WO1985001289A1

WO1985001289A1 - Benzoxazolone and benzothiazolone derivatives and process for their preparation

Info

Publication number: WO1985001289A1
Application number: PCT/JP1984/000452
Authority: WO
Inventors: Yoshihiko Kitaura; Teruo Oku; Yukihisa Baba; Chiyoshi Kasahara; Masashi Hashimoto
Original assignee: Fujisawa Pharmaceutical Co., Ltd.
Priority date: 1983-09-22
Filing date: 1984-09-20
Publication date: 1985-03-28
Also published as: IT1176770B; IT8422785A0; IT8422785A1; AU3431784A; GB8325370D0

Abstract

Novel benzoxazolone and benzothiazolone derivatives represented by formula (I), (wherein R1 represents an aryl or heterocyclic group optionally having a suitable substituent, R2 represents halogen, lower alkyl, lower alkoxy or hydroxy, R3 represents hydrogen or lower alkyl, X represents sulfur or oxygen, and Y represents CO, S, SO2 or NH), salts thereof, process for their preparation, medicinal composition containing them, and use of them for treating inflamation or thrombosis of men and animals.

Description

Meiyanagi Benzoxazolone and Benzothiazolone Derivatives and Their Manufacturing Technology

The present invention relates to novel benzoxazolones and benzothiazone derivatives. More specifically, the present invention relates to novel benzoxazoconone and benzothiazozone derivatives having anti-inflammatory and antithrombotic effects, a process for producing them, and a process for producing them. The invention relates to pharmaceutical compositions containing the same and to their use as medicaments in the treatment of inflammation or thrombosis in humans and animals.

That is, one object of the present invention is to provide novel benzoxazolones and benzothiazolone derivatives which are useful as pharmaceuticals such as anti-inflammatory agents or antithrombotic agents. This is ο

Another object of the present invention is to provide a process for producing the benzoxoxa; σ- and benzothiazolone derivatives.

Still another object of the present invention is to provide a pharmaceutical composition containing the benzoxazolone and the benzothiazolone derivative as active ingredients. .

Yet another object of the present invention is to provide a method of using benzoxazolone and benzothiazolone derivatives in the treatment of inflammation or thrombosis of humans and animals. What to provide

OMPI WIPO The disclosure of Kishimei

Benzoxazozolone and Benzothiazozo ^σ derivatives are new for the purpose], which can be represented by the following one-boat formula (I) ο

(In the formula, S ¹ is a aryl group or a heterocyclic group which may have a suitable substituent,

Represents a halogen, a lower alkyl group, a lower alkoxy group or a hydroxy group,

Is hydrogen or a lower alkyl group,

X is S or 0,

- means respectively CO, S, S 0 ₂ or is a ΪΓΗ). According to the present invention, the novel benzoxazolone and benzothiazone derivative (I) are produced by the production method represented by the following reaction formula! ? Can be manufactured.

Manufacturing method 1

Ο ΡΙ

WIPO

Or its salt (la)

Or its salt or its salt Production method 2

H

(F)

Or its or salt Production method 3

Manufacturing method 4

(Id) (Ie)

Or its salt or its salt Manufacturing method 5

R ¹ — Y

Manufacturing method 6

(Where R ¹ ,, R ³ , X and Y have the same meanings as before,

Is a lower alkyl group,

R is a lower alkyl group,

H · CO or S 0 ₂ ,

Z and each represent a leaving group). Among the starting compounds of the present invention, some of the compounds of the formula ΦΠ are novel and can be produced by the following method.

Production method of raw material compounds 1 ',

ΟΜΡΙ

. WIPO ー Y — H +

E ²

m (vi) (I) Production method of starting compound 2 ー

(X) Raw material compound production method 3

E ¹ — Y-Vintage

R ²

(X)

Or its salt

(Wherein, and, respectively, have the same meaning as before, and ぁ represents a lower alkyl group,-represents S or, and represents an acid residue, respectively).

In the above and following description of this specification, preferred examples and explanations of various definitions included within the scope of the present invention are described in detail below.

OMPI "Lower" shall mean a group having from 1 to 6 carbon atoms, unless otherwise indicated.

Suitable “lower alkyl group” is a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethynole, propynole, Examples include isoppropinole, butynole, isobutynole, tertiary butyl, pentyl, hexyl, and the like, preferably those having 1 to 4 carbon atoms.

A preferred "lower alkoxy group" is a straight-chain or branched alkoxy group having 1 to 6 ^ -atoms, such as methoxy, ethoxy. , Butoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, hexoxy, etc. It preferably has from 1 to 4 carbon atoms.

Preferable "aryl groups" include phenyl, trinole, xylyl, mesyl, and tarmenyl, and these "aryl groups" Is a halogen, such as fluorine, chlorine, bromine, or iodine; for example, methoxy, ethoxy, propoxy, isop sigma, and tertiary butane. It may have a suitable substituent such as a lower alkoxy group such as xyl. .

A preferred "heterocyclic group" has at least one heteroatom such as an oxygen atom, a zirconium atom, a nitrogen atom, etc., and is therefore referred to as "heterocyclic group". Examples thereof include a “heteromonocyclic group” such as a 3- to 7-membered heteromonocyclic group containing phenyl or the like.

Preferred examples of "leaving group" of "z and z '" include

(O PI For example, halogens such as fluorine, chlorine, bromine or iodine, for example, methoxy, ethoxy, propoxy, isopropoxy, tertiary Lower grades such as butoxy, etc., alkoxy groups, such as Trik sigma oxime, Trifnoremo oxime, 2, 2, 2 Tris (2,2,2) —tricyclo mouths—tri-mouth (lower) terrexoxy, amino, imidazolyl groups such as tertiary butoxy And the like.

Preferable examples of the “acid residue” include, for example, a halogen such as fluorine, chlorine, bromine, or oxygen, and a sulfonyloxy group (for example, a methyl group). Groups such as oxy group, ethanol group, benzene group, benzene group, benzene group, etc.). Can be

Suitable "halogens" include chlorine, bromine, fluorine and oxygen. Suitable salts of the target compound (I) are pharmaceutically acceptable salts, ie, common non-toxic salts, such as acetate, maleate, tartrate, methansulfonate Organic salts such as salts, benzenesulfonate, formate, and toluenesulfonate, for example, hydrochloride, hydrobromide, hydrobromide, Inorganic acid salts such as thiocyanates, sulfates, phosphates, etc., or amino acids such as, for example, alginine, azuno, 'raginic acid, glutamate, etc. And the like. The process for producing the target compound (I) of the present invention will be described in detail below.

OMPI To

Manufacturing method 1

The target compound (la) or a salt thereof can be produced by reacting the compound (Π) or a salt thereof with the compound (0Π) or a salt thereof.

This reaction is usually carried out in the presence of luciferic acid, but the most preferred acid is polyphosphoric acid.

This reaction is preferably performed without a solvent. In other words, in this reaction, polyphosphoric acid is used both as an acid and as a solvent.

The reaction temperature is not particularly limited, and the reaction is usually carried out at room temperature, under heating or under heating, or under heating.

The salt of the chemical compound (Π) is, for example, an alkali metal salt such as sodium salt or potassium salt, for example, calcium salt or magnesium salt. Salts such as earth metal salts, etc.¾Salts with inorganic bases, organic bases such as trimethinoleamine, triethynoleamine, pyridine And salts with an acid such as hydrochloric acid or hydrobromic acid.

Suitable salts of the target compound (la) and the outline thereof include those exemplified for the target compound (I). Manufacturing method 2

The target compound (I) or a salt thereof can be produced by reacting the compound (IV) or a salt thereof with the compound (V).

^ o

OMPI Preferable examples of the compound (V) include phosgene, carbonyl carbon fluoride, dimethyl carbonate, dimethyl chloroformate, methionyl chloroformate, chloroformic acid, and the like. Echinole, ku σ σ Trichloromethinole formate, 1,2-chloroformate, urea, 尿素, Ή, Ή-canole, etc. These include:

This reaction is usually performed in the presence of a base.

Suitable bases include, for example, alkali metal hydrides such as sodium hydride, for example, alkali metal hydroxides such as sodium hydroxide and hydroxide hydroxide. Alkali earth metal hydroxides such as magnesium hydroxide, calcium hydroxide, etc.Alkali metals such as sodium carbonate, calcium carbonate, etc. Alkali metal carbonates such as magnesium carbonate and calcium carbonate Alkali metal carbonates such as sodium bicarbonate and potassium bicarbonate Bicarbonate, for example sodium acetate, aluminum acetate such as acetate acetate Metal acetate, for example magnesium phosphate, calcium phosphate, etc. Calcium earth metal phosphates, such as sodium hydrogen phosphate and hydrogen phosphate Inorganic bases such as metal hydrogen phosphites, etc., and triaminoquinoamins such as, for example, trimethylammine, triethylamine, etc. Organic bases such as picolin, piperidine, U-methylol.pi-lysine, N-methylolmonolefolin and the like.

This reaction is usually carried out in a solvent such as ethyl acetate, acetate, methyl ether, tetrahydrofuran, and toluene, If the solvent does not adversely affect the reaction,

OMPI The reaction can be performed in any other solvent. The reaction temperature is not particularly limited, and the reaction is usually performed under rejection, normal temperature, heating or heating.

When urea is used as a reagent, the reaction is usually carried out in a solvent-free solvent while heating.

Suitable salts of the compounds include those exemplified for the target compound (I). Manufacturing method 3

The target compound (Ic) or a salt thereof can be produced by subjecting the compound (lb) or a salt thereof to an oxidation reaction.

Preferred examples of the oxidizing agent used in the reaction include hydrogen peroxide, perbenzoic acid, perphthalic acid, formic acid, peracetic acid, triflic acid persulfate, and meta-sigma. Peroxyacids such as perbenzoic acid are mentioned.

This reaction is usually carried out in a solvent such as acetic acid, chlorophoronem, dichloromethane, diethanolamine, dioxane or benzene. The reaction can be performed in any other solvent that does not adversely affect the reaction.

The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling, at room temperature, under heating or under heating.

Examples of the salt having a good interference with the target compounds () and (Ic) include those exemplified for the target compound (I). Manufacturing method 4

The compound (Ie) or a salt thereof can be produced by subjecting the compound (I) or a salt thereof to an ether cleavage reaction. '

Suitable reagents to be used in this reaction include, for example, sigma hydrogen, such as hydrogen tribromide, and hydrogen halide, such as hydrogen bromide and hydrogen bromide. Examples include luic acid.

This reaction is usually carried out in the form of edromethane, acetic acid, and anhydrides such as dichloro sigma methane, macroporous film, and, for example, diethyl ether ether and tetrahydrofuran. Performed in a solvent such as acetic acid.

When using lysic acid, it is preferable to use a non-pitonic solvent such as dichromane, chloroform, polyester and the like.

The reaction temperature is not particularly limited, and the reaction is carried out under cooling, at room temperature, under heating or under heating.

Suitable salts of the compounds (Id) and (Ie) include those exemplified for the target compound (I). Manufacturing method 5

The target compound (Ig) or a salt thereof can be produced by subjecting the compound (If) or a salt thereof to an N-alkylation reaction.

The IT—Alkylating agent used in the alkylation reaction is, for example, mono (or di) -low, such as dimethyl sulfate.

OMPI Lower alkyl sulphonic acid (lower) alkyl esters such as methansulphonic acid methyl olester, etc. And σ-genated (lower) alkyls such as methylated methyl and ethyl terephthalate.

This reaction is usually carried out in the presence of a base.

Suitable bases include alkaline metal hydrides, such as, for example, hydrogenated sodium hydride, for example, sodium methoxide, sodium methoxide, sodium hydroxide, etc. Alkali metal alkoxides such as lithium tertiary butoxide, for example, Alkali metal hydroxides such as sodium hydroxide, hydroxide hydroxide, etc. Alkaline earth metal hydroxides such as magnesium oxide and calcium hydroxide, for example, Alkali metal carbonates such as sodium carbonate and carbonated carbonate, for example Alkali metal carbonates such as magnesium carbonate, calcium carbonate, etc.Alkali metal bicarbonates such as sodium bicarbonate, bicarbonate lithium, etc. Alkali metal acetates such as sodium acetate, potassium acetate, etc. Alkaline earth metal phosphates, such as calcium and calcium phosphate, for example, aluminum salts such as sodium phosphate sodium phosphate and sodium phosphate phosphate Inorganic bases, such as metal hydrogen phosphinates, and, for example, trimethylamine, triethylamine, triethylamine, picolini, and the like. And organic bases such as methacrylonitrile, pyrrolidine, methamine pyrrolidin, and methionolemorpholin.

This reaction is usually carried out in a solvent such as dichloromethane, chlorophoronelem, aceton, or jetinole ether,

ΟΜΡΙ The reaction can be performed in any other solvent that does not adversely affect the reaction.

The reaction temperature is not particularly limited, and the reaction is usually performed under cooling, at room temperature, or under heating.

Examples of suitable salts of the target compounds (If) and (Ig) include those exemplified for the target compound (I). Manufacturing method £

The target compound (If) or its salt is obtained by subjecting compound (1) or its salt to a ring-closing reaction! ) Can be manufactured.

The reagent used for this ring-closing reaction is, for example, an alkali metal azide such as sodium azide or a lithium azide, for example, diphenyloxyphosphorus Azide, di (p-trino-reoxy) resin, etc. Azide derivatives such as di (lower) alkoxyphosphorinoleazide such as noreazide and jetkoxyphosphorinolazide.

This reaction is usually associated with toluene, xylene, N, N-dimethylaminophenol, for example, trimethylaminoamine, triethylamine, etc. The reaction is carried out in a solvent such as triaminophenol or chlorophorone, but the reaction can be carried out in any other solvent that does not adversely affect the reaction. You can do it.

The reaction temperature is not particularly limited, and the reaction is usually performed under heating or heating. Examples of suitable salts of compound W include salts with bases as exemplified for chemical compound (II).

Preferred salts of compound () are as exemplified above. The method for producing the starting compound will be described in detail below.

Manufacturing method of application fee compound 1

Compound (E) can be produced by reacting compound (ΫΠ) with compound (观).

This reaction is usually performed in the presence of a base.

Suitable bases are, for example, alkali metal hydrides such as sodium hydride, for example sodium methoxide, sodium methoxide, potassium hydride. Alcohols such as tertiary butoxy and other metal alkoxides, such as sodium hydroxide, hydroxylated lime and other metal hydroxides For example, alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, and alkaline metal carbonates such as sodium carbonate and potassium carbonate Alkali earth metal carbonates such as magnesium carbonate and canecarbonate, for example, Alkali metal carbonates such as sodium bicarbonate and hydrogencarbonate-lithium Alkali metal acetates, such as bicarbonates, for example sodium acetate, potassium acetate, etc. Alkaline earth metal phosphates such as magnesium and calcium phosphate, for example, sodium phosphate sodium phosphate, dicalcium hydrogen phosphate, etc. Inorganic bases such as alkali metal phosphoric acid hydrogen salts, and, for example, trimethylamine, trimethylamine, triethylamine, etc. Picolin, pico

OMPI Organic bases such as peridine, N—methinole pyrrolidine, and N—methinole monolefolin.

The reaction is usually carried out with water, for example, methanol, ethanol, etc., acetic acid, acetate, dioxan, acetonitrinole, chlorophenol. , Dichloromethan, shiojiride ethylene, tetrahydrofuran, alcoholic acid, IT, N—dimethinole honolem amido pyridin The reaction is carried out in such conventional solvents, but the reaction can be carried out in any other organic solvent as long as it does not adversely affect the reaction. Among these solvents, the hydrophilic solvent may be used by mixing with water.

The base to be used is, for example, an alkali metal hydride such as hydrogen hydride, or a metal hydride such as sodium methoxide, sodium methoxide, or potassium hydride. In the case of alkaline metal alcohols, such as tertiary butoxy chloride, this reaction usually takes place, for example, in the presence of methanol, ethanol, etc. A / C / A / C / A / C / A / C / C / A O Lan, N, N — done in dimethylformamide and pyridin or mixtures thereof o

The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling, at room temperature, under heating or under heating. Production method of raw compound 2

Compound (X) can be produced by subjecting compound (K) to an ether cleavage reaction. This reaction can be carried out in substantially the same manner as in Production method 4.o Production method of starting compound 3

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

This reduction reaction includes, for example, aluminum metal bisulfite such as sodium bisulfite or aluminum metal sulfide and ammonia such as sodium sulfide. Combination of near water, (2) combination of metal and organic acid,) catalytic reduction, etc.

When a combination of metal bisulfites or sulfides and ammonium hydroxide water is used, this reaction is usually carried out with water, for example, methanol, ethanol, etc. The reaction is carried out in a solvent such as the above-mentioned solvent, but can be carried out in any other solvent that does not adversely affect the reaction.o

When a combination of a metal and an organic acid is used, suitable metals include iron, zinc, and the like, and suitable organic acids include formic acid and acetic acid. And others.

In the case of using catalytic reduction, examples of suitable catalysts include a catalyst such as a platinum metal catalyst such as platinum oxide and a palladium metal catalyst such as palladium-carbon.

Suitable salts of the compound (ffa) include those exemplified for the target compound (I).

OMPI The target compound of the present invention is a novel compound and has an anti-inflammatory effect and an antithrombotic effect.

For therapeutic use, the compounds of the invention are pharmaceutically acceptable, such as organic or inorganic solid or liquid excipients suitable for oral, parenteral administration or external use The compound can be used in the form of a pharmaceutical preparation containing the compound as an active ingredient after being mixed with a carrier. Pharmaceutical preparations include capsules, tablets, dragees, solutions, suspensions, emulsion and the like. If necessary, the above preparations may contain auxiliaries, stabilizers, wetting agents or emulsifiers, buffers and other commonly used additives. The dose of the compound will vary depending on the age and condition of the patient, but the compounds of this invention will be irritated or irritated at an average single dose of about 10, 50, 100 mg 250, 500, 1000. It is effective in treating thrombosis. In general, an amount of 1 individual to about 6000 ^ / individual or more per day? Just give it. In order to show the usefulness of the target compound (I), pharmacological test results of representative compounds of the target compound (I) are shown below.

[I] Test compound

(1) 6—Venzo Nole 5—Cross mouth 2—Venzoxazolone Is) 6—Benzo No 1-5—Phone 2 1—Benzox

[11] Test

Carrageenin foot edema

1.Test method

A group of 5 Sprague-Dawley male rats weighing about 200 ^ were used.

One-day _zero force ratgenin (0. rat) was injected subcutaneously into the right hind paw to create force-lagenin foot edema. The test drug was suspended in methylcellulose and given orally 60 minutes before the administration of ligamentin.

The foot volume was measured by a water displacement method by immersing the foot volume just above the peroneal malleolus using a blemistomometer (manufactured by Yugo Basil). The difference in paw volume between before and 3 hours after lactogenin administration was considered as edema volume. Test results are based on Student's t-test].

2. t? \ Test Articles

Note): P <0.05 * * *: P <0.00 P: Risk factor B. Alsus-type foot edema

1.Test method,

Sprague-Dawley male rats weighing approximately 200 ^ were used in groups of five.

By intravenous injection of albumin (0.5 lat) and subcutaneous injection of anti-albumin serum (0.1 Z lat) in the ffi? Then, we created an althus-type foot edema. The test drug is suspended in methylcellulose, and the antigen and antibody are administered.

Oral administration was performed 60 minutes before.

The foot volume was measured by a water displacement method using a plethysmometer (made by Yugo Basil) and immersing it just above the peroneal malleolus. The difference in paw volume between before administration of the antigen and antibody and 1 hour and 3 hours after administration was regarded as edema volume. The test results were statistically analyzed and solved by Student's t-test.

2. Article

Note) *: P less 0.05 **: P <0.0 ***: P less 0.001

P: Risk factor

O PI

,> WIPO C. Platelet aggregation test

1.Test method

Blood was collected from the central ear artery of male Japanese white rabbits weighing 2.5-3.0 ^. 3.8 de for 9 volumes of blood. The blood was subjected to anticoagulation treatment by adding 1 volume of sodium citrate. Blood was centrifuged at 1300 rpm for 10 minutes at room temperature to prepare platelet-rich plasma. Platelet-poor plasma (PPP) obtained by further centrifuging blood at 3000 rpm for 10 minutes: PRP was diluted. The number of platelets in PRP used for the agglutination test was about 4 × 10 ⁵ / raj !. Platelet aggregation was measured by a Bonn and Box turbidimetric method in a double channel aggregometer (Shenko, DP-247E). In most experiments, a saline Z-blocker mixture (a block of PRP O.25 m plus saline 0.02) was stirred (100 rpm) during aggregation. The bottom was incubated at 37 C for 2 minutes and then the flocculant (0.03) was added. Platelet aggregation was measured by D-turbidimetry by recording the change in light transmittance during aggregation. The activity of the inhibitor was determined by the IC _{5 ()} value, ie 50 de. It was expressed as the concentration required for the platelet aggregation inhibition response.

Arachidonic acid (Sigma II) was used as a flocculant at a final concentration of 5M.

2. R ^ test; ta fruit

(1) IC ₅₀ = 0.29 /

ΟΜΡΙ (2) C 5 0 8 / mi

BEST MODE FOR CARRYING OUT THE INVENTION

Preferred embodiments of the target compound (I) are as follows. Preferred embodiments of R ¹ may have a halogen. ■ aryl group; or a heteromonocyclic group, more preferably fluorine or chlorine. Is a phenyl group which may have a methyl group; or a phenyl group.

Preferred embodiments are a halogen, a lower alkyl group, a lower alkoxy group or a hydroxy group.

Preferred embodiments of R ³ are hydrogen or lower alkyl groups o

Y of preferred correct embodiments CO, s or is so ₂ der ', preferred correct embodiments of X is 0 or is Ru S der. Hereinafter, the present invention will be described with reference to Production Examples and Examples. Production Example 1

To a solution of chionoenole (2.24 ^) in N, N-dimethyl honoleamide (2) was added force tertiary butoxide (2.28) Then, add 4,5-dichloro-1--2-nitroanisole (4.1 ^) at 5 ° C.

After the addition is completed, raise the temperature of the mixture to room temperature, stir for 40 minutes, and then pour into a mixture of ethyl acetate and water. The organic layer is washed six times with 6II hydrochloric acid, sequentially with water and an aqueous solution of sodium chloride, dried, and the solvent is distilled off under reduced pressure.

Ο ΡΙ The residue is crystallized from n-hexan to obtain 4-alk an — 2 — dito σ — 5 — phenylthioanisole (5.15 ^) as crystals.

m p 76 to 77 ° C

IR (Nudiol): 1600, 1560, 1500 cm ' ¹ Production Example 2

4 Monochrome σ — 2 — Two trol 5 — Phenyl benzothiol (5.03 ^) anhydrous dicyclo σ rometan (60 At once at 5 ° C. After stirring at the same temperature for half an hour, add 6ίΓ hydrochloric acid (100 dropwise to this at 5 ° C. Separate the organic layer, and add Times, then wash with water, dry and distill off the solvent under reduced pressure.Residue is subjected to a silica gel (100 chromatographs using a column chromatography, n — Elution with a 1: 1 mixture of hexane and benzene, 4 — chloro 2 — 2 to 1 5 — phenyl phenol

(2.15) is obtained as colorless crystals.

m p 1 2 2 to 1 24 ° C

IR (Nujiyoru): 1 6 1 0, 1 5 70, 1 5 0 0 ατΓ 1 Production Example 3

4 — Chlorine 2 — Two-to-one mouth 5 — Mixture of phenol (0.75 ^) in water (14.5 and ethanol (14 m)) Add ammonia water (0.71 ^) and add a small amount of sodium bisulfite (2.53) to the yellow solution. Add at room temperature. After stirring for 2 minutes at room temperature, the mixture is cooled in an ice bath and adjusted to pH 7 with acetic acid. Water is added to the mixture to precipitate the product. The precipitate is removed, washed with water, and dried to obtain 2-amino-4-chloro-5-vinylthiophenol (0.57 ^).

mpl32-; L35. C (decomposition)

IR (Nujo 1): 3380, 3300, 1580, 149 OCOT- ¹ Production Example 4

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

(1) 4---一 5 5 ((4 クロ口口 2 一一一一一)

m p 1 3 8 to 1400C

R (Nujol): 16 Ocm ' ¹

NMR (DMS 0-d ₆ , d): 3.70 (3H, s), 6.67 (1H, s),

7.60 (4H, s), 8.12 (1H, s)

(2) 4—Crolow 5— (4—Funoleo Rondino) 1 2—2 Troisani Sonore

m p 1 14 to 1 15 ° C

IR (Nujiol): 1 600cm- ¹

MR (DMS 0-d ₆ , d): 3.6K3H, s), 6.47 (1H, s),

7.23-7.83 (4H, m), 8.08 (111, s)

(3) 4 — Black mouth 5 — (2 — methyl thiol) 2 — 2 Troisone

mp 77-78. C

U IR (Nujo one Norre): 1590, 1560 ero one ¹

ίΓΜΕ (DMS 0-d ₆ , d): 2.36 (3H, s), 3.53 (3H, s),

6.27 (1H, s), 7.20 -7.33 (4H, s), 8.13 (1H, s) Production Example 5

The following compound is obtained in the same manner as in Production Example 2.

(1) 4 CRO 5 — (4 CLO PORT PENINOLETCH) 1 2 1 NITRO PHONO

m p 4 1 to 1 4 2. C

IR: 3080, 1605em ^-1

jfMR (DMS 0- d _6, Ri: 6.47 (1H, s), 7.67 (4H, s),

8.07 (1H, s)

(2) 4 — Black mouth 1 5 — (4-Normal)

m p 98 to 99 ° C

I H (Nujo-no-Nore): 3100, 1610, 1590 COT—

1 M (DMS 0-d ₆ , d): 6.35 (1H, s), 7.27-7.83 (4H, m), 8.00 (1H, s)

(3) 4—Cross mouth 1 5— (2-Methyl thiol)

m p. 104: L 0 5 ° C

IR (Nujanore): 3250, 1605 — ¹

MR (DMS 0-d ₆ , δ): 2.33 (3Η, s), 6.22 (IE, s) _;

7.23 — 7.80 (4H, m), 8.00 (1H, s)

OMPI Manufacturing example

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

) 2 — Amino 4 — Black mouth 1 5 — (4 1 Black mouth)

mp144-: L45. C

IH: 3390, 3300, 1580 αιΓ ¹

NMR (DMS 0-d ₆ , d): 6.77 (1H, s), 6.80 (1H, s),

6.97 (2H, d, J = 8Hz), 7.30 (2H, d, J = 8Hz)

(2) 2—Amino 4—Crolow 5— (4—Fonore o Lo Fenni Nore)

m p 12 9 to 13 0 ° C

IR: 3380, 3300, 1680 an ' ¹

ΉΜΉ. (DMS 0-d ₆ , d) ： 6.77 (2H, s), 7.07 (2H, s),

7.50 (2H, s)

(3) 2 — Amino 1 4 — Black mouth 1 5 — (2 — チ二）フフ)

mp 1887-: L92C (decomposition)

IR (Nujanore): 3600—3100, 3490, 331 QarT ¹

ME (DMS 0-d ₆ , 3): 2.30 (3Η, s), 6.70 (1Η, s),

6.77 (2Η, s), 6.83-7.33 (3H, m) Production example 7

Two-port benzene of anhydrous aluminum chloride (31.8 ^)

To the (200) solution was added 4-cyclohexyl——2-hydroxybenzoic acid (34 ... 4 ^) and benzoyl chloride (33.89). Nitrogen atmosphere

OMPI

K U ^PO Heat the mixture at ambient temperature and at 130 ° C for 1.5 hours with stirring. After cooling, pour the mixture into a mixture of ice and hydrochloric acid. The organic layer is separated, and the aqueous layer is extracted with cyclo-α-methane. Combine the organic layers, extract with 1Ν sodium hydroxide, adjust the alkaline solution to PS 4 to 5 with concentrated hydrochloric acid, and then extract with dimethylmethane. The organic layer is washed with water, dried, and the solvent is distilled off under reduced pressure. The residue obtained is crystallized from benzene to give 3-benzoyl, 14-alkoxy-2-hydroxybenzoic acid. The acid (26.31 ^) is obtained as crystals.

mp 17 0 ~ 1 7 1 ° C

IR (Nujo Norre): 3350- 2300, 1660, 1600 βπΓ 1

R (DMS 0— d ₆ ,: 7.16 (1H, d, J = 8 Hz), 7.36— 8.06 (6H, m), 8.05-9.40 (2H, br. S)

5—Chlorol 2—Benzoxazolone (13.56 ^) and a mixture of benzoic acid (11.72 ^) in poly (200 ^) Stir at 130 ° C for 4 hours in the atmosphere. After cooling, add water (200) to the mixture, extract the liberated solid with ethyl acetate (400 ^), wash the organic layer twice with aqueous sodium hydrogen carbonate and then with water, After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure to crystallize 6-benzoyl-5-chloro-2-benzobenzoxazolone (1442 ^). The crystals obtained above are recrystallized from benzene.

O PI

, U lPO mp 1 8 4 — '1 8 6 ° C

IR (Nujo Nore): 1 760, 1670 cm ' ¹

HME (DMS 0-d ₆ , d): 7.32 (1H, s), 7.52 (1H, s),

7.52-7.88 (5H, m)

Elemental analysis, and the C ₁₄ H ₈ I 0 ₃ C

Calculated value: C: 61.44, H: 2.95,: 5.12

Measured value: C: 60.94, Ξ: 3.11,: 5.11 Example 2

(1) In the same manner as in Example 1, 5-fluoro-2-benzobenzoquinone was reacted with benzoic acid and polyphosphoric acid to form 6-benzoic acid. Nore 1-5-Phoreo Mouth 1-Obtain Benzoxazolone.

m p 1 7 1 — 1 7 2 ° C

IR (Nujokure): 3 190, 1800, 1 630, 16 15COT one ^{_{1 NM (DMS 0 -d 6,}} d): 7.14 (1H, d, J = 6Hz), 7.20 (1 H,

brs), 7.41-7.88 (6H, m)

( ² ) In the same manner as in Example 1, 5-methoxy1-2: benzoxazolone was reacted with benzoic acid and polyphosphoric acid,

6 — Benzo no 1 5 — Methoxy 2 — Obtain Benzoxazolone.

m p 2 16 to 2 17. C

IR (Nujanore): 3200, 1790, 1780, 1620 — ¹ ) In the same manner as in Example 1, 5—chloro-2—benzothiazolone was converted to benzoic acid and polyphosphoric acid. And react with 6 — Bay down zone Lee Honoré -5 - click B B - 2 - Ru give base emission zone Chi A zone B emission _{c mp 2 1 5~ 2 1 7} ° C E H (Nujo one Honoré): 1665, 1635, 1 600 ατΓ ¹ ER (DMS 0-d ₆ , 8) ： 7.30 (1Η, s), 7.42-7.82 (5H, m), 7.81 (1H, s)

(4) In the same manner as in Example 1, 6-benzoxazozone was reacted with benzoic acid and polyphosphoric acid to give 6-benzoxazole. 1-5—Metinor 2—Get Benzoxazolone.

πι ρ 1 ύ 4τ 〜 1 ύ 5 °.

IH: 3120, 1770, 1760, 1670 an ' ¹

EMR (DMS 0 -d ₆ , d): 2.30 (3H, s), 7.08 (1H, s),

7.21 (1H, s), 7.42 - 7.82 (6H, m) Mass m / z: 254 (M + 4- 1, 10), 253 (M +, 65%), 252 (100 0)

Example 3 The following compound was obtained in the same manner as in Example 1.

(1) 6 — Benzo-nore 1 5 σ? 3 — Mechinore 1 21 Benzoxazolone mp 14 0 to 14 2 ° CIR (Nujo Nore): 1790, 1670, 63 QcnT ^L ΪΓΜΕ (DMS 0 -d ₆ , 8): 3.40 (3H, s), 7.38-7.90 (7H, m) (2) 6 — Benzoinori 5 — Hydroxy • 2 — Penzo Ox

f Huo 5 O PI mp 2 3 4 to 2 3 5. C

IR (Nujiol): 3150, 1760, 1650, 1620, 1600cm- ¹

(3) 6 Benzensorehoninorone 5 — Chlorine 2 — Benzoxazolone

mp 25 0 ~ 25 3 ^o C

IR (Nujo one Honoré): 3200, 1790, 1760, 1 620 em '1 NMR (DMS 0-d 6, d): 7.34 (1H, s), 7.44 - 8.08 (5H, m), 8.20 (1H, s )

Example 4

2—Amino 1—4—Black mouth—5—Feninolethiophene (1.55 55 ^), Trimethyl chloride formic acid (0.73 3) w.1) A mixture of sodium acetate (0.62 ^) in ethyl acetate (43) is stirred at room temperature for 50 minutes. After cooling, the reaction mixture is stirred. Add water, extract with ethyl acetate, wash the organic layer with 6N hydrochloric acid, water and aqueous sodium chloride solution, dry over anhydrous magnesium sulfate, and remove the solvent under reduced pressure. To give 5—chloro-6—phenol 2—benzoxazoconone as an oily residue. Addition of ter and crystallization result in the desired compound (1.585 ^) as crystals, which are recrystallized from ethanol.

m ρ 19 3 〜: 195 ° C

IR (Nujo Nore): 1770, 1605 cm " ¹ Example 5

The following compound is obtained in the same manner as in Example 4.o

OMPI (1) 6—Venzo-noise 5—1 Crawl 2—Venzoxazolone

m p 18 4 to 1 86 ° C

IR (Nujanore): 1760, 167 Oem ^-1

ίΓΜΕ (DMS 0-d ₆ , d): 7.32 (IH, s), 7.52 (lH, s),

7.52-7.88 (5H, m)

Elemental folding, and the _{_{_{C 14 H 8 ΪΓ0 3 C,}}} ,

Calculated value: C: 61.44, Η: 2.95, Ή: 5.12

Measured value: C: 60.94, Η: 3.11, Ν: 5.11

(2) 6 — Benzo Nore 5 — Phenorero 2 — Benzoxazo

D

m 17 1 to 17 2 ° C

IR (Nujo Norre): 3190, 1800, 1630, 1615 πΓ ¹ ΙΓΜΕ (DMS 0 -d ₆ , δ): 7.14 (IE, d, J = 6 Hz), 7.20 (IH,

brs), 7.41-7.88 (6H, m)

(3) 6—Venzo Inlay 5—Methoxy 1 2—Venzo Mixer

mp 2 1 6 to 2 1 7 ⁰ C

IR (Nujo Nore): 3200, 1790, 1780, 1620 arT ¹ (4) 6 — Benzoi Nore 5 — Chloro 2 — Benzothia Zorone mp 2 15 to 2 17 ° C

(Sujo): 1665, 1 635, 1 600 αιΓ ¹

_{NMR (DMS0-d 6, d} ): 7.30 (IH, s), 7.42 - 7.82 (5H, m), 7.81 (1H, s)

(5) 6 — Penzo-no-le 5 — Methi-no-one 2 — Benzoxazolone f O PI mp 1 3 4 ~: L 3 5 ° C

-i IR (Nujokure): 3120, 1770, 760, 1670 cm 'NMR (DMS 0-d 6, d: 2.30 (3H, s), 7.08 (1H, s),

7.21 (lH, s), 7.42-7.82 (6H, m.) Mass m / z: 254 (M + + 1, 10 d.), 253 (M ⁺ , 65) 252 (100 d.) (6) 6 — base down zone Lee Honoré -5 - arsenide mud key sheet 2 Baie emission zone O key Sa solo emissions mp 2 3 4 ~ 2 3 5 ° C IR ( Nujiyoru): 3150, 1760, 1650, 1620, 1600 one ¹

(7) 6 — Benzoinorane 5 — Chlorine 3 — Methiorane 2 — Benzoxazolone mp 14 0-: L 42 ° C

IH: 1790, 1670, 1630 enT ¹ NMR (DMS 0-d ₆ , <?): 3.40 (3Η, s), 7.38 -7.90 (7H, m)

(8) 6 ベベンンン — — — — — 5 5 ク — ロ — — — — — — mp C IR (Nujonore): 3200, 1790, 760, 162 OarT 1 NMR (DMS 0-d 6, d): 7.34 (1H, s), 7.44 one _{8.08 (5H, m): '} 8.20 (1H, s)

Example 6

5-π π π 6 fenorenote 2 — Benzoxazolone (0.9 ^) in anhydrous dichloromethane (45 solution,

OMPI Add σ-perbenzoic acid (1.4 ^ ^) in two portions at a time. After the addition, the mixture # Γ is refluxed for 5 hours, and then stirred at room temperature overnight. The precipitate is filtered off, washed with a small amount of sigma-methine, then recrystallized from ethanol to give a 6-benzolone quinolone. 2 Obtain 1-benzoxazolone (0.54 ^) as crystals.

m p 25 0 to 25 3 ° C

IR (Nujonore): 3200, 1790, 1760, 1620 cm '1 EM.R (MS 0-d 6, δ: 7.34 (lH, s), 7.44- 8.08 (5Ε, m), 8.20 (1H, s) carried Example 7

6—Venzocinone 5—Methoxy 2—Venzoxazolone (1.05 ^) in anhydrous di-σ π methane (18 A 1-mol solution of boron bromide in sigma rometan (3.9) is added dropwise at room temperature over 5 minutes 1. After stirring for 5 hours, the mixture is poured into ice water and then Extract with a mixed solution of rometan and ethanol (10: 1) Wash the organic layer with water, dry, and evaporate the solvent under reduced pressure.

The residue is triturated in a petroleum ether, and the resulting powder is crystallized from ethanol, and 6 — benzoin 1 5 — —Benzo Kisazo. (0.67 ^) as pale yellow crystals. -mp 2 3 4 — 2 3 5 ° C

IH: 3150, 1760, 1650, 1620, 1600cm ^-1

ΟΜΡΙ Example 8

6 Benzoinone 5 — Chlorine 2 — Benzoxazolone (2.0 ^), methyl iodide (1.56 ^) and carbonic acid A suspension of lithium (1.51 ^) in anhydrous acetone (40) is stirred at room temperature for half an hour.

Cool the mixture in an ice-water bath and add water. The mixture is concentrated under reduced pressure to produce a precipitate, and acidified with 6M hydrochloric acid. Extract the released product twice with cyclomethane. The combined organic layers are washed twice with water, dried and evaporated under reduced pressure. The oily residue is crystallized from ethanol to give 6-benzoylone 5-black mouth 3-methinole 2-benzoxazozone (1.75) Is obtained as a crystal.

mp 140-; L 42 ° C

IR (Nujo Nore): 1 790, 1670, 1630 em ' ¹

NME (DMS 0-d ₆ , δ): 3.40 (3Η, s), 7.38-7.90 (7Η, m) Example 9

5 — phenolic mouth 2 — benzoxazolone (3 · 06 ′) and 2—thiophene of oleic acid (1.8.22 ^) The mixture in polyphosphoric acid (61 ^) is heated with stirring at 95-1000 for 3.5 hours. After cooling, the mixture is poured into water (200 ′) and extracted with ethyl acetate (150). The extract is washed with dilute aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution. After drying with magnesium sulfate and decolorizing with activated carbon, add n-hexane to the residue obtained by evaporating the solvent to form: wii-U (2.40 ^) was recrystallized from a mixed solution of ethyl acetate and n-hexan, and 5-fluoro 6-(2-tenol) 1-2- Obtain the zozoxazolone (0.865 ^).

mp 2 0 0 to 2 3 ^o C

IR (Nujiyoru): 3230, 1790, 1740, 1640, 1620cm -1 R (DMS 0 - d 6,: 7.10~7.33 (2E, m), 7.53~7.70 (2H, m), 8.03~8.20 (1H, m ) Example 10

The following compounds are obtained in the same manner as in Examples 1 and 9.

(1) 5 — Black 6 — (4 — Black outlet) — 2 — Benzoxazolone

mp 2 6 4 to 2 6 7 ° C

(Nujo Nore): 3 100, 1780, 1620, 1615 cm ' ¹ (2) 5 1 Black mouth — 6 — (4 1 Fukuroo mouth Vense, 1 Sun Nore Honinore)-2 1 Penzo Kisazo mouth

mp 2 5 4 to 2 5 6 ° C

IR (Nujiyoru): 3250, 1780, 1758, 1.618, 1590 «π _1

(3) 5 — Chlorine 6 — (2 — Methinorenzenshonorenhon) 1 2 — Benzoxoxazolone

mp2 3 8--240. C

IR (Nujonore): 3200, 1800, 1 770, 1620 one ¹

(4) 7 — Benzo no 1 6 — Black mouth 2 — Benzoxazolone

2 3 5 to 2 3 6 ° C IE (Nujo Norre): 3200, 1780, 1750, 1665 em ^_1 (5) 7 — Benzoinore 5 — Black mouth 1 2 — Benzoxazolone

mp 1 8 6 — 1 8 7 ° C

IR (Nujo Nore): 3300, 1800, 1760, 1665 cm '

The following compound is obtained in the same manner as in Example 4.

(1) 5 — Kroll 6 — (4 — Kuro mouth Feninolechi) 1 2 — Penzoxazolone

mp 203-204. C

IR (Nujanore): 3120, 1750, 1615 αι ¹

NMR (DMS 0-d ₆ , δ): 7.25 (1Η, d, J = 8 Hz), 7.35 (1H, s),

7.42 (1H, s), 7.50 (2H, d, J = 8Hz)

Elemental analysis, C ₁₃ H ₇ C £ ₂ H0 ₂ S

'Calculated value: C: 50.02, H: 2,26, N: 4.49, C: 22.71

Measured value: C: 50.02, H: 2.55, N: 4.44, C ^: 23.00

(2) 5 — Black mouth 6 — (4 — Holoreno) 1 2 1 Benzoxazolone

mp 201 to 202 ° C

IR -1

(Nujo Norre): 3210, 1750, 1700 cm

NMR (DMS 0-d ₆ , δ): 7.00-7.51. (6H, m)

(3) 5 — Black mouth 6 — (2 — Methylenol ferrio) 2 — Benzoxazo

mp 202 to 203 ° C

OMPI IE (Sujonore): 3260, 1 780, 1 76 OCOT -1 ίΓΜΕ (DMS 0-ά 6, d): 2.30 (3H, s), 6.88 (1H, s),

7.27 (1H, s), 7.00-7.43 (4H, m)

Elemental folding, and the _{_{_{C 14 H 10 C N0 2 S}}} ,

Calculated: C: 57.84, H: 3.47, IT: 482, C: 12.19 Actual: C: 57.65, H: 3.57, N: 4.79, Ο £: 120

Example 1 2

The following compound is obtained in the same manner as in Example 4.

(1) 5 — Fluoro 6 — (2 — Tenor) 1 2 — Penzoxazolone

mp 200 to 203 ° C

IH: 3230, 1790, 1740, 1640, 1620cm ^-1

(2) 5-Black mouth 1 6-(4-Black mouth bracelet, non-slip horn)-2 1

mp 2 6 4 〜 2 6 7 ° C

IR (Sujo one Norre): 3100, 1780, 1620, 1615 - ¹

(3) 5 1 chrome 6 — (4 ƒ ノ ƒ レ ƒ オ ƒ 口 ƒ 口 ƒ ベ ƒ 口 ƒ ス ƒ ス ƒ ス ƒ ス ƒ / ƒ ス ƒ ノ ƒ ƒ ƒ レ ƒ レ ƒ 一 ƒ ノ ƒ 一) 2 2 —- benzo-xazolone

mp 2 5 4 to 2 5 6. C

IH: 3250, 1780, 1758, 1618, 1590cm ^-1

(4) 5 — Black σ — 6 — (2 — Methinole Benzensorehoninore) — 2 — Benzoxazolone

mp 238-240. C

IR: 3200, 1800, 1770, 1620cm— ¹ (5) 7—Benzo ¹ 6—Cross σ—2—Benzoxazone

OMPI

WIPO mp 2 3 5 to 2 3 6 ⁰ C

IR (Nujo Norre): 3200, 1780, 1750, 1665

(6) 7—Venzo-no 1-5—Mouth row 2 Benzoxazolone mp186-: L87. C

-1E R (Nu.Jiol): 3300, 1800, 1760, 1665 em

The following compound is obtained in the same manner as in Example 6.

(1) 5 — Crawl 6 — (4 — Cuff Mouth Pensence) — 2 — Benzoxazolone mp 2 64 — 2 6 7 ° C

IR (Nujonore): 3100, 1780, 1620, 1.615 COT- 1 R (DMS 0 - d 6, Ri: 7.31 (lH, s), 7.67 (2H, d, J = 8Hz),

7.93 (2H, d, J = 8Hz), 8.13 (1H, s)

Elemental folding, and the _{_{_{_{C 13 H 7 C 2 W0 4}}}} S,

Calculated value: C: 45.37, H: 2.05, 4.07, C: 20.60 Observed value: C: 45.49, H: 2.30, N: 4.06, C: 20.82

(2) 5 — Crawl 6 — (4 — Ventilation outlet, nose horn) — 2 — Benzoxazolone mp 2 5 4 — 2 5 6 ° C

IR (Sujiyoru): 3250, 1780, 1758, 1618, 1590COT -1 NMR (DMS 0 - d 6, Ri: 7.30 (1H, s), 7.47 (2H, d, J = 8Hz),

8.00 (2H, d, J = 8Hz), 8.13 (1 H, s)

(3) 5 — Black mouth 6 — (2 — Methyl benzene レレ ―) ― 2 — Benzoxazolone mp 2 3 8 to 24 0 ° C

IR (Nujokure): 3200, 1800, 1770, 1620 onT 1 R (DMS 0 - d 6,): 2.30 (3H, s), 7 · 28 (1Η, s),

7.28 - 7.80 (3Η, s) , 8.13 (1H, a), 8.00 -8.27 (1H, m) Elemental analysis, as a _{_{_{C u H 10 C iT0 4 S}}} ,

Calculated value: C: 52.11, H: 3.12, ίΓ: 434, C: 10.98 Observed value: C: 51.66, H: 3.21, ίΓ: 420, C ^: ll.52

Example 14

3—Venzoinole 4-1-chloro-2—Hydroxyan, i, xylen (45 m) of peracid (4.14 ^) In a mixed solution with chinoleformamide (1.2 m), di7-hydroxyphosphorylazide (4.95 ^) and triethylamine (1.5 2 ^) and are sequentially added at room temperature in a nitrogen atmosphere. The mixture is stirred at the same temperature for 30 minutes and then refluxed for 1.5 hours. After cooling, the mixture is diluted with ethyl acetate (100), the organic solution is washed with saturated aqueous sodium hydrogen carbonate, dried, and the solvent is distilled off under reduced pressure. The styrene solution is allowed to stand at room temperature to obtain 7-benzoin 1-6-chloro 2-benzoxazozone (3.06 ^) as crystals.mp 2 3 5 to 2 3 6.C

IH (Nujo one Honoré): 3200, 1780, 1750, 1665 cm '1 NMR (DMS 0-d 6, d): 7.24 (1Ξ, d, J = 8Hz), 7.38 (1H, d, J = 8Hz), 7.44-7.96 (5H, m) R £ A OMPI Example ! ^

In the same manner as in Example 14, 7—benzoyl 5—black mouth 1—benzoxazolone is obtained.

mp 186 to 187. C

IR (Nujo Norre): 3300, 1800, 1760, 1665 cm— ¹ ITMR (DMS 0-d ₆ , d): 7.25 (1H, d, J = 2Hz), 7.35 (1H,

d, J = 2Hz), 7.47-8.00 (5H, m) Example 16

The following compounds were obtained in the same manner as in Example 14.

'(1) 6 — Benzo 1-5

mp 18 4 to .1 86 ° C

IR (Nujo Nore): 1760, 167 OCOT

(2) 6—Benzo-no-e 5—Phoneo σ—2—Benzo-no-so

mpl71-; L72. C

IR (Nujo-Nore): 3190, 1800, 1 630, 161 5 cm ' ¹

(3) 6 — Benzoire 1 5 — Methoxy 1 2 — Benzoxazolone

m p 2 16 to 2 17. C

1 (3), 1 790,-1 780, 1 620 ^-1

(4) 6—Venzo nose 1 5—Black mouth 2—Venzothiazolone m p, 2 15 to 21 7 ° C

IR (Nujo Nore): 1 665, 1 635, 1600 cm ' ¹

O PI (5) 6 One vent 1 — Methor 2 — Benzoxone

m p 1 3 4-: L 35 ° C

I (Nujonore): 3120, 1770, 1760, 1 β Ί αιΓ ¹ (6) 5 — Black mouth 1 6 — Bininolecho 2 — Benzokizozono

m p 193 to 195 ° C

IR (Nujo Nore): 1770, D 05 em

(7) 6 Benzensorehoninoren — 5 ark — 2 Benzoxazolone

m p 250-25 3. C

IH: 3200, 1790, 1760, 1620 cirT ¹ (8) 6 Benzo ¹ 5 — Hydroxy 2 — Benzoxazo

m p 2 3 4 — 2 3 5 ° C

in: 3150, 1760, 1650, 1620, ΙβΟΟωΓ ¹ (9) 6 —Venzoinore 5 —Chloro 3 —Mechinore 2 —Benzoxone

m p 14 ~ 12 ° C

(Nujo 1): 1790, 670, 1630cm— ¹

(10) 5 1 Fluoro 1 6 — (2 TN) 1 2 — Benzoxazolone

mp 2 0 0 to 2 3. C - IR (Sujiyoru): 3230, 1790, 1740, 1640, 1620 one ¹ (II) 5 - click b sigma - 6 - (4 one click b sigma full et two Norechi O one 2 - Benzoxazolone

m p 203 to 204 ° C

IR (Nujo Norre): 3120 1 750, 1 615 em ¹

2) 5 — Chlorine 6 — (4 'phenolic) 1 2 1 Benzoxazolone

m p 201 to 202 ° C

in (Nujoichi -1

Nore): 3210: 1750, 1700

(13) 5 — Chlorine 6 — (2-Methinolefino) 2 1 Penzoxazolone

mp202-203. C

IE (Suginore): 3260, 1 780, 1 760 cm ' ¹

(14) 5 — Black mouth 6 — (4 — Black mouth) — 2 — Benzoxazone

m p 2 6 4 — 2 6 7 ° C

IR (Nujanore): 3 100, 1 780, 1620, 1615 cm " ¹

(15) 5 — Black mouth 1 6 1 (41 Fluoro-ben-zensulfoninole) — 2 — Benzo-kisazolon

mp2254-4256. C

R (Sugionore): 3250, 1780, 1758, 1618, 1590 COT ^-1

(16) 5 — Mouth row 6 — (2 — Methylbenzene Sulfonyl) 1 2 1 Benzoxazolone

mp 2.38 to 240. C

IR (Nujo Nore): 3200, 1800, 1770, 162 O eirT ¹

O PI

WIPO

Claims

Billing

Single boat

(Wherein, is an aryl group or a heterocyclic group which may have a suitable substituent,

R ² is a halogen, a lower alkanol group, a lower alkoxy group or a hydroxy group,

E ³ is hydrogen or a lower alkyl group,

X is S or 0,

Y is CO, S, means S 0 ₂ or teeth, respectively) - Contact good beauty their salt compounds represented by.

2. The compound according to claim ^1, wherein S ¹ is an aryl group which may have a halogen; or a heterocyclic group.

3. a phenyl group which may have a boron, chlorine or methyl group; or a phenyl group,

Are fluorine, chlorine, methyl, methoxy or hydroxy,

3. The compound according to claim 2, wherein is a hydrogen or a methyl group.

4.6 — Benzoinorane 5 — Black mouth 2 — Benzoxazolone 6—Venzo-noise 5-

6—Venzo Inlet 5—Methoxy 2—Venzoxazolone,

6 — Benzoyl 1 5 — Chlorine 2 — Benzothiazolone ゝ

6 Benzo-Zone 1 5—Methyl 2- 2-Zenzoxazolone,

5 Black mouth 1 6 — Fenorecho 1 2 — Benzoxazolone,

6 — Vance, ^ ノ ^ — — 5 ク 2 2 — — —-2 — べべ

6 — Benzo noise 5 — Hydroxy 2 — Benzoxazolone,

6—Venzo Inlay 5—Crawl 3—Metinol 2—Venzoxazolone,

5 — Function port — 6 — (2 テ — ノ) — 2 べゾキサ

5 — Black mouth 6 — (4 — Chlorophyll) 1 2 — Benzoxazolone,

5 — Chlorine 6 — (4 — Fenole Oro Fenini Norrecho) One 2 — Benzoxazolone,

5 — Black mouth 6 — (2 — Methyl phenol) 1 2 Benzoxazolone,

5 — 口口口 6 — (4-1 口ベ口口口口ホ

OMPI 1 2 — Benzoxazolone,

5 · — Crawl 6 1 (4-口口口 2 2) 1 2 — Benzoxazolone,

5—Mouth row 6— (2-Methyl benzene)

7 — Benzoi Nore 6 — Krollo 2 — Benzoxa Zolone and

7. The compound according to claim 3, wherein the compound is selected from the group consisting of 7 — benzoquinone 5 — chloro-2 — benzoxazozone.

5. 6-Benzoimylene 5—Phenololo 2—The compound according to claim 4, which is benzoxazodone.

6. Equation (1):

R ¹ — Ya one 0H

(Wherein, H ¹ is a aryl group or a heterocyclic group which may have a suitable substituent,

Ya is CO or was or a compound represented by the S 0 ₂ mean, respectively) and salts thereof, wherein:

(Wherein, is a halogen, a lower alkyl group, a lower alkoxy group or a hydroxy group,

R ³ is hydrogen or lower alkyl group, W1PO X represents S or o, respectively) or a salt thereof, and is reacted with a compound represented by the formula:

R ¹ -Ya

(Wherein, R ¹ , R ² , R ³ , X and Ya have the same meanings as described above), or a salt thereof.

Equation (2):

R ¹ — Y

(Where R ¹ , E ² , R ³ , and X have the same meanings as before,

Y is CO, the other of Gobutsuma represented by S, S0 ₂ or means ITH) a salt thereof, wherein:

Z

C = 0

Z '

(Wherein Z and Z each represent a leaving group), and reacted with a compound represented by the formula:

1—Y

O PI (Wherein, R ¹ , R ³ _t X and Y have the same meanings as described above), or a salt thereof.

Equation (3):.

(Wherein R ¹ , R ² , and X have the same meanings as described above) or a salt thereof, which is subjected to an oxidation reaction to obtain a compound represented by the formula

R ¹ — S0 ₂

(Wherein, R ¹ , R ² , and X have the same meanings as described above) or a salt thereof,

Equation (4):

R ¹ — Y

(Where R ¹ ,, X and! Are the same as before!),-

^ Represents a lower alkyl group) or a salt thereof, which is subjected to a cleavage reaction of polyester to obtain a compound represented by the formula:

, O PI

(Wherein, Rl, R3, X and Y have the same meanings as described above), or a salt thereof.

Equation (5):

R ¹ — Y

(Wherein, R ¹ , and X and Υ each have the same meaning as above), or a salt thereof, by subjecting the compound to a Ν-alkylation reaction to obtain a compound represented by the formula:

Ε ¹ — Υ

(Where R ¹ , R ² , X and Y have the same meanings as before, i ?,

Ε means a lower alkyl group) or a salt thereof, or

Equation (6):

OMPI

(Wherein, E ¹ , R ² , X and? Have the same meanings as described above) or a salt thereof, which is subjected to a ring closure reaction to obtain a compound represented by the formula:

R ¹ -Y

(Wherein, R ¹ , X, and Y each have the same meaning as before) or a single-bottle type which is characterized by obtaining a salt thereof:

R ¹ — T

(Wherein, S ¹ , R ³ , X and Y have the same meanings as before), respectively, to produce the new benzoxazozone and benzothiazolone derivatives or their salts. Law.

Single boat type:

R ^1-

O PI (In the formula, E ¹ is a suitable aryl group or heterocyclic group which may have a substituent,

Means 3 or), respectively, and the salts thereof.

8. General formula

0

(Wherein, Ε ¹ is a aryl group which may have a suitable substituent, or is a heterocyclic group,

Is hydrogen or a lower alkyl group,

X is S or 0,

γ means co, s, so ₂ or im), respectively, or a salt thereof as an active ingredient, and a substantially non-toxic carrier or pharmaceutically acceptable carrier. Is a pharmaceutical composition characterized by containing an excipient.

9. General formula:

R ² ; but> 0 (Wherein, S ¹ is a aryl group or a heterocyclic group which may have a suitable substituent,

E ² is a halogen, lower alkyl group, lower alkoxy group or hydroxy group,

Is hydrogen or a lower alkyl group,

X is S or 0,

Y is CO, S, the use of the S 0 ₂ or teeth it. Compounds represented by respectively mean) Contact and salts thereof, of human contact and animals of inflammation or thrombosis to therapy.

O PI

, / WIPO