JPS5862176A - Tricyclic quinazolines - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to tricyclic quinazolinones, more specifically novel tricyclic quinazolinones and salts thereof, methods for producing these compounds, pharmacological compositions containing these compounds, and Concerning use as a drug.

In particular, the present invention relates to a free base type compound or an acid addition salt thereof.

[wherein (a) R1 is any group represented by (in the group, m is Oll, 2.3 or 4, P is 1 or 2
．． 9 is 0.1 or 2, R7 is hydrogen or C1-2 alkyl, square is hydrogen, halogen or 01-3 alkyl, 1? (a) water, halogen, C1-4 alkyl, trifluoromethyl or nitro; ) 顯, 抛 and 銛 are each individually hydrogen or ClN2 alkyl, phase is hydrogen, halogen, Cl, 4 alkyl, trifluoromethyl or nitro, 顯 is hydrogen, halogen or C1-3 alkyl, n is 0 or 1, ( where at least one of R2, R3 and paulownia is substituted 01-8 alkyl, ~ is fluorine, chlorine or trifluoromethyl present at the b position, n is 0 or 1, ζ ~, ζ and phase are each hydrogen, (fc and R61J<chlorine, when n is 1, kl is a group other than methyl), or (c)
R1 is C3N6 alkenyl, C3+v6 alkynyl,
C3N8 cycloalkyl, norbornyl, or C3N
7cycloalkyl (CIN3) alkyl, R2, R3 and - are each individually hydrogen or C1+v2 alkyl, bow is halogen, C1-4 alkyl or trifluoromethyl present at the b position, square is hydrogen, halogen or C1-3 alkyl , n represents 0 or 1. ].

Unless otherwise specified, 7% rogens have an atomic weight of 18-80. The alkyl group may be linear or branched. When m=2, the two radicals may independently be each other hydrogen or 01-2 alkyl.

'7) +7) Geller Fighting Spirit Test (Geller Con
The effect of reducing combativeness in the flick test) and Chang and 5nyder: Eu
r, J, Pharmacol.

48, p. 213 (1978), was carried out using a method similar to that described in the following slightly improved method.
ing assay) (Test B), retains pharmacological activity, especially central nervous system activity.

Fresh calf brain cortex was diluted with 19x Tris-HCl buffer (
Brinkman Polytro in PI (7,4)
Homogenize with n Fr2O, 5o, 10 with oooy
Centrifuge for minutes. The pellet was frozen at -20°C and prepared in 400x volume 0 Tris buffer (p
Resuspend in H7,4). Each test mixture' was a homogeneous suspension of 1.8 m7 (original assembly ll &
4.5 qK corresponding), [3H]-flunitrazenogum (final concentration 1.5'nM (0,0015PM)
) and 0.1 ml of buffer, unlabeled flunitrazepam (final concentration I
PM) 0.1-. To evaluate the inhibitory effects of various drugs on specific binding, drugs (instead of buffer) were added at concentrations of 1 nM to 10 PM (0,001 to 10 μM).
Prepare one pair (two pieces) of each of 5 to 9 different concentrations of M)O. After aging for 15 minutes at 0°C, the evaluation mixture is immediately filtered through a Whatman GF/B filter and washed twice with water-cold Tris-buffer 5-. Transfer the furnace liquid onto the LKB Rach-Beta liquid scintillation counter.
luma). Linear regression analysis (HILL-
The IC50 value (the concentration of the test drug that inhibits the specific binding of H-flunitrazepam by 50%) is determined by Plot).

Also written by R, C85peth et al.: Life 5ci
The test (Test C-a) can be conducted by a method similar to that described in J. ence, Vol. 22, p. 859 (1978), modified as follows.

Frozen caudate tissue
Thaw a portion of s) and extract metal ions (sodium chloride 12
9mM, potassium chloride 5mM, calcium chloride 2m
Dilute with 0.5 M Tris-buffer containing M and magnesium chloride (1 mM) to obtain a final concentration of 8 #/J (i.e., 25-fold) dilution. BrinkmλnnPolyt
Homogenize the suspension using a ron homogenizer with the rheostat set to 8 for 10 seconds. 3H
- Flunitrazepam solution lOλ was diluted in 0°05M Tris-buffer (pH 7, 1, 37°C) to concentrations o, o.
Make it 1o PM (a, x a x 1o-'da/-).

Add 0.1 d of 0.010 μM flunitrazepam solution to a 12×75ff borosilicate tube containing 0.1 d of freshly prepared 10% ethanol solution. This is a control tube to measure total binding.

2X10 M instead of 10% ethanol 0.1 m/
Diazepam (in 10% ethanol) is added to another tube to determine the amount of non-specific binding. The amount of specific binding is determined by subtracting the amount of non-specific binding from the total amount of binding.

All selected compounds have results expressed in specific binding, and the compounds are tested at a final concentration of I x 10-6M. - Place 311v of each compound in an 18 x 150111 borosilicate test tube, add 10 - of absolute ethanol, treat the test tube in a Branson ultrasonic cleaner for 15 minutes, and swirl to dissolve the compound. If the compound does not dissolve, add 3 drops of 2N hydrochloric acid. If the compound still does not dissolve and the liquid remains a homogeneous cloudy suspension, continue dilution. This concentration is 1×10 M.

The compound is further diluted using a serial dilution method as follows.

That is, 0.14 of a 10'''3M solution was added to 0.9 mJ of 100% ethanol, stirred thinly, and the solution was 0.14 mJ.
Add 1 mJ to 0.9-ml of water to obtain a 1X10 M solution. Place 0.1 - of this solution into 12 x 75 mg test tubes.

All tests are performed on pairs (two) of samples. Caudate tissue (
Caudate tissue) Q, 8 tnl was added to all test tubes, stirred thinly, aged at 2°C for 120 minutes, and immediately passed through a Whatman GF/G glass fiber filler under reduced pressure. Each test tube was cooled with 3 ml of water-cooled 50 mM) Lys-buffer (pH 7.1,
Rinse once with 3-3ml (37°C), followed by washing the filter once with 6mj of the same Tris-buffer. Add this lysate to a scintillation cocktail (scintillation cocktail) in a scintillation vial.
l) After rapid shaking for 45 min with l Qyd, liquid scintillation counter Beckmλn LS80
00 is used to count the 3H-flunitrazenozum collected on the filter. Be the results for the selected compound
Calculated by ck-manLS 8000 online data conversion system and expressed as specific % bound compared to control sample.

Benzodiazepine receptors are obtained from Holstein bulls. Immediately after blood removal, the brain is immediately excised and placed in water.

Within two hours of killing, the caudate nucleus
cleus) finish the incision and weigh the tissue to 0.0
Bri in 5M Tris-mild solution (pH 7, 1, 37°C)
Using the nkmann Polytron, set the rheostat to 8 and homogenize for 10 seconds (1:10 (W/V
) )do. This homogeneous liquid was placed on 5 orvall RC2B.
Centrifuge for 10 minutes at 20.0 rpm using a 5S34 head. The supernatant was decanted and the BrinkmannPo
Pellets 1 are washed twice by resuspending in lytron- to remove endogenous dopamine and recentrifuged.

The final pellet was dissolved in 0.05 M) Lys buffer (pH
Resuspend the wet starting material at a final concentration of 200 W/buffer in 7,1,37°C). 4d of the total suspension is stored in liquid nitrogen in a glass bottle.

In the above test, compound [I] exhibits relatively high affinity for benzodiazepine receptors.

Thus, compound [■] can be particularly pointed out for use as a minor tranquilizer for reducing anxiety and/or tension.

However, compound CI] interacts with benzodiazepine receptors in the rat brain in a manner different from that of benzodiazepines in two different test systems.

Flunitrazepam receptor binding test (test c-
In b), the compound [Engine] exhibits a higher affinity for benzodiazepine receptors in the cerebellum rather than in the seams (the protuberance in the temporal region of the lateral ventricle) compared to classical benzodiazepines, and exhibits a higher affinity for benzodiazepine receptors in the cerebellum than in the cerebellar The type suggests a large active interaction with the benzodiazepine receptor type II.

Compound CI) is basically Karobath and Su
Written by p@vilai: Neuroscience Le
After photoaffinity labeling with flunitrazenogum, 4 it exhibits specific interaction with benzodiazepine receptors when tested (Test D) according to the method described in Tters Vol. 31 (1982), pages 65-69. In this test, common benzodiazepines exhibited a 20-fold increase in IC50 after photoaffinity labeling with flunitrazebam when compared to untreated membranes, whereas benzodiazepine antagonists showed a greater increase in IC50 after photoaffinity labeling. There is no change in the IC50 value. Compound C
I) After photoaffinity labeling of benzodiazepine receptors, the IC50 values show only up to a 4-fold increase when compared to the values obtained with control membranes.

In addition, compound CI] exhibits increased affinity for benzodiazepine receptors in the rat brain cortex in the presence of 4-aminobutyric acid when compared to their respective affinities in the absence of 4-aminobutyric acid.

The mode of interaction of the inventive compound [I] with benzodiazepine receptors is different from that of ordinary benzodiazepines and that of benzodiazepine antagonists. Compound [I] possesses an interesting and favorable range of activity as a tranquilizer, particularly anxiolytic activity. In addition, Compound [I] generally lacks central nervous system depressant activity and can stimulate behavior in observational tests.

The compound [I] of the present invention also shows activity in the well-known hexobarbital reduction test (Test E). However, for example, the FBA exam and the Geller Conflict test
At the dosage of the compound [T] which shows utility as a minor tranquilizer due to the conflict segment of t), the present compound [T]
It is commonly used in conjunction with a number of other standard central nervous system depression tests, such as the monkey sleep test, the cat spinal reflex test, the chemically induced convulsion test (the mouse test using N-sulfamoylazepine), and the tanamum test. o-tarrod (Dunham)
ro, tarod) test and various intervals of further interest.Geller Conflict Test
t test) showed weak or virtually no activity of eutectic agents. Therefore, the compound [
The tranquilizers exhibit a very specific and favorable mode of tranquilizing activity, exhibiting tranquilizing effects that substantially reduce the sedative effects associated with drowsiness in most, but not all, cases of currently used tranquilizers. .

It is pointed out that a suitable daily dosage for use as a minor tranquilizer of the present invention is about 10-500 mt. This dose is approximately 2.5 to 250
It may be formulated into a unit dosage form or sustained release dosage form containing w1, and may be administered in divided doses 2 to 4 times a day, if necessary.

The compound [I] of the present invention is free lil! It can be used as a base form or a pharmacologically acceptable acid addition salt (hydrochloride) form. Such salt-type compounds have an activity comparable to that of free radicals.

Compound [I] can be administered in a manner analogous to known standards for use with, for example, diazepam, by formulation as described above.

The appropriate daily dosage depends on many factors, such as the relative potency of the compound's activity. For example, as a result of testing according to test B above, the IC50 value of diazepam was 0.0.
12 μM (12 nM) compared to the IC50 value of 7-chloro-1-(p-chlorobenzyl)-2,3-dihydroimidazo[2,1-b]quinazolin-5(IH)-one compound. was 0.004PM (4nM). Compound [■] can therefore be administered at lower doses than those normally used for diazepam.

The compound of the present invention can be prepared in tablets, together with conventional pharmacologically acceptable diluents, carriers and, if necessary, other excipients.
It can be formulated and administered in the form of capsules or injections.

In addition, the present invention provides a free base compound (CI) or a pharmacologically acceptable acid addition salt thereof for use as a tranquilizer, and a free base compound (I) or its drug for use in patients in need of mental stabilization. A method of tranquilization can be provided comprising administering a physiologically acceptable acid addition salt.

8-Chloro-1-ethyl-1,2,3,4-tetrahydropyrimido(2,1-b)quinazolin-6-one compounds are known from U.S. Pat. No. 3,598,823;
This only discloses a bronchodilatory effect.

However, the remaining compound [■] has not been disclosed as a drug having pharmacological activity. The present invention further has a use as a pharmaceutical formula: [wherein, kl, 弘ζ-究 and n have the same meanings as above (provided that when capital is chlorine, hq, ζ and 穆 are hydrogen, kl is a group other than methyl or ethyl). ] A free base type compound [IC] represented by [IC] and a pharmacologically acceptable acid addition salt thereof can be provided.

Furthermore, the present invention provides a pharmacological composition comprising a free base compound CIC1) or a pharmacologically acceptable acid addition salt thereof in a pharmacologically acceptable diluent or carrier. I can do it.

1-Benzyl-1,2,3,4-tetrahydropyrimide (2,1-b)quinashily7-6-yF7, J. Med.
.

Many compounds whose radicals are hydrogen are J, Chem, Soc
, (1△960), page 3551. However, no useful chemotherapeutic activity is observed with these compounds. The remaining compound ClCl is new and forms part of the invention.

The number of the present invention is expressed by the formula: [In the formula, Machi, HiroR3, R4 - and n have the same meanings as above (provided that when YO (chlorine, n is 1, 顯, 顯, ζ and phrase are each hydrogen) , kl is a group other than methyl or ethyl, when n is 0 or 1, town is a group other than benzyl,
and a group other than haphenyl, p-1-IJ or p-chlorophenyl when n is 0 and the remaining groups in each case are hydrogen. ). ] A free base type or acid-added group type compound (I
p).

Unless otherwise specified, halogen includes halogens having an atomic weight of 18 to 80. Alkyl may be linear or branched. When m = 2, the two groups may each independently be hydrogen or 01-2 alkyl.

Compound [IP] can be produced by the following method.

(a) Formula: [In the formula, R2, Ra, R4, R5, Re and n have the same meanings as above. ] A compound represented by [■] and the formula: % formula %] [In the formula, inside has the same meaning as above, and town may be hydrogen. ] A compound [111) represented by the above is reacted, or 5 [wherein the inkstone and Kinuta have the same meanings as above. ] Compound [■] represented by the formula: [In the formula, Machi, Hiro R3, R4 and n have the same meanings as above. R
IO represents C1-4 alkyl or benzyl. ] or react the compound (V) represented by the formula (C): [wherein, ζR4, R5, - and n have the same meanings as above. M represents an alkali metal. ] Compound [■
] and the formula: % formula % ([In the formula, town has the same meaning as above. X represents a halogen with an atomic weight of 35 to 130].
) Formula: [In the formula, town, %RB, R4, R5, -o and n have the same meanings as above. ] The compound of the present invention (
IP) can be obtained.

Process (a) can be carried out in a conventional manner, for example in the presence of an inert organic solvent such as dimethylacetamide or a lower alkanol (e.g. ethanol), at a temperature of 20 DEG to 160 DEG C., preferably 40 DEG to 90 DEG C.

Preparation method) can be prepared by conventional procedures such as 100 to 190
It can be carried out by heating to 140 to 180°C, preferably 140 to 180°C.

Further, manufacturing methods (C) and (d) are conventional methods, respectively, and US Pat.
No. 905.976 (for process (d)).

Starting material (III, [N), [■], [V], [■],
[■] and [■] are known or can be produced by methods similar to known methods. These compounds can be isolated and purified by conventional methods and recovered as free base or acid addition salt compounds. Such free bases and salts can be interconverted according to conventional methods.

Compounds [■] and [:IC) can be produced by the same method as the above-mentioned compound [Ip].

and these individual isomers can be resolved in a conventional manner. Unless otherwise specified, it is assumed that the racemic compound is described.

Examples of specific substituents are listed below.

Type a = R1-(1) group [Xa], (il) group (xb), (■)
Group [XC], or OV) or ethyl, especially methyl), m = 3.2 or 1 (preferably 2 or 1
, especially 1). ), R2% 飄顯贴和顯-Hl R5=(+)H, halogen or CF3 (each preferably present in position b), ``=(+)0 or (i)1, type b= R1= (i ) CIN6 alkyl, especially ClN4 alkyl, optionally substituted with chlorine (more preferably unsubstituted), or (i) branched C3-6 alkyl, (1) chlorine or CF3 , or (1) chlorine, type C: town = (1) C3-6 alkenyl (especially aryl), (i
t) C3-6 alkynyl (especially propargyl), (-)
C3-8 cycloalkyl, ~)05-7 cycloalkyl, (V) C3-7 cycloalkyl (C1-3) alkyl, also ha(VDC5-7 cycloalkylmethyl, "2
m 顯, ζ or 琐 = H1 1 = Group similar to type 3.

The substituents and m combinations thereof as above applied to the compounds (Il, (IC) and (Ip:l) form part of the invention.

Examples of compounds of interest are listed below.

A, R1 is C1-8 alkyl, phase is halogen at position b, n
is 0 or 1, and the remaining substituents are hydrogen (however, chlorine,
When n is 1, the compound CI is a group other than methyl).

B, a compound [IC] in which all substituents are groups as in the case of A (provided that when the mass is chlorine and n is 1, kl is a group other than methyl or ethyl);

C0R1 is C1-8 alkyl, R57! Li B C
F3, a compound in which n is O or 1 and the remaining substituents are hydrogen, [IC] and/or [IP].

D, R1 is C3,6 alkenyl, C3,6 alkynyl,
C3,8 cycloalkyl, norbornyl, c3-,
7 cycloalkyl (C1-3) alkyl, RzRa and each independently hydrogen or 01-2 alkyl, n
Compound [I] where is 0 or 1, halogen is halogen, C1-4 alkyl or trifluoromethyl (each present at position b), and cylindrical is hydrogen, halogen or C1-3 alkyl
, (IC) and/or [IP].

E, R1 are the above groups (Xa], (Xb: l, [XC] or [Xd], l'Q, inkstone and R475 (each individual T hydrogen or 01-2 alkyl, the phase is hydrogen, halogen,
01-3 alkyl, R6I! l (hydrogen, halogen, CI
, v4〒rukyl or trifluorostyl, n = 0 or 1, m = 0.1 or 2, p = 1 or 2, q = 1 or 2 (where hq and at least one of them is hydrogen) Compound [engineering].

F, a compound [IC] in which all substituents are groups as in E (provided that when n is 1 and the remaining substituents are hydrogen, kl is a group other than benzyl);

G, a group such as when all the substituents are E (however, when n is 0 or 1, groups other than Machihabezyl, and n
is 0, in each case R1 is a group other than phenyl, P-)yl or P-chlorophenyl when the remaining radicals are hydrogen), m is 0.1, 2.3 or 4 (in particular 0 .1 or 2), R7 is hydrogen or 61-2
alkyl, to hydrogen, halogen or ClN3 alkyl, phase to hydrogen, halogen or C1+++4 alkyl),
The phase is hydrogen, halogen, CF3 (preferably present in the b position)
or 01-4 alkyl, others, - and ~ are hydrogen, n is O or 1 ■) R1 is C1-8 alkyl, R51 (fluorine, chlorine or CF3 present in the b position, n
is 0 or 1, R2, R3, R4 and R64 (hydrogen (however, when the arch is chlorine and n is 1, 1 is a group other than methyl), (c) R
ψ(C3-6 alkenyl, C3-6 alkynyl, C3-6
8 cycloalkyl or 03-7 cycloalkyl (C1
) alkyl, Rz Ra and 顯 are each individually hydrogen or 61-
2 alkyl, halogen present in the b-position, 61-4 alkyl or CF3, hydrogen, halogen or C1-3 alkyl, compound where n is 0 or 1 [■].

(2) Compounds in which all substituents are groups as in the case of H above (however, Kame is chlorine, n is 1, R2, R&R4, and Tsuka (when hydrogen, R is a group other than methyl or ethyl) [ IC].

J, a group such as when all substituents are H above (only chlorine, n is 1, ζ-ζ and Tsuka (2, when hydrogen is a group other than methyl or ethyl, n is 0 or 1 A compound [Ip] where Δ is a group other than benzyl (a group other than enyl).

K, (a) Rm<hydrogen, halogen or CF3, a group as in the case where the remaining substituents are H(a) above, (b) R1
(c) a group in which R1 is C3N7 cycloalkyl or C3N8
cycloalkylalkyl, phase is uncyclic to halogen or C
F3, a compound [I] in which the remaining substituents are as in the case of H(c) above;

L, all substituents are groups as above (only when the bow is chlorine, n is 1, Hiroshi R3, 顯 and R61) <Hydrogen is a group other than methyl or ethyl) Compound (IC).

M, a group in which all substituents are as above (provided that when bichlorine, n is 1, and hydrogen is hydrogen, 1 is methyl or ethyl; n is 0 or 1; Compounds [IP ].

N, the substituents are the same as (a) defined in formula CI) and the compounds CI), [:IC] and (Ip) follow the conditions in each formula.

0, compounds CI), ClCl1 and (Ip) in which the substituents are the same as (b) defined in formula (1,) and comply with the conditions in each formula.

P, the substituent is the same as (C) defined in formula CI)
- Compounds [I], [IC] and [IP].

A compound according to any one of formulas [I], [IC] and (Ip), wherein at least one of qR5 and Stainless Steel is a group other than hydrogen.

The above compounds A, Q can each exist as free base or acid addition salt compounds, which form part of the present invention.

A particularly preferred single compound is 7-chloro-1-(p-chlorobenzyl)-2,3-''hydroimidazo[2,1-
b] A free base type or acid addition salt type compound of quinazolin-5(IH)-one.

Next, a method for producing a preferred compound of the present invention will be specifically explained with reference to Examples.

Example 1 l-(0-chlorobenzyl)-7-chloro-2°3-dihydroimidazo(2,1-b)quinazoline-5(IH)
-1/Production of (compound No. la) 50% ethanol
- and dimethylacetamide 1.0-, 3-(2-chloroethyl)-2,6-dichloro-3,4-dihydroquinazolin-4-one 1. A solution of OF and 1.5i of 2-chlorobenzylamine is stirred and heated to reflux for 12 hours. The solvent was evaporated under reduced pressure, the residue was dissolved in methylene chloride, washed with water and treated with active, filtered and concentrated under reduced pressure,
The resulting solid was recrystallized from methylene chloride/pentane,
Filtration L? 'x~(0-chlorobenzyl)-7-chloro-
2,3-dihydroimidazo[z,1-b)quinazoline-
5(IH)-one was obtained. Melting point: 173-174°C.

Similar method to Example 1 above Table A
Compound [I] shown below was obtained. The melting points of the products are shown in the right column of the same table.

Table A (n=0. R1=I:Xa) (m=1), ~=
In addition, Compound [VI] was prepared according to Example 1 above, and this was mixed with sodium hydride and then with dimethyl-l-reacetamide t'.
The corresponding compound (IC:) was obtained by reacting with phenylmethyl bromide for 15 hours at room temperature and recrystallizing the raw acid from ethanol.

Example 2 Table B was prepared in a manner similar to or according to the method described in Example 1 above.
The compound shown in [■] was obtained. The melting points of the products are listed in the right column of the same table.

Table B (n=Q, R1=[,Xa:] (m=0)
, RB=R-6-)(,l), is present at position b) Example 3 Table C
Compound [I] shown below was obtained. The melting points of the products are shown in the right column of the same table.

Table C (n = l, R+ = (Xa) (m = 1), RP
R4=phase=l (phase is present at position b) Example 4 The compound shown in the table was obtained according to a method similar to that of Example 1 or the production method described above. The melting points of the products are shown in the right column of the same table.

Table D (n-1, R1m= [:X, a] (m=0),
Inkstone = Inkstone Example 5 Compound (I) shown in Table E was obtained according to a method similar to that of Example 1 or the production method described above. The melting points of the products are shown in the right column of the same table.

Example 6 1-allyl-7-chloro-2,3-dihydroimidazo[
2,1-b] Quinazolin-5(IH)-one (Compound N
o, 5a) Preparation of (a) 3-(2-chloroethyl)-2, by the following method:
6-dichloro-3,4-dihydroxazolin-4-one is produced. 4-(2-chloroethoxy)-2,6-dichloroquinazoline 17.3F trichlorobenzene 50
After refluxing the 9 solution for 3 hours and backwashing the precipitate in the tube into the reaction mixture with methylene chloride, refluxing is continued for an additional 2 hours.

The resulting mixture was diluted with methylene chloride, filtered with activated carbon to concentrate the liquid, and diluted with methylene chloride and pentane (50%
:50) Add a small amount of the mixture to chromatography on silica gel with 1/C, elute trichlorobenzene spots with pure pentane, and remove the product by eluating with methylene chloride to obtain a solid product. Melting point: 161-163°C.

Φ) 3-(2-chloroethyl)-2,6-dichloro-3
A solution of 1.0 g of ,4-dihydroquinazolin-4-one in 50 tnl of ethanol is combined with a solution of 0.621 of allylamine in 10 mj of dimethylacetamide, and this mixture is added with dimethylacetamide (added as necessary to dissolve any remaining solid starting material). Heat to reflux. After heating under reflux for about 5 hours, the reaction mixture is cooled, the mixture is concentrated and pentane is added to the dimethylacetamitos free obtained. After adding water to dissolve the white solid, the organic layer was dried and concentrated under reduced pressure, and the resulting solid residue was washed with pentane.
Allyl-7-chloro-2,3-dihydroimidazo (2,
1-b] Quinazolin-5(IH)-one was obtained. Melting point 9
1-93℃.

Similar method to Example 1 above Table F
Shown below. The melting points of the products are shown in the right column of the same table.

itl n R2R3R6m point ('C) 6b
OHH-black hood b) H142-1465
c Q HH-Kuro ode b) H
181-1836d OHH-Kuro ode b) H125-1275e
Q)I)I-Chloorb+ H157-IRQ Example 7 Two-chloro-1-nityl-2,3-dihydroimidazo(
2,1-b) Quinazolin-5(IH)-one (Compound N
Preparation of 1-ethyl-2-methylthioimidacillin 2.2g, 2
A solution of 2,5F -amino-5-chlorobenzoic acid and 25 mj of dimethylacetamide is refluxed for 12 hours and the reaction mixture is concentrated under reduced pressure. The residue was dissolved in methylene chloride, washed with 2N sodium hydroxide, then water, dried over magnesium sulfate, filtered, and chromatographed on silica gel to give 7-chloro-1-ethyl-2,3-dihydroimidazo( 2,1-b]quinazolin-5(IH)-one was obtained, melting point 86-89°c0 The following compound was prepared, for example, according to a method analogous to Example 7.

8-chloro-1-ethyl-1,2,3,4-tetrahydropyrimido[2,1-b) quinazolin-6-one.

Melting point 96-97°C (compound NO, 7b).

1-Ethyl-7-trifluoromethyl-2,3-dihydroimidazo[2,1-b:]]quinazoline-5IH)-
(Compound No. 7c).

Example 8 1-Butyl-7-chloro-2,3-dihydroimidazole
:2,1-b) Preparation of quinazoline-5(iH)-men (compound No., sa) 1.5 μl of 4-(2-chloroethoxy)-2,6-dichloroquinazoline was added to a flask equipped with a Niaschiretor. , reduce the pressure to 150 pressure, and heat at 240±10°C for 3 hours. After cooling the flask to room temperature, the resulting solid residue was crystallized to give 3-(2-chloroethyl)-2,
6-dichloro-3,4-dihydroquinazolin-4-one is dissolved in ethanol and treated with 3 molar equivalents of n-butylamine. After refluxing the mixture for 3 hours, the ethanol was removed under reduced pressure and the residue was crystallized from ethanol/water to 1-butyl-7-chloro-2,3-dihydroimidazo[2,1-b)quinazoline-5 (IH)-one was obtained. Melting point 92-93°C.

Also, 3-(2-chloroethyl)-2,6-dichloro-3
, 4-dihydroquinazolin-4-one was prepared in Example 6 (
Even if you do the same thing as in a), you can get B and B. ..., 11+
- Compounds shown in Table G were obtained, for example following a method analogous to Example 7 or 8 above. The melting points of the products are shown in the right column of the same table.

Table G (R2=He ~ l ShuH) Compound 醇i, R1n R5 Melting point (°C) 8b n-
Puji fillet Oori mouth 112-1148C≠B
Shi O Chloro 141-142B d n
- Henrle 0 Rio 98-1008
e n-octyl 0 chloro 77
-78Bf n-buchitshi 1 rioo
120-1658g Zokagoroshi 0
Chloro 92-948h Chill
0 Chloro 153-15581 Sobal 0 Chloro 112-1158j
Chill 07 no 1: + 124-127gk
5ec-buso 0 rioo 9
3-956 1 16 w * −−fL, +
8 hr＊rt IM
J-11'sG Example 9 l-n-butyl-7-trifluoromethyl-2゜3-dihydroimidazo(2,1-b:)quinazoline-5(IH
)-one (Compound No. 9a) Preparation of 7-trifluoromethyl-2,3-dihydroimidazo[2,1-bl
A mixture of quinazolin-5(IH)-one 2, Ov and dimethylacetamide 25- was added to 0.450 ml of sodium hydride.
F and heat at 50°C for 3-5 hours. To this solution was added 1.6 g of bromobutane in 10-dimethylacetamide and stirred at room temperature for 15 hours. The mixture was evaporated to a rolling volume, dissolved in methylene chloride and water, the organic layer was separated, washed with water, dried and evaporated, the resulting oil was treated with activated charcoal, filtered through celite and washed with hot pentane. The product is crystallized and 1-n-butyl-7-
) Lifluoromethyl-2,3-dihydroimidazo(2,
1-b) Quinazolin-5(IH)-one was obtained. Melting point 6
7-68°C0 7-trifluoromethyl-2,3-
Dihydroimidazo(2,1-b:lquinazoline-5(I)
H)-one can be produced by a method similar to the above production method (a). In other words, out ≠ proboscis)
Cotton antiques≠coral→139 and the corresponding compound [■] 307 were reacted for 20 hours under nitrogen atmosphere, which was evaporated to give a thick oil, treated with methylene chloride/water, and the separated organic layer was separated. Washed with water, dried, evaporated, dissolved in methanol and treated with activated carbon, filtered and concentrated to a volume of 100 rnl.
Cool and crystallize the product (stir for 2 hours) L, ? -1-!
, Ifluoromethyl-2,3-dihydroimidazo[2,
1-l quinazoline is obtained. Melting point: 274°C0 Patent applicant: Sand Akchengesellschaft, patent attorney Aoyama Aoyama, and 1 other person

Claims (1)

[Claims] 1. Formula: [wherein (a) R1 is any group represented by (in the group, m is 0.1.2.3 or 4, P is 1 or 2)
．． 9 is 0.1 or 2, R7 is hydrogen or 61-2 alkyl, square is hydrogen, halogen or 01-3 alkyl-phase is hydrogen, halogen, C1-4 alkyl, trifluoromethyl or nitro. 2) 'I and ClN2 alkyl are each individually hydrogen or ClN2 alkyl, kA hydrogen, halogen, C1-4 alkyl, trifluoromethyl or f4 ii 2) o, square is hydrogen, halogen or 61-3 alkyl, n is O or 1, (However, C1-8 alkyl substituted with at least one of the following, fluorine, chlorine, or trifluoromethyl present in the b position, n is 0 or 1, R2, R3, R4, and are hydrogen, respectively (where I
M (chlorine, when n is 1, R1 is a group other than methyl), or (c) R+ is C3~
6-alkenyl, C3-6 alkynyl, C3-8 cycloalkyl, norbornyl matah C3++-7 cycloalkyl (CIN3) alkyl, square, he and square are each individually hydrogen or 01-2 alkyl, the tag is in the b position halogen, 61-4 alkyl or trifluoromethyl, square represents hydrogen, halogen or C1-3 alkyl, n represents 0 or 1; ] A free base type or pharmacologically acceptable acid addition salt type compound for use as a tranquilizer [■]. 2, Formula: [In the formula -1k1, R2, R3, Skull, R5, R6 and n
has the same meaning as described in paragraph 1 (however, inkstone is chlorine, n is 1, inkstone,
飄ζ and R6b (when each is hydrogen, town is a group other than methyl or ethyl). A free base type or pharmacologically acceptable acid addition salt type compound (IC) for use as a drug shown in ]. 3. Pharmacology characterized by containing the free base type or pharmacologically acceptable acid addition salt type compound (IC) according to item 2 together with a pharmacologically acceptable diluent or carrier. composition. 4, Formula: [In the formula, Rx R2, ~, R4, R5, inkstone and n have the same meanings as described in item 1 (however, the phase is chlorine, n is 1, inkstone, to,
When ζ and Rdi are each hydrogen, then 1 is a group other than methyl or ethyl, when n is 0 or l, 1 is a group other than benzyl, and in each case where n is 01, the remaining groups are hydrogen. Rt is a group other than haphenyl, P-tolyl or P-chlorophenyl. ). ] A free base type or acid addition salt type compound [I
p). 5. Formula (a): Same meaning as described. ] The compound [■] represented by the formula: R1-NO3[N,1 [in the formula, town has the same meaning as described in Section 4] is reacted with the compound [■] represented by the formula: [in the formula, Ai and etiquette have the same meaning as described in Section 4. ] Compound [■] and the formula: [In the formula, kl, Rh - and n have the same meanings as described in Section 4. RIO represents 01-4 alkyl or benzyl. ] A compound [v] represented by the formula (C) is reacted, where Hiroshi-, R4, Utsu- and n have the same meanings as described in Section 4. M represents an alkali metal. ] Compound [VI) represented by the formula:
Represents 30 halogens. ] The compound [■] represented by the formula (d) is reacted, or the compound [■] represented by the formula (d): [wherein, 麯顯, R4, ζ- and n have the same meanings as described in item 4. ] The method for producing the compound according to item 4, which comprises ring-closing the compound represented by the following and recovering the produced compound in a free base form or an acid addition salt form as desired. 6. Compound cuff-chloro-1-(p-chlorobenzyl)
-2,3-dihydroimidazo(2,1-b)quinazolin-5(IH)-one in free base form or □ is its pharmacologically acceptable acid addition salt form Claim 1
or the compound according to item 2, or the composition according to item 3. 7.7-chloro-1-(P-chlorobenzyl)-2,3
-dihydroimidazo[2,1-b]quinazolinone 5 (
Compounds of IH)-one in free base form or acid addition salt form.