JPH03258770A - Benzazole derivative, preparation thereof and synthetic intermediate theroef - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (R<1> is aryl, phenyl-lower alkyl or nitrogen, oxygen or sulfur-containing heterocyclic ring; R<2>, R<3> are H, lower alkyl, phenyl-lower alkyl, nitrogen-containing 5-9 membered heterocyclic ring formed together with N, etc., R<4> is H, lower alkyl, lower alkoxy, halogen, nitro, amino, etc., r<5> is H, lower alkyl; Y is O, S, imino; n is 0-2) and a salt thereof. EXAMPLE:2-(4-Chlorophenyl)-7-piperizinomethylhenzooxazolel.hydrochlride. USE:The compound of formula II depresses reflex micturition contraction, exhibits an excellent micturition internal elongation effect and is useful for treating pollakiuria, nocturnal enuresis, neurogenic bladder, etc. PREPARATION:A compound of formula II or a salt thereof is condensation- recated with an amine compound of formula III or a salt thereof in the presence or absence of an acid-removing agent (e.g. an alkali metal hydroxide) at 0-100 deg.C to provide the compound of formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a novel benzazole derivative, a method for producing the same, and a synthetic intermediate thereof.

[Conventional technology]

For the treatment of frequent urinary patients who urinate more frequently each day and night than those of healthy people, it is useful to suppress reflex urinary contractions of the bladder and prolong the micturition interval.

Conventionally, as a therapeutic agent for frequent urination having an effect of suppressing reflex micturition contraction, for example, flavoxate (chemical name: 3-methyl-4-oxo-2-phenyl-4H-) has been used.
1-benzopyran-8-caetic acid 2-piperidinoethyl ester] Hydrochloride is known [basic and clinical,
νo1.1B, Nα6.121-127 (1984)
) On the other hand, 2-phenyl-6-amino(lower alkyl)benzoxazole has an anti-inflammatory effect (Journ
al of MecHcal Chemistry,
1977, Vol.

20, No, 6.797-801), also 2-
Fer-6-piperidino (1-hydroxy lower alkyl)benzothiazole has weak antimalarial activity (Journal of Medjca) Che
mjstry, 196B, Vol.

11, No. 2.270-273), but the therapeutic effect of such compounds on frequent urination is unknown.

[Problems to be Solved by the Invention] The present invention has the effect of extending the urination interval, and is an excellent method for preventing frequent urination.
It is an object of the present invention to provide novel Hen's Azul derivatives having therapeutic effects.

[Means to solve the problem]

The present invention is based on the general formula (where R1 is a substituted or unsubstituted aryl group, a phenyl-lower alkyl group, or a nitrogen-containing, oxygen-containing or sulfur-containing 5
~6-membered heterocyclic group, R2 and R3 are a hydrogen atom, a lower alkyl group, a substituted or unsubstituted phenyl-lower alkyl group, a di-lower alkylamino-lower alkyl group, or are bonded to each other at the terminals and adjacent nitrogen Together with the atom, a substituted or unsubstituted nitrogen-containing 5- to 9-membered heterocyclic group is formed, R4 is a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, a nitro group, an amino group, or a lower alkanoylamino group, and R5 is hydrogen atom or lower alkyl group, Y represents an oxygen atom, a sulfur atom or an imino group, and n represents O~2. ) or a pharmaceutically acceptable salt thereof.

As a specific example of the object (I) of the present invention, R1 is an aryl group such as a phenyl group or a naphthyl group (
The aryl group includes a halogen atom, a lower alkyl group, a lower alkoxy group, a phenyl-lower alkoxy group, a hydroxyl group, a di-lower alkylamino group, a nitro group, an amino group, a lower alkanoylamino group, a trihalomethyl group, and a lower alkylenedioxy group. It may have 1 to 3 substituents selected from. ), phenyl-lower alkyl group, or a nitrogen-containing, oxygen-containing or sulfur-containing 5- to 6-membered heterocyclic ring such as furyl, thienyl, pyridyl, pentufuryl, benzothienyl, quinolyl or isoquinolyl group group, and R2 and R3 are, for example, a hydrogen atom, a lower alkyl group, a phenyl-lower alkyl group (the phenyl-lower alkyl group may have a lower alkoxy group as a substituent), di-lower alkyl amino-lower alkyl groups or terminally bonded to each other and together with adjacent nitrogen atoms, such as pyrrolidyl, piperidino, homopiperidino, azacyclooctyl, azabicyclononyl, morpholino, piperazinyl or imidazolyl groups; Nitrogen-containing 5- to 9-membered heterocyclic group (These nitrogen-containing 5- to 9-membered heterocyclic groups may have 1 to 3 substituents selected from lower alkyl groups, hydroxyl groups, and phenyl groups.) Examples include compounds that form.

Among these, the therapeutically preferable object (I) is that R1 has a phenyl group or a lower alkoxy group as a substituent, which may have a substituent selected from a halogen atom, a lower alkoxy group, and a lower alkylene dioxy group. is a naphthyl group which may be a phenyl-lower alkyl group, and R2
and R3 are lower alkyl groups, or are bonded to each other at the terminals, and together with adjacent nitrogen atoms are piperidino groups, homopiperidino groups, or morpholino groups (these piperidino groups, homopiperidino groups, or morpholino groups have a lower alkyl group as a substituent) ), and R4
is a hydrogen atom, a lower alkyl group, a lower alkoxy group, or a halogen atom, R5 is a hydrogen atom, Y is an oxygen atom, and n=0.

Furthermore, in a particularly preferred therapeutic object (1), R1 is a lower alkoxy-phenyl group, R2 and R3 are bonded to each other at their terminals to form a piperidino group or a morpholino group together with the adjacent nitrogen atom, and R4 is a hydrogen atom or a lower alkoxy-phenyl group. It is a compound with an alkoxy group.

In the objects of the present invention, specific examples of lower alkyl groups, lower alkoxy groups, lower alkylene groups, and lower alkanoyl groups include alkyl groups, alkoxy groups, and alkylene groups having 1 to 4 carbon atoms, and alkanoyl groups having 2 to 5 carbon atoms. It is.

According to the present invention, the target compound (1) converts the hydroxyl group of an alcohol compound represented by the general formula (however, the symbols have the same meanings as above) into a reactive residue; However, the symbols have the same meanings as above) are treated with a halogenating agent, and the general formula thus obtained is (where xl represents a reactive residue, and other symbols have the same meanings as above). ) and an amine compound represented by the general formula (however, the symbols have the same meanings as above) can be produced by condensation reaction.

Furthermore, among the target compounds (1), the compound represented by the general formula (however, the symbols have the same meanings as above) is a carbon compound represented by the general formula (however, the symbols have the same meanings as above). It can also be produced by subjecting an acid compound or its reactive derivative to a condensation reaction with an amine compound (V) and reducing the resulting amide compound represented by the general formula (however, the symbols have the same meanings as above). .

In the above reaction, the reactive residue (xl) is, for example, a halogen atom, a lower alkylsulfonyloxy group,
Substituted or unsubstituted phenylsulfonyl, I (e.g., phenylsulfonyl group, 4-methylbenzenesulfonyl group), etc., and as reactive derivatives of carboxylic acid compounds (Vf), for example, corresponding acid halides, mixed acid anhydrides, etc. , active ester, etc. can be used as appropriate.

Intermediate (IV) can be produced by reacting starting compound (II) with a hydroxyl group activating reagent. Examples of hydroxyl group activation reagents include thionyl halide, concentrated hydrochloric acid,
Commonly used phosphorus trihalides, hydrohalic acids, methanesulfonyl halide, 4-methylbenzenesulfonyl halide, and the like can be used. The reaction is carried out in an appropriate solvent (methylene chloride, chloroform, tetrahydrofuran, dioxane, benzene, toluene, lower alkanol, acetone, etc.) under ice cooling to heating, for example, from 0 to 80°C.
Proceed preferably with C.

Further, the halogenation of the starting compound (I[[) can be carried out using a commonly used halogenating agent, such as N-halogenosuccinimide. The reaction proceeds suitably in a suitable solvent (carbon tetrachloride, chloroform, methylene chloride, etc.) under heating, for example, at 50 to 80°C.

The condensation reaction between the intermediate (■) thus obtained and the amine compound (V) can be carried out in the presence or absence of a deoxidizing agent. As the deoxidizing agent, any commonly used deoxidizing agent can be used. Organic bases such as lower alkyl) aniline, N-(lower alkyl)morpholine, and pyridine can be suitably used. Also,
If a catalyst such as alkali metal iodide is used, the reaction can proceed rapidly. The reaction is carried out without a solvent or in the same solvent as used in the above reaction, under ice cooling to heating, e.g.
Proceeds preferably at 00''C.

The condensation reaction between the carboxylic acid compound (Vl) or its reactive derivative and the amine compound (V) can be carried out according to a conventional method for peptide synthesis. For example, compound (Vl)
When using reactive derivatives of , the reaction can be carried out in the presence or absence of a deoxidizing agent. As the deoxidizing agent, any one used in the reaction between the intermediate (TV) and the amine compound (V) can be suitably used. on the other hand,
When using free carboxylic acid compound (V), the reaction can be carried out in the presence or absence of a condensing agent. As the condensing agent, any conventional condensing agent can be suitably used. For example, carbodiimides such as N,N'-dicyclohexylcarbodiimide and N-cyclohexyl-No-morpholinocarbodiimide, carbonyldiimidazole, etc. It can be suitably used. These reactions can be carried out using a suitable solvent (tetrahydrofuran,
dimethylformamide, methylene chloride, ethyl acetate, acetonitrile, etc.) under ice cooling to heating, e.g. 0 to 50
Proceeds suitably at °C.

The reduction reaction of the amide compound (■) can be carried out by treating it with a reducing agent. As the reducing agent, conventional ones such as lithium aluminum hydride, sodium borohydride, diborane, alkali metal or magnesium and lower alkanol can be used as appropriate. The reaction proceeds suitably in a suitable solvent (tetrahydrofuran, dioxane, diethyl ether, etc.) under cooling to heating, for example, 0 to 50°C.

In each of the above reactions, each of the starting compounds (II) to (■) can be used as is or in the form of a salt thereof. Examples of the salt include organic acid addition salts and inorganic acid addition salts. Can be used. Moreover, compounds (II) to (■) having a hydroxyl group are, for example, alkali metal salts,
It can also be used in the reaction as an alkaline earth metal salt or ammonium salt.

In addition, the object (I) of the present invention can also be mutually converted as appropriate according to a conventional method. For example, in the target product (1), when R1 is a phenyl-lower alkoxy group-substituted aryl group, it can be catalytically reduced to a hydroxy-aryl group, and the substituent of R1 and/or R4 is a nitro-substituted aryl group. If it is a group, it can be reduced to an amino group, and if desired, can be further converted to a lower alkanoylamino group.

The object (1) of the present invention can be used for pharmaceutical purposes both in its free form and in its pharmacologically acceptable salt form. Examples of pharmacologically acceptable salts include inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, and fumarate;
Examples include organic acid addition salts such as maleate, acetate, oxalate, and Hensensulfonate. Also, the object (1
) has a hydroxyl group, for example, sodium salt,
It can also be used as a salt with an inorganic or organic base such as an alkali metal salt such as a potassium salt, an alkaline earth metal salt such as a calcium salt or a magnesium salt, or an ammonium salt.

Although optical isomers may exist in the objects (1) and (I-a) and the starting compounds (I[), (IV), (V) and (■) of the present invention], the present invention It includes both isomers and mixtures thereof.

The object (I) of the present invention and its pharmacologically acceptable salts can be administered orally or parenterally, for example, as pharmaceutical preparations such as tablets, capsules, powders, and injections. , you can use it as appropriate.

The dose of the object of the present invention (1) or a pharmacologically acceptable salt thereof varies depending on the patient's age, weight, condition, degree of disease, etc., but usually the daily dose is for oral administration. In case of parenteral administration, it is preferably 0.01 to 10 .mu./kg, and in case of parenteral administration, it is preferably 0.001 to 1 .mu./kg.

In addition, the raw material compound (II) is, for example, a compound represented by the following general formula (wherein, R6 is a lower alkyl group, yl represents a hydroxyl group or an amino group, and the other symbols have the same meanings as above); After reacting with the compound represented by the general formula % formula %) (where x2 represents a halogen atom and R1 has the same meaning as above), it is subjected to an intramolecular ring-closing reaction, or ■Compound (■) and a compound represented by the general formula % formula % (however, R1 has the same meaning as above), and then oxidize, or ) is diazotized, then treated with an alkali metal halide, and the product is reacted with a compound represented by the general formula %) (wherein ``has the same meaning as above.''). , ■ Reduce the ester compound represented by the general formula % (% formula %) (however, the symbols have the same meanings as above) obtained by the reactions of ■ to ■ above with lithium aluminum hydride, etc., ■ If necessary, , and can be further produced by reacting the product with a halogenated lower alkylmagnesium.The raw material compound (II) thus obtained can be prepared by, if necessary,
For example, “Yasuo Inubushi, Organic Chemistry (Koyo Shoten) P.
218-223 The number of n can also be increased according to the method described in "Creation of C--C Bonds".

The raw material compound (III) can be prepared by, for example, the general formula () after hypogastric nerve transection and sham surgery W (4-
7 days ago) The specimen (10 mg/kg) was orally administered to rats. Physiological saline (4d/100g) was orally administered 15 minutes after administration, and micturition intervals were measured over 5 hours.

The maximum micturition interval during the measurement period was compared with that of the hypogastric nerve non-section group.

(Results) The compounds listed in Table 1 below extended the maximum micturition interval by 30% or more.

It can be produced by reacting the compounds shown in Table 1 (however, the symbols have the same meanings as above) with compound (IX) and then subjecting it to an intramolecular ring-closing reaction.

Further, carboxylic acid (VI) can be produced, for example, by hydrolyzing ester compound (X).

[Effect] According to Experimental Example 1 Rat Experimental Example 2 (Method) A urinary bladder catheter was inserted from the external urethral orifice of a female rat anesthetized with urethane, and a pressure transducer was connected to the other end of the catheter. The bladder was loaded with an appropriate amount of saline and the evoked rhythmic bladder contractions were recorded. Specimen dissolved in physiological saline or 5% glucose aqueous solution (0.3-1 m
g/kg) was administered intravenously, and rhythmic bladder contractions were recorded after administration.

(Results) The compounds listed in Table 2 below reduced the number of contractions 15 minutes after administration to 70% or less of the number of contractions 15 minutes before administration.

Table 2 [Examples] Example 1 (1) 2-(4-chlorophenyl)-7-benzoxazole methanol 11.04 g methylene chloride 200 m
10.1 g of thionyl chloride is added dropwise to the suspension under water cooling. Stir at room temperature for 1 hour and evaporate the solvent. Ethyl acetate is added to the residue, washed with water, saturated aqueous sodium bicarbonate solution, and brine, dried, and the solvent is distilled off. The residue was recrystallized from ethyl acetate-hexane to give 7-chloromethyl-2-(4-chlorophenyl)benzoxazole 11
Obtain 46g.

Fog, p, 116-118°C (2) 10.4 g of the product from (1) above in chloroform 2
0〇-To the solution, add 15.9 g of piperidine under water cooling,
Stir overnight at room temperature. The solvent was distilled off, ethyl acetate was added, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution and brine.
After drying, concentrate. Hydrochloric acid-methanol is added to the residue to obtain a hydrochloride, which is recrystallized from methanol diethyl ether to obtain 10.85 g of 2-(4chlorophenyl)-7-piperidinomethylbenzoxazole hydrochloride.

o+, p, 268-271°C Examples 2-27 (1) The corresponding raw material compounds are treated in the same manner as in Example 1-(1) to obtain the compounds listed in Table 3 below. (In the table, Me represents a methyl group. The same applies hereinafter.) Table 3 (2) The product of (1) above was treated in the same manner as in Example 1-(2), and the following Tables 4 and 5 The compounds listed in the table are obtained.

(In the table, Et is an ethyl group, n-Bu is a linear butyl group, t
-Bu represents a tertiary butyl group, the same applies hereinafter) Table 4 Examples 28 to 49 The corresponding raw material compounds were treated as in Example 1-(2) and interpolated,
The compounds listed in Tables 6 and 7 below are obtained.

Table 6 Table 7 (However, in Example 49, Y represents a sulfur atom, and in the case of , represents an oxygen atom.) Other Examples 50 2-(4-Methoxyphenyl)-7-penzoxazole methanol 9 8. Thionyl chloride in a suspension of .30 g of methylene chloride I20IR1. Add OJd and stir at room temperature for 1 hour. The solvent was distilled off, and 160 methylene chloride was added to the residue.
Add m. Under water cooling, homopiperidine 18d was added dropwise,
Stir for 1 hour at room temperature. The solvent is distilled off, ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution are added to the residue, and the ethyl acetate layer is separated. Wash the ethyl acetate layer with brine and dry. Ethyl acetate was distilled off, and hydrochloric acid-methanol was added to the residue to obtain the hydrochloride, which was recrystallized from isopropyl alcohol to obtain 11.80 g of 7-homopiperidinomethyl-2-(4-methoxyphenyl)benzoxazole hydrochloride. get.

m, p, 230-231.5°C Example 51 (1) 7-methyl-2-(4-chlorophenyl)benzoxazole 0.73 g, N-bromosuccinimide 0
．． A mixture of 56 g, 0.03 g of benzoyl peroxide and 10 affi of carbon tetrachloride is refluxed for 24 hours. After filtering off insoluble matter and distilling off the solvent, the residue is dissolved in ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution and brine, and dried. The solvent was distilled off, the residue was purified by silica gel column chromatography [solvent: hexane-ethyl acetate (5:1)], and then crystallized in isopropyl ether to give 7-
0.60 g of promomethyl-2-(4-chlorophenyl)benzoxazole is obtained.

■, p, 127-128°C (2) Chloroform 1 of 0.16 g of the product of (1) above
0.20 g of piperidine is added to the 0d solution under water cooling, and the mixture is stirred at room temperature for 1.5 hours. The solvent is distilled off, ethyl acetate and an aqueous sodium hydrogen carbonate solution are added, and the ethyl acetate layer is washed and dried. The solvent was distilled off, and the residue was made into a hydrochloride with hydrochloric acid-methanol, and then recrystallized from methanol-diethyl ether to give 0.13 g of 2-(4-chlorophenyl)-7-piperidinomethylbenzoxazole hydrochloride.
get.

m, p, 267-270°C Example 52 (1) 1.36 g of 2-phenylbenzoxazole-7-carboxylic acid in 20 ad? Add 1.5 m of oxalyl chloride and 2 m of dimethylformamide to the solution.
After adding drops and stirring for 1 hour at room temperature, the solvent is distilled off.

3011 dl of tetrahydrofuran is added to the residue, and 5 d of piperidine is added dropwise while stirring while cooling with water. After stirring at room temperature for 1 hour, water was added to the reaction mixture, extracted with ethyl acetate, and the ethyl acetate layer was washed and dried. The solvent was distilled off, and the residue was diluted with ethyl acetate.
Recrystallization from hexane yields 1.47 g of 1-(2-phenylbenzoxazole-7-carbonyl)piperidine.

Cabinet, p, 127-128°C (2) To a suspension of 0.20 g of the product from (1) above and 0.25 g of sodium borohydride in tetrahydrofuran, 1.21 g of boron trifluoride ether complex salt was added under water cooling. and stirred at room temperature for 1 hour. 10 methanol to the reaction solution
d, 0.6 g of oxalic acid was added, and the mixture was refluxed for 2 hours.

Add aqueous sodium hydrogen carbonate solution, extract with ethyl acetate, wash and dry the ethyl acetate layer. The solvent was distilled off, and hydrochloric acid-methanol was added to the residue to obtain a hydrochloride salt, which was then recrystallized from methanol-diethyl ether to give 2-phenyl-
7-Piperidinomethylbenzoxazole hydrochloride 0.
Obtain 13g.

m, p, 222-225°C Examples 53-67 The corresponding starting compounds are treated in the same manner as in any of Examples 50-52 to obtain the compounds listed in Table 8 below. (However, R
4 represents a 5-methyl group in Example 67 and a hydrogen atom in other cases) Table 8 Example 68 (Chlorination of 2.0 g of IN-(2-phenyl-7-henzoxalyl)ethanol) methylene 10mRWj?fl,
Under water cooling, phosphorus tripromide 0. Add 71d. The reaction solution is stirred at room temperature overnight, ice and saturated aqueous sodium bicarbonate solution are added, and then extracted with ethyl acetate. The extract was washed with water and brine, dried, and the solvent was distilled off to obtain 2.4 g of 7-(1-bromoethyl)-2-phenylbenzoxazole as crude crystals.

Peng, p. 83 ~ B 7.5 °C (2) 1.20 g of the product from (1) above was added to piperidine 8I11 under water cooling.
and stir at room temperature for 1 hour. Excess veridine is distilled off, and the residue is dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and brine, and dried. After distilling off the solvent, silica gel column chromatography [solvent:
After purification with chloroform-methanol (20:1)) and converting it into a hydrochloride, it was recrystallized from acetone to give 2-phenyl-7-(1-piperidinoethyl)benzoxazole.
1.06 g of hydrochloride is obtained.

■, p, 239-241.5°C (decomposition) Example 6
9 (1) 7-chloromethyl-2-phenylbenzoxazole3. A mixture of Og, 0.76 g of sodium cyanide and 20 d of dimethyl sulfoxide is stirred at room temperature for 4 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. After washing the extract with brine and drying, the solvent is distilled off and recrystallized from ethyl acetate-hexane to obtain 2.47 g of (2-phenyl-7-penzooxaduryl)acetonitrile.

Seagull, p, 109-113°C (2) 2°30g of the product of (]) above in chloroform
Hydrogen chloride gas is passed through the methanol (10d-10d) solution for 15 minutes, and the mixture is further stirred at room temperature for 2 hours. After distilling off the solvent, 10 d of methanol and 1 - of water are added, and the mixture is stirred at room temperature for 1 hour. Add chloroform, wash with water, aqueous sodium bicarbonate solution and brine, and then dry. After distilling off the solvent, the residue is recrystallized from isopropyl ether-hexane to obtain 2.09 g of 2-phenyl-7-benzoxazole acetic acid methyl ester.

m, p, 74-77°C (3) To a suspension of 0.34 g of lithium aluminum hydride in 10 d of tetrahydrofuran, a solution of 2.0 g of the product from (2) above in 10 d of tetrahydrofuran was added dropwise under water cooling. and stir at the same temperature for 1 hour. Add water 1I11 and 15 to the reaction solution.
% aqueous sodium hydroxide solution is added, and insoluble matter is filtered off. The solvent was distilled off, ethyl acetate was added to the residue, and the mixture was washed with water and brine, and dried. After evaporating the solvent, the residue was recrystallized from ethyl acetate-hexane and 2-phenyl-7-benzoxazole ethanol 1. 30g
get.

Cabinet. p. 126-130″C (4) Pyridine 10 of the product 1.208 of the above (3)
d solution, 4-methylbenzenesulfonyl chloride 1.

Add 06g and stir overnight at room temperature. The reaction solution was poured into ice water and extracted with ethyl acetate. Add the extract to 10% hydrochloric acid,
Washing with water, saturated aqueous sodium bicarbonate solution and saline;
After drying, the solvent was distilled off to obtain 1.72 g of 4-methylbenzenesulfonic acid 2-(2-phenyl-7-benzoxazolyl)ethyl ester as a caramel-like crude product.

Mass (m/z): 393 (M”) (5) Above (
A mixture of 0.85 g of the product from 4) and piperidine 8- is stirred overnight. Excess piperidine is distilled off, and the residue is dissolved in ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution and brine, dried, and then the solvent is distilled off. The residue was purified by silica gel column chromatography [solvent: chloroform-methanol (20:1)], converted into a hydrochloride, and recrystallized from ethanol to give 2-phenyl-7-(2-piperidinoethyl)benzoxazole hydrochloride. 0.57
get g.

m. p. 255-258°C (decomposition) Example 70 The corresponding raw material compound was treated in the same manner as in Example 69 to obtain 7-(2
-(diethylamino)ethyl-2-phenylbenzoxazole hydrochloride is obtained.

m. p. 205.5~206.5°C (Z
Example 71 (1) A suspension of 0.38 g of 63% sodium hydride in tetrahydrofuran was added with di-tert malonic acid. A solution of 2.13 g of butyl ester in 5d of tetrahydrofuran is added dropwise at room temperature and stirred for 30 minutes. 2. 7-chloromethyl-2-phenylbenzoxazole was added to the solution. A 20-solution of Og in tetrahydrofuran is added dropwise over 45 minutes and stirred overnight at room temperature.

After adding ethyl acetate and washing the mixture with water and brine,
dry. After distilling off the solvent, 30 m of toluene and 1.45 g of p-1-luenesulfonic acid monohydrate were added to the residue, and the mixture was refluxed for 1 hour. After distilling off the toluene, chloroform is added, and the mixture is washed with water and brine, and then dried. After chloroform was distilled off, the residue was purified by silica gel column chromatography [solvent: chloroform-methanol (20:1)] and recrystallized from ethyl acetate-hexane to give 3-(2-phenyl-7-benzooxane). 1.09'g of zolyl)propionic acid are obtained.

m. p. 164-167, 5°C (2) To a solution of 1.0 g of the product from (1) above in 10 m of tetrahydrofuran, add 0 of carbonyldiimidazole.

Add 91 g little by little and stir at room temperature for 1 hour.

Furthermore, 1.91 g of piperidine and 3 d of tetrahydrofuran
Add the solution and stir at room temperature for 1 hour. After distilling off the solvent and adding ethyl acetate, washing with water and brine, and drying,
The solvent is distilled off. The residue was subjected to silica gel column chromatography [solvent: chloroform-ethyl acetate (20:1)]
) to give 1.21 g of N-(3-(2-phenyl-7-benzoxazolyl)propionyl]piperidine.
obtained as caramel.

(3) A solution of 1.15 g of the product obtained in (2) above in tetrahydrofuran 15d is added dropwise to a suspension of 0.39 g of lithium aluminum hydride in tetrahydrofuran 5d while cooling with water. After stirring at the same temperature for 1.5 hours, water and a 15% aqueous sodium hydroxide solution were added, and insoluble matter was filtered off. After evaporating the solvent, the residue is dissolved in ethyl acetate, washed with water and brine, and dried.

The solvent was distilled off, and the resulting oil was converted into a hydrochloride, which was then recrystallized from ethanol-diethyl ether to obtain 1.14 g of 2-phenyl-7-(3-piperidinopropyl)benzoxazole hydrochloride. get.

Peng, p. 237-240°C (decomposition) Example 72 3.20 g of 2-(4-benzyloxyphenyl)-7-piperidinomethylbenzoxazole, 0.6 g of 10% palladium-carbon and tetrahydrofuran-ethanol ( 1:2) Mixture 90- is stirred under hydrogen at normal pressure. After filtering off the catalyst and distilling off the solvent, the hydrochloride is obtained.

Recrystallization from ethanol yields 2.44 g of 2-(4-hydroxyphenyl)-7-piperidinomethylbenzoxazole hydrochloride.

m, p, 284-286°C Example 73 2.70 g of 2-(4-nitrophenyl)-7-piperidinomethylbenzoxazole, 0.5 g of 10% palladium-carbon, 60 ml of tetrahydrofuran and 60 ml of methanol! The mixture is stirred for 30 minutes under normal pressure of hydrogen. After filtering off the catalyst, the solvent was distilled off and the residue was recrystallized from ethyl acetate-hexane to give 2-(4-aminophenyl)-7piperidinomethylbenzoxazole 2.3
get g.

m, p, 144.5-147°C Example 74 A mixture of 1.25 g of 2-(4-aminophenyl)-7-piperidinomethylbenzoxazole, 10 d of acetic anhydride, and 10 d of chloroform was stirred at room temperature for 3 hours. do. After distilling off the solvent and acetic anhydride, ethyl acetate and a saturated aqueous sodium bicarbonate solution are added to the residue. The ethyl acetate layer is washed with brine and then dried. After distilling off the solvent, the obtained solid was converted into a hydrochloride and recrystallized from methanol to obtain 1.12 g of 2-(4-acetylaminophenyl)-7-piperidinomethylbenzoxazole hydrochloride. obtain.

m, p, 283-2B4, 5°C (decomposition) Example
75 5-nitro-2-phenyl-7-piperidinomethylbenzoxazole 2.47 g, stannous chloride dihydrate 8
．． A mixture of 26 g and 150 d of -1-tanol is refluxed for 2 hours. Water was added to the reaction solution, the mixture was made alkaline with a 10% aqueous sodium hydroxide solution, and then extracted with ethyl acetate. The extract is washed with brine, dried, and the solvent is distilled off. The residue was recrystallized from ethyl acetate-hexane to give 5-amino-
1.93 g of 2-phenyl-7-piperidinomethylbenzoxazole are obtained.

Gourd, p, 133.5-134.5°C Example 76 5 d of acetic anhydride is added to 0.72 g of 5-amino-2-phenyl-7-piperidinomethylbenzoxazole, and the mixture is stirred at room temperature for 10 minutes. Hexane-isopropyl ether is added to the reaction solution, the precipitate is collected by filtration, and then dissolved in ethyl acetate. Hydrochloric acid-diethyl ether was added to obtain the hydrochloride salt, which was recrystallized from ethanol-diethyl ether to give 5-
48 g of acetylamino-2-phenyl-7-piperidinomethylbenzoxazole hydrochloride Q-4 is obtained.

m, p, 281-2B2.5 °C [Preparation of raw material compound] Reference example 1 (1) To a tetrahydrofuran solution of 8.60 g of 3-amino-2-hydroxybenzoic acid methyl ester and dimethylaniline was added p - A solution of chlorobenzoic acid chloride in tetrahydrofuran is added dropwise and stirred at the same temperature. The reaction solution is extracted with ethyl acetate, and the extract is washed and dried. After distilling off the solvent, the residue was recrystallized from ethyl acetate-hexane to obtain 14.15 g of 3-(4-chlorobenzoylamino)-2-hydroxybenzoic acid methyl ester.

(2) A few drops of dimethylformamide is added to a mixture of 13.5 g of the product from (1) above and thionyl chloride, and the mixture is refluxed. After thionyl chloride is distilled off, the mixture is extracted with ethyl acetate, and the extract is washed and dried. After distilling off the solvent, it was recrystallized from tetrahydrofuran-hexane to give 2-(4-
10.13 g of chlorophenyl)hendioxadioxadi-roof-carboxylic acid methyl ester are obtained.

m, p, 141 to 144°C (3) A solution of 17.0 g of the product obtained in (2) above in tetrahydrofuran is added dropwise to a solution of lithium aluminum hydride in tetrahydrofuran while cooling with water, and the mixture is stirred at the same temperature. Water, a 15% aqueous sodium hydroxide solution, and water were sequentially added to the reaction solution, insoluble matter was filtered off, the solvent was distilled off, washed, and recrystallized from tetrahydrofuran-hexane to obtain 2-(4
-chlorophenyl)-7-benzoxazole methanol (13.22 g) was obtained.

Reference Example 2 (1) 3-Amino-2-hydroxybenzoic acid methyl ester and 2-naphthoyl chloride were treated in the same manner as in Reference Example 1 (1) to obtain 2-hydroxy -3-(2-naphthoylamino)benzoic acid methyl ester is obtained.

m, p, 124-125 °C (ethyl acetate-hexane) (2) 6.53 g of the product of (1) above and polyphosphoric acid trimethylsilyl ester (PPSE) solution [phosphorus pentoxide, hexamethyldisiloxane and 1,2 - prepared by refluxing a mixture of dichlorobenzene under argon]
The mixture is stirred at 150°C under argon. After cooling, the reaction solution was extracted with ethyl acetate, the extract was washed, dried, the solvent was distilled off, and recrystallized from methanol to obtain 2-(2
546 g of benzoxazole-7-carboxylic acid methyl ester are obtained.

m, p, 105-108°C (3) The product of (2) above is treated in the same manner as in Reference Example 1-(3) to obtain 2-(2-naphthyl)-7-benzoxazolemethanol.

Peng, p, 168-169 °C (ethyl acetate) Reference Example 3 (1) 3-Amino-2-hydroxybenzoic acid methyl ester and p-dimethylaminobenzoic acid chloride were mixed in the same manner as in Reference Example 1-(]). Treatment yields 3-(4-dimethylaminobenzoylamino)-2-hydroxybenzoic acid methyl ester.

m, p, 162-165 °C (TetrahyF [Run-He #9) (2) 5.11 g of the product of (1) above,
A mixture of pyridinium littleenesulfonate and xylene is refluxed, and after cooling, ethyl acetate and tetrahydrofuran are added, and the mixture is washed and dried. After distilling off the solvent, recrystallization from tetrahydrofuran-hexane gave 2
2.94 g of -(4-dimethylaminophenyl)benzoxazole-7-carboxylic acid methyl ester are obtained.

m, p, 142-144°C (3) The product of (2) above was treated in the same manner as in Reference Example 1-(3) to obtain 2-(4-dimethylaminophenyl)-7penzoxazole methanol. obtain.

m, p, 203-204.5°C (Tetrahuman Furan-Hexane) Reference Example 4 (1) Mixture of 5.30 g of 3-amino-2-hydroxybenzoic acid methyl ester, 4-methoxy-1-naphthaldehyde and toluene Reflux. After distilling off the solvent,
The obtained crystals were washed to give 2-hydroxy-3-(4-
8.77 g of methoxy-1-naphthylmethyleneamino)benzoic acid methyl ester are obtained.

(2) p, 166-170°C (2) A mixture of 8.77 g of the product obtained in (1) above, manganese dioxide and methylene chloride is stirred at room temperature, then insoluble matter is filtered off and the solvent is distilled off. The residue was purified with a silica gel column and then recrystallized from ethyl acetate to obtain 476 g of 2-(4-methoxy-1-naphthyl)benzoxazole-7-carboxylic acid methyl ester.

Plow, p, 170-171.5°C (3) The product of (2) above was treated in the same manner as in Reference Example 1-(3) to obtain 2-(4-methoxy-1-naphthyl)-7-
Obtain benzoxazole methanol.

Cabinet, p, 150-151.5 °C (ethyl acetate-hexane) Reference example 5 (1) Into an 85% phosphoric acid solution of 22.23 g of 2-aminobenzothiazole-7-carboxylic acid ethyl ester, -1
At 0°C, add the sodium nitrite aqueous solution dropwise and stir. Copper sulfate pentahydrate and an aqueous sodium bromide solution are added dropwise to the reaction solution at 0°C or below, and then stirred at room temperature. After pouring into ice water and extracting with chloroform, the solvent was distilled off and the resulting crystals were washed to give 2-bromobenzothiazole-7-
19.1 g of carboxylic acid ethyl ester are obtained.

(2) 7.15 g of the product from (1) above, tri(n-butyl)(4-methoxyphenyl)tin, dichlorodi(triphenylphosphino)palladium, zinc chloride and dioxane. The mixture is refluxed under argon. After cooling, a saturated aqueous sodium hydrogen carbonate solution and an aqueous potassium fluoride solution are added, and the mixture is stirred at room temperature. Insoluble materials are filtered off and extracted with tetrahydrofuran-ethyl acetate (1:1). After distilling off the solvent, it was purified using a silica gel column and purified with ethyl acetate.
2-(4-methoxyphenyl)benzothiazole-7-carboxylic acid ethyl ester 5 was recrystallized from hexane.
．． Obtain 90g.

m, p, 126-127°C (3) The product of (2) above is treated in the same manner as in Reference Example 1-(3) to obtain 2-(4-methoxyphenyl)-7-benzothiazolemethanol.

m, p, 137-139°C (Vinegar modified ethylhexane) Reference Example 6 (1) 3-Amino-2-hydroxybenzoic acid methyl ester and benzoic acid chloride were treated in the same manner as in Reference Example 1-(1). Thus, 3-benzoylamino-2-hydroxybenzoic acid methyl ester is obtained.

a+, p, 100-103°C (ethyl acetate) (2) To an acetic acid solution of 7.84 g of the product obtained in (1) above, 69% nitric acid is added dropwise under water cooling, and the mixture is stirred at room temperature. The reaction solution was poured into ice water, and the precipitate was collected by filtration, washed, and recrystallized from tetrahydrofuran-methanol to obtain 7.93 g of 3-benzoylamino-2-hydroxy-5-nitrobenzoic acid methyl ester.

11, p, 198.5-200.5°C (3) Above (
A mixture of 7.93 g of the product from 2) and the PP5E solution was added to 1
Stir at 50°C. After cooling, the precipitated crystals were collected by filtration and washed to give 5-nitro-2-phenylbenzoxazole-7.
-obtain carboxylic acid methyl ester.

m, p, 193-194 °C (4) The product of (3) above is treated in the same manner as in Reference Example 1-(3) to obtain 5-nitro-2-phenyl-7-benzoxazole methanol.

m, p, 172-175 °C (tetrahydrofuran-hexane) Reference Examples 7-35 (1) The corresponding raw material compounds were treated in the same manner as in Reference Examples 1-6 to obtain the compounds listed in Tables 8 and 9 below. obtain.

Table 8 (However, Y represents an imino group in Reference Example 29, and represents an oxygen atom in other cases.) Table 9 Reference Example 36 (1) 2-Amino-6-methylphenol hydrochloride 2.
A suspension of 08 g of 4-chlorobenzoyl chloride and 5.27 g of dimethylaniline in 50 d of tetrahydrofuran is cooled with ice, and a solution of 2.50 g of 4-chlorobenzoyl chloride in 10 d of tetrahydrofuran is added dropwise. After stirring for 1 hour, water is added and extracted with ethyl acetate, and the ethyl acetate layer is washed and dried. The solvent was distilled off, and the residue was recrystallized from ethyl acetate-hexane to give 2-(4-chlorobenzoylamino)-6-methylphenol 2.8
Obtain 3g.

m, p, 183-185°C (2) 1.31 g of the product from (1) above, 0.1 g of p-toluenesulfonic acid monohydrate, and 1511 f of xylene!
The mixture is refluxed for 2 hours. Add ethyl acetate, wash with aqueous sodium bicarbonate solution and brine, and dry. The solvent was distilled off and the residue was recrystallized from isopropyl ether-hexane to give 7-methyl-2-(4-chlorophenyl).
105 g of benzoxazole are obtained.

m, p, 133-135°C Reference Example 37 (1) 3-benzoylamino-2-hydroxybenzoic acid methyl ester was treated in the same manner as in Reference Example 1-(2),
2-phenylbenzoxazole-7-carboxylic acid methyl ester is obtained.

m, p, 78-81 °C (2) A dioxane 20-solution of 2.48 g of the product from (1) above was heated to 50 °C, and IN sodium hydroxide 40
- and stir for 5 minutes. After cooling, 10% hydrochloric acid and water are added, and the precipitate is collected by filtration, dried, and recrystallized from tetrahydrofuran-hexane to obtain 2.13 g of 2-phenylbenzoxazole-7-carboxylic acid.

■, 1), 219-223°C Reference Example 38 (1) In a mixture of 96% sulfuric acid and 69% nitric acid, under water cooling,
2-phenyl-7-penzoxazole methanol4.
Add 50g and stir at 0-5°C.

The reaction solution was poured into ice water, extracted with ethyl acetate, and then the solvent was distilled off. After adding methanol, tetrahydrofuran and 10% aqueous sodium hydroxide solution to the residue and stirring,
Extract toluene. After distilling off the solvent, the residue is recrystallized from ethyl acetate-hexane to obtain 3.45 g of 6-nitro-2-phenylbenzoxazole-7-carbaldehyde.

173-174°C (2) Add lithium aluminum hydride little by little to a solution of 1.39 g of the product obtained in (1) above in tetrahydrofuran at -20°C. The reaction solution is extracted with ethyl acetate, and the extract is washed and dried. After distilling off the solvent, the obtained crystals are washed to obtain 105 g of 6-nitro-2-phenyl-7-benzoxazole methanol.

m, p, 154-158°C Reference Example 39 (1) A mixture of 4.0 g of 2-phenyl-7-penzoxazole methanol, manganese dioxide and methylene chloride is stirred at room temperature and then refluxed. After filtering off the insoluble matter, the solvent is distilled off, and the obtained crystals are recrystallized from isopropyl ether to obtain 297 g of 2-phenylbenzoxazole-7-carbaldehyde.

m, p, 106-108 °C (2) To a tetrahydrofuran solution of 2.30 g of the product of (1) above, a tetrahydrofuran solution of methylmagnesium bromide was added at -50 °C, and then at the same temperature, the solution was heated to -20 °C. After stirring at around C, saturated aqueous ammonium chloride solution was added and extracted with ethyl acetate.

After washing and drying the extract, the solvent is distilled off. The residue was purified with a silica gel column and then recrystallized from isopropyl ether-hexane to obtain 230 g of 1-(2-phenyl-7-benzoxazolyl)ethanol.

m, p, 97.5-99.5°C [Effects of the Invention] The thus obtained object (1) of the present invention or a pharmacologically acceptable salt thereof exhibits reflex urinary contractions. Because it suppresses urination and has an excellent effect of extending the urinary interval, it can be used to treat and prevent diseases related to the contractile function of the urinary tract such as the bladder and ureter, such as frequent urination, nocturnal enuresis, and neurogenic bladder. . In particular, the object (1) of the present invention or a pharmacologically acceptable salt thereof has the advantage of exhibiting the above-mentioned effects without reducing the contractile force of the bladder.

Claims (1)

[Claims] 1. General formula ▲ Numerical formulas, chemical formulas, tables, etc. 6-membered heterocyclic group, R^2 and R^3 are a hydrogen atom, a lower alkyl group, a substituted or unsubstituted phenyl-lower alkyl group, a di-lower alkylamino-lower alkyl group, or are bonded to each other at the terminals; Forms a substituted or unsubstituted nitrogen-containing 5- to 9-membered heterocyclic group together with adjacent nitrogen atoms,
R^4 is a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, a nitro group, an amino group or a lower alkanoylamino group, R^5 is a hydrogen atom or a lower alkyl group,
Y represents an oxygen atom, a sulfur atom or an imino group, and n represents 0-2. ) A benzazole derivative or a pharmacologically acceptable salt thereof. 2. R^1 is a phenyl group, a naphthyl group, a phenyl lower alkyl group, a furyl group, a thienyl group, a pyridyl group, a benzofuryl group, a benzothienyl group, a quinolyl group, or an isoquinolyl group (the phenyl group and naphthyl group are halogen atoms, 1 to 3 groups selected from a lower alkyl group, a lower alkoxy group, a phenyl-lower alkoxy group, a hydroxyl group, a di-lower alkylamino group, a nitro group, an amino group, a lower alkanoylamino group, a trihalomethyl group, and a lower alkylenedioxy group. ), and R^2 and R^3 are hydrogen atoms, lower alkyl groups, phenyl-lower alkyl groups, lower alkoxy-substituted phenyl-lower alkyl groups, di-lower alkylamino-lower Nitrogen-containing groups that are alkyl groups or are bonded to each other at the terminals and together with adjacent nitrogen atoms are selected from pyrrolidyl, piperidino, homopiperidino, azacyclooctyl, azabicyclononyl, morpholino, piperazinyl, and imidazolyl groups. Forming a 5- to 9-membered heterocyclic group (the nitrogen-containing 5- to 9-membered heterocyclic group may have 1 to 3 substituents selected from a lower alkyl group, a hydroxyl group, and a phenyl group) The compound according to claim 1. 3. R^1 is a phenyl group which may have a substituent selected from a halogen atom, a lower alkoxy group or a lower alkylenedioxy group, or a naphthyl group which may have a lower alkoxy group as a substituent and R^2 and R^3 are lower alkyl groups, or are bonded to each other at the terminals, and together with the adjacent nitrogen atom, a piperidino group, a homopiperidino group, or a morpholino group (these piperidino groups,
The homopiperidino group or morpholino group may have a lower alkyl group as a substituent. ), forming R^4
3. The compound according to claim 2, wherein is a hydrogen atom, a lower alkyl group, a lower alkoxy group, or a halogen atom, R^5 is a hydrogen atom, Y is an oxygen atom, and n=0. 4, R^1 is a lower alkoxy-phenyl group, R^
2 and R^3 are bonded to each other at the terminals to form a piperidino group or a morpholino group together with the adjacent nitrogen atom, and R
4. The compound according to claim 3, wherein ^4 is a hydrogen atom or a lower alkoxy group. 5. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (However, R^1 is a substituted or unsubstituted aryl group, phenyl-lower alkyl group, or nitrogen-containing, oxygen-containing, or sulfur-containing 5- to 6-membered heterocyclic group , R^4 is a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, a nitro group, an amino group, or a lower alkanoylamino group, R^5 is a hydrogen atom or a lower alkyl group, Y is an oxygen atom, a sulfur atom, or an imino group. group, n is 0 to 2, and X^1 represents a reactive residue.) Compounds or salts thereof and general formulas ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (However, R^2 and R^3 are a hydrogen atom, a lower alkyl group, a substituted or unsubstituted phenyl-lower alkyl group, a di-lower alkylamino-lower alkyl group, or are bonded to each other at the terminals and together with adjacent nitrogen atoms are substituted or unsubstituted nitrogen-containing 5 to forming a 9-membered heterocyclic group) and a condensation reaction with an amine compound or a salt thereof,
Benzene represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ (However, the symbols have the same meanings as above.) A method for producing an azole derivative or a pharmacologically acceptable salt thereof. 6. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (However, R^1 is a substituted or unsubstituted aryl group, phenyl-lower alkyl group, or a nitrogen-containing, oxygen-containing, or sulfur-containing 5- to 6-membered heterocyclic group , R^2 and R^3 are a hydrogen atom, a lower alkyl group, a substituted or unsubstituted phenyl-lower alkyl group, a di-lower alkylamino-lower alkyl group, or are bonded to each other at their terminals and substituted together with adjacent nitrogen atoms. or forming an unsubstituted nitrogen-containing 5- to 9-membered heterocyclic group,
R^4 is a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, a nitro group, an amino group or a lower alkanoylamino group, Y is an oxygen atom, a sulfur atom or an imino group,
n represents 0-2. ) The general formula ▲ is characterized by reducing the amide compound or its salt represented by ▲ and converting the product into its pharmacologically acceptable salt ▲ There are mathematical formulas, chemical formulas, tables, etc.▼ (However, the symbol has the same meaning as above.) A method for producing a benzazole derivative or a pharmacologically acceptable salt thereof. 7. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (However, R^1 is a substituted or unsubstituted aryl group, a phenyl-lower alkyl group, or a nitrogen-containing, oxygen-containing, or sulfur-containing 5- to 6-membered heterocyclic group , R^4 is a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, a nitro group, an amino group, or a lower alkanoylamino group, R^5 is a hydrogen atom or a lower alkyl group, Y is an oxygen atom, a sulfur atom, or an imino group. group, n is 0 to 2, and X^1 represents a reactive residue) or a salt thereof. 8. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (However, R^1 is a substituted or unsubstituted aryl group, a phenyl-lower alkyl group, or a nitrogen-containing, oxygen-containing, or sulfur-containing 5- to 6-membered heterocyclic group , R^2 and R^3 are hydrogen atoms, lower alkyl groups, substituted or unsubstituted phenyl-lower alkyl groups, di-lower alkylamino-lower alkyl groups, or are bonded to each other at their terminals and substituted together with adjacent nitrogen atoms or forming an unsubstituted nitrogen-containing 5- to 9-membered heterocyclic group,
R^4 is a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, a nitro group, an amino group or a lower alkanoylamino group, Y is an oxygen atom, a sulfur atom or an imino group,
n represents 0-2. ) An amide compound or a salt thereof.