QUINAZOLINE DERIVATIVES

TECHNICAL FIELD This invention relates to quinazoline derivatives . More particularly, this invention relates to quinazoline derivatives and pharmaceutically acceptable salts thereof which have pharmacological activities , processes for preparation thereof , a pharmaceutical composition comprising the same and a use of the same.

Accordingly, one object of this invention is to provide the new and useful quinazoline derivatives and pharmaceutically acceptable salts thereof which possess a strong inhibitory activity on the production of nitric oxide.

Another object of this invention is to provide process for preparation of the quinazoline derivatives and salts thereof.

A further object of this invention is to provide a pharmaceutical composition comprising said quinazoline derivatives or a pharmaceutically acceptable salt thereof.

Still further object of this invention is to provide a use of said quinazoline derivatives or a pharmaceutically acceptable salt thereof as a medicament for prophylactic and therapeutic treatment of NOS - mediated diseases such as adult respiratory distress syndrome , myocarditis , synovitis , septic shock , insulin - dependent diabetes mellitis , ulcerative colitis , cerebral infarction , rheumatoid arthritis , osteoarthritis , osteoporosis , systemic lupus erythematosis , rejection by organ transplantation , asthma , pain , ulcer, and the like in human being and animals.

DISCLOSURE OF INVENTION The object quinazoline derivatives of the present invention are novel and can be represented . y the following general formula ( I) :

wherein R ¹ is hydrogen, halogen or lower alkylamino which has suitable substituent ( s ) , R ² is hydrogen or halogen, R ³ is hydrogen or lower alkyl which may have suitable substituent ( s), R ⁴ is lower alkyl which has suitable substituent (s) ; or

R ³ _ N ^κ is 4-( lower alkyl) piperazinyl,

\ _R 4

R ⁵ is hydrogen or lower alkyl, and A is lower alkylene, and pharmaceutically acceptable salts thereof.

According to the present invention, the object compound ( I) can be prepared by the following process.

Process 1

(ID (III) or its reactive derivative or its reactive derivative at the carboxy group at the amino group or a salt thereof or a salt thereof

or a salt thereof

wherein R ¹ , R ² , R ³ , R\ R ⁵ and A are each as defined above.

The starting compound ( II ) or a salt thereof can be prepared by the procedures described in the Preparations mentioned later or by the similar manner.

Suitable salts of the compound ( I) are conventional non¬ toxic, pharmaceutically acceptable salt and may include a salt with a base or an acid addition salt such as a salt with an inorganic base, for example , an alkaline metal salt [ e. g . sodium salt ,

potassium salt, etc.], an alkaline earth metal salt [e. g. calcium salt, magnesium salt, etc.], an ammonium salt ; a salt with an organic base , for example , an organic amine salt [ e . g . triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt , dicyclohexylamine salt , N , N ' - dibenzylethylenediamine salt, etc. ] ; an inorganic acid addition salt [ e . g . hydrochloride , hydrobromide , sulfate , phosphate , etc . ] ; an organic carboxylic or sulfonic acid addition salt [e. g. formate, acetate , trifluoroacetate , maleate , tartrate , methanesulfonate , benzenesulf onate, toluenesulfonate, etc. ] ; a salt with a basic or acidic amino acid [e. g. arginine salt, aspartic acid salt, glutamic acid salt, etc. ] ; and the like.

In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions to be included within the scope of the invention are explained in detail as follows.

The term "lower" is intended to mean 1 to 6, preferably 1 to 4 carbon atom(s), unless otherwise indicated.

Suitable "lower alkyl" and "lower alkyl moiety" in the term " lower alkylamino " or " lower alkylpiperazinyl " may include straight or branched ones having 1 to 6 carbon atom(s) such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl, hexyl, in which the preferable one is (C1-C3) alkyl.

Suitable substituent ( s ) in the term " lower alkylamino which has suitable substituent (s)", "lower alkyl which may have suitable substituent ( s ) " and " lower alkyl which has suitable substituen (s)" may include hydroxy, carboxy, lower alkoxy(e. g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, t- butoxy, etc. ), lower alkoxycarbonyl ( e . g . methoxycarbonyl , ethoxycarbonyl , propoxycarbonyl , isopropoxycarbonyl , butoxycarbonyl , t - butoxycarbonyl, etc.), amino, lower alkoxycarbonylamino ( e. g.

methoxycarbonylamino , ethoxycarbony lamino , propoxycarbony lamino , isopropoxycarbonylamino , butoxycarbonylamino , t - butoxycarbonylamino , etc . ) , di ( lower ) alkylamino ( e . g . dimethylamino , diethylamino , N - methyl - N - ethylamino , dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, N- t- butyl- N- buty lamino, dipenty lamino, dihexy lamino, etc. ), diary lamino ( e . g . dipheny lamino , dibenzy lamino, etc . ) , aryK e. g . phenyl , naphtyl, etc. ), cyclic amino in which it may have the other hetero atom ( s) in its ring member ( e. g. 1 - pyrrolidinyl, piperidino, 1 - piperazinyl, morpholino, 1 - pyridyl, 4- pyridyl, pyridyl ( lower) alkyl ( e. g . methylpyridyl , ethylpyridyl , etc . ) , 1 - dihydropyridinyl , 1 - imidazolyl , etc . ) , or the like . These may have one or more ( preferably 1 to 3) substituents.

Suitable " halogen " may include fluoro, chloro, bromo and iodo, in which the preferable one is chloro.

Suitable " lower alkylene " may include methylene, ethylene, trimethylene, and the like.

The process for preparing the object compound ( I) of the present invention is explained in detail in the following.

Process 1

The object compound ( I) or salts thereof can be prepared by reacting the compound ( II ) or its reactive derivative at the carboxy group or a salt thereof with the compound ( III ) or its reactive derivative at the amino group or a salt thereof .

Suitable reactive derivative at the carboxy group of the compound ( II ) may include an ester, an acid halide , an acid anhydride, an activated amide, an activated ester, and the like. The suitable example of the reactive derivative may be an acid

chloride ; an acid azide ; a mixed acid anhydride with an acid such as substituted phosphoric acid ( e . g . dialkylphosphoric acid , pheny Iphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc. ) , dialky -phosphorous acid, lower alkanesulfonic acid ( e . g . methanesulfonic acid , ethanesulfonic acid, etc. ), sulfurous acid, thiosulfuric acid, sulfuric acid, aliphatic carboxylic acid ( e. g . acetic acid, propionic acid, butyric acid, isobutyric acid , pivalic acid , valeric acid , isovaleric acid, 2 - ethylbutyric acid , trichloroacetic acid, etc. ) or aromatic carboxylic acid ( e . g . benzoic acid , etc . ) ; a symmetrical acid anhydride ; an activated amide with imidazole , 4 - substituted imidazole , dimethypyrazole , .triazole or tetrazole ; or an activated ester ( e . g . cyanomethy ester , methoxymethyl ester , dimethyliminomethyl [ ( CH ₃ CH -] estr , vinyl ester, propargyl ester, p- nitrophenyl ester, 2, 4- dinitrophenyl ester, trichlorophenyl ester, pen tach lorophenyl ester, mesy lpheny 1 ester, pheny lazophenyl ester, phenyl thioester, p- nitrophenyl thioester, p- cresyl thioester, carboxymethy thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8- quinolyl thioester, etc. ) or an ester with a N-hydroxy compound ( e. g. N, N-dimethylhydroxylamine, l-hydroxy- 2-( lH)-pyridone, N - hydroxysuccinimide , N - hydroxy phthalimide , 1 - hydroxy - 1H - benzotriazole, etc. ), and the like. These reactive derivatives can optionally be selected from them according to the kind of the compound ( II) to be used.

Suitable reactive derivative at the amino group of the compound ( III ) may include Schiff ' s base type imino or its tautomeric enamine type isomer formed by the reaction of the compound ( III ) with a carbonyl compound such as aldehyde , ketone or the like ; a silyl derivative formed by the reaction of the compound ( III ) with a silyl compound such as N , 0 - bis ( trimethylsilyl) acetamide, N-( trimethyl- silyl) acetamide or the like ; a derivative formed by reaction of the compound ( III ) with

phosphorus trichloride or phosgene, and the like.

Suitable salts of the compound ( II) and the compound (III) can be referred to the ones as exemplified for the compound ( I).

The reaction is usually carried out in a conventional solvent such as alcohol [ e. g . methanol , ethanol , etc. ] , acetone, dioxane , acetonitrile , chloroform , methylene chloride , ethylene chloride, tetrahydrofuran, ethyl acetate, N , N - dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction . Additionally , in case that the above mentioned bases to be used are liquid, they can also be used as a solvent.

When the compound ( II) is used in a free acid form or its salt form in the reaction, the reaction is preferably carried out in the presence of a conventional condensing agent such as N, N ' - dicyclohexylcarbodiimide , N - cyclohexyl - N ' - morpholinoethylcarbodiimide , N - cyclohexyl - N ' - ( 4 - diethylaminocyclohexyl) carbodiimide, N, N ' - diethy .carbodiimide, N, N ' - diisopropylcarbodiimide, N- ethyl- N ' -( 3- dimethylaminopropyl) carbodiimide , N , N ' - carbonylbis - ( 2 - methylimidazole ) , pentamethyleneketene - N - cyclohexylimine , diphenylketene - N - cyclohexylimine, ethoxyacetylene, 1-alkoxy- l-chloroethylene, trialkyl phosphite , ethyl polyphosphate , isopropyl polyphosphate , phosphorus oxychloride ( phosphoryl chloride ) , phosphorus trichloride, thionyl chloride, oxalyl chloride, lower alkyl haloformate ( e . g . ethyl chloroformate, isopropylchloroformate, etc ) , triphenyl phosphine, 2- ethyl- 7- hydroxybenzisoxazolium salt, 2- ethyl- 5-( m - sulfophenyl ) isoxazolium hydroxide intramolecular salt , 1 - ( p - chlorobenzenesulfonyloxy ) - 6 - chloro - IH - benzotriazole , so - called Vilsmeier reagent prepared by the reaction of N , N - dimethylformamide with thionyl chloride , phosgene , phosphorus oxychloride, etc. , or the like.

The reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate, tri ( lower) alkylamine, pyridine, N - ( lower ) alkylmorpholine, N , N - di ( lower) alkylbenzylamine, or the like.

The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating.

The object compound ( I ) of the present invention can be isolated and purified by a conventional method such as extraction, pulverization , reprecipitation , recrystallization , column chromatography, or the like.

The object compound ( I ) of the present invention may include a solvate [e. g. enclosure compound (e. g. , hydrate, etc. )].

The object compounds ( I ) and pharmaceutically acceptable salts thereof possess a strong inhibitory activity on the production of nitric oxide ( NO).

Accordingly, the object compound ( I) and pharmaceutically acceptable salts thereof are expected to possess a nitric oxide synthase ( NOS)- inhibitory activity or a NOS- production inhibitory activity.

Accordingly , they are useful for prevention and or treatment of adult respiratory distress syndrome , myocarditis , synovitis , septic shock , insulin - dependent diabetes mellitis , ulcerative colitis , cerebral infarction , rheumatoid arthritis , osteoarthritis, osteoporosis, systemic lupus erythematosis, rejection by organ transplantation, asthma, pain, ulcer, and the like.

In order to illustrate the usefulness of the object

compound (I), the pharmacological test data of the representative compounds of the compound (I) are shown in the following.

Test: Binding assay using nitric oxide synthase (NOS)

(l)Test Method

A crude preparation of NOS was obtained from the brains of male SD rats . The whole brain ( including cerebellum ) was homogenized in 5 volume (W V) of 50 mM Tris buffer (pH 7.0 at 4°C), centrifuged at 48, 000 x g for 20 minutes, the pellet was discarded and the supernatant was passed through 1 4 volume

(V V) of Dowex AG50WX-8 resin (Na ^* form), in order to remove of endogenous arginine. The supernatant was collected, the pH adjusted to 7.0 at 22 °C and this cytosolic preparation was frozen and stored at -80°C until required. In the binding assay, each drug was incubated with the brain cytozole ( 200 μ g protein tube) in a final volume of 0. 15ml of 50 mM Tris buffer including 10 μ M CaCl ₂ and 10 nM ³ [H] Na( Amersham, Amersham,

UK). Incubations were performed at 27 °C for 90 minutes and were terminated by vacuum filtration over 0.3% polyethyleneimine pretreated GF B glass fibre filters which were subsequently washed with 4mlx4 of 4°C distilled water. Non specific binding was defined by use of 100 μ M Na. Data were expressed as inhibition % of specific binding.

(2) Test compounds

(a) N-(3-Morpholinopropyl)-2-(5, 7- dichloro- 2, 4-dioxo-l, 2, 3, 4- tetrahy droquinazolin- 1-yl) acetamide

(b) N- [2-( 4- Pyridyl) ethyl] -2-( 5, 7- dichloro- 2, 4- dioxo- 1, 2, 3, 4- tetrahydroquinazolin- 1-yl) acetamide

(c) N- [2-(N\ N'- Dimethylamino) ethyl] -2- [7-chloro-2, 4-dioxo-5- [2-(N\ N '-dimethylamino) ethylamino] -1, 2,

3, 4- tetrahydroquinazolin- l - yl] acetamide

( 3) Test Results

Test Compound ( IO ⁵ g ' ml) Inhibition (%)

(a) 97.7 (b) 97.6 (c) 98.0

For therapeutic administration, the object compound ( I) of the present invention and pharmaceutically acceptable salts thereof are used in a form of the conventional pharmaceutical preparation in admixture with a conventional pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient which is suitable for oral , parenteral or external administration . The pharmaceutical preparation may be compounded in a solid form such as granule, capsule, tablet, dragee or suppository, or in a liquid form such as solution, suspension or emulsion for injection, ingestion, eye drops, etc. If needed, there may be included in the above preparation auxiliary substance such as stabilizing agent, wetting or emulsifying agent, buffer or any other commonly used additives.

, The effective ingredient may usually be administered with a unit dose of 0. 001 mg kg to 500 mg kg, preferably 0. 01 mg kg to 10 mg kg, 1 to 4 times a day. However, the above dosage may be increased or decreased according to lage, weight and conditions of the patient or the administering method.

The following Preparations and Examples are given for the purpose of illustrating the present invention in more detail.

Preparation 1

A solution of methyl 2- (4, 6- dichloro- 2, 3-dioxo-lH- indol

- 1 - yl ) acetate (31.9g), 3 - chloroperoxybenzoic acid (33.9g) in dichloromethane (900ml) was stirred at 10 ^C C for 1 hour. To this solution was added 0.5N aqueuos solution of sodium hydroxide

(300ml) and stirred for 5 minutes. The separated organic layer was washed with water, a saturated aqueous solution of sodium bicarbonate and brine successively , dried over anhydrous magnesium sulfate and then evaporated in vacuo. The residue was triturated with diethyl ether and collected by filtration to give methyl 2-(5, 7- dichloro- 2H- 3, l-benzoxazine-2, 4(lH)-dione-

1-yl) acetate (22.4g). mp : 219- 222 °C

IRC Nujol) : 3140, 1765, 1730, 1710, 1615, 1605, 1580 cm ^"1 NMR ( DMSO- dβ, δ) : 3.74 (3H, s), 4.92 (2H, s), 7.66 (2H, s)

Preparation 2

To a suspension of methyl 2 - ( 5 , 7 - dichloro - 2H - 3 , 1 - benzoxazine- 2, 4 ( IH)- dione- 1- yl) acetate ( 18. 8g) in N, N- dimethylformamide ( 100ml ) was added 28 % aqueous ammonia (39ml) below 10 °C and then stirred at 5~10°C for 30 minutes. The resulting precipitates were collected and washed with water (3 times) and diethyl ether to give methyl N-( 2- carbamoyl- 3, 5- dichlorophenyl) aminoacetate (13.2g). mp : 186- 187 °C IRC Nujol) : 3380, 3200, 1730, 1655, 1615, 1580, 1560 cm ^"1 NMR(DMSO-d ₆₎ δ) : 3.67(3H, s), 4.01 (2H, d, J = 5.8Hz), 8.57 (IH, t, J = 5.8Hz), 6.55C1H, d, J=l.6Hz), 6.77C1H, d, J=l.6Hz), 7.77 (IH. br. s), 7.96 (IH, br. s)

Preparation 3

A mixture of methyl N-( 2- carbamoyl- 3, 5- dichlorophenyl) aminoacetate (13. Og) and N, N'- carbonyldiimidazole (22.9g) was stirred at 150 °C for 20 minutes. After cooling, the resultingl material was triturated with a mixture of ethylacetate and water. The resulting precipitates were collected and recrystallized from methanol- ethyl acetate to give methyl 2-(5, 7- dichloro-2, 4-dioxo -1, 2, 3, 4-tetrahydroquinazolin-l-yl) acetate (10.46g). mp : 253- 255 °C

IRC Nujol) : 3150, 1735, 1690, 1590 cm ¹

NMRCDMSO-d ₆ , δ) : 3.71C3H, s), 4.93C2H, s), 7.49C1H, d, J=l.8Hz), 7.58C1H, d, J=l.8Hz), 11.18C1H, br. s)

Preparation 4

A mixture of methyl 2-C 5, 7- dichloro- 2, 4-dioxo-l, 2, 3, 4- tetrahydroquinazolin- 1-yl) acetate C909mg) and sodium hydride (60 % in mineral oil, 120mg) in N, N- dimethylformamide (10ml) was stirred at room temperature for 1 hour and methyl iodide (0.5ml) was added dropwise to the mixture. After stirring for 2 hours, the resulting precipitates were collected by filtration, washed with diisopropyl ether and recrystallized from methanol- acetone to give methyl 2 - ( 5 , 7 - dichloro -2, 4- dioxo - 3 - methyl - 1 , 2 , 3 , 4 - tetrahy droquinazolin- 1-yl) acetate (720mg). . mp : 187- 189 °C IRC Nujol) : 1735, 1710, 1670, 1585 cm ^'1

NMRCDMSO-d ₆ , 5) : 3.26C3H, s), 3.72C3H, s), 4.99C2H, s), 7.53 (IH, d, J=l.8Hz), 7.64(1H, d, J=l.8Hz)

Preparation 5

A mixture of chloral hydrate (8.89g), anhydrous sodium sulfate ( 109g), 3, 5 - dibromoaniline ( 11. 24g), concentrated hydrochloric acid (3.8ml) and hydroxylamine hydrochloride (lOg)

in a mixture (120ml) of 10% dioxane and water was stirred at 100 °C for 6 hours. After cooling, the resulting precipitates were diluted with ethyl acetate . The separated organic layer waswashed with brine, dried over anhydrous sodium sulfate and then evaporated in vacuo. The residue was recrystallized from ethyl acetate - chloroform to give 3 , 5 - dibromo - hydroxyiminoacetanilide (5.9g). mp : 220- 222 °C

IRC Nujol) : 3380, 3150, 1660, 1630, 1585, 1530 cm ^'1

NMRCDMSO-de, <5) : 7.51-7.62C2H, m), 7.96-7.99C2H, m),

10.43C1H, br. s), 12.32C1H, s)

MassCm, e) : 322 (M

Preparation 6

To concentrated sulfuric acid ( 20ml) was added 3, 5- dibromo - hydroxyiminoacetanilide (5. 61g) at 60 ~ 70 °C for 15 minutes and then stirred at 70 °C for 10 minutes. The resultant mixture was diluted with chilled water and extracted with ethyl acetate (50ml). The extract was washed with brine ( 100ml x 5), dried over anhydrous sodium sulfate and then evaporated in vacuo. The residue was triturated with diisopropyl ether to give 4, 6- dibromo- 2, 3- dioxo- IH- indole (4.3g). mp : 263- 265 °C , IR( Nujol) : 3200, 1770, 1730, 1595, 1560 cm ^"1 NMR(DMSO-d ₆ , <5) : 7.06 (IH, d, J=l.5Hz), 7.51 (IH, d, J=l. 5Hz) Mass (m/e) : 360 (M ^M )

Preparation 7

To a solution of 4, 6-dibromo-2, 3- dioxo- IH- indole (4.15g) in N, N- dimethylformamide (60ml) was added sodium hydride (60

% in mineral oil, 583mg) at 0~10°C under nitrogen atmosphere

and the mixture was stirred for 1 hour at room temperature. To thereaction mixture was added dropwise methyl bromoacetate (2. 23g) in N, N- dimethylformamide (10ml) at 5°C and stirred for 2 hours atroom temperature. The reaction mixture was diluted with chilled water and acidified to pH 3 with 6N-HC1. The resulting precipitates were collected and washed with water to give methyl 2-(4, 6- dibromo- 2, 3- dioxo- lH-indol- 1-yl) acetate (5. Og) mp : 182- 184 °C

IR( Nujol) : 1750, 1735, 1590, 1560, 1220 cm ^"1 NMR (DMSO-de, δ) : 3.71 (3H, s), 4.64 (2H, s), 7.63 (IH, d, J=l.3Hz), 7.65 (IH, d, J=l.3Hz) MassCm, e) : 378CM")

Preparation 8

A solution of methyl 2-(4, 6- dibromo- 2, 3-dioxo-lH-indol-

1 - yl) acetate ( 4.8g ) , 3 - chloroperoxybenzoic acid ( 2. 56g ) in dichloromethane (120ml) was stirred at 10 °C for 1 hour. To this solution was added 28% aqueuos ammonia (15ml) below 10 °C and stirred at 20 °C for 2 hours. The resultant mixture was evaporated in vacuo and diluted with water. The resulting precipitates were collected , dissolved with a mixture of tetrahydrofuran and ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate , water and brine successively, dried over anhydrous sodium sulfate and then evaporated in vacuo. The residue was triturated with a mixture of ethyl acetate and diisopropyl ether to give methyl N - ( 2 - carbamoyl-3, 5- dibromophenyl) aminoacetate (1.5g). mp : 192- 193 °C

IRC Nujol) : 3400, 3200, 1730, 1655, 1630, 1570 cm ' NMRCDMSO-d ₆ , 5) : 3.67C3H, s), 3.99C2H, d, J=5.8Hz), 5.73 CIH, t, J=5.8Hz), 6.69C1H, d, J = l. iHz), 7.02C1H, d, J=l.6Hz), 7.74 (IH, br. s), 7.94 CIH, br. s)

MassCm/ e) : 367 C M

Preparation 9

A mixture of methyl N-( 2- carbamoyl- 3, 5- dibromophenyl) aminoacetate (1.36g) and N, N '- carbonyldiimidazole (2. lg) was stirred at 140 °C for 15 minutes. After cooling, the resulting material was triturated with a mixture of diisopropyl ether (30ml) and IN- HCl (20ml). The resulting precipitates were collected and washed with water to give methyl 2-(5, 7- dibromo- 2, 4- dioxo -1, 2, 3, 4 - tetrahy droquinazolin- 1-yl) acetate (1.4g). mp : 261- 262 °C

IRC Nujol) : 1735, 1720, 1580, 1555 cm '

NMR(DMSO-d ₆ , δ) : 3.71 (3H, s), 4.93(2H, s), 7.72 (IH, d,

J=l.6Hz), 7.78C1H, d, J=l.6Hz)

Preparation 10

Methyl 2-( 4- bromo- 2, 3- dioxo- lH-indol- 1-yl) acetate was obtained according to a similar manner to that of Preparation 7. mp : 125- 128 °C

IRC Nujol) : 1730, 1600, 1580 cm ¹

NMR ( DMSO- dβ, 5) : 3.70 (3H, s), 4.64 (2H, s), 7.20 (IH, d, J=7.9Hz), 7.34 (IH, d, J = 8.2Hz), 7.52-7.62 (IH, m)

Preparation 11

A solution of methyl 2-(4-bromo-2, 3-dioxo-lH-indol-l-yl) acetate ( 4. 54g ) , 3 - chloroperoxybenzoic acid ( 3. 61g ) in dichloromethane (100ml) was stirred at 10 °C for 3 hours. To this solution was added 0.5N aqueuos solution of sodium hydroxide (20ml) and stirred for 5 minutes. The separated organic layer was washed with water and brine successively , dried over anhydrous magnesium sulfate and then evaporated in vacuo to give methyl 2-C5-bromo-2H-3, l-benzoxazine-2, 4ClH)-dione-l-yl)

acetate (4.8g). mp : 121- 124 °C

IRC Nujol) : 1890, 1735, 1690, 1590, 1575 cm ¹

NMRCDMSO-d ₆ , δ : 3.75C3H, s), 4.92C2H, s), 7.35-8.00C3H, m)

Preparation 12

To a suspension of methyl 2-(5-bromo-2H-3, 1 - benzoxazine

-2, 4 CIH)- dione- 1-yl) acetate C5.28g) in N, N- dimethylformamide

C15ml) was added 28% aqueous ammonia Cl.15ml) below 10 °C and thenstirred at 5 ~ 10 °C for 20 minutes. The resultant mixture was diluted with chilled water and acidified to pH 4 with 6N-HC1 and then extracted with ethyl acetate. The extract was washed with water and brine successively , dried over anhydrous magnesium sulfate and then evaporated in vacuo. The residue was subjected to column chromatography on silica gel eluting with

10% methanol - chlorof orm to give methyl N-C 2- carbamoyl- 3 - bromophenyl) aminoacetate C2.27g). mp : 146- 150 °C

IRC Nujol) : 3400, 1725, 1650 cm ^"1

NMRCDMSO-d ₆ , δ) : 3.66C3H, s), 3.96C2H, d, J=5.9Hz), 5.50 CIH, t, J = 5.9Hz), 6.48C1H, d, J=7.7Hz), 6.74C1H, d. d, J=l.9, 7.7Hz), 7.01-7.10C1H, m), 7.68C1H, s), 8.90C1H, s) .MassCm' e) : 388 CM )

Preparation 13

Methyl 2-C5-bromo-2, 4-dioxo-l, 2, 3, 4-tetrahydroquinazolin -1-yl) acetate was obtained according to a similar manner to that of Preparation 9. mp : 227- 229 °C

IRC Nujol) : 3150, 1740, 1710, 1690, 1590 cm ^"1

NMR C DMSO- d ₆ , δ : 3.71C3H, s), 4.93C2H, s), 7.30-7.60C3H,

m), 11.81 CIH, br. s) MassCm e) : 314CM ⁺¹ )

Preparation 14

Methyl 2-C 6- bromo- 2, 3- dioxo- lH-indol- 1-yl) acetate was obtained according to a similar manner to that of Preparation 7. mp : 136- 138 °C IRC Nujol) : 1740, 1600 cm ^'1

NMRCDMSO-d ₆ , δ) : 3.72C3H, s), 4.63C2H, s), 7.38-7.61C3H, m)

Preparation 15

Methyl 2-C 7- bromo- 2H- 3, l-benzoxazine-2, 4C lH)-dione- 1- yl) acetate was obtained according to a similar manner to that of

Preparation 11. mp : 141- 145 °C

IRC Nujol) : 1790, 1785, 1740, 1700, 1600 cm ^'1

NMR C DMSO-de, 5) : 3.74C3H, s), 4.92C2H, s), 7.25-7.94C3H, m)

Preparation 16

Methyl N - C 2 - carbamoyl - 5 - bromophenyl ) aminoacetate was obtained according to a similar manner to that of Preparation 12. mp : 128- 133 °C

IRC Nujol) : 3350, 1750, 1725, 1640, 1610 cm ^'1 NMRCDMSO-de, δ) : 3.68C3H, s), 4.08C2H, d, J=5.7Hz), 6.70 -6.81C2H, m), 7.54C1H, d, J = 8.9Hz), 8.61 C IH, t, J = 5.7Hz)

Preparation 17

Methyl 2-C 7- bromo- 2, 4- dioxo- 1, 2, 3, 4-tetrahydroquinazolin -1-yl) acetate was obtained according to a similar manner to that

of Preparation 9. mp : 235- 238 °C

IRC Nujol) : 1740, 1710, 1690, 1595, 1570 cm ^'1 NMRCDMSO-d ₆ , δ) : 3.71C3H, s), 4.93C2H, s), 7.51 CIH, d. d, J=l.6, 7.2Hz), 7.72C1H, d, J=l.6Hz), 7.92C1H, d, J=7.2Hz), 11.9C1H, br. s)

Example 1

A mixture of methyl 2-C5, 7- dichloro- 2, 4- dioxo- 1, 2, 3, 4- tetrahydroquinazolin- 1-yl) acetate C606mg) and N-C2- aminoethyl) piperidine C2ml) was stirred at room temperature for 4 hours. The resultant mixture was diluted with ethyl acetate and stood for overnight. The resulting precipitates were collected and recrystallized from methanol - ethyl acetate to give N-( 2- piperidinoethyl ) - 2 - C 5 , 7- dichloro - 2 , 4 - dioxo - 1 , 2 , 3 , 4 - tetrahydroquinazolin - 1 - y 1 ) acetamide C 230mg ) . mp : 221- 223 °C

IRC Nujol) : 3230, 1705, 1690, 1625 cm ¹

NMRCDMSO-d ₆ , δ) : 1.27-1.59C6H, m), 2.20-2.46C6H, m),

3.10-3.27C2H, m), 4.69C2H, s), 7.20C1H, d, J=l.8Hz),

7.47C1H, d, J=l.8Hz), 8.14C1H, t, J = 5.7Hz), 11.69C1H, br. s)

MassCm. e) : 400CM ^*1 )

Elemental Analysis : calcd. for C ₁₇ H ₂ oCl ₂ N ₄ O3 : C 51.14, H 5.05, N 14.03 found : C 51.05, H 4.99, N 13.87

Example 2

N- [3-C Pyrrolidin- 1-yl) propyl)] -2-C 5, 7- dichloro- 2, 4- dioxo - 1 , 2 , 3 , 4 - tetrahydroquinazolin - 1 - yl ) acetamide was obtained according to a similar manner to that of Example 1. mp : 238- 239 °C

IRCNujol) : 3300, 1720, 1708, 1630, 1585 cm ^'1

NMRCDMSO-d ₆ , <5) : 1.43-1.78C6H, m), 2.23-2.48C6H, m),

3.00-3.20C2H, m), 4.68C2H, s), 7.21 C IH, d, J=l.7Hz), 7.47C1H, d, J=l.7Hz), 8.19C1H, t, J=5.4Hz) MassCm/e) : 400CM ⁺¹ )

Example 3

A mixture of methyl 2- 5, 7- dichloro- 2, 4- dioxo- 1, 2, 3, 4- tetrahydroquinazolin- 1-yl) acetate C606mg) and N-C3- aminopropyl) imidazole 2ml) was stirred at room temperature for 7 hours. The resulting precipitates were collected and washed with methanol. This material was dissolved with 2N HCl C30ml) and stood overnight. The resulting precipitates were collected to give N- [3- C imidazol- 1-yl) propyl)] -2-C 5, 7- dichloro- 2, 4- dioxo- 1, 2, 3, 4- tetrahydroquinazolin- 1-yl) acetamide dihydrochloride C550mg). mp : 168- 171 °C

IRCNujol) : 3300, 1700, 1650, 1585 cm ^'1

NMRCDMSO-de, <5) : 1.88-2.08C2H, m), 3.02-3.13C2H, m),

4.22C2H, t, J = 6.7Hz), 4.76C2H, s), 7.36C1H, d, J=l.6Hz),

7.47C1H, d, J=l.6Hz), 7.70C1H, d, J=l.4Hz), 7.79C1H, d, J

= 1.4Hz), 8.57C1H, t, J = 5.8Hz), 9.18C1H, s), 11.79C1H, s)

MassCm/ e) : 396 CM )

Elemental Analysis : calcd. for CKHΠCUNBOS : C 40.96, H 3.65, N 14.93 found : C 40.98, H 4.05, N 14.47

Example 4

A mixture of methyl 2-C5, 7- dichloro- 2, 4- dioxo- 1, 2, 3, 4- tetrahydroquinazolin- 1-yl) acetate C304mg) and 4- 3- aminopropyl) morpholine Clml) was stirred at room temperature for 4 hours. The resultant mixture was dissolved with methanol C 10ml) and then stood for overnight . The resulting precipitates were collected and washed with methanol to give N - C 3 -

morpholinopropyl ) - 2 - C 5 , 7- dichloro - 2 , 4 - dioxo - 1 , 2 , 3 , 4 - tetrahydroquinazolin- 1-yl) acetamide. mp : 248-251 °C

IRCNujol) : 3300, 1710, 1640, 1590 cm ^'1

NMRCDMSO-de, δ) : 1.42-1.63C2H, m), 2.21C2H, t, J = 7.

2Hz), 2.26-2.34C4H, m), 3.06-3.20C2H, m), 3.50-3.63C4H, m), 4.69C2H, s), 7.21 CIH, d, J=l.6Hz), 7.47C1H, d, J=l.6Hz),

8.18C1H, t, J = 6. OHz), 11.72C1H, br. s)

Mass C m/e) : 416CM ⁺¹ )

Elemental Analysis : calcd. for C7H20CI2N4O4 : C 49.17, H 4.85, N 13.49 found : C 48.83, H 4.86, N 13.28

Example 5

N- [2-CN\ N'- Dimethylamino) ethyl] -2-C 5, 7- dichloro- 2, 4- dioxo- 1, 2, 3, 4- tetrahydroquinazolin- 1-yl) acetamide was obtained according to a similar manner to that of Example 4. mp : 235- 238 °C

IRC Nujol) : 3230, 1705, 1690, 1630 cm ¹

NMRCDMSO-d ₆ , 5) : 2.14C6H, s), 2.28C2H, t, J = 6.6Hz), 3.09 -3.24C2H, m), 4.70C2H, s), 7.20C1H, s), 7.46C1H, s), 8.18C1H, t, J = 6.4Hz)

MassCm/ e) : 360 CM ) . Elemental Analysis : calcd. for C.4H.6CI2N4O3 : C 46.81, H 4.49, N 15.60 found : C 47.14, H 4.54, N 15.73

Example 6

N- [2-C 4- Pyridyl) ethyl] -2-C 5, 7-dichloro-2, 4-dioxo-l, 2, 3, 4- tetrahydroquinazolin- 1-yl) acetamide was obtained according to a similar manner to that of Example 4. mp : above 270 °C

IRC Nujol) : 3270, 1700, 1650 cm ^'1

NMRCDMSO-de, δ) : 2.72C2H, t, J=6.8Hz), 3.30-3.46C2H, m), 4.68C2H, s), 7.16-7.28C3H, m), 7.47C1H, d, J=l.7Hz), 8.29C1H, t, J = 5.6Hz), 8.36-8.47C2H, m), 11.74C1H, s) Mass C m/e) : 394CM ⁺¹ ) Elemental Analysis : calcd. for C ₁₇ H ₁₄ Cl ₂ N ₄ θ3 • H ₂ 0

: C 49.87, H 3.89, N 13.68 found : C 49.80, H 3.56, N 13.43

Example 7

N - Benzyl - 2 - C 5 , 7 - dichloro - 2, 4- dioxo - 1 , 2 , 3 , 4 - tetrahydroquinazolin- 1-yl) acetamide was obtained according to a similar manner to that of Example 4. mp : above 280 °C

IRC Nujol) : 3290, 1720, 1690, 1645, 1584, 1560 cm ' NMRCDMSO-de, δ) : 4.31C2H, d, J = 5.9Hz), 4.79C2H, s), 7.14 -7.40C6H, m), 7.48C1H, d, J = l.6Hz), 8.73C1H, t, J=5.9Hz), 11. 78C1H, s) MassCm/ e) : 379CM ^*1 )

Example 8

N-C 2- Hydroxyethyl)- 2-C 5, 7- dichloro- 2, 4- dioxo- 1, 2, 3, 4- tetrahydroquinazolin- 1- yl) acetamide was obtained by treating ethyl 2-C5, 7-dichloro-2, 4-dioxo-l, 2, 3, 4- tetrahydroquinazolin- 1

-yl) acetate according to a similar manner to that of Example 4. mp : 265- 270 °C

IRC Nujol) : 3280, 1650, 1580 cm ^'1

NMRCDMSO-d ₆ , δ) : 2.52-2.67C2H, m), 3.28-3.40C2H, m),

4.70C2H, s), 7.21 CIH, d, J=l.8Hz), 7.44C1H, d, J=l.8Hz)

MassCm e) : 333CM ^'1 )

Example 9

A solution of methyl 2-C 5, 1- dichloro- 2, 4- dioxo- 1, 2, 3, 4- tetrahydroquinazolin - 1-yl) acetate C 304m ) and diethanolamine C3ml) in methanol C 10ml) and chloroform C 20ml) was stirred under reflux for 75 hours. After cooling the resulting precipitates were collected and washed with methanol to give N, N-bis(2- hydroxyethyl ) - 2 - C 5 , 7 - dichloro - 2, 4- dioxo - 1 , 2 , 3 , 4 - tetrahydroquinazolin- 1-yl) acetamide C 180mg). mp : 260- 261 °C

IRC Nujol) : 3540, 3170, 1710, 1690, 1655, 1590 cm ¹ NMRCDMSO-de, δ ^~ ) : 3.24-3.75C8H, m), 4.73C1H, t, J=5. 1Hz), 5.07C2H, s), 5.26C1H, t, J = 4.1Hz), 7.36C1H, d, J=l.7Hz), 7.44C1H, d, J-1.7Hz), 11.75C1H, s) MassCm/ e) : 377CM ⁺¹ )

Example 10

A mixture of ethyl 2-C 5, 7- dichloro- 2, 4- dioxo- 1, 2, 3, 4- tetrahydroquinazolin - 1 - yl ) acetate C 317mg ) and N , N - dimethylaminoethylamine C440mg) was stirred at 100 °C for lhour. The resultant mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous sodium sulfate and then evaporated in vacuo. The residue was subjected to column chromatography on silica gel eluenting with 10% methanol- chloroform to give N- [2 -CN', N'- dimethylamino) ethyl] -2- [7-chloro-2, 4-dioxo-5- [2-CN\ N '-dimethylamino) ethylamino] -1, 2, 3, 4- tetrahydroquinazolin- 1-yl] acetamide C250mg). mp : 211- 214 °C

IRC Nujol) : 3280, 1700, 1660, 1595, 1580, 1545 cm ^'1 NMRCDMSO-de, δ) : 2.13C6H, s), 2.19C6H, s), 2.27C2H, t, J = 6.6Hz), 2.43-2.58C2H, m), 3.08-3.30C4H, m), 4.58C2H, s) , 6.13C1H, d, J=l.5Hz), 6.44C1H, d, J=l.5Hz), 8.15C1H, t,

J=5.5Hz), 9.04C1H, t, J=5.7Hz), 11.41 CIH. s)

Mass C m/e) : 411CM")

Elemental Analysis : calcd. for : C 52.62, H 6.62, N 20.45 found : C 52.62, H 6.47, N 20.26

Example 11

A mixture of ethyl 2-C 5, 7- dichloro- 2, 4- dioxo- 1, 2, 3, 4- tetrahydroquinazolin- 1-yl) acetate C634mg) and 4-(2- aminoethyl) pyridine C2ml) was stirred at 100 °C for 4 hours. The resultant mixture was diluted with ethyl acetate and stood for overnight. The resulting precipitates were collected and recrystallized from methanol- ethyl acetate to give N- [2-C 4- pyridyl) ethyl] -2- [7- chloro- 2, 4- dioxo- 5- [2-C 4- pyridyl) ethylamino] - 1, 2, 3, 4- tetrahydroquinazolin-1-yl] acetamide C360mg). mp : 207- 210 °C

IRC Nujol) : 3250, 1700, 1655, 1585 cm ^'1

NMR(DMSO-d ₆ , δ) : 2.72C2H, t, J = 6.7Hz), 2.94C2H, t, J = 6. 7Hz), 3.24-3.43C2H, m), 3.47-3.62C2H, m), 4.54C2H, s), 6. 15C1H, s), 6.55C1H, s), 7.18-7.38C4H, m), 8.26 CIH, t, J = 5. 7Hz), 8.40-8.54C4H, m), 8.95C1H, t, J=5.7Hz) MassCm, e) : 479CM ^'1 )

Example 12

CN-4-Methylpiperazinyl)-2-C5, 7-dichloro-2, 4-dioxo-l, 2, 3, 4- tetrahydroquinazolin- 1-yl) acetamide was obtained according to a similar manner to that of Example 11. mp : 219- 222 °C

IRCNujol) : 3160, 1740, 1700, 1580 cm ^'1

NMRCDMSO-de, δ) : 2.22C3H, s), 2.49C4H, br. s), 3.06C4H, br. s), 4.86C2H, s), 6.81 C IH, s), 6.88C1H, s)

Example 13

A mixture of methyl 2-C 5, 7- dichloro- 2, 4- dioxo- 1, 2, 3, 4- tetrahydroquinazolin - 1 - yl ) acetate C 608mg ) and N , N - diisobutylaminoethylamine C5ml) was stirred at 50 °C for 48 hours. The resultant mixture was diluted with ethyl acetate and stood for overnight. The resulting precipitates were collected and recrystallized from methanol - chloroform to give N - [ 2 - C N ' , N ' - diisobutylamino ) ethyl ] - 2 - C 5 , 7- dichloro -2, 4- dioxo - 1 , 2 , 3 , 4 - tetrahydroquinazolin - 1 - y 1 ) acetamide ( 280mg ) . mp : 240- 242 °C

IRC Nujol) : 3280, 1730, 1680, 1665, 1595, 1560 cm ^'1 NMRCDMSO-de, δ) : 0.82C12H, d, J = 6.5Hz), 1.50-1.86C2H, m), 2.07C4H, d, J = 7.2Hz), 2.35C2H, d, J = 8. OHz), 2.03-3.20 C2H, m), 4.67 C2H, s), 7.18C1H, d, J-1.8Hz), 7.47C1H, d, J = 1.8Hz), 7.98-8.09C1H, m), 11.75C1H, s) MassCm/ e) : 444CM ^*1 )

Example 14

N-[2-CN', N'-Diisopropylamino)ethyl]-2-C5, 7-dichloro-2, 4- dioxo-1, 2, 3, 4- tetrahydroquinazolin- 1-yl) acetamide was obtained according to a similar manner to that of Example 13. mp : 241- 242 °C

IRC Nujol) : 3380, 1705, 1635, 1585, 1560, 1525 cm ^'1 .NMRCDMSO-de, δ) : 0.93C12H, t, J = 6.5Hz), 2.36 (2H, t, J = 6.

9Hz), 2.80-3.07C6H, m), 4.68C2H, s), 7.21C1H, d, J=l.7Hz),

7.47C1H, d, J=l.7Hz), 8.08C1H, t, J=5.7Hz), 11.76C1H, br. s)

MassCm e) : 416(M )

Example 15

N-[2-CN', N'-Diethylamino)ethyl]-N-methyl-2-C5, 7-dichloro - 2, 4- dioxo- 1, 2, 3, 4- tetrahydroquinazolin- 1-yl) acetamide was obtained according to a similar manner to that of Example 13.

mp : 173- 175 °C

IRCNujol) : 3150, 1750, 1690, 1660 cm '

NMRCDMSO-de, δ) : 0.86C6H, t, J = 7.1Hz), 2.37C4H, q, J = 7.

1Hz), 2.55C2H, t, J=6.6Hz), 2.87C3H, s), 3.25C2H, t, J = 6.6Hz),

4.82C2H, s), 6.70C1H, d, J=l.6Hz), 6.81C1H, d, J=l.6Hz), 11.

24 CIH, br. s)

MassCm e) : 402CM ⁺¹ )

Example 16

N-[CN'-ethylpyrrolidin-2-yl)methyl]-2-C5, 7- dichloro- 2, 4- dioxo- 1, 2, 3, 4- tetrahydroquinazolin- 1-yl) acetamide was obtained according to a similar manner to that of Example 13. mp : 241- 246 °C

IRC Nujol) : 3200, 1710, 1690, 1585, 1560 cm '

NMRCDMSO-de, δ) : 1.00C3H, t, J=7.1Hz), 1.40-1.70C2H, m), 2.00-2.30C2H, m), 2.70-3.50C5H, m), 4.72C2H, s), 7.19

CIH, d, J=l.8Hz), 7.46C1H, d, J=l.8Hz), 8.20C1H, br. s)

MassCm e) : 400CM ^*1 )

Example 17

A solution of methyl 2-C 5, 7- dichloro- 2, 4- dioxo- 1, 2, 3, 4- tetrahydroquinazolin - 1 - yl ) acetate ( 1. Og ) and N , N - dibenzylaminoethylamine C2. Og) in N, N- dimethylformamide C15ml) was stirred at 80 °C for 2 hours. The solvent was evaporated in vacuo, the residue was diluted with water and extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous sodium sulfate and then evaporated in vacuo. The residue was subjected to column chromatography on silica gel eluting with 10% ethyl acetate- chloroform to give N-[2- CN\ N'-dibenzylamino)ethyl]-2-C5, 7-dichloro-2, 4- dioxo- 1, 2, 3, 4 -tetrahydroquinazolin- 1-yl) acetamide C640mg). mp : 146- 149 °C

IRC Nujol) : cm ^'1

NMRCDMSO-de, <5) : 2.55-2.75C2H, m), 3.30-3.42C2H, m), 3.57C4H, s), 4.83C2H, s), 6.36C1H, s), 6.40C1H, s), 7.10-7.50C10H, m), 9.22C1H, br. s), 11.70 CIH, s)

Mass (m e) : 512 C MO

Example 18

N-[2-CN\ N'- Dimethylamino) ethyl]- 2-C 5, 7-dichloro-2, 4- dioxo- 3- methyl- 1, 2, 3, 4- tetrahydroquinazolin- 1-yl) acetamide was obtained by treating 2-C5, 7-dichloro-2, 4- dioxo- 3- methyl- 1, 2, 3, 4- tetrahydroquinazolin- 1-yl) acetate according to a similar manner to that of Example 13. mp : 181- 182 °C

IRC Nujol) : 3220, 1720, 1665, 1590, 1565 cm ^'1 NMRCDMSO-de, <5) : 2.12C6H, s), 2.25C2H, t, J=6.6Hz), 3.10 -3.19C2H, m), 3.27C3H, s), 4.77C2H, s), 7.27C1H, d, J=l.9Hz), 7.51 CIH, d, J=l.9Hz), 8.15C1H, br. s) MassCm e) : 373 (M0

Example 19

N-[2-(N', N '-Dimethylamino) ethyl]-2-(2, 4- dioxo- 1, 2, 3, 4 - tetrahydroquinazolin - 1 - yl ) acetamide was obtained by treating methyl 2- (2, 4- dioxo- 1, 2, 3, 4- tetrahydroquinazolin- 1-yl) acetate according to a similar manner to that of Example 13. mp : 200- 201 °C

IR( Nujol) : 3250, 1680, 1640, 1600, 1560 cm ^'1 NMR(DMSO-d ₆ , <5) : 2.12(6H, s), 2.25(2H, t, J = 6Hz), 3.15 (2H, q-like, J = ca.6Hz), 4.67(2H, s), 7.14C1H, d, J = 8Hz), 7.26 (IH, d. d, J = 8, 8Hz), 7.70C1H, d. d. d, J = 2, 8, 8Hz), 8.01 (IH, d. d, 3 = 2, 8Hz), 8.19(1H, t, J = 5Hz), 11.60(1H, br. s) Mass(m e) : 291 (MO

Example 20

N-[2-(N', N '-Dimethylamino) ethyl]- 2-( 5- chloro- 2, 4-dioxo

-1, 2, 3, 4- tetrahydroquinazolin- 1-yl) acetamide was obtained by treating methyl 2 - ( 5 - chloro - 2 , 4 - dioxo - 1 , 2 , 3 , 4 - tetrahydroquinazolin- 1-yl) acetate according to a similar manner to that of Example 13. mp : 229- 232 °C

IR(Nujol) : 3240, 1710, 1690, 1635, 1595, 1570, 1545 cm ^'1 NMR(DMSO-d ₆ , δ) : 2.12(6H, s), 2.25(2H, t, J=6.7Hz), 3.10 -3.20(2H, m), 4.67(2H, s), 7.08(1H, d, J=8.5Hz), 7.86(1H, d, J=7.9Hz), 7.57-7.67(1H, m), 8.17(1H, t, J=5.1Hz), 11.55 (IH, br. s)

Example 21

N-(2-piperidinoethyl)-2-(5-chloro-2, 4- dioxo- 1, 2, 3, 4- tetrahydroquinazolin - 1 - yl ) acetamide was obtained by treating methyl 2-(5-chloro-2, 4- dioxo- 1, 2, 3, 4- tetrahydroquinazolin- 1-yl) acetate according to a similar manner to that of Example 13. mp : 215- 218 °C

IR( Nujol) : 3240, 1710, 1690, 1630 cm ¹

NMR(DMSO-d ₆ , δ) : 1.23-1.54(6H, m), 2.18-2.40(6H, m),

3.08-3.20(2H, m), 4.66(2H, s), 7.08(1H, d, J = 8.2Hz), 7.30

(IH, d, J = 7.5Hz), 7.54-7.66(1H, m), 8.11 (IH, t, J=5.4Hz),

.11.58 (IH, br. s)

Example 22

A mixture of methyl 2-( 5- bromo- 2, 4- dioxo- 1, 2, 3, 4- tetrahydroquinazolin - 1 - yl ) acetate ( 469mg ) and N , N - dimethylaminoethylamine (3.5ml) was stirred at room temperature for 24 hours. The resultant mixture was diluted with ethyl acetate and stood for overnight. ^' he resulting precipitates werecollected and washed with ethyl acetate to give N-[2-(N',N'

- dimethylamino ) ethyl ] - 2 - ( 5 - bromo - 2, 4- dioxo - 1 , 2 , 3 , 4 - tetrahydroquinazolin- 1-yl) acetamide (368mg). mp : 239- 240 °C

IRC Nujol) : 3230, 1710, 1690, 1655, 1630, 1595, 1560 cm ^'1 NMR(DMSO-d ₆₎ <5) : 2.12C6H, s), 2.25(2H, t, J = 6.7Hz), 3.10 -3.20(2H, m), 4.67(2H, s), 7.05-7.17C1H, m), 7.45-7.58(2H, m), 8.15C1H, t, J=5.6Hz), 11.56 (IH, br. s) Mass (m/e) : 370 (MO

Example 23

A mixture of methyl 2-( 7- bromo- 2, 4- dioxo- 1, 2, 3, 4- tetrahydroquinazolin - 1 - yl ) acetate ( 469mg ) and N , N - dimethylaminoethylamine (4ml) was stirred at room temperature for 24 hours. The resultant mixture was evaporated in vacuo and then recrystallized from methanol- ethyl acetate to give N-[2 -CN', N'- dimethylamino) ethyl]- 2-( 7- bromo- 2, 4- dioxo- 1, 2, 3, 4- tetrahy droquinazolin - 1 - y 1 ) acetamide ( 390mg ) . mp : 221- 222 °C

IRC Nujol) : 3240, 1708, 1690, 1635, 1600 cm ^'1 NMRCDMSO-de, <5) : 2.13C6H, s), 2.27C2H, t, J=6.6Hz), 3.05 -3.25C2H, m), 4.69C2H, s), 7.38-7.54C2H, m), 7.90C1H, d, J = 8.3Hz), 8.17C1H, t, J=5.4Hz), 11.57C1H, br. s) MassCm/ e) : 370 C M0

Example 24

N-[2-CN\ N'- Dimethylamino) ethyl] -2-C 5, 7-dibromo-2, 4- dioxo- 1, 2, 3, 4- tetrahydroquinazolin- 1-yl) acetamide was obtained by treating methyl 2 - ( 5 , 7 - dibromo -2, 4- dioxo - 1 , 2 , 3 , 4 - tetrahydroquinazolin- 1-yl) acetate according to a similar manner to that of Example 23. mp : 221- 224 ^C C (recrystallized from ethyl acetate- acetone) IRC Nujol) : cm ¹

NMRCDMSO-de, δ) : 2.13C6H, s), 2.26C2H, t, J = 6.7Hz), 3.10 -3.22C2H, m), 4.69C2H, s), 7.34 (IH, d, J=l.7Hz), 7.75(1H, d, J=l.7Hz), 8.16(1H, t, J=6.6Hz)

Example 25

To a suspension of 2-(5, 7- dichloro- 2, 4- dioxo- 1, 2, 3, 4- tetrahydroquinazolin- 1-yl) acetic acid (578mg), 3- amino- a- Boc - alanine ethyl ester (464mg), triethylamine (0.7ml) and molecular sieve 4A powder (900mg) in N, N- dimethylformamide (10ml) was added 2 - chloro - 1 - methylpyridinium iodide ( 613mg) and then stirredat room temperatureat for 2 hours. The resultant mixture was diluted with water and extracted with ethyl acetate. The extractwas washed with water and brine successively, dried over anhydrous sodium sulfate and then evaporated in vacuo to give 3 -[2-(5, 7-dichloro-2, 4- dioxo- 1, 2, 3, 4- tetrahydroquinazolin- 1-yl)] acetylamino- a- Boc- alanine ethyl ester (300mg). mp : 208- 210 °C

IR( Nujol) : 3320, 3170, 1720, 1690, 1680, 1660, 1590, 1560 cm '

NMR(DMSO-d ₆ , δ) : 1.16(3H, t, J = 7.1Hz), 1.38(9H, s), 3.28 -3.51 (2H, m), 3.95-4.10C3H, m), 4.69(2H, s), 7.09(1H, d,

J = 7.9Hz), 7.20 (IH, d, J = l.7Hz), 7.48(1H, d, J=l.7Hz), 8.30

(IH, t, J=5.7Hz), 11.80 (IH, s)

Example 26

To a solution of 3-[2-(5, 7-dichloro-2, 4-dioxo-l, 2, 3, 4- tetrahydroquinazolin- 1-yl)] acetylamino- a - Boc- alanine ethyl ester (460mg) in dioxane (5ml) was added 4N HCl in dioxane (4ml) and then stirred at room temperatureat for 3 hours. The resultant mixture was evaporated to half of its initial volume and then resulting precipitates were collected and washed with ethyl acetate to give 3 - [ 2 - ( 5 , 7 - dichloro - . , 4 - dioxo - 1 , 2 , 3 , 4 - tetrahydroquinazolin - 1 - yl ) ] acetylaminoalanine ethyl ester

hydrochloride (396mg). mp : 227- 228 °C

IR( Nujol) : 1735, 1720, 1700, 1685, 1675, 1585 cm ^'1 NMR(DMS0-d ₆₎ δ) : 1.22(3H, t, J-7.2Hz), 3.51-3.6K2H, m), 3.96-4.24(3H, m), 4.78(2H, s), 7.38(1H, d, J=l.7Hz), 7. 48(1H, d, J=l.7Hz), 8.61-8.82(3H, m), 11.80(1H, br. s) Mass(m e) : 404 (MO

Example 27

A mixture of 3-[2-(5, 7- dichloro- 2, 4- dioxo- 1, 2, 3, 4- tetrahydroquinazolin - 1 - yl ) ] acetylaminoalanine ethyl ester hydrochloride (340mg), lithium hydroxide monohydrate (161.6mg), water (lml) and ethanol (5ml) was stirred at room temperature for 90 minutes and then 4N HCl in dioxane (3.5ml) was added thereto. The resulting precipitates were collected and washed with acetoneto give 3 - [ 2 - ( 5 , 7- dichloro - 2 , 4 - dioxo - 1 , 2 , 3 , 4 - tetrahydroquinazolin- 1-yl)] acetylaminoalanine ( 280mg). mp : 245- 247 °C

IR( Nujol) : 3330, 3170, 1720, 1700, 1670, 1635, 1590 cm ^'1 NMR(DMSO-d ₆ , <5) : 3.70-4.00(2H, m), 4.15-4.35(1H, m), 5.0K2H, s), 7.27(1H, s), 7.47(1H, s)