JPH0366309B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a tetracyclic imidazo-fused quinazolinone compound () having a platelet aggregation inhibiting effect. [In the formula, R ¹ is hydrogen or a lower alkyl group, A is a divalent group [In the formula, R ² and R ³ each represent hydrogen or halogen, and B is -(CH ₂ ) ₁ -, -(CH ₂ ) _n -CH
=CH-( _CH2 ) _o -,-( _CH2 ) _n- (C=0)-( _CH2 )
_o - or represents. However, 1 is 3, 4, or 5, m
and n is any integer from 0 to 4, 1≦m+n≦
4 and p is 2 or 3)] The compound of the present invention may exist as a tautomer, such as a formula [a] or a formula [b], in addition to the formula (). , in the present invention, will be represented by formula []. Furthermore, the compound of the present invention may exist in its racemic or optically active form when R ¹ is a lower alkyl group or when R ⁴ is a hydroxyl group or an amino group. The compound of formula () of the present invention is a tetracyclic imidazo-fused quinazoline derivative, and the ring system thereof is exemplified by 2,3,7,8,9,11-hexahydro-1H
-Imidazo[2,1-b]cyclopenta[f]quinazolin-8-one (A) 2,3,5,7,8,9-hexahydro-1H
-Imidazo[2,1-b]cyclopenta[g]quinazolin-2-one (B) 1,2,3,4,8,9,10,12-octahydroimidazo[2,1-b]benzo[f ] Quinazolin-9-one (C) 1,2,3,5,7,8,9,10-octahydroimidazo[2,1-b]benzo[g]quinazolin-2-one (D), etc. It will be done. The compounds of the invention can be used as salts with suitable physiologically harmless acids. Non-toxic salts that can be used as pharmaceuticals include hydrochloric acid, hydrobromic acid,
sulfuric acid, phosphoric acid, alkyl or allyl sulfonic acid,
These are salts with organic acids or inorganic acids commonly used in the art, such as fumaric acid, maleic acid, succinic acid, and citric acid. Since the compound of the present invention has a platelet aggregation inhibitory effect, it can be used for the treatment and prevention of intravascular thromboembolism, prevention of short-term local anemia, and prosthetic devices (artificial heart, artificial kidney).
It is useful for preventing platelet thrombosis when used. Next, the platelet aggregation inhibitory effects of the compounds of the present invention are shown in a table. As is clear from the table, the compound of the present invention exhibits extremely strong platelet aggregation inhibiting action, proving that it is excellent as an antithrombotic agent.

[Table] The aggregation effect of platelets is measured using Born's nephelometric method [Born,
Nature, vol. 194, p. 927 (1962)], a)
In vitro, use rat platelet-rich plasma at a concentration (μM) that inhibits 50% of aggregation by collagen or adenosine diphosphate (ADP); b) ex
In vivo, 10 mg/Kg was orally administered to rats, blood was collected 1 hour later, and the aggregation inhibition rate of the platelet-rich plasma was compared with that of the control group. ^* p<0.05, ^** p<0.01 The method for producing the compound of the present invention will be described. (a) General formula () [In the formula, R ¹ and A are the same as above, R ⁵ is a lower alkyl group, and X represents a halogen up to chlorine or bromine] is treated with ammonia, or (b) general formula () [In the formula, R ¹ , A, and R ⁵ are the same as above] When the compound of formula (2) is reacted with a cyanogen halide, N-amidinopyrazoles, etc., the compound of formula () of the present invention is produced. Furthermore, the compound of formula () or its tautomer can be converted into an acid addition salt thereof, if desired. The reaction of the compound of formula () with ammonia according to embodiment (a) of the method is carried out in a sealed tube in a solvent such as a lower alcohol, e.g. methanol, ethanol.
Advantageously, this is carried out with heating to 100°C to 150°C. The reaction of the compound of formula () with the cyanogen halide or N-amidinopyrazoles according to embodiment (b) of the method is carried out in a solvent such as a lower alcohol, e.g. methanol, ethanol, under heating to reflux;
Alternatively, treatment at room temperature followed by treatment with acidic sodium carbonate or a weak base such as sodium carbonate is advantageous. Furthermore, some of the compounds represented by the formula () of the present invention can be produced by the method described below. A compound in which R ² or R ³ is chlorine or bromine in the general formula () can be prepared by a known method, for example, in a lower alcohol, such as methanol, ethanol and water, or a mixed solvent thereof, together with a catalyst containing palladium metal, etc. By catalytic reduction R ²
Alternatively, it can lead to a compound of formula () in which R ³ is hydrogen. In the general formula (), B is

【formula】 or

The compound of the formula can be prepared by a known method, or by heating to room temperature or around 150°C in a lower alcohol such as methanol, ethanol, or a mixed solvent thereof in the presence of a mineral acid such as hydrochloric acid.

A compound of formula () that is [formula] It can lead to things. In the general formula (), B is

[Formula] Compounds can be prepared by a known method, for example, by reacting with sodium borohydride in a lower alcohol, such as methanol, ethanol, water, or a mixed solvent thereof by heating at room temperature to around 50°C, so that R ⁴ becomes hydroxyl. This can lead to a compound of formula () which is a group. A compound in which the substituent R ⁴ in B in the general formula () is a hydroxyl group can be prepared in a lower alcohol such as methanol, ethanol, water, or a mixed solvent thereof in the presence of a mineral acid such as hydrochloric acid or sulfuric acid at room temperature or under heating under reflux. The following reaction can lead to a compound of formula () in which B is -( _CH2 ) _nCH =CH( _CH2 ) _o- . In the general formula (), B is −(CH ₂ ) _n CH=CH(CH ₂ ) _o
- in aqueous dimethyl sulfoxide,
Treatment with N-bromosuccinimide leads to the bromohydrin derivative, which upon treatment with a base such as sodium methylate in dimethyl sulfoxide provides the epoxide derivative. When this is heated in a sealed tube with ammonia in a lower alcohol such as methanol or ethanol to 100 to 150 degrees Celsius, the epoxy ring is cleaved and R ⁴ is an amino group (formula ())
When this compound and this epoxy derivative are heated to around 100℃ with a dilute mineral acid, such as dilute hydrochloric acid or dilute sulfuric acid, R ⁴
Compounds of formula () can be prepared in which is a hydroxyl group. In the general formula (), B is

A compound of the formula is heated in hydroxylamine and a lower alcohol, such as methanol or ethanol, to give an oxime derivative, which is then mixed with a catalyst containing palladium metal in a lower alcohol, such as methanol, ethanol or water, or a mixed solvent thereof. Catalytic reduction can produce compounds of formula () in which R ⁴ is an amino group. When producing the compound of formula () of the present invention, the compounds of formula () and () used in the reactions of embodiments (a) and (b) are prepared according to the method exemplified by the following reaction formula. Can be manufactured. [In the formula, R ¹ , R ⁵ , A, and X are the same as above. R ⁶ represents lower alkyl or phenyl] The compounds of formula () or their tautomers and physiologically compatible salts thereof of the present invention can be used in various preparations, e.g. with carriers compatible therewith. sell. The carrier material is an organic or inorganic inert carrier, such as lactose, starch, magnesium stearate, talc, etc., and the formulation can be in the form of tablets, capsules, powders, etc. The compound of formula () of the present invention is preferably administered orally, but a daily dose of 0.1 to 10 mg is sufficient for adults. Next, the present invention will be explained in detail with reference to examples, but the present invention is not limited thereto. Example 1 3.40 g of ethyl 3-chloro-1,2,7,8,9,10,-hexahydrobenzo[f]quinazoline-2-acetate was added to 40 ml of a 10% ammonia-ethanol solution.
Heat at 120-130°C for 3 hours in a sealed tube. After cooling, the precipitated crystals are collected by filtration, washed with water, and dried to give 1,2,3,4,8,9,10,12-octahydrobenzo[f]imidazo[2,1-b]quinazoline-9- You can get 1.80g of On. This is suspended in methanol, dissolved by adding concentrated hydrochloric acid until the pH becomes 1 to 2, and concentrated under reduced pressure to obtain the hydrochloride. Melting point 280° or more IR ν ^KBr _nax cm ^-1 : 3200-2000, 1780, 1690, 1620,
1590 ¹ H-NMR (CF ₃ COOH) δ: 1.8-2.1 (m, 4H), 2.6 (m, 2H), 2.8 (m, 2H), 4.51 (s, 2H), 4.68 (s, 2H), 6.77 (d, 1H), 7.17 (d, 1H) Elemental analysis C ₁₄ H ₁₅ N ₃ As O・HCl Calculated value C 60.54, H 5.81, N 15.13 Analysis value C 60.52, H 6.04, N 14.99 The raw materials are as follows. It was manufactured as follows. 6-Acetylamino-5-bromotetralin [Souji, Evans, J.Am.Chem.Soc., vol. 61,
2916 (1939)] and 2.1 g of cuprous cyanide were heated and stirred under reflux with 20 ml of dimethylformamide for 2 hours, poured into water, and extracted with benzene. After thorough washing with water and drying under reduced pressure, crude 6-acetylaminotetralin-5-carbonitrile (melting point 138-139
℃) 2.70g is obtained. 7.3g of this 5-carbonitrile compound was added to dioxane.
A solution of 6.8 g of sodium hydroxide in 100 ml of water was heated under reflux for 1 hour. After cooling, the organic layer is separated and the aqueous layer is extracted with benzene. When the benzene layers are combined, washed with water, and dried under reduced pressure, 6-aminotetralin-
5.8 g of 5-carbonitrile (melting point 112-113°C) are obtained. 5.8g of this aminocarbonitrile body is mixed with 12g of urea.
Mix and heat under reflux in an oil bath at 210-220° with stirring. After heating for 1.5 hours, cool and mash well, wash well with water and filter. The filtered material is 50ml of concentrated hydrochloric acid and water.
Heat and stir under reflux with 100 ml of the mixture overnight. After cooling, insoluble matter is collected by filtration, washed with water, and dried to obtain 1, 2, 3, 4,
7,8,9,10-octahydrobenzo[f]quinazoline-1,3-dione (melting point 280°C or higher) 4.1g
It can be grown. 3.0 g of this dione is mixed with 30 ml of phosphorus oxychloride and 3.0 g of phosphorus pentachloride, and the mixture is heated under reflux and stirred for 2.5 hours. Dry under reduced pressure and pour the residue into ice water. Extracted with chloroform, washed with water, distilled off the chloroform, and purified the residue with silica gel to yield 2.94 g of 1,3-dichloro-7,8,9,10-tetrahydrobenzo[f]quinazoline (melting point 132-134°C). It will be done. Dissolve 3.3 g of this dichloride in a mixture of 40 ml of chloroform and 40 ml of ethanol, and add 2.5 g of sodium borohydride little by little while stirring on ice. 30
After stirring for several minutes, the mixture was dried under reduced pressure, water was added, and the insoluble precipitate was collected by filtration. After washing thoroughly with water, 3-chloro-1,
2,7,8,9,10-hexahydrobenzo [f]
2.55 g of quinazoline (melting point unclear) is obtained. 2.50g of this monochloride was added to ethyl bromoacetate.
2.1 g, 0.1 g of tetrabutylammonium iodide and 11 ml of 10N sodium hydroxide in 80 g of methylene chloride.
Stir vigorously with ml. After 20 minutes, wash well with water and dry the organic layer under reduced pressure to form an oily 3-chloro-
Ethyl 1,2,7,8,9,10-hexahydrobenzo[f]quinazoline-2-acetate was obtained almost quantitatively. Examples 2-9 Compounds of Examples 2-9 were obtained in the same manner as in Example 1. These are shown in a table. The compounds used as raw materials for these compounds could be obtained according to the method described in Example 1.

【table】

[Table] Example 10 7.5 g of 6'-amino-7'-ethoxycarbonylmethylaminomethyl-4'-chlorospiro [[1,3]-dithiolane-2,1'-indan] was added to 50 g of benzene.
ml, cyanogen bromide dissolved in 150 ml of 95% ethanol
Add a solution of 2.20 g in 80 ml of 95% ethanol and stir under heating under reflux for 4 hours. Dry under reduced pressure, and add acidic sodium carbonate solution to the residue and stir. When the insoluble crystals are collected by filtration, washed with water, and washed with methanol, 4-chloro-
2,3,7,8,9,11-hexahydro-1H-
spiro[cyclopenta[f]imidazo[2,1-
b] Quinazoline-1,2'-[1,3]dithiolane]
3.9g of -8-one was obtained. Melting point Undefined (becomes colored at 260-270℃) IR ν ^KBr _nax cm ^-1 : 1640, 1560, 1470 ¹ H-NMR (DMSO-d ₆ ) δ: 2.75 (m, 2H) 2.90 (m, 2H) ) 3.51 (s, 4H) 4.35 (s, 2H) 5.10 (s, 2H) 7.19 (s, 1H) Elemental analysis C ₁₅ H ₁₄ Calculated value as ClOS ₂ C 51.20, H 4.01, N 11.94 Analysis value C 50.70, H 4.10, N 11.80 The raw material was manufactured as follows. Cool 110ml of fuming nitric acid to -10℃ and add 4.7-
Add 25 g of dichloro-1-indanone little by little. After stirring at the same temperature for 2 hours, pour into ice water.
Extracted with benzene, washed with water, dried under reduced pressure, and the residue was recrystallized from ethanol to give 4,7-dichloro-6-
Nitro-1-indanone (melting point 133-134℃) is 25
I got it. 28 g of this nitro compound is suspended in 250 ml of acetic acid, and 22 ml of ethanedithiol is added, followed by 22 ml of boron triborate etherate. After stirring at room temperature for 5 hours,
Pour into ice water and extract with chloroform. Wash the chloroform layer with water, wash with sodium hydroxide, wash with water,
After drying and distilling off the chloroform, 4',7'-dichloro-6'-nitrospiro [[1,3]dithiolane-2,1'-indane] [melting point 176-177°C] was obtained at 33.3%.
I got it. 33.3 g of this dithiolane compound was mixed with 10.4 g of cuprous cyanide.
g, added to a mixture of 80 ml of N-methylpyrrolidone,
Heat under reflux and stir at 115-120°C for 8 hours. The reaction solution was poured into ice water, the insoluble matter was collected by filtration, the filtered material was extracted with benzene, washed with water, and evaporated. The residue was recrystallized from benzene to form 7'-cyano-4'-chloro-6'-nitrospiro. 7.45 g of [[1,3]dithiolane-2,1'-indane] (melting point 215-217°C) was obtained. 7.45g of this cyano body 300g of tetrahydrofuran
Diborane generated by dropping a solution of 6.0 g of sodium borohydride in 150 ml of diglyme into a mixed solution of 34 ml of boron triboride-etherate and 37 ml of diglyme under a nitrogen stream is introduced into the solution. 6 at room temperature
After stirring for an hour, leave it overnight. The reaction solution was cooled on ice.
After adding 75 ml of 10% hydrochloric acid dropwise, the mixture was heated and stirred under reflux for 1.5 hours. Tetrahydrofuran is distilled off under reduced pressure, and the residual aqueous layer is washed with benzene to make it alkaline with ammonia. After extraction with benzene, washing with water and distilling off the benzene, 7'-aminomethyl-4'-chloro-6'-nitrospiro [[1,3] dithiolane-2,1'-indan] (melting point 114-117°C) was obtained. 3.86g was obtained. A mixture of 5.1 ml of ethyl bromoacetate and 40 ml of dimethylformamide is added dropwise to a mixture of 13.3 g of this reduced product, 2.4 g of sodium carbonate, and 110 ml of dimethylformamide while stirring over 1 hour. After dropping, heat to 80°C for 1 hour, cool, add 50ml of water, and dry under reduced pressure. The residue is dissolved in 5% hydrochloric acid and washed with benzene. The aqueous layer was made alkaline with ammonia and then extracted with benzene. The benzene layers were combined and washed with water. When the benzene was distilled off, 7'-ethoxycarbonylmethylaminomethyl-4'-chloro-6'-nitrospiro [[1,3 11.8 g of dithiolane-2,1'-indane (melting point 107-108°C) was obtained. This 7′-ethoxycarbonylmethyl substituted product 11.3
Dissolve g in 1000 ml of ethanol and 35 ml of concentrated hydrochloric acid to make 10%
Add 1.2 g of palladium-carbon and perform catalytic reduction at normal pressure. After hydrogen absorption has ceased, the catalyst is filtered off and the filtrate is dried under reduced pressure. The residue was dissolved in 5% hydrochloric acid and washed with benzene. The aqueous layer was made alkaline with ammonia and extracted with benzene. The benzene layers were combined, washed with water, dried, and benzene was distilled off to give 6'-amino-7'-ethoxycarbonylmethylamino. 7.5 g of methyl-4'-chlorospiro[[1,3]dithiolane-2,1'-indane] (melting point 99-100°C) was obtained. Example 11 5'-amino-4'-ethoxycarbonylmethylaminomethyl spiro[[1,3]dioxolane-2,
Dissolve 1.0 g of 2′-indane in 30 ml of ethanol,
Add 0.35 g of cyanogen bromide and stir at room temperature for 40 hours.
Add saturated acidic sodium carbonate solution to the reaction mixture under ice cooling to neutralize it, and stir for 30 minutes. Collect the precipitated crystals by filtration, wash with water and ethanol, 2, 3, 7.
0.61 g of 8,9,11-hexahydro-1H-spiro[cyclopenta[f]imidazo[2,1-b]quinazoline-2,2'-[1,3]dioxolane]-8-one was obtained. This was treated cold with concentrated hydrochloric acid in methanol and dried under reduced pressure below 15°C to obtain the hydrochloride. Melting point Undefined (becomes colored from 245℃) IR ν ^KBr _nax cm ^-1 : 3400, 2900, 1790, 1680, 1620,
1595 ¹ H-NMR (DMSO-d ₆ ) δ: 3.05 (s, 2H) 3.80 (s, 2H) 3.95 (s, 4H) 4.22 (s, 2H) 4.61 (s, 2H) 7.02 (d, 1H) 7.21 (d, 1H) Elemental analysis C ₁₅ H ₁₅ N ₃ O ₃・HCl Calculated value C 59.99, H 5.01, N 13.6 Analytical value C 55.99, H 5.33, N 12.92 Raw material is 4,7-dibromo-1-indanone was used as a raw material and converted into 4,7-dibromo-2-indanone according to a conventional method, which was obtained according to the method described in Example 10 below. Example 12 5-bromo-1,2,3,4,8,9,10,12
-octahydrobenzo[f]imidazo[2,1-
b] Quinazolin-9-one (compound of Example 2)
0.256g in methanol 70ml, concentrated hydrochloric acid 0.8g and 10%
Catalytic reduction is carried out under normal pressure with 0.3 g of palladium-carbon. After hydrogen absorption has stopped, the catalyst is separated by filtration, the filtrate is neutralized to pH 9 with sodium hydroxide, concentrated under reduced pressure, and the precipitated crystals are collected by filtration, washed with water, and dried to give 1, 2, 3, 4, 8. , 0.15 g of 9,10,12-octahydrobenzo[f]imidazo[2,1-b]quinazolin-9-one (compound of Example 1) was obtained. Example 13 1,2,3,4,8,9,10,12-octahydrospiro[benzo[f]imidazo[2,1-b]
Quinazoline-4,2'-[1,3]dithiolane]-9
-19.1g of the compound of Example 3 was added to 1200 g of concentrated hydrochloric acid.
ml and stir at reflux for 10 hours. After confirming that the raw materials have disappeared, it is cooled and shaken with ether. The aqueous layer is concentrated under reduced pressure, and the precipitated crystals are collected by filtration, washed with water, and dried to obtain 1,2,3,4,8,9,10,12- 13.7 g of octahydrobenzo[f]imidazo[2,1-b]quinazoline-4,9-dione hydrochloride were obtained. Melting point 300℃ or higher IR ν ^KBr _nax cm ^-1 : 2940, 1790, 1680, 1660, 1620,
1580 ¹ H-NMR (CF ₃ COOH) δ: 1.9-2.4 (m, 2H) 2.5-2.9 (m, 4H) 4.42 (s, 2H) 4.84 (s, 2H) 7.14 (d, 1H) 8.05 (d, 1H) Elemental analysis C ₁₄ H ₁₃ N ₃ O ₂・HCl・H ₂ O Calculated value C 54.28, H 5.21, N 13.57 Analysis value C 54.28, H 5.09, N 13.48 Examples 14-15 Same as Example 13 Compounds of Examples 14 and 15 were obtained. These are shown in a table. The compounds used as raw materials were those of Example 7 and Example 10, respectively.

[Table] Example 16 2,3,7,8,9,11-hexahydro-1H
-spiro[cyclopenta[f]imidazo[2,1
-b]quinazoline-2,2'-[1,3]dioxolane]-8-one hydrochloride (compound of Example 11)
Add 0.250 g to a solution of 80 ml of methanol and 15 ml of 10% hydrochloric acid, and stir at room temperature for 2.5 days. The precipitated crystals are collected by filtration, the filtrate is concentrated under reduced pressure at a bath temperature of 15°C or less, the precipitated crystals are collected by filtration, and the second crystal is collected.
0.14 g of 3,7,8,9,11-hexahydro-1H-cyclopenta[f]imidazo[2,1-b]quinazoline-2,8-dione hydrochloride was obtained. Melting point 265℃ ~ (undefined) IR ν ^KBr _nax cm ^-1 : 3400, 2700, 1750, 1680, 1620,
1600 ¹ H-NMR (DMSO-d ₆ ) δ: 3.50 (s, 2H) 3.57 (s, 2H) 4.23 (s, 2H) 4.63 (s, 2H) 7.10 (d, 1H) 7.34 (d, 1H) Element Analysis C ₁₃ H ₁₁ N ₃ O ₂・HCl・H ₂ O Calculated value C 52.80, H 4.77, N 14.21 Analysis value C 52.46, H 4.79, N 13.93 Example 17 1, 2, 3, 4, 8, 9 , 10,12-octahydrobenzo[f]imidazo[2,1-b]quinazoline-4,9-dione (compound of Example 13) 2.90 g
was added to 600 ml of ethanol, and 3.8 g of sodium borohydride was added little by little while stirring on a water bath at 50-60°C. After stirring at the same temperature for 2 hours, the mixture was dried under reduced pressure, water was added, and the mixture was neutralized to pH 7-8 with hydrochloric acid. When the precipitated crystals are collected by filtration, washed with water, and dried, 4-hydroxy-1,2,3,4,8,9,10,12-octahydrobenzo[f]imidazo[2,1-b]quinazoline-9 is obtained. -2.30g of On was obtained. This was treated with hydrochloric acid in methanol according to a conventional method to obtain a hydrochloride salt. Melting point 280℃ (decomposition) IR ν ^KBr _nax cm ^-1 : 3375, 3100~2500, 1790, 1685,
1625, 1595 ¹ H-NMR (DMSO-d ₆ ) δ: 1.46-2.1 (m, 4H) 2.2-2.6 (m, 2H) 4.33 (s, 2H) 4.56 (s, 3H, C ¹² -H, C ⁴ -H) 7.14 (d, 1H) 7.39 (d, 1H) Elemental analysis C ₁₄ H ₁₅ N ₃ O ₂・HCl・0.5H ₂ O Calculated value C 55.54, H 5.66, N 13.88 Analysis value C 55.41, H 5.84 , N 13.58 Examples 18-20 Compounds of Examples 18-20 were obtained in the same manner as in Example 17. These are shown in a table. The compounds used as raw materials were those of Examples 14, 19, and 20, respectively.

[Table] Example 21 4-hydroxy-1,2,3,4,8,9,
10,12-octahydrobenzo[f]imidazo[2,1-b]quinazolin-9-one (Example 17
compound) 2.30g in methanol 180ml, concentrated hydrochloric acid 90ml
Add to ml of the mixture under ice cooling. Then, the crystals were heated under reflux for 10 minutes, concentrated under reduced pressure, and the precipitated crystals were collected by filtration, washed with water, and dried to obtain 1,2,8,9,10,12-hexahydrobenzo[f]imidazo[2,1-b]quinazoline. 2.35 g of -9-one hydrochloride was obtained. Melting point 280℃ or higher IR ν ^KBr _nax cm ^-1 : 3150 to 2300, 1795, 1685, 1620,
1590 ¹ H-NMR (DMSO-d ₆ ) δ: 2.15-2.4 (m, 2H) 2.45-2.7 (m, 2H) 4.26 (s, 2H) 4.66 (s, 2H) 5.9-6.15 (m, 1H) 6.3 ~6.55 (m, 1H) 7.03 (d, 1H) 7.17 (d, 1H) Elemental analysis C ₁₄ H ₁₃ N ₃ O・HCl・H ₂ O Calculated value C 57.24, H 5.49, N 14.31 Analysis value C 57.39, H 5.55, N 14.16 Example 22 In the same manner as in Example 21, using the compound of Example 20 as a raw material, 4-chloro-7,8,9,11-tetrahydro-3H-cyclopenta[f]imidazo[2,1
-b] Quinazolin-8-one hydrochloride was obtained. Melting point 280℃ or higher IR ν ^KBr _nax cm ^-1 : 3600-2650, 1750, 1675, 1630 ¹ H-NMR (DMSO-d ₆ ) δ: 3.46 (m, 2H) 4.28 (s, 2H) 4.82 (s, 2H) ) 6.92 (m, 2H) 7.23 (s, 1H) Elemental analysis C ₁₃ H ₁₀ ClN ₃ O・HCl・H ₂ O Calculated value C 49.70, H 4.17, N 13.37 Analysis value C 49.79, H 3.92, N 13.33 Implemented Example 23 9,10-epoxy-1,2,3,5,7,8,
Add 0.30 g of 9,10-octahydrobenzo[g]imidazo[2,1-b]quinazolin-2-one to a mixture of 20 ml of ethanol, 4 ml of water, and 70 mg of concentrated sulfuric acid.
Stir at 80°C for 16 hours. Neutralize with potassium carbonate,
It was dried under reduced pressure, water was added to the residue, the insoluble matter was filtered off, and washed with water to give 9,10-dihydroxy-1,2,3,5,
7,8,9,10-octahydrobenzo[g]imidazo[2,1-b]quinazolin-2-one was obtained. This was treated with methanol and hydrochloric acid in a conventional manner to obtain a hydrochloride. Melting point 280℃ or higher IR ν ^KBr _nax cm ^-1 : 3350, 3100~2500, 1780, 1680,
1615 ¹ H-NMR (DMSO-d ₆ ) δ: 1.55-1.85 (m, 1H) 1.85-2.1 (m, 1H) 2.6-2.95 (m, 2H) 3.7 (m, 1H) 4.23 (s, 2H) 4.24 (d, 1H) 4.66 (s, 2H) 7.00 (s, 1H) 7.24 (s, 1H) Elemental analysis C ₁₄ H ₁₅ N ₃ O ₃・HCl・H ₂ O Calculated value C 51.30, H 5.53, N 12.82 Analytical values: C 51.96, H 5.46, N 12.67 The raw materials were produced as follows. 1,2,3,5,7,8-hexahydrobenzo[g]imidazo[2,1-b]quinazoline-2-
Dissolve 1.5 g of the compound of Example 5 in 20 ml of dimethyl sulfoxide, add 1 ml of water, and add N under ice cooling.
- Add 1.50 g of bromosuccinimide and
Stir for an hour. The reaction solution was poured into ice water, 0.85 g of sodium acid sulfite was added, and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration, washed with water, and dried to give 9-bromo-10-hydroxy-1,2,3,
5,7,8,9,10-octahydrobenzo [g]
1.4 g of imidazo[2,1-b]quinazolin-2-one (melting point 190-195°C (decomposed)) was obtained. 1.90 g of this bromohydrin compound was suspended in 20 ml of dimethyl sulfoxide, and 0.61 g of sodium methylate was added under a nitrogen stream, followed by stirring at room temperature for 16 hours. The precipitate is collected by filtration and washed well with water to give 9,10-epoxy-1,2,3,5,7,8,9,10-octahydrobenzo[g]imidazo[2,1-b]quinazoline-2- 1.25g of On (melting point 280°C or higher) was obtained. Example 24 6.30 g of the raw material of Example 23 was mixed with 10% ammonia.
Heat at 130°C for 76 hours in a sealed tube with 50 ml of ethanol. After cooling, insoluble matter is filtered off, and the filtrate is dried under reduced pressure.
Add the residue to water, filter out the insoluble matter, wash with water and acetone, and treat with methanol and hydrochloric acid according to the usual method.
10-amino-9-hydroxy-1,2,3,5,
7,8,9,10-octahydrobenzo[g]imidazo[2,1-b]quinazolin-2-one hydrochloride was obtained. Melting point Undefined (gradually decomposes at 230-250℃) IR ν ^KBr _nax cm ^-1 : 3400, 3100-2500, 1780, 1760,
1680, 1610 ¹ H-NMR (DMSO-d ₆ ) δ [200MHz]: 1.7-1.95 (m, 1H) 1.95-2.3 (m, 1H) 2.6-2.95 (m, 2H) 3.8-4.2 (m, 3H, C ⁹ , C ¹⁰ , 6H) 4.24 (s, 2H) 4.66 (s, 2H) 7.12 (s, 1H) 7.35 (s, 1H) Elemental analysis Calculated as C ₁₄ H ₁₆ N ₄ O ₂・2HCl・H ₂ O Value C 46.29, H 5.55, N 15.43 Analysis value C 46.67, H 5.48, N 15.00 Example 25 4-Hydroxyimino-1,2,3,4,8,
Add 0.20 g of 9,10,12-octahydrobenzo[f]imidazo[2,1-b]quinazolin-9-one to a mixture of 100 ml of methanol, 20 ml of water, and 5 ml of concentrated hydrochloric acid, and add 100 mg of 10% palladium-carbon to 4.3 atm. catalytic reduction under hydrogen pressure of After removing the catalyst by filtration, it is concentrated under reduced pressure and the precipitated crystals are collected by filtration to obtain 4-
0.145 g of amino-1,2,3,4,8,9,10,12-octahydrobenzo[f]imidazo[2,1-b]quinazolin-9-one hydrochloride was obtained. Melting point 254-257℃ (decomposition) IR ν ^KBr _nax cm ^-1 : 3440, 3025, 2930, 1795, 1690,
1635, 1605 ¹ H-NMR (DMSO-d ₆ ) δ: 1.8-2.15 (m, 4H) 2.4-2.7 (m, 2H) 4.23 (s, 2H) 4.43 (m, 1H) 4.64 (s, 2H) 7.19 (d, 1H) 7.62 (d, 1H) Elemental analysis C ₁₄ H ₁₆ N ₄ O・2HCl・0.5H ₂ O Calculated value C 49.71, H 5.66, N 16.57 Analysis value C 49.38, H 5.39, N 16.48 Raw material was manufactured as follows. 1,2,3,4,8,9,10,12-octahydrobenzo[f]imidazo[2,1-b]quinazoline-4,9-dione (compound of Example 13) 0.60 g
was added to 150 ml of methanol, 0.56 g of hydroxylamine hydrochloride was added, and the mixture was heated and stirred for 16 hours. After cooling, the precipitated crystals are collected by filtration, the filtrate is dried under reduced pressure, water is added to the residue, the insoluble matter is collected by filtration, and the second crystal is collected by washing with water and methanol to obtain 4-hydroxyimino-1. ,2,3,4,8,9,10,12-octahydrobenzo[f]imidazo[2,1-b]
Quinazolin-9-one (melting point 280℃ or higher) is 0.42
I got it. Examples 26-28 Compounds of Examples 26-28 were obtained in the same manner as in Example 1. These are shown in the table below. The compounds used as raw materials for these compounds are those in Example 1.
It could be obtained according to the method described in .

【table】

【table】

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ is hydrogen or a lower alkyl group, A is a divalent group (In the formula, R ² and R ³ each represent hydrogen or halogen, and B is -(CH ₂ ) ₁ -, -(CH ₂ ) _n -CH
=CH-( _CH2 ) _o -,-( _CH2 ) _n- (C=0)-( _CH2 )
_o - or represents. However, 1 is 3, 4, or 5, m
and n is any integer from 0 to 4, 1≦m+n≦
4 and p is 2 or 3) and its acid addition salt 2 1,2,3,4,8,9,10,12-octahydro Compound 3 of Claim 1 which is imidazo[2,1-b]benzo[f]quinazolin-9-one or a salt thereof 2,3,7,8,9,11-hexahydro-
1H-imidazo[2,1-b]cyclopenta[f]
Compound 4 of Claim 1 which is quinazolin-8-one or a salt thereof 1,2,8,9,10,12-hexahydroimidazo[2,1-b]benzo[f]quinazoline-9
-one or a salt thereof Compound 5 of Claim 1 1,2,3,4,8,9,10,12-octahydroimidazo[2,1-b]benzo[f]quinazoline-4 , 9-dione or a salt thereof.