JPH05148265A - 2-substituted methyl-2,3-dihydroimidazo- (1,2-c)quinazolin-5(6h)-one(-thione), prepara- tion thereof, and use thereof - Google Patents

Abstract

PURPOSE: To obtain a new 2-substd. methyl2,3-dihydroimidazo[1,2c]quinazolin5(6 H)-one (-thione) having α₁-adrenalin receptor antagonism activity and useful in the prevention and treatment of hypertension, etc.

CONSTITUTION: The 2-substd. methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)- one (-thione) is a compd. of formula I [where X is O or S; R₁ and R₂ are each H, a lower alkyl, an aryl, etc.; R₁ and R₂ may bond to each other to form a 4-10C alkylene, etc.; and R₃ and R₄ are each a halogen, H, an alkyl, trifluoromethyl, etc.], e.g. 2-(4-phenyl1-piperazinyl)methyl2,3dihydroimidazo[1,2 c]quinazolin-5(6H)-one. The compd. of formula I is obtd. by allowing a compd. of formula III (where Y is a halogen) obtd. by using a compd. of formula II as starting material to react with a compd. of IV in a solvent such as THF in the presence of a base such as triethylamine.

COPYRIGHT: (C)1993,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel and useful imidazo [1,2- c ] quinazolinone derivative, and more specifically,
2-Substituted methyl-2,3-dihydroimidazo [1,2-
c ] quinazolin-5 (6H) -one (-thione).

[0002]

The quinazoline ring system, which constitutes a class of antihypertensive agents, is well known in the art. The 2-substituted quinazoline derivative, prazosin, disclosed in U.S. Pat. No. 3,511,836, has been clinically demonstrated to act effectively as an α ₁ -adrenoceptor antagonist. U.S. Patent No. 4,
No. 335,127 discloses 3-substituted quinazolines such as ketanserin and thioketanserin which have been found to be effective serotonin antagonists. Junichi Imagawa et al. , Eur. J. Pharmacol. 1986, 131,
257-264 "Further Evaluation of the Selectivity o
fa Novel Antihypertensive agent, SGB-1534, for Pe
ripheral α ₁ -adrenoceptors in the Spinally Anesth
In the document entitled "etizedDog", a 3-substituted quinazoline derivative SGB-1534 is disclosed, which compound has been proved to have antihypertensive activity by α ₁ -adrenoceptor antagonists.

As a result of extensive research to develop more potent and clinically effective antihypertensive agents, a new series of imidazo [1,2- c ] quinazolinone derivatives, 2-substituted methyl-2,3- Dihydroimidazo [1,2- c ] quinazolin-5 (6H) -one (-thione) was newly synthesized in the present invention.

It is therefore an object of the present invention to provide new and useful 2-substituted methyl-2,3-dihydroimidazo [1,2-
c ] quinazolin-5 (6H) -one (-thione) and pharmaceutically acceptable salts thereof. Another object of the present invention is a method for preparing the 2-substituted methyl-2,3-dihydroimidazo [1,2- c ] quinazolin-5 (6H) -one (-thione) and pharmaceutically acceptable salts thereof. Is to provide.

A further object of the invention is 2-substituted methyl-
2,3-dihydroimidazo [1,2- c ] quinazoline-
It is intended to provide a pharmaceutical composition containing 5 (6H) -one (-thione) or a pharmaceutically acceptable salt thereof as an active ingredient. Yet another object of the invention is an effective amount of a 2-substituted methyl-2,3-dihydroimidazo [1,2- c ] quinazolin-5 (6H) -one (-thione) for mammals in need of hypertension treatment. Alternatively, it is to provide a method for treating hypertension, which comprises administering a pharmaceutically acceptable salt thereof.

[0006]

SUMMARY OF THE INVENTION The present invention has the general formula (I):

[Chemical 5] Wherein: X is O or S; R ₁ is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
R ₂ is hydrogen, lower alkyl, aryl or aryl-
Lower alkyl; or R ₁ and R _{2 taken} together are C ₄ -C ₁₀ alkylene or

[Chemical 6] Or

[Chemical 7] Wherein R ₅ is 1 or 2 each independently selected from the group consisting of (a) 2- (2-hydroxyethyloxy) ethyl; (b) pyrimidine; (c) C ₁ -C ₄ alkyl. 2-, 3- or 4-pyridinyl optionally substituted by one substituent; or (d) from the group consisting of halogen atom, methoxy, trifluoromethyl, C ₁ -C ₄ alkyl, nitro, acetyl and cyano. Selected 1
Or represents benzoyl, benzyl, phenyl or diphenylmethyl which may be substituted by two substituents; and (i) R ₆ and R ₇ together are C ₄ -C ₆ alkylene or (ii)

[Chemical 8] Or (iii) R ₆ represents a hydrogen atom or hydroxy, R ₇ represents 1 or 2 each independently selected from the group consisting of (a) pyrimidine; (b) C ₁ -C ₄ alkyl. May be substituted by 2 substituents 2-, 3-
Or 4-pyridinyl; or (c) substituted with 1 or 2 substituents selected from the group consisting of halogen atom, methoxy, trifluoromethyl, C ₁ -C ₄ alkyl, nitro, acetyl and cyano. Represents certain benzoyl, benzyl, phenyl or diphenylmethyl; R ₃ is halogen, hydrogen, alkyl, trifluoromethyl or lower alkoxy; and R ₄ is halogen, hydrogen, alkyl, trifluoromethyl or lower alkoxy] Provided is a novel series of imidazo [1,2- c ] quinazoline derivatives and pharmaceutically acceptable salts thereof.

The compounds of formula (I) include the racemic mixtures of the optically active compounds and the optically pure R and S stereoisomers. The compounds of formula (I) and salts thereof have excellent antihypertensive activity and are therefore useful as pharmaceuticals.

[0008]

Preferred Embodiments The term "lower alkyl" as used in the above definitions is meant to include straight or branched chain hydrocarbon groups having 1 to 6 carbon atoms and "alkylene". The term includes straight chain or branched alkylene and the term "halogen" refers to fluorine, chlorine and bromine. Pharmaceutically acceptable salts include inorganic acid salts such as hydrochlorides, sulfates, hydrobromides, perchlorates and nitrates; and organic acid salts such as oxalates, maleates, fumarates, Examples include succinate and methanesulfonate.

Preferred compounds within the scope of formula (I) are 2-
(4-phenyl-1-piperazinyl) methyl-2,3-
Dihydroimidazo [1,2- c ] quinazoline-5 (6
H) -one; 2- (4-phenyl-1-piperazinyl)
Methyl-2,3-dihydroimidazo [1,2- c ] quinazoline-5 (6H) -thione; and 2- [4- (1-
Phenyl) -piperazinyl] methyl-8,9-dimethoxy-2,3-dihydroimidazo [1,2- c ] quinazolin-5 (6H) -one. Among them 2- (4-
Most preferred is phenyl-1-piperazinyl) methyl-2,3-dihydroimidazo [1,2- c ] quinazolin-5 (6H) -one.

Suitable methods for the preparation of compounds of formula (I) include (a) compounds of formula (II):

[Chemical 9] Wherein R ₃ and R ₄ have the same meaning as defined above, and the compound of formula (III):

[Chemical 10] (B) the compound of formula (IV) obtained by reacting with (wherein X has the same meaning as defined above):

[Chemical 11] (Wherein R ₃ and R ₄ have the same meanings as defined above) with a base, and (c) the compound of formula (V) obtained:

[Chemical 12] (Wherein R ₃ and R ₄ have the same meanings as defined above) with N-halosuccinimide or halogen, and (d) the resulting compound of formula (VI):

[Chemical 13] (Wherein R ₃ and R ₄ have the same meaning as defined above; Y represents halogen) with a suitable side chain

[Chemical 14]

[Chemical 15] Or

[Chemical 16] Comprising reacting with R ₁ , R ₂ , R ₅ , R ₆ and R ₇ have the same meaning as defined above.

The reaction of compound (IV) with a suitable side chain can be carried out in a suitable solvent in the presence of a suitable base.
Examples of suitable bases used in this reaction include inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, silver carbonate, cesium carbonate; and organic bases such as triethylamine, pyridine, N, N-dimethyl aniline, N-methyl morpholine, DBU, DBN etc. are mentioned. The excess side chain used in this reaction can also function as a base.

The reaction can be carried out in any inert solvent which does not adversely influence the reaction. Examples of the inert solvent include ethers such as diethyl ether, tetrahydrofuran, dioxane and diglyme; ketones,
Examples thereof include MIBK and the like; and acetonitrile. The reaction temperature is not particularly limited, but preferably 0
The range is to 200 ℃. Generally, the reaction is complete within about 1-72 hours.

In step (a), the compound of formula (II) and the compound of formula (I
The condensation reaction with the compound of II) can be carried out neat or in a suitable solvent. Any solvent that does not affect the reactants can be used. Examples of suitable solvents include chloroform, dichloromethane, ether and the like. The reaction is generally performed at room temperature and is completed in 2 days. The ring closure of the compound (IV) in the step (b) can be carried out by using a base such as aqueous ammonia, triethylamine, pyridine, DB.
It is performed in the presence of N, DBU and the like. This reaction can be carried out in the presence or absence of a solvent. Any inert solvent that does not adversely affect the reaction can be used. Examples of solvents are water; alcohols such as methanol,
Ethanol and the like; ethers such as diethyl ether and tetrahydrofuran. The reaction is generally complete in about 15 minutes.

The halocyclization reaction of compound (V) in step (c) can be carried out in the presence of N-halosuccinimide or halogen, in the presence or absence of a solvent. Any solvent that does not adversely influence the reaction can be used, such as water, alcohols, ethers and dimethylsulfoxide. The reaction is generally performed at room temperature and is completed in about 30 minutes.

The compounds of formula (I) and salts thereof have excellent antihypertensive activity and are therefore useful for the prevention and treatment of hypertension. The potency of the compounds of the invention as antihypertensive agents is clearly demonstrated by the results obtained in the tests below. In the following test, 2- (4) synthesized in Example 4 described later was used.
-Phenyl-1-piperazinyl) methyl-2,3-dihydroimidazo [1,2- c ] quinazoline-5 (6H)-
Check on.

Antihypertensive activity Adult male or female cats weighing 2-3 kg anesthetized with sodium pentobarbital (30 mg / kg ip) were used. Inhaled into the trachea and performed artificial respiration using a Harvard respirator (respiratory rate = 16-20 / min, respiratory volume = 40-50)
ml / beat). The femoral artery and vein were cannulated with PE 150 for blood pressure measurement and dosing, respectively. Body temperature was maintained at 37.5 ° C with a heat pad and monitored with an anal thermometer. Blood pressure passes through a polyethylene cannula connected to the right femoral artery,
Measured with a Statham P23D pressure transducer. Heart rate was induced by pulses of arterial blood pressure and measured through a Grass Model 7B tachograph preamplifier. All data are Grass Model
Recorded on a 7B polygraph.

1. Intravenous 2- (4-phenyl-) in cats
Antihypertensive effect of 1-piperazinyl) methyl-2,3-dihydroimidazo [1,2- c ] quinazolin-5 (6H) -one (Example 4). FIG. 1 shows SB after iv administration of the compound of Example 4 to cats.
Figure 3 shows the dose response curve of maximal change in P, DBP and heart rate. The compound of Example 4 (10 μg to 1 mg / kg) decreases both SBP and DBP in a dose-dependent manner, with a biphasic change in heart rate (HR) (first increasing and then decreasing). Was given. The ED ₅₀ of the hypotensive action of the compound of Example 4 was 250 μg / kg. FIG. 2 shows the time course of the hypotensive action when the compound of Example 4 was administered iv to anesthetized cats. Solvent (50% DMSO) had no significant effect on BP or HR. The compound of Example 4 (250 μg / kg) was
BP was immediately reduced, reaching a maximum in 5-10 minutes with a duration of action of approximately 4 hours.

2. Effect of pretreatment with the compound of Example 4 on blood pressure induced by PE and 5-HT in cats. The data presented in Figure 3 demonstrate that ED ₅₀ doses of the compound of Example 4 significantly antagonized the blood pressure response to PE (p <
0.02), and showed no effect on 5-HT (p> 0.05). This result indicates that the imidazo [1,2- c ] quinazolinone derivative represented by the general formula (I) is a novel α ₁ -adrenoceptor antagonist.

The compounds of the present invention can be formulated into pharmaceutical compositions. Therefore, in a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or excipient. Compositions which can be administered to humans by the oral route can be formulated in the form of syrups, tablets or capsules. When the composition is a tablet, any pharmaceutical carrier suitable for formulating solid compositions may be used, such as magnesium stearate, starch, lactose, glucose and flavoring agents. The compound may also be presented in a sterile liquid carrier for injection. The present invention will now be described in more detail by way of examples, which should not be construed as limiting the present invention.

[0020]

Example 1 2- (3-Allylureido) benzonitrile A mixture of anthranilonitrile (10.0 g, 85 mmol) and allyl isocyanate (7.5 ml, 85 mmol) was dissolved by slight heating. The resulting solution was stirred at room temperature for 2 days. The obtained solid was collected by filtration and washed with ether (10 ml) to obtain 14.4 g (100%) of 2- (3-allylureiido) benzonitrile. An analytical sample was recrystallized from ethanol.

IR (KBr): 3331, 3263, 2226 (CN), 1639
cm ^-1 . ¹ H-NMR (300MHz, DMSO-d6): δ 3.74 (p, 2H, CH ₂ ), 5.
09 (q, 1H, = CH), 5.17 (q, 1H, = CH), 5.86 (m, 1H, CH), 7.
09 (t, 2H, Ar-H), 7.56 (t, 1H, Ar-H), 7.67 (d, 1H, Ar-
H), 8.43 (d, 1H, Ar-H), 7.65 (d, 1H, NH), 8.54 (s, 1H, N)
H). ¹³ C-NMR (75MHz, DMSO-d6): δ 41.47, 101.00, 114.
97, 116.99, 120.61, 120.73, 122.22, 132.96, 133.8
3,135.69, 142.66, 154.32. Calculated for C ₁₁ H ₁₁ N ₃ O (201.23): C 65.66; H
5.51; N 20.89. Found: C 65.38; H 5.51; N 21.0
Five .

Example 2 3,4-dihydro-4-imino-3-allyl-2 (1
H) -quinazolinone ethanol (70 ml) and a mixture of 2- (3-allylureido) benzonitrile (10.0 g, 50 mmol) in 28% aqueous ammonia (50 ml) on a steam bath for 15 minutes with occasional stirring. Heated. Then it was cooled to room temperature and water (100 ml) was added to the mixture. The solid obtained was collected by filtration and recrystallized from methanol containing a few drops of aqueous ammonia, giving 8.4 g (84%) of 3,4-dihydro-4.
-Imino-3-allyl-2 (1H) -quinazolinone was obtained.

Mp 223-224 ° C. IR (KBr): 3284, 3203, 3147, 1691, 1582 cm ^-1 . ¹ H-NMR (300MHz, DMSO-d6): δ 4.61 (d, 2H, = CH ₂ ),
5.08 (q, 2H, CH ₂ ), 5.85 (m, 1H, = CH), 7.07 (m, 2H, Ar-
H), 7.46 (t, 1H, Ar-H), 8.04 (d, 1H, Ar-H), 8.85 (br
s, 1H, NH), 10.74 (s, 1H, NH). ¹³ C-NMR (75MHz, DMSO-d6): δ 42.54, 115.08, 115.
81, 122.09, 126.13, 132.77, 133.15, 137.01, 149.7
6. Calculated value for C ₁₁ H ₁₁ N ₃ O: C 65.63; H 5.56; N
20.87. Found: C 65.67; H 5.51; N 20.86.

Example 3 2-Bromomethyl-2,3-dihydroimidazo [1,2]
- c] quinazolin -5 (6H) - On

[Chemical 17] Method A: To a solution of 3,4-dihydro-4-imino-3-allyl-2 (1H) -quinazolinone (10 g, 50 mmol) in tetrahydrofuran (70 ml) was added N-bromosuccinimide (9.0 g, 50 mmol). ) Was added and then the mixture was stirred at room temperature for 25 minutes. The resulting solid was collected by filtration and recrystallized from THF to give 2-bromomethyl-
2,3-Dihydroimidazo [1,2- c ] -quinazolin-5 (6H) -one (11.18 g, 95%) was obtained.

Mp 213-214 ° C. ¹ H NMR (300MHz, DMSO-d6): δ 3.67 (m, 2H, CH ₂ ), 3.
74 (q, 1H, CH), 3.94 (t, 1H, CH), 4.57 (m, 1H, = CH), 7.0
7 (q, 2H, Ar-H), 7.51 (t, 1H, Ar-H), 7.78 (d, 1H, Ar-H),
10.65 (s, 1H, NH). ¹³ C-NMR (75MHz, DMSO-d6): δ 47.80, 64.16, 110.2
7, 115.13, 122.23, 125.80, 133.59, 139.97, 147.47,
153.98, 206.07. Calculated for C ₁₁ H ₁₀ N ₃ OBr: C 47.16; H 3.59;
N 15.00. Measured value: C 47.09; H 3.41; N 14.90.

Method B: Dimethyl sulfoxide (2.5 ml)
And 3,4-dihydro-4-imino-3 in water (1 ml)
A solution of -allyl-2 (1H) -quinazolinone (0.5 g, 2.5 mmol) in N-bromosuccinimide (0.87 g, 5.
(0 mmol) was added, the mixture was stirred at room temperature and then quenched with water (100 ml). The resulting solid was collected by filtration and washed with water to give 2-bromomethyl-2,3
-Dihydroimidazo [1,2- c ] -quinazoline-5
(6H) -one (450 mg, 64%) was obtained.

Method C: A suspension of 3,4-dihydro-4-imino-3-allyl-2 (1H) -quinazolinone (0.5 g, 2.5 mmol) in water (30 ml) was treated with N-bromosuccinimide ( 443 mg, 2.5 mmol) was added and the mixture was stirred at room temperature for 30 minutes. The solid was collected by filtration and washed with water (10
ml), 2-bromomethyl-2,3-dihydroimidazo [1,2- c ] -quinazoline-5 (6H)-
On (680 mg, 97%) was obtained.

Example 4 2- (4-phenyl-1-piperazinyl) methyl-2,
3-Dihydroimidazo [1,2- c ] quinazoline-5
(6H) -ON

[Chemical 18] 2-Bromomethyl-2,3-dihydroimidazo [1,2
A mixture of -c ] quinazolin-5 (6H) -one (0.5 g, 1.78 mmol), N-phenylpiperazine (0.28 ml, 3.56 mmol) and acetonitrile (25 ml) was refluxed for 13 hours. The mixture was hot filtered and washed with acetonitrile (10 ml) to give 2- (4-phenyl-1-piperazinyl) methyl-2,3-dihydroimidazo [1,
2- c ] quinazolin-5 (6H) -one (490 mg, 76%)
Got An analytical sample was prepared from a mixture of acetonitrile and methanol (1: 1).

Mp 257-258 ° C. ms: m / z 361 (M ⁺ ). ¹ H-NMR (300MHz, DMSO-d6): δ 2.43-2.73 (m, 7H, C
H ₂ ), 3.11 (t, 3H, CH ₂ ), 3.65 (q, 1H, CH), 3.91 (t, 1H, C
H), 4.41 (m, 1H, CH), 6.75 (t, 1H, Ar-H), 6.91 (d, 2H, A
rH), 7.06 (q, 2H, Ar-H), 7.17 (q, 2H, Ar-H), 7.48 (p,
1H, Ar-H), 7.78 (d, 1H, Ar-H), 10.53 (s, 1H, NH). Calculated for C ₂₁ H ₂₃ N ₅ O: C 69.78; H 6.41; N
19.38. Found: C 69.79; H 6.45; N 19.37.

Example 5 3- {2,3-dihydroimidazo [1,2- c ] quinazolin-5 (6H) -on-2-yl} methyl-azaspiro [5,5] undecane

[Chemical 19] Using the same procedure as described in Example 4, yield 73%
Obtained in.

Mp 203-205 ° C. ms: m / z 166 (M ⁺ ). ¹ H-NMR (300MHz, DMSO-d6): δ 1.27 (s, 4H, CH ₂ ), 1.
34 (s, 6H, CH ₂ ), 2.28 (d, 2H, CH ₂ ), 2.48 (d, 2H, CH ₂ ),
3.39 (m, 7H, CH ₂ ), 3.85 (t, 1H, CH), 4.34 (m, 1H, CH),
7.03 (m, 2H, Ar-H), 7.47 (t, 1H, Ar-H), 7.74 (d, 1H, Ar-
H), 10.54 (s, 1H, NH). Calculated for C ₂₁ H ₂₈ N ₄ O: C 71.56; H 8.01; N
15.90. Actual value: C 71.50; H 8.02; N 15.89.

Example 6 2- (4-Piperonyl-1-piperazinyl) methyl-
2,3-dihydroimidazo [1,2- c ] quinazoline-
5 (6H) -on

[Chemical 20] 2-Bromomethyl-2,3-dihydroimidazo [1,2
- c] quinazolin -5 (6H) - on (0.5 g, 1.78 mmol), 1-piperonylpiperazine (0.78 g, 3.56 mmol) and acetonitrile (25 ml) was refluxed for 17 hours, then under reduced pressure and the solvent Did it evaporate. The oily residue was subjected to column chromatography [silica gel: 25 g, column diameter: 2.5 cm, solvent system: chloroform / ethyl acetate (9 /
1)], 2- (4-piperonyl-1-piperazinyl) methyl-2,3-dihydroimidazo [1,
2- c ] quinazolin-5 (6H) -one hydrobromide (62
0 mg, 67%) and 2-methyl-2,3-dihydroimidazo [1,2- c ] quinazolin-5 (6H) -one (90 m
g, 22%) was obtained.

2- (4-piperonyl-1-piperazinyl) methyl-2,3-dihydroimidazo [1,2-c]
Quinazolin-5 (6H) -one hydrobromide mp 236-238 ° C. Calculated value for C ₂₃ H ₂₃ N ₅ O ₃ / H ₂ O / HBr:
C 53.29; H 5.44; N 13.50. Measured value: C 53.45; H
5.46; N 13.54. 2-Methyl-2,3-dihydroimidazo [1,2- c ]
Quinazolin-5 (6H) -one ¹ H-NMR (300MHz, DMSO-d6): δ 2.32 (s, 3H, CH ₃ ), 7.27
(t, 1H, Ar-H), 7.35 (d, 1H, Ar-H), 7.57 (s, 1H, Ar-H),
8.10 (d, 1H, Ar-H). Calculated value for C ₁₁ H ₉ N ₃ O: C 66.3
2; H 4.55; N 21.09. Measured value: C 66.37; H 4.56;
N 21.09.

Example 7 2- [4- (2-methoxy) phenyl-1-piperazinyl] methyl-2,3-dihydroimidazo [1,2- c ]
Quinazolin-5 (6H) -one

[Chemical 21] Using the same procedure as described in Example 4, yield 66%
Obtained in.

Mp 226-227 ° C. ms: m / z 391 (M ⁺ ). ¹ H-NMR (300MHz, DMSO-d6): δ 2.44-2.69 (m, 6H, C
H ₂ ), 2.95 (br s, 4H, CH ₂ ), 3.67 (q, 1H, CH), 3.76 (s, 3
H, O-CH ₃ ), 3.87 (t, 1H, CH), 4.40 (m, 1H, CH), 6.88 (d, 4
H, Ar-H), 7.06 (m, 2H, Ar-H), 7.48 (t, 1H, Ar-H), 7.78
(d, 1H, Ar-H), 10.50 (br s, 1H, NH). Calculated for C ₂₂ H ₂₅ N ₅ O ₂ : C 67.50; H 6.44; N
17.89. Actual value: C 67.54; H 6.44; N 17.90.

Example 8 2- [4-benzyl-1-piperazinyl] methyl-2,
3-Dihydroimidazo [1,2- c ] quinazoline-5
(6H) -ON

[Chemical formula 22] Using the same procedure described in Example 4 yield 64%
Obtained in.

Mp 222-224 ° C. ¹ H-NMR (300MHz, DMSO-d6): δ 2.50-3.00 (br s, 10
H, CH ₂ ), 3.74-3.80 (br s, 3H, CH ₂ ), 4.04 (t, 1H, CH),
4.53 (m, 1H, CH), 6.99-7.10 (m, 2H, Ar-H), 7.24-7.41
(m, 6H, Ar-H), 7.90 (d, 1H, Ar-H), 9.15 (br s, 1H, NH)
. Calculated for C ₂₂ H ₂₅ N ₅ O: C 70.38; H 6.71; N
18.65. Measured value: C 70.39; H 6.67; N 18.68.

Example 9 2- [4-benzyl-1-piperidinyl] methyl-2,
3-Dihydroimidazo [1,2- c ] quinazoline-5
(6H) -ON

[Chemical formula 23] Using the same procedure described in Example 4 yield 64%
Obtained in.

Mp 225-227 ° C. ¹ H-NMR (300MHz, DMSO-d6): δ 1.56-1.66 (br s, 5
H, CH ₂ ), 2.21-2.33 (br s, 2H, CH ₂ ), 2.54 (br s, 2H, C
H), 2.75 (br s, 1H, CH), 2.90 (br s, 1H, CH), 3.09 (br
s, 1H, CH), 3.29 (br s, 1H, CH), 3.80 (q, 1H, CH), 4.06
(t, 1H, CH), 4.60 (m, 1H, CH), 6.99-7.29 (m, 7H, Ar-H),
7.39 (t, 1H, Ar-H), 7.89 (d, 1H, Ar-H), 9.49 (br s, 1H,
NH). Calculated for C ₂₃ H ₂₆ N ₄ O: C 73.77; H 7.00; N
14.96. Measured value: C 73.64; H 7.02; N 15.02.

Example 10 2- [4- (2-pyridinyl) -1-piperazinyl] methyl-2,3-dihydroimidazo [1,2- c ] quinazolin-5 (6H) -one

[Chemical formula 24] Using the same procedure as described in Example 4, yield 81%
Obtained in.

Mp 242-243 ° C. ¹ H-NMR (300MHz, DMSO-d6): δ 2.65-2.83 (br s, 6
H, CH ₂ ), 3.59 (brs, 4H, CH ₂ ), 3.91 (q, 1H, CH), 4.09
(t, 1H, CH), 4.57 (m, 1H, CH), 6.62 (t, 2H, Ar-H), 6.98
(d, 1H, Ar-H), 7.11 (t, 1H, Ar-H), 7.45 (q, 2H, Ar-H),
7.95 (d, 1H, Ar-H), 8.17 (d, 1H, Ar-H), 9.04 (br s, 1H,
NH). Calculated for C ₂₀ H ₂₂ N ₆ O: C 66.28; H 6.12; N
23.19. Found: C 66.23; H 6.10; N 23.1.

Example 11 2- [4- (4-Fluorobenzyl) -1-piperazinyl] methyl-2,3-dihydroimidazo [1,2- c ]
Quinazolin-5 (6H) -one

[Chemical 25] Using the same procedure as described in Example 4, yield 61%
Obtained in.

Mp 248-249 ° C. Calculated for C ₂₁ H ₂₂ N ₅ OF: C 66.48; H 5.84; N
18.46. Measured value: C 66.54; H 5.85; N 18.49.

Example 12 2- [1-Benzylpiperidin-4-yl] aminomethyl-2,3-dihydroimidazo [1,2- c ] quinazolin-5 (6H) -one

[Chemical formula 26] Using the same procedure described in Example 4, yield 76%
Obtained in.

Mp 206-208 ° C. Calculated for C ₂₃ H ₂₇ N ₅ O: C 70.93; H 6.99; N
17.98. Actual value: C 70.71; H 6.87; N 17.97.

Example 13 8- {2,3-Dihydroimidazo [1,2- c ] quinazolin-5 (6H) -one-2-yl} -methyl-1-phenyl-1,3,8-triazaspiro [ 4, 5] decan-4-one

[Chemical 27] Using the same procedure as described in Example 4, yield 74%
Obtained in.

Mp 250-251 ° C. (acetonitrile). ¹ H-NMR (300MHz, DMSO-d6): δ 1.52 (q, 2H, CH ₂ ),
2.44-2.64 (m, 4H, 2CH ₂ ), 2.78-2.89 (m, 4H, 2CH ₂ ), 3.71-
3.77 (m, 1H, CH), 3.96 (m, 1H, CH), 4.37 (m, 1H, CH), 4.
55 (s, 2H, CH ₂ ), 6.71-6.82 (m, 3H, Ar-H), 7.06 (t, 2H, A
rH), 7.22 (t, 2H, Ar-H), 7.46 (t, 1H, Ar-H), 7.77 (d,
1H, Ar-H), 8.59 (s, 1H, NH), 10.54 (s, 1H, NH). _{C 24 H 26 N 6 O 2} · 1/4 H 2 O (430.508) Calculated for: C
66.27; H 6.14; N 19.32. Measured value: C 66.32; H
6.14; N 19.21.

Example 14 2- [1- (4-chlorobenzhydryl) piperazinyl] methyl-2,3-dihydroimidazo [1,2- c ]
Quinazolin-5 (6H) -one

[Chemical 28] Using the same procedure described in Example 4, yield 40%
Obtained in.

Mp 245-246 ° C. (acetonitrile). ¹ H-NMR (300MHz, DMSO-d6): δ 2.29-2.57 (m, 10H, CH
₂ ), 3.29 (m, 1H, CH), 3.59 (m, 1H, CH), 3.84 (t, 1H, C)
H), 4.31 (s, 2H, CH ₂ ), 7.01-7.75 (m, 13H, Ar-H), 10.50
(br s, 1H, NH). Calculated for C ₂₈ H ₂₉ N ₅ OCl (486.015): C 69.20;
H 5.81; N 14.40. Measured value: C 68.85; H 5.84; N
14.26.

Example 15 2- [1- (4-p-Fluorobenzoyl) piperidinyl] methyl-2,3-dihydroimidazo [1,2- c ]
Quinazolin-5 (6H) -one

[Chemical 29] Using the same procedure as described in Example 4, yield 81%
Obtained in.

Mp 220-221 ° C. (acetone). ¹ H-NMR (300MHz, DMSO-d6): δ 1.51-1.73 (m, 4H, 2CH
₂ ), 2.10-2.42 (m, 5H, 2CH ₂ + CH), 2.87 (d, 1H, CH), 3.06
(d, 1H, CH), 3.36 (m, 1H, CH), 3.62 (m, 1H, CH), 3.88
(m, 1H, CH), 4.37 (m, 1H, CH), 7.06 (m, 2H, Ar-H), 7.33
(m, 2H, Ar-H), 7.76 (d, 1H, Ar-H), 8.04 (m, 2H, Ar-H), 1
0.50 (s, 1H, NH).

Example 16 2- [1- (4-Methoxyphenyl) piperazinyl] methyl-2,3-dihydroimidazo [1,2- c ] quinazolin-5 (6H) -one

[Chemical 30] Using the same procedure described in Example 4, yield 54%
Obtained in.

Mp 229-231 ° C. (CH ₃ CN). ¹ H-NMR (300MHz, DMSO-d6): δ 2.42-2.71 (m, 6H, 3CH
₂ ), 3.09 (m, 4H, 2CH ₂ ), 3.65 (m, 1H, CH), 3.69 (s, 3H, CH
₃ ), 3.90 (m, 1H, CH), 4.41 (m, 1H, CH), 6.33-6.51 (m, 3
H, Ar-H), 7.03-7.11 (m, 3H, Ar-H), 7.48 (t, 1H, Ar-H),
7.78 (d, 1H, Ar-H), 10.50 (s, 1H, NH). ms: m / z 391 (M ⁺ ), 229, 205. Calculated for C ₂₂ H ₂₅ N ₅ O ₂ (391.475): C 67.50; H
6.44; N 17.89. Measured value: C 67.67; H 6.36; N 1
7.82.

Example 17 2- [1- (3-Methoxyphenyl) piperazinyl] methyl-2,3-dihydroimidazo [1,2- c ] quinazolin-5 (6H) -one

[Chemical 31] Using the same procedure as described in Example 4 yield 88%
Obtained in.

Mp> 300 ° C. Calculated for C ₂₂ H ₂₅ N ₅ O ₂ (391.475): C 67.50; H
6.44; N 17.89. Measured value: C 67.47; H 6.31; N 1
7.72.

Example 18 3,4-Dihydro-4-imino-3-allyl-quinazoline-2 (1H) -thioneanthranilonitrile (10.0
g, 85 mmol) and allyl isothiocyanate (15 ml,
The mixture of 151 mmol) was slightly heated to dissolve. The resulting solution was stirred at room temperature for 5 days, the solid was collected by filtration, washed with acetonitrile (10 ml) and recrystallized from ethanol to give 8.05 g (44%) 3,4-dihydro-4-. Imino-3-allyl-quinazoline-2 (1
H) -Thion was obtained.

Mp 168-169 ° C. ¹ H-NMR (300MHz, DMSO-d6): δ 5.07-5.25 (m, 4H, = CH
₂ + CH ₂ ), 5.75-6.06 (m, 1H, = CH), 7.13-7.63 (m, 3H, Ar-
H), 8.05-8.13 (d, 1H, Ar-H), 9.40 (s, 1H, NH), 12.13
(s, 1H, NH). ¹³ C-NMR (75MHz, DMSO-d6): δ 48.43, 115.56, 116.
63, 123.92, 125.96, 132.20, 133.04, 135.59, 174.3
8. ms: m / z 217 (M ⁺ ), 201, 183, 160. Calculated for C ₁₁ H ₁₁ N ₃ S (217.295): C 60.80; H
5.10; N 19.34. Measured value: C 60.95; H 5.13; N 1
9.34.

Example 19 2-Bromomethyl-2,3-dihydroimidazo [1,2]
- c] quinazolin -5 (6H) - thione

[Chemical 32] To a solution of 3,4-dihydro-4-imino-3-allyl-quinazoline-2 (1H) -thione (5.5 g, 25.31 mmol) in acetonitrile (60 ml) was added N-bromosuccinimide (6.0 g, 33.52 mmol). Was added and the mixture was stirred at room temperature for 50 minutes. The resulting solid was collected by filtration and recrystallized from a mixture of acetonitrile and methanol to give 2-bromomethyl-2,3-dihydroimidazo [1,2- c ] quinazoline-5 (6H) -thione (3.01
g, 40%) was obtained.

Mp> 300 ° C. ¹ H-NMR (300MHz, DMSO-d6): δ 3.90 (m, 2H, CH ₂ ), 4.
54-4.73 (m, 3H, CH & CH ₂ ), 7.66,7.71 (t, 2H, Ar-H), 7.97-
9.02 (m, 1H, Ar-H), 8.54 (d, 1H, Ar-H), 9.80 (s, 1H, N
H), 10.50 (s, 1H, NH). ¹³ C-NMR (100MHz, DMSO-d6): δ 47.80, 64.16, 110.2
7, 115.13, 122.23, 125.80, 133.59, 139.97, 147.47,
153.98, 206.07. ms: m / z 296 (M ⁺ ), 295 (M ⁺ -1), 216 (M ⁺ -80),
202 (M ⁺ -94). Calculated value for C ₁₁ H ₁₀ N ₃ SBr ・ HBr (377.10): C 35.
04; H 2.94; N 11.14. Measured value: C 35.14; H 3.01;
N 10.94.

Example 20 2- (4-phenyl-1-piperazinyl) methyl-2,
3-Dihydroimidazo [1,2- c ] quinazoline-5
(6H) -Thion

[Chemical 33] 2-Bromomethyl-2,3-dihydroimidazo [1,2
- c] quinazolin -5 (6H) - thione (3.0 g, 10.13
Mmol), N-phenylpiperazine (2.5 ml, 15.41
Mmol), sodium hydrogen carbonate (1.7 g, 20.24 mmol) and acetonitrile (70 ml) were refluxed for 24 hours. The mixture was filtered hot and washed with acetonitrile (10 ml) to give 2- (4-phenyl-1-piperazinyl).
Methyl-2,3-dihydroimidazo [1,2- c ] quinazoline-5 (6H) -thione (490 mg, 76%) was obtained. Samples for analysis are acetonitrile and methanol (1:
Prepared from the mixture of 1).

Mp 257-258 ° C. ms: m / z 361 (M ⁺ ). ¹ H-NMR (300MHz, DMSO-d6): δ 2.43-2.73 (m, 7H, C
H ₂ ), 3.11 (t, 3H, CH ₂ ), 3.65 (q, 1H, CH), 3.91 (t, 1H, C
H), 4.41 (m, 1H, CH), 6.75 (t, 1H, Ar-H), 6.91 (d, 2H, A
rH), 7.06 (q, 2H, Ar-H), 7.17 (q, 2H, Ar-H), 7.48 (p,
1H, Ar-H), 7.78 (d, 1H, Ar-H), 10.53 (s, 1H, NH). ¹³ C-NMR (75MHz, DMSO-d6): δ 29.43, 48.14, 51.91,
52.67, 61.18, 115.33, 118.75, 124.75, 124.92, 125.6
0, 128.81, 132.41, 145.39, 150.86, 159.50, 179.22.

Example 21 2-Nitro-4,5-dimethoxybenzonitrile 3,4-Dimethoxybenzonitrile (5.0 g, 30.6 mmol) was added to nitric acid (40 ml) in an ice bath and stirred for 2 hours. .. The solution was then allowed to come to room temperature gradually. Addition of ice (200 ml) to this solution resulted in a pale yellow precipitate which was collected by filtration and found to be 6.25 g (98%) 2-nitro-.
4,5-Dimethoxybenzonitrile was obtained.

¹ H-NMR (100 MHz, DMSO-d6): δ 3.69
(s, 3H, CH ₃ ), 3.90 (s, 3H, CH ₃ ), 7.53 (s, 1H, Ar-H), 7.7
5 (s, 1H, Ar-H). ms: m / z 208 (M ⁺ ), 192 (M ⁺ -16), 178 (M ⁺ -30),
162 (M ⁺ -46).

Example 22 2-Amino-4,5-dimethoxybenzonitrile A suspension of 2-nitro-4,5-dimethoxybenzonitrile (6.0 g, 28.8 mmol) in water (200 ml) up to 90 ° C. Heat and add sodium dithionite in small portions until it is completely dissolved. The obtained solution was filtered and then cooled to room temperature to obtain crystals. The solid was collected by filtration to give 4.99 g (97%) of 2-amino-4,5-dimethoxybenzonitrile. The analytical sample was recrystallized from acetonitrile.

[0065]¹H-NMR (100MHz, DMSO-d6): δ 3.64 (s, 3
H, CH₃), 3.73 (s, 3H, CH₃), 4.32 (brs, 2H, NH₂), 6.41
(s, 1H, Ar-H), 6.86 (s, 1H, Ar-H).¹³ C-NMR (25MHz, DMSO-d6): δ 55.55, 56.87, 83.67,
92.08, 113.96, 140.33, 148.12, 154.33. ms: m / z 178 (M⁺ ), 163 (M⁺-15), 147 (M⁺ -31),
 132 (M⁺-43), 120 (M ⁺ -58).

Example 23 3,4-Dihydro-3-allyl-4-imino-6,7-
Dimethoxyquinazolin-2 (H) -one was obtained in 72% yield using a procedure similar to that described in Example 2.
Obtained in%. The analytical sample was recrystallized from ethanol.

¹ H-NMR (100 MHz, DMSO-d6): δ 3.78 (s, 6
H, 2 (CH ₃ )), 4.62 (d, 2H, J = 4.8Hz, CH ₂ ), 5.05 (d, 2H, J = 1
2.8Hz, CH ₂ ), 5.94-6.03 (m, 1H, CH), 6.62 (s, 1H, Ar-H),
7.54 (s, 1H, Ar-H). ms: m / z 260 (M ⁺ -1), 246 (M ⁺ -15), 230 (M ⁺ -3)
1), 216 (M ⁺ -45), 206 (M ⁺ -55).

Example 24 2-Bromomethyl-8,9-dimethoxy-2,3-dihydroimidazo [1,2- c ] quinazoline-5 (6H)-
on

[Chemical 34] Using a procedure similar to that described in Example 3
Obtained in%.

¹ H-NMR (100 MHz, DMSO-d6): δ 3.78 (s, 3
H, CH ₃ ), 3.83 (s, 3H, CH ₃ ), 3.78-4.21 (m, 4H, 2 (CH ₂ )),
6.68 (s, 1H, Ar-H), 7.32 (s, 1H, Ar-H). ms: m / z 341 (M ⁺ ), 259 (M ⁺ -82), 246 (M ⁺ -95)
.

Example 25 2- [4- (1-phenyl) piperazinyl] methyl-
8,9-dimethoxy-2,3-dihydroimidazo [1,
2- c ] quinazolin-5 (6H) -one

[Chemical 35] Using a procedure similar to that described in Example 4
Obtained in%. The analytical sample was recrystallized from ethanol.

Mp 283-284 ° C. ms: m / z 421 (M⁺), 303 (M⁺-118), 289 (M⁺-13
2), 275 (M⁺-146).¹ H-NMR (100MHz, DMSO-d6 + 1N D₂SO_Four): δ 3.37 (br
s, 8H, 4 (CH₂)), 3.81 (s, 3H, CH₃), 3.88 (s, 3H, CH₃), 3.
62-4.20 (m, 3H, CH₂+ CH), 4.46 (t, 1H, CH), 4.95 (br s,
1H, CH), 6.79 (s, 1H, Ar-H), 6.82-7.23 (m, 5H, Ar-H),
7.56 (s, 1H, Ar-H). ¹³ C-NMR (25MHz, DMSO-d6 + 1N D₂SO_Four): δ 46.35, 4
9.70, 52.15, 52.50, 56.78, 57.19, 58.82, 96, 33, 9
8.55, 107.05, 116.66, 121.11, 130.22, 141.02,146.0
2, 146.66, 148.53, 158.37, 158.55. C_{twenty three}H₂₇N_FiveO₃Calculated value for (421.50): C 65.54; H 1
6.62; N 6.46. Found: C 65.33; H 16.54; N 6.51
 .

[Brief description of drawings]

FIG. 1 is a graph of blood pressure 2-in 5-cats.
(4-phenyl-1-piperazinyl) methyl-2,3-
Dihydroimidazo [1,2- c ] quinazoline-5 (6
Figure 3 is a dose response plot of (H) -one (Example 4).

FIG. 2 shows the time course of each dose of the compound of Example 4 on blood pressure in cats.

FIG. 3 is a plot showing the antagonistic effect of the compound of Example 4 (0.025 mg / kg) on blood pressure induced by phenylephrine (0.015 mg / kg) or serotonin (0.020 mg / kg).

Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI technical display location C07D 239: 00) (C07D 519/00 487: 04 471: 10) (72) Inventor Syau Chia-Yang Taiwan, Taipei, Roosevelt Road, 24 lanes, 25 arrays, number 16-3, floor 5 (72) Inventor Yeng Mao Siyun Taiwan, Taipei, Ching-Zao Road, 626 lanes, 5 arrays, number 43, floor 2 (72) ) Inventor Lugan-Yu Taiwan, Taipei, P. Oh. Box 90048-512

Claims (12)

[Claims] 1. The general formula (I): Wherein: X is O or S; R ₁ is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
R ₂ is hydrogen, lower alkyl, aryl or aryl-
Lower alkyl; or R ₁ and R _{2 taken} together are C ₄ -C ₁₀ alkylene or Or [Chemical formula 3] Wherein R ₅ is 1 or 2 each independently selected from the group consisting of (a) 2- (2-hydroxyethyloxy) ethyl; (b) pyrimidine; (c) C ₁ -C ₄ alkyl. 2-, 3- or 4-pyridinyl optionally substituted by one substituent; or (d) from the group consisting of halogen atom, methoxy, trifluoromethyl, C ₁ -C ₄ alkyl, nitro, acetyl and cyano. Selected 1
Or represents benzoyl, benzyl, phenyl or diphenylmethyl which may be substituted by two substituents; and (i) R ₆ and R ₇ together are C ₄ -C ₆ alkylene or (ii) 4] Or (iii) R ₆ represents a hydrogen atom or hydroxy, R ₇ represents 1 or 2 each independently selected from the group consisting of (a) pyrimidine; (b) C ₁ -C ₄ alkyl. May be substituted by 2 substituents 2-, 3-
Or 4-pyridinyl; or (c) substituted with 1 or 2 substituents selected from the group consisting of halogen atom, methoxy, trifluoromethyl, C ₁ -C ₄ alkyl, nitro, acetyl and cyano. Represents some benzoyl, benzyl, phenyl or diphenylmethyl; R ₃ is halogen, hydrogen, alkyl, trifluoromethyl or lower alkoxy; and R ₄ is halogen, hydrogen, alkyl, trifluoromethyl or lower alkoxy] Imidazo [1,2- c ] quinazoline derivatives and pharmaceutically acceptable salts thereof, as indicated, including racemic mixtures of the optically active compounds and optically pure R and S stereoisomers. 2. A pharmaceutical composition for the prevention and treatment of hypertension, which comprises a prophylactically or therapeutically effective amount of the imidazo [1,2- c ] quinazoline derivative of formula (I) as an active ingredient. Alternatively, a pharmaceutical composition comprising a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent. 3. A method for preventing and treating hypertension, comprising:
Administering a prophylactically or therapeutically effective amount of the imidazo [1,2- c ] quinazoline derivative of formula (I) according to claim 1 as an active ingredient to a mammal in need of such prophylaxis and treatment. A method consisting of. 4. 2- (4-Phenyl-1-piperazinyl) methyl-2,3-dihydroimidazo [1,2- c ]
The compound of claim 1, which is quinazolin-5 (6H) -one. 5. The imidazo [1,2- c ] quinazoline derivative is 2- (4-phenyl-1-piperazinyl) methyl-2,3-dihydroimidazo [1,2- c ] quinazoline-5 (6H)-. The pharmaceutical composition according to claim 2, which is on. 6. The imidazo [1,2- c ] quinazoline derivative is 2- (4-phenyl-1-piperazinyl) methyl-2,3-dihydroimidazo [1,2- c ] quinazoline-5 (6H)-. The method of claim 3, wherein the method is on. 7. 2- (4-Phenyl-1-piperazinyl) methyl-2,3-dihydroimidazo [1,2- c ]
The compound of claim 1, which is quinazoline-5 (6H) -thione. 8. The imidazo [1,2- c ] quinazoline derivative is 2- (4-phenyl-1-piperazinyl) methyl-2,3-dihydroimidazo [1,2- c ] quinazoline-5 (6H)-. The pharmaceutical composition according to claim 2, which is thione. 9. The imidazo [1,2- c ] quinazoline derivative is 2- (4-phenyl-1-piperazinyl) methyl-2,3-dihydroimidazo [1,2- c ] quinazoline-5 (6H)-. The method of claim 3, which is thione. 10. 2- [4- (1-phenyl) piperazinyl] methyl-8,9-dimethoxy-2,3-dihydroimidazo [1,2- c ] quinazolin-5 (6H) -one. Item 2. The compound according to Item 1. 11. The imidazo [1,2- c ] quinazoline derivative is 2- [4- (1-phenyl) piperazinyl].
The pharmaceutical composition according to claim 2, which is methyl-8,9-dimethoxy-2,3-dihydroimidazo [1,2- c ] quinazolin-5 (6H) -one. 12. The imidazo [1,2- c ] quinazoline derivative is 2- [4- (1-phenyl) piperazinyl].
The method of claim 3, which is methyl-8,9-dimethoxy-2,3-dihydroimidazo [1,2-c] quinazolin-5 (6H) -one.