WO1999009986A1 - 4-aminoquinazoline derivatives - Google Patents

Abstract

Insulin secretion promoters which contain as the active ingredient 4-aminoquinazoline derivatives represented by general formula (I) or pharmacologically acceptable salts thereof wherein R?1A and R1B¿ are the same or different and each represents hydrogen, lower alkyl, lower alkoxy, halogeno, nitro, -NR3R4 (wherein R?3 and R4¿ are the same or different and each represents hydrogen or lower alkyl), etc., or R1A may form together with R1B adjacent thereto -O-(CH¿2?)nO- (wherein n is 1 or 2); Cy represents optionally substituted aryl; R?2¿ represents hydrogen or optionally substituted lower alkyl; and A represents hydrogen or optionally substituted lower alkyl, optionally substituted cycloalkyl, etc., or R2 and A may form together with the nitrogen atom adjacent thereto an optionally substituted heterocycle.

Description

 Specification

4 —Aminoquinazoline derivatives Technical field

 The present invention relates to an insulin secretagogue and a therapeutic agent for diabetes containing a 4-aminoquinazoline derivative as an active ingredient. The present invention also relates to a 4-aminoquinazoline derivative having a glucose concentration-dependent promoting action on insulin secretion and a suitable hypoglycemic action, and being useful as a therapeutic agent for diabetes.

Background art

 Diabetes is a condition characterized by inappropriately elevated blood sugar levels, abnormal insulin secretion and various metabolic and vascular abnormalities, in which various treatments are ineffective or ineffective. If left untreated-severe complications may occur due to arterial and neurological disorders caused by hyperglycemia. For this reason, measures for lowering blood glucose have been studied for a very long time.

Among non-insulin-dependent diabetic patients, glycemic control can be performed by a combination of exercise therapy and drugs that lower blood glucose levels. As a drug, an insulin secretagogue is currently widely used in clinical practice as one of the oral hypoglycemic agents. However, currently available insulin secretagogues induce insulin secretion independent of the concentration of dalcos, so that wrong doses can cause severe hypoglycemia or It is unsatisfactory because it can only improve the blood sugar control to the extent that it cannot be performed.Therefore, there is a danger of causing hypoglycemia by inducing insulin according to the blood glucose level. Few as insulin secretagogues What is effective for blood sugar management of diabetic patients is desired.

 For example, the following are known as 2-styrene-4-aminoquinazoline derivatives.

 (a) US Pat. No. 4,661,621 discloses that the following compounds and salts thereof are useful as anti-inflammatory agents.

 (a)

(Wherein, R ^la represents hydrogen, halogen, lower alkyl or lower an alkoxy, R ^2a represents hydrogen, lower alkyl, etc., R ^3a represents a full Weniru etc., R ^4a, 1 ^{5 &} Oyobi 1 ^{6 £ 1} represents hydrogen, halogen, nitro, etc.)

 (b) JP-A-47-22927 discloses that the following compounds and their acid addition salts are useful as anti-inflammatory agents.

(Wherein, R ^lb represents hydrogen, lower alkyl, lower alkoxy, etc., R ^2b and R ^3b are the same or different and represent hydrogen, lower alkyl, hydroxy lower alkyl, etc., and R ^4b is hydrogen, halogen, lower Alkyl Or represents lower alkoxy)

Invention

 An object of the present invention is to provide an insulin secretagogue and a therapeutic agent for diabetes, which comprise a 4-aminoquinazoline derivative as an active ingredient. The present invention provides a compound of the formula (I)

Wherein, R ^1A and R ^{1 B} are the same or different and each is hydrogen, lower alkyl, lower alkoxy, halogen, two collected by filtration, - NR ^{3 4} (wherein, R ³ Contact and R ⁴ are hydrogen or the same or different , — NHCOR ⁵ (where R ⁵ represents lower alkyl), — NHS〇 ₂ R ⁶ (where R ^fi represents lower alkyl), — CONR ⁷ R ⁸ (wherein, R ⁷ and R ⁸ are the same or different and each is hydrogen, lower alkyl or represents Ararukiru), lower alkoxycarbonyl, or carboxy or is a lower Arukanoiru or become R ^1B guard緖adjacent to the R ^1A - Represents (CH ₂ ) _n 0-(where n represents 1 or 2), Cy represents a substituted or unsubstituted aryl, and R ² represents hydrogen or substituted or unsubstituted. Represents a substituted lower alkyl, where A is hydrogen, substituted or unsubstituted lower alkyl Substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyl lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted Heterocyclic groups, substituted or unsubstituted heterocyclic lower alkyl, Or substituted or unsubstituted unsaturated heterocyclic lower alkyl, or R ² and A together with the adjacent nitrogen atom represent a substituted or unsubstituted heterocyclic group.] 4—Aminoquinazolin derivative [Hereinafter, formula

The compound represented by (I) is called compound (I). The same applies to compounds of other formula numbers.] Or an insulin secretagogue containing a pharmaceutically acceptable salt thereof as an active ingredient.

 The present invention also relates to a therapeutic agent for diabetes comprising Compound (I) or a pharmacologically acceptable salt thereof as an active ingredient.

 Further, the present invention provides a method for preventing or treating diabetes comprising administering an effective amount of compound (I) or a pharmacologically acceptable salt thereof, and insulin secretion deficiency or insulin secretion. The present invention relates to a method for preventing or treating a disease state caused by a decrease in susceptibility.

 The present invention also relates to a method for preventing or treating diabetes and the production of a pharmacological composition useful for preventing or treating a condition caused by insulin secretion deficiency or reduced insulin sensitivity. For use of compound (I) or a pharmaceutically acceptable salt thereof.

 In addition, the present invention relates to a compound (I) or a pharmacologically active compound thereof for the prevention or treatment of diabetes and the prevention or treatment of a condition caused by insulin secretion deficiency or decreased insulin sensitivity. The use of acceptable salts.

Further, the present invention provides a compound of the formula (IA) R ^2X , _n 'A ^X

 1AX (IA)

 R people .. one, X

R ^1BX

Wherein, R ^1AX and R ^1Bx the same or different and each is hydrogen, lower alk kill, lower alkoxy, Nono androgenic, two collected by filtration, - NR ³ R ⁴ (wherein, R ³ and R ⁴ are each as defined above Yes), — NHC 0 R ⁵

(Wherein, R ⁵ has the same meaning as described above), — NHS 0 ₂ R ^β (wherein, R ⁶ has the same meaning as described above), one C〇NR ⁷ R ⁸ (where the formulas, R ⁷ and R ⁸⁾ Is the same as defined above), lower alkoxycarbonyl, carboxy or lower alkanol, or R ^1ΛΧ and adjacent R ^1ΒΧ are joined together to form —〇 (CH ₂ ) _n O— (1) When both R ^{1 AX} and R ^nix are other than hydrogen, or R ^{1 AX} is hydrogen and R ^{1 BX} is —NHC 0 R “'(where R ⁵ the same meaning as defined above is), _ NHS_〇 ₂ R is ^|; (Shikihaba, R ^(; the Ru as defined above der) one C_〇 NR ⁷ R ⁸ (wherein, R ⁷ and R ⁸ wherein each synonymous with), lower alkoxycarbonyl, -◦ or represents carboxy or lower Arukanoiru, or R ^1Bx adjacent to R ^1AX Te summer together (CH _{2) n} O- (in wherein, n If representing the same meaning as defined above)

C y represents substituted or unsubstituted aryl, R ^2X represents hydrogen or substituted or unsubstituted lower alkyl, A ^x represents hydrogen, substituted or unsubstituted lower alkyl, substituted Unsubstituted or substituted cycloalkyl, substituted or unsubstituted cycloalkyl lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted Represents an unsubstituted or unsubstituted heterocyclic group, a substituted or unsubstituted heterocyclic lower alkyl or a substituted or unsubstituted unsaturated heterocyclic lower alkyl,

R ^2X and A ^x together with the adjacent nitrogen atom represent a substituted or unsubstituted heterocyclic group;

② R ^1AX and R ^1Bx Do both represent hydrogen, or R ^1AX is hydrogen and R ^1Bx lower alkyl, lower alkoxy, halogen, two collected by filtration or - NR ³ R ⁴ (wherein, R ³ and R ⁴ are Is as defined above):

i) C y ^x is substituted off Weniru [the substituent off Weniru is adjacent substituents has decreased with _{- 0 (CH 2) m 0} - ( wherein, m is Ru as defined above der), substituted Or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, trifluoromethoxy, lower alkylthio, nodogen, nitro, hydroxy, amino, lower alkoxycarbonyl, carboxy and —NR ⁹ R ¹⁰ (wherein, R ⁹ and R ^{1 Q} are the same or different as defined above) and are substituted with 1 to 3 groups, and at least one of them is adjacent substitution When the groups are unified—〇 (CH ₂ ) _m 0-(where m is as defined above), substituted lower alkyl, substituted lower alkoxy, trifluoromethoxy, lower alkylthio, lower alkoxycarbonyl, carboxy Ma Is - NR ⁹ R ¹⁰ (wherein, R ⁹ and R ^{1 Q} is as defined above, respectively Ru der) is replaced by or substituted or unsubstituted § Re excluding phenylalanine - Le [the substituent Ariru is Adjacent substituents are joined together—0 (CH ₂ ) _m 0 — (where m is as defined above), substituted or unsubstituted lower alkyl, substituted or unsubstituted Lower alkoxy, trifluoromethoxy, lower alkylthio, nodogen, nitro, hydroxy, amino, lower alkoxycarbonyl, carboxy and -NR ⁹ R ¹⁰ (wherein R ⁹ and R ^{1 1} are the same as or different from each ^{other as} defined above), and are substituted with 1 to 3 groups].

R ^{2 X} represents hydrogen or substituted or unsubstituted lower alkyl, A ^x is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cycloalkyl lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclic lower alkyl or Represents a substituted or unsubstituted unsaturated heterocyclic lower alkyl, or R ^{2 X} and A ^x together with an adjacent nitrogen atom represent a substituted or unsubstituted heterocyclic group;

 ii) Cy is substituted or unsubstituted phenyl (the substituted phenyl is the same or different from unsubstituted lower alkyl, unsubstituted lower alkoxy, halogen, nitro, hydroxy and amino) 3)

R ^{2 X} represents hydrogen or substituted or unsubstituted lower alkyl, A ^x is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyl lower alkyl, substituted aralkyl, substituted Or an unsubstituted heterocyclic group or a substituted or unsubstituted unsaturated heterocyclic lower alkyl]] or a pharmacologically acceptable salt thereof.

In the definition of each group of the formula (I) and the formula (IA), the lower alkyl moiety of lower alkyl, lower alkoxy, lower alkylthio, lower alkoxycarbonyl, cycloalkyl lower alkyl, heterocyclic lower alkyl and unsaturated heterocyclic lower alkyl Examples include linear or branched C 1 -C 8 carbon atoms such as methyl, ethyl, propyl, and isoprene. Mouth pill, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, etc., and the alkylene of aralkyl represents a group obtained by removing a hydrogen atom from the lower alkyl moiety described above, Lower alkanols include straight-chain or branched-chain C 1 to C 9, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, norrelyl, isono, relinole, pino'royl, hexanoyl. , Heptanyl, octanoyl, nonanoyl and the like. Examples of the cycloalkyl moiety of cycloalkyl and cycloalkyl lower alkyl include a carbon ring having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Nodrogens include fluorine, chlorine, bromine and iodine atoms.

The aryl portions of aryl and aralkyl include phenyl, naphthyl and anthryl. Examples of the heterocyclic group and the heterocyclic group portion of the heterocyclic lower alkyl include an aromatic heterocyclic group and an alicyclic heterocyclic group. Examples of the aromatic heterocyclic group include pyridyl and pyrazinyl. , Pyrimidinyl, biridazinyl, benzimidazolyl, indazolyl, indolyl, isoindril, prenyl, quinolyl. Triazolyl, tetrazolyl, imidazolyl, oxazolyl, thiazolyl, phenyl, phenyl and the like.Examples of the alicyclic heterocyclic group include, for example, pyrrolidinyl, thiazolidinyl, oxazolidinyl, piperidyl, and the like. Piperidino, piperazinyl, homopiperazinyl, morpholinyl, thiomorpholinyl, tetra Human Doropi Ranil, Te Torahi Dorofuraniru, Te tiger human Dorokino Lil, Te Torahi Doroi Sokino Lil, O click sunset Dorokino Lil, mercy Doroi down drill And so on. Examples of the unsaturated heterocyclic group portion of the unsaturated heterocyclic lower alkyl include, in addition to the above aromatic heterocyclic group, pyrrolinyl, thiazolinyl, oxazolinyl, dihydrobilanyl, dihydrofuranyl and the like. Examples of the heterocyclic group bonded to the adjacent nitrogen atom include pyrrolidinyl, thiazolidinyl, oxazolidinyl, piperidino, piperazinyl, homopiperazinyl, morpholino, thiomorpholino, and tetrahydrin. Loquino Linole, Tetrahydrolin Sokino Linole, Okuyu Hydrokinolil, Benzimidazolyl, Indazolyl, Indril, Isoindolyl, Purinyl, Jihydrin Examples include doliryl, pyrrolyl, virazolyl, triazolylyl, tetrazolyl, and imidazolyl.

 The lower alkyl, cycloalkyl, cycloalkyl lower alkyl, alkylene portion of aralkyl and lower alkoxy have the same or the same or same substituents as those having 1 to 3 substituents, such as lower alkoxy, halogen, hydroxy, lower alkoxycarbonyl, carboxy, Mono or di-lower alkylamino may, for example, be mentioned. In the definition of the substituent, the lower alkyl portion of the mono- or di-lower alkylamino has the same meaning as the lower alkyl, and the lower alkoxy, halogen and lower alkoxycarbonyl have the same meanings as above.

The substituents on the aryl portion of the aryl and aralkyl and the heterocyclic portion of the heterocyclic group, the heterocyclic lower alkyl and the unsaturated heterocyclic lower alkyl may be the same or the same having 1 to 3 substituents. Differently substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, trifluoromethyoxy, lower alkylthio, no, logen, nitro, hydroxy, amino, lower alkoxy Carbonyl, carboxy, mono- or di-lower alkylamino, substituted or unsubstituted aryl, aryl Aralkyl, a group in which adjacent substituents are joined together, (◦ (CH ₂ ) _m 0-(where m is as defined above), and a substituted or unsubstituted heterocyclic group. In the definition of the substituent, lower alkyl, lower alkoxy, halogen, lower alkoxycarbonyl, mono- or di-lower alkylamino, aryl, aralkyl and heterocyclic group are as defined above. The substituents of lower alkyl and lower alkoxy may be the same or different and have 1 to 3 substituents, such as lower alkoxy, halogen, hydroxy, lower alkoxycarbonyl, carboxy, mono- or di-lower alkylamino, and alicyclic heterocyclic. Lower alkoxy, nodogen, lower alkoxycarbonyl, mono- or di-lower alkylamino and alicyclic heterocyclic group are as defined above. The substituents of aryl are the same or different and have 1 to 3 substituents such as lower alkyl, lower alkoxy, halogen, nitro, hydroxy, lower alkoxycarbonyl, carboxy, mono- or di-lower alkylamino, complex A lower alkyl, a lower alkoxy, a halogen, a lower alkoxycarbonyl, a mono- or di-lower alkylamino, and a heterocyclic group are as defined above. Examples of the substituent of the substituted heterocyclic group include the same or different substituted or unsubstituted lower alkyl having 1 to 3 substituents, substituted or unsubstituted lower alkoxy, nodogen, and nitrogen. Toro, hydroxy, amino, lower alkoxycarbonyl, carboxy, mono- or di-lower alkylamino, substituted or unsubstituted aryl, aralkyl, substituted or unsubstituted heterocyclic groups And the like. In the definition of the substituent, lower alkyl, lower alkoxy, halogen, lower alkoxycarbonyl, mono- or di-lower alkylamino, aryl, aralkyl and heterocyclic group are as defined above. Lower alkyl and Examples of the substituent of the lower alkoxy include lower alkoxy, halogen, hydroxy, lower alkoxycarbonyl, carboxy, mono- or di-lower alkylamino, alicyclic heterocyclic group, and the like. Lower alkoxy, nodogen, lower Alkoxycarbonyl, mono- or di-lower alkylamino and alicyclic heterocyclic group have the same meanings as above. Substituents for aryl and heterocyclic groups include lower alkyl, lower alkoxy, nodogen, nitro, hydroxy, lower alkoxycarbonyl, carboxy, mono- or di-lower alkylamino, and complex ring groups. The lower alkyl, halogen, lower alkoxy, lower alkoxycarbonyl, mono- or di-lower alkylamino and heterocyclic groups are as defined above.

As a substituent of the heterocyclic group bonded to the adjacent nitrogen atom, the same or different substituted or unsubstituted lower alkyl having 1 to 3 substitutions, or a substituted or unsubstituted lower alkyl Alkoxy, halogen, nitro, hydroxy, amino, lower alkoxycarbonyl, carboxy, mono- or di-lower alkylamino, substituted or unsubstituted aryl, aralkyl, substituted or unsubstituted heterocyclic group And the like. In the definition of the substituent, lower alkyl, lower alkoxy, halogen, lower alkoxycarbonyl, mono- or di-lower alkylamino, aryl, aralkyl and heterocyclic group are the same as defined above for lower alkyl and lower alkoxy. Lower alkoxy, halogen, hydroxy, lower alkoxycarbonyl, carboxy, mono- or di-lower alkylamino, alicyclic heterocyclic group, etc .; lower alkoxy, halogen, lower alkoxycarbonyl mono- or di-lower alkylamino And alicyclic heterocyclic groups are as defined above. Aryl and heterocyclic group substituents Lower alkyl, lower alkoxy, nodogen, nitro, hydroxy, lower alkoxycarbonyl, carboxy, mono- or di-lower alkylamino, heterocyclic group, etc., and lower alkyl, halogen, lower alkoxy, lower alkoxycarbonyl, The mono- or di-lower alkylamino and the heterocyclic group are as defined above. As the pharmacologically acceptable salt of compound (I), a non-toxic, water-soluble salt is preferred, for example, hydrochloride, hydrobromide, nitrate, sulfate, phosphate, etc. Inorganic, acetate, benzenesulfonate, benzoate, citrate, fumarate, gluconate, lactate, maleate, lignate, oxalate, methanesulfonic acid Salts, acid addition salts such as organic acid salts such as tartrate, alkali metal salts such as sodium salts and calcium salts, alkaline earth metal salts such as magnesium salts and calcium salts, ammonium salts And ammonium salts such as tetramethylammonium and the like, and organic amine addition salts such as morpholine addition salt and piperidine addition salt.

 Next, a method for producing the compound (I) will be described.

 In the following production methods, if the defined groups change under the conditions of the method or are inappropriate for carrying out the method, methods commonly used in organic synthetic chemistry, such as protection of functional groups, It can be easily implemented by applying means such as deprotection.

 Compound (I) can be produced by a series of reactions shown below.

Production method A:

Compound (I) can be produced according to the following reaction steps.

R 1A. '

 N CH2 CH-Cy

R 1B _{/ v} ,

 (X) 2— A (X!)

(Wherein, R ^1A , R ^1B , R ² , A and Cy are as defined above). The compound (X) is a 2-styryl-4-quinazolinone derivative

(IX) in a solvent free or in an inert solvent such as 1,2-dichloroethane at a temperature between room temperature and the boiling point of the solvent to be used. Can be obtained by treating with a clotting agent such as oxylin chloride or thionyl chloride for 1 to 24 hours at a temperature between room temperature and the boiling point of the clotting agent used. At this time, if necessary, a tertiary amine such as dimethylaniline, triethylamine, N, N-diisopropylethylamine or the like may be allowed to coexist. Next, the compound (I) is prepared by converting the compound (X) with 1 equivalent to an excess amount of the amine (XI) to a lower alcohol such as ethanol or isoprononol, tetrahydrofuran, N, N-dimethylformamide or the like. Reaction in an organic solvent, if necessary, in the presence of a base such as N, N-diisop-piruethylamine at a temperature between room temperature and the boiling point of the solvent used, for several hours to several days, preferably 5 to 48 hours Can be obtained.

 2-Styryl_4-monoquinazolinone derivative (IX) is a compound

 (11), from the compound (VII) or the compound (VIII), or from a known method (Dot Patent No. 21351712, Journal of American Chemical Society, Vol. 82, 3152 page, 1960).

Compound (IX) can be prepared by using a compound (II) described in US Pat. No. 3,970,648 or the like as an aldehyde which is commercially available or can be produced by a known method. (V) is dissolved in a solvent such as acetic anhydride, acetic acid, or trifluoroacetic acid, in the presence of 1 to 10 equivalents of ammonium acetate, sodium acetate, or the like, or an alcohol, N, N— Metallic alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, or organic amines such as pyridin in a solvent such as dimethylformamide It can be obtained by reacting at a temperature between 100 and 200 ° C. for 1 to 48 hours in the presence. Preferably, compound (IX) is the same as compound (II) and 2 Reacting 〜5 equivalents of compound (V) with acetic acid in the presence of 2-5 equivalents of ammonium acetate at a temperature between 100 ° C. and the boiling point of acetic acid for 1-48 hours Can be obtained.

 Compound (IX) is obtained by combining compound (III) or compound (IV) with compound (VI) which is commercially available or can be produced by a known method in a solvent such as pyridine. —Reaction in the presence of dimethylaminoviridine at a temperature between 0 ° C. and room temperature for 1 to 24 hours to obtain compound (VII) or compound (VIII). 0 to 30% sodium hydroxide, hydrating power In an aqueous solution such as room temperature, if necessary, in the presence of an alcohol such as ethanol, between 70 ° C and the boiling point of the solvent used This can be obtained by heating at a temperature for 1 to 24 hours. In the case of compound (VIII), it is necessary to prepare the compound (VIII) in an aqueous solution of hydrogen peroxide in the presence of 1 to 10 equivalents of a hydration power. More in the presence of alcohol such as ethanol, at a temperature between 70 and 100 ° C for 1 to 10 hours. It is possible to obtain Ri due to be. Production method B:

Compound (I) can also be produced according to the method described in US Pat. No. 4,661,621 or a modification thereof, according to the following reaction steps.

(Wherein R ^1A , R ^1B , R ² , A and Cy are as defined above). The compound (XII) is produced in the same manner as in the production method A, in which the compound (X) is obtained from the compound (IX). Thus, the compound (II) can be obtained by treating the compound (II) with a chromating agent. Compound (XIII) can be obtained by reacting compound (XII) with amine (XI) in the same manner as in production method A to obtain compound (I) from compound (X). Can be. Next, compound (I) is a compound

 (XIII) and compound (V) in a solvent such as acetic acid or acetic anhydride in the presence of a base such as piperidine at a temperature between 120 and 200 ° C for 1 to 48 hours. It can be obtained by reacting. In this case, the compound (V) is used in an amount of 2 to 5 equivalents (molar ratio) to the compound (XIII).

 A part of the compound (I) obtained here can be used as a synthetic intermediate to further lead to a new derivative (I).

For example a compound R ^1A or R ^1B is § Mi Roh among the compounds (I) (la), the compound (I) No Chi R ^1A or of the R ^1B crab collected by filtration Compound (lb) in acetic acid or concentrated hydrochloric acid or in a mixed solvent of these with an organic solvent such as ethanol, 3 to 10 equivalents, preferably 3 to 5 equivalents of zinc, tin, iron, tin dichloride, etc. Of the compound (lb) in methanol for 0.5 to 24 hours, preferably 1 to 5 hours, at room temperature to the boiling point of the solvent used, in the presence of a reducing agent , In a mixed solvent of an organic solvent such as ethanol and water and water, in the presence of 3 to 10 equivalents, preferably 3 to 5 equivalents of a reducing agent such as sodium dithionate, at 0 ° C to the boiling point of the solvent used. By treating for 0.5 to 24 hours, preferably 1 to 5 hours, at a temperature between 0.1 to 1 wt. In an organic solvent such as methanol, ethanol, etc. %, Preferably 0:! To 0.2% by weight in the presence of 5% palladium-carbon, room temperature to At a temperature between the boiling points of the solvents used, for 1 to 24 hours, preferably

1-5 hours, 1-5 atmospheres, preferably 1-2 atmospheres of hydrogen gas, or the compound (lb) in an inert solvent such as tetrahydrofuran. 1 to 24 equivalents, preferably 1 to 5 hours at a temperature between 0 ° C and room temperature in the presence of ~ 5 equivalents, preferably 1-2 equivalents of a reducing agent such as lithium aluminum hydride Can be obtained by doing so.

Compound (Ic) in which R ^1A or R ^{1B in} compound (I) is —NHC 0 R ⁵ (wherein R ⁵ is as defined above) is a compound (I a)

1-2 (wherein, R ⁵ has the same meaning as defined above) equivalents of carboxylic acid R ⁵ C 0 ₂ H acid halide derived from an acid anhydride or mixed acid anhydride, 1-2 equivalents of In a solvent such as N, N-dimethylformamide or tetrahydrofuran in the presence of a base such as triethylamine or pyridine, a temperature between 0 ° C and the boiling point of the solvent used is 1 to 24. Time-reaction or 1-5 equivalents with compound (la), preferably The 1-3 (wherein, R ⁵ is as defined above) equivalents of carboxylic acid R ⁵ C 0 ₂ H and, dichloromethane emissions, Te tiger arsenide Dorofuran, N, inert solvent such as N- di Mechiruhorumuami de Medium, 1 to 5 equivalents, preferably 1 to 3 equivalents, in the presence of a condensing agent such as N, N-dicyclohexylcarbodiimide, 1-ethyl 3- (3, -dimethylaminopropyl) carbodiimide In the presence of 1 to 5 equivalents, preferably 1 to 3 equivalents of a base such as pyridin or triethylamine, at a temperature between 0 ° C and the boiling point of the solvent used, preferably 0 ° C. The reaction can be carried out at a temperature of about to room temperature for 1 to 24 hours, preferably 1 to 4 hours. Compound (I) No Chi R ^{1 A} or R ^{1 B} gar NHS_〇 ₂ R ^beta (wherein, R ⁶ has the same meaning as defined above) compound is (I d), the compound

 (la) and 1 to 5 equivalents, preferably 1 to 2 shades of the corresponding alkylsulfonyl chloride (such as methanesulfonyl chloride) or alkylsulfonic anhydride, are combined with N, N-dimethylform Use in a solvent such as amide or tetrahydrofuran in the presence of a base such as 1-5:, (, preferably 1-2 equivalents of a base such as triethylamine, pyridine, etc., at 0 ° C. It can be obtained by reacting at a temperature of the boiling point of the solvent for 1 to 24 hours, preferably 2 to 8 hours.

Compound (I) wherein R ^1A or R ^{1 B} is _C 0 NR ⁷ R ⁸ (wherein R ⁷ and R ⁸ are as defined above)

(I e) is a compound (I f) in which R ^1A or R is 1 C ₂ H of the compound (I) in an inert solvent such as dichloromethan or tetrahydrofuran in an amount of from 1 equivalent to 1 equivalent. With a solvent amount of a halogenating agent such as thionyl chloride, at a temperature between 0 ° C and the boiling point of the solvent used, or with a solvent amount of a halogenating agent, at a boiling point of the halogenating agent for 0.5 to 6 hours, Acid halide, preferably obtained by treating for 1 to 3 hours, or Is the compound (If) and 1 to 2 equivalents of ethyl chlorocarbonate in an inert solvent such as dichloromethane and tetrahydrofuran at a temperature of 0.5 ° C to 0.5 ° C at a temperature between 0 ° C and room temperature. For 1 hour, preferably 1 to 2 hours, and 1 to 5 equivalents, preferably 1 to 3 equivalents of HNR ⁷ R ⁸ (wherein R ⁷ and R ⁸ Is as defined above) in an inert solvent such as dichloromethane, tetrahydrofuran, N, N-dimethylformamide, 1 to 5 equivalents, preferably 1 to 3 equivalents of pyridine, In the presence of a base such as triethylamine, at a temperature between 0 ° C and the boiling point of the solvent used, preferably at a temperature between 0 ° C and room temperature, for 1 to 24 hours, preferably 1 to 4 hours It can be obtained by reacting. Alternatively, the compound (I e) is a compound

(If) and 1 to 5 equivalents, preferably:! To 3 equivalents of HNR ⁷ R ⁸ (wherein R ⁷ and R ⁸ are as defined above) in an inert solvent such as dichloromethane, tetrahydrofuran or N, N-dimethylformamide. In the presence of a condensing agent such as 1 to 5 equivalents, preferably 1 to 3 equivalents of N, N-dicyclohexylcarpoimide, 1-ethyl-3_ (3'-dimethylaminopropyl) carpoimide, In addition, in the presence of 1 to 5 equivalents, preferably 1 to 3 equivalents of a base such as pyridine or triethylamine, a temperature between 0 ° C and the boiling point of the solvent used, preferably

It can also be obtained by reacting at a temperature between 0 ° C. and room temperature for 1 to 24 hours, preferably for 1 to 4 hours.

Among the compounds (I), the compound (Ig) in which R ^1A or R ^1B is a lower alkynyl group other than formyl is a compound in which R or R ^{1B in} the compound (I) is halogen, preferably iodine. (Ih) and 1 to 5 equivalents, preferably 1 to 2 equivalents of the corresponding trialkyl (1-alkoxyalkenyl) tin, are treated with N, N-dimethylformamide, In an inert solvent such as lahydrofuran, in the presence of 0.1 to 1 equivalent, preferably 0.1 to 0.2 equivalent of a catalyst such as dichlorobistriphenylphosphine palladium, between room temperature and the boiling point of the solvent used. It can be obtained by reacting at a temperature for 1 to 12 hours, preferably for 1 to 4 hours.

 Among the compounds (I), the compound (Ii) having a hydroxymethyl moiety in Cy is a compound (Ij) having a lower alkoxycarbonyl moiety in Cy, and a compound such as tetrahydrofuran. 1 to 10 equivalents, preferably 1 to 3 equivalents, of a reducing agent such as lithium borohydride or lithium aluminum hydride in a solvent such as a ter-based solvent at a temperature between 0 ° C and room temperature. , 1 to 24 hours, preferably 1 to 3 hours. The compound (Ii) is obtained by converting a compound (Ik) having a lower alkoxy moiety in Cy into an inert solvent such as dichloroethane, benzene, cyclohexane, or a Lewis compound such as aluminum chloride or getylaluminum. The treatment can be carried out for 1 to 48 hours in the presence of an acid or in a strong acid such as trifluoroacetic acid or hydrobromic acid at a temperature between room temperature and the boiling point of the solvent used.

Of the compound (I), the compound (Im) having a mono- or di-lower alkylaminomethyl moiety or a heterocyclic methyl moiety together with an adjacent nitrogen atom in Cy is the compound (Ii) 1 to: L 0 equivalents, preferably 1 to 2 equivalents of methanesulfonyl chloride, p-toluenesulfonyl chloride, etc., and inactive such as methylene chloride, chloroform, N, N-dimethylformamide, tetrahydrofuran, etc. In a solvent, if necessary, in the presence of 1 to 10 equivalents, preferably 1 to 3 equivalents of a base such as pyridine or triethylamine, a temperature between 0 ° C and the boiling point of the solvent to be used, preferably At a temperature between 0 ° C and room temperature for 1-48 hours, preferably 1 By reacting for up to 10 hours, a compound (Ii) in which the hydroxyl group is protected by an appropriate leaving group is obtained, and then the obtained protected form is used in an amount of 1 to 10 equivalents, preferably 1 to 5 equivalents. Equivalent amount of the corresponding mono- or di-lower alkylamine or heterocyclic amine in a solvent such as methanol, ethanol, N-methylbilidone, tetrahydrofuran, etc. 1 to 24 hours, preferably 5 to 12 hours, at a temperature between room temperature and 150 ° C using a sealed container (such as a sealed tube) as necessary. It can be obtained by reacting.

 Compound (I n) of compound (I) having a halogenomethyl moiety in Cy can be obtained by converting compound (I i) without solvent or dichloromethane, tetrahydrofuran, N, N-dimethylformamide 1 to equivalent of solvent in a solvent such as thionyl chloride, at a temperature between 0 ° C and the boiling point of the solvent used, for 1 to 24 hours, preferably 1 to 24 hours. Treat for 10 hours or compound (Ii) in a solvent such as tetrahydrofuran, N, N-dimethylformamide with 1-3 equivalents of lithium halide and 1-3 equivalents. 1 to 3 equivalents of methanesulfonyl chloride in the presence of a base such as collagen, at a temperature between 0 ° C and the boiling point of the solvent used, preferably at a temperature between 0 ° C and room temperature, It can be obtained by treating for 24 hours, preferably for 3 to 12 hours.

Compound (Im) is prepared by combining compound (In) with 1 to 10 equivalents, preferably:! To 5 equivalents of the corresponding mono- or di-lower alkylamine or heterocyclic amide, In a solvent such as drofuran or N, N-dimethylformamide, 1 to 10 equivalents, preferably 1 to 5 equivalents of a base such as potassium carbonate or N, N-diisopropylethylamine Below. It can also be obtained by reacting at a temperature between room temperature and the boiling point of the solvent used, preferably at room temperature, for 1-24 hours, preferably 3-8 hours. You.

 The intermediates and the target compound in the above production method are purified by methods commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, and high performance liquid chromatography using silica gel. First, it can be purified and isolated by applying it to various types of chromatography such as thin-layer chromatography and column chromatography. In addition, the intermediate can be subjected to the next reaction without purification. When it is desired to obtain a salt of compound (I), if compound (I) is obtained in the form of a salt, it may be purified as it is, or if compound (I) is obtained in a free form, compound (I) May be dissolved or suspended in a suitable solvent. A salt may be formed by adding a suitable acid or base to isolate.

 The compound (I) may have various resting holidays: {\: which are all included in the concept of the present invention.

 Compound (I) and its pharmaceutically acceptable salts may be in the form of adducts with water or various solvents, and these adducts are also included in the present invention. .

Table 1 shows specific examples of the compound (I) obtained by the above production method.

Compound

第 1表つづき

Table 1 continued

A

Compound No.R ^1A , R ^1B Cy

第 1表つづき

Table 1 continued

^R, _N ^'A

 R 1A N

R B

R H2, _N

Compound number R ^1A , R ^1B Cy 3

19 6, 7-OCH ₃ 0 -C0 ₂ CH3

23 6,7- OCH ₃ Q \ ^CH 3 = \ .CH ₃

24 6,7- OCH3 0 N

'CH,

Table 1 continued »Number R ^1A , R ^B Cy

Table 1 continued

Example No. 1 1 AA 1 BR ²ヽ… A

C y

 OH

35 6, 0CH ₃

実施例番号 1 A 1 B ,,Α Boc: t—butoxycarbonyl Ph: phenyl Bn: benzyl Table 1 continued

Example number 1 A 1 B ,, Α

 C y

H ₃ C, _N , CH ₃ H3

49 6, 7-OCH3

N, CH ₃

実施例番号 1 A 1 B R²、 ,Α Boc: t-butoxycarbonyl Table 1 continued

Example No. 1 A 1 BR ² ,, Α

 C y

_{50 6, 7 - 0CH 3 -N} (CH 3) 2

H, C., Ph

51 6, 7-0CH ₃ -N (CH ₃ ) ₂

52 OCH3

55 6, 7-OCH3

56 6, OCH3 H ₃ C ゝ -OC ₂ H ₅

Ph: phenyl n- Bu: n-butyl Table 1 continued

Example number 1 A 1 B, Α

C y

Ph: Phenyl

Ph: Phenyl Real

Ph: Phenyl 1 table continued

, Α

 Example number N Cy

Ph: Phenyl

Table 1 continued

 Example number 1 A 1 B .A

 N C y

8 6 6-H, 7-CONHBn ^H3C ~~

"O

 Ph: phenyl Bn: benzyl

 Next, the pharmacological action of compound (I) will be specifically described with reference to test examples.

 Miyazaki et al. (Endocrino Jichi, 127, 1

(26-131, pp. 1900) The established strain of MIN6 cells showed that the insulin content and the amount of insulin secreted by glucose stimulation were close to those of the living cells and glucose Well preserves the properties of in vivo Teng cells in that insulin secretion increases in response to concentration (The above-mentioned literature and Takasaki et al., Die Avert Logi, 36, 111-111-145, 1993). In addition, MIN6 cells promote insulin secretion in response to sulfonylprea agents used as antidiabetic agents, such as glibenclamide (Beng et al., Cellular Signaling, Vol. 5). , Pp. 777-7786, 1993).

Test Example (1) Insulin secretion promoting activity by 5 cultured cells

 The culture of MIN 6 cells and the insulin secretion test using MIN 6 cells were basically carried out according to the literature (Ishihara et al., Diabethology, Vol. 36, pp. 113-114-145, 1993). The effect of the compound on insulin secretion activity in the presence of 14.5 mM glucose was determined by measuring the amount of insulin in the cell culture supernatant collected as follows. The MIN6 cells cultured in the 24-well plate were added to buffer A containing 2 mM glucose (119 mM sodium chloride, 4.74 mM calcium chloride, 2.54 mM calcium chloride, 1.1 9 mM magnesium sulfate, 1.19 mM lithium dihydrogen phosphate, 10 mM 2— [4- (2-hydroxyshethyl) 1-1—pirazinyl] ethanesulfonic acid, 0.1% After washing twice with 1 ml of bovine serum albumin pH 7.3), the mixture was incubated at 37 ° C. for 45 minutes in buffer A containing 1 ml of 2 mM glucose. After the incubation, the culture supernatant was replaced with a buffer A (0.9 ml) containing various concentrations of the test compound and 2 mM glucose, and further incubated at 37 ° C for 15 minutes. MIN6 cells were stimulated with glucose by adding buffer A (O.lml) containing 127 mM glucose (final glucose concentration: 14.5 mM). After stimulation, the cells were incubated at 37 ° C for 45 minutes, and the culture supernatant was collected.

On the other hand, the effect of the compounds on insulin secretion activity in the presence of 5 mM glucose was determined by measuring the amount of insulin in the cell supernatant collected as follows. Cultured on 24 plates MIN6 cells were washed twice with 1 ml of buffer A containing 5 mM glucose, and then replaced with buffer A (0.9 ml) containing various concentrations of the test compound and 5 mM glucose. Thereafter, the cells were incubated at 37 ° C for 45 minutes (final glucose concentration: 5 mM), and the culture supernatant was collected.

Antibody-reactive insulin secreted into the culture supernatant is a phosphate buffer containing 1% bovine serum albumin, 0.1% Tween 20, 0.12% EDTA'2Na, and 0.1% sodium azide. After dilution, quantification was performed by enzyme immunoassay or radioimmunoassay. The insulin secretion promoting activity of the test compound was calculated by the following formula. The results were shown as the average value (avg) of 3 to 4 cases. Insulin secretion promoting activity (ng / ml)-Insulin secretion in the presence of test compound-Insulin secretion in the absence of test compound Table 2

In the presence of 5mM glucose

 Compound No.Drug concentration Insulin secretion promoting activity

 (μΜ) (ng / ml)

 avg

 1 10 59

 2 10 54

 6 10 5

 14 10 -6

 27 10 30

 41 1 12

 48 10 11

 63 10 42

 64 10 33

 67 10 142

 77 10 86

 Gliben 0.1 317

Cramido Table 2 continued

 In the presence of 14.5 mM glucose

第 2表に示されるよう に、 本発明化合物は高濃度のグルコース下 でイ ンス リ ン分泌活性を有するこ とが示された。 また、 これら化合 物は低濃度のグルコース （5 mM ) 下では、 顕著'な分泌促進活性はな かった。 一方、 比較対照と して用いたグリベンクラ ミ ド （フ ァ一マ コセラビィ、 5巻、 43頁、 1985 年） は低濃度グルコース下でも顕著 な分泌促進活性を有した。

As shown in Table 2, the compound of the present invention was shown to have insulin secretion activity under high concentration of glucose. In addition, these compounds had no significant secretion promoting activity under low concentration of glucose (5 mM). On the other hand, glibenclamide (Pharma Coserabi, Vol. 5, p. 43, 1985), which was used as a control, had a remarkable secretion promoting activity even under low concentration of glucose.

 Further, it was confirmed that the compound of the present invention did not show an insulin secretion promoting effect even when orally administered to a fasted normal rat (SD male).

 The inhibitory effect of the compound of the present invention on the increase in blood glucose level is based on a report by Hillaire-Buys et al. (British Journal Journal of Pharmacy, Vol. 109, Vol. 1, pp. 183, 1993). The blood glucose levels before and after administration of the compound of the present invention and before and after the glucose load were tested.

 Test example (2): Inhibition test of blood sugar increase in glucose load in a diabetic model animal (hypoglycemic effect on blood glucose level after GK rat glucose load)

The test compound (10 mg / kg) was dissolved in dimethyl acetate After mixing with polyoxy-hardened ethylene castor oil, it was further mixed with physiological saline to obtain a drug solution. The mixing ratio of each solvent was such that dimethyl acetate: polyoxyhardened ethylen castor oil: physiological saline = 1: 2: 7. Glucose was dissolved in distilled water and adjusted to a concentration of 50% (W / V%).

 A 12-week-old male GK rat was used for the experiment. The animals were anesthetized by intraperitoneal injection of pentobarbi sodium at a dose of 5 Omg / kg body weight. After fixation in the dorsal position, an incision was made on the analogous part, and a force neura was inserted into the left carotid artery and the left jugular vein. The other end of the force neuron passed under the skin and was fixed outside the body from the back. The patient was fasted for 16 hours postoperatively, but had free access to water for the experiment.

 To prevent blood coagulation during blood collection, heparin was administered at a dose of 1000 U / kg body weight through an intravenous indwelling forcenula. The drug solution was administered via an intravenous force neuron, immediately followed by 0.3 ml of saline from the same force neuron. In addition, the solvent used for the drug solution was similarly administered to the control group. Two minutes after drug administration, the glucose solution is

Oral administration was performed at a dose of 4 ml / kg body weight. Blood was collected from the urea indwelling in the artery 4 minutes before glucose loading and at 15 330 · 60 · 120 · 180 minutes after sugar loading, and at 300 rpm at 4 ° C. The mixture was centrifuged for 15 minutes, and the concentration of glucose in the supernatant was measured by the glucose oxidase method (Clinini Chemistry, Vol. 6, p. 4666, 1960). The results were shown as the average value of glucose concentration and the standard dose of one case in four cases.

Table 3 Time after glucose loading (min) -4 15 30 60 120 180 vs. IB group glucose concentration 227.8 ± 68.17 478.3 ± 5.87 478.8 ± 22.57414.1 person 22.33 386.8 person 18.9 356.3 ± 22.29 o (mg / d 1 person SE )

Glucose concentration in the group treated with danigata〗 278.3 ± 25.74334.2 ± 19.53354,0 ± 11.70346.3 ± 13.53 384.1 ± 6.95 320.8 ± 86.85 (mg / d 1 SE)

Compound (I) and a pharmacologically acceptable salt thereof are useful for the treatment of diabetes because they exhibit an insulin secretion-promoting action in 5 cultured cells and a hypoglycemic action in rats.

 Compound (I) or a pharmacologically acceptable salt thereof may be a commonly used drug such as tablets, pills, capsules, powders, granules, syrups, injections, drops, suppositories, etc. It can be prepared in a form that can be administered orally or parenterally, such as by intramuscular injection, intravenous injection, infusion, or rectally via suppositories. For the preparation of dosage forms for oral or parenteral administration, generally known methods are applied, for example, various excipients, lubricants, binders, disintegrants, suspending agents, etc. It may contain a tonicity agent, an emulsifier and the like.

 Pharmaceutical carriers to be used include, for example, sucrose, gelatin, lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, methylcellulose, carboxymethylcellulose, alginic acid, talc and sodium citrate. Tritium, calcium carbonate, calcium hydrogen phosphate, starch, polyvinylpyrrolidone, magnesium aluminum silicate, magnesium stearate, cellulose calcium glycolate, urea, silicone resin, sorbitan Fatty acid esters, glyceric acid esters, distilled water for injection, physiological saline, propylene glycol, polyethylene glycol, oil oil, and ethanol.

In order to use the compound (I) and a pharmacologically acceptable salt thereof for the above purpose, it is usually administered systemically or locally in an oral or parenteral form. The dosage varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, and the like. Usually, in the range of 1 to 1, OOO mg / adult per adult, 1 time per person, or per adult, It is orally or parenterally administered once to several times a day in the range of 1 to 100 mg per dose, or is continuously administered intravenously for 1 to 24 hours a day. Of course, as described above, since the dose varies depending on various conditions, a dose smaller than the above dose may be sufficient, or administration outside the range may be necessary.

 Formulation examples are shown below.

Formulation Example 1: Tablet

 A tablet having the following composition was prepared by a conventional method.

 Formulation Compound 1 20 mg

 Lactose 143.4 mg

 Potato starch 30 mg

 Hydroxypropyl cell mouth 6 mg

 Magnesium stearate 0.6 mg

 (Total 200mg)

Formulation Example 2: Forcepsel

 A capsule having the following composition was prepared by a conventional method.

 Formulation Compound 1 20 mg

 Avicel 99.5 mg

 Magnesium stearate 0.5 mg

 (Total 120 mg)

Hereinafter, the present invention will be described in detail with reference to Examples and Reference Examples. BEST MODE FOR CARRYING OUT THE INVENTION

The proton nuclear magnetic resonance spectra (NMR) used in the examples and reference examples were measured at 270 MHz unless otherwise specified. Reference example 1a

 6, 7—Dimethoxy 2— (E) —Styrylquinazoline 1 (3H) 1one

 6,7-Dimethoxy-2-methylquinazoline-IV (3H) -one (5.00 g, 22.7 mmol), benzaldehyde (4.61 ml, 45.4 mmol) and ammonium acetate (7.00 g, 90.8 mmol) Heated in acetic acid (90ml) at 100 ° C for 10 hours. After allowing to cool to room temperature, water was added, and the deposited precipitate was collected by filtration. The obtained precipitate was washed with a small amount of ether and dried to obtain the title compound (7.68 g, quantitative).

'H-NMR (DMSO-d G) δ (ppm): 3.89 (s, 3H), 3.93 (s, 3H), 6.96 (d, J = 16.2Hz, 1H), 7.05 (s, 1H), 7.15- 7.46 (m, 3H), 7.46 (s, 1H), 7.61-7.64 (m, 2H), 7.90 (d, J = 16.2Hz, 1H), 12.2 (brs, 1H).

Reference example 1 b

 7 —Black mouth 2 — (E) —Styrylquinazoline-1 4 (3H) —On In the same manner as in Reference example 1a, 7—Black mouth—2—Methylquinazoline-1 4 (3H) From the -one (2.00 g, l (). 3 mmol) and benzaldehyde (2.10 ml, 20.6 mmol), the target and the chloride (2. lg, quantitative) were obtained.

-NMR (DMSO-d ₆ ) δ (ppm): 7.00 (d, J = 16.2Hz, 1H), 7.40- 7.51 (m, 4H), 7.65-7.67 (m, 2H), 7.70 (d, J = 2.0 Hz, 1H), 7.97 (d, J = 16.2Hz, 1H), 8.10 (d, J = 8.2Hz, 1H), 12.5 (brs, 1H).

Reference example 1 c

 6, 7 —Dimethoxy 1 2 — [2 — (E) 1 (4 — methoxyphenyl) vinyl] quinazoline 1 4 (3 H) — On

According to the same method as in Reference Example 1a, 6,7-dimethoxy-2-methylthioquinazoline-14 (3H) one (2.00 g, 9.08 mmol) and methoxybenzaldehyde (2.20 ml, 18.2 mmol) ) From the title compound (3.43 g, quantitative) was obtained.

¾-NMR (DMSO-d ₆ ) δ (ppm): 3.81 (s, 3H), 3.88 (s, 3H), 3.92 (s, 3H), 6.80 (d, J = 16.2Hz, 1H), 7.01 (d , J = 8.9Hz, 2H), 7.12 (s, 1H), 7.44 (s, 1H), 7.57 (d, J = 8.9Hz, 2H), 7.85 (d, J = 16.2Hz, 1H), 12.1 (brs , 1H).

Reference example 1 d

 2-[2-(E)-(4-chlorophenyl) vinyl]-6, 7-dimethoxyquinazolin-1 4 (3 H)-on

 In the same manner as in Reference Example 1a, ', 6,7-dimethoxy-2-methylquinazolin_4 (3H) -one (2.00g, 9.08mmol) and 4-cyclohexylbenzaldehyde (2.55g, 18.2g) mmol) from the title compound

 (3.02 g, 97%).

NMR-NMR (DMSO-d ₆ ) δ (ppm): 3.89 (s, 3H), 3.92 (s, 3H), 6.96 (d, J = 16.5Hz, 1H), 7.14 (s, 1H), 7.46 (s , 1H), 7.50 (d, J = 8.4Hz, 2H), 7.64 (d, J = 8.4Hz, 2H), 7.87 (d, J = 16.5Hz, 1H), 12.2 (brs, 1H).

Reference example 1 e

 6, 7-dimethoxy 2-[2-(E)-(4-methoxycarbonyldivinyl) vinyl] quinazoline-4 (3 H)-on

 According to the same method as in Reference Example 1a, 6,7-dimethoxy-2-methylthioquinazoline-14 (3H) -one (2.00 g, 9.08 mmol) and methyl 4-formylpentoxide (2.98 g, 18.2 g) mmol) from the title compound

(3.33 g, quantitative).

_{-NMR (DMSO-d 6) δ} (ppm): 3.88 (s, 3H), 3.89 (s, 3H), 3.93 (s, 3H), 7.09 (d, J = 16.2Hz, 1H), 7.16 (s, 1H), 7.46 (s, 1H), 7.76 (d, J = 8.3Hz, 2H), 7.94 (d, J = 16.2Hz, 1H), 8.02 (d, J = 8.3Hz, 2H), 12.3 (brs, 1H).

Reference example 1 f

 6, 7-Dimethoxy-1 2 — [2- (E) (4-Methylphenyl) vinyl] quinazoline-1 4 (3H) -On

 In the same manner as in Reference Example 1a, 6,6-dimethoxy-2- 2-methylquinazolin-IV (3H) -one (2.00g, 9.08mmol) and p-tolualdehyde (2.14ml, 18.2mmol) The title compound (3.30 g, quantitative) was obtained.

_{^ -NMR (DMSO-d 6)} δ (ppm): 2.34 (s, 3H), 3.88 (s, 3H), 3.92 (s, 3H), 6.90 (d, J = 16.2Hz, 1H), 7.13 (s , 1H), 7.27 (d, J = 8.1Hz, 2H), 7.44 (s, 1H), 7.52 (d, J = 8.1Hz, 2H), 7.85 (d, J = 16.2Hz, 1H), 12.2 (brs , 1H).

Reference example 1 g

 2-[2-(E)-(4-dimethylaminophenyl) vinyl]-6, 7-dimethoxyquinazoline _ 4 (3 H)-one

 According to the same method as in Reference Example 1a, 6,7-dimethoxy-2- 2-methylquinazoline-4 (3H) -one (2.00 g, 9.08 mmol) and 4-dimethylaminobenzaldehyde (2.71 g, 18.2 mmol) to give the title compound (2.44 g, 80%).

¾-NMR (DMSO-d ₆ ) δ (ppm): 3.02 (s, 6H), 3.90 (s, 3H), 3.94 (s, 3H), 6.69 (d, J = 16.0Hz, 1H), 6.78 (d , J = 8.7Hz, 2H), 7.12 (s, 1H), 7.45 (s, 1H), 7.48 (d, J = 8.7Hz, 2H), 7.82 (d, J = 16.0Hz, 1H), 12.0 (brs , 1H).

Reference example 1 h

6 —Black mouth 2 — [2- (E)-(4—Dimethylaminophenyl) vinyl] quinazoline 1 4 (3H) one In the same manner as in Reference Example la, 6-chloro-2—methylquinazolin-14 (3H) one (2.00 g, 10.3 mmol) and 4-dimethylaminobenzaldehyde (3.10 g, 20.6 mmol) From the title compound

 (3.18 g, 95%).

_{-NMR (DMSO-d 6) δ} (ppm): 3.00 (s, 6H), 6.70 (d, J = 16.2Hz, 1H), 6.75 (d, J = 8.6Hz, 2H), 7.48 (d, J = 8.6Hz, 2H), 7.62 (d, J = 8.6Hz, 1H), 7.75 (dd, J = 8.6, 2.3Hz, 1H), 7.87 (d, J = 16.2Hz, 1H), 8.00 (d, J = 2.3Hz, 1H), 12.3 (brs, 1H).

Reference example 1 i

 7—ethoxycarbonyl—2— (E) —styrylquinazoline-1 4 (3H) —one

 In the same manner as in Reference Example 1a, 7-ethoxycarbonyl-2-methylquinazoline-14 (3H) -one (3.04 g, 13.1 mmol) and benzaldehyde (2.70 ml, 26.2 mmol) were converted to the title compound (2.70 ml, 26.2 mmol). 2.09 g, 50%).

_{^ -NMR (DMSO-d 6)} <5 (ppm): 1.38 (t, J = 7.1Hz, 3H), 4.39 (q, J = 7.1Hz, 2H), 7.02 (d, J = 16.2Hz, 1H) , 7.43-7.50 (m, 3H), 7.66- 7.69 (m, 2H), 7.95 (dd, J = 8.3, 1.7 Hz, 1H), 8.01 (d, J = 16.2 Hz, 1H), 8.19-8.23 (m , 2H), 12.5 (brs, 1H).

Reference example 1 j

 2-[2-(E) 1-(3-dimethylaminophenyl) vinyl]-6, 7-dimethoxyquinazoline 1 4 (3 H)-one

In the same manner as in Reference Example 1a, 6,7-dimethoxy-12-methylquinazoline-14 (3H) -one (5.90 g, 26.8 mmol) and 3-dimethylaminobenzaldehyde (4.00 g, 53.6 mmol) to give the title compound (6.53 g, 69%). ¾-NMR (DMSO-d ₆ ) δ (ppm): 2.96 (s, 6H), 3.89 (s, 3H), 3.92 (s, 3H), 6.69 (d, J = 16.2Hz, 1H), 6.89-6.95 (m, 2H), 7.12 (s, 1H), 7.22-7.28 (m, 1H), 7.45 (s, 1H), 7.85 (d, J = 16.2 Hz, 1H), 8.29 (s, 1H), 12.1 ( brs, 1H).

Reference example 2a

 4—Black mouth 6, 7—Dimethoxy 2 — (E) —Styrylquinazoline

 6,7-Dimethoxy-l2- (E) -styryl quinazoline-l-4 (3H) -one (lO.Og, 32.4mmol) obtained in Reference Example 1a in oxylline chloride (50ml) And a few drops of N, N-dimethylformamide were added and heated at 100 ° C. for 4 hours. After the reaction mixture was concentrated under reduced pressure, the obtained residue was poured into a saturated aqueous sodium hydrogen carbonate solution, and the precipitated solid was collected by filtration. The obtained solid was dried to give the title compound (13.14 g) as a crude product.

 NMR-NMR (CDC13) (5 (ppm): 4.08 (s, 6H), 7.27-7.44 (m, 6H), 7.65-7.67 (m, 2H), 8.07 (d, J = 1.2H, 1H).

Reference example 2 b

 4, 7 —Dichloromono 2 — (E) Styrilquina V

 In the same manner as in Reference Example 2a, oxychlorine chloride (10 ml) and 7-chloro-2- (E) -styrylquinazoline-4 (3H) -one obtained in Reference Example 1b were obtained. (2.70 g, 9.62 mmol) to give the title compound (2.78 g) as a crude product.

^ -NMR (CDC13) δ (ppm): 7.31 (d, J = 15.8Hz, 1H), 7.37-7.46 (m, 3H), 7.58 (dd, J = 8.7, 2.0Hz, 1H), 7.66-7.70 ( m, 2H), 8.06 (d, J = 2.0Hz, 1H), 8.16 (d, J = 8.7Hz, 1H), 8.17 (d, J = 15.8Hz, 1H) .Reference example 2c 4 — Black mouth 6, 7 — Dimethoxy 1 2 — [2 — (E)-(4-methoxyphenyl) biel] quinazoline

 In the same manner as in Reference Example 2a, oxychlorine chloride (10 ml) was used to obtain the 6,7-dimethoxy-2— [2- (E) — (4) obtained in Reference Example 1c.

—Methoxy phenyl) vinyl] quinazoline 1 4 (3H) —on

 (3.00 g, 8.87 mmol) and N, diisopropyldiethylamine (2.3 ml, 13.3 mmol) to give the title compound (2.88 g) as a crude product.

¹ H-NMR (CDC13) δ (ppm): 3.86 (s, 3H), 4.08 (s, 3H), 4.11 (s, 3H), 6.95 (d, J = 8.6Hz, 2H), 7.31 (d, J = 15.8Hz, 1H), 7.39 (s, 1H), 7.59 (s, 1H), 7.65 (d, J = 8.6Hz, 2H), 8.14 (d, J = 15.8Hz, 1H).

Reference example 2 d

 4 —Cross mouth 2 — [2 — (E) — (4 Cross phenyl) vinyl] 1, 6, 7 —Dimethoxyquinazoline

 In the same manner as in Reference Example 2a, oxychlorine chloride (10 ml) was obtained in Reference Example 1d. 2 — [2— (E)-(4-chlorophenyl) vinyl) —6, 7 —Dimethoxyquinazolin-IV (3H) -one (2.63g, 7.67mmol) and N, N-diisopropylethylamine (2.0ml, 11.5mmol) to give the title compound (2.94g) crude I got it as a thing. ¾-NMR (CDC13) δ (ppm): 4.09 (s, 3H), 4.12 (s, 3H), 7.39 (d, J = 8.7Hz, 2H), 7.41 (d, J = 16.0Hz, 1H), 7.40 (s, 1H), 7.57 (s, 1H), 7.61 (d, J = 8.7Hz, 2H), 8.11 (d, J = 16.0Hz, 1H).

Reference example 2 e

 4 —Black mouth _ 6, 7 —Dimethoxy-1 2 — [2 — (E) — (4 —Methoxycarbonylphenyl) vinyl] quinazoline

In the same manner as in Reference Example 2a, oxychlorinated chloride (10 ml) Example 1 6,7-Dimethoxy-2— [2— (E) -1- (4-methoxycarbonylphenyl) vinyl] quinazoline-1 (3H) —one obtained in e (2.95 g, 8.05 mmol) ) And N, N-diisopropylethylamine (2.1 ml, 12.1 mmol) to give the title compound (3.29 g) as a crude product.

 ¾-NMR (CDC1a) δ (ppm): 3.94 (s, 3H), 4.09 (s, 3H), 4.10 (s, 3H), 7.38-7.43 (m, 3H), 7.70-7.73 (m, 2H) , 8.06-8.13 (m, 3H).

Reference example 2 f

 4 — Black mouth 6, 7 — Dimethoxy _ 2 _ [2 — (E)-(4-methylphenyl) vinyl] quinazoline

In the same manner as in Reference Example 2a, oxyl chloride (10 ml), 6,7-dimethoxy-2— [2— (E) 1- (4-methylphenyl) vinyl] obtained in Reference Example 1f were obtained. The title compound (3.50 _g ) was obtained as a crude product using quinazoline-14 (3H) one (3.00 g, 9.31 mmol) and N, N-diisopropylethylamine (2.4 ml, .Ommol). . iH-NMR (CDC13) δ (ppm): 2.42 (s, 3H), 4.01 (s, 3H), 4.10 (s, 3H), 7.26 (s, 1H), 7.27 (d, J = 8.1Hz, 2H) , 7.44 (s, 1H), 7.59 (d, J = 15.8Hz, 1H), 7.67 (d, J = 8.1Hz, 2H), 8.38 (d, J = 15.8Hz, 1H). Reference example 2 g

 4 — Black mouth 2 — [2 — (E) — (4 — dimethylaminophenyl) vinyl] — 6, 7 — dimethoxyquinazoline

In the same manner as in Reference Example 2a, oxychlorine chloride (70 ml), 2— [2- (E) — (4-dimethylaminophenyl) vinyl] obtained in 1 g of Reference Example 1, 6 and 7 —Dimethoxyquinazoline 1-4 (3H) —one (13.Og, 37.0 mmol) and N, Ν-diisopropylpyrethylamine (12.9 ml, 74.0 mmol) to give the title compound (14.5 g) as a crude product And as Obtained.

 ¾-NMR (CDC1a) δ (ppm): 3.02 (s, 6H), 4.06 (s, 6H), 6.73 (d, J = 8.9Hz, 2H), 7.07 (d, J = 15.8Hz, 1H), 7.28 (s, 1H), 7.35 (s, 1H), 7.55 (d, J = 8.9Hz, 2H), 8.00 (d, J = 15.8Hz, 1H).

Reference example 2 h

 4, 6-Dichloro-1- (2- (E)-(4-dimethylaminophenyl) vinyl] quinazoline

 In the same manner as in Reference Example 2a, oxychlorinated chloride (3 ml) and 6-chloro-2- [2- (E)-(4-dimethylaminophenyl) vinyl] quinazolyl obtained in Reference Example lh were obtained. 4 (3H) 1 ON

 (500 mg, 1.53 mmol) and N, N-diisoprovirethylamine (0.27 ml, 1.53 mraol) to give the title compound (202 mg) as a crude product.

 ^ -NMR (CDC13) δ (ppm): 3.04 (s, 6H), 6.72 (d, J = 8.9Hz, 2H), 7.08 (d, J = 15.8Hz, 1H), 7.57 (d, J = 8.9Hz, 2H), 7.80-7.86 (m, 1H), 8.08 (d, J = 15.8Hz, 1H), 8.13-8.16 (m, 1H), 8.16 (d, J = 2.3Hz, 1H ).

Reference example 2 i

 4 _ Chloro 7 — ethoxycarbonyl 2 — (E) — Styrylquinazoline

In the same manner as in Reference Example 2a, oxychlorine chloride (10 ml), 7-ethoxycarbonyl-2- (E) —styrylquinazoline 1-4 (3H) obtained in Reference Example 1i— The title compound (1.76 g) was obtained as a crude product using on (1.80 _g , 5.62 mmol) and N, diisopropyldiethylamine (0.98 ml, 5.62 mmol).

'H-NMR (CDC13) δ (ppm): 1.32 (t, J = 7.3Hz, 3H), 4.34 (q, J = 7.3Hz, 2H), 7.14 (d, J = 9.9Hz, 1H), 7.11-7.31 (m, 3H), 7.52-7.55 (m, 2H), 8.00-8.15 (m, 3H), 8.54 (s, 1H) ).

Reference example 2 j

 4—Black 2 — [2- (E) — (3—Dimethylaminophenyl) vinyl] — 6,7-Dimethoxyquinazoline

 In the same manner as in Reference Example 2a, oxychlorine (10 ml) was used to obtain 2_ [2- (E) -1- (3-dimethylaminophenyl) vinyl] obtained in Reference Example 1j. —Dimethoxyquinazoline _ 4 (3H) 1 year old (2.00 g, 5.69 mmol) and N, di-diisopropylpropylethylamine (1.98 ml, 11.4 mmol) were used to give the title compound (2.06 g) as a crude product. I got it.

 ^ -NMR (CDC13) δ (ppm): 3.02 (s, 6H), 4.07 (s, 6H), 6.86 (br, 1H), 7.09 (br, 2H), 7.25-7.31 (m, 2H), 7.32 ( s, 1H), 7.38 (s, 1H), 8.04 (d, J-16.2Hz, 1H).

Example 1

 6, 7-Dimethoxy-1 4-piperidino-1 2 — (E) -Styrylquinazolin (Compound 1)

 Reference Example 2 The 4_ macro mouth—6,7—dimethoxy-2— (E) —styrylquinazoline (500 mg, 1.53 mmol) obtained in a was dissolved in N, に -dimethylformamide (10 ml). Piperidine (0.6ml,

6.12 mmol) and heated at 80 ° C. for 6 hours. After allowing the reaction solution to cool, water was added, and the precipitated crystals were collected by filtration and dried. The obtained solid was purified by silica gel chromatography (chloroform / ethyl acetate = 10/1) to give the title compound (0.37 g, 64%).

¾-NMR (CDC1a) δ (ppm): 1.70-1.95 (m, 6H), 3.60-3.75 (m, 4H), 3.99 (s, 3H), 4.02 (s, 3H), 7.13 (s, 1H) , 7.23 (d, J = 15.8 Hz, 1H), 7.24 (s, 1H), 7.30-7.42 (m, 3H), 7.62-7.65 (m, 2H), 7.97 (d, J = 15.8Hz, 1H).

Example 2

 6,7-Dimethoxy-14-morpholino-2- (E) -Styrylquinazolin (Compound 2)

 Reference Example 2 The 4-morphone 6, 7-dimethoxy-12- (E) -styrylquinazoline (500 mg, 1.53 mmol) obtained in a was prepared from morpholin (0.67 ml, 7.65 mmol) to give the title compound (300 mg, 52%).

¹ H-NMR (CDC13) δ (ppm): 3.70-3.74 (m, 4H), 3.94-3.98 (m, 4H), 4.00 (s, 3H), 4.03 (s, 3H), 7.11 (s, 1) H), 7.24 (d, J = 16.2Hz, 1H), 7.26 (s, 1H), 7.32-7.43 (m, 3H), 7.63-7.66 (m, 2H), 7.97 (d, J = 16.2Hz, 1 H).

Example 3

 4—Benzylamino 6 and 7—Dimethoxy-1 2— (E) —Styrylquinazoline (Compound 3)

 Reference Example 2 4—Black mouth—6, 7—Dimethoxy—2—obtained in a

(E) -N, N-Diisopropylethylamine from styrylquinazoline (250 mg, 0.77 mmol) in the same manner as in Example 1.

 (0.13 ml, 0.77 mmol) and benzylamine (0.17 ml, 1.53 mmol) to give the title compound (102 mg, 40%).

¹ H-NMR (CDC1a) δ (ppm): 3.94 (s, 3H), 3.99 (s, 3H), 4.99 (d, J = 5.6Hz, 2H), 5.8 (br, 1H), 6.92 (s, 1H), 7.16-7.51 (m, 9H), 7.22 (s, 1H), 7.60-7.63 (m, 2H), 7.97 (d, J = 15.8Hz, 1H).

Example 4

6, 7 —Dimethoxy-1 4— (4-Methylbiperidino) 1 2— (E) —Styrylquinazoline (compound 4)

 Reference Example 2 4-Black mouth obtained in a, 6, 7-Dimethoxy 2-

(E) -N, N-Diisopropylethylamine was prepared from styrylquinazoline (250 mg, 0.77 mmol) in the same manner as in Example 1.

 (0.13ml, 0.77mmol) and 4-Methylbiperidine (0.18ml,

1.53 mmol) to give the title compound (140 mg, 47%).

1 H-NMR (CDC13) δ (ppm): 1.06 (d, J = 6.3Hz, 3H), 1.38-1.93 (m, 5H), 3.02-3.18 (m, 2H), 4.00 (s, 3H), 4.03 (s, 3H), 4.17-4.32 (m, 2H), 7.12 (s, 1H), 7.23 (d, J = 15.8Hz, 1H), 7.24 (s, 1H), 7.29-7.42 (m, 3H), 7.62-7.65 (m, 2H), 7.97 (d, J = 15.8Hz, 1H).

Example 5

 4 — (4-hydroxypiperidino) 1 6, 7 — dimethoxy 1 2 —

(E) Ostyrylquinazoline (Compound 5)

 Reference Example 2 4 Monochrome obtained in a _ 6,7 —Dimethoxy 2 —

(E) -N, N-diisopropylethylamine was prepared from styrylquinazoline (250 mg, 0.77 mmol) in the same manner as in Example 1.

 (0.13 ml, 0.77 mmol) and 4 -hydroxypiperidine (0.16 g, 1.53 mmol) to give the title compound (119 mg, 41%).

1 H-NMR (CDC1a) δ (ppm): 1.75-1.93 (m, 2H), 2.08-2.23 (m, 2H), 3.30-3.45 (m, 2H), 3.99 (s, 3H), 4.00-4.18 (m, 3H), 4.03 (s, 3H), 7.12 (s, 1H), 7.23 (d, J = 15.8Hz, 1H), 7.26 (s, 1H), 7.31-7.42 (m, 3H), 7.62- 7.65 (m, 2H), 7.97 (d, J = 15.8Hz, 1H).

Example 6

 6,7-dimethoxy-1-4-propylamino 2 _ (E) -styrylquinazoline (compound 6)

4—Chloro-6,7—dimethoxy—2—obtained in Reference Example 2a (E) -N, N-Diisopropylethylamine from styrylquinazoline (250 mg, 0.77 mmol) in the same manner as in Example 1.

 (0.13 ml, 0.77 mmol) and propylamine (0.13 ml, 1.53 mmol) to give the title compound (113 mg, 42%).

¹ H-NMR (CDC13) ^ (ppm): 1.08 (t, J = 7.4Hz, 3H), 1.75-1.88 (m, 2H), 3.70-3.75 (m, 2H), 3.97 (s, 3H), 3.99 (s, 3H), 5.56 (brs, IH), 6.91 (s, IH), 7.20 (d, J = 15.8 Hz, IH), 7.21 (s, IH), 7.29-7.41 (m, 3H), 7.62- 7.65 (m, 2H), 7.98 (d, J = 15.8Hz, IH).

Example 7

 4 _ (4 -ethoxycarbonylbiperidino) 1, 6, 7-dimethoxy 1 2-(E)-styrylquinazoline (compound 7)

 Reference Example 2 4—Cross mouth 6 and 7—Dimethoxy 2—obtained in a

(E) -N, N-diisopropylethylamine from styrylquinazoline (250 mg, 0.77 mmol) in the same manner as in Example 1.

 (0.13ml, 0.77mmol) and ethyl isodipecotate (0.24ml,

1.53 mmol) to give the title compound (189 mg, 55%).

 1 H-NMR (CDC13) δ (ppm): 1.31 (t, J = 7.1Hz, 3H), 1.5-1.8 (br, 2H), 1.95-2.25 (m, 4H), 2.60-2.75 (m, IH) , 3.15 (brt, 2H), 4.00 (s, 3H), 4.03 (s, 3H), 4.21 (q, J = 7.1Hz, 2H), 7.11 (s, IH), 7.24 (d, J = 15.8Hz, IH), 7.27-7.42 (m, 4H), 7.63-7.66 (m, 2H), 7.97 (d, J = 15.8 Hz, IH).

Example 8

 6, 7 —Dimethoxy-1 4 — (2 —morpholinoethylamino) — 2 — (E) —Styrylquinazoline (Compound 8)

Reference Example 2 Example 4 was obtained from 4-black mouth _ 6, 7-dimethoxy 2-(E)-styrylquinazoline (250 mg, 0.77 mmol) obtained in a. In a similar manner, N, N-diisopropylethylamine

 (0.13 ml, 0.77 mmol) and N- (2-aminoethyl) morpholine (0.20 ml, 1.53 mmol) gave the title compound (154 mg, 48%).

1 H-NMR (CDC1a) δ (ppm): 2.59-2.63 (m, 4H), 2.79 (t, J = 6.0Hz, 2H), 3.76-3.80 (m, 4H), 3.82-3.88 (m, 2H ), 4.02 (s, 6H), 6.95 (brs, 1H), 6.95 (s, 1H), 7.20 (d, J = 15.7Hz, 1H), 7.23 (s, 1H), 7.31-7.42 (m, 3H) , 7.62-7.65 (m, 2H), 7.97 (d, J = 15.7Hz, 1H).

 4- (2-Dimethylaminoethylamino) -1,6,7-dimethoxy-1-2- (E) -styrylquinazoline (Compound 9)

 Reference Example 2 From the 4-chloro-6,7-dimethoxy-1 2 _ (E) -styrylquinazoline (250 mg, 0.77 mmol) obtained in a by the same method as in Example 1, N, N-diisopropyrethylamim was prepared. N

(0.13 ml, 0.77 mmol) and N, N-dimethylethylenediamine (0.15 ml, 1.53 mmol) to give the title compound (94 _mg , 33%).

1 H-NMR (CDC13) δ (ppm): 2.39 (s, 6H), 2.74 (t, J = 5.6Hz, 2H), 3.85 (dt, J = 5.3, 5.6Hz, 2H), 4.02 (s, 3H) ), 4.03 (s, 3H), 6.3 (brt, 1H), 7.02 (s, 1H), 7.20 (d, J = 15.8Hz, 1H), 7.22 (s, 1H), 7.30-7.41 (m, 3H) , 7.62-7.64 (m, 2H), 7.97 (d, J = 15.8 Hz, 1H).

Example 10

 6, 7 —Dimethoxy-1 4— (4-Pyridylmethylamino) 1 2—

(E) Ostyrylquinazoline (Compound 10)

 4—Cross mouth _ 6,7 obtained in Reference Example 2a—Dimethoxy 2—

(E) -N, N-diisopropylethylamine was prepared from styrylquinazoline (250 mg, 0.77 mmol) in the same manner as in Example 1.

(0.13 ml, 0.77 mmol) and 4—aminomethylviridine (0.16 ml, 1.53 mmol) to give the title compound (133 mg, 44%).

¹ H-NMR (CDC13) δ (ppm): 4.01 (s, 3H), 4.02 (s, 3H), 5.00 (d,

J = 5.6Hz, 2H), 6.1 (brs, 1H), 7.02 (s, 1H), 7.19 (d, J = 15.8Hz,

1H), 7.24-7.40 (m, 6H), 7.81-7.86 (m, 2H), 7.83 (d, J = 15.8 Hz,

1H), 8.59 (d, J = 5.9Hz, 2H).

Example 1 1

 4- (3,4—Dimethoxybenzylamino) 1-6,7—Dimethoxy—2— (E) —Styrylquinazoline (Compound 11)

 Reference Example 2 4-chloro-6,7-dimethoxy-1 2 — obtained in a

(E) N, N-Diisopropylethylamine was prepared from styrylquinazoline (250 mg, 0.77 mmol) in the same manner as in Example 1.

 (0.13 ml, 0.77 mmol) and veratrilulamin (0.35 ml, 1.91 mmol) to give the title compound (196 mg, 56%).

¹ H-NMR (CDC13) δ (ppm): 3.86 (s, 3H), 3.89 (s, 3H), 3.96 (s, 3H), 4.01 (s, 3H), 4.92 (d, J = 5.3Hz, 2H ), 5.6 (brs, 1H), 6.86 (s, 1H), 6.88 (d, J = 8.4Hz, 1H), 7.04 (d, J = 8.4Hz, 1H), 7.09 (s, 1H), 7.21-7.41 (m, 5H), 7.62-7.65 (m, 2H), 8.03 (d, J-15.8Hz, 1H)

 6,7-Dimethoxy-1 2-(E) -Styryl-1 4-(3 -Thiazolidinyl) quinazoline (Compound 12)

 Reference Example 2 4 4 1-, 6-, 7-Dimethoxy-1 2 —

(E) -Styrylquinazoline (250 mg, 0.77 mmol) was prepared in the same manner as in Example 1 by N, N-diisopropylethylamine.

 (0.13 ml, 0.77 mmol) and thiazolidin (0.18 ml, 1.91 mmol) to give the title compound (133 mg, 46%).

¹ H-NMR (CDC13) <5 (ppm): 3.21 (t, J = 6.1Hz, 2H), 4.01 (s, 3H), 4.03 (s, 3H), 4.24 (t, J = 6.1Hz, 2H), 5.01 (s, 2H), 7.19-7.42 (m, 6H), 7.62-7.64 (m, 2H), 7.94 (d , J = 15.8Hz, 1H).

Example 13

 6, 7 —Dimethoxy-1 4 —Phenethylamino 2 — (E) —Styric ruquinazoline (Compound 13)

 Reference Example 2 4-—Mouth—6,7—Dimethoxy-1—

(E) -Styrylquinazoline (250 mg, 0.77 mmol) was prepared in the same manner as in Example 1 by N, N-diisopropylethylamine.

 (0.13 ml, 0.77 mmol) and phenethylamine (0.19 ml, 1.91 mmol) to give the title compound (61 mg, 20%).

¹ H-NMR (CDC13) δ (ppm): 3.11 (t, J = 6.9Hz, 2H), 3.94 (s, 3H), 4.00 (s, 3H), 4.02 (m, 2H), 5.5 (brs, 1H) ), 6.74 (s, 1H), 7.23 (d, J = 15.8Hz, 1H), 7.23 (s, 1H), 7.27-7.42 (m, 8H), 7.64-7.66 (m, 2H), 8.02 (d, J = 15.8Hz, 1H).

Example 14

 4-dimethylamino-6,7-dimethoxy-12- (E) styrylquinazoline (compound 14)

 Reference Example 2 From the 4,6-dimethoxy-2— (E) -styrylquinazoline (1.50 g, 4.59 mmol) obtained in Reference Example 2a, N, N— The title compound (971 mg, 56%) was obtained using diisopropylethylamine (1.41 ml, 4.59 mmol) and a 50% aqueous dimethylamine solution (3.0 ml, 33.3 mmol).

^{1 H-NMR (CDC1 a)} 6 (ppm): 3.37 (s, 6H), 3.99 (s, 3H), 4.03 (s, 3H), 7.24-7.41 (m, 6H), 7.63-7.66 (m, 2H ), 7.99 (d, J = 15.8 Hz, 1H).

Example 15 4— [2— (2-Fluorophenyl) ethylamino] 1-6,7-dimethoxy—2— (E) —styrylquinazoline (Compound 15)

 4_Chloro-6,7-dimethoxy-2- obtained from Reference Example 2a

(E) -Styrylquinazoline (330 mg, lmmol) was prepared from N, N-diisopropylethylamine (0.17 ml, lmmol) and 2- (2-fluorophenyl) ethylamine in the same manner as in Example 1. N

 (0.52 ml, 4.0 mmol) to give the title compound (240 mg, 55%).

1 H-NMR (CDC1a) δ (ppm): 3.17 (t, J = 6.9Hz, 2H), 3.97 (s, 3H), 4.00 (s, 3H), 4.03 (m, 2H), 5.61 (br, 1H), 6.82 (s, 1H), 7.05-7.43 (ra, 9H), 7.64-7.67 (m, 2H), 8.04 (d, J = 16.2Hz, 1H).

Example 16

 7—Black 4— [2— (4-Pyridyl) ethylamino] —2— (E) —Styrylquinazoline (Compound 16)

 The N, N-diisopropylethylethyla was prepared from the 4,7-dichroic mouth-2- (E) -styrylquinazoline (0.24 g, 0.80 mmol) obtained in Reference Example 2b in the same manner as in Example 1. The title compound (77 mg, 25%) was obtained using min (0.14 ml, 0.80 mmol) and 4- (2-aminoethyl) pyridine (0.18 ml, 1.60 mmol).

¹ H-NMR (CDC13) δ (ppm): 3.14 (t, J = 6.9Hz, 2H), 4.03-4.10 (m, 2H), 6.25 (brs, 1H), 7.23-7.45 (m, 7H), 7.58 -7.67 (m, 3H), 7.84 (d, J = 1.7Hz, 1H), 8.07 (d, J = 15.8Hz, 1H), 8.56 (d, J = 4.6Hz, 2H).

Example 17

 6, 7-Dimethoxy 2 — [2- (E)-(4-Methoxyphenyl) vinyl] — 4-Pyridinoquinazoline (Compound 17)

4-Mouth—6,7—Dimethoxy—2—obtained in Reference Example 2c [2- (E)-(4-Methoxyphenyl) vinyl] quinazoline

 (0.36 g, l.OOmmol) and N, N-diisopropylethylamine (0.17 ml, l.OOmmol) and piperidine (0.20 ml, 2.OOmmol) in the same manner as in Example 1. ) Was used to obtain the title 3d conjugate (285 mg, 70%).

1 H-NMR (CDC13) δ (ppm): 1.85-2.05 (br, 6H), 3.75-3.85 (br, 4H), 3.99 (s, 3H), 4.14 (s, 3H), 4.17 (s, 3H) , 7.07 (d, J = 8.6Hz, 2H), 7.25 (d, J = 15.8Hz, 1H), 7.39 (s, 1H), 7.42 (s, 1H), 7.73 (d, J = 8.6Hz, 2H) , 8.08 (d, J = 15.8 Hz, 1H).

Example 18

 2 — [2 — (E)-(4-chlorophenyl) vinyl] 1, 6,7-dimethoxy-1 4-piperidinoquinazoline (compound 18)

 Same as Example 1 from 4_chloro-2— [2- (E)-(4-chlorophenyl) vinyl] —6,7-dimethoxyquinazoline (0.36 g, l.OOmmol) obtained in Reference Example 2d The title compound (336 mg, 82%) was obtained using N, N-diisop-piruethylamine (0.17 ml, l.OOmmol) and piperidine (0.20 ml, 2.OOmmol) by the Noi method.

1 H-NMR (CDC1a) δ (ppm): 1.75-1.90 (br, 6H), 3.60-3.70 (br, 4H), 3.99 (s, 3H), 4.02 (s, 3H), 7.13 (s, 1H ), 7.19 (d, J = 15.8Hz, 1H), 7.23 (s, 1H), 7.35 (d, J = 8.3Hz, 2H), 7.55 (d, J = 8.3Hz, 2H), 7.90 (d, J = 15.8Hz, 1H).

Example 19

 6,7-Dimethoxy-1 2 — [2- (E) -1- (4-Methoxycarbonylphenyl) vinyl] —4-piperidinoquinazoline (Compound 19) Reference 4 2 1 6, 7 —Dimethoxy 2 —

[2- (E) - (4- main Tokishikarubo two Rufuweniru) vinyl] quinazolinylmethoxy emissions (0. ³ 8g, l.OOmmol) in the same manner as in Example 1 from, N N-Diisopropylethylamine (0.17 ml, l.OO mmol) and pyridine (0.20 ml, 2.00 mmol) were used to obtain the title compound (246 mg, 57%). ¹ H-NMR (CDC13) δ (ppm): 1.90-2.05 (br, 6H), 3.75-3.90 (br, 4H), 3.93 (s, 3H), 4.00 (s, 3H), 4.03 (s, 3H) ), 7.13 (s, 1H), 7.26 (s, 1H), 7.47 (d, J = 15.8Hz, 1H), 7.68 (d, J = 8.4Hz, 2H), 7.97 (d, J = 15.8Hz, 1H) ), 8.05 (d, J = 8.1 Hz, 2H).

Example 20

 2-[2-(E) 1-(4-hydroxymethylphenyl) vinyl] 1, 6, 7-dimethoxy-14-piperidinoquinazoline (compound 20) 6, 7 obtained in Example 19 —Dimethoxy— 2— [2- (E) — (4—Methoxycarbonylphenyl) vinyl] —4—Piperidinoquinazoline (4.00 g, 10.2 mmol) was dissolved in tetrahydrofuran (40 ml). After cooling the reactor with ice, lithium aluminum hydride (360mg,

10.2 mmol) was added. After removing the ice bath and stirring at room temperature for 1 hour, sodium sulfate decahydrate was added and the mixture was stirred. After filtration through celite and concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform / methanol = 97/3) to give the title compound (1.54 g, 40% ).

¹ H-NMR (CDC13) δ (ppm): 1.72- 1.93 (br, 6H), 3.60-3.78 (br, 4H), 3.99 (s, 3H), 4.02 (s, 3H), 4.72 (s, 2H) ), 7.13 (s, 1H), 7.21 (d, J = 15.9Hz, 1H), 7.25 (s, 1H), 7.38 (d, J = 8.3Hz, 2H), 7.61 (d, J = 8.3Hz) , 2H), 7.95 (d, J = 15.9Hz, 1H).

Example 2 1

 2 — [2 — (E) ― (4-Chloromethylphenyl) vinyl] — 6, 7 — Dimethoxy 4 — Biperidinoquinazoline (Compound 21)

2— [2- (E)-(4—hydroxymethy) obtained in Example 20 Ruphenyl) vinyl] — 6,7-Dimethoxy-4-piperidinoquinazolin (1.40 g, 3.45 mmol), s —collidine (0.55 ml, 4.14 mmol) and lithium chloride (146 mg, 3.45 mmol) in N, N — The suspension was suspended in dimethylformamide (10 ml), and methanesulfonyl chloride (0.32 ml, 4.14 mmol) was added under ice cooling. The ice bath was removed and the mixture was stirred at room temperature for 12 hours. Water and ethyl acetate were added to the reaction mixture, liquids were separated, and the obtained organic layer was washed with brine. The obtained organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (1.49 g, quantitative).

1 H-NMR (CDC1a) δ (ppm): 1.72-2.00 (br, 6H), 3.60-3.80 (br, 4H), 3.99 (s, 3H), 4.02 (s, 3H), 4.61 (s, 2H) ), 7.12 (s, 1H), 7.23 (d, J = 15.8Hz, 1H), 7.25 (s, 1H), 7.40 (d, J = 7.3Hz, 2H), 7.62 (d, J = 7.3) Hz, 2H), 7.95 (d, J = 15.8 Hz, 1H).

Example 22

 2- {2- (E)-[4- (dimethylaminomethyl) phenyl: vinyl]} — 6,7-dimethoxy-14-piperidinoquinazoline (compound 22)

Example 21 2— [2— (Ε)-(4—chloromethylphenyl) vinyl] _6,7—dimethoxy-1-4-piperidinoquinazoline (200 mg, 0.47 mmol) obtained in 1 was converted to N, N—dimethylform The solution was dissolved in amide (5 ml), potassium carbonate (0.32 g, 2.35 mmol) and a 50% aqueous dimethylamine solution (0.06 ml, 1.42 mmol) were added, and the mixture was stirred at room temperature for 7 hours. The solvent was distilled off from the reaction mixture under reduced pressure, and the obtained residue was extracted with chloroform and water. The obtained organic layer was washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform / methanol = 100/1 to 100/3) to give the title compound (160 mg, 49%). ¹ H-NMR (CDC1a) 6 (ppm): 1.75-1.90 (br, 6H), 2.29 (s, 6H), 3.48 (s, 2H), 3.65-3.70 (br, 4H), 3.99 (s, 3H ), 4.02 (s, 3H), 7.13 (s, 1H), 7.22 (d, J = 15.8Hz, 1H), 7.24 (s, 1H), 7.34 (d, J = 8.0Hz, 2H), 7.60 (d , J = 8.0Hz, 2H), 7.96 (d, J = 15.8Hz, 1H).

Example 23

 6, 7-Dimethoxy-1 2 — [2 — (E)-(4-methylphenyl) vinyl] — 4-biperidinoquinazoline (Compound 23)

 Reference Example 2 4-chloro-6,7-dimethoxy-1 2 obtained from f

 [2— (E)-(4-methylphenyl) vinyl] quinazoline (0.34 g, l.OOmmol) in the same manner as in Example 1 by N, N-diisop-piruethylamine (0.17 ml, l.OOmmol) And piperidine (0.20 ml, 2.00 mmol) to give the title compound (135 mg, 35%).

1 H-NMR (CDC13) δ (ppm): 1.70-1.90 (br, 6H), 2.37 (s, 3H), 3.60-3.70 (br, 4H), 3.98 (s, 3H), 4.02 (s, 3H) , 7.11 (s, 1H), 7.17 (s, 1H), 7.19 (d, J = 8.1Hz, 2H), 7.25 (d, J = 15.8Hz, 1H), 7.53 (d, J = 8.1Hz, 2H) , 7.94 (d, J = 15.8 Hz, 1H).

Example 2 4

 2-[2 — (E) — (4 — dimethylaminophenyl) vinyl] — 6, 7 — dimethoxy 4 — piperidinoquinazoline (compound 24)

 Reference Example 2 — 4-Mouth— 2 — [2— (E)-(4—Dimethylaminophenyl) vinyl] obtained in 2 g—6,7—Dimethoxyquinazoline

(l.OOg, 2.99 mmol) and N, N-diisoprovirethylamine (0.52 ml, 2.99 mmol) and piperidine in the same manner as in Example 1.

(1.20 ml, 12.0 mmol) target words himself I匕合product with (830mg, 66%) was obtained _{0 1 H-NMR (CDC1 a} ) δ (ppm): 1.72-1.90 (br, 6H), 3.01 ( s, 6H), 3.60-3.70 (br, 4H), 3.98 (s, 3H), 4.02 (s, 3H), 6.72 (d, J = 8.9Hz, 2H), 7.05 (d, J = 15.8Hz, 1H), 7.11 (s, 1H), 7.24 (s, 1H), 7.54 (d, J = 8.9Hz, 2H), 7.92 (d, J = 15.8Hz, 1H).

Example 2 5

 6—Chloro-4-dimethylamino-1— [2- (E) — (4—dimethylaminophenyl) vinyl] quinazoline (Compound 25)

 Reference example 4, 6—Dichrolic mouth—2— [2-(E) one obtained in 2 h

 (4—Dimethylaminophenyl) vinyl] quinazoline (200 mg, 0.58 mmol) was prepared in the same manner as in Example 1 by N, N-diisop-piruethylamine (0.10 ml, 0.58 mmol) and a 50% aqueous dimethylamine solution ( The title compound (169 mg, 83%) was obtained using 0.25 ml, 2.70 mmol).

¹ H-NMR (CDC13) δ (ppm): 3.02 (s, 6H), 3.40 (s, 6H), 6.72 (d, J = 8.7Hz, 2H), 7.03 (d, J = 15.8Hz, 1H), 7.54 (d, J = 8.7Hz, 2H), 7.60-7.61 (m, 1H), 7.76-7.80 (m, 1H), 7.96-7.99 (m, 1H), 7.96 (d, J = 15.8Hz, 1H)

Example 26

 7 _Ethoxycarbonyl-14-piperidino-2- (E) -styrylquinazoline (Compound 26)

 Reference Example 2 The N, N-diisomethane was obtained from the 4-monocloth-7-ethoxycarbonyl-2- (E) -styrylquinazoline (500 mg, 1.48 mmol) obtained in i by the same method as in Example 1. Propylethylamine

 (0.26 ml, 1.48 mmol) and piperidine (0.59 ml, 5.92 mmol) to give the title compound (553 mg, 96%).

¹ H-NMR (CDC13) 6 (ppm): 1.44 (t, J = 7.1Hz, 3H), 1.75-1.90 (br, 6H), 3.70-3.85 (br, 4H), 4.44 (q, J = 7.1Hz) , 2H), 7.23-7.43 (m, 4H), 7.65 (d, J = 6.6Hz, 2H), 7.89 (d, J = 8.6Hz, 1H), 7.96-7.99 (m, 1H), 8.02 (d, J = 16.2Hz, 1H), 8.56 (s, 1H).

Example 2 7

 4 — dimethylamino 2 — [2 — (E) 1-(3-dimethylaminophenyl) vinyl] — 6,7-dimethoxyquinazoline (compound 27) 4 — chloro-2 obtained in Reference Example 2j — [2- (E)-(3-Dimethylaminophenyl) vinyl] — 6,7-Dimethoxyquinazoline (200mg, 0.60mmol) by the same method as in Example 1 to give N, N-diisopropyl Ethylamine (() .10 ml, 0.60 mmol) and 50% aqueous solution of dimethylamine (0.10 ml, l.lOmmol) were purified to give the title compound (90 mg, 23%).

¹ H-NMR (CDC13) <5 (ppm): 3.00 (s, 6H), 3.36 (s, 6H), 3.99 (s, 3H), 4.03 (s, 3H), 6.71-6.73 (m, 1H), 7.00-7.03 (m, 1H), 7.03 (s, 1H), 7.19-7.29 (m, 3H), 7.26 (s, 1H), 7.96 (d, J = 15.8Hz, 1H).

Example 2 8

 6, 7-dimethoxy-1 2-[2-(E) 1-(4-morpholinomethylphenyl) vinyl]-4-piperidininoquinazoline (compound 28) 2-[2-obtained in Example 21. (E)-(4-Chloromethylphenyl) vinyl] —6,7-Dimethoxy-14-piperidinoquinazoline (200 mg, 0.47 mmol) was prepared in the same manner as in Example 22 using morpholin (0.08 ml, 0.94 mmol) to give the title compound (149 mg, 67%).

¹ H-NMR (CDC13) δ (ppm): 1.70-1.90 (br, 6H), 2.40-2.50 (br, 4H), 3.51 (s, 2H), 3.60-3.68 (br, 4H), 3.68-3.80 ( br, 4H), 3.99 (s, 3H), 4.03 (s, 3H), 7.13 (s, 1H), 7.16 (d, J = 15.8Hz, 1H), 7.25 (s, 1H), 7.34 (d, J = 8.1Hz, 2H), 7.59 (d, J = 8.1Hz, 2H), 7.96 (d, J = 15.8Hz, 1H). Example 2 9

 4-dimethylamino-6,7-dimethoxy-2- (2- (E)-(4-piperidinophenyl) vinyl] quinazoline (compound 29)

 Reference Example 1a and then 4-chloro-6,7- obtained by the same method as Reference Example 2a from 6,7-dimethoxy-12-methylquinazolin-14 (3H) -one and 4-piperidino dibenzaldehyde. Dimethoxy—2— [2- (E) — (4-piperidinophenyl) vinyl] quinazoline (20 mg, 0.05 mmol) was prepared in the same manner as in Example 1 by N, N-diisopropylethyla. The title compound (9 mg, 43%) was obtained using min (0.01 ml, 0.05 mmol) and a 50% aqueous dimethylamine solution (0.10 ml, 110 mmol).

¹ H-NMR (CDC1a) δ (ppm): 1.50-1.80 (br, 6H), 3.23-3.27 (br, 4H), 3.34 (s, 6H), 3.98 (s, 3H), 4.02 (s, 3H) ), 6.91 (d, J = 8.9Hz, 2H), 7.07 (d, J = 15.8Hz, 1H), 7.25 (s, 1H), 7.28 (s, 1H), 7.53 (d, J = 8.9Hz, 2H) ), 7.92 (d, J = 15.8 Hz, 1H).

Example 30

 2- [2- (E)-(4_ethoxycarbonylmethoxyphenyl) vinyl] — 6,7-Dimethoxy-1-4-piperidinoquinazoline (Compound 30)

Reference Example 1a and then 4-chloro-chloro obtained by the same method as Reference Example 2a from 6,7-dimethoxy-1-2-methylquinazolin-14 (3H) -one and 4-ethoxycarbonylmethoxybenzaldehyde 2 From [2— (E)-(4-ethoxycarbonylmethoxyphenyl) vinyl] —6,7—dimethoxyquinazoline (500 mg, 1.20 mmol), N, N— Diisopropylethylamine (0.20 ml, 1.20 mmol) and piperidine (0.47 ml, 4.80 mmol) This gave the title compound (525 mg, 92%).

¹ H-NMR (CDC13) δ (ppm): 1.31 (t, J = 7.3Hz, 3H), 1.60-1.95 (br, 6H), 3.60-3.75 (br, 4H), 3.99 (s, 3H), 4.02 (s, 3H), 4.29 (q, J = 7.3Hz, 2H), 4.62 (s, 2H), 6.92 (d, J = 8.7Hz, 2H), 7.12 (d, J = 15.7Hz, 1H) , 7.12 (s, 1H), 7.24 (s, 1H), 7.58 (d, J = 8.7Hz, 2H), 7.92 (d, J = 15.7Hz, 1H).

Example 3 1

 2-{2- (E)-[4- (2-Hydroxyethoxy) phenyl] vinyl} — 6,7-Dimethoxy-1 4 —piperidinoquinazoline (Compound 31)

 The 2— [2- (E)-(4—ethoxycarbonylmethoxyphenyl) vinyl] —6,7—dimethoxy-14-piperidinoquinazoline (328 mg, 0.69 mmol) obtained in Example 30 was converted to te. After dissolving in trahydrofuran (4 ml) and cooling the reactor with ice, lithium aluminum hydride (30 mg, 0.69 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Add sodium sulfate decahydrate, stir, filter with celite, concentrate under reduced pressure, and concentrate the resulting residue on silica gel column chromatography.

(Form: methanol / methanol = 100/0 to 100/3) to give the title compound (267 mg, 89%).

¹ H-NMR (CDC1a) δ (ppm): 1.70-1.90 (br, 6H), 3.62-3.75 (br, 4H), 3.99 (s, 3H), 4.03 (s, 3H), 3.96-4.10 (m , 2H), 4.13 (t, J = 4.5Hz, 2H), 6.94 (d, J = 8.9Hz, 2H), 7.12 (s, 1H), 7.13 (d, J = 15.7Hz, 1H), 7.26 ( s, 1H), 7.58 (d, J = 8.9Hz, 2H), 7.93 (d, J = 15.7Hz, 1H).

Example 3 2

7 —Carboxy 4 —Piperidino 1 2— (E) —Styrylquinazoli (Compound 32)

 Example 26 7-Ethoxycarbonyl-4- (piperidino-2- (E))-styrylquinazoline (200 mg, 0.52 mmol) obtained in 6 was obtained by adding 10 ml of tetrahydrofuran and 5 ml of tetrahydrofuran. The mixture was dissolved in a mixed solvent, 1N aqueous sodium hydroxide solution (3 ml) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction solution was washed with ether and separated, the obtained aqueous layer was adjusted to pH 3 with 1N hydrochloric acid. The precipitated crystals were collected by filtration and dried to give the title compound (143 mg, 77%).

-NMR (DMSO-d ₆ ) δ (ppm): 1.70-1.90 (br, 6H), 3.70-3.85 (br, 4H), 7.21 (d, J = 15.8Hz, 1H), 7.35-7.45 ( m, 3H), 7.72 (d, J = 7.3Hz, 2H), 7.94-7.95 (m, 2H), 7.94 (d, J = 15.8Hz, 1H), 8.26 (s, 1H).

Example 3 3

 6—Acetyl-4—Piperidino-1 2— (E) Styrylquinazoline (Compound 33)

6-phenyl-4- 4-piperidino-2- (E) -styryleki obtained by the same method as in Example 1 or according to the method described in German Patent No. 2,135,172. Nazolin (361 mg, 0.82 mmol) is dissolved in N, N-dimethylformamide (5 ml), and triptyl (1-ethoxyvinyl) tin (0.55 ml, 1.64 mmol) and dichlorobistriphenylphosphine are dissolved. Innoradium (58 mg, 0.08 mmol) was added and heated at 100 ° C for 4 hours. After allowing the reaction solution to cool, 5% hydrochloric acid (8 ml) was added, and the mixture was stirred at room temperature. After neutralizing with a saturated aqueous sodium hydrogen carbonate solution and extracting with ethyl acetate, the obtained organic layer is washed by stirring with a 10% aqueous ammonium fluoride solution, and the precipitated solid is removed by filtration. Was separated. The obtained organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate). = 4/1) to give the title compound (l ⁹³ _mg , ⁶ %).

¾-NMR (CDC13) δ (ppm): 1.75-1.95 (br, 6H), 2.69 (s, 3H), 3.80-3.95 (br, 4H), 7.26 (d, J = 15.8Hz, 1H), 7.34- 7.43 (m, 3H), 7.64-7.67 (m, 2H), 7.89 (m, 1H), 8.06 (d, J = 15.8Hz, 1H), 8.22 (dd, J = 8.9, 2.0Hz, 1H), 8.52 (d, J = 2.0Hz, 1H).

Example 3 4

 4-(4-Benzylpiperidino)-1, 6, 7-dimethoxy-1-

 (E) Styrylquinazoline (compound 34)

 Reference Example 2 4—black mouth—6, 7—dimethoxy-1 2—obtained in a

(E) -Styrylquinazoline (250 mg, () .77 mmol) was prepared in the same manner as in Example 1 by N, N-diisopropylpyrethylamine.

 (0.13 ml, 0.77 mmol) and 4 monobenzylpiperidine (0.27 ml,

1.3 mmol) to give the title compound (177 mg, 50%).

_{1 H- NMR (CDC1 3) δ} (ppm): 1.52-1.89 (m, 5H), 2.67 (d, J = 6.6Hz, 2H), 3.02-3.11 (m, 2H), 3.99 (s, 3H), 4.02 (s, 3H), 4.22- 4.27 (m, 2H), 7.10 (s, 1H), 7.20-7.41 (m, 10H), 7.63 (d, J = 7.3 Hz, 2H), 7.96 (d, J = 15.8Hz, 1H).

Example 3 5

 4— [41- (2-hydroxyhydricyl) piperazine-1 1-yl] —6,7—dimethoxy—2— (E) —styrylquinazoline (compound 35) Reference example 2 4 —Cross mouth— 6,7—Dimethoxy-1- (E) styrylquinazoline (250 mg, 0.77 mmol) by the same method as in Example 1 to give N, N-diisopropylpyrethylamine (0.13 ml, The title compound (184 mg, 57%) was obtained using 0.77 mmol) and 1- (2-hydroxyhydridyl) pidazine (0.20 g, 1.3 mmol).

_{'H-NMR (CDC1 3)} δ (ppm): 2.71 (t, J = 5.2Hz, 2H), 2.75-2.92 (m, 4H), 3.73 (t, J = 5.2Hz, 2H), 3.74-3.90 (m, 4H), 3.99 (s, 3H), 4.03 (s, 3H), 7.11 (s, 1H), 7.22-7.42 ( m, 5H), 7.64 (d, J = 6.9Hz, 2H), 7.97 (d, J = 16.2Hz, 1H).

Example 3 6

 4 — (4 — tert-Butoxycarbonylbiperazine-1 1-yl) 1, 6,7-Dimethoxy 2 — (E) —Styrylquinazoline (Compound 36) 4 —Cross mouth—obtained in Reference Example 2a 6, 7 —Dimethoxy 1 2 —

(E) N, N-Diisopropylethylamine (0.26 ml, 1.5 mmol) and ten-butyl 1-piperazinecarboxylate from styrylquinazoline (500 mg, 1.5 mmol) in the same manner as in Example 1. Rate

(0.57 g, 3.06 mmol) to give the title compound (623 mg, 85%). _{^ -NMR (CDC1 3) δ (} ppm): 1.53 (s, 9H), 3.70 (m, 8H), 4.01 (s, 3H), 4.05 (s, 3H), 7.12 (s, 1 H), 7.22- 7.43 (m, 5H), 7.65 (d, J = 6.9Hz, 2H), 7.98 (d, J = 15.8Hz, 1H).

Example 3 7

 4 — (Piperazine-1 1 -yl) 1, 6,7 —Dimethoxy 2 — (E) ostyrylquinazoline (compound 37)

4— (4-tert-butoxycarbonylbiperazine-1—yl) -16,7—dimethoxy-1 2— (E) —styrylquinazoline (134 mg, 0.261 mmol) obtained in Example 36 Was stirred at room temperature for 30 minutes with trifluoroacetic acid (3.0 ml). After concentrating the reaction mixture, it was separated with a saturated aqueous solution of sodium hydrogencarbonate and chloroform, and the selected organic layer was washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The selected residue was purified by silica gel chromatography (chloroform / methanol = 100/1-chromate form (including ammonia) / methanol = 20/1) to give the title compound (89 mg, 91%). I got 'H-NMR (CDCI3) δ (ppm): 3.13 (m, 4H), 3.68-3.71 (m, 4H), 3.99 (s, 3H), 4.02 (s, 3H), 7.12 (s, 1H), 7.20 -7.41 (m, 5H), 7.63 (d, J = 6.9Hz, 2H), 7.96 (d, J = 15.8Hz, 1H).

Example 3 8

 4- (4-benzylpiperazine-1 1-yl) -1 6,7-dimethoxy-12- (E) -styrylquinazoline (compound 38)

 Reference Example 2 4—Black mouth—6, 7—Dimethoxy—2—obtained in a

(E) —Styrylquinazoline (250 mg, 0.77 mmol) was prepared in the same manner as in Example 1 by N, N-diisopropylpyrethylamine.

 (0.13ml, 0.77mmol) and 4—benzylpiperazine (0.27ml,

1.3 mmol) to give the title compound (245 mg, 69%).

^ -NMR (CDCI3) 6 (ppm): 2.65-2.80 (m, 4H), 3.64 (s, 2H), 3.70-3.83 (m, 4H), 3.97 (s, 3H), 4.02 (s, 3H), 7.12 (s, 1H), 7.17-7.41 (m, 10H), 7.63 (d, J = 6.9Hz, 2H), 7.96 (d, J = 15.5Hz, 1H).

Example 3 9

 6, 7—dimethoxy-1 4 [2— (2—pyridyl) ethylamino]

— 2 — (E) —Styrylquinazoline (Compound 39)

 Reference Example 2 The N, N-diisomethane was obtained from 4- (6,7) -dimethoxy-2 ((E))-styrylquinazoline (250 mg, 0.77 mmol) obtained in a by the same method as in Example 1. Provirethylamine

 (0.13 ml, 0.77 mmol) and 2-((2-aminoethyl) pyridine (0.18 ml, 1.3 mmol) gave the title compound (170 mg, 54%).

_{Ή-NMR (CDC1 3) δ} (ppm): 3.26 (t, J = 6.1Hz, 2H), 4.02 (s, 3H),

4.05 (s, 3H), 4.12-4.18 (m, 2H), 6.94 (s, 1H), 7.02-7.42 (m, 7H),

7.64-7.70 (m, 3H), 8.01 (d, J = 15.8Hz, 1H), 8.59 (d, J = 4.6Hz, 1H). 4- (1,2,3,4-tetrathroquinoline-12-yl) -16,7-dimethoxy-1- (E) -styrylquinazoline (compound 40)

 Reference Example 2 From the 4-chloro-6,7-dimethoxy-2- (E) -styrylquinazoline (250 mg, 0.77 mmol) obtained in a, N, N-diisopropyl was obtained in the same manner as in Example 1. Etilamine

(0.13 ml, 0.77 mmol) and 1, 2, 3, 4-te tiger arsenide Doroi Sokino Li down (0.19 ml, 1.3 mmol) the title compound with (237 mg, 73%) was obtained iH-NMR (CDC1 ₃ ) (5 (ppm): 3.18-3.30 (m, 2H), 3.98-4.18 (m, 2H), 4.01 (s, 3H), 4.04 (s, 3H), 4.91 (s, 2H), 7.22-7.41 ( m, 10H), 7.67 (d, J = 7.6Hz, 2H), 8.01 (d, J = 15.8Hz, 1H).

Example 4 1

 6, 7 —Dimethoxy-1 4 — (N-methylphenethylamino) 1 2 —

(E) -styrylquinazoline (compound 41)

 Reference Example 2 4 _ black mouth obtained in a-6, 7-dimethoxy-1 2-

(E) -N, N-Diisopropylpyrethylamine from styrylquinazoline (100 mg, 0.31 mmol) in the same manner as in Example 1.

 (0.05 ml, 0.31 mmol) and N-methylphenethylamine (0.14 ml, 0.93 mmol) to give the title compound (54 mg, 41%).

^ -NMR (CDCI3) δ (ppm): 3.17 (t, J = 7.8Hz, 2H), 3.41 (s, 3H), 3.93 (s, 3H), 4.04 (s, 3H), 3.98-4.04 (m, 2H), 7.22-7.43 (m, 11H), 7.66 (d, J = 7.3Hz, 2H), 8.04 (d, J = 16.2Hz, 1H).

Example 4 2

6,7-Dimethoxy-1-4- [N-methyl_N— [2- (2-pyridyl) ethyl] amino} -2- (E) styrylquinazoline (compound 42) Reference Example 2 The N-, N-, N-, N-, N-, N- and N- methoxides were obtained from the 4-chloro-6,7-dimethoxy-12- (E) styrylquinazoline (100 mg, 0.31 mmol) obtained in a in the same manner as in Example 1. Diisopropylethylamine

The title compound (51 mg, 39%) was obtained using (0.05 ml, 0.31 mmol) and 2-((2-methylaminomethyl) pyridin (0.13 ml, 0.93 mmol). _{iH-NMR (CDC1 3) δ} (ppm): 3.36 (t, J = 7.7Hz, 2H), 3.45 (s, 3H), 3.99 (s, 3H), 4.05 (s, 3H), 4.19 (t, J = 7.7Hz, 2H), 7.14-7.48 (m, 8H), 7.58-7.64 (m, 1H), 7.65 (d, J = 6.6Hz, 2H), 8.03 (d, J = 15.8Hz, 1H), 8.55 (d, J = 4.3 Hz, 1H).

Example 4 3

 6, 7-Dimethoxy-1-N- (N-methyl-N- (3-dimethylaminopropyl) amino] — 2— (E) -Styrylquinazoline (Compound 43)

4-chloro-6,7-dimethoxy-1 2— (E) -styrylquinazoline (2 (K) mg, () .61mmol), N, N-diisopropyl obtained in Reference Example 2a From tilamine (O.llml, O.fUmmol), N, N,, N'-trimethyl-1,3, -prono, was obtained in the same manner as in Example 1. ¹ L! Compound (168 mg, 57%) was obtained from diamine (0.27 ml, 1.8 mmol) ^ -NMR (CDC13) ₃ · (ppm): 2.05-2.12 (m, 2H), 2.35 (s , 6H), 2.52 (t, J = 7.4Hz, 2H), 3.37 (s, 3H), 3.78 (t, J = 7.4Hz, 2H), 4.00 (s, 3H), 4.03 (s, 3H), 7.19 -7.42 (m, 6H), 7.63 (d, J = 7.3Hz, 2H), 7.94 (d, J = 16.2Hz, 1H).

Example 4 4

 6, 7 —Dimethoxy 2 — [2- (E) -1- (3—methoxyphenyl) vinyl] — 4-piperidinoquinazoline (compound 44)

6,7-Dimethoxy-1-2-methylquinazoline_4 (3H) -one And m—anisaldehyde obtained from Reference Example 1a and then to Reference Example 2a by the same method as in Reference Example 4a. 4-—Methoxy-1,6—7-Dimethoxy—2 -— [2- (E)-(3-Methoxyf: ϋ Nyl) vinyl] quinazoline (285 mg, 0.80 mmol) and N, N-diisop-piruethylamine (0.14 ml, 0.80 mmol) and piperidine (0.16 ml, 1.6 ramol) in the same manner as in Example 1. Thus, the title compound (265 mg, 82%) was obtained.

 'H-NMR (CDC13) δ (ppm): 1.75-1.95 (m, 6H), 3.77-3.92 (m, 4H), 3.94 (s, 3H), 3.99 (s, 3H), 4.06 (s, 3H) , 6.93 (d, J = 8.2Hz, 1H), 6.96-7.02 (m, 1H), 7.10 (s, 1H), 7.26-7.33 (m, 3H), 7.72 (d, J = 7.6Hz, 1H), 8.05 (d, J = 15.8 Hz, 1H).

Example 4 5

 4- (4-tert-butoxycarbonylbiperazine-1-1-yl) -1,6,7-dimethoxy-2- [2- (E)-(4-methoxycarbonylphenyl) vinyl] quinazoline (compound 4 Five )

 In the same manner as in Example 1, the 4-chloro-1,6-dimethoxy-1-2— [2— (E)-(4-methoxycarbonylcarbonyl) vinyl] quinazoline obtained in Reference Example 2e obtained in Reference Example 2e (0.65 g, 1.5 mmol), N, N-diisopropylethylamine (0.26 ml, 1.5 mmol) and 1-tert-butoxycarborylbiperazine (0.56 g, 3.0 mmol)

₀ was obtained (642mg, 80%)

_{'H-NMR (CDC1 3)} δ (ppm): 1.52 (s, 9H), 3.60-3.80 (m, 8H), 3.93 (s, 3H), 4.00 (s, 3H), 4.04 (s, 3H), 7.11 (s, 1H), 7.29 (s, 1H), 7.32 (d, J = 16.0Hz, 1H), 7.68 (d, J = 8.2Hz, 2H), 7.97 (d, J =

16.0Hz, 1H), 8.06 (d, J = 8.2Hz, 2H).

Example 4 6

6, 7 —Dimethoxine 2 — [2 — (E)-(4 —Methoxycarbonyl (Ruphenyl) vinyl] 1-4 — (piperazine-1 1-yl) quinazoline (compound 4 6)

 Example 4 4 — (4 — tert-butoxycarbonylbiperazine-1-yl)-1, 6, 7-dimethoxy-2-[2-(E)-(4-methoxycarbonyl) obtained in 5 Enyl) vinyl] quinazoline (551 mg, 1.03 mmol) and trifluoroacetic acid (5.0 ml) were obtained in the same manner as in Example 37 to give the title compound (369 mg, 82%).

_{LH-NMR (CDC1 3) δ} (ppm): 3.05-3.10 (m, 4H), 3.60-3.80 (m,

4H), 3.93 (s, 3H), 4.00 (s, 3H), 4.04 (s, 3H), 7.13 (s, 1H), 7.26 (s, 1H), 7.32 (d, J = 15.8Hz, 1H), 7.69 (d, J = 8.2Hz, 2H), 7.98 (d, J = 15.8Hz, 1H), 8.06 (d, J = 8.2Hz, 2H).

Example 4 7

 6, 7 —Dimethoxy-1 2 — [2-(E) — (4 —Methoxycarboxylvinyl) vinyl] — 4 — {N —Methyl_N_ [2 — (2 —Pyridylethyl) amino] Quinazoline (compound 47)

 Reference Example 2 4 —Black mouth— 6, 7 —Dimethoxy-1 2 — obtained in e

 [2- (E)-(4-Methoxycarbonylphenyl) vinyl] From quinazoline (500 mg, 1.30 mmol), 2- (2-methylaminoethyl) pyridine (0.69 ml) was obtained in the same manner as in Example 1. , 5.0 mmol) to give the title compound (0.50 g, 80%).

 'H-NMR (CDCI3) δ (ppm): 3.32-3.38 (m, 2H), 3.38 (s, 3H), 3.93 (s, 3H), 3.99 (s, 3H), 4.02 (s, 3H), 4.10 -4.15 (m, 2H), 7.12- 7.16 (m, 1H), 7.20-7.33 (m, 4H), 7.59 (ddd, J = 7.6, 7.6, 2.0 Hz, 1H), 7.67 (d, J = 8.2 Hz , 2H), 7.99 (d, J = 16.2Hz, 1H), 8.05 (d, J = 8.2Hz, 2H), 8.55 (d, J = 5.0Hz, 1H).

Example 4 8 6,7-dimedoxy 4 -— {N-methyl-N_ [2- (2-pyridyl) ethyl] amino}-2-[2- (E)-(4-dimethylaminophenyl) vinyl] quinazoli (Compound 48)

 Reference Example 4—Black mouth—6,7—Dimethoxy—2—obtained with 2 g

 [2— (E)-(4-Dimethylaminophenyl) vinyl] From quinazoline (50 mg, 0.14 mmol) in the same manner as in Example 1, N, N-diisopropylethylamine (0.15 ml , 0.14 mmol) and 2- (2-methylaminoethyl) pyridine (0.08 ml, 0.54 mmol) to give the title compound (31 mg, 47%).

 'H-NMR (CDClj) δ (ppm): 3.02 (s, 6H), 3.30-3.36 (m, 2H), 3.42 (s, 3H), 3.97 (s, 3H), 4.03 (s, 3H), 4.12 -4.16 (m, 2H), 6.70 (d, J = 8.6Hz, 2H), 7.10 (d, J = 15.5Hz, IH), 7.22-7.27 (m, 3H), 7.40-7.50 (m, IH), 7.53 (d, J = 8.6Hz, 2H), 7.57-7.60 (m, IH), 7.93 (d, J = 15.5Hz, IH), 8.54 (d, J = 2.0Hz, IH).

Example 4 9

 6,7-Dimethoxy-1-4-dimethylamino-2— [2- (E) -I- (4-dimethylaminophenyl) vinyl] quinazoline (Compound 49) Reference Example 2 — 6, 7 — Dimethoxy 2 —

 [2- (E)-(4-Dimethylaminophenyl) vinyl] quinazoline (50 mg, 0.14 mmol) was prepared in the same manner as in Example 1 by N, N-diisopropylethylamine (0.15 ml, 0.14 mmol) and an aqueous solution of dimethylamine (about 40%, 0.06 ml) using the title compound (37 mg,

65%).

_{'H-NMR (CDC1 3)} δ (ppm): 2.99 (s, 6H), 3.49 (s, 6H), 3.92 (s, 3H), 3.98 (s, 3H), 6.61 (d, J = 8.4Hz, 2H), 7.20 (d, J = 15.3Hz, IH), 7.20 (s, IH X2), 7.52 (d, J = 8.4Hz, 2H), 7.94 (d, J = 15.3Hz, IH). Example 5 0

 6,7-Dimethoxy-1-41- (2-methoxyphenethylamino) 1-2- [2— (E)-(4-dimethylaminovinyl) vinyl] quinazoline (Compound 50)

 Reference Example 4 Monochrome mouth obtained with 2 g—6, 7—Dimethoxy—2—

 From [2- (E)-(4-dimethylaminophenyl) vinyl] quinazoline (30 mg, 0.08 mmol), N, N-diisopropylethylamine (0.014 ml, () .08 mmol) and 2-methoxyphenethylamine (0.094 ml, () .64 mmol).

(20 mg, 52%).

_{^ -NMR (CDC1 3) δ (} ppm): 3.09 (s, 6H), 3.14 (t, J = 6.6Hz, 2H), 3.89 (s, 3H), 3.96 (s, 3H), 3.99 (s, 3H ), 3.96-3.99 (m, 2H), 5.70 (brs, 1H), 6.72 (d, J = 8.9Hz, 2H), 6.77 (s, 1H), 6.87-6.98 (m, 2H), 7.02 (d, J = 15.8Hz, 1H), 7.20 (s.1H) '7.23-7.26 (m, 2H), 7.55 (d, J = 8.9Hz, 2H), 7.96 (d, J = 15.8Hz, 1H).

Example 5 1

 6, 7 —Dimethoxy-1- 2-[2- (E)-(4-dimethylaminovinyl) vinyl] _ 4 _ (N-methylanilino) quinazoline (Compound 51)

4-Chloro-6,7-dimethoxy-1 2 _ [2- (E)-(4-dimethylaminov) obtained in Reference Example 2 g in N-methyl-2-pyrrolidone (5.0 ml) Enyl) vinyl] quinazoline (300mg, 0.81mmol), N, N-diisopropylethylamine (() .14ml, 0.81mmol) and N-methylaniline (0.35ml, 3.2mmol) Then, the mixture was heated and stirred at 120 ° C for 5 hours and at 140 ° C for 6 hours. The reaction mixture was poured into water, extracted with ethyl acetate, and the obtained organic layer was dried over magnesium sulfate. solvent And the resulting residue is purified by silica gel column chromatography.

(Hexane / ethyl acetate = 5/1 to 2/1) to give the title compound

₀ was obtained (251mg, 70%)

_{tH-NMR (CDC1 3) δ} (ppm): 3.02 (s, 6H), 3.31 (s, 3H), 3.74 (s, 3H), 3.96 (s, 3H), 6.38 (s, 1H), 6.74 (d , J = 8.9Hz, 2H), 7.10 (d, J = 15.6Hz, 1H), 7.16 (s, 1H), 7.21-7.26 (m, 3H), 7.36-7.42 (m, 2H), 7.57 (d, J = 8.9Hz, 2H), 7.99 (d, J = 15.6Hz, 1H).

Example 5 2

 2- [2- (E)-(4-dibutylaminophenyl) vinyl] — 6,7-dimethoxy-l 4- {N-methyl-1-N— [2- (2-pyridyl) ethyl] amino} Quinazoline (compound 52)

 Reference Example 1a from 6,7-Dimethoxy-2-methylquinazolin-1-4 (3H) -one and 4-dibutylaminobenzaldehyde, then obtained by the same method as Reference Example 2a 2 — [2— (E)- (4-Dibutylaminophenyl) vinyl] —N, N-diisopropyl ester from 4,6,7-dimethoxyquinazoline (20 mg, 0.044 mmol) in the same manner as in Example 1. Tilamine (0.01 ml, 0.044 mmol) and 2-((2-methylaminoethyl) pyridine (0.02 ml,

0.18 mmol) to give the title compound (15 mg, 62%).

_{^ -NMR (CDC1 3) 0 ·} (ppm): 0.97 (t, J = 7.3Hz, 6H), 1.30-1.44 (m, 4H), 1.54-1.65 (m, 4H), 3.28-3.36 (m, 6H ), 3.37 (s, 3H), 3.97 (s, 3H), 4.01 (s, 3H), 4.07-4.12 (m, 2H), 6.64 (d, J = 8.7 Hz, 2H), 7.00 (d, J = 15.8Hz, 1H), 7.12-7.16 (m, 1H), 7.22-7.27 (m, 3H), 7.49 (d, J = 8.7Hz, 2H), 7.57-7.64 (m, 1H), 7.91 (d, J = 15.8Hz, 1H), 8.55 (d, J = 4.0Hz, 1H).

Example 5 3 6,7-Dimethoxy-1-4- (N-methylphenethylamino) 1-2- [2- (E)-(4-piperidinophenyl) vinyl] quinazoline (Compound 53)

 6,7-Dimethoxy-1-2-methylquinazoline-1 (3H) -one and 4-piperidinobenzaldehyde obtained from Reference Example 1a followed by the same method as Reference Example 2a. 6,7—Dimethoxy—2— [2- (E)-(4-piperidinophenyl) vinyl] quinazoline (20 mg, 0.05 mmol) was prepared in the same manner as in Example 1 by N, N-diisomethine. Use propylethylamine (0.01 ml, 0.05 mmol) and N-methylphenethylamine (0.03 ml, 0.20 mmol) to give the title compound.

(23 mg, 93%) was obtained.

_{^ -NMR (CDC1 3) 6 (} ppm): 1.50-1.80 (m, 6H), 3.10-3.18 (m, 2H), 3.23-3.27 (m, 4H), 3.36 (s, 3H), 3.92 (s, 3H), 3.93-4.00 (m, 2H), 4.02 (s, 3H), 6.93 (d, J = 8.7Hz, 2H), 7.07 (d, J = 15.7Hz, 1H), 7.13-7.36 (m, 7H ), 7.53 (d, J = 8.7Hz, 2H), 7.94 (d, J = 15.7Hz, 1H).

 6, 7-dimethoxy-1 2 _ [2-(E) 1-(2, 4-dimethoxyphenyl) vinyl] 1-4-piperidinoquinazoline (compound 54)

6-, 7-Dimethoxy-1-2-methylquinazolin-14 (3H) one and 2,4-dimethoxybenzaldehyde obtained in the same manner as in Reference Example 1a and Reference Example 2a. , 7—Dimethoxy-1 2— [2- (E) — (2,4-Dimethoxyphenyl) vinyl] quinazoline (300 mg, 0.78 mmol) in the same manner as in Example 1 to give N, N —Diisopropylethylamine (0.14 ml, 0.78 mmol) and piperidine (0.31 ml, 3.1 mmol) gave the title compound (247 mg, 73%). _{'H-NMR (CDC1 3)} δ (ppm): 1.70-1.90 (m, 6H), 3.60-3.70 (m, 4H), 3.85 (s, 3H), 3.91 (s, 3H), 3.99 (s, 3H ), 4.02 (s, 3H), 6.49 (d, J = 2.3Hz, 1H), 6.53 (dd, 8.4, 2.3Hz, 1H), 7.11 (s, 1H), 7.23 (d, J = 15.8Hz, 1H) ), 7.27 (s, 1H), 7.61 (d, J = 8.4Hz, 1H), 8.24 (d, J = 15.8Hz, 1H).

Example 5 5

 6, 7 —Dimethoxy 1 2 — [2 — (E)-(3, 4 —Dimethoxyphenyl) vinyl] 1 4 _ {N—Methyl-1-N— [2 — (2—Pyridyl) ethyl] Amino} quinazoline (Compound 55)

6,7-Dimethoxy-2-methylquinazolin-14 (3H) -one and piperonyl aldehyde obtained by the same method as in Reference Example 1a and Reference Example 2a. Toxic 2— [2- (E)-(3,4-dimethoxyphenyl) vinyl] quinazoline (300 mg, 0.78 mmol) from N, N-diisopropylethylamine by the same method as in Example 1. down (0.14 ml, 0.78 mmol) and 2 - to give a - (Mechiruami aminoethyl 2) pyridinium Gin (0.43 ml, 3.1 mmol) the title compound using ^{(2 0 2 mg, 53%} ).

 ^ -NMR (CDCI3) 6 (ppm): 3.36 (t, J = 7.9Hz, 2H), 3.42 (s, 3H), 3.93 (s, 3H), 3.95 (s, 3H), 3.99 (s, 3H) , 4.04 (s, 3H), 4.16 (t, J = 7.9Hz, 2H), 6.89 (d, J = 8.3Hz, 1H), 7.14-7.28 (m, 6H), 7.57-7.64 (m, 2H), 7.96 (d, J = 15.8Hz, 1H), 8.55 (d, J = 4.0Hz, 1H).

Example 5 6

 2 — [2 — (E) 1-(4-ethoxyphenyl) vinyl]-6,7-dimethoxy 4-{N-methyl-N-[2-(2-pyridyl) ethyl] amino] quinazoly (Compound 56)

6, 7 —Dimethoxy-1 2 —Methylquinazoline 1 4 (3 H) one And 4-ethoxybenzaldehyde can be obtained by the same method as in Reference Example 1a and then in Reference Example 2a. 4 —Black mouth— 2 _ [2-(E)-

(4-Ethoxyphenyl) vinyl] N, N-diisopropylethylamine (0.14 ml, 0.81 mmol) from 1,6,7-dimethoxyquinazoline (300 mg, 0.81 mmol) in the same manner as in Example 1. ) And 2 —

The title compound (272 mg, 71%) was obtained using (2-methylaminoethyl) pyridine (0.45 ml, 3.2 mmol).

_{'H-NMR (CDC1 3)} 6 (ppm): 1.44 (t, J = 6.9Hz, 3H), 3.35 (t, J = 7.6Hz, 2H), 3.41 (s, 3H), 3.98 (s, 3H) , 4.03 (s, 3H), 3.97-4.17 (m, 2H), 4.08 (q, J = 6.9Hz, 2H), 6.92 (d, J = 8.7Hz, 2H), 7.14 (d, J-15.7Hz, 1H), 7.11-7.41 (m, 4H), 7.58 (d, J = 8.7 Hz, 2H), 7.56-7.64 (m, 1H), 7.96 (d, J = 15.7 Hz, 1H), 8.55 (d, J = 4.3Hz, 1H).

Example 5 7

 2-[2 — (E)-(4-ethoxyphenyl) vinyl] 1, 6, 7-dimethoxy 1 4-1 (N-methylphenethylamino) quinazoline (compound 57)

 4 — Black mouth 2 — [2- (E) — (4—ethoxyphenyl) vinyl] — 6,7—Dimethoxyquinazoline (see Example 56, 300 mg, 0.81 mmol) and Example 1 In a similar manner, the cH-shaped compound (312 mg, 82%) was prepared using N, N-diisop-piruethylamine (0.14 ml, 0.81 mmol) and N-methylpheninoleamine (0.47 ml, 3.2 mmol). Obtained.

'H-NMR (CDCI3) δ (ppm): 1.44 (t, J = 7.1Hz, 3H), 3.16 (t, J = 7.8Hz, 2H), 3.38 (s, 3H), 3.92 (s, 3H), 4.03 (s, 3H), 3.91-4.01 (m, 2H), 4.08 (q, J = 7.1Hz, 2H), 6.92 (d, J = 8.7Hz, 2H), 7.13 (d, J = 15.8Hz, 1H), 7.20 (s, 1H), 7.23-7.41 (m, 6H), 7.58 (d, J = 8.7 Hz, 2H), 7.97 (d, J = 15.8 Hz, 1H).

Example 5 8

 6,7-Dimethoxy-41- {N-methyl-N- [2- (2-pyridyl) ethyl] amino} -1 2— [2— (E) — (2-methylphenyl) vinyl] quinazoline (Compound 58)

 6,7-Dimethoxy-2-methylquinazoline-1 (3H) -one. — Obtained from tolualdehyde by the same method as in Reference Example 1a and then in Reference Example 2a.

(E) From 1 (2-methylphenyl) vinyl] quinazoline (300 mg, 0.88 mmol), in the same manner as in Example 1, N, N-diisop-open-piruethylamine (0.15 ml, 0.88 mmol) and 2 — ( 2-Methylaminoethyl pyridine (0.49ml, 3.5mmol) to give the title compound

(249mg, 64%) was obtained ₀

_{'H-NMR (CDC1 3)} ό "(ppm): 2.48 (s, 3H), 3.36 (t, J = 7.6Hz, 2H), 3.41 (s, 3H), 3.98 (s, 3H), 4.04 (s , 3H), 4.17 (t, J = 7.6Hz, 2H), 7.12-7.30 (m, 7H), 7.38 (s, 1H), 7.59 (ddd, J = 7.6, 7.6, 2.0Hz, 1H), 7.73- 7.76 (m, 1H), 8.30 (d, J = 15.8Hz, 1H), 8.53 (d, J = 5.0Hz, 1H).

 6, 7-Dimethoxy-1 2 — [2- (E) -1- (4-methylthiophenyl) vinyl] —4-piperidinoquinazoline (Compound 59)

6,7-Dimethoxy-1-2-methylquinazoline-1 (3H) -one and 4-methylthiobenzaldehyde obtained in the same manner as in Reference Example 1a and Reference Example 2a. —Dimethoxy-2- (2- (E)-(4-methylthiophenidyl) vinyl) quinazoline (300 mg, 0.80 mmol) was prepared in the same manner as in Example 1 by N, N-diisoprovir Ethylamine (0.14ml, 0.80mmol) Jin (0.32 ml, 3.2 mmol) the title compound using (329mg, 98%) was obtained ^{X H-NMR (CDCI3) δ} (ppm): 1.75-2.00 (m, 6H), 2.52 (s, 3H), 3.65-3.80 (m, 4H), 3.99 (s, 3H), 4.04 (s, 3H), 7.11 (s, 1H), 7.24-7.31 (m, 3H), 7.42 (s, 1H), 7.58 (d, J = 8.3Hz, 2H), 7.96 (d, J = 15.8Hz, 1H).

Example 6 0

 2-[2-(E)-(3-fluorophenyl) vinyl]-6,7-dimethoxy-1-piperidinoquinazoline (compound 60)

 6,7-Dimethoxy-2-methylquinazoline-1 4 (3H) -one and 3-Fluoro mouth obtained from Benzaldehyde in the same manner as in Reference Example 1a and Reference Example 2a. — [2- (E)-(3-Fluorophenyl) vinyl] — 6,7-Dimethoxyquinazoline (300mg, 0.87mmol) from N, N-diisopropylethyl by the same method as in Example 1. The title compound (315 mg, 92%) was obtained using pyridine (0.14 ml, 0.87 mmol) and piperidine (0.34 ml, 3.5 mmol). 'H-NMR (CDCI3) δ (ppm): 1.75-1.90 (ppm) m, 6H), 3.63-4.00 (m, 4H), 4.00 (s, 3H), 4.04 (s, 3H), 6.94-7.06 (m, 1H), 7.12 (s, 1H), 7.25-7.44 (m, 5H), 7.94 (d, J = 15.8Hz, 1H).

Example 6 1

 6, 7-Dimethoxy-1 2— [2- (E)-(2,6-Dimethoxyphenyl) vinyl] 1-41 (N-methylphenethylamino) quinazoline (Compound 61)

Reference Example 1a from 6,7-Dimethoxy-1-2-methylquinazolin-1-4 (3H) -one and 2,6-dimethoxybenzaldehyde, then obtained by the same method as Reference Example 2a. 1-6,7-dimethoxy-1 2— [2— (E) — (2,6-dimethoxyphenyl) vinyl Quinazoline (300 mg, 0.78 mmol) in the same manner as in Example 1 to obtain N, N-diisopropylpropylamine (0.14 ml, 0.78 mmol) and N-methylphenethylamine (0.46 ml, 3.1 mmol) to give the title compound (290 mg, 77%).

_{'H-NMR (CDC1 3)} 6 (ppra): 3.15-3.21 (m, 2H), 3.36 (s, 3H), 3.87 (s, 6H), 3.92 (s, 3H), 3.63-3.97 (m 2H) , 4.01 (s, 3H), 6.59 (d, J = 8.3Hz, 2H), 7.34-7.18 (m, 8H), 7.69 (d, J = 15.8Hz, 1H), 8.51 (d, J = 15.8Hz, 1H).

Example 6 2

 6, 7-dimethoxy 1 2-[2-(E)-(2, 4, 6-trimethoxyphenyl) vinyl] 1-4 (N-methylphenethylamino) quinazoline ( Compound 62)

 6, 7—Dimethoxy-1 2—Methylquinazoline-1 4 (3H) —one and 2,4,6—Trimethoxybenzaldehyde Reference Example 1a followed by the same method as Reference Example 2a 4—6,7-Dimethoxy-1 2— [2- (E)-(2,4,6—trimethoxyphenyl) vinyl] quinazoline (300mg, 0.72mmol) obtained by In the same manner as in Example 1, N, N-diisopropylethylamine (0.13 ml, 0.72 mmol) and N-methylphenethylamine (0.42 ml,

2.9 mmol) to give the title compound (0.24 g, 65%).

_{'H-NMR (CDC1 3)} δ (ppm): 3.14-3.20 (m, 2H), 3.35 (s, 3H), 3.84 (s, 3H), 3.86 (s, 6H), 3.89-3.96 (m, 2H ), 3.92 (s, 3H), 4.00 (s, 3H), 6.16 (s, 2H), 7.31-7.20 (m, 7H), 7.58 (d, J = 16.0Hz, 1H), 8.45 (d, J = 16.0Hz, 1H).

 Example 6 3

6, 7 —Dimethoxy 2 — [2 — (E) — (2, 5 — Dimethoxif Phenyl) vinyl] — 4- (N-methylphenethylamino) quinazoline (compound 63)

 6-, 7-Dimethoxy-1-2-methylquinazoline-1 4 (3H) -one and 2,5-dimethoxybenzaldehyde obtained in the same manner as in Reference Example 1a and Reference Example 2a. Mouth 6,7—Dimethoxy-1 2— [2- (E) — (2,5—Dimethoxyphenyl) vinyl] quinazoline (300 mg, 0.78 mmol) ^ In the same manner as in Example 1 Therefore, the title compound (0.35 g, 93%) was obtained by using N-methinolephneethylamine (0.73 ml, 5.0 mmol).

_{'H-NMR (CDC1 3)} δ (ppm): 3.15-3.21 (m, 2H), 3.38 (s, 3H), 3.82 (s, 3H), 3.85 (s, 3H), 3.91-3.97 (m, 2H ), 3.92 (s, 3H), 4.02 (s, 3H), 6.86 (s, 2H), 7.34-7.22 (m, 9H), 8.35 (d, J = 16.2Hz, 1H).

Example 6 4

 6, 7-dimethoxy 2-[2-(E) 1-(2, 5-dimethoxyphenyl) vinyl]-4 _ {N-methyl-1-N-[2-(2-pyridyl) ethyl] amine Quinazoline (compound 64)

 6-, 7-Dimethoxy-1-2-methylquinazoline-1-4 (3H) -one and 2,5-dimethoxybenzaldehyde obtained by the same method as in Reference Example 1a and Reference Example 2a. Mouth 6,7—Dimethoxy-1 2— [2— (E) -1- (2,5-Dimethoxyphenyl) vinyl] quinazoline (300 mg, 0.78 mmol) was prepared by the same method as in Example 1. 2 — (2-Methylaminoethyl) pyridine (0.69 ml,

5.0 mmol) to give the title compound (0.35 g, 93%).

LH-NMR (CDCI3) δ (ppm): 3.34-3.39 (m, 2H), 3.39 (s, 3H), 3.82 (s, 3H), 3.85 (s, 3H), 3.98 (s, 3H), 4.02 ( s, 3H), 4.07-4.13 (m, 2H), 6.86 (m, 2H), 7.11-7.16 (m, 1H), 7.21-7.32 (m, 5H), 7.56-7.62 (m, 1H), 8.32 (d, J = 16.2 Hz, 1H), 8.54 (d, J = 5.0 Hz, 1H).

Example 6 5

 2-[2-(E)-(4-trifluorometoxifenyl) vinyl]-6,7-dimethoxy-1-dimethylaminoquinazoline (compound 65)

 6,7-Dimethoxy-1-methylquinazoline-1 (3H) -one and 4-trifluoromethoxybenzaldehyde can be obtained by the same method as in Reference Example 1a followed by Reference Example 2a. —Black mouth— 2 — [21- (E)-(4-trifluoromethoxyphenyl) vinyl] — 6,7—Dimethoxyquinazoline (300 mg, 0.73 mmol), 50% by the same method as in Example 1. The title compound (20 mg, 65%) was obtained using dimethylamine aqueous solution (10 ml, 0.1 lmol).

_{^ -NMR (CDC1 3) δ (} ppm): 3.34 (s, 6H), 3.99 (s, 3H), 4.02 (s, 3H), 7.18 (d, J = 16.0Hz, 1H), 7.22 (d, J = 8.9Hz, 2H), 7.27 (s, 2H), 7.64 (d, J = 8.9Hz, 2H), 7.93 (d, J = 16.0Hz, 1H).

Example 6 6

 2-[2-(E)-(3 — trifluoromethoxyphenyl) vinyl] — 6,7-dimethoxy- 14 1-morpholinoquinazoline (compound 6

6)

 6,7-Dimethoxy-1-2-methylquinazolin-1 4 (3H) -one and 3— obtained from trifluorome ethoxybenzaldehyde in the same manner as in Reference Example 1a followed by Reference Example 2a 4— Chloro-2- [2- (E)-(3-trifluoromethoxyphenyl) vinyl] —6,

The title compound (0.30 g, 89%) was obtained from 7-dimethoxyquinazoline (300 mg, 0.73 mmol) using morpholine (0.44 ml, 5.0 mmol) in the same manner as in Example 1. . _{^ -NMR (CDC1 3) δ (} ppm): 3.71-3.74 (m, 4H), 3.94-3.98 (m, 4H), 4.00 (s, 3H), 4.04 (s, 3H), 7.11 (s, 1H) , 7.16 (d, J = 7.9Hz, 1H), 7.25 (d, J = 15.7Hz, 1H), 7.26 (s, 1H), 7.41 (dd, J = 7.9, 7.9Hz, 1H), 7.47 (s, 1H), 7.55 (d, J = 7.9Hz, 1H), 7.92 (d, J = 15.7Hz, 1H).

 6, 7 —Dimethoxy-1 2 — [2 — (E)-(3,4-methylenedioxyphenyl) vinyl] — 4 _ (N-methylphenethylamino) quinazoline (Compound 67)

 6,7-Dimethoxy-1-2-methylquinazolin-14 (3H) -one and biveronyl aldehyde can be obtained by the same method as in Reference Example 1a and Reference Example 2a. —Dimethoxy-1 2— [2 (E)-(3,4-methylenedioxyphenyl) vinyl] quinazoline (170 mg, 0.46 mmol) was prepared by the same method as in Example 1 to obtain N, N —Diisopropylethylamine (0.08ml, 0.46mmol) and N-methylphenethylamine (0.27ml, 1.8mmoI) to give the title compound

(149 mg, 69%).

^ -NMR (CDCI3) δ (ppm): 3.13-3.18 (m, 2H), 3.38 (s, 3H), 3.92 (s, 3H), 3.95-4.02 (m, 2H), 4.03 (s, 3H), 6.00 (s, 2H), 6.83 (d, J = 7.9Hz, 1H), 7.08-7.33 (m, 10H), 7.93 (d, J = 15.8Hz, 1H).

 6, 7-Dimethoxy-1 2 — [2- (E) -1- (3,4-methylenedioxyphenyl) vinyl] — 4_ [2_ (4-pyridyl) ethylamino] quinazoline (Compound 68)

6,7-Dimethoxy-2-methylquinazolin-1- (4- (3H))-one and piperonylaldehyde obtained by the same method as in Reference Example 1a and Reference Example 2a. 4-Chloro-6,7-dimethoxy-1-one twenty two -(E)-(3,4-Methylenedioxyphenyl) vinyl] quinazoline (180 mg, 0.49 mmol) in the same manner as in Example 1 by N, N-diisopropylethylamine (0.09ml, 0.49mmol) and 4-

The title compound (116 mg, 52%) was obtained using (2-aminoethyl) pyridine (0.22 ml, 1.96 mmol).

_{iH-NMR (CDC1 3) δ} (ppm): 3.34 (t, J = 7.6Hz, 2H), 3.43 (s, 3H), 3.85 (s, 3H), 3.87 (s, 3H), 3.93 (s, 3H ), 4.17 (t, J = 7.6Hz, 2H), 6.49 (d, J = 2.3Hz, 1H), 6.55 (dd, J = 8.6, 2.3Hz, 1H), 6.93 (dd, J = 9.2, 2.6Hz) , 1H), 7.12-7.32 (m, 4H), 7.56- 7.64 (m, 2H), 7.87 (d, J = 9.2Hz, 1H), 8.30 (d, J = 16.2Hz, 1H), 8.56 (d, J = 4.3Hz, 1H)

Example 6 9

 6,7-Dimethoxy-1-4-dimethylamino-2— [2— (E)-(2,3-Methylenedioxyphenyl) vinyl] quinazoline (Compound 69)

 6,7-Dimethoxy-2-methylquinazoline-l-4 (3H) -one and 2,3-methylenedioxybenzaldehyde can be obtained in the same manner as in Reference Example 1a and then in Reference Example 2a. 4 _Mouth—6,7-Dimethoxy-2— [2— (E)-(2,3-methylenedioxyphenyl) vinyl] quinazoline (300 mg, 0.81 mmol) Same as Example 1 The title compound (0.25 g, 81%) was obtained by using a 50% aqueous dimethylamine solution (10.0 ml, O.llmol) according to the method described above.

 'H-NMR (CDCI3) 5 (ppm): 3.33 (s, 6H), 3.99 (s, 3H), 4.02 (s, 3H), 6.06 (s, 2H), 6.77 (d, J = 7.6Hz, 1H ), 6.84 (dd, J = 7.6, 7.6Hz, 1H), 7.05 (d, J = 7.6Hz, 1H), 7.25 (s, 1H), 7.26 (s, 1H), 7.41 (d, J = 15.8Hz) , 1H), 7.92 (d, J = 15.8Hz, 1H).

Example 7 0 2— [2— (E)-(1,4-benzodioxan-1-yl) vinyl] —6,7-dimethoxy-4-dimethylaminoquinazoline (Compound 70)

 6,7-Dimethoxy-2-methylquinazoline-14 (3H) -one and 1,4-benzodioxane-6-carboxyaldehyde obtained in the same manner as in Reference Example 1a and Reference Example 2a. [2- (E)-(1,4-benzodioxane-1-6-yl) vinyl] — 4-chloro-1,6-dimethoxyquinazoline (300mg, 0.78mmol) by the same method as in Example 1. The title compound (0.25 g, 82%) was obtained using 50% aqueous dimethylamine solution (10 ml, O.llmol).

_{LH-NMR (CDC1 3) δ} (ppm): 3.33 (s, 6H), 3.98 (s, 3H), 4.02 (s, 3H), 4.28 (s, 4H), 6.86 (d, J = 8.3Hz, 1H ), 7.06 (d, J = 15.8Hz, 1H), 7.11-7.26 (m, 4H), 7.86 (d, J = 15.8Hz, 1H).

Example Ί 1

 2-[2-(E) — (4-ethoxycarbonylmethoxyphenyl) vinyl] — 6,7-dimethoxy-1 4 1 {N-methyl-1 N— [2 —

(2_pyridyl) ethyl] amino} quinazoline (Compound 71)

 According to the same method as in Example 30, 4—Crawl 2— [2— (E) −

(4-ethoxycarbonylmethoxyphenyl) vinyl] —6,7-dimethoxyquinazoline (500 mg, 1.20 mmol), N, -diisopropylethylamine (0.21 ml, 1.2 mmol) and 2— (2-methylamido) The title compound (590 mg, 93%) was obtained from (ethyl) piperidine (0.66 ml, 4.8 mmol).

_{'H-NMR (CDC1 3)} δ (ppm): 1.31 (t, J = 7.1Hz, 3H), 3.32-3.38 C m, 2H), 3.38 (s, 3H), 3.98 (s, 3H), 4.02 ( s, 3H), 4.09-4.14 (m, 2H), 4.29 (q, J = 7.1Hz, 2H), 4.66 (s, 2H), 6.93 (d, J = 8.7Hz, 2H), 7.11 (d, J = 15.8Hz, 1H), 7.12-7.27 (m, 4H), 7.57 (d, J = 8.7Hz, 2H), 7.56-7.63 (m, 1H), 7.93 (d, J = 15.8Hz, 1H), 8.55 (d, J = 4.0Hz, 1H).

 2 — {2-(E) -I- [4- (2-hydroxyethoxy) phenyl] vinyl} — 6,7-Dimethoxy-1 4-— {N-Methyl-1-N— [2 —

(2-pyridyl) ethyl] amino} quinazoline (compound 72)

 2— [2—obtained in Example 7 1 by the same method as in Example 31

(E)-(4-Ethoxycarbonylmethoxyphenyl) vinyl] -16,7-dimethoxy-14- {N-methyl-1-N— [2- (2-pyridyl) ethyl] amino] quinazoly (540 mg, 1.02 mmol) and lithium aluminum hydride (40 mg, 1.02 mmol) gave the title compound (233 mg, 47%).

_{'H-NMR (CDC1 3)} 6 (ppm): 3.32-3.38 (m, 2H), 3.38 (s, 3H), 3.98 (s, 3H), 4.02 (s, 3H), 3.98-4.02 (m, 2H ), 4.09-4.15 (m, 4H), 6.94 (d, J = 8.9Hz, 2H), 7.11 (d, J = 15.8Hz, 1H), 7.13-7.24 (m, 4H), 7.57 (d, J = 8.9Hz, 2H), 7.56-7.63 (m, 1H), 7.94 (d, J = 15.8Hz, 1H), 8.55 (d, J = 4.0Hz, 1H).

Example Ί 3

 6, 7 —Dimethoxy-1 2— {2- (E)-[4- (2—Dimethylamino ethoxyphenyl) vinyl} —4-Piperidinoquinazoline (Compound 73)

 Example 3 2— {2- (E)-[4- (2-hydroxyethoxy) phenyl] vinyl] obtained in 1} -6,7-Dimethoxy 4—pyridinoquinazoline (217 mg, 0.50 mmol) in tetrahydrofuran

(5.0 ml) and methanesulfonyl chloride (0.05 ml, 0.60 mmol) and N, N-diisopropylethylamine (0.10 ml, 0.60 mmol) and stirred for 2.5 hours. Further, methanesulfonyl chloride (0.01 ml, 0.15 mmol) and N, N-diisopropylpropylethylamine (0.03 ml, 0.15 mmol) were added, and the mixture was stirred for 1.5 hours. An aqueous solution of dimethylamine (40%, 0.2 ml) was added to the reaction system, and the mixture was stirred at room temperature overnight. Further, an aqueous dimethylamine solution (2 ml) was added, and the mixture was heated under reflux for 4.5 hours, and then ethyl acetate and water were added thereto to carry out liquid separation. The obtained organic layer was washed with brine and dried over magnesium sulfate. The solvent is distilled off and the obtained residue is purified by silica gel column chromatography (chlorophorelem to chlorophosolem).

(Containing ammonia) / methanol = 20/1) to give the title compound

(155 mg, 50%).

_{^ -NMR (CDC1 3) δ (} ppm): 1.70-1.95 (m, 6H), 2.37 (s, 6H), 2.77 (t, J = 5.7Hz, 2H), 3.60-3.80 (m, 4H), 3.99 (s, 3H), 4.02 (s, 3H), 4.12 (t, J = 5.7Hz, 2H), 6.93 (d, J = 8.6Hz, 2H), 7.10 (d, J = 15.8Hz, 1H), 7.12 (s, 1H), 7.24 (s, 1H), 7.57 (d, J = 8.6Hz, 2H), 7.88 (d, J = 15.8Hz, 1H).

Example 7 4

 6, 7 —Dimethoxy-4-one {N-methyl-N— [2— (2-pyridyl) ethyl] amino} —2— {2- (E)-[4- (2-dimethylaminoaminoethoxyphenyl) ] Vinyl} quinazoline (Compound 74) 2— {21- (E)-[41- (2—hydroxyethoxyphenyl) vinyl obtained in Example 72 by the same method as in Example 73 }-6,7-Dimethoxy-1 4 — {N-methyl-1-N— [2— (2-pyridyl) ethyl] amino} quinazoline (180mg, 0.37mmol), methanesulfonyl chloride (0.08ml , l.lmmol), dimethylamine aqueous solution

(40%, 3ml) gave the title compound (99mg, 41%).

XH-NMR (CDCI3) δ (ppm): 2.35 (s, 6H), 2.76 (t, J = 5.6Hz, 2H), 3.32-3.37 (m, 2H), 3.37 (s, 3H), 3.98 (s, 3H), 4.02 (s, 3H), 4.08-4.13 (m, 4H), 6.94 (d, J = 8.7Hz, 2H) , 7.08 (d, J = 15.8Hz, 1H), 7.14-7.27 (m, 4H), 7.56 (d, J = 8.7Hz, 2H), 7.57-7.60 (m, 1H), 7.93 (d, J = 15.8Hz, 1H), 8.55 (d, J = 4.0Hz, 1H).

Example 7 5

 7—Methoxy 2— [2— (E)-(2—Methoxyphenyl) vinyl] —4— (N—Methylphenethylamino) quinazoline (Compound 75)

 7 —Methoxy 2 —methylquinazoline _ 4 (3 H) —one and o — obtained from anisaldehyde in the same manner as in Reference Example 1a, then Reference Example 2a 4 —Chromone 1 7 —Methoxy 1 2 — [2-(E) ― (2 — methoxyphenyl) vinyl] quinazoline (300 mg,

0.92 mmol) in the same manner as in Example 1 by using N, N-diisop-piruethylamine (0.16 ml, 0.92 mmol) and N-methylphenethylamine (0.54 ml, 3.7 mmol). Compound (117 mg, 30%) was obtained.

_{'H-NMR (CDC1 3)} δ (ppm): 3.14-3.20 (m, 2H), 3.46 (s, 3H), 3.90 (s, 3H), 3.95 (s, 3H), 4.01 -4.07 (m, 2H ), 6.92-7.00 (m, 3H), 7.26-7.35 (m, 8H), 7.70-7.74 (m, 1H), 7.87 (d, J = 9.2Hz, 1H), 8.44 (d, J = 15.8Hz, 1H).

Example 7 6

 7—Methoxy 1 2— [2- (E) 1 (2,4—Dimethoxyphenyl) vinyl] —4— {N—Methyl-N— [2- (2—Pyridyl) ethyl] amino} Quinazoline (Compound 76)

7—Methoxy-1 2—Methylquinazoline_4 (3H) one and 2,4—Dimethoxybenzaldehyde Reference Example 1a then Reference Example 2a 4 —Black mouth 7 —Methoxy 1 2 —

 From [2- (E)-(2,4 dimethoxyphenyl) vinyl] quinazoline (300mg, 0.84mmol), N,

The title compound (339 mg, 88%) was prepared using N-diisopropylethylamine (0.15 ml, 0.84 mmol) and 2 — (2-methylaminoethyl) pyridin (() .47 ml, 3.4 mmol). Obtained.

_{^ -NMR (CDC1 3) δ (} ppm): 3.07 (t, J = 7.1Hz, 2H ,, 3.84-3.91 (m, 2H), 3.89 (s, 3H), 3.91 (s, 3H), 6.06 (s , 2H), 6.94 (d, J = 7.9Hz, 1H), 6.94 (d, J = 15.8Hz, 1H), 7.09-7.11 (m, 1H), 7.09 (s, 1H), 7.31-7.35 (m , 3H), 7.55 (s, 1H), 7.79 (d, J = 15.8Hz, 1H). 7.95-8.28 (brt, 1H), 8.48 (d, J = 5.9Hz, 2H)

Example 7 7

 7—Methoxy 1 2 [2— (E) 1 (2, 4—dimethoxyphenyl) vinyl] —4 (N—methylphenethylamino) quinazoline (Compound Ί7)

 4 Monochloro-7 methoxy 2 — [2 — (E) — (2, 4 — dimethoxyphenyl) vinyl] quina V lin ('See Example 76, 300 mg, 0.84 mmol). Depending on the method, N, N-diisop-piruethylamine (0.15 ml, 0.84 mmol) and N-methylphenethylamine (0.49 ml, 3.4 mmol) were used to form a vomit (377 mg, 99%). I got

'H-NMR (CDCI3) δ (ppm): 3.14-3.19 (m, 2H), 3.43 (s, 3H), 3.86 (s, 3H), 3.88 (s, 3H), 3.94 (s, 3H), 3.97 -4.03 (m, 2H), 6.49 (d, J = 2.3Hz, 1H), 6.54 (dd, J = 8.4, 2.3Hz, 1H), 6.93 (dd, J = 2.6, 9.2Hz, 1H), 7.20- 7.34 (m, 7H), 7.54 (d, J = 8.4Hz, 1H), 7.86 (d, J = 9.2Hz, 1H), 8.34 (d, J = 15.8Hz, 1H). Example Ί 8

 2- [2-(—)-(4-ethoxyphenyl) vinyl] _7-methoxy-4-4-piperidinoquinazoline (Compound 78)

 7-Methoxy-2-methylquinazoline-4 (3Η) -one and 4-ethoxybenzaldehyde obtained in the same manner as in Reference Example 1a and Reference Example 2a. [2— (E)-(4-ethoxyphenyl) vinyl] _7—Methoxyquinazoline (300 mg, 0.88 mmol) was prepared in the same manner as in Example 1 by N, N-diisopopenvirethylamine (0%). , 15 ml, 0.88 mmol) and piperidine (0.35 ml, 3.5 mmol) to give the title compound (202 mg, 59%).

_{1H-NMR (CDC1 3) 6} (ppm): 1.43 (t, J = 6.9Hz, 3H), 1.70-1.90 (m, 6H), 3.67-3.82 (m, 4H), 3.94 (s, 3H), 4.07 (q, J = 6.9Hz, 2H), 6.91 (d, J = 8.7Hz, 2H), 6.98 (dd, J = 9.1, 2.6Hz, 1H), 7.15 (d, J = 15.8Hz, 1H), 7.28 -7.33 (m, 1H), 7.59 (d, J = 8.7Hz, 2H), 7.73 (d, J = 9.1Hz, 1H), 7.98 (d, J = 15.8Hz, 1H).

Example 7 9

 7—Methoxy-1 4— {N—Methyl-1-N— [2- (2-Pyridyl) ethyl] amino} —2— [2— (E) — (2-Methylphenyl) vinyl] quinazoline (Compound 79)

7—Methoxy-1 2—Methylquinazoline 1 4 (3H) —On and o—Tolualdehyde obtained by the same method as in Reference Example 1a and Reference Example 2a. I 2 — [2- (E)-(2-Methylphenyl) vinyl] quinazoline (300 mg, 0.97 mmol) by the same method as in Example 1 to give N, N-diisopropylethylamine (0.17 ml, 0.97 mmol) and 2-((2-methylaminoethyl) pyridine (0.54 ml, 3.9 mmol) to give the title compound (198 mg, 50%). Was.

¹ H-NMR (CDCI3) δ (ppm): 2.42 (s, 3H), 3.29 (t, J = 7.4Hz, 2H), 3.37 (s, 3H), 3.89 (s, 3H), 4.17 (t, J = 7.4Hz, 2H), 6.91 (dd, J = 9.2, 2.3Hz, IH), 7.07-7.22 (m, 7H), 7.50-7.55 (m, IH), 7.67-7.70 (m, IH), 7.84 ( d, J = 9.2Hz, IH), 8.26 (d, J = 15.8Hz, IH), 8.50 (d, J = 5.0Hz, IH).

Example 8 0

 7—Methoxy 14—Dimethylamino 2— [2— (E) — (3,4—Methylenedioxyphenyl) vinyl] quinazoline (Compound 80)

7—Methoxy_2-methylquinazoline_4 (3H) —one and pyronylaldehyde obtained by the same method as in Reference Example 1a and Reference Example 2a 4—Chloro 7—Methoxy-1- 2 — [2- (E)-(3,4-methylenedioxyphenyl) vinyl] quinazoline

 The title compound (0.30 g, 98%) was obtained from (300 mg, 0.88 mmol) in the same manner as in Example 1 using a 50% aqueous solution of dimethylamine (10 ml, O.llmol).

 ^ -NMR (CDCI3) δ (ppm): 3.37 (s, 6H), 3.92 (s, 3H), 5.99 (s, 2H), 6.82 (d, J = 8.3Hz, IH), 6.95 (dd, J = 9.2, 2.6Hz, IH), 7.04 (d, J = 15.7Hz, IH), 7.10 (d, J = 2.6Hz, IH), 7.17-7.20 (m, 2H), 7.88 (d, J = 9.2Hz, IH), 7.91 (d, J = 15.7 Hz, IH).

Example 8 1

 2 — [2 — (E)-(2 — methoxyphenyl) vinyl] 1-4 (N-methylphenethylamino) 1, 6, 7-methylenedioxyquinazoline (compound 81)

2—Methyl-1,6,7—methylenedioxyquinazolin-14 (3H) one and o—anisaldehyde from Reference Example 1a and Reference Example 2a Example 1 from 4-chloro-2- (2- (E)-(2-methoxyphenyl) vinyl) —6,7-methylenedioxyquinazoline (300 mg, 0.88 mmol) obtained by a similar method. In the same manner as described above, the title compound was prepared using N, N-diisopropylethylamine (0.15 ml, 0.88 mmol) and N-methylphenethylamine (0.51 ml, 3.5 mmol).

(312mg, 81%) o

_{iH-NMR (CDC1 3) 6} (ppm): 3.12-3.20 (m, 2H), 3.37 (s, 3H), 3.90 (s, 3H), 3.90-3.96 (m, 2H), 6.10 (s, 2H) , 6.92-7.02 (m, 2H), 7.24-7.34 (m, 9H), 7.71 (d, J = 7.6Hz, 1H), 8.38 (d, J = 15.8Hz, 1H).

 2-[2-(E)-(2, 4-dimethoxyphenyl) vinyl]-6,7-methylenedioxy-4-{N-methyl-1-N-[2-(2-pyridyl) ethyl] amino} Quinazoline (compound 82)

 2—Methyl-1,6,7-methylenedioxyquinazoline-1 4 (3H) —one and 2,4—dimethoxybenzaldehyde from Reference Example 1a followed by the same method as Reference Example 2a Example 4 from the obtained 4-chloro-2 -— [2- (E) -I- (2,4-dimethoxyphenyl) vinyl] —6,7-methylenedioxyquinazoline (300 mg, 0.81 mmol) N, N-Diisopropylpyretilamine (0.14 ml, 0.81 mmol) and 2- (2-methylaminoethyl) pyridine are prepared in the same manner as described above.

 (0.45 ml, 3.2 mmol) to give the title compound (0.25 g, 66%).

'H-NMR (CDCI3) δ (ppm): 3.28-3.33 (m, 2H), 3.33 (s, 3H), 3.84 (s, 3H), 3.87 (s, 3H), 4.04-4.10 (m, 2H) , 6.06 (s, 2H), 6.48 (d, J = 2.3Hz, 1H), 6.54 (dd, J = 8.3, 2.3Hz, 1H), 7.10-7.29 (m, 5H), 7.55-7.63 (m, 2H ), 8.25 (d, J = 15.8 Hz, 1H), 8.55 (d, J = 5.0 Hz, 1H). 4— {N—Methyl-N_ [2- (2-pyridyl) ethyl] amino} —6,7—Methylenedioxy-2- (2- (E)-(2-methylphenyl) vinyl] quinazoline ( Compound 83)

 2—Methyl-6,7—methylenedioxyquinazolin-1- (4H) —one. ― Tolualdehyde obtained by the same method as in Reference Example 1a and Reference Example 2a. 4-Crosin-1,6-methylenedioxy —2— [2- (E)-(2-methylphenyl) vinyl] quinazo From phosphorus (300 mg, 0.92 mmol), N, N-diisopropyrethylamine (0.16 ml, () .92 mmol) and 2_ (2-methylaminoethyl) pyridine (0.51 ml, 3.7 mmol) to give the title compound (304 mg, 78%).

_{^ -NMR (CDC1 3) δ (} ppm): 2.46 (s, 3H), 3.28-3.33 (m, 2H), 3.33 (s, 3H), 4.12 (t, J = 7.4Hz, 2H), 6.09 (s , 2H), 7.09-7.26 (m, 8H), 7.57 (ddd, J = 7.6, 7.6, 2.0 Hz, 1H), 7.71-7.74 (m, 1H), 8.26 (d, J = 15.5 Hz, 1H), 8.54 (d, J = 4.3 Hz, 1H).

Example 8 4

 6, 7 —Methylenedioxy-1 2 — [2— (E) — (3,4-Methylenedioxyphenyl) vinyl] — 4— (N—Methylphenethylamino) quinazoline (Compound 84)

6,7-Methylenedioxy1-2-methylquinazolin-14 (3H) -one and pyronylaldehyde obtained in the same manner as in Reference Example 1a and Reference Example 2a. Methylenedioxy-2— [2— (E) — (3,4-methylenedioxyphenyl) vinyl] quinazoline (300 mg, 0.85 mmol) from N-methylphenethylamine by the same method as in Example 1 (0.73 ml, 5.0 mmol) was used to give the title compound (0.40 g, 100%). _{'H-NMR (CDC1 3)} δ (ppm): 3.09-3.14 (m, 2H), 3.31 (s, 3H), 3.86-3.92 (m, 2H), 5.99 (s, 2H), 6.08 (s, 2H ), 6.82 (d, J = 7.9 Hz, 1H), 7.03 (d, J = 15.8 Hz, 1H), 7.05-7.08 (m, 1H), 7.17-7.36 (m, 8H), 7.89 (d, J = 15.8Hz, 1H).

Example 8 5

 N-Methyl-1 7 — {2- [2— (E)-(3,4—Methylenedioxyphenyl) vinyl] -14— (N-methylphenylethylamino)} quinazolinecarboxamide (Compound 85)

Or 7— (N-methylcarbamoyl) -1-2— [2- (E)-(3,4-methylenedioxyphenyl) vinyl] _4_ (N-methylethylenamino) quinazoline (compound 8 5)

 7-Carboxy-2— [2— (E)-(3,4—methylenedioxyphenyl) vinyl] —4— (N-methylphenethylamino) obtained in the same manner as in Example 32 Quinazoline (453 mg, lOOOOmmol) was dissolved in thionyl chloride (10 ml) and refluxed at 80 ° C for 30 minutes. After concentrating the reaction mixture, the residue was added to 30 ml of a 40% methylamine solution, and the mixture was stirred at room temperature for 30 minutes. Unnecessary methylamine was distilled off under reduced pressure, and the deposited precipitate was collected by filtration to obtain the title compound (310 mg, 67%).

 ^ -NMR (CDCI3) δ (ppm): 3.07 (d, J = 4.9Hz, 3H), 3.16 (t, J = 7.7Hz, 2H), 3.43 (s, 3H), 4.03 (t, J = 7.7Hz) , 2H), 6.01 (s, 2H), 6.34 (m, 1H), 6.84 (d, J = 7.9Hz, 1H), 7.04 (d, J = 15.5Hz, 1H), 7.08 (dd, J = 7.9, 1.7Hz, 1H), 7.18 (d, J = 1.7Hz, 1H), 7.20-7.37 (m, 5H), 7.78 (dd, J = 8.9, 2.0Hz, 1H), 7.95 (d, J = 15.5Hz. 1H), 8.02 (d, J = 8.9 Hz, 1H), 8.12 (d, J = 2.0 Hz, 1H).

 Example 8 6

N-benzyl 1 7 _ {2-[2-(E)-(3, 4-methylenedioxyphenyl) vinyl] -4-1 (N-methylphenethylamino)} Quinazoline carboxamide (Compound 86)

Or 7— (N-benzylcarbamoyl) -1-2— [2- (E) -1- (3,4-methylenedioxyphenyl) vinyl] —4 -— (N-methylphenethylamino) quinazoline (compound 86 )

 7-Carboxy-2_ [2- (E)-(3,4-methylylenedioxyphenyl) vinyl] 14- (N-methylphenethylamino) obtained in the same manner as in Example 32 Quinazoline (453 mg, lOOOOmmol) was dissolved in thionyl chloride (10 ml) and refluxed at 80 ° C for 30 minutes. After concentrating the reaction solution, the residue was added to a separately prepared benzylamine (2.0 mmol) solution of pyridine (20 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (form: black form to black form / methanol = 50/1) to give the title compound.

(160mg, 32%) o

_{^ -NMR (CDC1 3) δ (} ppm): 3.15 (t, J = 7.8Hz, 2H), 3.43 (s, 3H 4.03 (t, J = 7.8Hz, 2H), 4.69 (d, J = 5.3Hz, 2H), 6.01 (s, 2H), 6.56 (m, 1H), 6.83 (d, J = 8.2Hz, 1H), 7.00 (d, J = 15.8Hz, 1H), 7.07 (dd, J = 8.2, 1.6 Hz, 1H), 7.17 (d, J = 1.6Hz, 1H), 7.21-7.39 (m, 10H), 7.82 (dd, J = 8.7, 2.0Hz, 1H), 7.94 (d, J = 15.8Hz.1H ), 8.00 (d, J = 8.7Hz, 1H), 7.93 (d, J = 2.0Hz, 1H).

Example 8 7

 7 —Amino 1 2 — [2 — (E) — (3,4-methylenedioxyphenyl) vinyl] 1 4- (N-methylphenethylamino) quinazoline (Compound 87)

7_ {2- [2— (E) -I- (3,4-methylethylenedioxyvinyl) vinyl] —4— (N-methylenethylamino)} quinolinecarboxylic obtained by the same method as in Example 32 The acid (2.27 g, 5.00 mmol) was suspended in t-butyl alcohol (20 ml), and triethylamine was added at room temperature. (0.764 ml, 5.50 mmol) and diphenylphosphorinoreazide (1.38 g, 5.00 mmol) were added, and the mixture was refluxed at 10 CTC for 1 hour. The reaction solution was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (form: chloroform / hexane / ethyl acetate = 1/1/2) to give hexane / ethyl acetate. And recrystallized to give 7-tert-butoxycarbonylamino -2-[2-(E)-(3, 4-methylenedioxyphenyl) vinyl] 1-4-(N-methylphenethylamino) quinazoly (300 mg) was obtained. The obtained crystals were dissolved in methylene chloride (10 ml), trifluoroacetic acid (10 ml) was slowly added at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction solution was evaporated under reduced pressure, and the residue was recrystallized from hexane / chloroform to give the title compound (341 mg, 16%).

_{^{L H-NMR (CDC1 3)}} δ (ppm): 2.35 (brs, 2H), 3.13 (t, J = 7.3Hz, 2H), 3.51 (s, 3H), 4.16 (t, J = 7.3Hz, 2H) , 6.05 (s, 2H), 6.72 (dd, J = 9.3, 2.0Hz, 1H), 6.87 (d, J = 7.9Hz, 1H), 7.03 (d, J = 15.5Hz, 1H), 7.11 (dd, J = 7.9, 1.7Hz, 1H), 7.16 (d, J = 2.0Hz, 1H), 7.20-7.40 (m, 6H), 7.76 (dd, J = 9.3Hz, 1H), 8.01 (d, J = 15.5 Hz. 1H).

Example 8 8

 7 —Acetylamino _ 2 — [2- (E)-(3,4—Methylenedioxyphenyl) vinyl] — 4 _ (N-methylphenethylamino) quinazoline (Compound 88)

Example 8 7-amino—2— [2— (E)-(3,4-methylenedioxyphenyl) vinyl] —4— (N-methylphenethylamino) quinazo obtained in Example 7 Lin (20 mg, 0.047 mmol) was dissolved in pyridine (1.0 ml), acetyl chloride (0.007 ml, 0.1 mmol) was added at room temperature, and the mixture was stirred for 4 hours. The reaction mixture was concentrated and purified by preparative thin-layer chromatography (chloroform / methanol = 10/1) to obtain the title compound (12 mg, 55%). ^ -NMR (CDCI3) δ (ppm): 2.23 (s, 3H), 3.14 (t, J = 7.8Hz, 2H), 3.40 (s, 3H), 4.00 (t, J-7.8Hz, 2H), 5.79 (brs, 1H), 5.99 (s, 2H),

6.82 (d, J = 8.2Hz, 1H), 7.03 (d, J = 15.8Hz, 1H), 7.06 (dd, J = 8.2, 1.6Hz, 1H), 7.21-7.37 (m, 6H), 7.63 (m , 1H), 7.85 (m, 1H), 7.90 (d, J = 8.9Hz, 1H), 7.93 (d, J = 15.8Hz, 1H).

Example 8 9

 7 —Methanesulfonylamino — 2 — [2— (E) — (3,4—Methylenedioxyphenyl) vinyl] — 4— (N-methylphenethylamino) quinazoline (Compound 89)

 Example 8 7-Amino obtained in 7—2— [2— (E)-(3,4-methylenedioxyphenyl) vinyl] —4_ (N-methylphenethylamino) quinazoline (20 mg, 0.047 mmol) was dissolved in pyridine (1.0 ml), methanesulfonyl chloride (0.008 ml, 0.1 mmol) was added at room temperature, and the mixture was stirred for 4 hours. The reaction solution was concentrated, and purified by preparative thin-layer chromatography on macropores (chloroform / ethanol = 10/1) to obtain the title compound (I5 mg, 64%).

_{Ή-NMR (CDC1 3) δ} (ppm): 3.15 (t, J = 7.8Hz, 2H), 3.43 (s, 3H), 3.49 (s, 3H), 4.02 (t, J = off .8Hz, 2H) , 5.99 (s, 2H), 6.81 (d, J = 7.9Hz, 1H), 6.96 (d, J = 15.8Hz, 1H), 7.03 (dd, J = 7.9, 1.3Hz, 1H), 7.11 (brs, 1H), 7.23-7.37 (m, 6H), 7.76 (dd, J = 9.2, 2.0 Hz, 1H),

7.83 (d, J = 2.0Hz.1H), 7.93 (d, J = 9.2Hz, 1H), 7.93 (d, J = 15.8Hz, 1H).

Industrial applicability

 According to the present invention, it is possible to provide an insulin secretagogue and a therapeutic agent for diabetes containing a 4-aminoquinazoline derivative as an active ingredient.

Claims

 Range of request  Equation (I) Word

[Wherein, R ^1A and R ^1B are the same or different and are hydrogen, lower alkyl, lower alkoxy, halogen, nitro, — NR ³ R ⁴ (wherein R ³ and R ⁴ are the same or different and are hydrogen or , —NH C 0 R ⁵ (where R ⁵ represents lower alkyl), —NHS 0 ₂ R ⁶ (where R ⁶ represents lower alkyl), —CONR ⁷ R ⁸ (Wherein R ⁷ and R ⁸ are the same or different and represent hydrogen, lower alkyl or aralkyl), lower alkoxycarbonyl, carboxy or lower alkanol, or R ^1Λ adjacent to R ^1Λ Represents (CH ₂ ) _n 0 — (where n represents 1 or 2), Cy represents a substituted or unsubstituted aryl, and R ² represents hydrogen or substituted A represents hydrogen, substituted or unsubstituted lower alkyl, or unsubstituted lower alkyl. Killed, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyl lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted complex A ring group, substituted or unsubstituted heterocyclic lower alkyl or substituted or unsubstituted unsaturated heterocyclic lower alkyl, or R ² and A together with the adjacent nitrogen atom can be substituted Or an unsubstituted heterocyclic group] or a 4-aminoquinazoline derivative represented by the formula An insulin secretagogue containing a physiologically acceptable salt as an active ingredient.  2. A therapeutic agent for diabetes, comprising the 4-aminoquinazoline derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.  3. Expression (IA)

Wherein, R ^1AX and R ^1Bx are the same or different and each is hydrogen, lower alk kill, lower alkoxy, halogen, two collected by filtration, One NR ³ R ⁴ (wherein, R ³ and R ⁴ are each as defined above ), One NHCOR ⁵ (Wherein, R ⁵ is as defined above), _ NHS 〇 ₂ R (wherein, R ⁶ is as defined above), one CONR ⁷ R ⁸ (wherein, R ⁷ and R ⁸ wherein each synonymous), lower alkoxycarbonyl, or represents Cal Bokishi or lower Arukanoiru or connexion one such R ^1Bx is together adjacent to the _{^{R 1AX 0 (CH 2) n}} O- ( wherein, n as defined above represents der Ru), ① when other than R ^1AX and R ^1Bx are both hydrogen, there have the R ^1AX hydrogen and R ^1Bx is - NHCOR ⁵ (wherein, R ⁵ is as defined above), single NHS 0 ₂ R ⁶ (wherein, R ⁶ is as defined above), — CONR ⁷ R ⁸ (wherein, R ⁷ and R ⁸ are as defined above), lower alkoxycarbonyl, carboxy or lower alkanol or represents, or a R ^1Bx is Te summer together adjacent to the _{^{R 1AX 0 (CH 2) n}} O - represents a (wherein, n has the same meaning as defined above) Place C y ^x represents substituted or unsubstituted aryl, R ^2X represents hydrogen or substituted or unsubstituted lower alkyl, A ^x is hydrogen, substituted or unsubstituted lower alkyl, substituted Unsubstituted or substituted cycloalkyl, substituted or unsubstituted cycloalkyl lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocyclic group Represents a substituted or unsubstituted heterocyclic lower alkyl or a substituted or unsubstituted unsaturated heterocyclic lower alkyl, or R ^2X and A ^x may be substituted with an adjacent nitrogen atom. Represents an unsubstituted heterocyclic group, ② or R ^1AX and R ^1Bx both represent hydrogen, or R ^1AX is hydrogen and R ^1Bx lower alkyl, in lower alkoxy, halogen, two collected by filtration or -NR ³ R ⁴ (wherein, R ³ and R ⁴ Is as defined above): i) C y ^x is substituted off Weniru [the substituent off Weniru is adjacent substituents has decreased with _{- 0 (CH 2) m 0} - ( wherein, m is Ru as defined above der), substituted Or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, trifluoromethoxy, lower alkylthio, nitrogen, nitro, hydroxy, amino, lower alkoxycarbonyl, carboxy and —NR ⁹ R ¹⁰ (wherein, R ⁹ and R ^{1 Q} are each the same as defined above) and are substituted with 1 to 3 groups which are the same or different, and at least one of them is adjacent The substituents are joined together—0 (CH ₂ ) _m 0-(wherein m is as defined above), substituted lower alkyl, substituted lower alkoxy, trifluoromethoxy, lower alkylthio, lower alkoxycarbonyl, Power Reporto Kishi - N ⁹ R ¹⁰ (wherein, R ⁹ and R ^{1 Q} is as defined above, respectively Ru der) is replaced by or substituted or unsubstituted § Re excluding phenylalanine [The substituted aryl is a group in which adjacent substituents are joined together—0 (CH ₂ ) _m 0-(wherein m is as defined above), or a substituted or unsubstituted lower alkyl. , substituted or unsubstituted lower alkoxy, Application Benefits Furuorome butoxy, during lower alkylthio, Nono androgenic, two Toro, hydroxycarboxylic, § Mi Roh, lower alkoxycarbonyl, carboxy and one NR ^{9 1 0} (wherein, R ⁹ And R ^{1 Q} have the same meanings as defined above, respectively, and are the same or different and are substituted with 1 to 3 groups]. R ^{2 X} represents hydrogen or substituted or unsubstituted lower alkyl, A ^x is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cycloalkyl lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclic lower alkyl Or represents a substituted or unsubstituted unsaturated heterocyclic lower alkyl, or R ^{2 X} and A ^x together with an adjacent nitrogen atom represent a substituted or unsubstituted heterocyclic group; ii) C y ^x is substituted or unsubstituted off Weniru (said substituent full: [pi nil is unsubstituted lower alkyl, unsubstituted lower alkoxy, halogen, same selected from two preparative port, human Dorokishi and § Mi Bruno Or differently substituted with 1 to 3 groups) R ^{2 X} represents hydrogen or substituted or unsubstituted lower alkyl, and A ^x is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyl lower alkyl, substituted aralkyl, and substituted. Or an unsubstituted heterocyclic group or a substituted or unsubstituted unsaturated heterocyclic lower alkyl.] Or a pharmacologically acceptable salt thereof.