WO1994020475A1

WO1994020475A1 - Isoxazole derivative

Info

Publication number: WO1994020475A1
Application number: PCT/JP1994/000308
Authority: WO
Inventors: Hisashi Takasugi; Atsushi Kuno; Mitsuru Ohkubo
Original assignee: Fujisawa Pharmaceutical Co., Ltd.
Priority date: 1993-03-02
Filing date: 1994-02-23
Publication date: 1994-09-15
Also published as: AU6115794A

Abstract

A compound useful as a drug and represented by the general formula: M-W-Y-A-Q, (wherein M represents a group of general formula (I), wherein R?1 and R2¿ represent each hydrogen, 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 of general formula (II), etc., wherein R4 represents lower alkyl, etc.; and symbol.^_.^_.^_.^_.^_.^_ represents either a single or a double bond), a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the above compound and having an acetylcholine esterase inhibitor activity.

Description

Specification

Y Oxazole derivative

Technical field

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

Background art

Many acetylcholinesterase inhibitors are known, but the isooxoazole derivative 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 isoxazole derivative and a pharmaceutically acceptable salt thereof.

More specifically, the present invention relates to an acetylcholinesterase inhibitor, which is useful for treating amnesia, dementia (for example, Alzheimer-type senile dementia, vascular dementia). The present invention also relates to a novel isoxazole derivative 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 isoxazole derivatives to which the present invention is directed are new and represented by the following general formula (I): M-W-Y-A-Q (I)

[Where M is the formula:

(Wherein, R ¹ represents hydrogen oc =, lower alkyl, a heterocyclic group which may have a suitable substituent, or a heterocyclic group which may have a suitable substituent,ノ

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

A group represented by the formula:

W represents a bond, lower alkylene or lower alkylene,

Y is lower alkylene, Formula: One CO— N—

R ⁰

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

(Wherein R ⁷ represents a hydroxy or a protected hydroxy).

A represents a bond or lower alkylene,

Q is the formula:

8

One N,

R 9

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

(Wherein R ⁴ represents lower alkyl or a lower alkyl which may have a suitable substituent, Represents a single bond or a double bond. ).]

The target compound (I) of the present invention can be produced by the following various methods.

Manufacturing method (1)

M— W-COOH

(IIa)

Or to its carboxy group

Anti-sexual derivatives or

Is their salt

M— W-CON-A-Q

(la)

Or its salt Manufacturing method (2)

H

M— W-CON-A-Q

(lb)

Or its salt

X ¹ its salt

(I c)

Or salt production method (3)

M—W ¹ -CHO

(K)

Or its salt

Return

M—W ¹ -CH ₉ -NH-AQ

(Ie)

Or its salt manufacturing method (4)

(If)

Or its salt

Response of hydroxy protecting group

(Ig)

Or its salt Manufacturing method (5)

(Ig)

Or its salt

Oxidation

M— W-C-A-Q

II

O

(Ih)

Or a salt thereof, wherein R ³ , M, W, A, and Q are each as defined above,

R ³ * is lower alkyl,

X ¹ represents an acid residue,

W ¹ is a bond, - C 5 alkylene-les-down or is C ₂ ~

C 5

R ⁷ a represents a protected human mud key sheet. 'The starting compounds or their salts can be prepared by the following methods. Manufacturing method (A)

M— W ² — CHO

(Kb)

Or its salt

M— W ² — CH = CH-COOH (XII)

Or its salt

② τ £ vit

M— 2— CH ₂ CH ₂ -COOH (XIII)

Or its salt Production method (B)

0 H 0

! II I II

R-C-C-C-W-R

1 ₂

(V)

Or its salt

(lib) or its salt Production method (C)

MW ² — R ⁵

(He)

Or its salt

① M vit

MW ² — CHoOH or its salt

② Formylation

\ 1 MW ² — CHO

(Kb)

Or its salt

In the above formula, R ¹ , R ² , M and W are each as defined above,

R ⁵ is a carboxy sheet protected was carboxy sheet or, W ² is a bond, - C 4 A Ruki les down or represents C ₂ ~ C ₄ A Rukeni les down. Suitable pharmaceutically acceptable salts of the target 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 Salts, for example, organic base salts (for example, triethylenamine salts, pyridin salts, picolin salts, earth ethanol salts, triethanol amine salts, etc.) , Dicyclohexylaminate, N, N'-dibenzyldiethylenediamine, etc.); inorganic acid addition salts (eg, hydrochloride, hydrobromide, sulfate) , Phosphates, etc.); organic carboxylic acid or sulfonate added salts (eg, formate, acetate) , Trifluoroacetate, maleate, tartrate, fumarate, methansulfonate, benzenesulfonate, tonorensolefonate Such as salts with basic or acidic amino acids (eg, alginin, aspartic acid, glutamic acid, etc.), and salts with bases. Or acid addition salts. In the above and the following description of the present specification, preferred examples and specific examples of various definitions that are not included in the scope of the present invention 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.

Preferred lower alkyl moieties in the term "lower alkyl" and "alkyl (lower) alkyl" include methynole, ethyl, propynole, isoprone. C1-C6 linear or branched, such as pinole, butynole, isobutyl, secondary butyl, tertiary butyl, pentyl, tertiary pentyl, hexyl, etc. Examples of the chain include those having a chain shape, and preferred are those having 1 to 4 carbon atoms.

Suitable "lower grades" include methoxy, ethoxy, proboxy, isoproboxy, butoxy, isobutoxy, secondary butoxy. Linear or branched chain having 1 to 6 carbon atoms, such as tertiary butoxy, pentoxy, tertiary pentoxy, hexyloxy, etc. Some examples are:

Preferred "heterocyclic groups" are saturated or unsaturated monocyclic or polycyclic rings containing at least one heteroatom such as an oxygen atom, a sulfur atom or a nitrogen atom. It means a formula heterocyclic group.

More preferred heterocyclic groups include the following heterocyclic groups: 3- to 8-membered unsaturated heterocyclic groups containing 14 nitrogen atoms. For example, pylori, pylori Nil, imidazolinole, villazolinole, pyridyl and its N-oxide, dihydridyl, tetrahydropyridine, pyrimidyl , Pyrazinyl, pyridazinyl, triazolyl (for example, 4H-1.2, 4—triazolinole, 1H—1,2,3—triazolyl Nore, 2H—1,2,3—triazolyl, etc., tetrazolinole (for example, 1H—tetrazole, 2H—tetrazole) Etc.), dihydrotriazinyl (for example, 4,5-dihydro12,4,1-triazine, 2,5-dihydro1,2 , 4 — tria ginil etc.);

3- to 8-membered saturated heterocyclic group containing 1 to 4 nitrogen atoms, such as azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinole, virazolidininole, pipera Dinyl, etc .;

A fused unsaturated heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolinole, isoindolinole, indolinyl, benzoimidazolinole, Quinolinole, Isoquinolinole, Indazolinole, Benzotriazolinole, Tetrazolopyridinole, Tetrazolopyridinole (for example, Tetra Zolo [1,5—b] pyridinyl), dihydrotriazolo pyridinyl, etc .;

3- to 8-membered unsaturated heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxoxazolyl, oxazodiazo Linole (for example, 1,2,4) 2, 5 — oxaziazolinole etc.);

A 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 Condensed unsaturated heterocyclic groups containing two nitrogen atoms, such as benzoxazolyl, benzoxazodiazolinolene, etc .;

3- to 8-membered unsaturated heterocyclic groups containing 1-2 sulfur atoms and 1-3 nitrogen atoms, for example 1,3-thiazolinole, 1,2-thiazoline Linole, thiazolinole, thiadiazolinole (for example, 1,2,4—thiadiazolinole, 1,3,4—thiadiazolinole, 1,2,5— Thia diazolinole, 1, 2, 3-thiadiazolinole);

Contains 1-2 sulfur atoms and 1-3 nitrogen atoms

A 3- to 8-membered saturated heterocyclic group such as thiazolidinyl; a 3- to 8-membered unsaturated heterocyclic group containing one sulfur atom, such as chenyl;

Condensed unsaturated heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as benzothiazolyl and benzothiadiazolyl;

Preferred "lower alkylenes" include methylene, ethylene, trimethylene, tetramethylene, pentamethylen, hexamethylene. More preferred are straight-chain or branched-chain ones having 1 to 6 carbon atoms, such as styrene, methinolethylene, ethynolethylene, and propylene. A good example is C! ~ C <alkylene. Suitable "lower alkenylene" include vinylene, plorenylene, 1- 1 (or 2-) butenylene, 1-1 (or 2-or 3-) —) Pentenelen, 1-11 (or 2 — or 3 —) hexenylene, methylenobilene, etilbinylene, 1- (or 2 — Or 3 —) methylpropenylene, 1 (or 2 — or 3 —) chillidopenylene, 1 1 (or 2 — or 3 — or 4 1) straight-chain or branched-chain ones having 2 to 6 carbon atoms, such as methyl-111 (or 2-) butenylene, and more. A preferred example is C 2 -C anolekenylene.

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 carboxyls and the like.

Suitable examples of the ester moiety of the esterified carboxy include lower alkyl esters (for example, methyl tertenol, ethinoles tenore, propinores tenore, isopropinores tenore, butinorees tenore, a Sobutinoester, tertiary butinoester, pentinoester, hexylester, etc.), lower alkyl esters having at least one suitable substituent, such as lower alka No-lokish lower alkyl esters [for example, acetonitrile chillo-stenolé, propioninoleoxyl chitinol-estenol, butyrinolé キシレテテテテテテテピテテテピピピピピピピピピピピピピピピピピピTer, 1 (or 2 —) acetokische estel, 1 (or 2 — or 3 —) acetoxy propyl estenor, 1 1 (or 2 — or 3-or 4-) acetoxybutyrol ester, 1 1 (or 2 1) propionyl leucil ester, 1 (or 1 Is 2 — or 3 —) propionyloxy oxypropyl ester, 1 (or 2 —) butyrinoxyxethyl ester, 1 ( Is 2 —) Iso Buti Linoleki Shechinorestel, 1 (or 2 —) Pivalo y Loki E Ji Noreesu ether, 1 one (or 2 -) to the key Sa Bruno Lee Noreo key market shares Ji Ruesu ether, isobutyrate Li Noreo key sheet main switch Noreesu Te clay, 2 - E Chi Rubuchi Li Ruo key sheet menu Chinorees tenoré, 3, 3 — dimethino olebuti linoleoxy stenole, ten (or 2-) pentanole fox enole stenole], low grade Anolecanth Crehonyl Lower Alkylester (eg 2-Mesylethylester), Mono (or Di or Tri) No, Mouth Lower Alkynol Estenole (For example, 2-Pedro-Echinorestenor, 2, 2, 2-Trichoro-Echinorestenoren, etc.) Noreki Rue Ste Nore [えはトトトメメメメメポポメポ力力力力力力力力力力力力力力力力力力力One- or two-way boninoleo oxymethylester 一キチテテテテテテ一一ま一一ま一ままま一まま一一一一一（（（まEtc.), phthalidene (lower) phanolecylester, (5 lower phenolic quinolettes 2-oxo 1, 3-gioxol-4 (Lower) Alkyl ester [For example, (5—Metinole 2—Oxo 1 and 3—Dioxono 1-4—Innole) Mechinore Stenore, (5—Echinore 2—Oxo 1, .3—Giochione 1 4-inore) Mechinores tenore, etc.]; Low-grade alkenies ruster (for example, Vininoles , Arylester, etc.); Esters (for example, ethininolestenore, propynylestenoles, etc.); al (lower) anolequinolesters which may have at least one suitable substituent (For example, Benzylester, 4—Methoxypenzinoles Tenoré, 412 Trobenzinoles Tenoré, Fénécénétélés Tenoré, Tricínoles Tenoré, Benzhi Dolinores Tenoré, bis (methoxyphenol) methylester, 3,4-methoxybenzil estenore, 4-hydroxy 3,5 -tブレチチな；；；；；；；；；；；；；；；も；も；ァァァァァァァァァァァァァァァァァァァもももももァ. Mouth Ninorés Tenoré, Trinorés Tenoré, t Butinore Fénéré Noréténé, Kisiri Norrest Tenoré, Mesti Norrester, Kumeni Norrester, etc.); And so on. W

1 7

Suitable "acid residues" include halogen (eg, chlorine, bromine, iodine or fluorine); alkanoyloxy (eg, acetoxy, etc.). ), And low-alkane sulphones (for example, methance norehoniloxy), and the like, and the preferred is halogen. You.

Suitable "protected hydroxy" are acyloxy; phenyl-lower alkyl optionally having one or more suitable substituents (e.g. And hydroxy-substituted with conventional 10-protected groups such as benzyl, 4-methoxybenzyl, etc.) and tetrahydroviranyl.

Preferred "acyl moieties" in the expression "asyloxy" include carbamoyl, an aliphatic acyl group, and an aromatic or heterocyclic ring And an acyl group. Preferable examples of the acyl include lower-grade alkanol (for example, honole minore, acetinole, propionolone, butyrinole, isotino). Buchi Rinore, Valerinore, Isoha * Relinore, Oxariinore, Succininole, Vivaroinore, etc.); For example, mexican caneboninole, ethoxycarbonyl, propoxy canebonyl, isopropoxy canebonyl, butyl 20 cantoneboninole, tertiary butane Kishikanore Bonir, Penchinore Bonile, Hexilor Khonore Boninole, etc.);レレ、, ェレレレホ、ピピピピピピピピロピピ 5 ロロ 5 ロピ 5 ピ 5 2 2 5 Nores Nore Honinore, Toshinore etc.); Aroinore (for example, Benzoinore, Tonoreo Inore, Xyloile, Naphthoinole, Phthaloinore, Indian Power Bonile, etc.); (Lower) alcanoinole (for example, phenylacetyl, phenylpropionyl, etc.); anore (lower) anoreco kishika nore boninole (for example, penzinoleo kishika) Norebonil, phenethyloxycarbonyl, etc.).

Suitable "Ci-C5 phenol" includes methylene, ethylene, trimethylene, tetramethylene, pentamethylene. And linear or branched ones such as methionolemethylene, ethynoleethylene, and propylene.

Suitable “C i -c phenol” includes methylene, ethylene, trimethylene, tetramethylene, ethynoleethylene, and propylene. Examples thereof include linear or branched ones such as pyrene.

Suitable “C ₂ -C ₅ alkenylene” includes vinylene, p-phenylene, 1 — (or 2-) butenylene, 1-1 (or 2 — or Or 3 —) Pentylene, methylvinylene, ethylvinylene, 11 (or 2 — or 3 —) methylpropenylene, 1 ( Or 2 — or 3 —) ethyl propylene, 11 (or 2 — or 3 — or 4 1) methinoure 11 (or 2 —) buteni Examples include straight or branched ones such as ren.

Suitable “C ₂ -C 4 alkenylene” includes vinylene, propenylene, 11- (or 2-) butenylene, Linear or branched ones such as chinolevinilene, ethinovinylene, and 11 (or 2— or 3—) methylprobelene Is mentioned.

Preferred "substituents" in the expression "optionally substituted aryl" include lower alkyl (for example, methyl, ethyl, Propyl, isopropyl, butyryl, isobutyl, tertiary butyl, pentyl, neopentyl, tertiary pentyl, hexyl, etc.), lower alkoxy For example, methoxy, ethoxy, pro box, isopropoxy, isobutoxy, tertiary butoxy, pentiloki, neopentillo, tertiary Grade pentinoleoxy, hexyloxy, etc.), lower alkenyl (for example, butyl, 1-propylinole, arinole, 1-methylinole, 1- or 2-- or 3 — Buteninole, 1 or 2 — or 3 — or 4-Pentenil, 1 1 or 2 — or 3 — or 4 1 or 5 ^ xenyl, etc.), lower alkynyl

(E.g., ethinyl, 1-propynyl, propargyl, 1-methylprono, ° lugil, 1- or 2-- or 3--butul, 1- or 2-- or 3-- Is a pair of pliers, 1 or 2 — or 3 — or 4 1 or 5 — hex, mono (or di or tri) ) Halo low-ranking quinole (for example, quinole olomethinole, diphnole olomethinole, trifnoleolomechinore, chloromethinole, dichloromethyl, Tri-Chrome Mole, Brom Memo, Jib Mouth Mole, Tri-Brom Memo, 1- or 2--Fnole Mole 1 or 2 — Bromo チ chinore, 1 or 2 — Krolo チ chinore, 1,1 一 1 フ 2 レ 2 ロ 2 ロ 2 ジ 2 , Etc.), halogens (eg, chlorine, bromine, fluorine, iodine), carboxes, protected carboxes, hydroxys, protected sheds as described above. Doxy, aryl (for example, vinyl, naphthyl, etc.), phenolic low-grade quinole (eg, -benzinole, fenenchinole) , Lower alkenyl (lower) alkyls (lower alkyl moieties such as those mentioned above), protected, etc. Carboxy (lower) anoalkyl (lower alkyl moiety is exemplified above. And the protected carboxyl moieties may be those cited above), nitro, amino, protected amino, di-lower alkylamino ( For example, dimethylamino, diethanolamine, diisopropylamino, ethylmethylamino, isopropylmethylinorea, ethylinopropylamine, etc. E.g., hydroxy lower alkyl, protected hydroxy lower alkyl, acyl, cyano, mercapto, lower alkylthio (e.g., methylorethio, etc.) as exemplified above. Ethnorecho, propylpicio, isopropiochio, butylthio, etc., lower alkylsulfinyl (for example,-methinoles finoleno, eschinoles enole) Fininore, 'Propinoresnofinino, Isopropinolesnorennojenole, Butinolessurfinyl, etc.), and imino.

Suitable "protected aminos" include asilamino (For example, the cited examples are cited as examples of the acylation part.)

A preferred “substituent” in the expression “heterocyclic group optionally having substituent (s)” is a lower alkyl (for example, methyl, ethyl, propyl). L-pill, isopropyl, butino, iso-butino, tertiary-butino, pentinole, neopentyl, tertiary-pentyl, hexyl, etc., lower-alkoxy (for example, Tokishi, Etokishi, Pro Bokshi, Isopropokishi, Isobutoki, Tertiary Butoxy, Pentyloxy, Neopentinoleki, Tertiary Pentinoleki, Hexyloxy, etc.), lower alkenyl (for example, vinyl, 1-propinolone, arrynole, 1-methinorea linole, 1- or 2- or 3- — Butenyl, 1 1 or 2 — or 3 — or 4 1 Nthenyl, 1 or 2 — or 3 — or 4 1 or 5 — hexinole, lower alkynyl (eg ethynyl, 1-propynyl, propargyl, 1 1-methylpropargyl, 1 1 or 2 — or 3 — butchur, 1 1 or 2 — or 3 — or 4 1 pentyne, 1 1 or 2 — or Is 3-or 4-1 or 5-hex, etc., mono (or di or tri), halo-low-order quinole (for example, funore oromechi) Nore, diphneolenomethylen, trifrenolenomethylen, chloromethinele, dichloromethine, trichloromethinele, etc.), halogen ( (Eg, chlorine, bromine, fluorine, iodine), carboxes, protected carboxes, hydro Kishi, Protected Hydroxy Rial (For example, phenyl, naphthyl, etc.), and phenyl lower-grade (for example, benzene, phenylene, phenylpropinole, etc.) Anore low-grade alkole, low-strength alkyl (lower) alkyl, protected carboxy (lower) alkino, nitro, amino, protected amino, di (lower) ) Alquila Mino (for example, dimethylamino, getyliamino, diisopropilamino, ethilmethilamino, isopropinoremethinoleamino, etinoreisopropinomino) ), Hydroxy (lower) alkyl, protected hydroxy (lower) alkyl, cyano, menolecapto, lower alkylthio (for example, methylthio, ethyl) Oh, pro-pill Chio, Lee Sopuro Piruchio, etc. butylthio), etc. I Mi Roh and the like.

A suitable “substituent” in the expression “Alkyl (lower alkyl) which may have a suitable substituent” is lower alkyl (eg, methylol, ethyl, Propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, neopentyl, tertiary pentyl, hexyl, etc., lower phenolic (eg, methacrylate) Kishi, ethoxy, propoxy, isopro box, isobutoki, tertiary butoxy, pentizoleoki, neopentillo, tertiary pentyl Kishi, Hekisilo Kishi, etc.), lower alkenyl (for example, 'bininole, 1-propinolone, alinole, 1-methinole allyl, 1-in-1 or 2—or Or 3 — butenyl, 1 1 or 2 — or 3 — The other is 4 Ichipe down thenyl, 1 - or 2 - or Or 3 — or 4 1 or 5 — hexenyl, etc., lower alkynyl (eg, ethynyl, 1-propynyl, prono, ^0- gil, 1-methylpropargyl, 1- Is 2 — or 3 — butynyl, 1 1 or 2 — or 3 — or 4 pentinyl, 1 or 2 — or 3 — or 4 1 or Is 5 — ^ ^ xinyl, etc.), mono (or di or tri) halo, lower alkyl (for example, phnolelomethyl, diphnolelomethine, trifnolerome) Chinore, Chloromethinolle, Dichloromethinolle, Trichloromethinolle, etc.), halogens (eg, chlorine, bromine, fluorine, iodine), carboxyls, protected canopy , Hydroxy, protected hydroxy, ary (For example, phenyl, naphthyl, etc.), and lower-class aluminum (for example, venezinole, venezinole, vinolepropyl). Lower Archicle, Canoleboxy (Lower) Alkyl, Protected Carboxy (Lower) Alkynole, Nitro, Amino, Protected Amino, Di (Lower) Anolequinoleamino For example, dimethylamino, ethylethylamino, diisopropinoleamino, ethylethylamino, isopropylamino, ethylethylpropino, etc., hydroxy (low-grade) ) Alkyl, protected hydroxy (lower) alkynole, cyano, methylcapt, lower alkylthio (eg methylthio, ethylthio, pro) Lucio, Lee Sopuro Piruchio, etc. butylthio), etc. I Mi Roh and the like. The method for producing the target compound and the starting compound will be described in detail below.

Manufacturing method (1)

Compound (Ia) or a salt thereof is converted to compound (IIa) or a reactive derivative at the carboxyl group or a salt thereof to compound (II) or a salt thereof. It can be produced by reacting with a reactive derivative or a salt thereof.

As a suitable reactive derivative of the compound (III), a Schiff base type formed by the reaction of the compound (III) with a phenolic compound such as an phenol or ketone is exemplified. Min or its enamine type tautomer, compound (III), bis (trimethinolene) acetoamide, mono (trimethinolene) Reaction with silyl compounds such as acetate amide [for example, N- (trimethylsilyl) acetamide], bis (trimethylsilole) and urea And the derivatives formed by the reaction of compound (III) with trichloride or phosgene.

Suitable reactive derivatives at the carboxyl group of the compound (Πa) include, for example, acid halides, acid anhydrides, active amides and active esters. Preferred examples of such reactive derivatives include acid chlorides; acid azides; substituted phosphoric acids (eg, dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzic acid). Dizylphosphoric acid, halogenated phosphoric acid), dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfuric acid (for example, methansulphonic acid), aliphatic acids Rubic acid For example, acetic acid, propionic acid, severe acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanic acid, 2-ethylbutyric acid, trichloroacetic acid. ), Mixed acid anhydrides with acids such as aromatic carboxylic acids (for example, benzoic acid); symmetrical acid anhydrides; imidazole, 4-monosubstituted imidazo , Dimethylpyrazole, triazole, 1-hydroxyl 1H-active amide with benzotriazole or tetrazole; Tenoré [For example, methyl ester, ethylenether, cyanometinole, methanol, methanol, stainless steel, dimethinole Ji Norre _{_{^{[(CH 3) 2 N +}}} = CH -] es Te Honoré, bi two Honoré et scan te Honoré, pro Bruno, ° Honoré Ginoree scan Nore, p-2 口口レレレステテ、 2 2 2 2 2 2 2 レ p レレレ p p二二レテテ, シテテ p p p p p 二二Tro Fue Ninorecho e Stenole, p — Cle Ginorecho Estel, Power Le Bocci Me Chinorecho Es Tenoré, Pira Ninolles Tezore, Pirigiles Tenore, Piperi Ginoletes Tenore, 8 — Quino Linolethiol ester, etc.) or N—hydroxy compound [eg, N, N—dimethyl hydrinoleamine, .1-hydroxyl 2 (1H) One pyridone, N—Hydroxy Succinimide, N—hydroxy shift, 1-hydroxyl 1H—benzotriazole, etc.] What is it? These reactive derivatives may be appropriately selected according to the type of the compound (IIa) to be used. The reaction is usually carried out in a conventional solvent, for example, water, alcohol (for example, methanol, ethanol, etc.), acetate, dioxane, acetone. Tonitrinole, black mouth film, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylforma The reaction should be performed in an organic solvent that does not adversely affect mid, pyridin, or other reactions. These solvents for concern 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 compound (IIa) may be added to the N, N, one-dimensional mouth. N, N-cyclohexinolone N, N-cyclohexinolone, N-cyclohexinole N '— (4-Jetcinole aminocrine)キレ力力力力力力力力力力 N N N N N N N N 力力 N N N N N 力力力. No. N'-I (3-methylaminopropyl) force No., N, N, No. Boninolevis (2-No. 1), pen N-cyclohexylamine, N-cyclohexylamine Xinoleimin, Ethoxy acetylene, 1-chlorophenol, 1-chloroethylene, trialkyl phosphite, ethyl polyphosphate, polyethyl phosphate Isopropyl phosphate, oxyphosphorus chloride (phosphoryl chloride), phosphorous trichloride, zinc chloride, oxalyl chloride, haloformic acid lower alkynoles (for example, methyl ethyl formate, Black mouth formic acid, isopropyl, etc.), triphenylphosphine, 2 — ethynole 1 7 — hydroxybenzoy soxoxazolum salt, hydroxide 2 — Ethanol 5 — (m — Snorrehofeninole) Isosoxazolym inner salt, 11 (p — Black mouth Benzensulhoninoleoxy) 1 6 — Chloro 1H — benzotriazolone, N, N-dimethylformamide and thionyl chloride, phosgene, trichloromethyl chloroformate, It is preferred to carry out the reaction in the presence of a conventional condensing agent such as the so-called Vilsmeier reagent, which is prepared by reaction with phosphorus oxychloride.

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

The reaction can be carried out by alkaline metal bicarbonate, tri- (lower) alkylamine, pyridin, N-lower acrekyl phenol olefin, N, N—di (lower) alkyl benzylamine. It can also be performed in the presence of any inorganic or organic base.

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

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.), chlorophorol, air Perform in ter, tetrahydrofuran, benzene, N, N—dimethyl honolem 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, an alkali metal bicarbonate, an alkali metal carbonate, an alkali metal acetate, a tri (lower) alkylamine, Lucari metal hydride, pyridin, norethidin, picolin, dimethinorea minopyridine, N—lower phenolic, N, N—di (lower ) Performed in the presence of inorganic or organic bases such as benzoylbenzylamine, N, N-di (lower) alkylanilinine. When the base and / or the starting compound are in liquid form, they can be used as a solvent.

Manufacturing method (3)

Compound (Ie) or a salt thereof is obtained by reacting compound (K) or a salt thereof with compound (Ilia) or a salt thereof, and subjecting the resulting compound to a reduction reaction. This enables production.

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

Suitable reducing agents to be used in chemical reduction are hydrides (eg, hydrogen iodide, hydrogen sulfide, aluminum hydride, sodium borohydride, sodium hydride). With boron (such as sodium) or metal (for example, tin, zinc, iron, etc.) or metal compound (for example, chromium chloride, chromium acetate, etc.) Organic or inorganic acids (for example, formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesnolephonic acid, hydrochloric acid, hydrobromic acid, etc.) It is a combination of and. Suitable catalysts to be used for catalytic reduction are platinum catalysts (for example, platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (for example sponge Jono, ⁰ La di cormorant-time, Roh, ⁰ La Ji-time black, oxide Roh,. La-di-um, Roh,. La di ©-time charcoal, co-b A de-like para-di-c-time, Nono Radium sulphate barium, no., Radium carbonate, etc.), nickel catalyst

(For example, reduced nickel, nickel oxide, Raney nickel), cobalt catalysts (for example, reduced cobalt, Raney cobalt, etc.), iron Conventional materials such as catalysts (eg, reduced iron, Raney iron, etc.) and copper catalysts (eg, reduced copper, Raney copper, Urman copper, etc.).

The reaction is usually carried out in water, alcohol (for example, methanol, ethanol), N, N-dimethylaminophenol, tetrahydrofuran, The reaction is performed in a solvent such as a mixture thereof or any other solvent that does not adversely influence the reaction.

Further, when the acids to be used in the above-mentioned chemical reduction are liquid, they can be used as a solvent.

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

Manufacturing method (4)

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

Suitable methods for this elimination reaction include hydrolysis and reduction. Examples of the common law include:

(i) For hydrolysis:

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

Suitable bases include alkaline metals (eg, sodium, potassium, etc.), alkaline earth metals (eg, magnesium, calcium, etc.). ), These hydroxides, carbonates or bicarbonates, tri (alkyl) amines (for example, trimethylaminoamine, tris). Inorganic and organic bases such as ethynoleamine, picolin, 1,5—diazabicyclo [4.3.0] non-5—ene Is mentioned.

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

Isolation using a trihaloacetic acid (for example, trichloroacetic acid, trifluoric acid, etc.), or other lewis acids, may be carried out using a cation trapping agent (for example, aniani). It is preferable to carry out the program in the presence of a source (such as a software or a phenol).

The reaction is usually carried out with water, alcohol (for example, methanol, ethanol, isopropinorea, etc.), tetrahydrofuran, diethanol, etc. Oxan, dichloromethan, ethylene dichloride, hologram hologram, N, N — dimethyl honolem amide, N, N-dimethyl acetamide, etc. A conventional solvent, The reaction is performed in any 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 usually the reaction is carried out 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 o

Suitable reducing agents to be used in chemical reduction are metals (for example, tin, zinc, iron, etc.) or metal compounds (for example, chromium chloride, chromium acetate, etc.) and organic acids. Or a combination with an inorganic acid (for example, formic acid, acetic acid, propionic acid, trifluoroacetic acid, P-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.). .

Suitable catalysts to be used for catalytic reduction include platinum catalysts (for example, platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (for example, For example, spongy-like, ^0- radium, no., Radium black, oxidized palladium, no., Radium charcoal, colloidal palladium, no., .Radium / Barium sulfate, palladium barium carbonate, etc.), nickel catalysts (for example, reduced nickel, nickel oxide, rankel, etc.), cobalt Catalysts (for example, reduced cobalt, Raney cobalt), copper catalysts (for example, reduced copper, Raney copper, uranium copper), iron catalysts (for example, Reduced iron, la Such as iron, uraman, etc.). This reduction is usually carried out with water, methanol, ethanol, prononor, N, N-dimethylaminophenol, dimethyl ether, diol. The reaction is performed in a conventional solvent such as san, tetrahydrofuran, or a mixture thereof that does not adversely influence the reaction.

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

Manufacturing method (5)

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

The oxidation is carried out according to a conventional method. Suitable oxidizing agents include dimethinolethrenofoxide and N, N'-dicyclohexynolecalpodiimide, lower alkanoic anhydride (eg, Anhydrous acetic acid, etc.), sulfur pentoxide, sulfur trioxide-pyridinine, N-nitrosuccinimide (for example, · -chlorosuccinimide) ), Oxalyl chloride and the like.

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

Suitable acids include organic acids (eg, formic acid, acetic acid, propionic acid, trichloroacetic acid, trichloroacetic acid, etc.) and inorganic acids (eg, Hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.). The reaction may be carried out on an alkali metal (for example, sodium or potassium), an alkali metal hydroxide (for example, sodium hydroxide, potassium hydroxide). ), Alkali metal bicarbonate (eg, sodium bicarbonate, potassium bicarbonate), Alkali metal carbonate (eg, sodium carbonate, carbonate) ), Tri-lower alkylamines (for example, trimethylamine, triethylamine, diisopropizoleamine, etc.), alkali metal hydrides (E.g., sodium hydride), Alkali metal lower alcohols (e.g., sodium methoxide, sodium ethoxide, etc.) ), Pyridines (eg, pyridin, noretidine, C, dimethylaminopyridine, etc.), N—lower alkanol, hololin, N, N—lower alkanol benzoylamine, N, N—lower alk It may be carried out in the presence of an inorganic or organic base such as chiranilin.

When the base, acid, or starting compound is in liquid form, it can be used as a solvent.

This reaction is usually carried out in water, phenolic (eg, methanol, ethanol), benzene, N, N—dimethylformamide, Solvents such as lahydrofuran, tonolene, methylene chloride, methylene dichloride, ethylene dichloride, chlorophonolem, dioxane, and getyl ether, and other reactions Perform in any solvent that does not adversely affect it. These conventional solvents may be used by mixing with water.

The reaction temperature is not particularly limited, but is usually not cooled or Perform reaction under heating ₀

Manufacturing method (A) —①

Compound (XII) or a salt thereof can be produced by reacting compound (Kb) or a salt thereof with compound (XI) or a salt thereof.

The reaction is usually alcohol (for example, methanol, ethanol, ethyl alcohol, etc.), chro-honolem, ether, The reaction is carried out in a conventional solvent such as transhydran, benzene, or acetate, or any other organic solvent that does not adversely influence the reaction.

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

Reactions include alkaline metal hydroxides, alkaline metal carbonates, alkaline metal carbonates, alkaline metal acetates, tri (lower) alkylamines, pyridines, Noretidine, picolin, dimethinoreaminopyridine, N-lower acetyl morpholine, N, N-di-lower alkyl benzyl benzylamine, N, N-di-lower This can be done in the presence of an inorganic base such as alkylaniline or an organic base. When the base and the starting compound are in liquid form, they can be used as a solvent. Manufacturing method (A) —②

Compound (XII) 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 in the same manner as in the above-mentioned production method (3). Therefore, the reagents to be used and, for example, the solvent and reaction temperature For the reaction conditions such as the above, the description of the production method (3) may be referred to.

Manufacturing method (B)

Compound (（b) 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, phenolic alcohol (for example, methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, etc. , Dioxane, chlorofonolem, methylene chloride, dimethylinoreacetamide, N, N—dimethinole honolem, and other conventional solvents, and other reactions Perform in any organic solvent that does not adversely affect the performance.

The reaction is preferably performed in the presence of an acid.

Suitable acids include organic acids (eg, formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.) and inorganic acids (eg, Hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, trifluoroacetic acid, etc.).

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

Manufacturing method (C) ー ①

Compound (W) or a salt thereof can be produced by subjecting compound (IIc) or a salt thereof to a reduction reaction. 'This reaction can be carried out by the method disclosed in Production Example 3 or by a method similar thereto. Manufacturing method (C) ー ②

Compound (Kb) or a salt thereof can be produced by subjecting compound (VII) or a salt thereof to a formylation reaction.

This reaction can be carried out by the method disclosed in Production Example 5 or a method similar thereto.

Suitable salts of the target compound and the starting compound in the methods (1) to (5) and (A) to (C) are those exemplified for the compound (I). Can be mentioned. Preferred specific examples of the target compound (I) are as follows.

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 3 to 8 members (more preferably 5 or 6 members) which may have 1 to 3 (more preferably 1 or 2) substituents Heterocyclic group

[Preferably, pyridyl or lower alkyltetrahydropyridyl]; or lower alkyl, lower alkoxy, acylamino, acyl, lower acrequino Halo (lower) alkyl, cyano, lower alkinorecho, halogen and nitrite A funnel which may have 1 to 3 (more preferably 1 or 2) substituents selected from the group consisting of the mouth [more preferred Or phenyl, lower alkyl phenyl, mono (or di) lower alkoxy phenyl, halo phenyl, nitro phenyl, lower phenol, lower phenol, lower alkynole Snorre honole phenolic, low-grade phenolic phenolic phenol, trino, mouth (lower) phenolic phenol, cyanophenyl, or lower alkanoyl Norea Minophenyl]

R ² is hydrogen; lower alkyl; has 1 to 4 nitrogen atoms, and is a substituent 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 group, which may have 1 to 3 (more preferably 1 or 2) [Preferably pyridyl, or lower alkyltetrahydropyridyl]; or lower alkyl, lower alkoxy, asilamino, halogen, and It may have from 1 to 3 (more preferably 1 or 2) substituents selected from the group consisting of nitro and phenyl [more preferably Or phenyl, dinitrophenyl, or lower alkoxyphenyl) or

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

A group represented by the formula:

W is a bond, lower alkylene or lower alkylene

[More preferred is C ₂ -C 4 alkenylene; particularly preferred is vinylene]

Y is a low-level anorekiren,

-NH-,,

Expression:

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

(Wherein, R ⁷ is a hydroxy or protected hydroxy group [more preferably an axyloxene, particularly preferably a lower alcanoinoyloxy] ).

A is a bond or a lower alkylene [preferably C 4 alkylene; particularly preferably ethylene]

Q is the formula:

(Wherein, R ⁸ is lower alkyl, and R ⁹ is al (lower) alkyl [more preferably phenyl (lower) alkyl, particularly preferably benzyl. Jill]) or a formula:

(In the formula, R ⁴ is lower alkyl or 1 to 3 (more preferably 1 or 2; particularly preferably 1) substituents. Good phenyl (lower) alkyl [more preferably a group consisting of lower alkyl, lower alkoxy, lower alkylthio, halogen, cyano and nitro One to three (more preferably one or two; particularly preferably one) selected substituents which may have one or more substituents

(Lower) phenols; particularly preferred are benzyl, cyanobenzyl, nitrobenzene or halobenzyl.]

Is a single bond or a double bond) Objective compound (I) of the present invention and a pharmaceutically acceptable salt thereof show a strong acetylcholinesterase inhibitory action, but have an effect on butyrinolecholinesterase. On the other hand, it shows almost no inhibitory effect. That is, the target compound (I) of the present invention and a pharmaceutically acceptable salt thereof are selective inhibitors of acetylcholinesterase, and thus have amnesia and dementia. For example, it is useful for the treatment of central nervous system diseases such as Alzheimer-type senile dementia, vascular dementia, and cerebrovascular disorders.

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

In the following tests, Example 1 means the compound produced in Example 1.

[A] Inhibition of acetylcholinesterase

(I) Test method:

The acetylcholinesterase inhibitory activity was measured by the method described in G. Clinica Chimi ca Acta, 115 (1981) 163-170 (enzyme assay). The acetyl colinase used in this test was obtained from rat linear bodies. (II) Test results:. Test compounds ί C ₅₀ (M) Example 1 2 0 X 1 0 - ⁸ The target compound (I) or a pharmaceutically acceptable salt thereof is generally used in mammals including humans in conventional pharmaceutical preparations such as capsules, microcapsules, tablets, and granules. It is administered in the form of powders, powders, troches, syrups, aerosols, inhalants, liquids, injections, clouding agents, emulsions, etc.

In the pharmaceutical composition of the present invention, various organic or inorganic carriers commonly used for pharmaceutical applications, for example, excipients (for example, sucrose, starch, mannitol) , Sonorebitone, lactose, gnorecose, senorose, talc, canola phosphate, canecarbonate, etc. For example, cellulose, methanol, cellulose, hydroxypropyl, cellulose, polypropynole, silicone, arabic, rubber , Polyethylene glycol, sucrose, starch, etc.), disintegrators (for example, sucrose, carboxymethyl tyl cellulose, carboxymethyl phenolic cellulose)ゥ Salt, Hydroxip Mouth Pilsch, Natrium Cornstarch, sodium bicarbonate, cannole phosphate, calcium citrate, etc.), lubricants (for example, stealine) Magnesium acid, tanolek, sodium laurenole sulfate, etc.), flavoring agents (for example, citric acid, menthol, glycine, oren) ), Preservatives (such as sodium benzoate, sodium bisulfite, methylparaben, propylparaben), stabilizing agents (such as For example, citric acid, sodium citrate, acetic acid, etc., emollients (for example, methylcellulose, polyvininolepyrrolidon, stearate) Phosphoric acid ), Dispersants, aqueous diluents (eg, water), base pills (eg, cocoa butter, polyethylene glycol, white petrolatum, etc.) Any combination is acceptable.

In general, a single dose of 0.1 mg Olmg / kg to 100 mgZ kg of the active ingredient should be administered 1 to 4 times a day, but it depends on the age, body weight, condition and administration method of the patient. The above dose may be increased or decreased.

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

Production Example 1

Etinole = 4- (12-tropininole) -12,4-dioxobutanoate (1.65 g) and hydroxylamine hydrochloride (1.73 g) A mixture of the above ethanol solution (20 ml) was refluxed with stirring. After 3 hours, the mixture is concentrated under reduced pressure. The residue is dissolved in ethyl acetate, washed with water and brine, dried over magnesium sulfate, concentrated under reduced pressure, and concentrated under reduced pressure. Obtain (0.72 g).

mp: 176-177 ° C

IR (Nujiol): 1720, 1600 cm- ¹

NMR (DMSO-de, ^): 1.46 (3H, t, J = 7.1Hz), 4.50 (2H, q, J = 7.1Hz), 7.12 (1H, s), 8.00 (2H, d, J = 9.0) Hz), 8.37 (2H, d, J = 9.0Hz)

Mass (m / z): 262 (M ⁺ )

Production Example 2

The following compound was obtained in the same manner as in Production Example 1.

3 — Ethanol Cannon Ponole 5 — (41 Cyanophenyl) Isosoxazole

mp: 187—188 ° C

IR (Nudiol :): 3450, 3130, 2220, 1720, 1590 cm- ¹ NMR (DMSO-de, δ ~): 1.45 (3Η, t, J = 7.1Hz), 4.49 (2H, q, J = 7.1Hz) ), 7.07 (1H, s), 7.79 (2H, d, J = 8.5Hz), 7.94 (2H, d, J = 8.5Hz)

Mass (m / z): 243 (M + + l) Production Example 3

3 — Ethanol boninole 5 — (412 trophenyl) Isoxazole (2.52 g) in methanol (25 ml)-tetrahydrofuran (25 ml) To the mixed solution is added sodium borohydride (0.36 g) at 0 ° C. The mixture is stirred at room temperature for 4 hours, poured into water and extracted with ethyl acetate. The extract is washed with water and saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is recrystallized from ether to give 5— (412-π-pheninole) -13-hydroxyl soxazole (1.84 g).

mp: 168.9 ° C

IR (Nudiyol): 3470, 1600 cm- ¹

NR (CDC13, 5-): 2.07 (1H, t, J = 5.8Hz), 4.86 (2H, d, J = 6.0Hz), 6.79 (1H, s), 7.96 (2H, d, J = 8.9Hz) , 8.35 (2H, d, J = 8Hz)

Mass (m / z): 221 (M + + l)

Production Example 4

The following compound is obtained in the same manner as in Production Example 3.

5-(4 ァ — フ 3 3 3 — — —)

mp: 122-123 ° C

IR (Nudiyol): 3230, 2225, 1595 cm- ¹

NMR (CDC13, 5 "): 4.84 (2H, s), 6.74 (1H, s), 7.77 (2H, dd, J = 6.7, 1.8Hz), 7.89 (2H, dd, J = 6.7, 2.0Hz) Mass (m / z): 201 (M + + l)

Production Example 5

5 — (412 Trofene) 1 3 — Hydroxymethyl isoisoxazole (1.82 g) and N, N'-cyclohexane (8.53 g)

(40 ml) Add phosphoric acid (4.05 g) at 0 ° C to the solution. After stirring for 1 hour at room temperature, the mixture is poured into water and extracted with ethyl acetate. The extract is washed with water and saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ether to give 5— (412-nitrophenol) 13—honoleminoleisoxazole (1.64 g).

mp: 180-181 ° C

IR (Nujiol): 1705, 1625, 1605 cm- ¹

_{NMR (CDC1 3, 5):} 7.09 (lH, s), 8.02 (2H, dt, J = 9.1, 2.1Hz), 8.39 (2H, dt, J = 9.1, 2.1Hz), 10.2 (1H, s)

Mass (m / z): 219 (M + + l)

Production Example 6

The following compound was obtained in the same manner as in Production Example 5.

5 — (4 シフフフ一一) 1 — 3 — Honore Mi Louis Soki Sazoru

mp: 152-153 ° C

IR (Nudiyol): 2220, 1700, 1620 cm- ¹

NMR (CDC1 a, ^): 7.03 (1H.s), 7.82 (2H.dd, J = 6.7.

1.9Hz), 7.95 (2H, dd, J = 6.7, 2.0Hz), 10.21 (1H, s)

Mass (m / z): 198 (M ⁺ )

Production Example 7

5 — (412 Trophenone) 13-Honoreminorisosozosazol (1.48 g), oxalic acid (2.82 g) and pyridin (0.34 ml) mixture Reflux the din (14 ml) solution for 1 hour. The mixture is cooled to room temperature and concentrated under reduced pressure. Dissolve the residue in ethyl acetate, acidify the pH to 2.0 with 4 N hydrochloric acid, wash with water and brine, dry over magnesium sulfate, and concentrate under reduced pressure. The residue was recrystallized from ether to give (E) —3— [5— (412 trophenyl) isosoxazolone 3—inole] propenoic acid (1.39 g) ).

mp: 241 ° C (decomposition)

IR (Nujiol): 1705, 1650, 1620, 1600 cm- ¹

_{NMR (D S0-d 6,} δ ~): 6.79 (1H, d, J = 16.1Hz), 7.51 (1H, d, J = 16.1Hz), 7.86 (lH, s), 8.13 (2H, d, J = 8.9Hz), 8.42 (2H, d, J = 9.0Hz), 12.90-13.09 (1H, br)

Mass (m / z): 260 (M ⁺ )

Production Example 8

The following compound was obtained in the same manner as in Production Example 7.

(E) — 3 — [5 — (4-cyano benzoinole) i-Soki sazonore 1-yl] propenoic acid

mp: 265 ° C (decomposition) IR (j di yaw Le): 3320, 3120, 2225, 1710, 1620 era one ^{1 NMR (DMSO-de, ^} ): 6.77 (1 H, d, J = 16.1 H z), 7.50 (1H, d, J = 16. LHz), 7.75 (lH, s), 8.05 (4H, s), 12.94-13.03 (lH.br)

Mass (m / z): 275 (M + Cl)

Example 1

3 — Ethanol Cane Boninole 5 — (412 Trofenyl) Isoxazole (0.5 g) and 2 — (1 Benzyl Pigment 1 4 1 Heat the N, N-dimethylhonolem amide (lml) solution of a mixture of ethylamylamine (0.7g) to 120 ° C while stirring for 1 hour. . After cooling to room temperature, the mixture is dissolved in ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to silica gel chromatography, eluted with a 3% methanol / monochrome form solution, and the fraction containing the target compound was evaporated under reduced pressure. — [[2— (1 Benzylpyrrolidin 14-ino) echinore] canolenomoinore] 1-5— (412-trophenyl) isoxazole . This compound was dissolved in a 4N hydrogen chloride-ethanol solution and evaporated under reduced pressure to give 3 — [[2— (1-Penzinole biperidine 14-n-inole)). [Chinore] canoleno * moinore] 1-5 — (412 trofenonole) isosoxazole hydrochloride (0.37 g) is obtained.

mp: 233-234 ° C

IR: 3360, 3130, 1660 cm- ¹

NMR (DMS0-d "): 1.50-1.65 (5H, m), 1.85-1.90 (2H, m), 2.75-2.90 ( 2H, m), 3.27-3.36 (4H, m), 4.23-4.38 (2H f in), 7.44-7.47 (3H, m), 7.61- 7.66 (2H, m) , 7.67 (1H, s), 8.21 (2H, d, J = 8.7Hz), 8.39 (2H, d, J = 8.7Hz), 8.94-8.98 (1H, m)

Elemental analysis: C _{2 4} H _{2 6} N-0 ₄ · As HC1

Calculated values: C 61.20, H 5.77, N 11.89

Observed: C 61.12, H 5.89, N 11.83

Mass (ra / z): 434 (M + of free compound)

Example 2

The following compounds are obtained in the same manner as in Example 1.

(1) 3 — [[2-(1 penzinole biperidine 14-yl) ethyl] canolebamoinole] 1 5 — (4-1 chanophenyl) i Soxazole / hydrochloride

mp: 264-265 "C

IR (Nudiol): 3250, 2220, 1660, 1600 cm— ¹

NMR (DMSO-de, ^): 1.43-1.55 (5H, m), 1.87-1.91

(2H, m), 2.80-2.90 (2H, m), 3.08 (lH, br), 3.25 -3.30 (3H, m), 4.23-4.38 (2H, m), 7.44-7.47 (3H, m), 7.57 -7.60 (2H, m), 7.61 (1H, s), 8.04

(2H, d, J = 8.6Hz), 8.13 (2H, d, J = 8.6Hz), 8.92 (1H, br), 10.43 (1H, br)

(2) 3 — [[2-I 1-(4-phenolic mouth benzyl) piperidine 1 4 1}]]] カ 5 5 — — — 5-(4 (1) Cyanophenyl) isoxoxazole. Hydrochloride mp: 265—267 ° C

IR (Nudiol): 3250, 2220, 1670, 1600 cm- ¹

NMR (DMSO-de, ^): 1.48-1.55 (5H, m), 1.86-1.92

(2H, m), 2.70-2.95 (2H, m), 3.05 (1H, br), 3.26 -3.36 (3H, m), 4.23-4.35 (2H, m), 7.25-7.33

(2H, m), 7.62 (lH, s), 7.64-7.71 (2H, m), 8.04 (2H, d, J = 8.6Hz), 8.13 (2H, d, J = 8.6Hz), 8.93 (1H, t, J = 5.8Hz), 10.80 (1H, br)

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

Example 3

(E) 1-3-[5-(412 Trofone) 1-Sokazolone 3-dino] propenoic acid (0.65 g), 2-[11- N, N of a mixture of (benzyl) piperidine-1-4-inole] ethylamine (0.59 g) and 1-hydroxybenzotriazole / monohydrate (0.38 g) — To a solution of dimethyl honole amide (13 ml), add 1-ethyl phenol 3- (3—dimethylaminopropyl) carbopimid (0.46 ml) at 0 ° C. The mixture is stirred for 2 hours at room temperature, poured into water and extracted with ethyl acetate.

The extract is washed with water and saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was applied to silica gel chromatography, eluted with 2% methanol-chlorophoronolate solution, and the fraction containing the target compound was concentrated under reduced pressure to 5 — ( 4 12 Trobininole) 1 3 1 [(E) 1 2 — [2 — {1-(4 — Phenomenon mouth benzene) Peripherine 1 4-dinore i H Noreka Noreba Moi Nore] Bini Nore] I Soxazonore. This compound was dissolved in a solution of fumaric acid (0.24 g) in ethanol, and 5— (4,2,1,2,3,2,3) -2- (2)-(2—I 1- (4-phenolic mouth benzene) pyridinone 41}}} ノレビビビイソソソソソソソ0.75 g).

mp: 240 ° C (decomposition)

IR (Nudiyol): 1660, 1635, 1600 cm- ¹

(DMS0-d ₆ , δ-): 1.15-1.47 (5H, m), 1.66-1.72 (2H, m), 2.83-2.89 (2H, m), 3.19-3.27 (2H, m),

6.60 (2H, s), 6.84 (1H, d, J = 15 · 9Hz), 7.11-7.20 (2H, m), 7.32-7.40 (3H, m), 7.62 (lH, s), 8.17 (2H , d, J = 9.0Hz), 8.38-8.43 (3H, m)

Mass (m / z) 478.82 (M ⁺ +1 of free compound)

Elemental analysis: as a _{_{_{C 2 6 H 2 7 FN 4}}} 0 4 · C 4 H <(K

Calculated values: C 60.60, H 5.25, N 9.42

Measured value: C 60.44, H 5.36, N 9.36

Example 4

The following compounds are obtained in the same manner as in Examples 1 and 3. (1) 5 — (412 Trofe 2 Nore) 1 3 — [(E) 1 2 —

[2-{1; N-pyrrolidine 1-4 1-1------------------------------------------can-can------------------------------------------------------------------

IR (Nudiyol): 1665, 1635 cm- ¹

_{NMR (DMS0-d 6, a} ):. 1. 16-1 7 (5H, π), 1.66-1.72 (2H, m), 2.02-2.13 (2H, t), 2.85-2.91 (2H, m), 3.17-3.27 (2H, m), 6.60 (2H, s), 6.84 (lH, d, J = 15.9Hz ), 7.32 (5H, s), 7.36 (lH, d,

J = 15.9Hz), 7.62 (lH, s), 8.17 (2H, d, J = 8.9Hz), 8.38-8.43 (3H, m)

Mass (m / z): 461 (M ⁺ +1 of free compound)

Elemental analysis C _{2 6} Η ₂₈ Ν, and the 04 · C _{_₄} H ₄ 0 ₄

Calculated values C 62.49, H 5.59, N 9.72

Measured value C 62.59, H 5.64, N 9.64

(2) 5 — (4-1) (3) [(E) 1-2 1

[2 — I 1-(4-口口口べぺぺ) ぺぺぺぺぺビ] ビビビビビイイイイイソソソMalate

mp: 248 ° C (decomposition)

IR (j Jiyoru): 3275, 2220, 1700, 1670, 1630 cm one ^{_{1 NMR (DMS0-d 6,}} a): 1.12-1.47 (5H, m), 1.67-1.73 (2H, m), 2.06-2.17 ( 2H, m), 2.86-2.92 (2H, m), 3.17-3.26 (2H, m), 6.60 (2H, s) _F 6.82 (1H, d, J = 15.9Hz), 7.16 (2H, t, J = 8.8Hz), 7.32-7.41 (3H, m), 7.56 (1H, s), 8.02-8.12 (4H, ra), 8.43 (1H, t, J = 5.5Hz)

Mass (m / z): 459 (M ⁺ +1 of the free compound)

(3) 5 — (4-Cyanophenyl) 1 3 — [(E) 1 2 — [2 — {1 1-benzene-piperidine 1-4-1-inole} Renomoinole] vinyl) isosoxazole fumarate mp: 234-235 ° C

IR (Nudiol): 3280, 2220, 1695. 1680, 1635 cm " ¹ NR (DMSO-de, 5"): 1.11-1.46 (5H, m), 1.67-1.73

(2H, m), 2.07-2.17 (2H, m), 2.87-2.93 (2H, m), 3.20-3.27 (2H, m), 6.59 (2H, s), 6.82 (1H, d,

J = 15.9Hz), 7.35 (5H, s), 7.36 (lH, d,

J = 15.9Hz), 8.02-8.12 (4H, m), 8.43 (lH, t,

(J = 5.5Hz)

Mass (m / z): 441 (M ++ 1 of free compound)

In the same manner as in Examples 1 and 3, the following compounds and salts of these compounds with acids (eg, hydrochloric acid, maleic acid, fumanoleic acid, etc.) are obtained. Can be.

1) 5 — (4-Metnolone LeFoninolefe 2) 1 3-[2-(1; Nginepole Pyridin 14 ーノレ）ェ])] Innore]

2) 5 — (4-Methyl Snoring Fininoringu) 1 3 _ [2-(1 Penguinoringpiperigin 14-Inoring)] * Moi Nore] Iso Kisazonore

3) 5-(4-Methylthiophene) 1 3-[[2-(1 Benzolole Biperidine 1-4 ノ）ェ) ethyl] Canoleba ]

4) 5-(4 トシヱヱヱ一) 1 3 — [[2-

1: Principle 1-Pinidine) Etinole] Canoleval] Isoxoxazole (5) 5 — (4-1-3-[[2-(1-1-1-4-1-4)] ]] ノ] イイイソ

(6) 5 — (4 1 black mouth dinosaurs) 1 3 — [[2 — (1 benzoinole pyridinone 4 ‐ レレェ）]]])] ]

(7) 5 — (4-Molecule squeezed horn) Ref. 1 3 — [[2-I 1-(4- sq.

一レレ]]]] ノソソソ 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3

[[2 — {1-(4 フレ口ジぺ)

4 イチェチチチカカカソソソソ

(9) 5 — (4-Menoratio vinyl) 1 3 — [[2-{1-(4-Mouth-opening benzene) Peripheral 1-4-Ninole } チチ] カカソソソソソソ

(10) 5 — (4-method vinyl) 1 3 — [[2-I1-(4-phenolic vent)]ノ力力力力力イイイイソ

(11) 5 — (4-1-(4-(1-(4-口べべべ）ぺ))

4 イチェェカカカ

(12) 5 — (41-mouth opening) 1-3-[[2-{11-(1-opening opening benzene) pyridin 14-opening] Chinore] (13) 5 — (412 trophene) 1 3 — [[2 — {11 (41 funo mouth benzene) pipeveridine 14 ino}} Chinore]

(14) 5 — (41 ヱヱヱレ一) 1 3 [[[2 — {1 ((412 trobenzinole)）ぺ一一一一チカ) Nore no mo i nore] i sosoxazonore

(15) 5 — (4-ノレレホホレレ 3 一 3 3 — 2 3 — 4 — 3 3 3 3 3 3 3ノチチチカカノ 16 16 16 16 16 16 16 3 3 3 3 3 3 3 3 3 — 3 3 3 3 3 3 3 3 3 3

[[2 — I 1-(412 Trouble)] [Electronic]

(17) 5-(4-Methyl thiophene) 1 3-[[2-{1-(412 benzene benzene) pyridin 14-1}} [Ethyl] Canoleva Moinole] Isosoxazole

(18) 5 — (4-Methoxysilane) 1 3 — [[2 — {1-(412 Trovendinole) peridine 1 41 ] [Rubamo]

(19) 5 — (4-1 1-(4 1 2-Trobenzinole) 1-4 ] カモ] ルカルルルルルルルルルルルル

(20) 5-(4-1-mouth (4-1-trobenginole) pyridin-14-1-ethyl ]

(21) 5 — (4 12 Trofe 2 Nore) 1 3 — [[2 — | 1 One (412 trovenzinole) peridine (41 ethyl) ethyl] [canolenomoinore] isosozozoru

(22) 5 — (41 Cyanopininole) 1 3 — [[2 — {11 (41 Cinoben Ginole) Pyridine 1 4 1 Cinole} ]]] イソイソソソ

(23) 5 — (4-レレレホホヱレヱ一) 1 3 一 [[2 — {1 1 [Sonozoru] [sonozoru]

(24) 5 — (4-Methyl phenolic resin) 1 3 — [[2 — {1-(4-cyanobenzinole) pyridine 1 4 1 イ}]]] カカソソソソソ

(25) 5-(4 メ二二一一) 1 3 — [[2 — {1-(4 ァ 1 (ベ）ぺぺぺ一 4 4)} [Ethyl] Canoleva Mole]

(26) 5 — (4-Met シヱヱレ) 1 3 — [[2 —

I 1-(41 Cyanobenzinole) Pyridin 1 4-Injection] Canoleva Moinole] Isozoxazole

(27) 5 — (4-1 trifluoromethyl phenyl) 1 3-[[2-{1-(4-1-benzoyl) pyridin-1-4 }} 力ババ力力力力力力力力力力力力力

(28) 5 — (4-Chlorobenzene) 1 3 — [[2-I1-(4-Cyanobenzine) Peridine 1 4- ] カイモイイイソソソ

(29) 5 — (412 Trophininole) 1 3 — [[2-I11 (41 cyanobenzinole) pyridin 14 1 inn} [Nore] [Kanoreha * Moi Nore]

(30) 5 — (4 メレスレホホニレ 3 3) 1 3 — [(E) 1 2 — [2 — (1; ) レレカ * * * モモモビビビビソソソ 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 31 3 3 31 3 3 3 3 3 31 31 31 31

[(E) 1 2 — [2 — (1 1 peninole biperidine 1 4 1 レ））) ノ] ビビニキサソ

(32) 5 — (4-レレオヱノ) 一 3 — [(E) 2 2 [[2 （(1: 1 ン 4 4 4 ィレ) [Lecanolevamoi nore] bininore] isosoxazole

(33) 5 — (4-Met キシノレ) 1 3 — [(E) 1 2 — [2 — (1 ペビビビペ 4 4) Nore Carno, 'No More]

(34) 5 — (4 1 trifluorene methyl phenyl) 1 3 — [(E) 1 2 — [2 — (1 1 Rubetone force) vinyl) isosoxazole

(35) 5 — (4 black mouth penny) 1 3 — [(E) 1 2

-[2— (1; N-pyridine) 4-vinyl] isoloxazole

(36) 5 — (4 メレレレレレ 3 3 3)

[(E) 1 2 — [2 — {1 1 (4 1 fukuroo vent veninole) piperinine 1 -4} ェチ] ビビビニニソソソキサキサキサソソ

(37) 5 — (4-Metnole フレニレレレ二一) 1 3-[(E) 1 2-[2-I 1-(4-一レ 3 一ジ一一 4 一一一一ビビビビビビビビビビビビビビ

(38) 5 — (4-レ二二二) 1 3 ([(E) 1 2 [[2-{1 1 (4 フ口ンべピ) Piberidineー 4 イイ} ェ]]]]]]] ソソソソ

(39) 5 — (4-Methoxy cinnamon) 1 3 — [(E) 1 2 — [2 — {1 1 (4- phenolic vent) 4 イレチビビビビビビビビビビビ

(40) 5 — (4-1-(4)-(4-1) (4-1-(4-4 レ口口ピ) 3ぺぺ 4 ジ一 4 4 一 4 一一ビビビビビビビビビビビビビ

(41) 5 — (4 1 mouth mouth penny) 1 3 — [(E) 1 2

― [2 — {1-(4 フノ口ジジぺぺぺ) ぺ一一一一ビ一ビビビビビビビビイイLe

(42) 5 — (4-Cyanopininole) 1 3 — [(E) 1 2 1 [2 — {1-(4 12 trobenzyl)) 1 4 ] * イ * モビモビビビビビビソソソソソ

(43) 5 — (4-レレレホホレレ 3 一) 1 3 [[(E) 2 2 [[2 4 I 1-(412 trobenzyl)一 4 4 4 一一 4 4 一ビビビビビビビビ Soxazole

(44) 5 — (4-レレレニレ二一) 1 3 — [(E) 1 2 — [2 — {1-(4 12 Trovendinole) Pipe一ジ 4 4 一 4 4 4 一ビビ 4 一ビビビビビビビビ

(45) 5 — (4-Methyl thiophene) 1 3-[(E)-2-[2-{1-(412 benzene)] {1 4 1 ノ} ェチチチチビビビビビビビビビビビビビビビビビビ

(46) 5 — (4-Met transfer) 1 3 — [(E) 1

2 — [2 — {1-(412 benzene)] ジ一一ビビビビビビビイイイソソソOne hole

(47) 5 — (4 Tri-Fin-O-L-Me-N-F-N-F-N-I-N-O) 1 3 — [(E) 1 2 — [2 — i 1- (4—Ni-Tro-Ven-Ginole) Pipe Rinsin 4 yl} echinoreka norebamoinore] bininore] sisoxazole

(48) 5 — (4-crole phenyl) 1 3 — [(E) 1 2 1 [2 — {1-(4 1 -2 benzene) 4 1 } ビレビビビビビビビビビビビビビビビビ

(49) 5 — (412 Trophininole) 1 3 — [(E) 1 2 1 [2 — {1-(4 12 Troveninole) Pigment 1 4 ] *] レ * モモモモビビビビビモビビソソビ (50) 5 — (4-Cyanophenyl) 1 3 — [(E) 1 2 1 [2—I 1-(4 1-Chenobenzene) Pyridine 1 4ノレェビカビビビビビビビビビビソソ

(51) 5 — (4 — チレレレレ 3 3 3 1 一 3 —

[(E) 1 2 — [2-{1-(4-1-benzoyl) piperidine 1-4 ノレ! [Echinore]

(52) 5 — (4-レスレスレスレ一) 1 3 — [(E) 1 2 — [2 — {1-(4 シ 1 ジ) Piperi 4 パ一ェェェェ

(53) 5 — (4-Metinoretofino) 1 3 — [(E)-2-[2 — {1-(4-1) } チチチビビビビビビビビビ

(54) 5 — (4-method shift) 1 3 — [(E) 1 2 — [2 — {1-(4-cyanobenzinole) pyridin 1 4 [Infinity] power [binoinole]

(55) 5 — (4-1-(4-1- (4-1-benzoyl)) pipe一一 4 一一一一一一一 4 一一一力力一一一力力 4 4 4 一一

(56) 5 — (4 black mouth penny) 1 3 — [(E)-2 I [2-{1-(41-cyano-benzene]) pyridin-1-4-i-n]} カモビビビビビソイソソソソソZone

(57) 5 — (4 — nitrofeninole) 1 3 — [(E)-2-1 [2 — {1-(4 1 cyanobenzinole) 1-4 } {イキサビビソキサキサキサキサビキサキサキサキサキサキサ

(58) 5 — (4 — Cyanopheno 2) 1 3 — [(E) 1 2 1 [2 — (1 1 Page 2 1,2,5,6—Tetrahydrid [4-Pinylene] ethynole] [canine] [bininole] isosoxazole

(59) 5 — (4-レレレホホレレ一 3 3 3 — — — — 3 [[(E)-2-[2 一 (1 ペ 1, 2, 5, 6- Tetrahydropyridine (4-inole) ethinole cane enomore] bininole] isosoxazole

(60) 5 — (4-Met Nores レニレノ) 3 3 — [(E) 1 2 — [2 — (1 ジ 1, 2, 5, 6 — Tetrahedro pyridine (41 yl) ETHINORE KANOREVA MOISORE] BINNORE] ISOSOKISOL

(61) 5 — (4-ノレチヱ) 1 3 [[(E) 1 2 [[2 （(1 1 1, 2, 5, 6 テ Tetra [Hydroxy pyridine] 4-vinyl) [vinyl] iso-oxazole

(62) 5 — (4-Met シシレ) 1 3 — [(E) 1 2 — [2 — (1 ジ 1, 2, 5, 6 — Tetrahi Mouth pyridin-4)

(63) 5 — (4) (3) [(E) 1 2 — [2 — (1 1, 2, 5, 6) — Tetrahedro-Pyrrolidine 1-4 ェレェェ]]] ビビビビビソソソソソソ

(64) 5 — (4-chlorophenyl) 1 3 — [(E) 1 2 1 [2 — (1 pengeo rail 1, 2, 5, 6 — tetrahydro Propylene resin (41 yl)

(65) 5 — (412 Trondinore)-3 — [(E) 1 2 1 [2 — (1 1 ^: 1,2,5,6—Tetrahi 4-Pyrrolidine 4-N-)) eth-nor-re-ka-nor-re-b-mo-in-ole] vinyl] -isoxoxazole

(66) 5-(4-1-(4) (1-(4)) (1, 2, 5) , 6-tetrahydropyridine-41-ethyl-carno-modile-bininole] -isoxazole

(67) 5 — (4-methylsulphonyl benzoyl) 1 3 — [(E) 1 2 — [2 — {1 1 (4 1 fluorene benzene) 1 1 , 2,5,6—Tetrahydridine 1 4 1 2 1 2 3 4 5 6 7 6 7 8 7 8 9 10 10 10 10 10 10 20 25 30 20 25 20 25 20 25 20 25 20 25 20 25 20 25 20 25 30 40 40 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 have specified)

(68) 5 — (4-Methyl phenolic phenolic phenolic) 1 3-[(E) 1 2-[2-{1 1 (4 1 fluorobenzene) 1 1, 2, 5, 6 — tetrahydropyridine Chinore canonore] [bino]

(69) 5 — (4-Met)-3-[(E) 1 2-[2-{1-(-4-benzene) 1 1, 2 , 5, 6 — tetrahydropyridine 1-inole} ethyl carbamoinole] bininole] isosoxazole

(70) 5 — (4-METHOSH ヱヱレ) 3 1 3 [[(E)-2 [[2 {{1 （(4 ノレ口口ン 1) 一 1, 2, 5, 6 — tetrahydropyridine 1-4-ethyl vinyl alcohol-vinyl) isoxoxazol

(71) 5 — (4) (3)

[(E)-2-[2-{1-(4-fluorene benzene)-1, 1, 2, 5, 6-tetrahydropyridin-4 1-inole}}ビカビビビビビビビビビビビ

(72) 5-(4 1-mouth opening porcelain) 1 3-[(E)-2-1 [2-{1-(4-mouth opening benzene) 1 1, 2, 5,

6-Tetrahedro-Pyridine 1 4 1}} ビビビビビビビビビビビニニソ

(73) 5 — (412 Trondinole) 1 3 — [(E) 1 2 1 [2 — I 1-(4-Frout mouth Benzinole) 1 1, 2, 5 , 6 — Tetrahedro pyridine 1 4 1} チチチチビビビビビビビビニビソニニ

(74) 5 — (4 — Cyanophony) 1 3 — [(E) 1 2 1 [2-1-(4-Nitrobenzene Ginole) 1 1, 2, 5, 6 -Tetrahedro-Pyrrolidine- 1 4 1}} チチビビビビビビビビ] ソビソソ (75) 5 — (4-レレレレホホレレ一) 1 3 — [(E) 1 2 — [2 — I 1-(4 1 2 trobenzinol) 1 1, 2,5,6—Tetrahydridyline 1 4 レレ] ビビビ] イ] イソ

(76) 5 — (4-レレスレレ 3) 1 3 —

[(E) 1 2 — [2 — I 1-(412 Trovendinole) 1, 1, 2, 5, 6 — Tetrahydropyridine 1 4 1 2} Noreka nore no mo i nore] bino nore]

(77) 5 — (4−Metinoreofinore) 1 3 — [(E) 1 2 — [2 — j 1-(4 12 Trovendinole) 1 1, 2,

5, 6 — tetrahydropyridine 1 4 — butyl benzoyl] butyl] isoxoxazole

(78) 5 — (4-METHOPS ヱレ) 3 3 3 [(E) 2 2-[2 I I 1-(一トロロ一) 1 1, 2, 5 , 6 — tetrahydropyridine 1 4 1 イレ力力力ビビビビビビビビビニイソソソ

(79) 5 — (4-1-2-[(E) 1-2-[2-{1-(4-1-trobenzyl)) 1 1, 2 , 5,6-Tetrahydropyridin-one-methyl-vinyl-mono-methyl * vinyl] -isoxazole

(80) 5 — (4 1 mouth opening) 1 3 — [(E)-2-1 [2 — I 1-(412 Trovendinole) 1, 1, 2, 5, 6-tetrahydropyridine 1 4 1} イモモモモモモモモモビビビビ] イ] ソソソソソソ

(81) 5 — (4-Nitrobenzene) 1 3 — [(E) 1 2 1 [2 — I 1-(412 Trovenogene) 1, 1, 2, 5, 6-tetrahydropyridin 1 4 1 Innore} [Ill.]

(82) 5 — (41) (2) I 1-((4) 1- (4) 1-, 2-, 5-, 6-Tetrahedro-Pyrrolidine 4 1 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 4 4 5 6 7 6 7 6 7 8

(83) 5 — (4-レレレレホホレ 3 3) 1 3 [[(E)-2-[2 — I 1-(4 シ 1 ベベジ一) 1 1, 2, 5, 6 — Tetrahedro pyridine 1 4 レレレビビビビソソソソソソ

(84) 5 — (4-Methyl Sulfur Reinforcement) 1 3 — [(E) 1 2 — [2-I 1-(4 1 Sheno Benzil)-

1, 2, 5, 6 — tetrahydropyridine 1 4 1 2 1 2 3 4 5 6 7 6 7 6 7 8 9 10 10 10 10 10 20 25 30 20 25 20 20

(85) 5 — (4-Methyl thiophene) 1 3-[(E) 1 2-[2-{1 1 (41 cyanobenzyl) 1, 2, 5, 6 — tetrahydropyridine 1-41-ethyl benzoylamine] [butyl] isoxoxazole

(86) 5 — (4-method vinyl) 1 3 — [(E) 1

2 — [2 — I 1-(41-cyanobenzene) 1, 1, 2, 5, 6-tetrahydropyridine 1 4 1}}}}- [Nore] Vinyl] Iso Xoxazole

(87) 5 — (4-1) (3-[(E) 1-2-[2-{1-(4-1-benzoyl)]-] 1, 2, 5, 6 — Tetrahydropyridine 1 4 1}} チェモイビビビビビビイイイイイ

(88) 5-(4 ク 1 'フヱヱレ一) 1 3-[((E) 1 2-1] [2-{1-(4-1, cyano-benzene) 1, 1, 2, 5 , 6 — tetrahydropyridine 1-4-------------------------------------------

(89) 5 — (412 trough unit) 1 3 — [(E) 1 2-[2 — I 1-(4 1 cyanobenzyl) 1 1, 2, 5 , 6-tetrahydropyridine 1-4---------------------------------------

(90) 5 — (4-cyanovinyl) 1 3 — [[2 — (1 1-, 2-, 5-, 6-tetrahydropyridine) 4 ノレェチチチチカカカソソソソキサキサソ

(91) 5 — (4-レレレレホホレレ 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 [Resin 1 4]) Etch]

(92) 5 — (4-チレフフレ一一 3 3 — 3 3 3 — 3 3 一 [[2 3 (1 ジ 1, 2, 5, 6 テPyrinine 4-ethyl) ethyl] canoleba moinole]

(93) 5 — (4-Medium re-orientation) 1 3 — [[2 — (1 page 1, 2, 5, 6 — Tetrahydro pyridine一ーー 4 チチカカカカ 94 94 94 94 94 94 94 94 94 94 94-3 3 3 3 3 3 3 3 3 3 3 3 (1: benzene 1, 2, 5, 6-tetrahydropyridine 14 yl) ethyl] canoleva moinole] isoxoxazole

(95) 5 — (4-1-2-(1 ^: N 1-1, 2, 5, 6-Tetrahi) Drip pyridine 1 4 チ]]]]]] カノソソソソソ

(96) 5 — (4 — Black mouth) 1 3 — [[2 — (1 1, 2, 5, 6 — Tetrahydro pyridine 1) 4-レ]]] カカゾソソ 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 1-ー 1, 2, 5, 6 — Tetrahedro pyridine 1 4 ノレチチチチチチチノ] イイソソソ

(98) 5 — (41-no-no-fu-n-no-re) 1 3-[[2-I 1-one (4-no-no-re-o-venge-no-re) 1, 1, 2, 5, 6-tetra Hydridone-one-one-one-one}

(99) 5 — (4-Molecule-Les-Fonore-No-Fen-No-Re) 1 3-[[[2 — {1-(4-F-No-Re-O-Ben-Ben-No-Re)] 1 1, 2, 5, 6 — Tetrahydridylamine 4 1 1 2 3 4 5 6 7 6 7 6 7 8 7 8 9 10 10 10 10 20 25 30 20 20

(100) 5-(4-Met,,,,,,,,,,,,,,,,,,,,,) , 6-tetrahydropyridine 1-1-------------------------------------------------------------------------------------------------------------.

(101) 5 — (4-チレレフ一) 1 3 — [[2 1 {1-(4-phenolic benzene) 1, 1, 2, 5, 6-tetrahydropyridine 1 4 1}] カカノノ[L]

(102) 5 — (4-Met transfer) — 3 — [[2—I 1-(4-French outlet) 1 1, 2, 5, 6—Tetra Hydridine} 4 4} レチチチソソソソソソ

(103) 5 — (4-1-(1-(1-(4-)) 1 1, 2, 5 , 6 — tetrahydropyridine 1-1-1------------------------------------------------------------------------------------------------------------------------------------------------------------------

(104) 5 — (4-1 Black mouth) 1 3 — [[2 — {1-(41 Fluoro benzene) 1-1, 2, 5, 6—Tetra Hydridone-one-one-one}

(105) 5 — (4-Nitrofe 2nole) 1 3 — [[2— {1 1 (4 1 1 open mouth benzene) 1 1,2,5,6—Tetrahi [Dropiridine-1-4 yl] チレ] カ * * * モ * モモモモソソキサキサキサキサ

(106) 5 — (4-1)-3-[[2-

{1-(412 Trovendinole) 11, 1, 2, 5, 6 —Tetrahydropyridine 1 41 Innole} チチ] カカSoxazole

(107) 5 — (4-1 レレホホホレレ一一 — [[— — 3 [[[2-{1-( ー Tetrahedro-pyridin-1 4 1 レレチチチカイイソソ

(108) 5 — (4-Methyl phenol phenol phenol) 1 3-1 [[2-I 1-(4-nitrobenzene phenol) 1 1, 2, 5, 6 — Tetrahydropyridin-1 4-ethyl] canolenomoyl] isoxazole

(109) 5 — (4-チレ二二二一) 1 3 — [[2-1 {1-(412 ロロジ）) ΐ, 2,, 5, 6 — Tetra [4-Pyrrolidine] 1-oxinazole] canoxenazole

(110) 5 — (4-Met シヱノレ一) 1 3 2 [[2-{1-(412 ロレ）一) 一 1, 2, 5, 6 — Tetra Hydridoline 4-hydroxyethyl] canolenomoinole] isosoxazole

(111) 5 — (4-1-C-2-I 1-(4-1-2, 5, 6) — Tetrahydropyridin-1 4-yl} echinole] canoleva moinole] isoxazole

(112) 5 — (41-Cross Mouth) 1 3 — [[2 — {1-(412 Trobenzil) 1 1, 2, 5, 6 — Tetrahydrid Propylene-dioxin 4-butanol} canolebamo i-isoxazole

(113) 5 — (412 Trobininole) 1 3 — [[2 — I 1-(412 Troveninole) 1 1, 2, 5, 6 — Tetrahiドロ一一一 4 一一ロロ 4 一ロ 4 4 Soxazole

(114) 5 — (41 Cyanophoninole) 1 3 — [[2 — {1-(4 Cyanobenzinole) 1 1, 2, 5, 6 — Tetrahi [Dropyridin-one-but-one]

(115) 5 — (4-Methyl-N-O-H-N-O-N-F) 1 3 — [[2 — I 1-(4-I-A-N-V-Z-NO) 1 1, 2, 5, 6-T 4-hydroxyl-methyl] -carno-mo-inore] isosoxazole

(116) 5 — (4-Methyls fin fin レヱノ) 1 3 1 [[2-1 1-(4 シ 1, 2, 5, 6) 1, 2, 5, 6 — Tetrahydropyridin-1 4-ethyl] canolenomoinole] isoxazole

(117) 5 — (4-Methyl-North) 2 1 — 3 — [[2 1 {1-(4 1-Cyanobenzinole) 1 1, 2, 5, 6 — Tetra Hydrolyzine-one-methyl

(118) 5 — (4-Met シフヱレ一) 1 3 [[[2 — {1-(4 シ 1 ベベジジレ) 1 1, 2, 5, 6 — Tetrahi [Dropiridine 1 4 1}} レレェカカカカソソソソソソソ

(119) 5 — (4,1 Trif Cleolo Metinolen Feninole) 1 3 1 [[2 — {1-(4 1 Cyanobenginole) 1 1, 2, 5, 6 — Tetrahydropyridin-1 4 ノ] レチチチ]] イソソソソソソ (120) 5-(4 1-mouth dinosaur) 1 3-[[2-{1-1 (41-cyano-benzene) 1 1, 2, 5, 6-Tetrahi [Dropiridine 1-41] [Ethyl] Canolenomoinore] Sosoxazonole

(121) 5-(412 Troponinole) 1-3 [[2-

{1-(41 cyanobenzinole) 1, 1, 2, 5, 6 — tetrahydropyridine 1 4 1 ethyl} ethyl] canolebamoinole] disoxazole

Claims

The scope of the claims

1. General formula:

M—W—Y—A—0

[Where Μ is the formula:

(Wherein, 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 optionally having a suitable substituent, or phenyl even if having an appropriate substituent. , Or

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

A group represented by the formula:

W represents a bond, lower alkylene or lower alkylene,

Y is lower alkylene,

Formula I CO— N—

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

(Wherein R ⁷ represents a hydroxy or a protected hydroxy).

A represents a bond or lower alkylene,

Q is the expression ':

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

(In the formula, R ⁴ represents lower alkyl or anore (lower) alkyl which may have a suitable substituent,

Represents a single bond or a double bond. ) And the salts thereof, which are pharmaceutically acceptable.

2. M is the formula:

R "

(Wherein, R ¹ may be hydrogen, lower alkyl, a heterocyclic group which may have 1 to 3 substituents, or 1 to 3 substituents. Phenyl,

R ² is hydrogen, lower alkyl, a heterocyclic group which may have 1 to 3 substituents, or a heterocyclic group which may have 1 to 3 substituents. -Represents or is

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

A group represented by) which forms a group of Q is the formula

Wherein R ⁸ represents lower anoalkyl and R ⁹ represents phenyl (lower) alkyl.

(Wherein R ⁴ is lower alkyl or phenyl (lower) alkyl which may have 1 to 3 substituents,

Represents a single bond or a double bond. 3. The compound according to claim 1, which is a group of the formula (1).

3. M is the formula:

R "

(In the formula, R ¹ is nitro, cyano, lower alkylsulfonyl, lower alkylsulfinyl, lower alkylthiol, lower alkoxyl, trialkyl Halo (Lower) Alkyl and Haloge May have one substituent selected from the group consisting of

R ² represents hydrogen), a group represented by

Is a bond or a lower alkenylene,

Y is the formula:

(Wherein, R ³ represents hydrogen.)

A is lower alkylene,

Q is the formula:

(Wherein, R ⁴ is a phenyl (lower) alkyl which may have one substituent selected from the group consisting of nitrogen, nitrogen and cyano,

Represents a single bond or a double bond. 3. The compound according to claim 2, which is a group of the above.

4. M is the formula:

(Wherein, R ¹ is a phenyl which may have one substituent selected from the group consisting of nitro and cyano,

R ² represents hydrogen), a group represented by

Q is the formula:

(In the formula, R ⁴ may have one halogen and represents phenyl (lower) alkyl.)

The compound according to claim 3, which is a base of the compound.

5. M is the formula:

(Wherein, R ¹ represents nitrophenyl or cyanophenyl R ² represents hydrogen),

Q is the formula:

(Wherein R ⁴ represents benzyl or halobenzyl). The compound according to claim 4, wherein the compound is a group represented by the following formula:

6. (1) 3 — [[2 — (1-Pin pyridine) 14 — レ] チチカノ 5 5 — 5 — (412 フフ) Soxazole and its hydrochloride,

(2) 3 — [[2 — (1-diphenylpyridine 14-yl) ethyl] canolebamoin] 1 5 — (4-diphenyl) isoxazole And its hydrochloride,

(3) 3 — [[2 — {1-(4- phenolic mouth benzyl) pyridine 1 4 1} レ}} チカカカカ) (Non-Fénénéré) isosoxazole and its hydrochloric acid,

(4) 5-(4 12 trophenyl) 1 3 — [(E) 1 2 — [2 — {1-(4-phenolic mouth benzyl) Perylene 1 4 1 } カレレビビビビビビソビビビビビニニニニフフフ

C5) 5 — (412 Tronininore) 1 3 — [(E) 1 2 — [2 — {1 1 Benzinolepiperidine 1 4 1 Ino} Echinoré Power Rubamo Innore] Biel ] Sozoxone and its fumarate,

(6) 5 — (4-Cyanophenyl) 1 3 — [(E) 1 2 — [2-I1- (4-benolole)] Peripheral 4-yl} レビビビビイニソソソソソソソFumarate,

(7) 5-(4 Cyanopininole) 1 3 — [(E)-2-

C2-{1-1-benzene-pyridin-1-4-1-----------------------------------.

The compound according to claim 5, which 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 may be hydrogen, lower alkyl, a heterocyclic group which may have a suitable substituent, or may have a suitable substituent. The

R ² represents hydrogen, lower alkyl, an optionally substituted heterocyclic group, or an optionally substituted aryl group. Les,

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

A group represented by the formula:

W represents a bond, lower alkylene or lower alkylene,

Y is lower alkylene,

-ΝΉ-, -C-

II

0 expression

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

-CH-

(Wherein R ⁷ represents a hydroxy or a protected hydroxy).

A represents a bond or lower alkylene,

Q is the formula:

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

(Wherein, R ⁴ represents lower alkyl or an alkyl (lower) alkyl which may have a suitable substituent,

Represents a single bond or a double bond. ) Represents a process for producing an isoxazole derivative or a salt thereof represented by the formula:

(1) General formula:

M-W-C O O H

(Wherein, M and W have the same meanings as described above), or a reactive derivative at the carboxyl group or a salt thereof.

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

M— W— CON— A— Q

(Wherein M, W, R ³ , A and Q have the same meanings as described above), or a salt thereof,

(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-

(Wherein, R ³ is a lower alkyl

X ¹ represents an acid residue. ) Reacting with the compound represented by or a salt thereof

General formula:

Or obtained ^{_{(wherein, M, W, R 3 a}} , A Contact and Q mean the same as before, respectively.) The compound or represented by a salt thereof, or,

(3) General formula:

M-W ¹ -CH 0

(Where M has the same meaning as before,

W ¹ is a bond, - C 5 was alkylene-les-down or shows the C ₂ ~ C ₅ alkenylene-les-down. ) Or a salt thereof,

General formula:

H ₂ N-A-Q

(Wherein, A and Q have the same meanings as described above), or a salt thereof, and the resulting compound is then subjected to a reduction reaction.

General formula:

M-W ^ C H ^ N H-A-Q

(Wherein, M, W ¹ , A and Q have the same meanings as described above), or a salt thereof is obtained. (4) General formula

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

R ⁷ J represents a protected hydroxy compound) or a salt thereof, by subjecting the compound to the elimination reaction of a hydroxy protecting group.

General formula:

(Wherein, M, W, A and Q have the same meanings as described above), or a salt thereof is obtained, or (5) 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. The compound according to claim 1 or a pharmaceutically acceptable salt thereof is contained as an active ingredient together with a pharmaceutically acceptable carrier. A pharmaceutical composition.

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

10. Prevention of diseases of the central nervous system by administering to a human or animal a compound or a pharmaceutically acceptable salt thereof as defined in claim 1 or a pharmaceutically acceptable salt thereof. Or treatment.

1 1. Production of a pharmaceutical composition characterized by containing the compound of Claim 1 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier. Law.