The present invention relates to novel antihypertensive quinazoline 
compounds and to their preparation and use. More particularly, the 
invention relates to quinazoline compounds and their non-toxic 
pharmaceutically acceptable salts, which have now been found to have 
excellent antihypertensive properties and are useful for the treatment of 
hypertensive patients, to a pharmaceutical composition containing them, 
and to their preparation and use. 
It is known that certain quinazoline derivatives are effective in reducing 
blood pressure of hypertensive patients (U.S. Pat. No. 3,511,836). In 
particular, Parzosin, 
2-[4-(2-furoyl)-1-piperazinyl]-4-amino-6,7-dimethoxyquinazoline has been 
used for the treatment of hypertensive or congestive heart failure 
patients in certain countries including U.S.A. It is reported, however, 
that Prazosin tends to cause orthostatic hypotension in patients. Such 
undesirable temporary hypotension is said to be attributable to the potent 
.alpha.-adrenagic receptor blocking activity of Prazosin. 
As the result of a study, it has now been found that the quinazoline 
compounds of the formula (I) mentioned below have an excellent 
antihypertensive activity and are useful for the treatment of 
hypertension. On experiments in normotensive and spontaneously 
hypertensive rats, the compounds of the present invention were found to 
have a potent long acting antihypertensive activity by oral 
administration. Unlike Prazosin, the compounds of the present invention 
exert a relaxing or spasmolytic effect on the smooth muscle of blood 
vessels, and its .alpha.-adrenagic receptor blocking activity is 
relatively weak in comparison with its potent hypotensive activity. So 
they exhibit characteristically a long acting antihypertensive effect 
without causing adverse effects such as orthostatic hypotension. Thus, the 
compounds of the present invention can conveniently be used for the 
treatment of hypertensive patients with essential hypertension and renal 
hypertension. 
The quinazoline compounds of the present invention are represented by the 
formula: 
##STR4## 
wherein A is 
##STR5## 
wherein n is an integer of 1 or 2, or 
##STR6## 
wherein X is 0 or CH.sub.2, and n and m are independently an integer of 1 
or 2. 
In a preferred aspect, the present invention provides the following 
compounds: 
2-{4-(1-Adamantanecarbonyl)-1-piperazinyl}-4-amino-6,7-dimethoxyquinazoline 
4-Amino-6,7-dimethoxy-2-[4-{3-oxatricyclo[4,2,1,0.sup.4,8 
]nonane-1-carbonyl}-1-piperazinyl]quinazoline 
4-Amino-6,7-dimethoxy-2-[4-{3-oxatricyclo[4,3,1,0.sup.4,9 
]decane-1-carbonyl}-1-piperazinyl]quinazoline 
4-Amino-6,7-dimethoxy-2-[4-{3-oxatricyclo[4,2,1,0.sup.4,8 
]nonane-9-carbonyl}-1-piperazinyl]quinazoline 
4-Amino-2-[4-{bicyclo[2,2,1]hept-2-ene-5-carbonyl}-1-piperazinyl]-6,7-dimet 
hoxyquinazoline 
4-Amino-6,7-dimethoxy-2-[4-{4-oxatricyclo[5,2,1,0.sup.5,9 
]decane-1-carbonyl}-1-piperazinyl]quinazoline 
4-Amino-6,7-dimethoxy-2-[4-{tricyclo[4,2,1,0.sup.4,8 
]nonane-1-carbonyl}-1-piperazinyl]quinazoline 
4-Amino-6,7-dimethoxy-2-[4-{tricyclo[5,2,1,0.sup.5,9 
]decane-1-carbonyl}-1-piperazinyl]quinazoline 
4-Amino-6,7-dimethoxy-2-[4-{4-oxatricyclo[5,3,1,0.sup.5,10 
]undecane-1-carbonyl}-1-piperazinyl]quinazoline 
4-Amino-2-[4-{bicyclo[2,2,2]oct-2-ene-5-carbonyl}-1-piperazinyl]-6,7-dimeth 
oxyquinazoline 
The compounds of the present invention may be prepared by using 
conventional processes. For instance, they can be prepared by reacting a 
compound of the formula: 
##STR7## 
wherein Y is an halogen atom or an alkylthio group, with a compound of the 
formula; 
##STR8## 
wherein A is as defined above. 
With respect to the compounds of the formula [II], the halogen atom for Y 
may preferably be chlorine or bromine, and the alkylthio group for Y may 
preferably be methylthio or ethylthio. This reaction can be carried out in 
a suitable inert organic solvent at a temperature ranging from 0.degree. 
C. to a boiling point of the solvent used. As the solvent used in this 
reaction, there may be exemplified benzene, toluene, xylene, 
dimethylformamide, pyridine, methanol, ethanol, propanol, butanol, 
pentanol and a mixture thereof. 
The compounds of the present invention may also be prepared by reacting a 
compound of the formula; 
##STR9## 
with a compound of the formula; 
EQU A--COOH [V] 
wherein A is as defined above, or its reactive derivatives in an inert 
organic solvent. 
As the reactive derivatives of the compounds of the formula [V], there may 
be exemplified acid halides (e.g., chloride, bromide), mixed acid 
anhydrides with lower alkoxycarbonyl halides (e.g., ethyl chloroformate, 
isobutyl chloroformate), or lower aliphatic carboxylic acids (e.g., 
pivaloyl acid), active esters (e.g., o-nitrophenyl ester, 
N-hydroxysuccinimide ester, N-hydroxydiphthalimide ester, 
hydroxybenzotriazole ester), and the like. 
When the compounds of the formula [V] are used in the form of a free acid, 
the reaction may preferably be carried out in the presence of a coupling 
reagent such as N,N'-dicyclohexylcarbodiimide, 
N-cyclohexyl-N'-morpholinoethylcarbodiimide, triphenylphosphine and the 
like. The reaction can preferably be carried out in a solvent at a 
temperature ranging from 0.degree. C. to a boiling point of the solvent 
used. Preferred solvents used in this reaction are benzene, toluene, 
xylene, acetone, tetrahydrofuran, chloroform, dichloroethane, dioxane, 
dimethylsulfoxide and a mixture thereof. 
For the production of the compounds of the present invention, some other 
methods can also be applied. Examples of such methods are those disclosed 
in U.S. Pat. No. 3,511,836. 
The compounds obtained as mentioned above may easily be converted into 
pharmaceutically acceptable salts form by treating with acids such as 
hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic 
acid, acetic acid, citric acid, malic acid, succinic acid, malonic acid, 
lactic acid, maleic acid, salicylic acid, p-toluenesulfonic acid and the 
like. 
The compounds [I] of the present invention and their non-toxic salts can be 
administered parenterally or orally with dosage adjusted to individual 
requirements (0.1-200 mg/human body (60 kg of body weight)/day) in the 
form of conventional pharmaceutical preparations. For instance, they may 
be administered in the form of a conventional solid pharmaceutical 
preparation such as tablets or capsules or in the form of a conventional 
liquid pharmaceutical preparation such as suspensions, emulsions or 
solutions.

The following examples are given to illustrate the present invention more 
precisely, but it is not intended to limit the present invention thereto. 
EXAMPLE 1 
A mixture of 2-chloro-4-amino-6,7-dimethoxyquinazoline (2.4 g), 
1-(1-adamantanecarbonyl)piperazine (2.5 g) and n-butanol (60 ml) was 
refluxed for 10 hours. After cooling, the solvent was evaporated under 
reduced pressure, and water was added to the residue. After treating with 
aqueous ammonia, the precipitated crystals were collected to give crude 
2-{4-(1-adamantanecarbonyl)-1-piperazinyl}-4-amino-6,7-dimethoxyquinazolin 
e, m.p. 237.degree.-240.degree. C. Recrystallization from methanol gave 
pure 2-{4-(1-adamantanecarbonyl)-1-piperazinyl}-4-amino-6,7-dimethoxyquina 
zoline, m.p. 242.degree.-243.degree. C. 
EXAMPLE 2 
To a mixture of 2-piperazino-4-amino-6,7-dimethoxyquinazoline (1 g), 
chloroform (50 ml) and triethylamine (0.42 g), was gradually added 
1-adamantanecarbonyl chloride (0.83 g). The almost dissolved mixture was 
heated at 45.degree.-50.degree. C. for 2 hours. After cooling, the mixture 
was washed with water, dried over anhydrous sodium sulfate and evaporated 
under reduced pressure to give 
2-{4-(1-adamantanecarbonyl)-1-piperazinyl}-4-amino-6,7-dimethoxyquinazolin 
e, m.p. 240.degree.-242.degree. C. 
The following compounds were also prepared by the same procedures as 
mentioned in Example 1: 
4-Amino-6,7-dimethoxy-2-[4-{3-oxatricyclo[4,2,1,0.sup.4,8 
]nonane-1-carbonyl}-1-piperazinyl]quinazoline, m.p. 
277.degree.-279.degree. C. 
4-Amino-6,7-dimethoxy-2-[4-{3-oxatricyclo[4,3,1,0.sup.4,9 
]decane-1-carbonyl}-1-piperazinyl]quinazoline, m.p. 
294.degree.-295.degree. C. 
4-Amino-6,7-dimethoxy-2-[4-{3-oxatricyclo[4,2,1,0.sup.4,8 
]nonane-9-carbonyl}-1-piperazinyl]quinazoline, m.p. 
4-Amino-2-[4-{bicyclo[2,2,1]hept-2-ene-5-carbonyl}-1-piperazinyl]-6,7-dimet 
hoxyquinazoline, m.p. 199.degree.-200.degree. C.