QUINAZOLINE DERIVATIVES AND THEIR PREPARATION

Abstract: A compound of formula (I) in which R<1> is substituted heterocyclic-(lower)alkyl, and R<2> is hydrogen, halogen, nitro, amino, protected amino, hydroxyamino, lower alkyl, hydroxy, protected hydroxy, sulfamoyl, carboxy, protected carboxy, mercapto, optionally substituted heterocyclic-carbonyl, optionally substituted heterocyclic-(lower)alkyl, lower alkylthio, hydroxy(lower)alkyl or protected hydroxy(lower)alkyl, R<3> is aryl which may have suitable substituent(s), and A is lower alkylene, or pharmaceutically acceptable salts thereof, useful as a dopamine receptor agonist, 5-HT receptor antagonist or alpha 1 receptor antagonist.

Description: DESCRIPTION QUINAZOLINE DERIVATIVES AND THEIR PREPARATION The present invention relates to novel quinazoline derivatives and pharmaceutically acceptable salts thereof. More particularly, it relates to novel quinazoline derivatives and pharmaceutically acceptable salts thereof, which display effects on the peripheral or central nervous system, to processes for the preparation thereof, to a pharmaceutical composition comprising the same, to a use of the same as a medicament and to a method of the therapeutic treatment of diseases in a human being or animal. INDUSTRIAL APPLICABILITY Accordingly, one object of the present invention is to provide novel quinazoline derivatives and pharmaceutically acceptable salts thereof, which display effects on the peripheral or central nervous system, in particular on the peripheral nervous system. Another object of the present invention is to provide processes for the preparation of novel quinazoline derivatives and salts thereof. A further object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, said quinazoline derivatives and pharmaceutically acceptable salts thereof. Still further object of the present invention is to provide a use of said quinazoline derivatives and pharmaceutically acceptable salts thereof as a dopamine receptor agonist, 5-HT receptor antagonist, especially 5-HT2 receptor antagonist; e- receptor antagonist; and th like and a method of the therapeutic treatment of dopamin receptor; 5-HT receptor, especially 5-HT2 receptor; αi-receptor; mediated diseases, particularly hypertension, cardiovascular disorder (e.g. angina pectoris, myocardial infarction, etc.), Parkinsonism, and the like, in a human being or animal. DISCLOSURE OF INVENTION The object quinazoline derivatives are novel and can be represented by the following general formula: in which R 1 is substituted heterocyclic-(lower)alkyl, and R 2 is hydrogen, halogen, nitro, amino, protected amino, hydroxyamino, lower alkyl, hydroxy, protected hydroxy, sulfamoyl, carboxy, protected carboxy, mercapto, optionally substituted heterocyclic-carbonyl, optionally substituted heterocyclic-(lower)alkyl, lower alkylthio, hydrox (lower)alkyl or protected hydrox (lower)alkyl, 3 R is aryl which may have suitable substituent(s), and A is lower alkylene, and pharmaceutically acceptable salts thereof. Suitable salts of the object compound (I) are pharmaceutically acceptable, conventional non-toxic salts and may include a salt with a base such as an inorganic base salt, for example, an alkali metal salt (e.g. sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt, for example, an organic amine salt (e.g. triethylamine salt, pyridine salt, picoline salt, ethanola ine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.) ; a salt with an acid such as inorganic acid addition salt (e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.), an organic acid addition salt (e.g. formate, acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, etc.); a salt with a basic or acidic amino acid (e.g. arginine, aspartic acid, glutamic acid, etc.); and the like. According to the present invention, the object compound (I) or pharmaceutically acceptable salts thereof can be prepared by the processes as illustrated by the following reaction schemes. Process 1 : (II) (I) or salts thereof or salts thereof Process 2 : Reduction (I-a) (I-b) or salts thereof or salts thereof Process 3 Introduction (I-c) (I-d) or salts thereof or salts thereof (IV) (I) or salts thereof or salts thereof Process 5 : Removal of the (i-e) (1-f) or salts thereof or salts thereof Process 6 : (i-g) (I-h) or salts thereof or salts thereof wherein R1, R2, R3 and A are each as defined above, hydroxy- (lower)alkyl, alkyl, s ester f ed carboxy, and X is a leavinσ group. The compounds (II) and (IV) used in the Processes 1 and 4 are new and can be prepared, for example, by the following methods or a conventional manner. Method A : (V) (ID or salts thereof or salts thereof Method B : Reduction (VII) (ID or salts thereof or salts thereof Method C : t ereo (VIII) (IV ) or its reactive derivative or salts thereof at the carboxy group, or salts thereof Method D : thereof (IX) (VII) or its reactive derivative or salts thereof at the carboxy group, or salts thereof 1 2 3 4 in which R , R , R , R and A are each as defined above. Some of the starting materials of the above Method A are new and can be prepared, for example, according to the method of Preparation as mentioned below, or in a conventional manner. In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention includes within the scope thereof are explained in detail as follows. The term "lower" is intended to mean 1 to 6 carbon atom(s), preferably 1 to 4 carbon atom(s), unless otherwise indicated. Suitable "lower alkyl" may include straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, and the like. Suitable "lower alkoxy" may include straight or branched one such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, trbutoxy, pentyloxy, hexyloxy, and the like. Suitable "aryl which may have suitable substituent(s)" may include phenyl, tolyl, xylyl, cumenyl, mesityl, naphthyl, and the like, each of which may be substituted by one or more, preferably one or two substituent(s) such as halogen (e.g. fluorine, chlorine, bromine, iodine), lower alkyl as mentioned above (e.g. methyl, etc.), and the like, in which more preferred example may be phenyl which is substituted or unsubstituted by a group consisting of halogen and lower alkyl, and the most preferred one may be phenyl. Suitable "protected carboxy" may include carbamoyl, esterified carboxy wherein "esterified carboxy" can be referred to the ones as mentioned below, and the like. Suitable examples of the ester moiety of an esterified carboxy may be the ones such as lower alkyl ester (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, hexyl ester, etc.) which may have at least one suitable substituent(s) , or example, lower alkanoyloxy(lower)alkyl ester [e.g. acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, l-(or 2-)acetoxyethyl ester, l-(or 2- or 3-)acetoxypropyl ester, l-(or 2- or 3- or 4-)acetoxybutyl ester, l-(or 2-)propionyloxyethyl ester, l-(or 2- or 3-)propionyloxypropyl ester, l-(or 2-)butyryloxyethyl ester, l-(or 2-)isobutyryloxyethyl ester, l-(or 2-)pivaloyloxyethyl ester, l-(or 2-)hexanoyloxyethyl ester, isobutyryloxymethyl ester, 2-ethylbutyryloxymethyl ester, 3,3-dimethylbutyryloxymethyl ester, l-(or 2-)pentanoyloxyethyl ester, etc.], lower alkanesulfonyKlower)alkyl ester (e.g. 2-mesylethyl ester, etc.), mono(or di or tri)halo(lower)alkyl ester (e.g. 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.); lower alkoxycarboriyloxy(lower) lkyl ester [e.g. methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester, t-butoxycarbonyloxymethyl ester, l-(or 2-)methoxycarbonyloxyethyl ester, l-(or 2-)ethoxycarbonyloxyethyl ester, l-(or 2-)isopropoxycarbonyloxyethyl ester, etc.], phthalidylidene{lower)alkyl ester, or (5-lower alkyl-2-oxo-l,3-dioxol-4-yl) (lower)alkyl ester [e.g. (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl ester, (5-ethyl-2-oxo-l,3-dioxol-4-yl)methyl ester, (5-propyl-2-oxo-l,3-dioxol-4-yl)ethyl ester, etc.]; lower alkenyl ester (e.g. vinyl ester, allyl ester, etc.); lower alkynyl ester (e.g. ethynyl ester, propynyl ester. etc.); ar(lower)alkyl ester [e.g. mono- or di- or triphenyKlower)alkyl ester, etc.] which may have at least one suitable substituent(s) (e.g. lower alkoxy, nitro, hydroxy, lower alkyl, etc.), for example, mono- or di- or tripheny lower)alkyl ester which may have (lower)alkoxy [e.g. benzyl ester, benzhydryl ester, trityl ester, phenethyl ester, 4-methoxybenzyl ester, 3,4-dimethoxybenzyl ester, bis(methoxyphenyl) ethyl ester, etc. ], nitrophenyl(lower)alkyl ester (e.g. 4-nitrobenzyl ester, etc.), [hydrox ]-(lower)alkylphenyl(lower)alkyl ester (e.g. 4-hydroxy-3,5-di-t-butylbenzyl ester, etc.); aryl ester which may have at least one suitable substituent(s) (e.g. phenyl ester, 4-chlorophenyl ester, tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.); phthalidyl ester; and the like. More preferable example of the protected carboxy thus defined may be carbamoyl and lower alkoxycarbonyl. Suitable "protected amino" may include amino protected-by a conventional amino-protective group as mentioned below. Suitable "amino-protective group" may include acyl such as aliphatic acyl, aromatic acyl, heterocyclic acyl and aliphatic acyl substituted with aromatic or heterocyclic group(s) derived from carboxylic, carbonic,. sulfonic and carbamic acids. The aliphatic acyl may include saturated or unsaturated, acyclic or cyclic ones, for example, alkanoyl such as lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc.), alkylsulfonyl such as lower alkylsulfonyl (e.g. mesyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, pentylsulfonyl, hexylsulfoπyl, etc.), carbamoyl. N-alkylcarbamoyl (e.g. methylcarbamoyl, ethylcarbamoyl, etc.), alkoxycarbonyl such as lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbαnyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, etc. ) , alkenyloxycarbonyl such as lower alkenyloxycarbonyl (e.g. vinyloxycarbonyl, allyloxycarbonyl, etc.), alkenoyl such as lower alkenoyl (e.g. acryloyl, methacryloyl, crotonoyl, etc. ) , cycloalkanecarbonyl such as cyclo(lower)alkanecarbonyl (e.g. cyclopropanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, etc.), and the like. The aliphatic acyl substituted with aromatic group(s) may include aralkoxycarbonyl such as phenyl(lower)alkoxycarbonyl (e.g. benzyloxycarbony1, phenethyloxycarbonyl, etc.), and the like. These acyl groups may be further substituted with one or more suitable substitueht(s) such as nitro, halogen as mentioned below, and the like, and preferable acyl having such substituent(s) may be nitroaralkoxycarbonyl (e.g. nitrobenzyloxycarbonyl, etc.), trihalo(lower)alkyl (e.g. trifluoroacetyl, etc.), and the like. Preferable example of amino-protective group thus defined may be : - lower alkanoyl (e.g. acetyl, etc.); - trihalo(lower)alkanoyl such as trifluoro(lower)- alkanoyl (e.g. trifluoroacetyl, etc.); - lower alkoxycarbonyl (e.g. ethoxycarbonyl, etc.); - carbamoyl; - N-{lower)alkylcarbamoyl (e.g. N-ethylcarbamoyl, etc.); - lower alkylsulfonyl (e.g. mesyl, ethylsulfonyl, etc.); and the like. "Protected hydroxy" means a hydroxy group protected by a conventional hydroxy-protective group, and suitable "hydroxy-protective group" may include lower alkyl as defined above, acyl as defined above, ar(lower)alkyl such as mono-, di- or triphenyl(lower)alkyl (e.g. trityl, etc.), preferably lower alkyl and triphenyl(lower) lkyl. Suitable heterocyclic group in "optionally substituted heterocyclic-carbonyl", "optionally substituted heterocyclic-{lower) lkyl" and "substituted heterocyclic-(lower)alkyl" may include 3 to 10, preferably 5 or 6-membered heterocyclic group, preferably heteromonocyclic group containing at least one hetero atom such as oxygen atom, nitrogen atom and sulfur atom (e.g. morpholino, etc.), and the like. Particularly such "heterocyclic group" means saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one hetero-atom such as an oxygen, sulfur, nitrogen atom and the like. More preferable heterocyclic group may be heterocyclic group such as : -unsaturated 3 to 8-membered, preferably 5 or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, and its N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-l,2,4-triazolyl, lH-l,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g., lH-tetrazolyl, 2H-tetrazolyl, etc.), dihydrotriazinyl (e.g., 4,5-dihydro-l,2,4-triazinyl, 2,5-dihydro-l,2,4-triazinyl, etc. ), etc. ; -saturated 3 to 8-membered, preferably 5 or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrazolidinyl, piperazinyl. etc. ; -unsaturated condensed 7 to 12-membered heterocyclic group containing 1 to 5 nitrogen atom(s), for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridyl, tetrazolopyridazinyl (e.g., tetrazolo[l,5-b]pyridazinyl, etc. ), dihydrotriazolopyridazinyl, etc. ; -unsaturated 3 to 8-membered, preferably 5 or 6-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl, (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-σxadiazolyl, etc. ) , etc. ; -saturated 3 to 8-membered, preferably 5 or 6-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholinyl, etc. ' -unsaturated condensed 7 to 12-membered heterocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, etc.; wherein said heterocyclic group may be substituted by one or more, preferably one or, two suitable substituent(s) such as lower alkyl as mentioned above, lower alkoxy as mentioned above, in which more preferable example may be saturated 5 or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), or containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), optionally substituted by lower alkyl. Suitable lower alkyl group in "heterocyclic- (lower)alkyl" can be referred to the ones as mentioned above. More preferable example of substituted heterocyclic-(lower)alkyl thus defined may be lower alkylpiperazinyl(lower)alkyl and morpholinyl(lower)alkyl, and the most preferable one may be 4-methylpiperazin-l-ylmethyl. More pre erable example of heterocyclic-carbonyl thus defined may be lower alkylpiperazinylcarbonyl and morpholinylcarbonyl. Suitable "halogen" may be fluorine, chlorine, bromine, iodine, and more preferred example may be chlorine. Suitable "lower alkylene" may include straight or branched one such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, ethylethylene, propylene, and the like, in which the most preferred one may be tetramethylene. Suitable "leaving group" may include i idazole, lower alkylimidazole (e.g. 2-methylimidazole, etc.), an acid residue such as halogen as mentioned above (e.g. chlorine, etc.), and the like. Suitable "lower alkylthio" may include straight or branched one such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, t-butylthio, pentylthio, hexylthio, and the like. Suitable "esterified carboxy" means the same ones as mentioned in the explanation of protected carboxy, in which more preferable example may be lower alkoxycarbonyl. Suitable "hydrox (lower)alkyl" may include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyhexyl, and the like. Suitable "protected hydroxy(lower)alkyl" means hydroxy(lower)alkyl protected by a conventional hydroxy-protective group as mentioned in the explanation of "protected hydroxy", in which more preferable example may be lower alkoxy(lower)alkyl and triphenyl(lower)alkox {lower)alkyl. The processes for the preparation of the object compound (I) of the present invention are explained in detail in the following. (1) Process 1 : The compound (I) or salts thereof can be prepared by reacting the compound (II) or salts thereof with the compound (III). Suitable salts of the compound (II) may be acid addition salts such as those given for the compound (I). Suitable example of the compound (III) may include N, '-carbonyldiimidazole, N,N'-carbonylbis(2-methyl¬ imidazole), phosgene or its reactive equivalent (e.g. dimer or trimer thereof, etc. ) , and the like. This reaction can be carried out in a conventional solvent which does not adversely influence the reaction such as dichloromethane, pyridine, N,N-dimethylfo___namide, 4-methyl-2-pentanone, tetrahydrofuran, etc., or a mixture thereo . The reaction temperature is not critical and the reaction is usually carried out under from warming to heating. (2) Process 2 : The compound (I-b) or salts thereof can be prepared by subjecting the compound (I-a) or salts thereof to reduction of nitro group of R_. Suitable salts of the compounds (I-a) and (I-b) may be the same as those for the compound (I) . The present reaction is usually carried out by a conventional method as mentioned below. Reduction method : The reduction method applicable for this reaction may include conventional ones which are capable of converting a nitro group to a hydroxyamino or amino group, for example, reduction using ti (II) chloride or zinc powder; reduction using a combination of a metal (e.g. zinc, zinc amalgam, etc.) or a salt of chrome compound (e.g. chromous chloride, chromous acetate, etc.) and an organic or inorganic acid .e.g. acetic acid, propionic acid, hydrochloric acid, sulfuric acid, etc. ); conventional catalytic reduction in the presence of a conventional metallic catalyst such as palladium catalysts (e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, palladium hydroxide on carbon, etc.), nickel catalysts (e.g. reduced nickel, nickel oxide, Raney nickel, etc.), platinum catalysts (e« « platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.); reduction using aluminum amalgam, electrolytic reduction; and the like. In case that the catalytic reduction is applied, the reaction is preferably carried out around neutral condition. This reaction is usually ' carried out in a conventional solvent which does not adversely influence the reaction such as water, alcohol (e.g. methanol, ethanol, propanol, etc.), dioxane, tetrahydrofuran, acetic acid, buffer solution (e.g. phosphate buffer, acetate buffer, etc.), and the like, or a mixture thereof. The reaction temperature is not critical and the reaction is usually carried out under from warming to heating. (3) Process 3 : The compound (I-d) or salts thereof can be prepared by introducing an amino-protective group into the compound (I-c) or salts thereof. Suitable salts of the compounds (I-c) and (I-d) may be the same as those or the compound (I) . Suitable introducing agent of the amino-protective group used in this reaction may be a conventional one which is capable of introducing the amino-protective group such as acyl as mentioned before, for example, lower alkyl isocyanate (e.g. ethyl isocyanate, etc.); alkali metal cyanate (e.g. potassium cyanate, etc.); lower alkyl halo(lowerJalkanate (e.g. ethyl chloroformate, etc.); carboxylic acid, carbonic acid, sulfonic acid and their reactive derivative (e.g. an acid halide, an acid anhydride, an activated amide, an activated ester, etc. ) ; and the like. Preferable example of such reactive derivative may include lower alkanoic acid halide (e.g. acetyl chloride, etc.); lower alkanesulfonyl halide (e.g. mesyl chloride, ethanesulfonyl chloride, etc. ); a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g. dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid sulfonic acid (e.g. methanesulfonic acid, toluenesulfonic acid, etc.), mono(lower)alkyl ester of carbonic acid, aliphatic carboxylic acid (e.g. pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.), aromatic carboxylic acid (e.g. benzoic acid, etc.); a symmetrical acid anhydride such as lower alkanoic anhydride (e.g. acetic anhydride, etc.), trihalo(lower)alkanoic anhydride (e.g. trifluoroacetic anhydride, etc.); an activated acid amide with a heterocyclic compound containing imino function such as imidazole, 4-substituted imidazole, dimethylpyrazole, triazole and tetrazole; an activated ester (e.g. p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester. mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyridyl ester, piperidinyl ester, 8-quinolyl thioester, or an ester with a -hydroxy compound such as N,N-dimethylhydroxylamine, 1-hydroxy-2-{1H)-pyridone, N-hydroxysucciπimide , N-hydroxyphthalimide, 1-hydroxybenzotriazole, 1-hydroxy-6-chlorobenzotriazole, etc.); and the like. This reaction can be carried out in the presence of a base or an acid according to the introducing agent of the amino-protective group to be used. Suitable base may include an organic or inorganic base such as alkali metal (e.g. lithium, sodium, potassium, etc.), alkaline earth metal (e.g. calcium, etc.), alkali metal hydride (e.g. sodium hydride, etc.), alkaline earth metal hydride (e.g. calcium hydride, etc.), alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc.), alkali metal alkoxide (e.g. sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), alkali metal alkanoic acid (e.g. sodium acetate, etc.), trialkyla ine (e.g. triethylamine, etc.), pyridine compound (e.g. pyridine, lutidine, picoline, 4-dimethylaminopyridine, etc.), quinoline, and the like. Suitable acid may include an organic acid (e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. ) and an inorganic acid (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.). In case that the introducing agent of the amino-protective group used in a free form or its salt in this reaction, the reaction is preferably carried out in the presence of a condensing agent such as a carbodiimide compound [e.g. N,N'-dicyclohexylσarbodiimide, N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide, , '-diethylcarbodiimide, , '-diisopropylcarbodiimide, N-ethyl- '-(3-dimethylaminopropyl)carbodiimide, etc.], a ketenimine compound (e.g. N,N'-carbonylbis-(2- methylimidazole) , pentamethyleneketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, etc.); an olefinic or acetylenic ether compounds (e.g. ethoxyacetylene, β-chlorovinylethyl ether), a sulfonic acid ester of N-hydroxybenzotriazole derivative [e.g. 1-(4-chlorobenzenesulfonyloxy)-6-chloro-lH-benzotriazole, etc.] , a combination of trialkylphosphite or triphenylphosphine and carbon tetrachloride, disulfide or diazenedicarboxylate (e.g. diethyl diazenedicarboxylate, etc.), a phosphorus compound (e.g. ethyl polyphosphate, isopropyl polyphosphate, phosphoryl chloride, phosphorus trichloride, etc.), thionyl chloride, oxalyl chloride, N-ethylbenzisoxazolium salt, N-ethyl-5-phenylisoxazolium- 3-sulfonate, a reagent (referred to a so-called "Vilsmeier reagent") formed by the reaction of an amide compound such as N,N-di(lower)alkylformamide (e.g. dimethylformamide, etc. ) , N-methylformamide or the like with a halogen compound such as thionyl chloride, phosphoryl chloride, phosgene or the like. The reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, acetone, dichloromethane, alcohol (e.g. methanol, ethanol, etc.), tetrahydrofuran, pyridine, N,N-dimethyIformamide, etc., or a mixture thereof, and further in case that the amino-introducing agent is in liquid, it can also be used as a solvent. The reaction temperature is not critical and the reaction is usually carried out under from cooling to heating. (4) Process 4 : The compound (I) or salts thereof can be prepared by reacting the compound (IV) or salts thereof with a base. Suitable salts of the compound (IV) may be the same as those for the compound (I). Suitable base used in this reaction may be the same as those given in the explanation of Process 3. This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as tetrahydrofuran, dioxane, water, methanol, ethanol, etc., or a mixture thereof. The reaction temperature is not critical, and the reaction is usually carried out under from warming to heating. (5) Process 5 : The compound (I-f) or salts thereof can be prepared by subjecting the compound (I-e) or salts thereof to a 2 removal reaction of the hydroxy protective group in R . Suitable salts of the compounds (I-e) and (I-f) may be the same as those for the compound (I) . The present reaction is usually carried out by a conventional method such as hydrolysis, reduction, and the like. (i) Hydrolysis : The hydrolysis is preferably carried out in the presence of a base or an acid. Suitable base may include an alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), an alkaline earth metal hydroxide (e.g. magnesium hydroxide, calcium hydroxide, etc.), alkali metal hydride (e.g. sodium hydride, potassium hydride, etc.), alkaline earth metal hydride (e.g. calcium hydride, etc.), alkali metal alkoxide (e.g. sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), an alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), and alkaline earth metal carbonate (e.g. magnesium carbonate, calcium carbonate, etc.), an alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc. ) , and the like. Suitable acid may include an organic acid (e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.) and an inorganic acid (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.). The acidic hydrolysis using trifluoroacetic acid is usually accelerated by addition of cation trapping agent (e.g. phenol, anisole, etc. ) . This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, dichloromethane, alcohol (e.g. methanol, ethanol, etc.), tetrahydrofuran, dioxane, acetone, etc., or a mixture thereof. A liquid base or acid can be also used as the solvent. The reaction temperature is not critical and the reaction is usually carried out under from cooling to heating. (ii) Reduction : The reduction method applicable for this removal reaction may include, for example, reduction by using a combination of a metal (e.g. zinc, zinc amalgam, etc.) of a salt of chrome compound (e.g. chromous chloride, chromuos acetate, etc. ) and an organic or inorganic acid (e.g. acetic acid, propionic acid, hydrochloric acid, sulfuric acid, etc.); and conventional catalytic reduction, in the presence of a conventional metallic catalyst such as palladium catalysts (e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on __ • _ barium carbonate, palladium hydroxide on carbon, etc.), nickel catalysts (e.g. reduced nickel, nickel oxide, Raney nickel, etc.), platinum catalysts (e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), and the like. In case that the catalytic reduction is applied, the reaction is preferably carried out around neutral condition. This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, alcohol (e.g. methanol, ethanol, propanol, etc.), dioxane, tetrahydrofuran, acetic acid, buffer solution (e.g. phosphate buffer, acetate buffer, etc.), and the like, or a mixture thereof. The reaction temperature is not critical and the reaction is usually carried out under from cooling to warming. The removal reaction can be selected according to the kind of hydroxy-protective group to be removed. (6) Process 6 : The compound (I-h) or salts thereof can be prepared by subjecting the compound (I-g) or salts thereof to a 2 removal reaction of the carboxy-protective group in R . Suitable salts of the compounds (I-g) and (I-h) may be the same as those for the compound (I). This reaction is usually carried out by a conventional method such as hydrolysis, reduction and the like. The method of hydrolysis and reduction, and the reaction conditions (e.g. reaction temperature, solvent etc.) are substantially the same as those illustrated for removal reaction of the hydroxy-protective group of the compound (I-a) in Process 5, and therefore are to be referred to said explanation. The object compound (I) obtained according to the Processes 1 to 6 can be isolated and purified in a conventional manner, for example, extraction, precipitation, fractional crystallization, recrystallization, chromatography, and the like. Methods A to C for preparing the new starting compounds (II) and (IV) or salts thereof are explained in detail in the following. (A) Method A : The compound (II) or salts thereof can be prepared by reacting the compound (V) or salts thereof with the compound (VI) or salts thereof. Suitable salts of the compound (V) may be salts with bases such as those given for the compound (I) . Suitable salts of the compound (VI) may be the same acid addition salts as those for the compound (I) . This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as dichloromethane, pyridine, ,N-dimethylformamide, 4-methyl-2-pentanone, tetrahydrofuran, etc., or a mixture thereof. The reaction temperature is not critical and the reaction is usually carried out under from warming to heating. (B) Method B : The compound (II) or salts thereof can be prepared by reducing the nitro group of the compound (VII) or salts thereof. Suitable salts of the compound (VII) may be the same as those for the compound (I) . The method of reduction and the reaction conditions (©•_ . • reaction temperature, solvent, etc.) are substantially the same as those illustrated in Process 2, and therefore are to be referred to said explanation. (C) Method C : The compound (IV) or salts thereof can be prepared b reacting the compound (VIII) or its reactive derivative a the carboxy group, or salts thereof with the compound (VI) or salts thereof. Suitable salts of the .compound (VIII) may be the sam as those for the compound (I). Suitable reactive derivative of the compound (VIII) may include an acid halide, an acid anhydride, an activated amide, an activated ester, and the like. The suitable example may be an acid chloride; an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g. dialkylphosphoric acid, ^henylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid etc.), dialkylphosphorous acid, lower alkanesulfonic acid (e« « methanesulfonic acid, ethanesulfonic acid, etc.), sulforous acid, thiosulfuric acid, sulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid (e.g. pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid or trichloroacetic acid, etc.) or aromatic carboxylic acid (e.g. benzoic acid, etc.); a symmetrical acid anhydride; an activated amide with imidazole, -substituted imidazole, dimethylpyrazole, triazole or tetrazole; or an activated ester (e.g. cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH3)2N=CH-] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2, -dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl 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-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, l-hydroxy-6-chloro-lH-benzotriazole, etc.) , and the like. These reactive derivatives can optionally be selected from them according to the kind of the compound (VIII) to be used. When the compound (VIII) is used in 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 f -dicyclohexylcarbodiimide; N-cyclohexyl- '-morpholinoethylcarbodiimide; N-cyclohexyl- '-(4-diethylaminocyclohexyl)carbodiimide; N, '-diethylcarbodiimide, , '-diisopropylcarbodiimide; N-ethyl- '-(3-di ethylaminopropyl)carbodiimide; 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; triphenylphosphine; 2-ethy1-7-hydroxybenzisoxazoli m salt; 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intramolecular salt; l-(p-chlorobenzenesulfonyloxy)-6- chloro-lH-benzotriazole; so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylformamide with thionyl chloride, phosgene, phosphorus oxychlroide, etc. ; or the like. The reaction may also be carried out in the presence of an inorganic or organic base such as those given in the explanation of Process 3. The reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine, etc. or a mixture thereof. The reaction temperature is not critical, and the reaction is usually carried out under warming to heating. (D) Method D : The compound (VII) or salts thereof can be prepared by reacting the compound (IX) or its reactive derivative at the carboxy group, or salts thereof with the compound (VI) or salts thereof. Suitable salts and reactive derivative of the compound (IX) may be the same as those for the compound (VIII) . The method of reaction and the reaction conditions (e.g. reaction temperature, solvent, etc.) are substantially the same as those illustrated in Method C, and therefore are to be referred to said explanation. The object quinazoline derivatives (I) stimulate presynaptic(neuronal) and/or postsynaptic( ascular) dopamine receptors that mediate inhibition of neurogenic release of catecholamine and/or dilatation of renal vasculature and remission of Parkinsonism, respectively. Quinazoline derivatives (I) effect on the cardiovascular system as a consequence of its interaction with dopaminergic and adrenergic receptors. The object compound (I) and pharmaceutically acceptable salts thereof of the present invention are novel and display dopamine receptor stimulating effects; 5-HT receptor antagonism, especially 5-HT- receptor antagonism; α- receptor antagonism; and the like, and are useful as a dopamine receptor agonist; 5-HT receptor antagonist, especially 5-HT 2 receptor antagonist; __- receptor antagonist; and the like, for treating or preventing hypertension such as essential hypertension. renal hypertension, pulmonary hypertension, and other cardiovascular disorders (e.g. angina pectoris, congestive heart failure, myocardial infarction, etc.); Parkinsonism; hyperprolactinemia; disorders of peripheral perfusion such as Raynaud's phenomenon, Bruger's diseases, and intermittent claudication; thrombotic and/or smooth muscle cell proliferative disease such as restenosis after perculaneous transluminal coronary angioplasty; hypercholesterolemia, hyperlipemia; urinary disturvance; cardiac hypertrophy; nephropacy such as nephritis, renal failure, etc.; arteriosclerosis obliterans; obstructive thrombus; arterial embolus; Burger-Grϋts syndrome; acrocyanosis; chilblain; frostbite; prolactin-producing ovulation disorder; prolactin-producing pituitary tumor; puerperal galactoschesia; galactorrhea; distal hypertrophy; pituitary gigantism; mental illness such as melancholia, anxiety, schizophrenia, etc.; cerebrovascular diseases such as cerebral infarction, cerebral circulation insufficiency; tachycardia accompanied by sympathetic hypertonia; hyperaldosteronism; diabetic complication such as diabetic hypertriglyceromia, and the like. And further, the object compound (I) has vasodilating activity, blood flow increasing activity such as renal blood flow increasing activity, and the like. The compound " (I) and pharmaceutically acceptable salts thereof may be also useful as an adrenolytic, tranquilizer, sedative, anti-emetic, hypothermic, skeletal muscle relaxant, anti-inflammatory, hypoglycemic, anti-viral agent. Now in order to show the usefulness of the object compound (I) and pharmaceutically acceptable salts, the pharmacological test data of the representative compound of the compound (I) of this invention are shown in the following. Test Compound : Compound A TThe product of Example 1] Test 1 Dopamine receptor (DA 2 receptor) binding assay Test Method 1 : The affinity for DA- receptor of a Test Compound was determined following in vitro receptor binding assays. Male rats weighing 150-300g were decapitated and the stratum were dissected from their brains. The tissue was homogenized in 40 volumes of buffer which consisted of 50 mM Tris-HCl (pH 7.5 at 25°C), 1 mM tetraethylenediamine tetraacetic acid, 5 mM potassium chloride, 2 mM calcium chloride, and 1 mM magnesium chloride. The homogenate was centrifuged at 50,000 g for 15 minutes. The pellet was resuspended in 80 volumes of the buffer. The tissue suspension was centrifuged and suspended again in the same way. 3 Incubation tubes received 100 μl of (2-N-[2,3(n)- H]- propyl-N-(2-thiofuranyl)-2'-ethylamino)-5-hydroxy-l,2,3,4- tetrahydronaphthalene, 10 μl of the Test Compound and 0.89 ml of tissue suspension during binding assays. The concentration of (2-N-[2,3(n)- H]propyl-N-(2-thiofuranyl)- 2'-ethylamino)-5-hydroxy-l,2,3,4-tetrahydronaphthalene, was 1.5 nM. The final tissue concentration of rat stratum was 160 μg/ml. The tubes were incubated at 25°C for 45 minutes, and then filtered under vacuum through Whatman GF/B filters and washed three times with 3 ml of ice-cold buffer. The filters were counted by liquid scintillation counter. Specific binding of the (2-N-[2,3(n)- 3 H]propyl-(N-(2- thiofuranyl)-2'-ethylamino)-5-hydroxy-l,2,3,4-tetrahydro¬ naphthalene was determined in the presence of 1 μM apo orphine. The IC- Q value of the Test Compound was calculated from the data of (2-N-[2,3(n)- 3 H]propyl-N-(2- thiofuranyl)-2'-ethylamino)-5-hydroxy-l,2,3,4-tetrahydro- naphthalene, binding in the presence of 10 -_M, 10-8M, 10 M and 10 M Test Compound. Test Result 1 : Test 2 [Inhibition of reserpine-induced DOPA accumulation] Test Method 2 : Male SD rats weighing 300-400 g were used in this test. Rats were pretreated with reserpine (1 mg/kg, S.C) 17-19 hours before sacrifice and then fasted. Test Compound was given orally to the rats 2 hours before sacrifice. [m-Hydroxybenzylhydrazine (100 mg/kg, i.p.) was given 30 minutes before sacrifice.] Each rat was exposed to microwaves using a head-focus microwave applicator for 1.5 seconds. The whole brain was removed and further separated into the striatum. DOPA was determined as follows; the striatum was homogenized in 9 volumes of 0.1N perchloric acid solution (0.4% EDTA»2Na). The homogenate was centrifuged at 10,000 rpm for 1 minute. The supernatant was applied to high performance liquid chromatography. Test Result 2 Test 3 t5-HT- Binding Assay] Test Method 3 : The affinity for Serotonin 2 receptor of a test compound was determined following in vitro receptor binding assays. Male Wistar rats weighing 150-300 g were decapitated and the frontal cortex were dissected from their brains. The tissue was homogenized in 15 volumes of ice-cold buffer which consisted of 0.32 M Sucrose, 50 mM Tris-HCl (pH 7.5 at 25°C). The homogenate was centrifuged at 3,300 rpm at 4 β C for 10 minutes. The supernatant was centrifuged at 20,000 rpm for 20 minutes. The pellet was resuspended again in the same way, and incubated at 37 C C for 15 minutes. The tissue suspension was centrifuged at 20,000 rpm for 20 minutes. The final pellet was resuspended in 15 volumes of ice-cold assay buffer (50 mM Tris/HCl, 4 mM CaCl-, 0.1% Ascorbic acid, 10 μM pargyline, pH7.7 at 25 β C). 3 Incubation tubes received 100 μl of [ethylen- H]- ketanserin, 10 μl of the test compound and 0.2 ml of tissue suspension, and 0.69 ml assay buffer during binding 3 assays. The final concentration of [ethylen- H]- ketanserin was 0.05 nM. The tubes were incubated at 37°C for 30 minutes, and then filtered under vacuum through Whatman GF/B filters and washed three times with 3 ml of ice-cold buffer (50 mM tris/HCl, pH 7.5 at 25°C). The filters were counted by liquid scintillation counter. Specific binding of [ethylen- H]-ketanserin was determined in the presence of 1 μM mianserin. The IC 50 value of the test compound was calculated from the data of [ethylen- 3H]-ketanserin binding in the presence of 10-9M, —8 —7 —6 10 M, 10 M, and 10 M test compound. Test Result 3 : For therapeutic administration, the object compound (I) and the pharmaceutically acceptable salts thereof of the present invention are used in the form of conventiona pharmaceutical preparation which contains said compound, as an active ingredient, in admixture with pharmaceutically acceptable carriers such as an organic o inorganic solid or liquid excipient which is suitable for oral, parenteral and external administration. The pharmaceutical preparations may be in solid form such as tablet, granule, powder, capsule, or liquid form such as solution, suspension, syrup, emulsion, lemonade, and the like. If needed, there may be included in the above preparations auxiliary substances, stabilizing agents, wetting agents and other commonly used additives such as lactose, stearic acid, magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butter, ethylene glycol, tartaric acid, citric acid, fumaric acid, and the like. While the dosage of the compound (I) may vary from and also depend upon the age, conditions of the patient, kind of diseases, a kind of the compound (I) to be applied, etc. In general, amount between about 0.001 g and about 300 mg, preferably about 0.1 mg to about 50 mg per day may be administered to a patient. An average single dose of about 0.001 mg, 0.01 mg, 0.03 mg, 0.1 mg, 0.3 mg, 0.6 mg, 1.0 mg, 3.0 mg, 10.0 mg, 50.0 mg, 100.0 g, of the object compound (I) of the present invention may be used as adrenolytic, hypotensive, cardiovascular, tranquilizer, sedative, anti-emetic, hypothermic, skeletal muscle relaxant, anti-inflammatory, and anti-viral agents. The following Preparations and Examples are given for the purpose of illustrating this invention in more detail. Preparation 1-1. To a stirred mixture of 4-(4-methylpiperazin-l- ylmethyl)-2-nitrobenzoic acid (0.28 g), hydroxybenzotriazole (0.14 g) and dry dimethylformamide (5 ml) was added dicyclohexylcarbodiimide (0.21 g), and the mixture was stirred for 1 hour at room temperature. Then 4-(4-phenyl-l,2,3,6-tetrahydropyridin-l-yl)butylamine hydrochloride (0.27 g) and triethylamine (0.20 g) were added and the stirring was continued for additional 1 hour. IN Hydrochloric acid (2 ml) and water (20 ml) were added and the mixture was washed with ethyl acetate, adjusted to pH 8 with aqueous sodium bicarbonate solution and extracted with ethyl acetate (x2). The combined organic extracts were dried over magnesium sulfate and solvent was evaporated to give 4-(4-methylρiperazin-l- ylmethyl)-2-nitro-N-[4-(4-phenyl-l,2,3,6-tetrahydro- pyridin-1-yl)butyl]benzamide (0.21 g) . NMR (CDCI3, S) t 1.78 (4H, m) , 2.23 (2H, m), 2.30 (3H, s), 2.43 (8H, ), 2.52 (2H, m), 2.62 (2H, m), 3.00 (2H, m), 3.28 (2H, s), 3.49 (2H, m), 5.75 (1H, m), 7.1-7.4 (7H, m), 7.75 (1H, s), 8-78 (1H, m) Preparation 1-2. To a stirred mixture of 4-(4-methylpiperazin-l- ylmethyl)-2-nitro-N-[4-(4-phenyl-l,2,3,6- tetrahydropyridin-1-yl)butyl]benzamide (0.21 g), ethanol (5 ml) and dry tetrahydrofuran (10 ml) was added tin (II) chloride (0.33 g) and the mixture was refluxed for 1 hour. After cooling, chloroform (15 ml) and IN sodium hydroxide (25 ml) were added and the mixture was stirred. The organic layer was separated and the remained aqueous laye was extracted with chloroform. The organic layer and extract were combined and dried over magnesium sulfate an evaporated to give 2-amino-4-(4-methylpiperazin-l- ylmethyl)-N-[4-(4-phenyl-l,2,3,6-tetrahydropyridin-l-yl)- butyl]benzamide (0.25 g) . NMR (CDCI3, δ ) : 1.72 (4H, m), 2.31 (3H, s), 2.50 (10H, ), 2.71 (2H, m), 3.15 (2H, ), 3.33 (2H, s), 3.45 (2H, m), 3.75 (2H, m), 5.50 (2H, br s), 6.03 (1H, m), 6.49 (1H, dd, J=8, 1Hz), 6.65 (1H, d, J=lHz), 6.41 (1H, m), 7.2-7.45 (6H, m) Example 1 A mixture of 2-amino-4-(4-methylpiperazin-l- ylmethyl)-N-[4-(4-phenyl-l,2,3,6-tetrahydropyridin-l- yl)butylJbenzamide (0.25 g), carbonyldiimidazole (0.45 g) and dry tetrahydrofuran (10 ml) was stirred under reflux for 14 hours. After evaporation of the solvent, the crud residue was taken up with ethyl acetate, washed with water, dried over magnesium sulfate and evaporated to give crystals. Recrystallization from ethanol afforded 7-(4-methylpiperazin-l-ylmethyl)-3-[4-(4-phenyl-l,2,3,6- tetrahydropyridin-1-yl)butyl]-1,2,3,4- tetrahydroquinazoline-2,4-dione (0.16 g). mp : 167-168 β C IR (Nujol) : 1700, 1660, 1620, 1590 cm-1 NMR (CDCI3, δ ) : 1.75 (4H, m), 2.30 (3H, s), 2.50 (12H, m), 2.72 (2H, m), 3.18 (2H, ), 3.56 (2H, s), 4.12 (2H, ), 6.05 (1H, m) , 7.00 (1H, s), 7.15-7.40 (6H, at), 8.03 (1H, d, J=8Hz), 9.28 (1H, br s)

Claims: CLAIM 1. A compound of the formula r in which R is substituted heterocyclic-(lower)alkyl, and 2 R is hydrogen, halogen, nitro, amino, protected amino, hydroxyamino, lower alkyl, hydroxy, protected hydroxy, sulfamoyl, carboxy, protected carboxy, mercapto, optionally substituted heterocyclic-carbonyl, optionally substituted heterocyclic-(lower)alkyl, lower alkylthio, hydroxy{lower)alkyl or protected hydroxy(lower) lkyl, R is aryl which may have suitable substituent(s) , and A is lower alkylene, or pharmaceutically acceptable salts thereof. 2. The compound of Claim 1, wherein 2 R is hydrogen. 3. The compound of Claim 2, wherein R is unsaturated 3 to 8 membered heteromonocyclic group containing 1 to 4 nitrogen atoms, which is substituted by lower alkyl or lower alkoxy, and R is phenyl optionally substituted by halogen or lower alkyl. The compound of Claim 3, wherein R is pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, and its N-oxide, pyri idyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl or dihydrotriazinyl, each of which is substituted by lower alkyl or lower alkoxy. 5. The compound of Claim 4, wherein R is lower alkylpiperazinyl(lower)alkyl, and 3 is phenyl. 6. The compound of Claim 5, which is 7-(4-methylpiperazin-l-ylmethyl)-3-[4-(4-phenyl- 1,2,3,6-tetrahydropyridin-l-yl)butyl]-1,2,3,4- tetrahydroquinazoline-2, -dione. 7. A process for the preparation of a compound of the formula : 1 2 • . in which R , R , Br and A are eachas defined in Claim 1, or salts thereof, which comprises (a) reacting a compound of the formula : or salts thereof, with a compound of the formula C0(X) 2 to give a compound of the formula or salts thereof; or (b) reducing the nitro group of cl of a compound of the formula : or salts thereof, to give a compound of the formula or salts thereof; or (c) introducing the amino-protective group into a compound of the formula : or salts thereof, to give a compound of the formula or salts thereof; or (d) reacting a compound of the formula : or salts thereof, with a base to give a compound of the formula : or salts thereof; or (e) subjecting a compound of the formula or salts thereof, to a removal reaction of the 2 hydroxy-protective group in R , to give a compound of the formula : or salts thereof; or (f) subjecting a compound of the formula : or salts thereof, to a removal reaction of the 2 ccaarrbbooxxyy--pprrootteeccttive group in R , to give a compound y of the formula or salts thereof; wherein R 1, R , R3 and A are each as defined above, R α is nitro, T 2 is hydroxyamino or amino, R„ is amino, 2 is protected amino. _» w" is protecred hydroxy or protected hydroxy- (lower) lkyl, - is hydroxy or hydroxy(lower)alkyl, * 2 is protected carboxy, S. is carboxy, R is esterified carboxy, and X is a leaving group. 8. A pharmaceutical composition comprising, as an active ingredient, a compound of Claim 1 in admixture with a pharmaceutically acceptable carrier or excipient. 9. Use of a compound of Claim 1 as a medicament. 10. Use of a compound of Claim 1 as a dopamine receptor agonist, 5-HT receptor antagonist or α- receptor antagonist. 11. A method for the treatment of dopamine receptor mediated diseases, 5-HT receptor mediated diseases or α. receptor mediated diseases which comprises administering a compound of Claim 1 to a human being or animal.

Inventors: HASHIMOTO MASASHI, ITOH YOSHIKUNI, SHIMAZAKI NORIHIKO, TANAKA HIROKAZU, YAMAZAKI HITOSHI, YATABE TAKUMI, HASHIMOTO, MASASHI, ITOH, YOSHIKUNI, SHIMAZAKI, NORIHIKO, TANAKA, HIROKAZU, YAMAZAKI, HITOSHI, YATABE, TAKUMI
Applicants: FUJISAWA PHARMACEUTICAL CO, FUJISAWA PHARMACEUTICAL CO., LTD.
Application year: 1992
Main classification: A61K31
IPC codes: A61K31, A61P43, C07D401