JPH10175972A - Quinazoline compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a quinazoline compound that has phosphodiesterase inhibitory activity of selective calmodulin dependence, and is effective for various ischemic heart diseases, hypertension, arteriosclerosis, osteoporosis, etc. SOLUTION: This quinazoline derivative of the formula [R<1> -R<3> are each H, a halogen, a (halogen-substituted) lower alkyl, a (halogen-substituted) lower alkoxy, cyano, nitro, etc.; R<4> is H, a halogen, amino, a (halogen-substituted) lower alkyl, etc.; R<5> and R<6> are each hydroxyl group, a (halogen-substituted) lower alkyl, etc.; however, except the cases when all of R<1> -R<4> are H, when any two of R<1> -R<3> are H, and when both R<5> and R<6> are hyroxyl groups], or its pharmacologically permissible salt or their hydrates, for example, 4-(4- hydroxy-4-phenylpyperidino)-6,7,8-trimethoxyquinazoline, etc., is obtained, for example, by making a 4-cloroquinazoline derivative react with 4-piperidine hydrate hydrochloride.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a quinazoline compound having excellent action as a medicine.

[0002]

2. Description of the Related Art Phosphodiesterase (PDE) includes:
It is known that seven types of isozymes exist to date. Among them, it is known that calmodulin-dependent phosphodiesterase (CaM-PDE or PDE1) further has a subisozyme, and there are a type that degrades cGMP and a type that degrades both cGMP and cAMP. Therefore, PDE1 inhibitors increase the concentration of cGMP, an intracellular second messenger, or both cGMP and cAMP in organ tissues, and can be a therapeutic agent for various diseases. However, no PDE1 inhibitor having a satisfactory effect has been found so far.

[0003]

Accordingly, the present inventors have intensively studied for a long time a compound having a selective PDE1 inhibitory action.

[0004]

As a result, the following nitrogen-containing condensed heterocyclic compounds have the above-mentioned effects, and are used for various ischemic heart diseases, pulmonary hypertension, hypertension, peripheral circulatory insufficiency, arteriosclerosis. The present invention was found to be effective for restenosis after PTCA, cerebral circulatory insufficiency, cerebral dysfunction, renal insufficiency, osteoporosis and leukemia, and also useful as a diuretic. Examples of quinazoline derivatives useful as pharmaceuticals include, for example, JP-T-2-502462 and WO 93/07124.
Which differ from the compound of the present invention in both structure and action. JP-A-7-126255 discloses a compound having a similar structure, except that the substituent on the piperidine ring at the 4-position of the quinazoline skeleton is different. The present invention is a quinazoline compound represented by the following general formula (I), a pharmacologically acceptable salt thereof, or a hydrate thereof.

[0005]

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(Wherein R ¹ , R ² and R ³ are the same or different from each other and are a hydrogen atom, a halogen atom, a lower alkyl group which may be halogen-substituted, a lower alkoxy group which may be halogen-substituted, R ⁴ represents a hydrogen atom, a halogen atom, a halogen atom, an alkoxy group, an aryl group which may have a substituent, an arylalkyl group which may have a substituent, a cyano group or a nitro group. A lower alkyl group, a lower alkoxy group optionally substituted with halogen, an amino group, an alkylamino group and a cycloalkyl group optionally having a hetero atom, wherein R ⁵ and R ⁶ are the same as or different from each other; Differently, hydroxyl group, lower alkyl group which may be halogen-substituted, lower alkoxy group which may be halogen-substituted, halogen substitution A lower alkoxyalkyl group which may be substituted, a cycloalkoxy group which may have a hetero atom and may have a substituent, an aryl group which may have a substituent, and a substituent A heteroaryl group, an optionally substituted arylalkyl group, an alkenyl group or an alkynyl group, provided that
When R ¹ , R ² , R ³ and R ⁴ are all hydrogen atoms,
This excludes the case where any ^{two of} R ¹ , R ² and R ³ are both hydrogen atoms, and the case where both R ⁵ and R ⁶ are hydroxyl groups. )

In the definition of R ¹ , R ² , R ³ and R ⁴ ,
The halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

The term "lower alkyl group" defined in the definitions of R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ means a straight or branched one having 1 to 6 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-
Butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, 1,1-dimethylpropyl group,
1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 2-ethylpropyl group, n-hexyl group, 1,2
-Dimethylbutyl group, 1,3-dimethylbutyl group, 2,
3-dimethylbutyl group, 2,2-dimethylbutyl group,
3,3-dimethylbutyl group, 1,1-diethylpropyl group, 1,2-diethylpropyl group, 2,2-diethylpropyl group, 1-ethyl-2-methylpropyl group, 1-methyl-2-ethylpropyl A 1,1-diethylethyl group and the like. Further, these alkyl groups may be substituted with 1 to 3 halogen atoms such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

The lower alkoxy group in the definition of R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ means a straight or branched alkoxy group having 1 to 6 carbon atoms. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, t
ert-butoxy group, n-pentyloxy group, 1,1-dimethylpropyloxy group, 1,2-dimethylpropyloxy group, 2,2-dimethylpropyloxy group, 2-ethylpropyloxy group, n-hexyloxy group , 1,2-
Dimethylbutyloxy group, 1,3-dimethylbutyloxy group, 2,3-dimethylbutyloxy group, 1-ethyl-
Examples thereof include a 2-methylpropyloxy group and a 1-methyl-2-ethylpropyloxy group. Further, these alkoxy groups may be substituted with 1 to 3 halogen atoms such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

The cycloalkoxy group defined in the definitions of R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ means cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.

The lower alkoxyalkyl group as defined in R ⁵ and R ⁶ means methoxyethyl group, methoxypropyl group, methoxybutyl group, ethoxyethyl group, ethoxypropyl group, ethoxybutyl group and the like.

The optionally substituted aryl group defined in R ⁵ and R ⁶ means a phenyl group, a 1-naphthyl group, a 2-naphthyl group or an anthracenyl group.

The optionally substituted heteroaryl group as defined in R ⁵ and R ⁶ refers to a monocyclic or condensed ring containing from 1 to 4 sulfur, oxygen or nitrogen atoms. Derived groups are meant. For example, a phenyl group, a furyl group, a benzophenyl group, a benzofuranyl group,
Isobenzofuranyl group, pyrrolyl group, imidazolyl group,
Pyrazolyl group, isothiazolyl group, isoxazolyl group,
It means pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, indolizinyl group, isoindolyl group, indolyl group, isoquinolinyl group, quinolyl group, phthalazinyl group, quinoxalinyl group, naphthyridinyl group, quinazolinyl group, acridinyl group or furazanyl group.

The aryl in the optionally substituted arylalkyl group defined in R ⁵ and R ⁶ has the same meaning as the above aryl group. The alkyl in this case means a lower alkylene group, and examples thereof include a methylene group, an ethylene group, a propylene group, and a butylene group.

An aryl group which may have a substituent, a heteroaryl group which may have a substituent, an arylalkyl group which may have a substituent, and a substituent which may have a substituent In the heteroarylalkyl group, the substituent means a linear or branched lower alkyl group such as methyl, ethyl, n-propyl and isopropyl, and a linear or branched lower alkyl group such as methoxy, ethoxy, n-propoxy and isopropoxy. Lower alkoxy group, fluorine atom, chlorine atom,
A halogen atom such as a bromine atom and an iodine atom, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, an arylalkyl group which may have a substituent, and a substituent Means a heteroarylalkyl group, a hydroxyl group, a hydroxyalkyl group, an alkoxyalkyl group, etc. which may have

In the present invention, the pharmacologically acceptable salt includes, for example, inorganic salts such as hydrochloride, sulfate, hydrobromide and phosphate, formate, acetate, trifluoroacetate, and the like.
Organic acid salts such as maleate, fumarate, tartrate, methanesulfonate, benzenesulfonate and toluenesulfonate can be mentioned. Some compounds form hydrates, which are also included in the scope of the present invention. Further, when there is an asymmetric carbon and optical isomers exist, they are also included in the present invention.

The main production methods of the compound of the present invention are shown below. The compound represented by the general formula (I) can be produced by the following method. Manufacturing method 1

[0018]

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First Step The 4-chloroquinazoline derivative (II) disclosed in JP-A-7-126255 is reacted with 4-piperidone hydrate hydrochloride by a commonly used method. As the reaction solvent, any organic solvent that does not participate in the reaction can be used, but it is preferable to use an ether solvent such as tetrahydrofuran or an alcohol solvent such as isopropyl alcohol. Further, when the reaction is carried out while heating and refluxing in the presence of a tertiary amine such as triethylamine to remove the generated hydrochloric acid, more preferable results can be obtained.

Second step The compound (III) obtained in the first step and a compound of the general formula R ⁶ -M (where R ⁶ has the same meaning as described above. M means lithium or magnesium halide or the like). The compound of the formula (1) is reacted by a commonly used method. As the reaction solvent, any organic solvent that does not participate in the reaction can be used, but it is preferable to use an ether solvent such as tetrahydrofuran or diethyl ether. The reaction temperature is from −78 ° C. to the reflux temperature of the solvent, preferably −20 ° C. or lower.

Manufacturing method 2

[0022]

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Step 1 The 4-piperidone derivative (IV) having a protecting group is converted to a compound of the general formula R
^6- M (wherein R ⁶ and M have the same meaning as described above.
R ⁷ represents a protecting group such as a benzyl group and a tert-butyloxycarbonyl group. The compound of the formula (1) is reacted by a conventional method. As the reaction solvent, any organic solvent that does not participate in the reaction can be used, but an ether organic solvent such as tetrahydrofuran or diethyl ether is preferable.

Step 2 The protecting group of the compound represented by the formula (V) can be removed by catalytic reduction or a general method depending on the protecting group such as an acid.

Third step The deprotected compound (VI) is reacted with a 4-chloroquinazoline derivative. The reaction is carried out in an ether solvent such as tetrahydrofuran or an alcohol solvent such as isopropyl alcohol in the presence of an alkali such as triethylamine, sodium carbonate or potassium carbonate.

Next, pharmacological experimental examples will be given in order to detail the usefulness of the compound of the present invention. Pharmacological Experimental Example Calmodulin-dependent cGMP-ho obtained from porcine aorta
Enzyme inhibitory action using sphodiesterase Experimental Method The activity of calmodulin-dependent phosphodiesterase (hereinafter referred to as CaM-PDE) enzyme prepared from porcine aorta was determined by Thomps.
It was measured according to the method of on et al. 1 mM calcium ion (C
a ⁺⁺ ), 1 μM cGM in the presence of calmodulin (250 U / ml)
P was measured as a substrate. The compound of the present invention was dissolved in DMSO, added to the reaction solution, and examined for inhibitory activity. The final concentration of DMSO in the reaction solution was adjusted to 4% or less. The preparation of CaM-PDE was carried out according to the method of Saeki et al. (Saeki,
T. and Saito, I., Isolation of cyclic nucleotide p
hosphodiesterase isozymes from pig aorta, Biochem.
Pharmacol. 46 (5), 833-839, 1993) using porcine aorta. 2. Experimental results Table 1 shows that CaM-PD of the compounds of the present invention was obtained by the above method.
Shows E inhibitory effect.

[0027]

[Table 1]

From the above experimental examples, the compound of the present invention is PD
E, in particular, had a CaM-PDE inhibitory effect. That is, the compound of the present invention is CaM-PDE
By showing an inhibitory effect, cGMP or cAMP
Has the effect of increasing the concentration of in vivo. Therefore, the quinazoline compound of the present invention is expected to be effective for the prevention and treatment of diseases for which CaM-PDE inhibitory effect is effective. Examples of these diseases include, for example, angina pectoris, myocardial infarction, ischemic heart diseases such as chronic and acute heart failure, pulmonary hypertension with or without pulmonary heart, and hypertension due to any other cause Disease, peripheral circulatory insufficiency, arteriosclerosis, restenosis after PTCA, cerebral circulatory insufficiency, cerebral insufficiency, renal insufficiency, osteoporosis, leukemia and the like.
It is also useful as a diuretic.

Furthermore, since the compounds of the present invention have low toxicity and high safety, the value of the present invention is high also in this sense.

When the present invention is used as these medicaments, it is administered orally or parenterally. Dosage varies depending on the severity of symptoms, age, sex, weight of the patient, sensitivity to drugs, administration method, administration timing, administration interval, types of pharmaceutical preparations, types of drugs to be administered together, types of active ingredients, etc. There is no particular limitation. In the case of oral administration, the dose is usually about 0.1 to 1000 mg, preferably 1 to 500 mg per day for an adult, divided into 1 to 3 times a day. In the case of injection, it is usually about 1 to 3000 μg / kg, preferably about 3 to 1000 μg / kg per day.

When an oral solid preparation is prepared, the active ingredient is used in combination with an excipient and, if necessary, a binder, a disintegrant, a lubricant,
After adding coloring agents, flavoring agents, etc., tablets,
Examples include coated tablets, granules, powders, capsules and the like. As excipients, for example, lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose,
Silicon dioxide and the like, as a binder, for example, polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl cellulose,
Hydroxypropyl methylcellulose, calcium citrate, dextrin, pectin, etc., as lubricants, for example, magnesium stearate, talc, polyethylene glycol, silica, hydrogenated vegetable oil, etc., as coloring agents, are allowed to be added to pharmaceuticals As flavoring agents, cocoa powder, peppermint brain, aromatic acid, peppermint oil, dragon brain, cinnamon powder and the like are used. These tablets and granules are appropriately coated with sugar coating, gelatin coating, and the like, if necessary.

When preparing an injection, a pH adjuster, a buffer, a suspending agent, a solubilizing agent, a stabilizing agent, an isotonic agent, a preservative, and the like are added to the main drug as necessary. Intravenous, subcutaneous, and intramuscular injections are used according to the method. At that time, if necessary, it is necessary to prepare a freeze-dried product by a conventional method.

Examples of the suspending agent include methylcellulose, polysorbate 80, hydroxyethylcellulose, gum arabic, powder of tragacanth, sodium carboxymethylcellulose, polyoxyethylene sorbitan monolaurate and the like. Examples of the dissolution aid include polyoxyethylene hydrogenated castor oil, polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate, macrogol,
Castor oil fatty acid ethyl ester and the like can be mentioned.

[0034]

EXAMPLES Next, the present invention will be described in detail with reference to Examples, but the present invention is not limited thereto. Production Example 4- (4-oxopiperidino) -6,7,8-trimethoxyquinazoline

[0035]

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A mixed solution of 5.00 g (19.6 mmol) of 4-chloro-6,7,8-trimethoxyquinazoline, 4.00 g (26.0 mmol) of 4-piperidone hydrate hydrochloride, 25 ml of triethylamine, 25 ml of tetrahydrofuran and 25 ml of isopropyl alcohol Is heated to reflux for 6 hours. The solvent was distilled off from the reaction solution under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methylene chloride-methanol) and recrystallized (chloroform-hexane) to give the title compound as white crystals (5.25).
g (yield 84%) was obtained. 135-136 ° C ¹ H NMR (CDCl ₃ ) δ: 2.68 (4H, t, J = 6.0 Hz), 3.98 (3H, s), 4.0
0 (4H, t, J = 6.0Hz), 4.08 (3H, s), 4.15 (3H, s), 6.97 (1H, s),
8.77 (1H, s) Mass m / e (FAB) 318 (MH ⁺ ) Elemental analysis Calcd. For C ₁₆ H ₁₉ N ₃ O ₄ C: 60.56, H: 6.03, N: 13.24 Found C: 60.34, H: 6.03 , N: 13.13

Example 1 4- (4-hydroxy-4-methylpiperidino) -6
7,8-trimethoxyquinazoline

[0038]

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0.30 g (0.95 g) of 4- (4-oxopiperidino) -6,7,8-trimethoxyquinazoline obtained above.
mmol) in tetrahydrofuran (25 ml) was stirred under ice-cooling with methylmagnesium bromide (3.0M ether solution 0.1%).
5 ml) is added dropwise. After stirring with ice cooling for 1.5 hours, a saturated aqueous ammonium chloride solution was added to the reaction solution, and the temperature was raised to room temperature.
Extract with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and filtered, and the filtrate is evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride-methanol) and recrystallized (chloroform-hexane) to give 0.18 g of the title compound as white crystals (yield 58).
%). Melting point 140-141 ° C ¹ H NMR (CDCl ₃ ) δ: 1.36 (3H, s), 1.76 (2H, m), 1.87 (2H, m),
3.59 (2H, m), 3.89 (2H, m), 3.96 (3H, s), 4.06 (3H, s), 4.13 (3
H, s), 6.93 (1H, s), 8.71 (1H, s) Mass m / e (FAB) 334 (MH ⁺ ) Elemental analysis Calcd. For C ₁₇ H ₂₃ N ₃ O ₄ C: 61.25, H: 6.95 , N: 12.60 Found C: 60.88, H: 7.02, N: 12.52

The following compounds were synthesized in the same manner as in Example 1 (Examples 2 to 4). Example 2 4- (4-ethyl-4-hydroxypiperidino) -6
7,8-trimethoxyquinazoline

[0041]

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Yield 34% Melting point 118-119 ° C. ¹ H NMR (CDCl ₃ ) δ: 0.99 (3H, t, J = 7.6 Hz), 1.60 (2H, q, J = 7.
6Hz), 1.72 (2H, m), 1.83 (2H, m), 3.54 (2H, m), 3.96 (3H, s),
3.98 (2H, m), 4.06 (3H, s), 4.13 (3H, s), 6.93 (1H, s), 8.71 (1
H, s) Mass m / e (FAB) 348 (MH ⁺ ) Elemental analysis Calcd. For C ₁₈ H ₂₅ N ₃ O ₄ C: 62.23, H: 7.25, N: 12.10 Found C: 61.94, H: 7.22, N : 12.08

Example 3 4- (4-hydroxy-4-vinylpiperidino) -6
7,8-trimethoxyquinazoline

[0044]

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Yield 39% Melting point 140-141 ° C. ¹ H NMR (CDCl ₃ ) δ: 1.75 (2H, m), 1.99 (2H, m), 3.61 (2H, m),
3.96 (3H, s), 3.98 (2H, m), 4.06 (3H, s), 4.13 (3H, s), 5.16 (1
H, dd, J = 10.8,0.8Hz), 5.35 (1H, dd, J = 17.2,0.8Hz), 6.03 (1
H, dd, J = 17.2,10.8Hz), 6.93 (1H, s), 8.72 (1H, s) Mass m / e (FAB) 346 (MH +) Elemental analysis Calcd. For C ₁₈ H ₂₃ N ₃ O ₄ C : 62.59, H: 6.71, N: 12.17 Found C: 62.36, H: 6.78, N: 12.06

Example 4 4- (4-ethynyl-4-hydroxypiperidino) -6
7,8-trimethoxyquinazoline

[0047]

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Yield 14% Melting point 150-151 ° C. ¹ H NMR (CDCl ₃ ) δ 2.02 (2H, m), 2.14 (2H, m), 2.61 (1H, s), 3.
60 (2H, m), 3.95 (2H, m), 3.96 (3H, s), 4.06 (3H, s), 4.13 (3H,
s), 6.91 (1H, s), 8.73 (1H, s) Mass m / e (FAB) 344 (MH ⁺ ) Elemental analysis Calcd. for C ₁₈ H ₂₁ N ₃ O ₄・ 0.2H ₂ OC: 62.31, H : 6.22, N: 12.11 Found C: 62.33, H: 6.14, N: 12.12

Example 5 4- (4-hydroxy-4-phenylpiperidino) -6
7,8-trimethoxyquinazoline

[0050]

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A mixed solution of 5.00 g (19.6 mmol) of 4-chloro-6,7,8-trimethoxyquinazoline, 4.00 g (22.6 mmol) of 4-hydroxy-4-phenylpiperidine, 25 ml of triethylamine, 25 ml of tetrahydrofuran and 25 ml of isopropyl alcohol Is heated at reflux for 5 hours. The solvent was distilled off from the reaction solution under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized (ethyl acetate-hexane) to give 6.80 g of the title compound as white crystals.
(88% yield). Melting point 141-142 ° C ¹ H NMR (CDCl ₃ ) δ: 1.94 (2H, m), 2.34 (2H, m), 3.68 (2H, m),
3.96 (3H, s), 4.06 (3H, s), 4.14 (3H, s), 4.16 (2H, m), 6.97 (1
H, s), 7.31 (1H, m), 7.41 (2H, m), 7.56 (2H, m), 8.74 (1H, s) Mass m / e (FAB) 396 (MH ⁺ ) Elemental analysis Calcd. For C ₂₂ H ₂₅ N ₃ O ₄ C: 66.82, H: 6.37, N: 10.63 Found C: 66.82. H: 6.33, N: 10.55

The following compounds were synthesized in the same manner as in Example 5 (Examples 6 to 27). Example 6 4- (4-benzyl-4-hydroxypiperidino) -6
7,8-trimethoxyquinazoline

[0053]

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Yield 90% Melting point 130-131 ° C. ¹ H NMR (CDCl ₃ ) δ: 1.68 (2H, m), 1.92 (2H, m), 2.85 (2H, s), 3.51 (2H, m), 3.96 (3
H, s), 4.01 (2H, m), 4.06 (3H, s), 4.13 (3H, s), 6.92 (1H, s),
7.24 (2H, m), 7.30 (1H, m), 7.35 (2H, m), 8.71 (1H, s) Mass m / e (FAB) 410 (MH ⁺ ) Elemental analysis Calcd. For C ₂₃ H ₂₇ N ₃ O ₄ C: 67.46, H: 6.65, N: 10.26 Found C: 67.85, H: 6.64, N: 10.14

Example 7 4- [4- (4-Fluorophenyl) -4-hydroxypiperidino] -6,7,8-trimethoxyquinazoline

[0056]

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Yield 88% Melting point 154-155 ° C. ¹ H NMR (CDCl ₃ ) δ: 1.92 (2H, m), 2.30 (2H, m), 3.66 (2H, m),
3.96 (3H, s), 4.06 (3H, s), 4.14 (3H, s), 4.16 (2H, m), 6.96 (1
H, s), 7.07 (2H, m), 7.52 (2H, m), 8.74 (1H, s) Mass m / e (FAB) 414 (MH ⁺ ) Elemental analysis Calcd. For C ₂₂ H ₂₄ FN ₃ O ₄ C: 63.91, H: 5.85, N: 10.16 Found C: 63.76, H: 5.91, N: 10.08

Example 8 4- [4- (4-Chlorophenyl) -4-hydroxypiperidino] -6,7,8-trimethoxyquinazoline

[0059]

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Yield 89% Melting point 149-150 ° C. ¹ H NMR (CDCl ₃ ) δ: 1.90 (2H, m), 2.30 (2H, m), 3.66 (2H, m),
3.96 (3H, s), 4.06 (3H, s), 4.14 (3H, s), 4.16 (2H, m), 6.96 (1
H, s), 7.36 (2H, d, J = 8.6Hz), 7.48 (2H, d, J = 8.6Hz), 8.74 (1
H, s) Mass m / e (FAB) 430 (MH ⁺ ) Elemental analysis Calcd. For C ₂₂ H ₂₄ ClN ₃ O ₄ C: 61.47, H: 5.63, N: 9.77 Found C: 61.47, H: 5.67, N : 9.68

Example 9 4- [4- (4-bromophenyl) -4-hydroxypiperidino] -6,7,8-trimethoxyquinazoline

[0062]

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Yield 88% Melting point 146-147 ° C. ¹ H NMR (CDCl ₃ ) δ: 1.89 (2H, m), 2.29 (2H, m), 3.65 (2H, m),
3.96 (3H, s), 4.06 (3H, s), 4.14 (3H, s), 4.16 (2H, m), 6.96 (1
H, s), 7.42 (2H, d, J = 8.8Hz), 7.52 (2H, d, J = 8.8Hz), 8.74 (1
H, s) Mass m / e (FAB) 474 (MH ⁺ ) Elemental analysis Calcd. For C ₂₂ H ₂₄ BrN ₃ O ₄ C: 55.71, H: 5.10, N: 8.86 Found C: 55.58, H: 5.13, N : 8.88

Example 10 4- [4-hydroxy-4- (2-methoxyphenyl) piperidino] -6,7,8-trimethoxyquinazoline

[0065]

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Yield 72% Melting point 143-144 ° C. ¹ H NMR (CDCl ₃ ) δ: 2.19 (2H, m), 2.28 (2H, m), 3.76 (2H, m),
3.94 (3H, s), 3.96 (3H, s), 4.06 (3H, s), 4.13 (3H, s), 4.16 (2
H, m), 4.18 (1H, s), 6.97-7.02 (2H, m), 6.98 (1H, s), 7.27-7.
33 (2H, m), 8.72 (1H, s) Mass m / e (FAB) 426 (MH ⁺ ) Elemental analysis Calcd. For C ₂₃ H ₂₇ N ₃ O ₅ C: 64.93, H: 6.40, N: 9.88 Found C: 64.98, H: 6.37, N: 9.85

Example 11 4- [4-hydroxy-4- (3-methoxyphenyl) piperidino] -6,7,8-trimethoxyquinazoline

[0068]

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Yield 88% Melting point 166-167 ° C. ¹ H NMR (CDCl ₃ ) δ: 1.93 (2H, m), 2.33 (2H, m), 3.66 (2H, m),
3.84 (3H, s), 3.96 (3H, s), 4.06 (3H, s), 4.14 (3H, s), 4.16 (2
H, m), 6.85 (1H, m), 6.97 (1H, s), 7.10-7.13 (2H, m), 7.32 (1
H, m), 8.74 (1H, s) Mass m / e (FAB) 426 (MH +) Elemental analysis Calcd. For C ₂₃ H ₂₇ N ₃ O ₅ C: 64.93, H: 6.40, N: 9.88 Found C: 64.86 , H: 6.43, N: 9.72

Example 12 4- [4-hydroxy-4- (4-methoxyphenyl) piperidino] -6,7,8-trimethoxyquinazoline

[0071]

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Yield 10% Melting point 163-164 ° C. ¹ H NMR (CDCl ₃ ) δ: 1.94 (2H, m), 2.30 (2H, m), 3.67 (2H, m),
3.82 (3H, s), 3.96 (3H, s), 4.06 (3H, s), 4.14 (3H, s), 4.15 (2
H, m), 6.93 (2H, d, J = 9.2Hz), 6.97 (1H, s), 7.47 (2H, d, J = 9.2Hz)
Hz), 8.73 (1H, s) Mass m / e (FAB) 426 (MH ⁺ ) Elemental analysis Calcd. For C ₂₃ H ₂₇ N ₃ O ₅ C: 64.93, H: 6.40, N: 9.88 Found C: 64.56, H: 6.50, N: 9.73

Example 13 4- [4-hydroxy-4- (3,4-methylenedioxyphenyl) piperidino] -6,7,8-trimethoxyquinazoline

[0074]

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Yield 91% Melting point 167-168 ° C. ¹ H NMR (CDCl ₃ ) δ: 1.91 (2H, m), 2.27 (2H, m), 3.65 (2H, m),
3.96 (3H, s), 4.06 (3H, s), 4.14 (2H, m), 4.14 (3H, s), 5.97 (2
H, s), 6.82 (1H, d, J = 8.0Hz), 6.96 (1H, s), 7.00 (1H, dd, J = 8.
0,2.0Hz), 7.06 (1H, d, J = 2.0Hz), 8.73 (1H, s) Mass m / e (FAB) 440 (MH ⁺ ) Elemental analysis Calcd. For C ₂₃ H ₂₅ N ₃ O ₆・0.1H ₂ OC: 62.60, H: 5.76, N: 9.52 Found C: 62.41, H: 5.64, N: 9.46

Example 14 4- [4- (2,3-Dimethoxyphenyl) -4-hydroxypiperidino] -6,7,8-trimethoxyquinazoline

[0077]

Embedded image

Yield 90% Melting point 148-149 ° C. ¹ H NMR (CDCl ₃ ) δ: 2.05 (2H, m), 2.31 (2H, m), 3.77 (2H, m),
3.89 (3H, s), 3.96 (3H, s), 4.01 (3H, s), 4.06 (3H, s), 4.14 (3
H, s), 4.18 (2H, m), 4.37 (1H, s), 6.90 (1H, dd, J = 8.0,1.6H
z), 6.92 (1H, dd, J = 8.0,1.6Hz), 6.98 (1H, s), 7.05 (1H, t, J =
8.0Hz), 8.72 (1H, s) Mass m / e (FAB) 456 (MH ⁺ ) Elemental analysis Calcd. For C ₂₄ H ₂₉ N ₃ O ₆ C: 63.28, H: 6.42, N: 9.23 Found C: 63.25 , H: 6.50, N: 9.08

Example 15 4- [4- (3,4-Dimethoxyphenyl) -4-hydroxypiperidino] -6,7,8-trimethoxyquinazoline

[0080]

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Yield 88% Melting point 143-144 ° C. ¹ H NMR (CDCl ₃ ) δ: 1.95 (2H, m), 2.31 (2H, m), 3.68 (2H, m),
3.89 (3H, s), 3.92 (3H, s), 3.96 (3H, s), 4.06 (3H, s), 4.14 (3
H, s), 4.16 (2H, m), 6.88 (1H, d, J = 8.4Hz), 6.97 (1H, s), 7.04
(1H, dd, J = 8.4,2.0Hz), 7.12 (1H, d, J = 2.0Hz), 8.74 (1H, s) Mass m / e (FAB) 456 (MH +) Elemental analysis Calcd. For C ₂₄ H ₂₉ N ₃ O ₆・ 0.1H ₂ OC: 63.03, H: 6.44, N: 9.19 Found C: 62.67, H: 6.38, N: 9.04

Example 16 4- [4- (2-furyl) -4-hydroxypiperidino]-
6,7,8-trimethoxyquinazoline

[0083]

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Yield 52% Melting point 157-158 ° C. ¹ H NMR (CDCl ₃ ) δ: 2.12 (2H, m), 2.33 (2H, m), 3.75 (2H, m),
3.89 (2H, m), 3.96 (3H, s), 4.06 (3H, s), 4.13 (3H, s), 6.30 (1
H, dd, J = 3.2,0.8Hz), 6.37 (1H, dd, J = 3.2,1.6Hz), 6.94 (1H,
s), 7.41 (1H, dd, J = 1.6,0.8Hz), 8.72 (1H, s) Mass m / e (FAB) 386 (MH ⁺ ) Elemental analysis Calcd. for C ₂₀ H ₂₃ N ₃ O ₅ C: 62.33, H: 6.02, N: 10.90 Found C: 62.29, H: 6.05, N: 10.86

Example 17 4- [4-hydroxy-4- (2-tetrahydrofuryl)
Piperidino] -6,7,8-trimethoxyquinazoline hydrochloride

[0086]

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Yield 37% Melting point 161-162 ° C. ¹ H NMR (DMSO-d ₆ ) δ: 1.55-1.85 (8H, m), 3.58-3.67 (2H,
m), 3.71-3.86 (3H, m), 3.978 (3H, s), 3.984 (3H, s), 4.01 (3
H, s), 4.58 (2H, brs), 7.26 (1H, s), 8.63 (1H, s) Mass m / e (FAB) 390 (MH ⁺ ) Elemental analysis Calcd. For C ₂₀ H ₂₇ N ₃ O ₅・ HCl C: 56.40, H: 6.63, N: 9.87 Found C: 56.13, H: 6.63, N: 9.74

Example 18 4- [4- (3-furyl) -4-hydroxypiperidino]-
6,7,8-trimethoxyquinazoline

[0089]

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Yield 77% Melting point 147-148 ° C. ¹ H NMR (CDCl ₃ ) δ: 2.03 (2H, m), 2.20 (2H, m), 3.69 (2H, m),
3.96 (3H, s), 3.99 (2H, m), 4.06 (3H, s), 4.13 (3H, s), 6.48 (1
H, dd, J = 1.6,0.8Hz), 6.95 (1H, s), 7.43 (1H, t, J = 1.6 Hz),
7.45 (1H, dd, J = 1.6,0.8Hz), 8.72 (1H, s) Mass m / e (FAB) 386 (MH +) Elemental analysis _{Calcd for C 20 H 23 N 3} O 5 C:. 62.33, H : 6.02, N: 10.90 Found C: 62.34, H: 6.05, N: 10.84

Example 19 4- [4-hydroxy-4- (2-hydroxyphenyl)
Piperidino] -6,7,8-trimethoxyquinazoline

[0092]

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Yield 80% Melting point 189-190 ° C. ¹ H NMR (CDCl ₃ ) δ: 2.21 (2H, m), 2.37 (2H, m), 2.71 (1H, br
s), 3.66 (2H, m), 3.95 (3H, s), 4.06 (3H, s), 4.13 (3H, s), 4.1
5 (2H, m), 6.87-6.92 (2H, m), 6.94 (1H, s), 7.17-7.24 (2H, m
m), 8.69 (1H, brs), 8.72 (1H, s) Mass m / e (FAB) 412 (MH ⁺ ) Elemental analysis Calcd. for C ₂₂ H ₂₅ N ₃ O ₅・ 2.5H ₂ OC: 57.88, H : 6.62, N: 9.20 Found C: 58.05, H: 5.50, N: 9.00

Example 20 4- [4-hydroxy-4- (3-hydroxyphenyl)
Piperidino] -6,7,8-trimethoxyquinazoline

[0095]

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Yield 62% Melting point 201-202 ° C. ¹ H NMR (DMSO-d ₆ ) δ: 1.75 (2H, m), 2.11 (2H, m), 3.62 (2H,
m), 3.93 (3H, s), 3.94 (3H, s), 4.01 (3H, s), 4.23 (2H, m), 5.1
6 (1H, s), 6.62 (1H, m), 6.92 (1H, brd, J = 8.0Hz), 6.96 (1H, t,
J = 2.0 Hz), 7.12 (1H, s), 7.12 (1H, t, J = 8.0Hz), 8.58 (1H,
s), 9.28 (1H, s) Mass m / e (FAB) 412 (MH ⁺ ) Elemental analysis Calcd. for C ₂₂ H ₂₅ N ₃ O ₅・ 0.5H ₂ OC: 62.85, H: 6.23, N: 9.99 Found C: 62.60, H: 6.04, N: 9.87

Example 21 4- [4-hydroxy-4- (4-hydroxyphenyl)
Piperidino] -6,7,8-trimethoxyquinazoline

[0098]

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Yield 84% Melting point 196-197 ° C. ¹ H NMR (DMSO-d ₆ ) δ: 1.74 (2H, m), 2.10 (2H, m), 3.53 (2H,
m), 3.91 (3H, s), 3.93 (3H, s), 4.01 (3H, s), 4.07 (2H, m), 4.9
8 (1H, s), 6.72 (2H, d, J = 8.8Hz), 7.05 (1H, s), 7.32 (2H, d, J =
8.8 Hz), 8.55 (1H, s), 9.23 (1H, s) Mass m / e (FAB) 412 (MH ⁺ ) Elemental analysis Calcd. For C ₂₂ H ₂₅ N ₃ O ₅ C: 64.22, H: 6.12, N: 10.21 Found C: 64.05, H: 6.10, N: 10.15

Example 22 4- (4-hydroxy-4-phenylpiperidino) -6
7,8-triethoxyquinazoline

[0101]

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Yield 79% Melting point 145-146 ° C. ¹ H NMR (CDCl ₃ ) δ: 1.43 (3H, t, J = 7.2 Hz), 1.47 (3H, t, J = 7.
2Hz), 1.53 (3H, t, J = 7.2Hz), 1.94 (2H, m), 2.34 (2H, m), 3.65
(2H, m), 4.14 (2H, m), 4.14 (2H, q, J = 7.2Hz), 4.26 (2H, q, J =
7.2Hz), 4.38 (2H, q, J = 7.2Hz), 6.97 (1H, s), 7.31 (1H, m), 7.
41 (2H, m), 7.56 (2H, m), 8.73 (1H, s) Mass m / e (FAB) 438 (MH ⁺ ) Elemental analysis Calcd. For C ₂₅ H ₃₁ N ₃ O ₄ C: 68.63, H : 7.14, N: 9.60 Found C: 68.50, H: 7.12, N: 9.51

Example 23 4- [4-hydroxy-4- (4-hydroxyphenyl)
Piperidino] -6,7,8-triethoxyquinazoline

[0104]

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Yield: 74% Melting point: 206-207 ° C. (decomposition) ¹ H NMR (CDCl ₃ ) δ: 1.43 (3H, t, J = 7.2 Hz), 1.46 (3H, t, J = 7.
2Hz), 1.52 (3H, t, J = 7.2Hz), 1.95 (2H, m), 2.26 (2H, m), 3.65
(2H, m), 4.11 (2H, m), 4.14 (2H, q, J = 7.2Hz), 4.25 (2H, q, J =
7.2Hz), 4.36 (2H, q, J = 7.2Hz), 6.87 (2H, d, J = 8.8Hz), 6.96
(1H, s), 7.38 (2H, d, J = 8.8Hz), 8.36 (1H, brs), 8.70 (1H, s) Mass m / e (FAB) 454 (MH ⁺ ) Elemental analysis Calcd. For C ₂₅ H ₃₁ N ₃ O ₅ C: 66.21, H: 6.89, N: 9.27 Found C: 65.94, H: 6.94, N: 9.08

Example 24 6,8-Diiodo-4- (4-hydroxy-4-phenylpiperidino) quinazoline

[0107]

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Yield 79% Melting point 146-147 ° C. ¹ H NMR (CDCl ₃ ) δ: 1.94 (2H, m), 2.29 (2H, m), 3.79 (2H, m),
4.29 (2H, m), 7.32 (1H, m), 7.41 (2H, m), 7.53 (2H, m), 8.23 (1
H, d, J = 2.0Hz), 8.56 (1H, d, J = 2.0Hz), 8.81 (1H, s) Mass m / e (FAB) 558 (MH ⁺ ) Elemental analysis Calcd. For C ₁₉ H ₁₇ I ₂ N ₃ OC: 40.96, H: 3.08, N: 7.54 Found C: 41.13, H: 3.19, N: 7.43

Example 25 6,8-Diiodo- [4-hydroxy-4- (4-hydroxyphenyl) piperidino] quinazoline

[0110]

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Yield 96% Melting point 128-129 ° C. ¹ H NMR (CDCl ₃ ) δ: 1.93 (2H, m), 2.23 (2H, m), 3.77 (2H, m),
4.27 (2H, m), 4.96 (1H, s), 6.85 (2H, d, J = 8.8Hz), 7.39 (2H,
d, J = 8.8Hz), 8.22 (1H, d, J = 1.8Hz), 8.55 (1H, d, J = 1.8Hz),
8.80 (1H, s) Mass m / e (FAB) 574 (MH ⁺ ) Elemental analysis Calcd. For C ₁₉ H ₁₇ I ₂ N ₃ O ₂ C: 39.82, H: 2.99, N: 7.33 Found C: 40.83, H : 3.45, N: 6.71

Example 26 6,8-Dimethoxy-7-ethoxy-4- (4-hydroxy-4-phenylpiperidino) quinazoline

[0113]

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Yield 94% Melting point 162-163 ° C. ¹ H NMR (CDCl ₃ ) δ: 1.44 (3H, t, J = 7.2 Hz), 1.94 (2H, m), 2.3
5 (2H, m), 3.67 (2H, m), 3.95 (3H, s), 4.13 (3H, s), 4.16 (2H, m
m), 4.28 (2H, q, J = 7.2Hz), 6.97 (1H, s), 7.31 (1H, m), 7.41 (2H
H, m), 7.56 (2H, m), 8.74 (1H, s) Mass m / e (FAB) 410 (MH ⁺ ) Elemental analysis Calcd. For C ₂₃ H ₂₇ N ₃ O ₄ C: 67.46, H: 6.65 , N: 10.26 Found C: 67.46, H: 6.67, N: 10.16

Example 27 6,8-Dimethoxy-7-ethoxy- [4-hydroxy-4- (4-hydroxyphenyl) piperidino] quinazoline

[0116]

Embedded image

Yield 87% Melting point 182-183 ° C. (decomposition) ¹ H NMR (CDCl ₃ ) δ: 1.44 (3H, t, J = 7.2 Hz), 1.94 (2H, m), 2.2
9 (2H, m), 3.67 (2H, m), 3.95 (3H, s), 4.12 (3H, s), 4.14 (2H, m
m), 4.27 (2H, q, J = 7.2Hz), 6.86 (2H, d, J = 8.8Hz), 6.96 (1H,
s), 7.41 (2H, d, J = 8.8Hz), 8.72 (1H, s) Mass m / e (FAB) 426 (MH ⁺ ) Elemental analysis Calcd. for C ₂₃ H ₂₇ N ₃ O ₅ C: 64.93, H: 6.40, N: 9.88 Found C: 64.79, H: 6.45, N: 9.68

────────────────────────────────────────────────── ─── front page continued (51) Int.Cl. ⁶ identifications FI A61K 31/505 ABX A61K 31/505 ABX ACD ACD ACV ACV ACX ACX ADV ADV AED AED C07D 405/14 211 C07D 405/14 211

Claims (12)

[Claims] 1. A compound of the general formula (I) (Wherein R ¹ , R ² and R ³ are the same or different from each other and are a hydrogen atom, a halogen atom, a lower alkyl group optionally substituted with a halogen, a lower alkoxy group optionally substituted with a halogen, a cycloalkoxy group, R ⁴ represents a hydrogen atom, a halogen atom, or a halogen-substituted aryl group which may have a substituent, an arylalkyl group which may have a substituent, a cyano group or a nitro group. A lower alkyl group, a lower alkoxy group which may be halogen-substituted, an amino group, an alkylamino group, and a cycloalkyl group which may have a hetero atom, wherein R ⁵ and R ⁶ are the same or different from each other;
A hydroxyl group, a lower alkyl group which may be halogen-substituted, a lower alkoxy group which may be halogen-substituted,
A lower alkoxyalkyl group which may be halogen-substituted, a cycloalkoxy group which may have a hetero atom and may have a substituent, an aryl group which may have a substituent, and a A heteroaryl group which may be substituted, an arylalkyl group which may have a substituent, an alkenyl group or an alkynyl group. Where R ¹ ,
When all of R ² , R ³ and R ⁴ are hydrogen atoms, R ¹ ,
This excludes the case where any ^two of R ² and R ³ are both hydrogen atoms, and the case where both R ⁵ and R ⁶ are hydroxyl groups. )
Or a pharmaceutically acceptable salt thereof or a hydrate thereof. (2) R ⁵ is a hydroxyl group, and R ⁶ is a lower alkyl group which may be halogen-substituted, a lower alkoxy group which may be halogen-substituted, a lower alkoxyalkyl group which may be halogen-substituted, A cycloalkoxy group which may have an atom and may have a substituent, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, and a substituent 2. The quinazoline derivative according to claim 1, which is an optionally substituted arylalkyl group, alkenyl group or alkynyl group, or a pharmaceutically acceptable salt thereof or a hydrate thereof. 3. R ¹ , R ² and R ³ are the same or different from each other and are a hydrogen atom, a halogen atom, a lower alkyl group which may be halogen-substituted or a lower alkoxy group which may be halogen-substituted, R ⁴ is a hydrogen atom, a halogen atom, a lower alkyl group optionally substituted with a halogen, a lower alkoxy group optionally substituted with a halogen, an amino group, an alkylamino group, a cycloalkyl group optionally having a hetero atom R ⁵ is a hydroxyl group, and R ⁶ is a lower alkyl group which may be halogen-substituted, an aryl group which may have a substituent, or an arylalkyl group which may have a substituent Claim 1
3. The quinazoline derivative or a pharmacologically acceptable salt thereof or a hydrate thereof according to item 1. 4. A method according to claim ¹ , wherein R ¹ , R ² and R ³ are lower alkoxy groups which may be halogen-substituted, R ⁴ is a hydrogen atom, R ⁵ is a hydroxyl group, and R ⁶ is halogen-substituted. A quinazoline derivative or a pharmaceutically acceptable salt thereof according to claim 1, which is a lower alkyl group, an aryl group which may have a substituent or an arylalkyl group which may have a substituent. Or its hydrate. 5. R ¹ , R ² and R ³ are a lower alkoxy group which may be halogen-substituted, R ⁴ is a hydrogen atom, R ⁵ is a hydroxyl group, and R ⁶ has a substituent. 2. The quinazoline derivative according to claim 1, which is an optionally substituted aryl group, a pharmacologically acceptable salt thereof, or a hydrate thereof. 6. R ¹ , R ² and R ³ are a lower alkoxy group which may be halogen-substituted, R ⁴ is a hydrogen atom, R ⁵ is a hydroxyl group, and R ⁶ has a substituent. The quinazoline derivative according to claim 1, which is a phenyl group which may be substituted, a pharmaceutically acceptable salt thereof, or a hydrate thereof. 7. R ¹ , R ² and R ³ are the same or different and each is a methoxy group or an ethoxy group, R ⁴ is a hydrogen atom, R ⁵ is a hydroxyl group, and R ⁶ has a substituent. The quinazoline derivative according to claim 1, which is a phenyl group which may be substituted, a pharmaceutically acceptable salt thereof, or a hydrate thereof. (8) the compound is 1) 4- (4-hydroxy-4);
-Phenylpiperidino) -6,7,8-trimethoxyquinazoline 2) 4- [4- (4-fluorophenyl) -4-hydroxypiperidino] -6,7,8-trimethoxyquinazoline 3) 4 -[4-hydroxy-4- (3-methoxyphenyl) piperidino] -6,7,8-trimethoxyquinazoline 4) 4- [4- (2-furyl) hydroxypiperidino]-
6,7,8-trimethoxyquinazoline 5) 4- [4- (3-furyl) -4-hydroxypiperidino] -6,7,8-trimethoxyquinazoline 6) 4- [4-hydroxy-4- (3-Hydroxyphenyl) piperidino] -6,7,8-trimethoxyquinazoline 7) 4- [4-hydroxy-4- (4-hydroxyphenyl) piperidino] -6,7,8-trimethoxyquinazoline 8) 4 -[4-hydroxy-4- (4-hydroxyphenyl) piperidino] -6,7,8-triethoxyquinazoline 9) 6,8-diiodo- [4-hydroxy-4- (4-hydroxyphenyl) piperidino] quinazoline 10) 6,8-Dimethoxy-7-ethoxy-4- (4-hydroxy-4-phenylpiperidino) quinazoline 11) 6,8-Dimethoxy-7-ethoxy- [4-hydroxy-4- (4-hydrido) Kishifeniru) piperidino] quinazoline derivative or a pharmacologically acceptable salt or hydrates thereof according to claim 1 is any one of quinazoline. 9. The compound according to claim 1, wherein 1) 4- (4-hydroxy-4)
-Phenylpiperidino) -6,7,8-trimethoxyquinazoline 2) 4- [4- (3-furyl) -4-hydroxypiperidino] -6,7,8-trimethoxyquinazoline 3) 4- [4-hydroxy-4- (3-hydroxyphenyl) piperidino] -6,7,8-trimethoxyquinazoline 4) 4- [4-hydroxy-4- (4-hydroxyphenyl) piperidino] -6,7,8 -Trimethoxyquinazoline 5) 4- [4-hydroxy-4- (4-hydroxyphenyl) piperidino] -6,7,8-triethoxyquinazoline 6) 6,8-dimethoxy-7-ethoxy- [4-hydroxy- The quinazoline derivative according to claim 1, which is any of 4- (4-hydroxyphenyl) piperidino] quinazoline, a pharmaceutically acceptable salt thereof, or a hydrate thereof. (10) the compound is 1) 4- [4-hydroxy-
4- (3-hydroxyphenyl) piperidino] -6,7,
8-trimethoxyquinazoline 2) 4- [4-hydroxy-4- (4-hydroxyphenyl) piperidino] -6,7,8-trimethoxyquinazoline 3) 6,8-dimethoxy-7-ethoxy- [4-hydroxy The quinazoline derivative according to claim 1, which is any of -4- (4-hydroxyphenyl) piperidino] quinazoline, a pharmaceutically acceptable salt thereof, or a hydrate thereof. (11) a selective inhibition of the calmodulin-dependent phosphodiesterase containing the quinazoline derivative according to any one of (1) to (10) or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient; Effective preventive and therapeutic agent for diseases. 12. A disease in which a selective inhibitory effect of calmodulin-dependent phosphodiesterase is effective is angina pectoris, myocardial infarction, chronic and acute heart failure, pulmonary hypertension, hypertension, peripheral circulatory insufficiency, arteriosclerosis, relapse after PTCA. The preventive / therapeutic agent for a disease in which a selective inhibitory action of calmodulin-dependent phosphodiesterase is effective according to claim 11, which is a disease in which stenosis, cerebral circulatory insufficiency, cerebral dysfunction, renal insufficiency, osteoporosis, leukemia and diuretic action are effective.