WO1993018769A2 - A new use of quinazoline derivative - Google Patents

Abstract

A use of a compound of formula (I) in which R?1 and R2¿ are each 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, R3 is aryl which may have suitable substituent(s), and A is lower alkylene, or a pharmaceutically acceptable salt thereof, for the treatment of various diseases selected from the group consisting of cardiac hypertrophy, nephropacy such as nephritis or renal failure, arteriosclerosis, obliterans, obstructive thrombus, arterial embolus, Bürger-Grütz syndrome, acrocyanosis, chilblain, frostbite, prolactin-producing ovulation disorder, prolactin-producing pituitary tumor, puerperal galactoschesia, galactorrhea, distal hypertrophy, pituitary gigantism, mental illness, cerebrovascular diseases, tachycardia accompanied by sympathetic hypertonia, hyperaldosteronism, and diabetic complication.

Description

DESCRIPTION

A NEW USE OF A QUINAZOLINE DERIVATIVE

The present invention relates to a new use or method of a quinazoline derivative or a pharmaceutically acceptable salt thereof.

More particularly, it relates to a new use of a

quinazoline derivative or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for

treating various diseases such as cardiac hypertrophy, nephropacy such as nephritis, renal failure, etc,

arteriosclerosis obliterans, obstructive thrombus, arterial embolus, Burger-Grutz 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, to a method for the treatment of various diseases such as cardiac hypertrophy, nephropacy such as nephritis, renal failure, etc,

arteriosclerosis obliterans, obstructive thrombus, arterial embolus, Burger-Grutz 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, which comprises

administering a quinazoline derivative or a

pharmaceutically acceptable salt thereof. Accordingly, one object of the present invention is to provide a new use of a quinazoline derivative or a

pharmaceutically acceptable salt thereof for the

manufacture of a medicament for treating various diseases such as cardiac hypertrophy, nephropacy such as nephritis, renal failure, etc, arteriosclerosis obliterans,

obstructive thrombus, arterial embolus, Burger-Grutz 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.

Another object of the present invention is to provide a new method for the treatment of various diseases such as cardiac hypertrophy, nephropacy such as nephritis, renal failure, etc, arteriosclerosis obliterans, obstructive thrombus, arterial embolus, Burger-Gnltz 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, which comprises

administering a quinazoline derivative or a pharmaceutically acceptable salt thereof to an animal including a human being.

The compound used in this invention is known to have dopamine receptor stimulating effects; 5-HT receptor antagonism, especially 5-HT₂ receptor antagonism; «ι receptor antagonism; and the like, and to be useful as a dopamine receptor agonist; 5-HT receptor antagonist, especially 5-HT₂ receptor antagonist; α₁ receptor

antagonist; and the like (e.g. European Publication No. 043 6157-A, etc.).

The inventors of this invention have found that the quinazoline derivative of this invention is also useful for the treatment of various diseases such as cardiac

hypertrophy, nephropacy such as nephritis, renal failure, etc, arteriosclerosis obliterans, obstructive thrombus, arterial embolus, Burger-Gnltz 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 completed this invention.

DISCLOSURE OF INVENTION The quinazoline derivative used in this invention can be represented by the following general formula:

in which R¹ and R² are each 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,

R³ 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,

ethanolamine 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, particularly sulfate thereof is preferable.1

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, t-butoxy, pentyloxy, hexyloxy, and the like, in which the most preferable one may be methoxy.

Suitable "aryl which may have suitable substituent(s)" may include phenyl, tolyl, xylyl, cumenyl, mesithyl, 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, 4-chloro(or fluorophenyl and 4-tolyl. Suitable "protected carboxy" may include carbamoyl, esterified carboxy wherein "esterifled 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), for example, lower alkanoyloxy(lower)alkyl ester [e.g. acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester,

pivaloyloxymethyl ester, hexanoyloxymethyl ester, 1-(or 2-)aeetoxyethyl ester, 1-(or 2- or 3-)acetoxypropyl ester, 1- (or 2- or 3- or 4-)acetoxybutyl ester, 1-(or 2- )propionyloxyethyl ester, 1-(or 2- or 3-)propionyloxypropyl ester, 1-(or 2-)butyryloxyethyl ester, 1-(or 2- )isobutyryloxyethyl ester, 1-(or 2-)pyvaloyloxyethyl ester, 1-(or 2-)hexanoyloxyethyl ester, isobutyryloxymethyl ester, 2-ethylbutyryloxymethyl ester, 3,3- dimethylbutyryloxymethyl ester, 1-(or 2-)pentanoyloxy- ethyl ester, etc.], lower alkanesulfonyl( lower)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

alkoxycarbonyloxy(lower)alkyl ester [e.g.

methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester, t-butoxycarbonyloxymethyl ester, 1-(or 2-)methoxycarbonyloxyethyl ester, 1-(or 2-)ethoxycarbonyloxyethyl ester, 1-(or 2-) isopropoxycarbonyloxyethyl ester, etc.], phthalidylidene- (lower)alkyl ester, or (5-lower alkyl-2-oxo-1,3-dioxol-4-yl)(lower)alkyl ester [e.g. (5-raethyl-2-oxo-1,3-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

triphenyl(lower)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 triphenyl(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)methyl ester, etc.], nitrophenyl(lower)alkyl ester (e.g. 4-nitrobenzyl ester, etc.), [hydroxy]-(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, hexylsulfonyl, etc.), carbamoyl, N- alkylcarbamoyl (e.g. methylcarbamoyl, ethylcarbamoyl, etc.), alkoxycarbonyl such as lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,

butoxycarbonyl, t-butoxycarbonyl, etc.),

alkenyloxycarbonyl such as lower alkenyloxycarboπyl (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, cyclopentanecarbσnyl, cyclohexanecarbonyl, etc.), and the like.

The aliphatic acyl substituted with aromatic group(s) may include aralkoxycarbonyl such as

phenyl(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, phenethyloxycarbonyl, etc.), and the like.

These acyl groups may be further substituted with one or more suitable substituent(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 trifluσro(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 triρhenyl(lower)alkyl, and the most preferably methyl and trityl.

Suitable heterocyclic group in "optioanlly substituted heterocyclic-carbonyl" and "optionally substituted

heterocyclic-(lower)alkyl" may include 3 to 12, preferably 5 or 6-membered 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 herero-atom such as oxygen, sulfur, nitrogen atom and the like.

More preferable heterocyclic group may be heterocyclic group such ast

-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-1,2,4~triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g., 1H-tetrazolyl, 2H-tetrazolyl, etc.), dihydrotriazinyl (e.g., 4,5- dihydro-1,2,4-triazinyl, 2,5-dihydro-1,2,4-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[1,5-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-oxadiazolyl, 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, 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 3 oxygen atom(s) and 1 to 3 nitrogen atora(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 optionally substituted heterocyclic-carbonyl thus defined may be lower

alkylpiperazinylcarbonyl and morpholinylcarbonyl, and the most preferable one may be 4-methylpiperazin-1-ylcarbonyl and morpholinocarbonyl.

More preferable example of optionally substituted heterocyclic(lower)alkyl thus defined may be lower

alkylpiperazinyl(lower)alkyl and morpholinyl(lower)alkyl, and the most preferable one may be 4-methylρiρerazin-l- ylmethyl and morpholinomethyl.

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 imidazole, 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 "hydroxy(lower)alkyl" may include

hydroxymethyl, hydroxyethyl, hydroxypropyl, hydrσxyhexyl, and the like.

Suitable "protected hydroxy(lower)alkyl" means hydroxy(lower)alkyl protected by a conventional hydroxy-protective group as mentionted in the explanation of

"protected hydroxy", in which more preferable example may be lower alkoxy(lower)alkyl and

triphenyl(lower)alkoxy(lower)alkyl, and the most preferable one may be methoxymethyl and trityloxymethyl.

For therapeutic administration, the quinazoline derivative (I) or the pharmaceutically acceptable salts thereof is used in the form of a conventional pharmaceutical preparation which contains said compound, as an active ingredient, in admixture with pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral and external administration, particularly oral administration or topical administration to eye is preferable (e.g. eye lotion, eye drop, etc.).

The pharmaceutical preparations may be in solid form such as tablets, granules, powders, capsules, dispersible granules or powders, or liquid form such as solutions, suspensions, syrups, emulsions, lemonades, and the like.

Formulations for oral use may also be presented as hard gelatine capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatine capsules wherein the active ingredient is mixed with an oil medium, for example arachis oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active compound in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose,

methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum trangacanth, and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatides, for example lecithin or

condensation products of an alkylene oxide with fatty acids, for example of polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaetyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol, for example polyoxyethylene sorbitol monooleate, or condensation product of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example

polyoxyethylene sorbitan monooleate. The said aqueous suspensions may also contain one or more preservatives, for example ethyl n-propyl or p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents such as sucrose, saccharin, or sodium or calcium cyclamate.

Dispersible powders and granules suitable for

preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agent may also be present.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and favoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example as a sterile injectable aqueous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a Bterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butane diol.

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, a kind of diseases, a kind of the compound {I) to be pplied, etc. In general, amount between about 0.001 mg 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 mg, of the object compound (I) of the present invention may be used.

The following Examples are given for the purpose of illustrating this invention in more detail. Example 1

6-Ethylsulfonylamino-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione sulfate 10 mg

Benzalkonium chloride 2 mg

Sodium chloride 28.8 mg Phosphate buffer (Ph 4.5) a proper quantity

(Total volume 10 ml)

The above-mentioned ingredients were mixed to provide 10 ml of the ophthalmic solution.

Example 2

6-Ethylsulfonylamino-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione sulfate 10 mg

Methylparaben 4 mg

Propylparaben 2 mg

Phosphate buffer (pH 7) a proper quantity

(Total volume 10 ml) The above-mentioned ingredients were mixed to provide 10 ml of the ophthalmic solution.

Example 3

6-Ethylsulfonylamino-3-[4-(4-phenyl- 1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione sulfate 10 mg Benzalkonium chloride 2 mg

Polysorbate 80 200 mg

Phosphate buffer (pH 7) a proper quantity

(Total volume 10 ml)

The above-mentioned ingredients were mixed to provide 10 ml of the ophthalmic solution. Example 4

6-Ethylsulfonylamino-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione sulfate 10 mg

Lactose 240 mg

Total 250 mg

The above-mentioned ingredients were mixed and the mixture was encapsulated to provide a capsule.

Example 5

6-Ethylsulfonylamino-3-[4-(4-phenyl-1,2,3,6-tetrahydroρyridin-l-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione sulfate 10 mg Mannitol 190 mg

Total 200 mg

The above-mentioned ingredients were mixed and the mixture was encapsulated to provide a capsule.

In order to show the novel utility of the compounds in this invention, the following pharmacological data are shown. Pharmacological Test;

Test Compounds

1) 6-Methylsulfonylamino-3-[4-(4-phenyl-1,2,3,6- tetrahydropyridin-1-yl)butyl]-1,2,3,4- tetrahydroquinazoline-2,4-dione

(hereinafter referred to as Compound 1)

2) 6-Ethylsulfonylamino-3-[4-(4-phenyl-1,2,3,6- tetrahydropyridin-1-yl)butyl]-1,2,3,4- tetrahydroquinazoline-2,4-dione

(hereinafter referred to as Compound 2)

Test 1:

Effect on the basal release of aldosterone from rat adrenal gland.

Test Method

Male Sprague Dawley rats, weighing 250-300 g, were killed by decapitation, and their adrenal glands were removed and dissect free of fat. Adrenal glands were immediately minced in medium 199 (pH 7.4), previously equilibrated under O₂-CO₂ (95-5%), to a final tissue concentration of 10-15 mg wet-weight/ml. Their tissues were preincubated at 37ºC for 30 minutes to stabilize the basal release of aldosterone, and were rinsed twice in warmed medium 199. The incubation was continued under the same conditions in fresh medium 199 containing the test compound for 15 minutes, and stopped by centrifugation at 5000 rpm for 10 minutes at 4°C. The basal release of aldosterone in the supernatant was determined by RIA with the commercial kit.

The basal release of aldosterone was attenuated by a existence of Compound 1 (1 μM). This effect was prevented by (-)sulpiride (10 μM).

Test 2:

Effect on the tachycardia induced by electrical stimulation of the stellate ganglion in cats

Test method

Adult male cats were anesthetized with pentobarbital (30 mg/kg i.p.), intubated and mechanically ventilated. Right femoral artery was cannulated for measuring blood pressure and heart rate. Left femoral vein was also cannulated for dosing the test compound. The chest was dissected and right stellate ganglion was carefully exposed. Silver electrode was placed around the right stellate ganglion for electrical stimulation and

parasympathetic nerve at the neck was excised and cut. The cats were allowed to recover from surgery for 30 minutes. and atropine (0.1 mg/kg) was intravenously injected. One hour later, tachycardia was induced by electrical

stimulation (5V, 1Hz, 20sec) twice at an interval of 15 minutes to obtain the control response. The test compound was administered, and 15 minutes later, the first

stimulation was induced. Two minutes after the first stimulation, sulpiride (3.2 mg/kg) was intravenously injected, and. then 20 minutes later the second stimulation was induced.

Intravenous administration of the Compound 2 completely inhibited the electrically stimulated

tachycardia. This inhibitory effect was reversed by selective D₂ antagonist, sulpiride.

Claims

CLAIM

1. A use of a compound of the formula:

in which R¹ and R² are each 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,

R³ is aryl which may have suitable

substituent(s), and

A is lower alkylene,

or a pharmaceutically acceptable salt thereof,

for the treatment of various diseases selected from the group consisting of cardiac hypertrophy, nephropacy such as nephritis or renal failure, arteriosclerosis obliterans, obstructive thrombus, arterial embolus, Bύrger-Grutz syndrome, acrocyanosis, chilblain, frostbite, prolactin-producing ovulation disorder, prolactin-producing pituitary tumor, puerperal galactoschesia, galactorrhea, distal hypertrophy, pituitary gigantism, mental illness, cerebrovascular diseases, tachycardia accompanied by sympathetic hypertonia, hyperaldosteronism, and diabetic

complication.

2. A use of a compound of the formula:

in which R¹ and R² are each 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,

R³ is aryl which may have suitable

substituent(s), and

A is lower alkylene,

or a pharmaceutically acceptable salt thereof,

for the manufacture of a medicament for treating various diseases selected from the group consisting of cardiac hypertrophy, nephropacy such as nephritis or renal failure, arteriosclerosis obliterans,

obstructive thrombus, arterial embolus, Bύrger-Griltz syndrome, acrocyanosis, chilblain, frostbite,

prolactin-producing ovulation disorder, prolactin- producing pituitary tumor, puerperal galactoschesia, galactorrhea, distal hypertrophy, pituitary gigantism, mental illness, cerebrovascular diseases, tachycardia accompanied by sympathetic hypertonia,

hyperaldosteronism, and diabetic complication.

3. A method for the treatment of various diseases selected from the group consisting of cardiac hypertrophy, nephropacy such as nephritis or renal failure,

arteriosclerosis obliterans, obstructive thrombus, arterial embolus, Burger-Grutz syndrome, acrocyanosis, chilblain, frostbite, prolactin-producing ovulation disorder, prolactin-producing pituitary tumor, puerperal galactoschesia, galactorrhea, distal hypertrophy, pituitary gigantism, mental illness, cerebrovascular diseases, tachycardia accompanied by sympathetic hypertonia, hyperaldosteronism, and diabetic complication, which comprises administering a compound of the formula:

in which R¹ and R² are each 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, R3 is aryl which may have suitable

substituent(s), and

A is lower alkylene,

or a pharmaceutically acceptable salt thereof, to an animal including a human being.