m / z): 290 (M ⁺ )

Production Example 20 1 Benzylisothiocyanate (1.27 ml) in acetonitrile (6 ml) solution in a solution of 1-penzinole 41 '(2-amino-etinore) (2.0 g) of acetate (6 m

1) Add the solution at room temperature. After 1 hour, the solvent is distilled off under reduced pressure. Add water and residue and extract with ethyl acetate. The organic layer is washed with water and brine, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. Dissolve the residue in 2.5 N sodium hydroxide (10 ml) and reflux the solution for 30 minutes. After cooling, the mixture is extracted with ethyl acetate, and the organic layer is washed with water and brine, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was subjected to silica gel chromatography and eluted with a mixture of fluorohonolem and methanol (95: 5), and the fraction containing the target compound was collected. Then, the solvent was distilled off, and N— [2— (1—benzylpyridin-1-4-inole) ethyl] thiorea (1.2 g) was obtained as an oil.

IR (thin layer): 3500, 3400, 1600, 1500 cm— ¹

_{NMR (CDC1 3,): 1.21-1.33} (3H, m), 1. 9-1.67 (4H, m), 1.90-2.00 (2H, m), 2.85-2.91 (2H, m),

3.10-3.20 (2H, ra), 3.49 (2H, s), 5.96 (2H, s),

6.48 (lH, m), 7.21-7.32 (5H, ra)

Mass (m / z): 277 ( ⁺ ) Example 1

(1) 4, 5-diphenyl 2-ethoxycanolebonylthiazolone (0.50 g) and 1-benzene (4-amino) The mixture of lysine (0.4, 2 g) is stirred and heated at 100 ° C for 3 hours. After cooling, dissolve this mixture in ethyl acetate and wash with water. The organic layer is separated, and the solvent is distilled off under reduced pressure. The residue was recrystallized from ether to give 4,5-diphenyl-2-4-[{2- (1-pentinylpyridin-1 4-inole) ethynole} * Moi Nore]

(0.32 g). mp: 109-111. C

IR: 3300, 1640 cm " ¹

NMR (CDClg. S): 1.28-1.40 (3H, m), 1.54-1.75 (4H, m), 1.90-2.02 (2H, m), 2.85-2.91 (2H, m)

3.49 (2H, s), 3.5-3.56 (2H, m), 7.23-7.34

(14H, m), 7.45-7.52 (2H, m)

Mass (M / Z): 481 (M +) Elemental analysis: as the C ₃₀ H ₃₁ N ₃ 0S

Calculated value: C 74.81, H 6.48, N 8.72 Observed value: C 74.46, H 6.45, N 8.43 The following compounds are obtained in the same manner as in Example (1). (2) 4, 5-VIS (4-METHOSE)

[I 2-(1; benzene pyridine) 4 ィレ] カ]] チチ

IR (CHCl ^): 3400, 1660, 1600 cm " ¹

_{NMR (CDC1 3, ^) '} ■ 1.30-1. 8 (3H, m), 1.55-1.74

(4H, m), 1.90-2.00 (2H, m), 2.85-2.91 (2H, m),

3.44-3.54 (2H, m), 3.49 (2H, s), 3.82 (3H, s),

3.83 (3H, s), 6.82-6.88 (4H, m), 7.25-7.46

(10H, m)

Mass (M / Z): 541 (M ⁺ )

(3) 4, 5-diphenyl 2-[{2-(1-methylpiperidine 1-4)] chinolepa, moinore] thiazol mp: 85- 87 "C

IR (Nuji Yoru): 3290, 1640 cm— ¹

NMR (CDC, δ-): 1.12-1.37 (3H, m), 1.55-1.62

(2Η, π, 1.73-1.78 (2H, m), 1.86-2.04 (2H, m),

2.26 (3H, s), 2.81-2.87 (2H, m), 3.50 (2H, dd,

J = 7Hz, 14Hz), 7.24-7.35 (9H, m), 7.45-7.52 (2

H, m)

Mass (M / Z): 405 (+) Elemental analysis: as the _{_{_{C 24 H 27 N 3 0S ·}}} 1 / 5H 2 0

Calculated value C 70.77, H 6.81, N 9.80 Observed value: C 70.45, H 6.74, N 10.26 Example 2

(1) 2 _ Ethoxy cane bonole 1-5 — meth oleone 4 (pyridine 1 3 ノレ) thiazo 1 (0.8 g) and 1 benzene 1 44 A mixture of 1- (2-aminoethyl) pyridine (0.84 g) is stirred and heated at 100 ° C for 2 hours. After cooling, the mixture is applied to a column chromatograph using alumina, and eluted with a cross-hole form, and the mixture is eluted with 4- (pyridin-3-inole) -15-me. Chinole 2 — [{2— (1—benzinole piperidin 1-4—innole) echinole} canolenomoinole] thiazole (0.9 g) is obtained as an oil. The compound (0.2 g) was treated with a solution of hydrogen chloride in ethanol, then evaporated under reduced pressure, and the residue was recrystallized from ether to give 41- Gin 1 3 — Innole) 1 5 — Methynole 2-. [{2 — (1 — Penzinole piperidin 1 4 — Innole) etinole} Power Rubamo Innole] Thiazole 2 This gives the hydrochloride (0.12 g).

mp: 135 ° C

NR (DMS0-d _fi , 8 ~): 1. 2-1.76 (5H, m), 1.80-1.92

(2H, m), 2.72 (3H, s), 2.75-3.10 (2H, m), 3.25-

3.35 (4H, m), 4.22 (2H, d, J = 6Hz), 7.43-7.62

(3H, m), 7.60-7.62 (2H, m), 8.04 (1H, dd, J = 5Hz,

8Hz), 8.75 (1H.d, J = 8Hz), 8.87 (1H.d, J = 5Hz),

9.00 (1H, t, J = 7Hz), 9.26 (1H, s)

Mass (M / Z): 420 (M + of free compound) Elemental analysis: C ₂₄ H ₂₈ N ₄₀ S'2HC1 · 3.5 H ₂₀

Calculated value: C 51.79, H 6.70, N 10.06 Observed value: C 51 · 77, H 6.66, N 9.85 Example 2 — The following compounds are obtained in the same manner as (1). (2) 4 — (1-Methinole 1, 2, 5, 6 — Tetrahydropyridine 1 3 — Ino) 2 — [[{2-(1ぺ一一ー 4 ーー 4 ェカ] * * * * * * * * Hydrochloride mp: 158-161 ° C (decomposition)

IR (nujol;): 1660, 1525 cm ^-1

_{NMR (DMS0-d 6, ^} ): 1.44-1.75 (5H, m), 1.80-1.95 (2H, m), 2.52-2.86 (2H, m), 2, 86, 2.88 ( total 3H, s), 3.05 -3.49 (6H, m), 3.70 (2H, s), 3.85-3.95

(1H, m), 4.21, 4.24 (2H, s), 4.34 (1H, s), 6.86

(1H, br), 7.42-7.45 (3H, m), 7.62-7.66 (2H, m),

7.96 (1H, s), 8.87 (1H, t, J = 5.8Hz), 10.99

(lH.br), 11.60 (1H, br)

Mass: 424 ⁽⁺⁾ Elemental analysis: as the _{_{_{C 24 H 32 N 4 0S'2HC1 ·}}} 1 · 3H 2 0

Calculated value: C 55.33, H 7.08, N 10.75 Observed value: C 55.27, H 7.21, N 10.46 (3) 4 — (1-methyl methane 1, 2, 5, 5, 6—tetrahydro pyridine 1-3-レ 5 5 1 — 5-メ 2 2 2 [[I 2-(1 ピレペリリーーレレ} カ) カカ] · 2-hydrochloride mp: 150. C

IR (thin layer): 3400, 1640, 1540 cm " ¹

_{NMR (DMS0-d 6, δ} ~): 1.45 - 1.75 (5H, m), 1.85-1.95 (2H, m), 2.55 (3H, s), 2.70-2.80 (2H, m), 2.84, 2.87 ( total 3H, s), 3 17-'3 49 (6H, m), 3.63 (2H, br), 3.80-3.92 (1H, m), 4.21, 4.23 (f † 2H, s),

4.28-4.36 (1H, m), 6, 28 (1H, br), 7.42-7.46

(3H, m), 7.61-7.64 (2H, m), 8.80 (1H, t,

J = 6Hz), 10.92 (1H, br), 11.51 (lH.br)

Mass (/ Z): 438 Elemental analysis (M + of free compound): © _{"11" 4 4 05 · 2HC1 ·} 0.5C 2 H 5 0H · 1.5H 2 0 and to Calculated: C 55.60, H 7.53, N 9.97 Found: C 55.57, H 7.52, N 9.79

Example 3 (1) 2 — Ethanol Cane Boninole 5 — Methinole 14 1 Fe 2 Norethia Sonole (0.5 g) and 1 Benzinole 4 1 ( A mixture of 2-aminopropyl) pyridine (0.53 g) is stirred and heated at 100 ° C for 1 hour. After cooling, the mixture was subjected to column chromatography on alumina, eluted with chloroform, and then eluted with 4-chlorophenol and 5-methylethylene.

2 — [{2-(1: N-Pin-Pyridine-1 4 -Pin-N-N-N-N-N-N-N-N-N-N-N-N-N-)-N-N-N-N-N-N-N-N] [0.8 g) is obtained. This compound is dissolved in ethanol (5 ml), and maleic acid (0.22 g) is added thereto, followed by stirring for 30 minutes. The solvent was removed under reduced pressure, and the residue was triturated. Ninole 5 — Methinole 2 — [{2 — (1-Penzinole piperidin 1-4 4-inole) echinole} Canoleha * Moinole] Tiazonole maleate (0.40 g). mp: 75 ° C

IR (nuclear): 3300, 1700, 1650 cm ¹

_{NMR (DMS0-d 6, d} ): 1.02-1.36 (5H, m), 1.90 - 1.96 (2H, m), 2.61 (3H, s), 3.30-3.35 (4H, m), 4.28

(2H, s), 6.08 (2H, s), 7.42-7.54 (8H, m),

7.73-7.76 (2H, m), 8.77 (lH.br)

Mass (M / Z): 419 (M + of free compound) The following compound is obtained in the same manner as in Example 3 (1).

(2) 4—Fennino 5—Metinol 2 — [{(1-benzinole pyridin 1-4inole) methinole} Canolenormoinole] Thiazol Maleate mp: 162-163 ° C

IR (nujyoru): 3350, 1660, 700 cm

_{NMR (DMS0 - d 6,)} : 1.2-1.6 (2H, m), 1.7-2.0 (3H, m), 2.61 (3H, s), 2.7-3.1 (2H, m), 3.1-3.

(4H, m), 4.24 (2H, s), 6.02 (2H, s), 7.4-7.6 (8H, m)., 7.7-7.9 (2H, m), 8.86 (1H, br) Elemental analysis: C ₂₈ H ₃₁ N ₃ 0 _r S

Calculated value C 64.47, H 5.98, N 8.05 Actual valueC 64.54, H 5.95, N 7.93

Example 4 4, 5 — diphenyl 2 — [1 2 — (1 PERININE-1 4 ィチチチチレノをををを A solution of thiazonole (1.2 g) in N, N-dimethinole honolem amide (10 m1) at 0 ° C Then, sodium hydride (0.1 g) is added thereto, and the mixture is stirred at 0 ° C for 1 hour. Add methyl iodide (0.16 ml) and stir for 1 hour. The reaction was quenched by adding aqueous ammonium chloride (1 O ml) to the mixture, and the mixture was extracted with ethyl acetate (50 ml). The extract is washed with water and brine, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was recrystallized from hexane to give 4, 5-diphenyl 2-[N-methyl-1-N-{2-(1-1-peninole biperidin-1-4-phenol). ) Thiazole (0.9 g) is obtained.

mp92-93 ° C

IR (Nudiol): 1610, 1495 cm- ¹

_{NR (CDC1 3, 5 ")} : 1.21-1.40 (3H, m), 1.61-1.80

(4H, m), 1.82-1.94 (2H, m), 2.77-2.90 (2.H, m),

3.14, 3, 45 (total 3H, s), 3.48, 3.65 (total 2H, s),

3.55-3.60 (ΙΗ, πι), 4.11-4.19 (1H, m), 7.23-

7.35 (13H, m), 7.45-7.50 (2H, m)

Mass (M / Z): 495 (M ⁺ )

(1) 2 —Ethoxy quinone poninole 5 —Methylene benzoyl azole (1.0 g) and 4-amino-1-benzyl biperidine (1.0 ml) of the mixture to 100. Heat with C. One hour later, the cooled mixture was removed using aluminum. Chromatography, elution with a chromatophore, recrystallization with ether hexane, and 2 — [(1 benzyl biperidine 14 Nore カモモ 5 5 methyl

— 4 To obtain one fertile sol (2 g) rap: 120—122 ° C

IR (thin layer): 3380, 3300, 1650, 1590 cm '

NMR (one CDC,): 1.52-1.72 (2H, m), .97-2.03

(2H, m), 2.10-2.27 (2H, m), 2.60 (3H, s), 2.83-

2, 89 (2H, m), 3.52 (2H, s), 3.87-4.04 (1H, m), 7.16-7.66 (11H, m)

Mass (ra / z): 391 (M +) Elemental _{_{analysis: C 23 H 25 N OS 0.5H}} 2 0

Calculated value: C 68.97, H 6.54, N 10.49 Observed value: C 69.11, H 6.31, N 10.51 Example 5 — The following compounds are obtained in the same manner as (1).

(2) 2 — [I 2-(1-peninole biperidin 14-1-i-n-1-e-i-n-i-i-i-nol}]}-レ--チ-フ-1-phenol

IR (thin layer): 3400, 1680, 1335 cm ^-1 NMR (DMS0-d ₆ , δ ~): 1.0-1.3 (3H, m), 1.3-1.5 (2H, m), 1.55-1.7 (2H, m ), 1.8-2.0 (2H, m), 2.60

(3H, s), 2.7-2.9 (2H, m), 3.2-3.5 (4H, m),

3.44 (2H, s), 7.2-7.6 (8H, m), 7.7-7.8 (2H, m),

8.84 (1H, t, J = 6Hz)

Mass (m / z): 403 ( ⁺ ) Example 6 The following compounds were obtained in the same manner as in Example 3 (1).

(1) 2-[{3-(1 peninole biperidine 1-inole) propinole} canoleha * moinole] 1-5 — methinole 1 4 1 fue Maleic acid salt

IR (thin layer): 3300, 1700, 1650, 1580 cm " ¹

Mass (m / z): 433 (M + of free compound)

NMR (D S0-d ₆ , ^): 1.06-1.27 (7H, m) .1.82-1.88 (2H, m), 2.61 (3H, s), 2.91 (2H, m), 3.25-3.36 (4H, m) ), 4.29 (2H, s), 6.07 (2H, s), 7.42-7.49

(8H, m), 7.73-7.77 (2H, m), 8.77 (1H, br)

(2) 2 — [{5-(N-ethylenicone N-penzinolemino) penninole} cannole く] 一 — — — — — — — Mono maleate

IR (thin layer): 1710, 1660, 865 cm ^-1

_{NMR (DMS0-d 6, a} ): 1.23 (3H, t, J = 7 · 2H z), 1.2-1.4 (2H, m), 1.4-1.8 (4H, m), 2.61 (3H, s), 2.9 -

3.2 (4H, m), 3.25 (2H, q, J = 7.2Hz), 4.31 (2H, s), 6.08 (2H, s), 7.-7.6 (8H, m), 7.7-7.8 (2H, m ), 8.76 (1H, t, J = 6Hz)

Mass (m / z): 421 (M ⁺ )

(3) 2-. [{2-(1 penzinole biperidine 1 4'1 inole) チチ]] ノノ — 5 — — — — — — — 5 — チ 4 — 4 フエDichloroazole fumarate mp: 165-168. C IR: 1710, 1660 cm " ¹

NMR (DMSO-c,): 1.06-1.48 '(5H, m), 1.75-1.81

(2H, m), 2.35-2.46 (2H, ra), 2.53 (3H, s), 3.01-

3.07 (2H, m), 3.29-3.32 (2H, m), 3.85 (2H, s), 6.60 (2H, s), 7.31-7.54 (8H, m), 7.72-7.77

(2H, m), 8.75 (1H, t, J = 5.9Hz)

Mass (m / z): 419 (M + of free compound)

(4) 2 — [I 2-(1-Penzinole biphenyl 4-Innole)} ノ 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 5 — methyl thiazole fumarate mp: 193-195 ° C

IR (j Jiyoru): 3350, 1720, 1660 era one ¹

_{NMR (DMS0-d 6, ^} ): 1.03-1.31 (5H, m), 1.47-1.50

(2H, m), 2.17-2.27 (2H, m), 2.57 (3H, s), 2.91-

2.97 (2H, m), 3.28, 3.30 (2H, m), 3.70 (2H, s),

3.81 (3H, s), 6.59 (2H, s), 7.04 (2H, d,

J = 8.8Hz), 7.28-7.45 (5H, m), 7.67 (2H, d,

J = 8.8Hz), 8.71 (1H, t, J = 5.9Hz)

Mass (m / z): 449 (M ^{+ of} free compound)

(5 ') 2-[i2-(1: Nil-biperidine) 1-4 (4-mouth phenyl) 1-5 — Methylthiazole fumarate mp: 199-201 ° C

IR (j di Yor): 3320, 1680. 1650 cm " 1 NMR (DMS0-d 6, a): 1.30-1.48 (5H, m), 1.72-1.78 (2H, m), 2.22-2.33 (2H, m), 2.61 (3H, s), 2.95-

3.00 (2H, m), 3.29-3.32 (2H, m), 3.75 (2H, s),

6.59 (2H, s), 7.34-7.38 (5H, m), 7.55 (2H, d, 8.4Hz), 7.79 (2H, d, J = 8.4Hz), 8.75-8.78 (1H, m)

Mass (m / z): 454 (M + of free compound)

(6) 2-[{2-(1-penipole biperidine 1-1)] チノ 4 4 4 ェェ ~ ノレ 4 4 5 — Methynorethiazole fumarate mp: 200-202 ° C

IR (Nudiyol;): 3350, 1720, 1660 cm " ¹

NMR (DMS0-d _fi ): 1.13-1.47 (5H, m), 1.71-1.77 (2H, m), 2.20-2.31 (2H, m), 2.36 (3H, s), 2.59

(3H, s), 2.93-2.99 (2H, m), 3.28-3.40 (2H, m),

3.73 (2H, s), 6.59 (2H, s), 7.28-7.35 (7H, m),

7.64 (2H, d, J = 8.1Hz), 8.71 (1H, t, J = 5.9Hz) Mass (m / z): 433 (M ⁺ of the free conjugate)

(7) 4 — (4-Acetinole Aminophenyl)-2 — [{{2-(1-Penzinolebiperidin-1 4-innole)}}} Noreha * Moi Nore] 1-5 — Mechinoretia Zonore 'Fumanoleic acid

IR: 1640 cm- ¹

NMR (DMSO-d, ^): 1.26-1.47 (5H, m), 1.71-1.76 (2H, m), 2.08 (3H, s), 2.15-2.56 (2H,), 2.59 (3H, s), 2.91 -2.96 (2H, m), 3.28-3.36 (2H.m), 3.74 (2H, s), 6.59 (2H, s), 7.34-7.45 (5H, m), 7.69-7.80 (4H, m), 8.70-8.72 (1H, m), 10.11 (1H, s)

Mass (m / z): 476 (M + of the free compound) (8) 2 — [{2 — (1 — pentinole biperidin 1-4 1)) etinole} 4 1-Finanoletizole fumarate mp: 198-200. C

IR (j di yaw ^{Le): 3320, 1670 cm "1} NMR (DMS0-d 6, δ ~): 1.31-1.51 (5H, m), 1.74-1.80

(2H, m), 2.23-2.34 (2H, m), 2.95-3.01 (2H, m),

3.33-3.56 (2H, m), 3.75 (2H, s), 6.60 (2H, s),

7.36-7.49 (8H, m), 8.06-8.10 (2H, m), 8.39

(1H, s), 8.88-8.90 (1H, m)

Mass (m / z): 405 (M ^{+ of} free compound)

(9) 2 — [{2-(1 ジレぺ 4 4 4 4 4 ェェチチチチチチ} カカカ] 一) 1 — 5 — 5 ノ一一Mouth thiazole. Fumarate mp: 168-170 ° C

IR (nuclear): 1700, 1660, 1600 cm " ¹

_{NMR (DMS0 - d 6,)} : 1.20-1.49 (5H, m), 1.78-1.85

(2H, m), 2.20-2.25 (2H, m), 2.69 (3H, s) 3.05-

3.10 (2H, m), 3.30-3.35 (2H, m), 3.92 (2H, s),

6.61 (2H, s), 7.37-7.45 (5H, ra), 8.07 (2H, d, J = 8.5Hz), 8.35 (2H, d, J = 8.5Hz), 8.86-8.88 (1H, m)

'ass (m / z): 464 (M + of the free compound) (1 0) 2 — [{2 — (1 benzyl piperidine 1-4 1)) [Nore-no-mo-no-no-re] 1 4 1 (3-methoxy phenol) 1 5-methinorethia ♦ Fumarate mp: 207-208. C

IR (nuclear) ··· 3440, 1700, 1650, 1600 cm " ¹

N R (DMSO-de,): 1.03-1.30 (5H, m), 1.47-1.50

(2H, m), 2.12-2.23 (2H, m), 2.61 (3H, s), 2.89-

2.95 (2H, m), 3.15-3.25 (2H, m), 3.66 (2H, s),

3.82 (3H, s), 6.59 (2H, s), 6.96-7.02 (1H.m),

7.28-7.45 (8H, m), 8.73 (1H, t, J = 5.9Hz) Mass (m / z): 449 Elemental analysis (M + of free _{_{_{compound): C 26 H 31 N 3}}} 0 2 S'C 4 H ₄ 0 ₄

Calculated value: C 63.69, H 6.23, N 7.42 Observed value: C 63.77, H 6.46, N 7.47

(1 1) 2-[I 2-(1 penzinole biperidine 1-4 レレレェェ} カカモモモモモ 5) 1, 5, 6-dihydro

4Hzo [6.7] cyclohepta [1,2—d] thiazol fumarate mp: 155-157 "C

IR (nujyoru): 3350, 1650, cm above

NMR (DMS0-d ₆ ): 1.35-1.49 (5H, m), 1.70-1.76 (2H, m), 2.12-2.28 (4H, m), 2.77-3..04 (6H, m),

3.30-3.34 (2H, m), 3.76 (2H, s), 6, 59 (2H, s), 7.29-7.36 (8H, m), 8.09-8.10 (lH, m), 8.76-

8.78 (1H, br)

Mass (m / z): 445 (M) Elementary analysis: as the _{_{_{_{C 27 H 31 N 3 0S'C 4}}}} H 4 0 4

Calculated value: C 66.28, H 6.28, N 7.48 Actual value: C 66.27, H 6.56, N 7.46

(1 2) 2 — [{2-(1: N-1-N-1-4-N-I-N-O)] ノノレ 5-1--(4-methoxy-phenyl)-1-4 -Metylthiazole 'fumarate mp: 166-167. C

IR (Nuziol): 3420, 1700, 1650, 1600 cm 丄

_{NMR (D S0-d 6,} a): 1.03-1.47 (5H, ra), 1.72-1.78

(2H, m), 2.22-2.33 (2H, m), 2.47 (3H, s), 2.96-

3.01 (2H, m), 3.28-3.31 (2H _f m), 3.78 (2H, s), 3.82 (3H, s), 6.59 (2H, s), 7.06 (2H, d,

J = 8.7Hz), 7.34-7.38 (5H, m), 7.47 (2H, d,

J = 8.7Hz), 8.78 (1H, t, J = 5.8Hz)

Mass (m / z): 449 Elemental analysis (M ⁺ of free compound): as a _{_{_{_{C 26 H 31 N 3 0 2}}}} S C 4 H 4 0 4.

Calculated value: C 63.69, H 6.23, N 7.42 Actual value: C 63.40, H 6.27, N 7.34

(1 3) 2 — [{2-(1: N-N-pyridine) 1-1-2- (2-methoxyphenyl) 1-5- Tilthiazole fumarate mp: 153-155 ° C IR (nuclear): 3420, 1700, 1640 cm- ¹

_{NMR (DMSO - d 6,)} : 1.06-1.44 (5H f m), 1.71-1.76

(2H, m), 2.22-2.28 (2H, m), 2.29 (3H, s), 2.94-

2.99 (2H, m), 3.25-3.28 (2H, m), 3.75 (2H, s), 3.77 (3H, s), 6.59 (2H, s), 7.04 (1H, t,

J = 7.3Hz), 7.13 (1H, d, J = 8.2Hz), 7.33-7.47

(7H, m), 8.67 (1H, t, J = 5.8Hz)

Mass (m / z) ··· 449 (M ⁺ of the free compound) Example 7 (1) 2 — [(1 — Penzinole biperidine-1 4 — ノレ) Nole] ― 5 — Methanol 4 Dissolve the sodium fermentation (0.4 g) and maleic acid (0.12 g) in warm ethanol (10 ml). I do. After allowing to stand at room temperature for 4 hours, the formed precipitate is collected, washed with ether, and used to remove 2-((1-benzinole-pyridine-1-4-inole) carbyl)

1-5—Methynole 4′-N-fluorothiazolone ′ maleate (0.45 g) is obtained.

mp: 212-213 ° C

IR (nujol): 3240, 1690, 1640, 1610 cm " ¹ NMR (DMSO-d ^. ^): 1.98 (4H, br), 2.60 (3H, s),

3.08 (2H, br), 3.30-3.47 (2H, ra), 4.03 (1H, br), 4.27 (2H, s), 6.07 (2H, s), 7.40-7.5 ^ 5

(8H, m), 7.71-7.76 (2H, m), 8.83 (1H, d,

(J = 7.0Hz)

Mass (m / z): 391 (M + of free compound) Example 7 The following compounds were obtained in the same manner as in (1).

(2) 2 — [(E) — 2 — 1 (1-1-1-1-1-1-1-4-----------------------------) 5 — Methithiazole maleate mp: 202-204 ° C

IR (Nudiol): 3330, 1680, 1650, 1610, 1570 cm ^-1

_{NMR (DMS0-d 6, ^} ): 1.60-1.70 (2H, m), 2.00-2.06

(2H, m), 2.60 (3H, s), 3.00-3.15 (2H, m), 3.30-

3.43 (2H, m), 3.90-3.94 (1H, m), 4.26 (2H, s),

6.08 (2H, s), 6.86 (1H, d, J = 15.4Hz), 7.37-7.53

(9H, m), 7.69 (2H, m), 8.9 (1H, d, J = 7.1 Hz) Mass (m / z): 417 (M + of free compound) Example 8 Example 4 and Example 7 — The following compounds are obtained in the same manner as in (1).

2 — [N — {2-(1: N-Ginolepiridin 14-in-no-re) echino-le} 1 N — Metino-re-ka-noreno-mo-in-ore] 14 — Fen-ru 5-Mechiltia-zole 'Fumar Salt mp: 167-169 ° C

IR (Nudiyol): 1705, 1650 cm- ¹

_{NMR (DMS0-d 6, δ} ~): 1.10-1.29 (3H, m), 1.50-1.73

(4H, m), 2.11-2.25 (2H, m), 2.60 (3H, s), 2.81-

2.94 (3H, m), 3.02, 3.52 (total 3H, s), 3.65,

3.72 (total 2H, s), 4.03-4.05 (lH, m), 6.59 (2H, s), 7.33-7.49 (8H, m), 7.64-7.72 (2H, m) Mass (m / z): 433 Elemental analysis (M + of free compound): as a C ₂₆ H ₃₁ N one 0S'C _{_₄} H ₄ 0 ₄

Calculated value: C 65.55, H 6.41, N 7.64 Actual value: C 65.94, H 6.59, N 7.59

Example 9

2 ホミミ — 5 5 4 4 4 — に 4 に (2 に) (Minoethyl) 11 1 Penzinole biperidine (0.38 g) is added at room temperature. After 1 hour, the mixture is added to sodium borohydride (0.06 g) and stirred at room temperature for 1 hour. Then the mixture is poured into water and extracted with ethyl acetate. The extract is washed with water and brine sequentially, dried over magnesium sulfate, and concentrated. The residue is treated with a solution of hydrogen chloride in ethanol, the solvent is distilled off under reduced pressure, and the residue is pulverized with ether to give 2 — [{2- (1-pentylene biperidine). 14-amino) hydroquinone] -15-methyl-4-phenylisoazole.2 hydrochloride (0.30 g) is obtained.

mp: 265-267 ° C IR (Nudiol): 3420, 2720, 2550, 2420, 1600,

1530 cm ^-1

_{NR (DMS0-d 6, ^} ): 1.58-1.82 (7H, m), 2.58 (3H, s), 2.80-2.90 (2H, m), 2.98-3.02 (2H, m), 3.24

-3. 0 (2H, m), 4.24 (2H, s), 4.50 (2H, s), 7.35-7.53 (6H, m), 7.68-7.71 (4H, m), 9, 79 (2H, br), 11.61 (lH.br)

Mass (m / z): 405 (M + of free compound) Example 10

(1) 2 — Ethanol boninole 4 — Methinole 5 — (1 — Methine 1, 2, 5, 6 — Tetrahydridine 1 3 — Nore) A mixture of thiazole (0.50 g) and 4-((2-aminotinole) -11-penzinole biperidin (0.4.9 g) was added at 100 ° C. Heat for 2 hours. After cooling, the mixture is subjected to chromatographing using an anoremina, eluted with a chromate port, treated with a solution of hydrogen chloride in ethanol, and [{2-(1 peninole biperidin 14-innole) echinole} バイ一一 5 — 5 — (1 ノメチ，

2,5,6—Tetrahydropyridine 1.3-Inole) -141-methylthiazole.2 hydrochloride (0.30 g) is obtained. _{NMR (DMS0-d 6, ^} ): 1.02-1.49 (7H, m), 2.45 (3H, s), 2.60-2.80 (2H, m), 2.83, 2.86 ( total 3H, s),

3.00-3.50 (6H, m), 3.93-3.97 (2H, m), 4.22

(2H, d, J = 4.8Hz), 4.38 (2H, s), 6.22 (1H, m),

7.43-7.46 (3H, m), 7.61-7.64 (2H, m), 8.85 (1H, m)

Mass (m / z): 438 (M ⁺ ) The following compounds are obtained in the same manner as in Example 10- (1).

(2) 2-[{2-(1-methyl biperidine 14-yl) echinore} kanorenomoinore] 15-methinole 4-1-fluorothiazole . Hydrochloride IR (nuclear): 3350, 1640, 1520 cm ^-1

NMR (DMSO-cU): 1.45-1.73 (5H, m), 1.89-1.90

(2H, m), 2.61 (3H, s), 2.64, 2.67 (3H, s), 2.85-3.00 (2H, m), 3.31-3.36 (4H, m), 7.38-7.55 (3H, m), 7.73-7.78 (2H, m), 8.80 (lH, t,

(J = 5.9Hz)

Mass (m / z): 343 (M ^{+ of} free compound)

(3) 2 — [I 2-(1 ジノレぺジ 4 レレェェ)} 4 4 — 4 ((4 トキOne 5 — methyl thiazole hydrochloride

NMR (DMSO-dg, <5 ~): 1.45-1.85 (7H, m), 2.58 (3H, s), 2.86-3.30 (6H, m), 3.81 (3H, s), 4.21-4.36

(2H, m), 7.04 (2H, d, J = 8.8Hz), 7.42-7.45

(3H, m), 7.61-7.70 (4H, ra), 8.76 (lH, t, J = 6.0Hz), 10.90 (1H, s)

Mass (m / z): 449 (M ^{+ of} free compound)

(4) 2 — [{2-(1 penzinole biperidine 1 4 1 ィレレェェェェェェ)} ノレ ♦ ♦ イ 4 4 4 ー 4 メノ 1 — 5-(Pyrizine I 3-thiol) thiazole. Dihydrochloride

IR (nuclear): 3400, 1640, 1540 cm— ¹

NMR (DMSO-dg, ^): 1.35-1.85 (7H, m), 2.53 (3H, s). 2.86-3.04 (2H, m), 3.30-3.42 (4H, m), 4.2.2

(2H, m), 7.42-7.46 (3H, m), 7.61-7.64 (2H, m),

7.89-7.92 (1H, m), 8.43 (1H, d, J = 7.6Hz), 8.81- 8.83 (1H, m), 8.98-9.02 (2H, m) Mass (m / z): 420 (M + of free compound)

(5) 2 — [I 5-(N — echnolino N — benzoinolemino) pentynole} — — — 5 メ 4 4 — フルルキサキサLe hydrochloride

IR (thin layer): 3400, 1680, 1540 cm ^-1

_{NMR (DMS0-d 6, a} ): 1.25 (3H, t, J = 7.2H z), 1.4-1.6 (2H, m), 1.6-1.8 (2H, m), 2.61 (3H, s), 2.8- 3.1

(4H, m), 3.25 (2H, q, J = 7.2Hz), 4.29 (2H, s),

7.2-7.6 (8H, m), 7.7-7.8 (2H, m), 8.84 (lH, t, J = 6Hz)

Mass (m / z): 405 (M ⁺ )

(6) 2 — [I 2-(1: non-pyridin-14-1-in-1-1----------------------. Nil) — 5 — Methyl thiazole 'hydrochloride

IR (thin layer): 3400, 3330, 1650, 1600 cm ^-1

(Free compound)

NMR (DMS0-d _fi , a): 1.51-1.90 (7H, m), 2.59 (3H, s), 2.81-2.86 (2H, m), 3.24-3.33 (2H, m), 3.81

(3H, s), 3.83 (3H, s), 4.13-4.15 (2H, m), 4.21-4.34 (2H, m), 7.03-7.66 (8H, m), 8.76

(1H, t, J = 5.8Hz)

Mass (m / z): 479 (M + of free compound) Example 11

2 — ((E) 1 2 — Power revolving) 1 4 4-Pinorn 5 — Mechinoretia Zonorre (0 — 50 g), 4 1 Ami No. 1-Penzinolebiperidine (0.42 ml), 3- (3-Dimethylinorea Minopropinole) -1-1—Ethylcarpodiimide (0.3) 7 ml) and 1-hydroxybenztriazole hydrate (0.31 g) in N, N-dimethylformamide (10 ml) at room temperature. Stir for 1 hour. The mixture is subjected to an evaporation operation under reduced pressure, and then extracted with ethyl acetate. The extract was washed with water and a saline solution, dried over magnesium sulfate, and concentrated under reduced pressure.

[(E) 1 2 — {(1; N-pyrrole pyridin 14-yl) cane-no-no-nore} テテ 5 一一 5 — — ノ 4 — 4 — 二レレ(0.60 g).

mp: 187-188 ° C

_{NMR (DMS0-d 6, δ} ~): 1.14 - 1.21 (2H, m), 1.36-1.51

(2H, m), 1.99-2.09 (2H, m), 2.59 (3H, s), 2.73-

2.79 (2H, m), 3.66 (2H, s), 4.01-4.05 (1H, m),

6.87 (1H, d, J = 15.6Hz), 7.21-7.71 (1.1H, m),

8.29 (1H, d, J = 7.6Hz)

Mass (m / z): 417 (M ⁺ )

Example 12 The following compounds are obtained in the same manner as in Examples 11 and 7 — (1).

(1) 2 — [2 — {(1 ン 1 ぺ 4 4 力力力力) Ethynole] 1-4 phenylene 5-methylthiazole maleate

mp: 154-157. C IR: 3300, 1680, 1660, 1620, 1570 cm " ¹

_{NMR (DMS0-d 6, δ} ~): 1.60-1.70 (2H, m), 1.90-1.96 (2H, m), 2.50 (3H, s), 2.54-2.61 (2H, m), 3.02 ·

3.26 (4H, m), 3.78-3.82 (1H, m), 4.23 (2H, s), 6.06 (2H, s), 7.31-7.48 (8H, m), 7.64 (2H, d,

J = 7.0Hz), 8.09 (1H , d, J = 7.1Hz) Elemental analysis: as the _{_{_{_{C 25 H 29 N 3 0S'C 4}}}} H 4 0 4

Calculated value: C 65.02, H 6.20, N 7.84 Actual value: C 64.89, H 6.24, N 7.80

Mass (m / z): 419 (M + of free compound)

(2) 2 — [2 — [{2 — (1: Origin ぺレ 4）) Echinore! 5 モ 5 — 5 — — — 5 — 5 5 5 メ — — 5 — — — — — — — — 5 — — — — — — 5 — — — — — — — — — — — — — —. C

_{NMR (DMS0-d 6, δ} "): 1.06-1.31 (5H, m), 1.64-1.69

(2H, m), 2.21-2.32 (2H, m), 2.49 (3H, s), 2.51-

2.58 (2H, s), 2.94-3.46 (6H, m), 3.77 (2H, s),

6.60 (2H, s), 7.31-7.49 (8H, m), 7.62-7.67

(2H, m), 7.92 (1H, t, J = 5.4Hz)

Mass (m / z): 447 (M + of free compound)

(3) 2-[(Ε) 1 2-[{2-(1 ジンビ一 4 ー 4 ーェェェカ) カエテュ 5 5 — — 5 メ. No.4 1-Fe2 Norezazole Nole 'malein salt

NMR (DMS0-): 1.12-1.4 (5H, m), 1.85-1.92 (2H, m), 2.59 (3H, s), 2.86-2.90 (2H, s), 3.21-

3.28 (4H, m), 4.27 (2H, s), 6.06 (2H, s), 6.84

(1H, d, J = 15.5Hz), 7.37-7.53 (9H, m), 7.67-7.71

(2H, m), 8.34-8.36 (lH, m)

Mass (m / z): 445 (M + of free compound)

(1) 2—Acetoxy 5— (1—Penzinole Biperidine—4-inole) Pentanchoamide (1.30 g)

1 i (2 -. Bed B mode profile Nono ⁰ Bruno I Honoré one 4-menu preparative key Sibe Nze switch (1 0 0 ethanolate over Honoré (2 0 ml) in a mixture of g) 1

Reflux for 8 hours. The solvent is distilled off under reduced pressure. Dissolve the residue in ethyl acetate, wash with saturated aqueous sodium bicarbonate, water and brine, dry with magnesium sulfate, and evaporate the solvent under reduced pressure. The residue was applied to silica gel chromatography and eluted with a mixture of methanol and chloroform (3: 100), and then 2-[1- Casey

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

4 1- (4-methoxyphenyl) 1-5-methyl-norethazole

(1.20 g) as an oil.

IR (thin layer): 1740, 1600 cm— ¹

N R (CDCI3, ^): 1.25-1.61 (9H, m), 1.82-2.02

(4H, m), 2.13 (3H, s), 2.51 (3H, s), 2.85-2.90

(2H, s), 3.50 (2H, s), 3.84 (3H, s), C.01 (1H, t, J = 6.5Hz), 6.94 (2H, d, J = 8.9Hz), 7.26-7.57 ( 5H, m). 7.92 (2H, d, J = 8.9Hz) Mass (m / z): 493 (M ⁺⁺ l) The following compound is obtained in the same manner as in Example 13-(1).

(2) 2 — [4 1 (1 ジノぺぺ 4 4 ーブブブブブ])] 1 5 — レレ 4 4 フ二チレレレノレ · ^ fit

IR (thin layer): 3050, 3010, 1600 cm " ¹

NMR (DMS0-d ₆ ): 1.26-1.75 (11H, m), 2.62 (3H, s), 2.76-3.03 (4H, m), 3.22-3.28 (2H, m), 4.21

-4.35 (2H, m), 7.34-7.67 (10H, m)

Mass (m / z): 404 (M ^{+ of} free compound)

(3) 2-[2-(1-pentinole biperidine 1-yl) ethynoleamino] 1 5-methynole 4 1-phenolenoazole. 2 Hydrochloric acid Salt mp: 194-196 ° C

IR (Nudiyol;): 3450, 3400, 1620 cm " ¹

_{NMR (DMS0-d 6,)} : 1.57-1.62 (7H, m), 2.25 (3H, s), 2.85-2.90 (2H, m), 3.25-3.50 (4H, m), 4.24

-4.36 (2H, m), 7.43-7.70 (10H, m), 11.20

(1H, m)

Mass (m / z): 391 (M + of free compound)

2 — [1-Hydroxy 1-41 (11-Penzinole Beverage) 4-14 (4-Methoxy Mix) 1-5 -1,3-Dicyclohexyl methionolezone (0.20 g) in dimethylsnorrefoxide (5 ml) solution Lucanole pozimidide (1.0 g) and honoletrinic acid (0.13 g) are added and the mixture is stirred at room temperature for 24 hours. Remove the precipitate and add ethyl acetate to the solution. The mixture is washed with water and brine, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was applied to silica gel chromatography and a mixture of methanol and chloro-honolem was obtained.

(3: 100) and eluted with 2 — [1 oxo-4-1 (1-benzoquinone pyridine 1-4-butyl) butynole]-4-1 (4-meth (5) Methylthiazole is obtained as an oil (0.18 g). This compound was dissolved in a solution of fumaric acid (46.6 mg) in ethanol (1 ml), and the crystals were collected to give 2- [1-oxo-one-one-one. 1-41- (4-methoxyphenyl) -5- (methinolethiazole / fumarate) (0.15 g) obtain.

mp: 172-173 ° C

IR: 1705, 1680 cm " ¹

_{NR (DMS0-d 6, ^} ): 1.10-1.28 (5H, m), 1.65 - 1.70

(4H, m), 2.10-2.20 (2H, m), 2.62 (3H, s), 2.88-

2.94 (2H, m), 3.08-3.12 (2H, m), 3.65 (2H, s),

3.82 (3H, s), 6.58 (2H, s), 7.05 (2H, d,

J = 8.8Hz), 7.30-7.35 (5H, m), 7.65 (2H, d,

(J = 8.8Hz)

Mass (m / z): 448 (M + of free compound) Elemental analysis: as the _{_{_{_{C 27 H 32 N 2 0 2}}}} SC 4 H 4 0 4

Calculated values: C 65.93, H 6.42, N 4.96

Measured value: C 65.93, H 6.49, N 4.93 Example 15

2 — [1−Axetoxy 4−1 (1; Nginole Piberi Gin−4−Innole) Butinole] 1−4— (4−Metxifil) 1−5 To a solution of Chinoletian zoneole (0.90 g) in methanol (15 ml) was added 4N sodium hydroxide (1.0 ml) at 0 ° C. After the mixture is stirred at room temperature for 1 hour for 3 hours, the solvent is distilled off under reduced pressure. Dissolve the residue in ethyl acetate, wash with water and brine, dry over magnesium sulfate, and evaporate the solvent under reduced pressure. A part (0.18 g) of the residue (0.38 g) was dissolved in a solution of fumaric acid (26 mg) in ethanol (5 ml), and the crystals were collected. — [1-Hydroxy 4-1 (1-Penzinole Biperidin-14-Innole) Butinole] 1-4— (4-Metoxyn) 1-5-Met This yields 0.15 g of Luciazole fumarate.

mp: 114-116 ° C

IR (Nudiol): 3200, 1710 cm ^-1

NMR (one CDC,): 1.10-1.45 (7H, m), 1.64-1.80

(4H, m), 2.40-2.50 (2H, m), 2.49 (3H, s), 3.01 '

3.07 (2Η, m), 3.79 (3H, s), 3.89 (2H, s), 4.70-

4.74 (1H, m), 6.61 (2H, s), 7.00 (2H, d,

J = 8.5Hz), 7.39-7.2 (5H, m), 7.56 (2H, d, (J = 8.5Hz)

Mass (m / z): 450 (M + of the free compound) Production Example 21 1-Fetrous nitric acid (d = l.52) (30 ml) solution was added to a solution of 2-ethoxysilane. Add Enolole 5-Methyl oxazole (4.0 g) at 130 ° C and 20 ° C and stir the mixture under the same conditions for 20 minutes. The reaction mixture is poured into cold water and the precipitate is collected. Dissolve the precipitate in ethyl sulphate, wash with saturated aqueous sodium bicarbonate and brine, and dry over magnesium sulfate. The solvent is concentrated under reduced pressure, and the residue is recrystallized from ethyl acetate to give 2- (ethoxycarbonyl) -4- (4-nitro-2-ene) -1-5-methyloxazole

(3.85 g).

mp: 160—162 ° C

IR (nuclear): 1720, 1600, 1545, 1510, 1350 cm ^-1

_{NMR (DMS0-d 6, ^} ): 1.35 (3H, t, J = 7 · 1 H z), 2.72 (3H, s), 4.39 (2H, q, J = 7.1Hz), 8.00 (2H, d,

J = 9.0Hz), 8.30 (2H, d, J = 9.0Hz)

Mass (m / z): 276 (M ⁺ ) Example 16 The following compound is obtained in the same manner as in Examples 2_ (1) and 10- (1).

2 — [{2 — (1: N-Pin-Prin- din 14-1) チ）チヽモモイイイイ 4 4 1-4 (4-12 Trofenyl) 1 5 —Methyloxazole '' hydrochloride mp: 240-242. C (decomposition)

IR (Nujiol): 3300, 1680, 1600, 1560, 1510 cm- ¹

NMR (DMSO-dg, <5 "): 1.03-1.10 (5H, m), 1.48-1.52 (2H, m), 2.69 (3H, s), 2.82-2.87 (2H, m), 3.29 '3.32 (4H , m), 4.24 and 4.33 (total 2H, each d, J = 4.9Hz), 7.44 (3H, m), 7.63 (2H, m),

7.99 (2H, d, J = 8.9Hz), 8.35 (2H, d, J-8.9Hz),

9.00 (lH _f m)

Mass (m / z): 448 (M ⁺ ) Example 17

Example 3 The following compounds are obtained in the same manner as in (1). (1) 2 — t [2 — {1-(4-phenolic mouth benzene) porridge 1-porcelain} echinore] kanoreha * moinore] one 4 one (4 (1) Trofene 2) 1-5 — Methynorethiazonole, fumarate

rap: 213-214 "C

IR (Nudiol): 3260, 1710, 1655. cm " ¹

NMR (DMS0-d _6> ): 1.09-1.27 (3H, m), 1.47-1.51 (2H, m), 1.69-1.74 (2H, m), 2.02-2.13 (2H, m),

2.69 (3H, s), 2.83-2.89 (2H, m), 3.29-3.3-2

(2H, m), 3.58 (2H, s), 6.60 (2H, s), 7. Ll-7.20

(2H, m), 7.32-7.40 (2H, m), 8.07 (2H, d,

J = 8.9Hz), 8.35 (2H, d, J = 8.9Hz), 8.83-8.87

(1H, m)

Elemental analysis: C ₂₅ H ₂₇ FN ₄ 0 ₃ S as C ₄ H ₄ 0 ₄ Calculated value: C 58.18. H 5.22, N 9.36 Actual value: C 58.02, H 5.08, N 9.27

(2) 2 — [[2 — I 1-(4 — fluorobenzinole) pyridin 1 4 1 ノレチチチチ 5] 5 5 — (4 二 1 二 2) Oxazole 'fumarate mp: 181-182. C

IR (Nudiyol): 3220, 1700, 1670 cm 丄

NMR (DMS0-d ₆ , δ-): 1.25-1.32 (aH, m), 1.48-1.55 (2H, m), 1.71-1.76 (2H, m), 2.05-2.16 (2H, m), 2.88-2.94 (2H, m), 3.33-3.70 (2H, m), 3.65

(2H, s), 6.59 (2H, s), 7.13-7.21 (2H, m), 7.32-

7.40 (2H, m), 8.08 (2H, d, J = 8.5Hz), 8.18 (H. s), 8.37 (2H, d, J = 8.5Hz), 9.09 (lH, br) Elemental analysis: C ₂₄ H ₂₅ FN ₄ 0 ₄ 'C ₄ H ₄ 0 ₄

Calculated value: C 59.15, H 5.14, N 9.85 Actual value: C 59.15, H 5.27, N 9.83

(3) 2-[[2-{1-(4-phenolic benzene), pyridin, 1, 1,,,,,,,,,,, "]

(412 Trofene) 1-5 — methyl oxazoline fumarate mp: 140-143 ° C (decomposition)

IR (Nudiol): 1660, 1600, 1550, 1500 cm— ¹

_{NMR (DMS0-d 6, ^} ): 1.15-1.25 (3H, m), 1.46-1.49 (2H, m), 1.67-1.93 (2H, m), 1.91-2.03 (2H f m), 2.69 (3H, s), 2.81-2.87 (2H, m), 3.27-3.30 (2H, m), 3.54 (2H, s), 6.59 (2H.s), 7.10-7.19

(2H, m), 7.31-7.39 (2H m), 8.01 (2H, d,

J = 9.0Hz), 8.35 (2H, d, J = 9.0Hz), 8.95 (1H, m) Mass (m / z): 466 (M) (4) 2 — [{2— (1 Biperidine (41-inole) ethynole} canolevamoinole] 1-4 (4-methoxyphenyl) 5-5-metyloxazole fumarate mp: 155-156. C

IR (Nujiyoru): 3350, 1710, 1670, 1250 cm "1 NMR (DMS0-d 6,): 1.05-1.60 (5H, m), 1.6-1.8

(2H, m), 2.1-2.3 (2H, m), 2.56 (3H, s), 2.9-3.0

(2H, m), 3.2-3.4 (2H, m), 3.80 (3H, m), 6.59

(2H, s), 7.05 (2H, d, J = 8.8Hz), 7.34 (5H, s),

7.63 (2H, d, J = 8.8Hz), 8.82 (1H, t, J = 5.9Rz) (5) 2 — [{2 — (1 penzinole biperidine 1 4-tinole) 4 ノ — 4 4 4 4 4 4 4 4 — — 5 — — — — — — — — — — — — — —

mp: 167-170 "C

IR (Nudiol) 3300, 1700, 1660, 1550, 830 cm " ¹ NMR (DMSO-d, ^): 1.10-1.60 (5H, m), 1.65-1.80

(2H, m), 2.1-2.35 (2H, m), 2.60 (3H, s), 2.90-

3.10 (2H, m), 3.20-3.40 (2H, m), 3.73 (2H, s),

6.59 (2H, s), 7.3-7.4 (5H, m), 7.53 (2H, d,

J = 6.7Hz), 7.72 (2H, d, J = 6.7Hz), 8.89 (lH, t, J = 5.8Hz) (6) 5-[I 2-(1: N-1-yl) ethyl] Canoleva-Mo-i-no] 1.3-(4-2-trophenyl) Sol 'fumarate mp: 232-233 ° C (decomposition)

IR: 3400, 1645, 1570, 1520 cm " ¹

NMR (DMS0-d ₆ , a): 1.06-1.50 (5H, m), 1.69-1.75 (2H, m), 2.04-2.15 (2H, m), 2.85-2.91 (2H, m),

3.29-3.47 (2H, m), 3.60 (3H, s), 6.58 (1H, s),

7.26- 7.37 (6H, ra), 8.06 (2H, d, J = 9.0Hz), 8.32 (2H, d, J = 9.0Hz), 8.48 (1H, m)

Mass (m / z): 433 (M +)

(7) 5-[{2-(1-peninole biperidin-14-1-inole) echinole}} レ] 一一 — 3-(4-4 チジエピラ) Zol 'fumarate rap: 220-222. C (decomposition)

_{NMR (DMS0-d 6, δ} ~): 1.09 - 1.48 (5Η, m), 1.69-1.75 (2H, m), 2.06-2.17 (2H, m), 2.87-2.93 (2H, m),

3.27-3.4 (2H, m), 3.62 (2H, s), 6.58 (lH, s), 7.09 (1H, s), 7.27-7.36 (7H, m), 7.54 (2H, d, J = 8 Hz), 8.27 (1H, m) Example 18 The following compounds are obtained in the same manner as in Examples 4 and 7— (1).

2 — [N-methyl-N-I2-(1-1)-------------------------------Indication] Methoxy fenol) 1-5 — Metyloxazole fumarate

mp: 124-126 ° C

IR: 3375, 1700, 1640, 1250 cm ^-1

_{NMR (DMS0- d 6, ^)} : 1.0- 1.9 (7H, m), 1.9-2.4 (2H, m), 2.55 (3H, s), 2.7-3.1 (2H, m), 2.99, 3.36

(Total 3H, s each), 3.3-3.6 (2H, m), 3.61,

3.67 (total 2H, s each), 6.59 (2H, s), 6.9

-7.2 (2H, m), 7.2-7.5 (5H, m), 7.5-7.7 (2H, m)

Claims

The scope of the claims

1.General formula

M-W-Y-A-Q

[Where M is the formula:

(In the formula, R ¹ is hydrogen, lower alkyl, a heterocyclic group which may have a suitable substituent, or a aryl which may have a suitable substituent. ,

R ² represents hydrogen, lower alkyl, a heterocyclic group optionally having a substituent, or an aryl group having an appropriate substituent, Yes,

R ¹ and R ² combine with each other to form the formula:

And form a group of

Z represents S or 0, respectively) or a group represented by

Expression:

(Wherein R ¹ and R ² are each as defined above),

W represents a bond, a lower alkylene or a lower alkylene phenylene,

Y is lower alkylene,

-H-,

Expression:

(Wherein R ³ represents hydrogen or lower alkyl.) Or a group of the formula:

-CH-

R 7

(Wherein R ′ represents a hydroxy or protected hydroxy).

A represents a bond or lower alkylene,

Q is the formula:

(Wherein, R ⁸ represents lower alkyl, and R ⁹ represents alkyl (lower) alkyl).

(Wherein, R ⁴ represents lower alkyl or ar (lower) alkyl which may have a suitable substituent.), Respectively.] A novel heterocyclic compound represented by the formula: And pharmaceutically acceptable salts thereof.

2. M is the formula:

R

Wherein R ¹ is hydrogen; lower alkyl; contains 1 to 4 nitrogen atoms, and is a group consisting of lower alkyl, lower alkoxy, nitro and halogen. An unsaturated 5- or 6-membered heterocyclic group optionally having 1 to 3 substituents selected; or lower alkyl, lower alkoxy, acylamino, A phenyl which may have 1 to 3 substituents selected from the group consisting of lower alkylthio, halogen and nitr; and

R ^Δ is hydrogen; lower alkyl; contains 1 to 4 nitrogen atoms. Unsaturated, which may have 1 to 3 substituents selected from the group consisting of lower alkyl, lower alkoxy, nitro and halogen Is a 6-membered heterocyclic group; or 1 to 3 substituents selected from the group consisting of lower alkyl, lower alkoxy, acylamino, nitrogen and nitrogen. Is it possible to have it, or is it

R ¹ and R ² are bonded to each other to form the formula:

And form a group of

Z stands for S or 0, respectively)

Expression:

(Wherein R ¹ and R ² are each as defined above)

Y is a low-grade anorekiren,

-NH-, -C-

0 Formula I CO-N—

(Wherein R ³ is hydrogen or lower alkyl) or a group of the formula:

-CH-

R 7

Wherein R ′ is hydroxy or acyloxy, and

Q is the formula:

Wherein R ⁸ is lower alkyl and R ⁹ is phenyl (lower) alkyl.

(Wherein, R ⁴ is lower alkyl; or 1 to 3 substituents selected from the group consisting of lower alkyl, lower anoreoxy, lower anorequinolethio, halogen, and nitrite) 2. The compound according to claim 1, wherein the compound is a phenyl (lower) phenol.

3. M is the formula

(Wherein R ¹ is hydrogen; lower alkyl; contains 1 to 4 nitrogen atoms and is selected from the group consisting of lower alkyl, lower alkoxy, nitro, and halogen) Unsaturated 5- or 6-membered heterocyclic group optionally having one or two substituents; or lower alkyl, lower alkoxy, acylami Phenyl, lower phenol, halogen, and nitro, which may have one or two substituents selected from the group consisting of: Yes,

R ² is hydrogen; lower alkyl; contains 1 to 4 nitrogen atoms, and is a substitution selected from the group consisting of lower alkyl, lower alkoxy, nitro, and halogen. Unsaturated 5- or 6-membered heterocyclic group which may have 1 or 2 groups; or lower alkoxy, lower alkoxy, acylamino, halogeno And one or more substituents selected from the group consisting of

Is it a very good feast or two?

R ¹ and R ² are bonded to each other to form the formula:

And form a group of Z represents S or 0, respectively) or a group represented by

(Wherein R ¹ and R ² are each as defined above),

Y is lower alkylene

-ΝΉ-,,

formula

Wherein R ³ is hydrogen or lower alkyl, or a group of formula:

-CH-

R 7

Wherein R ⁷ is hydroxy or lower alkanoyloxy;

Q is the formula:

Wherein R ⁸ is lower alkyl and R ⁹ is benzyl.

(Wherein R ⁴ is lower alkyl; or selected from the group consisting of lower alkyl, lower alkylene, lower alkyl, nitrogen, and nitrite) 1 3. The compound according to claim 2, which is a group of phenyl (lower) alkyl which may have two substituents.

4. The formula is:

(Wherein R ¹ is hydrogen; lower alkyl; pyridyl; lower alkynolete trahydropyridyl; phenylinole; lower alkyl phenol; mono (or di) lower radical Kure breath shea off e cycloalkenyl, Nono Russia full et two Honoré; two preparative port full et two Honoré; lower § Norekinorechiofu et sulfonyl; Ri or lower § Noreka Roh Lee Norea Mi Roh full et sulfonyl der, R ² is Hydrogen; lower alkyl; pyridyl; lower alkyl tert-hydroxypyridinole; feninole; nitrofeninole; or lower alkoxide phenyl. Is it or is it R ¹ and R ² are bonded to each other to form

Forming a group of

Z represents S or 0, respectively).

(Wherein R ¹ and R ² are each as defined above),

Q is the formula:

Wherein R ⁸ is lower alkyl and R is benzyl, or a group of formula:

^4. The compound according to claim 3, wherein R ⁴ is lower alkyl, benzyl or halobenzyl. object.

5. M is the formula

(Wherein, R ¹ is nitrophenol or nitrophenyl

R ² is lower alkyl,

Z is a group represented by each of S,

W is a bond, Y is a formula:

Where R ³ is hydrogen

A is lower alkylene,

Q is the formula:

The compound according to claim 4, which is a group represented by the formula: wherein R ^{4 is} benzyl.

6.2-[{2-(1-1-pen-1-4-di-no-)----------------------------------------------- 1-5 — Methithiazole fumarate and

2 — [{2-(1 perimeter) Chinole bamo innole] 1-5 — methionole 4 (412 trophenyl) thiazole 'fumarate

The compound according to claim 5, wherein the compound is selected from the group consisting of:

7. General formula:

M-W-Y-A-Q

[Where M is the formula:

(In the formula, R ¹ is hydrogen, lower alkyl, a heterocyclic group having an appropriate substituent, or a heterocyclic group having an appropriate substituent. ,

R ² represents hydrogen, lower alkyl, a heterocyclic group which may have a suitable substituent, or phenyl which may have a suitable substituent; Yes,

R 丄 and R ² combine with each other to form the formula:

And form a group of

Z represents S or 0, respectively) or a group represented by the following formula:

(Wherein R ¹ and R ² are each as defined above),

W represents a bond, lower alkylene or lower alkylene

Y is lower alkylene,

-ΝΉ-,,

formula

(Wherein R ³ represents hydrogen or lower alkyl.) Or a group of the formula:

-CH-

R 7

(Wherein R ⁷ represents hydroxy or protected hydroxy).

A represents a bond or lower alkylene,

Q is the formula:

(Wherein, R ⁸ represents lower alkyl, and R ⁹ represents alkyl (lower) alkyl.)

(Wherein, R ⁴ represents lower alkyl or ar (lower) alkyl which may have a suitable substituent.), Respectively. (1) General formula:

M ~~ W— COOH

(Wherein, M and W have the same meanings as described above), or a reactive derivative at the carboxyl group or a salt thereof, represented by the general formula:

R ³

HN-A-Q

(Wherein, R ³ , A and Q have the same meanings as above), or a reactive derivative thereof or a salt thereof, and General formula:

R 3

M— W— CON-A-Q

(Wherein, M, W, RA and Q have the same meanings as described above), or a salt thereof is obtained.

(2) General formula:.

H

M— W— CON-A-Q

(Wherein, M, W, A and Q have the same meanings as before), or a salt thereof.

General formula:

R X

(Where R is lower alkyl,

X ¹ represents an acid residue. )

By reacting with the compound represented by or a salt thereof.

General formula:

(Wherein, M, W, RIA and Q have the same meanings as described above), or a salt thereof is obtained or

(3) General formula

(Wherein, R ¹ and R ² have the same meanings as before, respectively.

X ² represents an acid residue. )

And a salt thereof or a salt thereof

General formula:

H ₂

(W, A, Y and Q have the same meanings as before.)

By reacting with the compound represented by or a salt thereof,

General formula:

1

-W-Y-A-0

R

(In the formula, R ¹ , R ² , W, Υ, Α, and Q have the same meanings as before.) To obtain a compound represented by or a salt thereof, or

(4) General formula:

M-W ¹ -CH 0

(Where M has the same meaning as before,

W ¹ is a bond, c, is ~ c ₅ Anoreki-les-down or show the c ₂ ~ c ₅ A Rukeni Les emissions. ) Or a salt thereof is represented by the general formula:

H ₂ N-A-Q

(Wherein, A and Q have the same meanings as above), and the resulting compound is then subjected to a reduction reaction to obtain a compound represented by the general formula:

M - W ^ CH .- NH - A - Q (.. In the formula, M, W ¹ A your good beauty Q is their respective before and the same meaning) compound or Ru is indicated in its salt Or get

(5) General formula:

(Where M, W, A and Q have the same meanings as before,

R

Represents a protected hydroxy) or a salt thereof, which is subjected to the elimination reaction of the hydroxy protecting group. As a result,

General formula:

(Wherein, M, W, A and Q have the same meanings as described above), or a compound thereof or a salt thereof is obtained, or (6) a general formula:

(Wherein, M, W, A and Q have the same meanings as described above), by subjecting the compound or a salt thereof to an oxidation reaction,

General formula:

(Wherein, M, W, A, and Q have the same meanings as described above), or a salt thereof.

8. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable carrier.

9. Contracting as a preventive or therapeutic agent for diseases of the central nervous system Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof.

10. Prevention of diseases of the central nervous system, which comprises administering the compound of claim 1 or a pharmaceutically acceptable salt thereof to a human or animal. Is a cure.

11. A process for producing a pharmaceutical composition, characterized by containing the compound according to claim 1 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier.