JPH02193992A - Quinazoline derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I {R<1> to R<3> represent H or lower alkyl; m is 0 or 1; n is 0-4; Z represents formula II [X represents O or S; R<4> represents H, (substituted) lower alkyl, lower alkenyl, aralkyl or lower alkanoyl] or formula III (dotted line represents single bond or double bond; Y represents O, S or >N-R<4>; R<5> represents H or lower alkyl; at least one of R<4> and R<5> represent groups other than H, when X represents 0 and m and n are 0)}. EXAMPLE:1-(6,7-Dimethoxyquinazolin-4-yl)-4-(2-oxoimidazolidin-1-yl)pip eridine. USE:A cardiac. PREPARATION:One equivalent compound expressed by formula IV (L represents leaving group) is reacted with >=1 equivalents compound expressed by formula V preferably in the presence of a base (example; sodium hydroxide), as necessary, in the coexistence of potassium iodide, etc., in an inert solvent at room temperature to the boiling point of the solvent for 10min-24hr.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to a novel quinazoline derivative having cardiotonic action or a pharmacologically acceptable acid addition salt thereof.

BACKGROUND OF THE INVENTION A group of compounds are known in which a biperidino group substituted directly with a heterocyclic group or via an alkylene group is bonded to the 4-position of the quinazoline ring as a substituent Y in quinazoline derivatives having cardiotonic action and represented by the following formula. It is being

For example, JP-A-51-36469 discloses a compound in which Yo is a compound, and JP-A-61-215389 discloses a compound in which Yo has a hydantoin or thiohydantoin derivative directly or via an alkylene group. There is.

Problems to be Solved by the Invention Cardiotropic agents have been used as a treatment for chronic heart failure, but none of them has yet been satisfactory in terms of intensity and durability of their effects.

The present invention provides novel quinazoline derivatives having cardiotonic effects.

Means for Solving the Problems The present invention provides a compound of formula (1), which is disclosed in JP-A-60-120872
o directly or via an alkylene chain (in the formula, R1,
R2 and R3 are the same or different and represent hydrogen or lower alkyl, m is 0 or 1, and n is 0.1
．． 2.3 or 4, Z is R", R4 is hydrogen, substituted or unsubstituted lower alkyl,
Lower alkenyl, aralkyl or lower r represents a single bond or double bond, Y represents oxygen or a sulfur atom or >NR4 (in the formula, R4 has the same meaning as above), R' represents hydrogen or lower alkyl , and X has the same meaning as above, but when X is an oxygen atom and m and n are both 0,
At least one of R'' and R5 is a group other than hydrogen]
(hereinafter referred to as compound (I)). The same applies to compounds of other formula numbers] and pharmacologically acceptable acid addition salts thereof.

In the definition of each group in formula (I), the alkyl moiety in lower alkyl and lower alkanoyl has 1 to 6 carbon atoms.
Straight or branched forms such as methinobethyl, propyl, isopropinopeptyl, isobutyl, sedibutyl tert-butynopebentyl, inpentyl, neopentyl, 5ec-pentynopehexynope5ec-hexyl and the like are included. The substituents in substituted alkyl are the same or different and have 1 to 3 substituents such as hydroxynope lower alkoxyl, lower alkanoyloxy, lower alkylthio, lower alkylsulfininope lower alkylsulfonyloxy, amine, mono-lower alkyl-substituted amino, di-lower alkyl Substituted amino, nitrogen-containing alicyclic heterocyclic groups, halogen, and the like are included. Here, the alkyl moiety in lower alkoxyl, lower alkanoyloxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyloxy, mono-lower alkyl-substituted amino and di-lower alkyl-substituted amino is a straight or branched alkyl group having 1 to 4 carbon atoms, e.g. Methyl, methyl, propyl, isopropyl,
Butyl, isobutyl, 5eC-butyl and tert-
Butyl, etc., nitrogen-containing alicyclic heterocyclic groups include pyrrolidinyl, piperidino, piperazininope N-methylpiperazinyl, morpholino, thiomorpholino, homopiperazinyl, and N-methylhomopiperazinyl, and halogens include fluorine, Examples include chlorine, bromine and iodine atoms, respectively.

Lower alkenyl includes vinyl having 2 to 6 carbon atoms, alinopepropeninopebtenyl, hexenyl, and the like.

Aralkyl includes benzyl, phenethio, benzhydryl, etc. having 7 to 15 carbon atoms.

Pharmaceutically acceptable acid addition salts of compound (I) include salts with various inorganic acids, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, phosphate, etc. Also, salts with various organic acids, such as formates, acetates, benzoates,
Examples include maleate, fumarate, succinate, tartrate, citrate, oxalate, glyoxylate, aspartate, methanesulfonate, and benzenesulfonate.

Next, a method for producing compound (1) will be explained.

Production method 1 Compound (1) is a compound (II) represented by the following formula (wherein R2 and R3 have the same meanings as above, and L represents a leaving group) and the following formula (wherein R', Z , m and n have the same meanings as above).

Here, the leaving group represented by is a halogen atom such as chlorine or bromine, an alkylthio group such as methylthio or ethylthio, an ary-1-lthio group such as phenylthio or naphthylthio,
Lower alkylsulfonyl groups such as methylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, arylsulfonyl groups such as phenylsulfonyl, p-)luenesulfonyl, arylsulfonyloxy groups such as oyohyphenylsulfonyloxy, p-toluenesulfonyloxy, etc. do.

The reaction is preferably carried out using one or more equivalents of compound (III) or its acid addition salt relative to compound (II), and if necessary in the presence of a base. Examples of acid addition salts include those similar to the acid addition salts of compound (I) described above,
Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide, and potassium carbonate, alkali metal salts such as sodium methoxide, potassium ethoxide, and botanical tert-butoxide, triethylamine, pyridine, 1,8-
Diazabicyclo[5,4,0]undec-7-ene (D
Examples include organic bases such as BU). In addition, it may be preferable to carry out the reaction in the presence of potassium iodide or the like in order to carry out the reaction smoothly.

Reaction solvents include solvents inert to the reaction, such as ketones such as acetone, halogenated hydrocarbons such as chloroform and methylene chloride, aprotic polar solvents such as dimethylformamide and dimethyl sulfoxide, benzene, toluene, chlorobenzene, etc. Aromatic hydrocarbons such as methanol, ethanol, lower alcohols such as isopropanol, and acetonitrile are used alone or in combination.

The reaction temperature ranges from 0 to 200°C, preferably between room temperature and the boiling point of the solvent used, and the reaction is completed in 10 minutes to 24 hours.

Production method 2 In compound (I), Z is each represented by the following formula (in the formula, R4
a means <R' excluding hydrogen, and X has the same meaning as above) The compound (ra) or (Ib) represented by Z
Compound (1-1) represented by the following formula (wherein, It can be obtained by reacting the compound (IV) represented by (synonymous with the above) in the presence of a base.

The bases used include those exemplified in Production Method 1 and sodium hydride, and the reaction solvents used include those exemplified in Production Method 1 and water, either singly or in combination.

Regarding the reaction time and reaction temperature, those described in Production Method 1 are similarly applied.

In addition, in this reaction, due to differences in reaction conditions such as the type of compound (1-1), alkylating agent, and base,
Compound (Ia) or (Ib) alone or a mixture of both compounds is produced.

Production method 3 Compound (Ib') in which Z is (in the formula, R4 and has the same meaning as above) can be obtained by treating the compound (V) represented by the following with an appropriate ring-closing reagent.

Examples of the ring-closing reagent include N,N'-carbonyldiimidazole, urea, phosgene, carbon disulfide, N,N'-thiocarponyldiimidazole, thiophosgene, and the like.

Regarding the reaction solvent, reaction temperature, time, etc., those described in the above-mentioned production method 1 or 2 are similarly applied.

In order to accelerate the reaction, for example, triethylamine,
A base such as pyridine, DBU, sodium carbonate or potassium carbonate may be present.

Production method 4 Compound (I c) in which Z is (in the formula, R5 and and n have the same meanings as above) It can be obtained by reacting the compound m(V'I) represented by the following with a metal complex compound such as lithium aluminum hydride or lithium borohydride, and further treating with an acid.

As the reaction solvent C, diethyl ether, tetrahydrofuran, benzene, etc. which do not participate in the reaction are used, and the reaction is completed in a few minutes to 6 hours at -50 to 50°C.

Production method 5 Compound (1) in which R4 is amino, mono-lower alkyl-substituted amino, di-lower alkyl-substituted amine, or lower alkyl having a nitrogen-containing alicyclic heterocyclic group as a substituent, the corresponding substituent is lower It can be obtained by reacting an alkylsulfonyloxy compound with a corresponding amine such as ammonia, a primary amine, a secondary amine, or a nitrogen-containing alicyclic heterocycle.

The reaction solvent used is methanol, chloroform, dimethylformamide, etc., which do not participate in the reaction, and the reaction is usually carried out in O
Finish in 30 minutes to 24 hours at ~150°C.

Production method 6 In compound (I), a compound in which R4 is lower alkyl having lower alkanoyloxy as a substituent can be obtained by acylating a compound in which the corresponding substituent is hydroxyl with a common acylating agent. .

As the acylating agent, acid anhydrides, acid halides, etc. are used, and it may be preferable to carry out the reaction in the presence of a base similar to that described in Production Method 1.

Production method 7 In compound (I), a compound in which R4 is lower alkyl having lower alkylsulfinyl as a substituent,
It can be obtained by treating a compound in which the corresponding substituent is lower alkylthio with an oxidizing agent such as hydrogen peroxide or m-chloroperbenzoic acid.

In addition, the compounds (n), (I[I), (V) and (Vl) used as raw material compounds in the above production method are:
It can be produced by a known method (for example, JP-A-51-36469; JP-A-61-215389, etc.), a method described in Reference Examples, etc., or a method similar thereto.

The intermediates and target compounds in the above-mentioned production methods can be isolated and purified by purification methods commonly used in organic synthetic chemistry, such as p-filtration, extraction, washing, drying, a-condensation, recrystallization, and various chromatography. Can be done. Further, the intermediate can also be subjected to the next reaction without being particularly purified.

When you want to obtain a salt of compound (1), if compound (I) is obtained in the form of a salt, you can simply purify it as is, or if it is obtained in a free form, you can obtain the salt by a conventional method. Just let it form.

In addition, compound (1) and its pharmacologically acceptable salts are:
It may exist in the form of adducts of water or various solvents, and these adducts are also included in the present invention.

Although some compounds (1) may have tautomers, the present invention is not limited to tautomers, but also includes all possible stereoisomers and mixtures thereof.

Specific examples and physical property values of Compound (1) obtained by each production method are shown in Table 1.

Next, the cardiotonic effect of the representative compound (1) will be explained using test examples.

Test Example Anesthetized an adult male and female mixed breed dog weighing 8 to 15 kg by intravenously administering pendoparvicool (IJ) salt at a rate of 30 mg/kg. Under artificial respiration, a catheter-type pressure transducer was retrogradely inserted into the left ventricle through the left common carotid artery, and left ventricular pressure was measured.

Additionally, peripheral blood pressure was measured using a pressure transducer via a catheter inserted into the femoral artery.

Myocardial contractile force is the maximum value of the first derivative of left ventricular pressure (dp/d
t ma

Anesthesia was maintained during the measurements by inhalation anesthesia using halothane and laughing gas. At the same time, a muscle relaxant (pancuronium bromide) was continuously injected into the left forelimb vein at a rate of 0.1 mg/kg. Using this method, we were able to obtain a stable state of anesthesia for a long period of time.

The test compound was dissolved in PEG-4QQ and injected into the right forelimb vein (
iv>, the doses shown in Table 2 were administered.

The maximum rate of change in myocardial contractile force, heart rate, and peripheral mean blood pressure from the pre-administration values and the duration of the change in myocardial contractile force up to 60 minutes after administration were determined.

The results are shown in Table 2.

2) The cardiotonic agent containing Compound (I) or its pharmacologically acceptable acid addition salt can be administered in the form of commonly applied tablets, capsules, syrups, injections, infusions, suppositories, etc. It can be administered orally or parenterally, such as by intramuscular injection, intravenous injection, intraarterial injection, infusion, or rectal administration via suppositories. Generally known methods are applied to formulate dosage forms for oral or parenteral administration, such as various excipients, lubricants, binders, etc.
It may contain a disintegrant, a suspending agent, a tonicity agent, an emulsifier, and the like.

Pharmaceutical carriers used include, for example, water, distilled water for injection, physiological saline, glucose, fructose, white sugar, mannitol, lactose, starch, cellulose, methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, alginic acid, talc, and citric acid. Examples include sodium acid, calcium carbonate, calcium hydrogen phosphate, magnesium stearate, urea, silicone resin, sorbitan fatty acid ester, glycerin fatty acid ester, and the like.

The dosage varies depending on the dosage form, patient's age, weight, symptoms, etc., but for example, the usual oral dosage is 5-=600 mg/60
kg/day is appropriate, and in the case of intravenous drip, 0.1 to 5 ■
/kg/min, preferably within a range that does not exceed the daily oral dosage limit.

The present invention will be explained in detail below using Examples and Reference Examples.

Example 1 4-chloro-6,7-simethoxyquinazoline 1.5g1
A mixture of 1.4 g of the compound a obtained in Reference Example 1, 1.4 g of triethylamine, and 50 ml of methanol was stirred under reflux for 1 hour. It was concentrated, water was added to the residue, the precipitated crystals were filtered and dried, and 1-(6,7dimethoxyquinazolin-4-yl)-4-(2oxoimidazolidin-1-yl)piperidine (compound 1) 1. 8g was obtained.

Example 2 Compound b1 obtained in Reference Example 2. og,) IJ ethylamine 0.7 g, carbon disulfide 1.0 g and ethanol 5
The ml mixture was stirred under reflux for 15 hours.

Cool to room temperature, filter and dry the precipitated crystals, 1-(
6,7-Simethoxyquinazolin-4-yl)4-(2-
Thioxoimidazolidin-1-yl)piperidine (Compound 2)1. Obtained Og.

Example 3 l-(6,7-simethoxyquinazolin-4-yl)-4
-(5-methyl-2,4-dioxoimidazolidine-3
-yl)piperidine 3.0g and tetrahydrofuran 10g
Dissolved in 0n+I, lithium aluminum hydride 0.
59 g was added and stirred at room temperature for 5 minutes.

Water was added, the precipitate was separated, and the p liquid was concentrated. 1
The mixture was made acidic by adding normal hydrochloric acid, and then made alkaline with a 1N aqueous sodium hydroxide solution. The mixture was extracted with chloroform, dried over anhydrous sodium sulfate, and concentrated. The residue was crystallized from diethyl ether to give 1-(6,7-simethoxyquinazolin-4-yl)-4-(4-methylimidazole-2
1.4 g of -on-1-yl)piperidine (compound 3) was obtained.

Example 4 l-(6,7-simethoxyquinazolin-4-yl)4-
(2-oxoimidazolidin-1-yl)piperidine 1
．． Dissolve 5 g in 10 ml of dimethyl sulfoxide and add 60
0.4 g of IJ (% hydrogenated) was added and stirred at room temperature for 15 minutes. 1.0 g of methyl iodide was added and the mixture was further stirred at room temperature for 1 hour. Water was added, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated. The residue was crystallized from methanol-diethyl ether to give 1-(6,7-simethoxyquinazolin-4-yl)-4-(3-methyl-2-oxoimidazolidin-1-yl)piperidine (compound 4).
0.9g was obtained.

Example 5 4-(3-ethyl-2-oxoimidazolidin-1-yl)-1-(6, 7-Simethoxyquinazolin-4-yl)piperidine (compound 5) 1
．． Obtained 0g.

Example 6 1.0 g of n-propyl iodide from methyl iodide of Example 4
1-(6゜7-Simethoxyquinazolin-4-yl)-4-(2-oxo-3-
0.9 g of n-propylimidazolidin 1-yl)piperidine (compound 6) was obtained.

Example 7 4-(3-methoxymethyl-2-oxoimidazolidin-1-yl)- was prepared in the same manner as in Example 4 except that 1.0 g of chloromethyl methyl ether was used for methyl iodide.
1.0 g of 1-(6,7-simethoxyquinazolin-4-yl)piperidine (Compound 7) was obtained.

Example 8 Methyl iodide of Example 4 was converted to 2-bromoethyl acetate)
4-(3-
Acetyl-2-oxoimidazolidin-1-yl)-1-
0.5 g of (6,7-simethoxyquinazolin-4-yl)piperidine (compound 8) was obtained.

Example 9 4-(3-allyl-2-oxoimidazolidin-1-yl)-1-(6,7-silyl) was prepared in the same manner as in Example 4 except that 1.0 g of allyl bromide was used instead of methyl iodide. Methoxyquinazolin-4-yl)piperidine (Compound 9) 1
．． Obtained 0g.

Example 10 1-(6,7
1.4 g of -cymethoxyquinazolin-4-yl)4-(3-methylthiomethyl-2-oxoimidazolidin-1-yl)piperidine (Compound 10) was obtained.

Example 11 100.4 g of the compound obtained in Example 10 was dissolved in 50% acetic acid I Q + nl, and 5 ml of 30% hydrogen peroxide solution Q was added.
was added and stirred for 2 hours under water cooling. 1N hydroxide) IJ
The reaction solution was made alkaline with an aqueous solution of aluminum, and extracted with chloroform. The mixture was dried over anhydrous magnesium sulfate and concentrated, and diethyl ether was added to the residue for crystallization. The crystals were filtered and dried, and 1-(6,7-simethoxyquinazolin-4-yl)-4-(3-methylsulfinylmethyl-2-oxoimidazolidin-1-yl)piperidine (Compound 11)
0.3g was obtained.

Example 12 15 g of the compound co obtained in Reference Example 3 was dissolved in 10 ml of acetonitrile, 0.12 g of N,N'-carbonyldiimidazole was added, and the mixture was stirred at 50°C for 3 hours. It was concentrated, water and chloroform were added to the residue for partitioning, and the organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was crystallized from diethyl ether to give 4-(3-benzyl-2-oxoimidazolidin-1-yl)-1-(6,7-cymethoxyquinazolin-4-yl)piperidine (compound 12).
) 0.1 g was obtained.

Example 13 1-benzyl-4-(3-β-benzyloxyethyl-
2-oxoimidazolidin-1-yl)piperidine3.
0 g, methanol 25 mL 1 N hydrochloric acid 25 mL and 1
A mixture of 0% palladium and 0.3 g of carbon was heated under a hydrogen stream for 6 hours.
The mixture was stirred at 0°C for 2 days. The reaction solution from which the catalyst had been removed was concentrated and added to 53 ml of methanol.

Add 3 ml of triethylamine and 1.0 g of 4-chloro-6,7-simethoxyquinazoline and heat at 60°C for 2 hours! l
Stirred. Add water, collect the precipitated crystals, dry them, and 4-
0.5 g of (3-β-hydroxyethyl-2-oxoimidazolidin-1-yl)-1-(6,7-cymethoxyquinazolin-4-yl)piperidine (Compound 13) was obtained.

Example 14 130.3 g of the compound obtained in Example 13, acetic anhydride Q
, 1 ml, pyridine 5 ml and triethylamine Q,
The 2ml mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, partitioned between water and chloroform, and the organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was crystallized from methanol-diethyl ether, purified and dried to give 4-(3-β
-acetoxyethyl-2-oxoimidazolidine-1-
0.3 g of piperidine (compound 14) was obtained.

Example 15 The acetic anhydride of Example 14 was converted into methanesulfonic acid chloride Q,
4-(3-β-methanesulfonyloxyethyl-2-oxoimidazolidin-1-yl)-1-(6,7-cymethoxyquinazolin-4-yl)piperidine ( 0.3 g of compound 15) was obtained.

Example 16 A mixture of 150.3 g of the compound obtained in Example 15, 2 ml of piperidine Q, 4 ml of ethylamine Q, and 20 ml of dimethylformamide was stirred at 60° C. for 7 hours. The reaction solution was concentrated, partitioned between chloroform and water, and the organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was crystallized from methanol-diethyl ether, filtered and dried to give 1-(6,7-simethoxyquinazolin-4-yl")-4-(3-β-(piperidin-1-yl)ethyl-2 0.16 g of -oxoimidazolidin-1-ylcopiperidine (compound 16) was obtained.

Example 17 4-(3-β, β-jethoxyethyl-2-oxoimidapridin-1-yl) was prepared in the same manner as in Example 4 except that 1.0 g of bromoacecur was used instead of methyl iodide.
0.8 g of -1-(6,7-simethoxyquinazolin-4-yl)piperidine (Compound 17) was obtained.

1-(6,7-diphthoquinquinazolin-4-yl)-4-(2-propylthio-2-imidacillin-1-yl)piperidine (compound 19) was prepared in the same manner from both of the obtained fractions.
44g was obtained.

Example 18 21.0 g of the compound obtained in Example 2 was dissolved in 1 Q ml of dimerformamide and 0.3 g of 60% sodium hydride was added.
2 g was added and stirred at room temperature for 10 minutes. 0.521111 l of n-propyl iodide was added and the mixture was further stirred at room temperature for 30 minutes. The reaction solution was condensed and diluted with water.

It was partitioned with form, and the organic layer was dried and concentrated. The fractions eluted with 1-2% methanol/chloroform were subjected to 50 g of silica gel column chromatography and crystallized from diethyl ether to give 1(6-bardimethoxyquinazolin-4-yl)-4-(3-n -propyl-2-thioxoimidazolidin-1-yl)piperidine (compound 1
8) Obtained 0.16g.

In addition, elution example 1 with 10% methanol/chloroform
9 Propyl iodide of Example 18 was converted into bromoacetal Q, 3
The same operation was performed except that the volume was changed to ml.

4 from both fractions eluted from 1% methanol/chloroform
- (3-β, β-jethoxyethyl-2-thioxoimidazolidin-1-yl)-1-(6°7-simethoxyquinazolin-4-yl)piperidine (Compound 20) 0.
55g was obtained.

In addition, from both fractions eluted with 4% methanol/chloroform, 4-(2-β,β-jethoxyethylthio-2-imidacillin-1-yl)-1-(6,7-cymethoxyquinazoline-4- yl) piperidine (compound 21) 0.2
8g was obtained.

Example 20 20.98 g of the compound obtained in Example 2 was dissolved in 1 Qml of dimethylformamide and hydrogenated to 60%) IJ
0.25 g of aluminum was added and stirred at room temperature for 10 minutes. After adding 0.33 ml of methyl iodide and stirring for an additional 10 minutes, the mixture was condensed and partitioned between water and chloroform. The organic layer was dried, condensed, and subjected to 40 g silica gel column chromatography, and the fraction eluted with 16% methanol/chloroform was
Shrunk. The residue was crystallized from diethyl ether,
Dried, 1-(6,7-simethoxynazolin-4-yl)4-(2-methylthio-2-imidacillin-1yl)
0.54 g of piperidine (compound 22) was obtained.

Example 21 The methyl iodide of Example 20 was replaced with 0.41 Tl of ethyl iodide.
] 4-(2-ethylthio-2-imidacillin-1-yl)-1-(6,7-simethoxyquinazolin-4-yl)piperidine (compound 23)
) 0.39g was obtained.

Example 22 Compound c obtained in Reference Example 3 0.25 g, carbon disulfide Q, 5+++! ,) A mixture of 0.25 ml of ethylamine and 5+nl of ethylamine was stirred under reflux for 20 hours. Add water and dry the precipitated crystals, 4(3-benzyl-2-thioxoimidazolidin-1-yl)-1-
0.2 g of (6,7-cymethoxyquinazolin 4-yl)piperidine (compound 24) was obtained.

Example 23 2.2 g of 4-β-(2-oxoimidazolidin-1-yl)ethylpyridine was dissolved in 2Qml of 1N hydrochloric acid, and 5
0.44 g of % rhodium-alumina was added and hydrogenated at room temperature and 3 atm for 2 days. The reaction solution from which the catalyst had been removed was concentrated. To the residue were added 1.5 g of 4-chloro o-5,7-simethoxyquinazoline, 20 ml of ethanol, and 2 ml of triethylamine, and the mixture was heated under reflux for 15 minutes. Add water, count the precipitated crystals, 1-(6,7-simethoxyquinazolin-4-yl)-4-β-(2-oxoimidazolidin-1-yl)ethylpiperidine (compound 25)1. 8g
I got it.

Example 24 250.3 g of the compound obtained in Example 23 was dissolved in 1Qml of dimethylformamide, 0.1 g of 60% sodium hydride was added, and the mixture was stirred at room temperature for 10 minutes. 1 ml of methyl iodide Q was added and the mixture was further stirred for 1 hour. The reaction solution was concentrated, the residue was distributed between water and chloroform, and the organic layer was dried.
Concentrated. l of the residue.

1-g was subjected to silica gel column chromatography.
(6,7-Simethoxyquinazolin-4-yl)4-β-
(3-methyl-2-oxoimidazolidin-1-yl)
0.19 g of ethylpiperidine (compound 26) was obtained.

Example 25 0.12 ml of ethyl iodide was added to the methyl iodide of Example 24.
4-β-(3ethyl-2
-oxoimidazolidin-1-yl)-1-(6,7-
cymethoxyquinazolin-4-yl)ethylpiperidine (
0.18 g of compound 27) was obtained.

Example 26 4-β-(2-oxoimidacillin-1-
1-(6,7-Simethoxyquinazolin-4-yl) was prepared using the same procedure except that 2.1 g of 4-α-(2-oxoimidazolidin-1-yl)ethylpyridine was used. )-4-α-(2-oxoimidacillin-1-yl)ethylpiperidine (Compound 28)1.
5g was obtained.

Example 27 1-(6,
7-Simethoxyquinazolin-4-yl)-4-α-(3
-Methyl-2-oxoimidazolidin-1-yl)ethylpiperidine (Compound 29) 0.15g was obtained.

Example 28 The methyl iodide of Example 27 was converted into ethyl iodide 0.12 ml
4-α-(3ethyl-2
-oxoimidazolidin-1-yl)-1-(6,7-
cymethoxyquinazolin-4-yl)ethylpiperidine (
Compound 30) 0.12g was obtained.

Reference Example 1 A mixture of 3.0 g of 1-benzyl-4-piperidone, 0.97 g of 2-aminoethanol, 20 ml of Improper Tools and 1.6 g of Molecular Sieves 4A was stirred at room temperature for 30 minutes. Then sodium borohydride 0
．． 6 g was added little by little and stirred for an additional 40 minutes. The reaction solution was concentrated, the residue was partitioned between water and chloroform, and the organic layer was dried over anhydrous magnesium sulfate and concentrated. 150 residue
1-benzyl-4-β-hydroxyethylaminopiperidine 3
．． 7g was obtained.

NMR (δ, ppm, CDIJa)' 7.3.5.
0.3.5.3.0-1.7 3.7 g of the above compound obtained here, 3.7 g of N,N'-carbonyldiimidazole
A mixture of g and acetonitrile 201T11 was stirred at room temperature for 1 hour.

The reaction solution was concentrated, the residue was partitioned between water and chloroform, and the organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was crystallized from diethyl ether to give 1-hensyl-4-(
2-oxooxazolidin-3-yl)piperidine2.
3g was obtained.

Melting point: 104-105°C NMR (δ, ppm, CDCj!s): 7
．． 2. 4.3-1.4. 3J obtained above compound 1
．． 0 g, methanol l Qml.

A mixture of 6.71 Tll of 0.6N hydrochloric acid and 0.2 g of 10% palladium-carbon was stirred at 40° C. for 3 hours under a hydrogen stream. The reaction solution with the catalyst removed was concentrated and crystallized from isopropanol to obtain 4-(2-oxooxazolidin-3-yl)piperidine hydrochloride (compound a).
) 0.35g was obtained.

Melting point: 236-237°C NMR (δ, ppm, DMSO-d,): 4J
~1.4 Reference Example 2 l-(6,7-simethoxyquinazolin-4-yl)-4
- A mixture of 3.0 g of piperidone, 6.5 gk of ethylenediamine and 3 Q ml of methanol was stirred at room temperature for 10 minutes. Next, 4.9 g of sodium borohydride was added little by little, and the mixture was further stirred for 2 hours. The reaction solution was concentrated, partitioned between water and chloroform, and the organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was crystallized from diethyl ether to give 4-β-aminoethylamino-1-(6,7
2.3 g of -dimethoxyquinazolin-4-yl)piperidine (compound b) was obtained.

Melting point: 99-104°C NMR (δ, ppm, CDCl!,): 8.6.
7.2.7.1.4.03.3 to 1.5 Reference Example 3 A mixture of 7 g of the compound bO obtained in Reference Example 2, 0.43 ml of benzaldehyde and 20 ml of methanol was stirred at room temperature for 15 minutes. Next, 0.16 g of sodium borohydride was added and the mixture was further stirred at room temperature for 30 minutes. The reaction solution was concentrated, partitioned between water and chloroform, and the organic layer was dried over anhydrous magnesium sulfate and concentrated to obtain 4-β.
-benzylaminoethylamino-1=(6,7-cymethoxyquinazolin-4-yl)piperidine (compound c) 0
．． 42g was obtained.

NMR (δ, ppm, CDCa): 8.6.7
．． 3.7.2.7.1゜4.0.3.8.3.2~1.
4 Effects of the Invention The compound (I) of the present invention and its pharmacologically acceptable salts are useful.

Claims (1)

[Claims] Formulas include mathematical formulas, chemical formulas, tables, etc. , n is 0, 1, 2, 3 or 4, and Z is ▲
There are mathematical formulas, chemical formulas, tables, etc.▼ (wherein, There are chemical formulas, tables, etc. ▼ [In the formula, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ represents a single bond or double bond, Y represents an oxygen or sulfur atom or ▲ Mathematical formula, chemical formula,
There are tables, etc. ▼ (In the formula, R^4 has the same meaning as above)
, R^5 represents hydrogen or lower alkyl,
X has the same meaning as above, but when X is an oxygen atom and m and n are both 0, at least one of R^4 and R^5 is a group other than hydrogen] Quinazoline represented by Derivatives and pharmacologically acceptable acid addition salts thereof.